US20050106267A1 - Zeolite molecular sieves for the removal of toxins

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Abstract

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US20050106267A1

Publication number: US20050106267A1
Application number: US10/965,799
Authority: US
Inventors: Gregory Frykman; Glenn Gruett
Original assignee: Framework Therapeutics LLC
Current assignee: Framework Therapeutics LLC
Priority date: 2003-10-20
Filing date: 2004-10-18
Publication date: 2005-05-19
Also published as: US11083748B2; US20180360875A1; CA2542968A1; US20180169143A1; CA2542968C; US20180369279A1; EP1679962B1; EP1679962A4; US20170056442A1; AU2004285450B2; US10555969B2; EP1679962A1; AU2004285450A1; WO2005041657A1

Medical use of natural and synthetic zeolites for treatment, prevention, and palliation in humans or animals of deleterious concentrations of ammonia, mercaptans, heavy metals and other toxins by oral administration.

This application is based on U.S. Provisional Patent Application No. 60/512,395, filed Oct. 20, 2003, the entire contents of which are incorporated herein by reference.
The present invention relates to methods and compositions for treating, preventing, and palliating elevated levels of certain toxins in humans.
Hepatic Encephalopathy Remains a Significant Health Problem
Predominantly because of the large degree of alcohol use in society, chronic liver disease progressing to cirrhosis remains a burdensome health problem. While other toxic liver insults are responsible to a lesser degree, the final common pathway remains the same: progressive hepatic fibrosis and decrease in the proportion of metabolically active hepatocytes. These pathological changes result in systemic health effects related to poor detoxification of endogenously produced ammonia and exogenously administered medications. Because of the cirrhotic liver's markedly reduced ability to neutralize and remove ammonia, a natural waste product from the metabolism of proteins, its blood level rises causing a decreased ability for affected patients to mentate, sense and move normally. This decrease in these functions when attributable to chronic liver disease is known as hepatic encephalopathy.
It is estimated that the economic burden to society related to just the costs of hospitalization for chronic liver disease is over $1 billion annually in the United States. A large portion of these costs is the daily charge for the hospital room; the average stay is approximately 6 days. Thus, if an intervention could be developed that would decrease the average length of hospital stay and/or diminish the need for patients to be hospitalized, patients with chronic liver disease would benefit and the economic burden to society would decrease.
Current standard of care includes the use of supportive care (hydration, vitamins, nutrition administered parenterally, treatment of any gastrointestinal bleeding,) and the drug lactulose, a non-absorbed disaccharide that functions to decrease the rate of absorption of and increase the rate of fecal elimination of ammonia. Lactulose, which is sold as a crystalline powder in a single-dose plastic package, is inconvenient to use in the acute hospital setting because of the need for suspension/dissolution in a sorbitol solution. Moreover, lactulose is only modestly effective and does not appear to have been subjected to randomized controlled trials prior to receiving marketing approval by the US Food and Drug Administration.
Lead Poisoning Remains a Significant Health Problem
Despite advances in the recognition and treatment of clinical and subclinical lead poisoning, a large number of children in the United States are considered lead poisoned. Effective therapy exists for lowering blood lead levels, however the long-term adverse event risk of these treatments limit their use, especially at the lower levels of blood lead.
As taught in a recent government publication (Eliminating Childhood Lead Poisoning: A Federal Strategy Targeting Lead Paint Hazards; President's Task Force on Environmental Health Risks and Safety Risks to Children; Department of Health and Human Services and the Environmental Protection Agency; February, 2000) lead is most hazardous to the nation's 24 million children under six years old of which approximately 4.4% or 1 million have blood lead levels (BLL) >10 μg/dL. The spectrum and severity of morbidity of lead poisoning increases as blood lead levels increase: reduced IQ, decreased hearing, decreased growth and behavior problems in children can be observed at BLL as low as 10 μg/dL, impaired nerve function at 20 μg/dL, reduced vitamin D metabolism at 30 μg/dL, damage to hematopoiesis at 40 μg/dL, severe stomach cramps above 50 μg/dL and severe brain damage, kidney damage and severe anemia between 50 and 100 μg/dL. Based on epidemiological models and estimates, a child is estimated to lose 2 IQ (intelligence quotient) points for each 10 μg/dL increase in blood lead level.
Current treatments include intravenous chelation therapy with EDTA (ethylenediamine tetraacetic acid) oral chelation therapy with drugs such as succimer, penicillamine and British anti-Lewisite (BAL). Chelation therapy with EDTA is indicated for severe lead poisoning and must be administered—either three times daily or as a continuous infusion—in combination with succimer. Succimer, an oral drug, is administered on a subchronic basis and is not indicated for BLL <20 μg/dL. Penicillamine may also be used, but is known for a particularly troublesome side effect profile, which limits its chronic use. Additional details are found below.
EDTA (edetate, versenate; CAS [62-33-9]) remains difficult to administer despite its demonstrable lead-chelating activity. It remains a component of standard of care for severe cases of lead poisoning where rapid decrease in the BLL is desired and requires hospitalization. Key pharmacological properties of EDTA include only intravenous administration and half-life of 20 to 60 minutes. Rapid clearance results in only one-half the drug remaining one hour following administration and only 5% of the administered dose remains after 24 hours. The dose must be adjusted for decreased renal clearance. Substantial monitoring is required for cardiac changes, renal function and serum electrolyte changes resulting in daily phlebotomy and attachment to a cardiac monitor. These precautions are recommended because of potential decreases in serum zinc, copper and iron, which are also chelated by EDTA. Because EDTA may only be administered parenterally, local pain and swelling are a risk. Systemic adverse events include fever, chills, malaise, nausea, vomiting, anorexia, myalgias, arthralgias and a histamine-like reaction. Nephrotoxicity can manifest as acute tubular necrosis, microscopic hematuria, proteinuria and elevated blood urea nitrogen and serum creatinine. The liver may be affected as evidenced by transient mild elevations of the transaminases and the bone marrow may also be affected as evidenced by the findings of anemia and thrombocytopenia.
Succimer (CHEMET, dimercaptosuccinic acid, DMSA; CAS [304-55-2]) is a white crystalline powder with an unpleasant odor and taste characteristic of mercaptans. It is administered orally in divided doses based on the size of the patient thereby making administration easier and not requiring hospitalization. It is indicated for blood lead levels >45 μg/dL and is expressly not indicated for prophylaxis against lead poisoning in a lead laden environment. It is effective in reducing the blood lead level, although several features limit and complicate its use. It is recommended to administer succimer every 8 hours for the first 5 days followed by twice daily for the next 14 days. A waiting period is recommended before a second 19-day cycle should begin. Weekly monitoring of the blood counts is recommended for proper management of the drug-induced neutropenia. If the absolute neutrophil count decreases below 1200 /μL, succimer administration should stop until recovery to >1500 /μL. Drug-induced elevations of liver transaminases, which are mild and transient and seen in up to 10% of patient, should be monitored for weekly. A particular toxicity in the form of recurrent mucocutaneous eruptions has been described and requires cessation of therapy. Systemic adverse events known with succimer administration include nausea, vomiting, diarrhea, anorexia, loose stools, metallic taste and occur singly or in combination in up to 12% of children and 21% of adults. In addition, back pain, abdominal cramps, chills and flu-like symptoms have been reported in 5% of children and 16% of adults. Succimer is known to interact with various laboratory tests resulting in incorrect values of urine ketones, uric acid and creatine phosphokinase activity.
Penicillamine (Cuprimine, D-Pen, beta,beta-dimethylcysteine, 3-mercaptovaline; CAS [52-67-5]) is a chelating agent, which has found utility in treating Wilson's disease, cystinuria and rheumatoid arthritis. It is a white, crystalline powder, which is freely soluble in water. Penicillamine is known to interfere with normal tropocollagen cross-linking resulting in newly formed collagen fibrils, which are cleaved. To achieve maximum bioavailability and avoid chelation of metals within ingested foods or vitamins, it is recommended that penicillamine be taken on an empty stomach 1 hour before or 2 hours after meals. Penicillamine is associated with a number of untoward reactions, which are potentially fatal. Serious blood dyscrasias including fatal aplastic anemia and fatal agranulocytosis have been observed during chronic treatment and close monitoring of white blood count, white cell differential and hemoglobin are strongly recommended by the manufacturer. Thrombocytopenia and eosinophilia are other hematological effects observed. Routine analysis of the urine is recommended to detect the insidious onset of proteinuria and microscopic hematuria, which may be associated with the Goodpasture's syndrome. Other adverse effects include several of the described subtypes of pemphigus (especially pemphigus foliaceous), increased skin friability at pressure points and sites of trauma, lupus-like syndrome (not associated with hypcomplementemia) with elevated anti-nuclear antibody (ANA) titer, aphthous ulceration of the oral mucous membranes, myasthenia gravis and hypoguesia, or blunting of the sense of taste. The manufacturer recommends close observation and frequent follow-up of any patient receiving penicillamine.
Dimercaprol (BAL, British anti-lewisite, 2,3-dimercapto-1-propanol; CAS [59-52-9]) is a clear, colorless, viscous oily fluid with a pungent odor typical of mercaptans. It is dissolved in and administered, intramuscularly, in peanut oil. Its mechanism of action appears to be complexation with and oxidation by heavy metal ions including lead, copper and arsenic. The dose administered is based on achieving a 2:1 molar ratio of dimercaprol to the heavy metal and it may be used in combination with EDTA. The half-life is short such that following intramuscular administration, dimercaprol is essentially all renally excreted within 4 hours. There are a number of pronounced and dose-related side effects which the amount or dimercaprol that may be administered. Approximately 50% of patients administered the 5 mg/kg dose will experience one of several adverse events. Amongst the most common of the side effects is a rise in systolic and diastolic blood pressure by up to 50 mmHg. Nausea is commonly reported and to a lesser degree vomiting. Headache is reported less commonly than nausea although further details about the headache are not described in the references cited. A burning sensation in the lips, mouth and throat accompanied with the feeling of constriction is well known. Conjunctivitis, blepharospasm, lacrimation, rhinorrhea and increased salivation are also known to be associated with dimercaprol use. Other less common side effects include tingling of the feet and hands, abdominal pain, sweating of the forehead and hands and painful, sterile abscesses at the injection sites. Dimercaprol is known to cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency and a transient decrease in the percentage of polymorphonuclear leukocytes has been observed. The manufacturer recommends that the urine be alkalinized to maintain the integrity of the metal-drug complex during transport through the renal tubule.
Although each of these interventions is effective at reducing the apparent blood level, following such therapy, it is well known that there is a rebound in the BLL, which arises from unchelated tissue stores such as the bone and soft tissues. There is at present no FDA-approved treatment for reducing the tissue stores of lead.
Wilson's Disease Contributes to the Burden of Heavy Metal Poisoning
Wilson's disease is a less common inborn error of copper metabolism in which the endogenous copper carrier protein, ceruloplasmin is decreased or absent. The result is elevated levels of tissue copper, which is responsible for the diseases neurological and hepatic complications. Effective therapy exists; however, it is associated with moderate to severe adverse effects that, in turn, limits its use.
One additional treatment for Wilson's disease is the use of zinc acetate (Galzin). It acts on the intestinal epithelium to prevent the absorption of copper from dietary sources, which is believed due to the zinc ion by increasing the production of metallothionein in the enterocyte. Zinc acetate is administered orally in the form of gelatin capsules though it should be separated from food and beverages by at least one hour, preferably on an empty stomach. Twenty-five to 50 mg should be taken three times per day in adults and strict adherence to the zinc regimen is essential for optimal control of copper distribution. Zinc acetate is indicated for the maintenance of patients with Wilson's disease who have been initially treated with a chelating agent and is specifically not recommended for the initial therapy of symptomatic patients because of the delay required for zinc-induced increase in enterocytic metallothionein and blockade of copper uptake. Source: Galzin (zinc acetate) package insert.
As taught by Scheinberg (Scheinberg I H “Wilson's Disease” in Harrison's Principles of Internal Medicine, 12^thed., Wilson J D, et al., eds, pp. 1843-1845) the prevalence of Wilson's disease is approximately 1/30,000 or approximately 8700 individuals in the US with this disease. Clinical manifestations of copper excess are rare before age 6 and half of untreated patients remain asymptomatic through adolescence. Liver manifestations of Wilson's disease may include acute hepatitis, fulminant hepatitis, chronic active hepatitis or cirrhosis. The only manifestation may be cirrhosis, which develops insidiously over decades. Neurological or psychiatric disturbances may be the initial presenting manifestation.
The drug of choice is penicillamine and should be started upon confirmation of the diagnosis and is administered in divided doses in conjunction with pyridoxine. Additional information about the toxicity of penicillamine may be found above. It usually appears in the first 2 weeks and may cause a rash, fever, leukopenia, thrombocytopenia, lymphadenopathy and/or proteinuria. Penicillamine must be discontinued if these adverse events supervene. Readministration with prednisone can be successful. Lifelong and continual treatment is required and non-compliance can be fatal. Successful treatment suggests that continued copper-lowering therapy could prevent virtually every manifestation of Wilson's disease. Second-line therapy such as trientine is available for patients unable to tolerate penicillamine.
Trientine hydrochloride (Syprine Capsules, bisaminomethylethanediamine dihydrochloride; CAS [112-24-3]) is a white to pale yellow crystalline powder, which is freely soluble in water. The mechanism appears to be increase cupriuresis though on a molar basis appears to be less effective than penicillamine. Trientine should be administered on an empty stomach at least one hour from ingestion of other drugs, food or milk. There have been reports of asthma, bronchitis and dermatitis following environmental exposure to inhaled trientine. In addition, systemic lupus erythematosus, dystonia muscular spasm and myasthenia gravis have been reported in conjunction with trientine use. Other effects noted in four patients with biliary cirrhosis included heartburn, epigastric pain, thickening, fissuring and flaking of the skin, hypochromic microcytic anemia, acute gastritis, aphthous ulcers, myalgias, weakness and rhabdomyolysis.
Arsenic Exposure and Arsenic Poisoning Is Becoming More Frequently Diagnosed
Arsenic has recently become more widely discussed in the public media in terms of its exposure through drinking water. Although EPA limits for municipal water supplies exist, some feel this level to be excessive. It appears that the federal government will reduce the current 50 ppb (parts per billion) limit to 10 ppb. In some defined geographic areas, extremely high levels of arsenic are found in certain wells. Chronic exposure to arsenic at elevated levels has been associated with skin diseases and skin cancer. At present, there are no FDA-approved treatments for chronic arsenic exposure.
The health effects of arsenic are well known from several sources: epidemiological studies, accidental exposures, animal toxicological studies and occupational and therapeutic exposures. There are also a number of factors that must be considered when the toxicity spectrum and severity are reported. These include the form of the arsenic introduced in vivo (inorganic vs. organic, valence, the salt form, the specific organic moiety), the route of exposure (inhalational, transdermal, enteral or parenteral), the rate at which the exposure took place (minutes, hours, days, weeks, years or decades) and the degree of prior exposure to arsenic.
Adverse health effects of arsenic are legion and are dependent on many of the factors listed above. Severe hemolysis followed by renal failure and death may complicate acute inhalational exposure to arsine gas (AsH₃). Hemorrhagic gastritis and gastroenteritis accompanied by nausea, vomiting, diarrhea, convulsions and eventually death from circulatory collapse may occur within 12 to 24 hours of oral ingestion of arsenic trioxide (As₂O₃) in the range of 1 to 3 mg/kg. There are also a number of neurologic signs and symptoms that may be associated with oral arsenic trioxide exposure at the same level including encephalopathy, headache, lethargy, confusion, hallucination, seizure and coma. Additional findings may include muscular cramps, facial edema, cytopenias, renal insufficiency, pulmonary edema and hemorrhagic bronchitis. Electrocardiographic abnormalities such as a prolonged QTc interval and T wave changes have been described.
Chronic exposure may occur by the inhalational, oral, or dermal routes. Numerous organ systems are affected causing a wide array of clinical signs and symptoms. Long term exposure may affect small blood vessels, which can manifest in several different ways including Raynaud's phenomenon, acrocyanosis of the toes leading to gangrene and Blackfoot disease requiring amputation. Post-mortem examination of children with cutaneous signs suggesting arsenic exposure revealed marked thickening of small- and medium-sized arteries specifically in the coronary, cerebral and mesenteric arteries resulting in myocardial infarction in 2 or 5 cases. Neurological signs and symptoms are known to accompany survivors of poisoning attempts including peripheral neuropathy and encephalopathy. The peripheral neuropathy begins as paresthesias, hyperesthesias and neuralgias that may later develop into frank pain and muscle weakness. Histopathological evidence of Wallerian degeneration exists, especially in the long-axon neurons. The findings tend to be bilaterally symmetrical. Recovery is slow and often incomplete. On clinical and electromyographic grounds, the diagnosis of arsenic-induced polyneuropathy may be confused with Guillain-Barre syndrome. Workers from copper smelters have noted a variety of upper respiratory signs and symptoms—presumably from chronic inhalation of arsenic-laden vapors and dusts—including rhinitis, laryngitis and bronchitis. Extreme cases have resulted in perforation of the nasal septum. Exposure in this same context may results in a spectrum of gastrointestinal findings including nausea, vomiting, and diarrhea. Oral exposure may include the same findings in addition to abdominal pain. Hepatic injury is also known to correlate with chronic oral arsenic exposure including swollen and tender livers, elevations of hepatic enzymes, and may reveal portal fibrosis under histopathological examination. Renal effects of arsenic are also known and include proteinuria, elevated creatinine, hematuria, pyuria and glycosuria in patients with sublethal oral exposure.
Although the specific mechanism has been convincingly described, several putative mechanisms have been proposed for the finding of arsenic-induced anemia, leukopenia and the myelodysplastic syndrome. Arsenic may be goiterogenic and diabetogenic. Skin effects of arsenic are well known and include both benign and malignant conditions including hyperpigmentation interspersed with small areas of hypopigmentation (the so-called “raindrop”-like appearance) distributed on the neck, chest and back; palmar-plantar hyperkeratosis with the characteristic small corn-like elevations observed in subjects exposed to arsenic through drinking water. Continued exposure may result in ulcerative lesions after several decades. Basal cell carcinoma, epidermoid carcinomas, intraepidermal carcinomas and Bowen's disease associated with arsenic exposure are well described in the medical and epidemiological literature. Cancers of other organs have been reported to be found in patients living in near proximity to copper smelters including kidney and bladder, in patients having received Fowler's solution (potassium arsenate) including lung cancer and in patients exposed to high arsenic levels in their drinking water in Taiwan including bladder, kidney, liver, lung and colon cancer.

SUMMARY

The invention relates to a method of for treating, preventing, and palliating elevated human blood lead levels, comprising administering to a human in need thereof a pharmaceutical formulation comprising a synthetic sodium aluminosilicate and a pharmaceutically acceptable adjuvant, wherein: (a) the synthetic sodium aluminosilicate is particulate and at least 90% of the particles are of particle size from about 90 μm to about 150 μm; (b) the formulation is administered in doses of about 10 mg to about 1000 mg sodium aluminosilicate.
The invention also relates to a method of treating, preventing, and palliating elevated human blood ammonia levels, comprising administering to a human in need thereof a pharmaceutical formulation comprising a synthetic sodium aluminosilicate and a pharmaceutically acceptable adjuvant, wherein: (a) the synthetic sodium aluminosilicate is particulate and at least 90% of the particles are of particle size from about 90 μm to about 150 μm; (b) the formulation is from about 50% (w/w) to about 95% (w/w) water; and (c) the formulation is administered in doses of 2 g to 15 g sodium aluminosilicate.
The invention also relates to a method including administering to a human in need thereof a pharmaceutical formulation comprising a synthetic sodium aluminosilicate and a pharmaceutically acceptable adjuvant, wherein: (a) the synthetic sodium aluminosilicate is particulate and at least 95% of the particles are of particle size from about 90 μm to about 150 μm; (b) the formulation is administered in doses of about 5 g to about 12 g sodium aluminosilicate; and (c) the human has a higher than normal risk of elevated blood levels of a toxic metal or has a higher than normal risk of hepatic encephalopathy.
The invention relates to a pharmaceutical formulation, comprising: (a) a particulate synthetic sodium aluminosilicate wherein at least 90% of the particles are of particle size from about 90 μm to about 150 μm, (b) about 50% to about 80% by weight water; and (b) a microbial preservative; and (c) a pharmaceutically acceptable adjuvant; wherein the formulation contains about 100 mg to about 10,000 mg by weight of sodium aluminosilicate.
The invention also relates to methods and formulations identical to those described above, but targeting elevated levels of other toxins, in particular copper or arsenic. Thus the invention relates to treatment, prevention, and palliation in humans or animals of excess levels of lead, ammonia, copper, and arsenic, as well as other toxins.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart showing particle size distribution for a zeolite.
FIG. 2 is a chart showing the relationship between zeolite particle size and ammonium absorption using a zeolite.
FIG. 3 is an analysis of the effect of zeolite particle size on ammonium absorption.

DETAILED DESCRIPTION

This invention relates specifically to a microporous or mesoporous silicate, also known as a molecular sieve, which is granular or powdered and which is administered orally, topically or rectally to humans once, daily for several days, weeks, months or years, or more than once daily for days to years for the purpose of treating human diseases. The zeolitic substance is administered in the form or a tablet, capsule or pharmaceutical suspension.
Synthetic zeolites are preferred. As used herein, “synthetic zeolite” means a zeolite manufactured or synthesized by one or more chemical reactions involving breaking and/or making chemical bonds. “(w/w)” means percent by weight, as calculated based on the weight of the component and the total weight of the composition or formulation. Generally, the terms used in this application are well known to persons of skill in the art.
The granules or powder particles are small enough that diffusion of a variety of ions or other organic or inorganic toxins may freely pass in and through the rigid and well-ordered crystalline structure. It is understood that water may or may not comprise the zeolitic material initially, but in an aqueous environment such as the human digestive tract, water will virtually completely fill the framework structure. Based on the specific details of the framework structure, it has been shown that there is a specificity of binding of ions, toxins and other classes of molecules.
In one embodiment, a gelatin capsule of the zeolite is swallowed by a person with a glass of water. In the acidic environment of the stomach, the gelatin capsule dissolve thereby releasing several hundred milligrams of the zeolite. The zeolite absorbs water to full saturation and forms a slurry. Aluminosilicates are known to be resistant to acidic degradation at room temperature or body temperatures and therefore the framework structure remains intact during passage through the stomach and is not susceptible to the actions of oral cavity-, stomach- or pancreas-, small bowel- and large-bowel-derived digestive enzymes and peristaltic movements. In the intestinal juices found in the stomach, duodenum, jejunum, ileum and colon poisonous ions and toxins will bind to the zeolite. These poisons or toxins include heavy metals such as lead, copper, potassium, ammonia, mercaptans and hydrogen sulfide. Additional toxins include those that are plant-, marine organism- and nuclear-derived. When a poisonous ion or molecule binds to the zeolite, it is prevented from exerting its toxic effects on the intestinal lining or from being absorbed into the bloodstream for systemic deposition. An important feature is that zeolites administered as described may be employed to remove toxic ions or molecules over the period of administration of hours, days, weeks, months or years. The purpose of the zeolite is not only intended to prevent the deposition of toxic effects of a heavy metal or toxin that may be a contaminant of ingested food, but additionally it is envisioned to be used in the emergency treatment of toxic ingestions, radioactive fallout (strontium and cesium), toxic marine organism ingestions, poisoned food ingestions, etc. The zeolite, which binds the adsorbed toxic ions or poisonous substances while coursing through the gastrointestinal tract, is eliminated from the body in the feces. An important consideration is having the correct surface area to weight ratio for optimal absorption and minimal toxicity. If the zeolite is powdered too finely, it could accumulate in undesirable anatomical locations such as the appendix or a divertuculum, resulting in a pathologic condition. If the zeolite is too large, the absorptive capacity as a function of weight decreases significantly and substantially larger amounts of the zeolite must be ingested to achieve the same amount of absorption.

The particle size distributions cited in this patent are derived from a technique known as analytical sieving. A full description may be found in the United States Pharmacopeia, 24^thedition (USP 24/NF 19) physical test number <786> as described on pp. 1969-1970, Method 1, which was followed to determine the particle size distribution of the CR-100 sodium aluminosilicate. The following table is illustrative.

TABLE 1


			Recommended
Sieve Size (μm)	U.S. Sieve No.	ASTM E-11*	USP Sieves**

4000	5	X	X
3350	6	X
2800	7	X	X
2360	8	X
2000	10	X	X
1700	12	X
1400	14	X	X
1180	16	X
1000	18	X	X
850	20	X
710	25	X	X
600	30	X
500	35	X	X
425	40	X
355	45	X	X
300	50	X
250	60	X	X
212	70	X
180	80	X	X
150	100	X
125	120	X	X
106	140	X
90	170	X	X
75	200	X
63	230	X	X
53	270	X
45	325	X	X

Source: United States Pharmacopeia, 24^thedition (USP 24/NF 19), United States Pharmacopeial Convention, Inc., Rockville, MD; Method <786>, pp. 1969-1970.
*American Society for Testing and Materials (ASTM) Specification E-11, U.S. Standard Sieve Series. Additional information may be found to ASTM procedure STP 447, “A Manual on Test Sieving Methods,” available from the ASTM, 100 Bar Harbor Drive, West Conshohocken, PA 19428-2959
**The equivalent ISO Standard sieves may be substituted.

The present invention relates to the use of zeolite molecular sieves to bind, sequester and eliminate heavy metals, potassium, ammonia and mercaptans, plant-, marine organism- and fungus/mushroom-derived toxins, radioactive fallout contaminants and hydrogen sulfide and hydrogen sulfide-related, endogenously produced chemicals from a human that may be the source of toxic effects.
For treating, preventing, and palliating high blood lead levels, preferably at least 95% of the particles are of particle size from 90 μm to 150 μm. The formulation may include from about 60% to about 95% by weight water. Preferably, the formulation is a capsule or tablet administered orally. The treatment is suitable for a human suffering from chronic lead poisoning. The human may have a blood lead level of at least about 10 μg/dL, at least about 20 μg/dL, at least about 30 μg/dL, at least about 40 μg/dL, or even of at least about 50 μg/dL. The human may be between about 2 and about 15 years of age, or may be under about 6 years of age. Dosages may be, e.g., about 10 mg to about 1000 mg sodium aluminosilicate, or about 100 mg to about 900 mg, or about 200 mg to about 800 mg. Preferably, the formulation further comprises an antimicrobial preservative or bacteriostat.
The present invention is preferably directed to patients with blood lead levels of <10.0 μg/dL, 10.0-14.9 μg/dL, 15.0-19.9 μg/dL, 20.0-44.9 μg/dL, 45.0-59.9 μg/dL, or >60.0 μg/dL, in each case in combination with one or more therapies recommended for use in the range by state or federal programs, as exemplified in the State of Minnesota Department of Health's Childhood Blood Lead Clinical Treatment Guidelines, March 2001.
For treating preventing, and palliating high human blood ammonia levels, preferably at least 95% of the particles are of particle size from 90 μm to 150 μm. The human may be suffering from hepatic encephalopathy or cirrhosis of the liver. The human may have a history of liver failure. Preferably the formulation is a liquid gel administered orally. The human may have an elevated blood ammonia level or may be at risk for such an elevated level. The human may be a hospital in-patient.
While certain particle size ranges are preferred, this is not meant to limit the scope of the invention. For example, in certain circumstances very fine particles of <44 μm may be preferred.
The term “elevated” blood lead level means a level of lead in the blood that is above normal, where normal is the specified laboratory's normal range as determined on blood from non-diseased, healthy volunteers in the local area, using the local technique-of-choice for the laboratory performing the assay (which could include conventional atomic absorption spectroscopy, graphite furnace atomic absorption spectroscopy, and anodic stripping voltametry) and processed according to the laboratory's procedure precisely specifying the type of collection container to use, specifying whether it should be placed immediately on ice, the timeframe in which it is to be delivered to the laboratory, and the use of a specified preservative, if any. A term frequently employed for the upper end of the normal range is the institutional upper limit of normal (IULN), and is intended to have the same meaning as normal for use in this patent. (Lewandrowski, pp. 820-821.)
By “hyerammonemia” or other terms used to indicate higher than normal levels of ammonia is meant higher levels than normal, where normal is the specified laboratory's normal range as determined on blood from non-diseased, healthy volunteers in the local area, using the local technique-of-choice for that laboratory that performed the assay (which could be venous blood, arterial blood, or some fraction of whole blood including plasma or serum) and processed according to the laboratory's procedure specifying whether it should be placed immediately on ice, the timeframe in which it is to be delivered to the laboratory, using the specified preservative, if any. A term frequently employed for the upper end of the normal range is the institutional upper limit of normal (IULN), and is intended to have the same meaning as normal for use in this patent. (Lewandrowski, pp. 733-735.)
These definitions avoid the controversial nature of clinical laboratory assay performance which remains unsettled for many reasons including that assay principles vary; assay sites differ (hospital laboratory versus point-of-care versus physician office laboratory versus home testing); specific reagents vary including proprietary reagents for commercially available assays; arterial or venous blood may offer advantages or be specified by method; whole blood versus specific fraction such as plasma, serum or erythrocyte; specific collection container that has been processed in a specified manner; requirements exist for the specific assay for preservatives, special handling, temperature, and others; analytical instrument on which assay is performed may vary; varying normal ranges for assay depending on geographical location; evolution of actual assay method based on the same principle. Source: Lewandrowski K., ed. Clinical Chemistry: Laboratory Management and Clinical Correlations, Lippincott Williams & Wilkins, 2002.
For treating, preventing, and palliating high human blood levels of copper or arsenic, the same methods and formulations may be used. Thus the invention relates to treatment, prevention, and palliation in humans or animals of excess levels of lead, ammonia, copper, and arsenic, as well as other toxins.
“Prevention” means actions, which usually emanate from the workers within the health sector that deals with individuals and populations identified as exhibiting identifiable risk factors for disease that may often be associated with different risk behaviors. Prevention also refers to measures not only to mitigate against the occurrence of disease, such as risk factor reduction, but also to arrest its progress and reduce its consequences once established. The use of the term prevention in this patent includes the following: primary prevention (which are actions directed towards preventing the initial occurrence of a disorder); secondary prevention (which are actions that seek to arrest or retard existing disease and its effects through early detection and appropriate treatment); and tertiary prevention (which are actions intended to reduce the occurrence of relapses and the establishment of chronic conditions through, for example, effective rehabilitation).
“Palliation” means any form of medical care or treatment that concentrates on reducing the severity of the symptoms of a disease or slows its progress rather than providing a cure. It aims at improving quality of life, and particularly at reducing or eliminating pain. The definition specifically focuses on the general unavailability of a cure in that it emphasizes the active total care of patients whose disease is not responsive to curative treatment. However, in some cases, palliation may involve alleviation of the side effects of curative treatments, such as relieving the nausea associated with chemotherapy. The term palliation is not intended for use in this patent to refer to a chronic disease, such as diabetes which, although technically incurable, has available treatments that are (ideally) effective enough that it is not considered a progressive or life-threatening disease in the same sense as resistant or refractory cancer.
“Treatment” refers to the coordinated healthcare interventions and communications for individuals and populations with disease conditions in which patient self-care efforts are significant. The definition of treatment in this patent additionally refers to the identification of one or more disease processes, use or modified use of evidence-based practice guidelines (when they exist), collaboration of physicians and supportive-service providers, patient self-management education, outcome measurement, and communication with the patient and other relevant providers about the outcome of the disease stemming from the interventions applied.
The present invention may also be used for the treatment of arsenic toxicity derived from arsenic trioxide therapy use in the treatment of acute promyelocytic leukemia (APL). Although arsenic trioxide has been demonstrated to be effective in the treatment of relapsed APL (one form of acute myelogenous leukemia), cardiac conduction side effects occur which appear to be related to the cumulative dose of arsenic administered and are exacerbated by other electrolyte abnormalities, such as hypokalemia and hypomagnesemia. If the electrolyte abnormalities are corrected and the patient continues to experienced a prolonged QTc (corrected QT) interval or abnormal heart rhythms or associated rapid and irregular heartbeats develop, the manufacturer recommended that the drug be temporarily discontinued until the QTc interval regresses to <460 milliseconds. Source: Trisenox (arsenic trioxide) package insert, March 2001 revision. Because of sodium aluminosilicates' ability to selective bind metal and metalloid ions, such zeolites assist in the treatment of arsenic toxicity in the treatment of APL. The present invention provides a formulation comprising a synthetic aluminosilicate and arsenic trioxide with a pharmaceutically acceptable adjuvant, and a method for treating APL by administering a synthetic aluminosilicate together with arsenic trioxide whether formulated together or separately. In this setting, both acute and subacute treatment with 1-10 grams orally administered once to multiple times per day is envisioned. However, chronic therapy in the range of 100-1000 milligrams once to several times per day is possible.
Recently, arsenic trioxide, administered intravenously, has become the FDA-approved standard of care for relapsed acute promyelocytic leukemia (APL) following therapy with all trans retinoic acid. Following conventional antineoplastic pharmaceutical development, it is likely that arsenic trioxide use will become more common and be used earlier in the management of APL. Patients may achieve a complete remission of their disease, leaving them susceptible to the health effects described above. At present, there is no described antidote for these effects beyond careful monitoring and cessation of the therapy when complications outweigh the benefit from continued treatment.
Potassium regenerated sodium aluminosilicate is an alternative for treatment of hepatic encephalopathy. An important principle in the clinical management of hepatic encephalopathy is treatment of the precipitating or underlying cause of the encephalopathic episode. That is, while a patient may have the established diagnosis of liver failure, only when his or her mental capacity declines is the diagnosis of HE firmly established. However, often other dietary, pharmacological, electrolyte or infectious influences alter the balance between normal mentation and encephalopathy. Many times, however, the exacerbating factor is not determined. While the treatment of HE remains similar to that described elsewhere in this specification, specific attention to the precipitating factor (such as a large dietary load of protein, underlying infection, unexpected reaction from an ingested drug or overuse of certain drugs leading to urinary loss of potassium) is warranted by the treating physician. Because the use of the potassium-depleting drugs (namely spironolactone and members of the same and different classes) is common in patients with liver failure, they can lead to total body loss of potassium and thereby precipitate an encephalopathic episode. The potassium form of sodium aluminosilicate may be used instead of the sodium form to treat patients with hepatic encephalopathy. In the manufacturing process, potassium may be exchanged for sodium in the regeneration process.
The synthetic aluminosilicate is preferably charged with sodium. Alternatively, the synthetic aluminosilicate may be charged with another alkali metal, e.g., Li, K, or Rb. The synthetic aluminosilicate may alternatively be charged with an alkali earth metals, e.g., Ca or Mg. The synthetic aluminosilicate may be chemically modified by methods including pegylation, silation, and glycosylation. The formulation may contain different particle size distributions of the zeolite of interest, and may comprise mixtures of one or more synthetic zeolites. The formulation may contain varying amounts of water, e.g., from about 40% or 50% (w/w) up to about 70%, 80%, or 95%(w/w).
The present invention may be used in diagnostic procedures, e.g., to determine the degree of metal poisoning, as a carrier for x-ray contrast agents, gadolinium based magnetic resonance imaging contrast agents and positron-emitting metabolites for use in positron emission tomography. The present invention may also be used to control diarrhea, especially in conjunction with lactulose in the treatment of hepatic encephalopathy. The present invention may be used in the prevention, treatment, and palliation of Alzheimer's disease, specifically through the binding of gut-derived ammonia and preventing its uptake into the systemic circulation and conferring its toxicity on the central nervous system over the course of many years.

A formulation containing the zeolite may also contain an antimicrobial preservative. The following Table lists examples of antimicrobial preservatives suitable for formulations of zeolites intended for oral, gastric, enteral or rectal administration.

TABLE 2


Antimicrobial Preservative	Further Specification	Reference

benzalkonium chloride		pp. 27-29
benzoic acid		pp. 32-34
benzyl alcohol		pp. 35-37
bronopol		pp. 40-42
butylparaben		pp. 49-51
chlorhexidine	as various salts	pp. 106-110
chlorobutanol		pp. 111-113
chlorocresol		pp. 114-116
cresol	includes ortho-, meta-	pp. 139-140
	and para- isomers
ethanol		pp. 7-9
ethylparaben		pp. 191-193
imidurea	includes monohydrate	pp. 238-239
methylparaben		pp. 310-313
phenol		pp. 336-337
propionic acid	as various salts	pp. 459-461
propylparaben		pp. 411-414
sodium benzoate		pp. 433-435
sorbic acid		pp. 470-472
triacetin		pp. 534-535

Source: Wade A and Weller P J. Handbook of Pharmaceutical Excipients, 2d ed., American Pharmaceutical Association, Washington, DC; 1994

The table below exemplifies microorganisms that require reduction or eradication in a zeolite formulation intended for oral, gastric, enteral or rectal administration. These include bacteria and fungi which are known to be more or less commonly pathogenic and are found in patients suffering from infections. It is therefore desirable to render the zeolite and associated pharmaceutical adjuvants sterile or with an acceptable low microorganism dose such that patients are not harmed. The list includes bacteria (gram positive, gram negative, anaerobic, aerobic, and others), fungi and spores in applicable species.

TABLE 3


Microorganisms

	Aeromonas aeorgenes	Proteus vulgaris
	Aspergillus niger	Pseudomonas aeruginosa
	Aspergillus oryzae	Pseudomonas cepacia
	Bacillus cereus	Pseudomonas fluorescens
	Bacillus subtilis	Pseudomonas stutzeri
	Candida albicans	Rhizopus nigricans
	Clostridium histolyticum	Saccharomyces cerevisiae
	Clostridium oedematiens	Salmonella enteritidis
	Clostridum sporogenes	Salmonella gallinarum
	Clostridium tetanii	Salmonella paratyphi
	Clostridium welchii	Salmonella typhosa
	Coynebacterium species	Sarcina lutea
	Enterobacter cloacae	Serratia marcescens
	Escherechia coli	Shigella dysenteriae
	Klebsiella pneumoniae	Staphylococcus aureus
	Microsporum species	Staphylococcus epidermidis
	Penicillium chrysogenum	Streptococcus faecalis
	Penicillium digitatum	Streptococcus pyrogenes
	Penicillium notatum	Trichoderma lignorum
	Penicullium roqueforti	Trichoderma mentagrophytes
	Pityrosporum ovale	Trichophyton mentagrophytes
	Proteus mirabilis	Vibrio cholerae

Zeolites Offer an Unexploited Family of Substances to Remedy Hepatic Encephaolpathy and Heavy Metal Poisoning

Nagan (U.S. Pat. No. 6,190,561) discloses a method of water treatment using zeolite crystalloid coagulants which is prepared by admixing aqueous sodium silicate and sodium aluminate solutions to form a reaction mixture and allowing a reaction to proceed for a sufficient time to form a zeolite crystalloid coagulant particles with sizes of at least 4 nanometers before the reaction is terminated. Demmel and Vierheilig (U.S. Pat. No. 6,103,949) disclose a family of alkaline phosphate-activated clay/zeolite catalysts, which can be prepared by a process wherein a composition of zeolite-clay-phosphate is brought to a pH level of about 7.0 to about 14.0. The resulting slurry is then age reacted for ½ to 24 hours and finally dried to produce particles that are particularly characterized by their high levels of zeolite stability for utilization in the catalytic cracking of petroleum-based materials. Levy (U.S. Pat. No. 5,612,522) describes the use of a zeolite gel to improve the quality and carbonation of water by the removal of dissolved gases and minerals. Features not disclosed in these patents include any application to the removal of heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins and no use in humans or animals is discussed.
As taught by Adams, et al. (U.S. Pat. No. 5,560,829), aluminosilicates of the zeolite P type may be used as calcium binders in aqueous solutions at low temperatures. Rushmere and Moffett (U.S. Pat. Nos. 5,470,435; 5,482,693; 5,543,014 and 5,503,820) describe the preparation of low concentration water soluble polyaluminosilicate microgels, which are used in the papermaking industry. Neither disclosure discusses any pharmaceutical or therapeutic use or additional utility in the removal of heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins from living animals.
Miller and Bruenger (U.S. Pat. No. 5,494,935) discuss the use of lipophilic polyaminocarboxylic acids for the use of heavy metal chelation by oral application. These drugs can be targeted to various organs by modification of the length of the alkyl side chain. Undiscussed in their disclosure is the utility of insoluble, finely powdered substances which can tightly bind heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins existing in gastric or intestinal juices inside these substances' interstitial crystalline cavities and channels. The method of excretion is unaddressed.
Hu, et al. (U.S. Pat. No. 5,487,882) disclose a method of producing crystalline synthetic faujasite of the zeolite “X” type. There is no disclosure of any medicinal, medical, or pharmaceutical uses or any application in the field of heavy metal binding, sequestering or removal from living organisms.
Leeper (U.S. Pat. No. 5,478,604) discloses a composition and method for preventing lead intoxication by the use of a coating which contains polyethylene imine, a calcium compound and/or a silicate that is applied to a surface which carries a coating of a lead based paint. The object of this invention is to reduce the digestion and absorption of lead from the intestinal tract in case the lead based paint is accidentally ingested. Specific features not found in this prior art is the use for treatment (as opposed to prevention) of lead poisoning, utility for heavy metals other than lead, months to years of administration, reduction of the total body burden of lead and other heavy metals, and deliberate oral administration in the form of a capsule or tablet all with the goal of reversing—partially or completely—adverse effects in heavy metal poisoned mammals. Additional utility for the removal of ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins is not discussed.
Perman and Schegel (U.S. Pat. No. 5,320,773) disclose a composition and method for purifying water in the form of a tablet containing betonite clay, attapulgite clay, polymeric coagulant and/or flocculent, biocide, zeolite and activated charcoal. The composition is added to contaminated water and removes turbidity, metal and organic contaminants. It is intended for personal use so that safe drinking water can be obtained by the simple addition of the composition to non-potable water. Schwarz, Putyera, Jagiello and Bandosz (U.S. Pat. No. 5,385,876) disclose a process and utility for molecularly engineered activated carbons which intercalates with a natural or synthetic clay producing a highly microporous absorbent material. An organic polymeric precursor is contacted therewith to fill the matrix interstices. The precursor is polymerized and carbonized to yield the absorbent material in which the carbon is intercalated into the mineral matrix. The material consists essentially of microporous sheets of active carbon spaced from one another to define slit-like micropores of a substantially uniform preselected width that is molecularly engineered such that interstices between the sheets correspond to a given target adsorbate. Only medical treatments such as “selective scavengers of ingested poisons” is mentioned as a potential medical use and is too general and non-specific to grasp the specific ideas the inventors had conceived of. Features not disclosed in these inventions include the use of the aforementioned compositions for biomedical use including the treatment of specifically heavy metal poisoning by oral administration of one or more capsules' worth of material daily for months to years intended, or an a more acute basis with administration into the stomach via nasogastric tube for the remediation of the effects of heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins and their removable from the human body.
Rainer (U.S. Pat. No. 5,096,946) describes a polymer product for the selective absorption of dissolved ions, which is a water-swellable polymer which may be physically bound to an open celled cellulosic sponge and which is produced by a thermal process, which induces amide-forming insolubilization of polyethyleneimine. It has a high affinity for transition metal ions and may comprise a portion of a cellulosic sponge that is permeable to water yet remains substantially unaffected by water-borne suspended matter. The patent describes no utility as a pharmaceutical product intended for use as an orally-administered drug in humans or animals. The number of metals that it has utility in removing further limits it. Yet another limitation is the absence of any description of other non-transition metal toxic substances that it binds such as drugs, organic toxins, heavy metals and toxic moieties of plant and animal material accidentally ingested.
Withiam (U.S. Pat. No. 5,085,705) discloses a method of preparation and numerous compositions of alumina-silica-sulfates wherein the sulfate is present as a bound network. The compositions include articles of manufacture in the form of catalysts, rubber, plastics, paint and paper. Specifically, hollow microspheres containing a porous network are formed by spray drying a gelled composition followed by calcining of the spray-dried hollow microspheres to eliminate the sulfate network.
Dodwell and Smith (U.S. Pat. No. 5,053,139) describe a process for the removal of heavy metals from aqueous systems containing competing ions utilizing amorphous tin and titanium silicates. The basic principle of cation exchange, which is a property of certain specific tin- and titanium-based molecular sieve zeolites, is exploited in the exchange of several heavy metals with calcium and/or magnesium cations. This invention suffers from no discussion about pharmaceutical applications or biomedical uses and does not discuss any utility in removal of toxins from the bodies of animals or humans. Furthermore, the tin- and titanium-based molecular sieves discussed have an amorphous structure differing substantially from the present invention in which the crystalline structure is an important feature.
Kuznicki and Thrush (U.S. Pat. No. 4,994,191) disclose a process for the removal of heavy metals from aqueous solutions through the use of the crystalline molecular sieve having the X-ray diffraction pattern of ETS-10 or ETAS-10. They provide examples of the lead absorbing utility of these molecular sieves showing how the rate of lead binding increases with the framework type used. Important features of the present invention that are missing from this cited prior art is any utility as a pharmaceutical product, envisioned for internal ingestion by a human, that it may be utilized to remove lead absorbed in the tissues of an animal or human or that it may be used to remove other non-metallic toxins found in plant and/or animal materials which are accidentally ingested by humans.
Wason (U.S. Pat. No. 4,812,299) describes a family of novel and unique synthetic alkali metal alumino-silicates, also known as SAMS, which essentially comprises altered kaolin clay platelets with an integral rim or protuberance of essentially amorphous alkali silicate-kaolin reaction product. The unique SAMS compositions are structured materials in which the structure can be controlled and are useful as functional fillers, as titanium dioxide extenders, as silica extenders or as reinforcing agents for paper, paint, rubber, plastics and specialty products. This references does not even remotely suggest the utility of these materials for use in the pharmaceutical industry, as excipients or active products in the manufacture of medications for human and animal use, as active components in the removal of harmful substances such as heavy metals and/or animal or plant-borne toxins.
Hinchey (U.S. Pat. No. 4,348,369) discloses the discovery of, synthesis of and some chemical and physical properties of a novel synthetic crystalline zeolite of the molecular sieve type, designated “LZ-200”, and envisioned to be used as an absorbent with demonstrated ability to absorb carbon dioxide, water and methanol. There is not the remotest suggestion of any biomedical uses, therapeutic uses or pharmacological uses of this material, especially in the treatment of toxin-based and heavy metal poisoning in humans is not discussed in the disclosure.
Etzel and Anand (U.S. Pat. No. 4,343,706) disclose a method of removing heavy from industrial waste streams by flocculation using a source of ferric ions and an alkaline material at a basic pH. Heavy metals are recovered by acidifying the floc in a narrow pH range, which liberates the heavy metals back into solution while leaving the floc particles intact and thus reusable. The concentrated heavy metals solution may also be recycled or disposed of in an acceptable manner. The use of this methods and material in humans, as pharmaceutical compositions or in any in vivo biomedical use is not even remotely described and is undesirable for several reasons including the administration of ferric ions and the basic pH which is required for this method to work and which is incompatible with administration by several routes into the human body.
Williams and Mays (U.S. Pat. No. 4,213,874) describe the synthesis of and several physicochemical properties of amorphous sodium aluminosilicate base exchange materials with ion exchange capacities equal or superior to known crystalline base exchangers and which may be used in water softening and detergents. Murrell, et al (U.S. Pat. No. 6,004,527) disclose a method for making molecular sieves with large pores and further describe novel molecular sieve compositions. Heller, Conger and Fitting (U.S. Pat. No. 5,994,933) disclose a method for distributing molecular sieve powder having a median particle size of less than about 350 microns, a method for maintaining the moisture content of the zeolite particles to greater than about 3 percent, and a method for refining the powder to reduce the size of the agglomerated clusters. The use of these materials in humans, as pharmaceutical compositions or in any in vivo biomedical use is not even remotely described.
MacDougall, et al (U.S. Pat. No. 5,882,625) describe a faujasite-like aluminosilicate, having a non-uniform aluminum distribution, which is synthesized by crystallizing the zeolite from a mixture of alkali metal aluminate and alkali metal silicate wherein the mixture has an alkali metal oxide ratio of at least 37. This zeolite has utility as a gas separation absorbent such as separating oxygen from nitrogen in the air. Otterstedt, Sterte and Schoeman (U.S. Pat. No. 5,863,516) describe colloidal suspensions of discrete particles of colloidal zeolite and a method for preparing such zeolite from clear tetraalkylammonium stabilized aluminum silicate solutions. The colloidal suspensions are characterized by an average particle size of less than 250 nanometers and a particle size distribution, expressed as a geometric standard deviation, of less than 1.30 nanometer. These zeolite sols exhibit Tyndall light scattering and very low rate of sedimentation owing to their small particle size. There is no suggestion of any biomedical, pharmaceutical or medical toxicology use.
Ueshima, et al (U.S. Pat. Nos. 5,810,920 and 5,769,938) describe a method for treating fly ash waste containing harmful metals in which the waste is mixed with a treating agent containing solid acids and/or cement and additionally a caking inhibitor, which is then kneaded with water where necessary and solidified by curing. Harmful metals, including lead, cadmium, mercury, chromium, copper, nickel and zinc are stabilized in solidified cakes from which they are not released. Reimers, Akers and Lo (U.S. Pat. No. 4,853,208) disclose a method of binding wastes in alkaline silicate matrix as a means of detoxifying wastes containing heavy metals including mercury, zinc, selenium, arsenic, antimony, copper and thallium. The alkaline silicate matrix binds the aforementioned metals and prevents their leaching out and contaminating the environment. There is not even a remote suggestion that the method and components described in this patent is intended for use in any biomedical, pharmaceutical or medical toxicology context for any of the metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins disclosed or others not mentioned.
Titterton and Summers (U.S. Pat. No. 5,744,404) describe a process and an article for delivering or applying a zeolitic molecular sieve to an odorous surface. The process involves contacting the surface with a porous article, which contains a slurry of a zeolitic molecular sieve having a SiO₂/Al₂O₃ratio of at least 18. The slurry also contains water, ethanol, a suspending agent, a preservative and optionally an emollient. The porous article can be woven or non-woven and includes wipes, pads, foams and towelettes. The patent describes a biomedical application in which said method and resultant slurry is used to control foot odor. There is not even the remotest suggestion that this invention could be used internally or in the remediation of heavy metal poisoning or toxic metal ingestion in humans or animals.
Henriksen (U.S. Pat. No. 6,136,859) discloses a pharmaceutical formulation for treating liver disorders which is comprised of selenium, beta-carotene or vitamin A, ascorbic acid in its salt or ester form, alpha-tocopherol, methionine and coenzyme Q10 with a pharmaceutically acceptable carrier suitable for treating such diseases as primary biliary cirrhosis, viral hepatitis, steatohepatitis, alcoholic cirrhosis and related hepatic and biliary disorders. What is not appreciated in this disclosure is that primary biliary cirrhosis is associated with an elevated serum copper level. The underlying reason for this is unknown. This disclosure does not offer the remotest suggestion that amelioration of certain clinical findings of primary biliary cirrhosis are achievable by reduction of the elevated serum copper level. One method by which this may be achieved is by chelation therapy, either intravenously or enterally.
Nilsson and Stendahl (U.S. Pat. No. 5,662,826) describe a process for the preparation of a coagulating chemical comprising dissolving a solid zeolite in a solution of trivalent metal salt. The composition described is a coagulant for water purification in the fields of treating sewage water, in pulp and paper manufacture, in dewatering organic matter, and in concentrating minerals. Kuhm, Salz and Blasey (U.S. Pat. No. 5,645,811) describe a process for the production of very fine-particle zeolitic alkali metal aluminum silicates. Following a mixture of alkali metal silicate and alkali metal aluminate, in the presence of a stoichiometrically excessive amount of alkali metal hydroxide a gel is obtained and matured. Freeman, et al (U.S. Pat. No. 5,591,256) describe methods, uses and compositions of high-performance synthetic alkali metal alumino-silicates which are characterized by low oil absorption values, high total pore volume and increased differential pore volumes. The products are useful as coating pigments for paper, paperboard, paper fillers, paint pigments and as reinforcing pigments for rubber. There is not even the remotest suggestion of utility in biomedicine, pharmaceuticals, or that the products could be used in the remediation of heavy metal poisoning or toxic metal ingestion in humans or animals.
Li, et al (U.S. Pat. No. 5,584,912) describe a composition, a synthesis of a composition and a method of using the composition for selectively adsorptively separating nitrogen from oxygen wherein the composition is a crystalline EMT with a Si/Al ratio less than 2.0 and a micropore volume of at least 0.20 cm³/g and a lithium cation exchange of at least 80%. No pharmaceutical, biomedical or human medicinal or therapeutic use is described in this disclosure.
Tissler, et al (U.S. Pat. No. 5,578,195) describe a synthetic crystalline aluminosilicate of the pentasil type and method for using the same as catalysts or catalyst components in petrochemical processes for the catalytic conversion of hydrocarbons and their derivatives into useful organic compounds and intermediates. Pryor and Chi (U.S. Pat. No. 4,424,144) describe the preparation of binderless 3A zeolite absorbents, in the form of beads or extrudates and are envisioned for use in drying a mixture of a hydrocarbon, such as ethylene, and water. No pharmaceutical, biomedical or human medicinal or therapeutic use is described in this disclosure.
Kuhrts (U.S. Pat. No. 5,641,511) discloses a granular drug delivery system comprising a gel-forming dietary fiber that can be made into an orally-ingestible dispersion by admixture with a liquid that can deliver an effective dose of a pharmaceutically-active compound. Although this system appears useful in delivering desired amounts of a drug to the gastrointestinal tract, it is not envisioned for use in removing toxic or deleterious substances from the gut. Luck and Crabb (U.S. Pat. No. 6,074,689) disclose a method and composition for delivering an active protein or peptide to the colon comprising an aqueous solution of polyethylene glycol (PEG), the active protein or peptide, and an outer enteric coating. The intended use for this method and composition is for treatment of antibiotic induced Clostridium difficile-induced diarrhea where the active protein is hyperimmune bovine colostrum immunoglobulin (HBCIg) against the toxin elaborated by Clostridium difficile.
Bleim and Steffier (U.S. Pat. No. 5,500,212) disclose the composition of and preparation of a crosslinked amine-containing polymer with a polyfunctional amine-reactive compound such that water insolubility is achieved and bile acid sequestering capacity is enhanced over cholestyramine alone. Dhal, Holmes-Farley and Petersen (U.S. Pat. No. 6,294,163) disclose polymers containing guanidinium groups as bile acid sequestrants envisioned for use in lowering serum cholesterol levels. Figuly and Matos (U.S. Pat. No. 5,874,522) disclose crosslinked polymeric ammonium salts comprised of n-alkylene or alkyl-substituted n-alkylene groups and hydrocarbylene radicals containing one or more hydroxyl, ether, amino, thioether, keto or silyl groups envisioned for use in bile acid binding and serum cholesterol lowering. Goto and Meno (U.S. Pat. No. 6,022,533) disclose a pharmaceutical composition comprising an anion exchange resin, silicon dioxide, crystalline cellulose and a pharmaceutical carrier. This disclosure relates primarily to the finding that formulation of non-crosslinked anion exchange resins, which had been considered impossible without water, is achievable with the use of silicon dioxide and crystalline cellulose. The tablets containing the anion exchange resin are envisioned for use in lowering cholesterol. Howard (U.S. Pat. No. 4,041,153) discloses methods and a pharmaceutical preparation for the treatment of hypercholesterolemia, which contains clofibrate, a basic anion exchange resin and a metal ion whose function is to form insoluble metal bile acid salts. The ingestible non-toxic metallic compound is capable of dissolving in the gastrointestinal juices to yield a metallic salt or ion that can react with bile acids to form an insoluble or poorly soluble metal salt of these bile acids. Huval, Holmes-Farley, Petersen and Dhal (U.S. Pat. No. 6,264,938) disclose a combination therapy for hypercholesterolemia, which is comprised of a conventional HMG-CoA reductase inhibitor and an unsubstituted polydiallylamine polymer, which acts as a bile acid sequestrant. Johnson (U.S. Pat. No. 4,649,048) discloses that quaternized vinylimidazole-ethylene glycol dimethacrylates useful to sequester non-absorbed bile acids in the intestinal tract to form a complex, which is then excreted in the feces. Jaxa-Chamiec, Hickey and Shah (U.S. Pat. Nos. 4,594,339; 5,230,885 and 5,273,740) disclose several classes of anion exchange polymers envisioned for use in treating hypercholesterolemia by binding free bile acids in gastrointestinal juice and sequestering them for eventual excretion out of the body with the feces. The specific anion exchange polymers disclosed include N,N-dimethyl-N-dodecylammoniomethyl-substituted polystyrene, N,N-dimethyl-N-dodecyl-ammoniomethylstyrene-ethyl methacrylate-divinylbenze and 6-(N,N-dimethyl-N-octylammonio)hexanoylated polystyrene chloride. Shaw and Sharma (U.S. Pat. No. 4,790,991) disclose ingestible aggregates comprising a pre-swelled anhydrous hydrocolloid and a substrate and are envisioned for use in treating a number of diseases including hypercholesterolemia and mineral deficiencies, in combination with the appropriate active pharmaceutical ingredient. Yang, Sharma, Sheu and Shaw (U.S. Pat. No. 4,778,676) disclose a chewable confectionery delivery system for active pharmaceutical ingredients and specifically cholestyramine intended for improve palatability in the treatment of hypercholesterolemia with a bile salt binding resin. Schulz (U.S. Pat. No. 5,167,965) discloses the composition of and method of producing palatable cholestyramine granules and tablets to be used in the treatment of hypercholesterolemia. These disclosures do not address any use in heavy metal poisoning and do not address any compositions such as zeolite molecular sieves.
McClelland and Zentner (U.S. Pat. No. 5,350,584) disclose a process for spheronization of charged resins, which produces multiparticulates 0.3-3 mm in diameter and which is microcrystalline free. Active pharmaceutical agents envisioned for incorporation into a granulation that is then spheronized include cholestyramine and trientine. Although each active pharmaceutical ingredient is used in specific circumstances, there is no specific mention of this process or these compositions to be used in the long-term remediation of heavy metal poisoning and removal of the heavy metal itself, nor is there any discussion about the use of zeolite molecular sieves.
Porath (U.S. Pat. No. 5,183,313) discloses an absorbent for metal ions, proteins and other inorganic and organic substances which is based upon a ligand with an atomic sequence of N—C—C—N where the specific sequence comprises part of a heteroaromatic ring system which is covalently bonded to a polymers such as a polysaccharide, polyvinyl alcohol or other organic hydrophilic polymer. The invention suffers from no description about any in vivo biomedical use such as may be effected by oral administration of a capsule or tablet. There is a further absence of any description of this material being employed in a heavy metal chelating mode for other heavy metals, including lead, uranium, and others, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins.
Hider, Kontoghiorghes and Silver (U.S. Pat. No. 4,585,780) disclose a series of pharmaceutical compositions containing a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by a substituted aliphatic hydrocarbon group to be used for the removal of toxic amounts of metals from the body.
These materials differ substantially from the present invention in that they are of an organic nature designed to permeate cellular membranes. In addition, the mode of action of these compounds is to enhance the water solubility and urinary excretion of metals such as iron, copper and aluminum. Yet another important difference from the present invention is the solubility of the chelating compound itself and its properties of systemic distribution.
Wieder (U.S. Pat. No. 4,352,751) discloses a series of species-linked diamine triacetic acids and their metal chelates whose general structure is comprised of an organic species containing at least one amine, hydroxyl or thiol functional group and a two or more atom long covalent bridge. Very different than the present invention, the utility proposed is in the monitoring the level of biologically and/or medically important molecules. This is achieved by incorporating into the metal binding sites, rare earth metal ions capable of forming fluorescent chelates that may be used in a fluorometric assay. No therapeutic intent is even remotely suggested in addition to the extremely small capacity to bind toxic metal or other toxins of medical interest for the purpose of their elimination.
Hinckley (U.S. Pat. No. 4,346,216) teaches the use of osmium carbohydrate complexes as pharmaceutical compositions for the treatment of heavy metal poisoning, arthritis and as a diagnostic aid as a radiographic contrast agent. Osmium-glucose complexes are proposed to be administered to mammals suffering from heavy metal poisoning which will result in a chelation of the heavy metal within the osmium complex in a harmless form which is then excreted from the system without further toxic effects on the treated animal. This approach suffers numerous disadvantages including the unavoidable and potentially deleterious deposition of osmium metal in tissues, unevaluated ability of the material to be absorbed from the gastrointestinal tract, and the need for multiple, frequent, chronic injections and undisclosed method of elimination from the body of a mammal. The mechanism of action also varies significantly from the present invention in that in that only lead is discussed as one of the heavy metals susceptible to this approach. Additionally, osmium is generally regarded as toxic to the human body and strict federal limits on the amount of osmium that may be deposited limits the utility of this approach.
Mandeville and Holmes-Farley (U.S. Pat. No. 5,702,696) disclose a family of hydrophilic anionic exchange resins for use in treating iron overload syndromes by decreasing the absorption of dietary iron. Sasaki and Ishii (U.S. Pat. No. 6,180,094) disclose a medicament, which comprises as an active ingredient a weakly basic anion exchange resin chelating with ferric ion, which adsorbs phosphate ions in vivo and is used for prevention and treatment of hyperphosphatemia. In this disclosure, the iron binding properties of cholestryamine are mentioned and the suggestion that iron deficiency anemia may be caused by its and other similar resins's use. Although there are certain advantages to this approach, there is no mention of any use of this method in the removal of heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins nor is there mention that zeolite molecular sieves can be employed in the same manner.
Rosenberg (U.S. Pat. No. 4,107,331) describes a zinc chelating fungicidal composition in which zinc ions—which are required by certain species of fungi for growth—is sequestered in the chelating agent thereby preventing growth of human fungal infections. The chelating or sequestering agents described include water soluble salts of one of several EDTA-like organic compounds which is mixed with an aqueous jelly and administered vaginally for the treatment of common yeast infections. This disclosure suffers from a number of disadvantages for the treatment of chronic heavy metal poisoning including its use as a topical treatment and the use of organic and toxic chemicals about which little toxicity information in man is known. Additionally, oral administration for months in the form of a capsule, tablet, suspension or slurry for the purpose of removing heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins from the body is not even remotely suggested.
Bergwitz-Larsen and Ulf (U.S. Pat. No. 5,643,560) disclose a drug formulation with ion exchangers of the carrageenan type for use in reducing toxic side effects and lethality when overdosing psychotropic medications. The drug and the carrageenan are administered together, but the carrageenan, through the process of ion exchange, in conjunction with an additional salt, minimizes absorption as reflected in animal model serum levels of clomipramine. This disclosure, however, fails to address the use of zeolite molecular sieves in vivo nor does it address the issue of chronic toxicity from tissue absorbed heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins, nor does it address use ranging from months to years.
Howes and Newman (U.S. Pat. No. 6,045,834) disclose compositions and methods for the removal of mycotoxins from animal feed whereby a combination of modified yeast cell wall extract and mineral clay is fed to animals in amounts sufficient to inactivate mycotoxins present in the feeds. These compositions are intended to be admixed with feeds, incorporated directly into pelleted feeds or fed directly to animals. This invention suffers from several deficiencies for use in the treatment of heavy metal poisoning or toxic ingestions in man including preparation using the cell wall of yeasts which may contain unknown and/or undesirable contaminants or biologically active molecules and no description of any kind that said composition may be useful in other toxins such as heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins.
Casas and Mosstam (U.S. Pat. No. 5,837,238) disclose a therapeutic method of treating rotavirus induced diarrhea by the administration of lyophilized and reconstituted Lactobacillus reuteni whose mechanism of action is unknown although it may be related to the elaboration of a substance named reuterin or improving the indigenous gastrointestinal microflora. Willoughby and Yolken (U.S. Pat. No. 5,192,551) disclose a neutral glycolipid GA1 (asialo-GM1 or asialo-gangliotetraosylceramide) as an adsorbent, either alone or bound to a non-absorbable resin or matrix, for the neutralization of enteric viral pathogens representing either prophylaxis in the case of a localized outbreak, or as a treatment in the case of florid gastroenteritis. Delivery modality is dependent on location; pharyngeal colonizing viruses is proposed to be accomplished by nebulization or gargling whereas gastrointestinal infection is treated specifically with internally ingested naked GA1 or GA1 bound to beads, resins, natural or synthetic polymers although yet additional delivery methods and pharmaceutical dosage forms are mentioned. This invention does not specifically claim to work by sequestration or ion exchange, it is not directed toward remediation of any toxic effect produced by heavy metal ingestion and it does not involve the use of zeolite molecular sieves.
Several disclosures reveal similar methods of increasing the nutritional value of mycotoxin-contaminated animal feed by feeding the animal montmorillonite clay [Beggs (U.S. Pat. No. 5,149,549)] or an acid-activated montmorillonite clay [Turk, Music and Beall (U.S. Pat. No. 5,639,492)] simultaneously with the contaminated animal feed. The clay, itself which is not absorbed in the gastrointestinal tract but which absorbs or adsorbs any one of several known toxins (aflatoxin, fumonisin, vomitoxin, ochratoxin, zearalenone, ergot, and ergotamine). Taylor, Delaney and Phillips (U.S. Pat. Nos. 5,165,946 and 5,165,946) disclose a dry solid animal feed composition in which biodegradable feed is contaminated with a mycotoxin and is admixed with a mycotoxin inactivating agent comprising particles of a phyllosilicate mineral capable of inactivating mycotoxins. The particles are coated with a sequestering agent in an amount sufficient to enhance the mycotoxin inactivating capacity of the phyllosilicate. These inventions suffer from several deficiencies including no mention of the use of zeolite molecular sieves, no mention of the chronicity of administration, no mention of any additional nutritional deficiencies that may result from the clay administration and no mention of specificity of toxin binding within the framework structure. Specific pharmaceutical preparation for human use is not discussed. Moreover, human use was not described in these disclosures.
Geneix, Alafourcade and Ribereau-Gayon (U.S. Pat. No. 4,765,992) disclose a method of improving the alcoholic fermentation yield by the addition of cell walls that have been boiled or autolysed and washed. The cell walls act to bind the offending substances which include certain fatty acids and their ethyl esters, pesticide residues and substances secreted by microorganisms. There is not even the remotest suggestion that this invention has utility in biomedicine, pharmaceuticals or could be used in the remediation of heavy metal poisoning or toxic metal ingestion in humans or animals.
Robbins and Seely (U.S. Pat. No. 4,251,519) disclose a process of lowering or preventing an increase in the level of cholesterol and triglycerides in the blood of mammals by including a yeast glycan in the daily diet in an amount of up to 30% of the total food intake. There is not even the remotest suggestion that this invention has utility in biomedicine, pharmaceuticals or could be used in the remediation of heavy metal poisoning or toxic metal ingestion in humans or animals.
Coe, Gafffiey, Srinivasan, Kirner, Pierantozzi and White (U.S. Pat. Nos. 4,925,460; 5,152,813 and 5,258,058) disclose different methods by which to achieve improved gas separation including the use of a lithium exchanged chabazite, a binary exchanged X-zeolite containing lithium, calcium and/or strontium ions, and additional divalent cation exchanged lithium X-zeolites. Maurer (U.S. Pat. No. 5,171,333) discloses a process for methane purification by pressure swing absorption employing a faujasite type of zeolite containing divalent and alkali metal and alkaline earth metal cations. Fitch, Bulow and Ojo (U.S. Pat. No. 5,464,467) disclose type X zeolites with charge compensating cations comprised of lithium, aluminum, cerium, lanthanum and/or mixed lanthanides are useful in gas separations. Chao, Sherman, Mullhaput and Bolinger (U.S. Pat. No. 5,413,625) disclose lithium/alkaline earth metal A and X zeolites are useful in separating oxygen and nitrogen from gas mixtures owing to their high absorptive capacity and high thermal stability. There is not even the remotest suggestion that the object of any of these inventions has utility in biomedicine, pharmaceuticals or could be used in the remediation of heavy metal poisoning or toxic metal ingestion in humans or animals.
A number of microporous compositions are described in the patent literature. Vaughan, Barrett, Strohmaier, Treacy and Newsam (U.S. Pat. Nos. 4,091,079; 4,333,859; 4,879,103 and 5,116,590) disclose the synthesis of several new materials including a synthetic large pore crystalline metalsilicate zeolite composition designated ECR-35, a crystalline aluminosilicate zeolite comprised of potassium and vanadium ions present in the reaction mixture designated VK-2, a high silica faujasite polymorph designated CSZ-3 which has claimed utility in sorption, separation and catalytic applications, and a zeolite characterized by triethyl methyl ammonium being entrapped in supercages of the aluminosilicate and designated ECR-30. Delprato, Guth, Angelrot, Didier and Zivkov (U.S. Pat. No. 5,393,511) disclose the synthesis of faujasite class zeolites in which numerous crown ethers and other carbon-containing macropolyrings of the polyoxadiazabicycloalkane class are employed as structuring agents. Wilson, Lok and Flanigen (U.S. Pat. No. 4,310,440) disclose a family of crystalline microporous aluminophosphate compositions, designated the AlPO₄family of zeolites, the members of which are synthesized by hydrothermal crystallization at elevated temperatures of aluminophosphate gels containing a molecular structure-forming template and which are envisioned for use as catalysts or catalyst bases. Patton and Gajek (U.S. Pat. No. 4,473,663) disclose another crystalline aluminophosphate, designated AlPO₄-33, although it is distinct from the aforementioned AlPO₄family described above. Chang, Chu, Dessau, Higgins, Lutner and Schlenker (U.S. Pat. No. 5,091,073) disclose a crystalline molecular sieve composition, designated MCM-37, which may be used in the catalytic conversion of organic compounds. Breck and Acara (U.S. Pat. No. 4,950,952) disclose a crystalline zeolite, designated T, and Breck, Blass, and Skeels (U.S. Pat. No. 4,503,023) disclose silicon substituted zeolite compositions which are contacted with an aqueous solution of a fluorosilicate salt using controlled proportions and temperature and pH conditions which avoid aluminum extraction. Casci, Lowe and Whittam (U.S. Pat. No. 4,537,754) disclose the composition of and the method of producing zeolite EU-1 which is useful in catalytic processes such as xylenes isomerization. Grose and Flanigen (U.S. Pat. No. 4,124,686) disclose a crystalline zeolite, designated phi, which is prepared hydrothermally from aqueous gels, exhibits large-pore adsorption characteristics and is envisioned for use in hydrocarbon conversion processes exemplified by isoparaffin alkylation, hydrocracking isomerization and reforming. Morimoto, Takatsu and Sugimoto (U.S. Pat. No. 4,578,259) disclose a crystalline aluminosilicate and its structural variations, collectively designated ISI-6, which are envisioned for use as catalysts for the conversion of oxygen-containing organic compounds such as alcohols and ethers into hydrocarbons. Plank, Rosinski and Rubin (U.S. Pat. No. 4,016,245) disclose a crystalline zeolite, designated ZSM-35, which is envisioned for use as an absorbent or a catalyst. Sand and Dodwell (U.S. Pat. No. 4,081,514) disclose a process for producing acid-stable, fluidizable mordenite particles in the size range of 20 to 150 nanometers and envisioned for use as an absorbant, catalyst support and ion-exchange medium. Sand (U.S. Pat. No. 4,093,699) independently discloses a method for making synthetic offretite, which is acid treated, and is capable of intercrystalline absorption of benzene and molecules greater than 5 Å. Cormier and Sand (U.S. Pat. No. 4,017,590) disclose the preparation of synthetic ferrierite by a hydrothermal process in which there is co-precipitation of silica-alumina gels and sodium and potassium carbonates and bicarbonates and which is envisioned for use in separating molecules 6.2 Å and smaller from larger molecules. Kuznicki and Whyte (U.S. Pat. No. 5,011,667) disclose a process of forming self-bound sodium chabazite and designated EC-20 which shows superiority in absorption and ion-exchange capacity when compared to the natural form. Velten and Demmel (U.S. Pat. No. 4,826,793) disclose a method of incorporating small crystalline catalytic ingredients into an attrition-resistant matrix by the use of binder formulations prepared from amorphous silica, alumina, and zirconia. The particles are less than 4 μm and contain the catalyst component ZSM-5, low-soda exchanged type Y-zeolite or ultra-stable type Y zeolite. The resulting material is spray-dried and calcined and which has shown resistance to attrition and particle density change. In each of these disclosures there is not even the remotest suggestion that these inventions have utility in biomedicine, pharmaceuticals or could be useful in the remediation of heavy metal poisoning or toxic metal ingestion in humans or animals.
Bacon Kurtz and Fitzpatrick (U.S. Pat. No. 6,270,755) disclose a series of anionic polymers as toxin binders intended for use in binding pathogenic toxins elaborated by microorganisms including bacteria and protozoa. Kurtz and Fitzpatrick (U.S. Pat. No. 6,290,946) disclose a series of polystyrene sulfonate-based polymers also intended for use in binding pathogenic toxins from microorganisms. Fitzpatrick, Huval, Bacon Kurtz, Mandeville and Neenan (U.S. Pat. Nos. 6,007,803 and 6,290,947) disclose a cationic polymer comprised of a monomer having a pendant ammonium group and a hydrophobic monomer envisioned for use in binding pathogenic toxins elaborated by microorganisms including bacteria and protozoa. Heerze and Armstrong (U.S. Pat. No. 6,107,282) disclose prevention and/or treatment of antibiotic associated diarrhea and pseudomembranous enterocolitis arising from Clostridium difficile toxin B using 8-methoxycarbonyl oligosaccharides. These compositions bind the toxin and neutralize it thereby mitigating and potentially preventing the toxin's pathological effects. Such oligosaccharides have been shown to be eliminated completely and rapidly from the rat gastrointestinal tract. These inventions suffer from no description of any use in removing heavy metals, ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins either recently ingested or absorbed into tissue from chronic exposure.
Other forms of heavy metal detoxification are clearly needed for chronic administration.
The inorganic structural class of molecular sieves or zeolites is comprised of more than 1000 members, many of which we believe possess useful medicinal, pharmacological and biopharmaceutical properties in this therapeutic area.
Zeolites are a class of inorganic crystalline microporous solids comprised mostly of silicates and phosphates although arsenates and germanates are also represented. Zeolites possess a framework density (FD) of approximately 12.1 to 20.6 tetrahedrally coordinated atoms (also known as T-atoms) per 1000 Å³(cubic angstroms). Such frameworks are comprised of a number of repeated identical or different structural components termed secondary building units (SBU). To date, approximately 20 SBUs have been described. The framework for a specific zeolite defines the pore and channel sizes; these pore and channel diameters vary across different zeolites. The pore and channel diameters, also termed “crystallographic free diameters,” influence the rate of diffusion of water and dissolved ions through the framework. A number of zeolite groups with 20-, 18-, 14-, 12-, 10-, 9-, and 8-ring structures are known to exist. Depending on the relative molecular charge in the space surrounding the pores positively or negatively charged ions are attracted or repelled. Ions of similar charge and size may be substituted for each other or “exchanged” thereby producing the “ion exchange” phenomenon for which zeolites are well known.
Zeolites offer a unique approach to treating heavy metal poisoning because of their intrinsic chemical and physical stability and their general biological inertness. The specific zeolite isotypic groups considered to be useful in the wide spectrum of heavy metal intoxication include the 20-, 18- and 14-ring structures designated by the terms and abbreviations: Cloverite (-CLO), VPI-5 (VFI), AlPO-8 (AET), CIT-5 (CFI), UTD-1F (DON), OSB-1 (OSO); the 12-ring structures AlPO-5 (AFI), SAPO-40 (AFR), MAPSO-46 (AFS), CoAPO-50 (AFY), ASU-7 (ASV), AlPO-31 (ATO), MAPO-36 (ATS), Beta (BEA), Boggsite (BOG), Beryllophosphate-H (BPH), Cancrinite (CAN), CIT-1 (CON), Chiral Zincophosphate (CZP), DAF-1 (DFO), EMC-2 (EMT), Faujasite (FAU), Gmelinite (GME), GUS-1 (GON), ITQ-4 (IFR), ITQ-7 (ISV), Linde Type L (LTL), Mazzite (MAZ), ZSM-18 (MEI), Mordenite (MOR), ZSM-12 (MTW), Offretite (OFF), UiO-6 (OSI), Roggianite (RON), STA-1 (SAO), UCSB-8Co (SBE), UCSB-6GaCo (SBS), UCSB-10GaZn (SBT), SSZ-48 (SFE), VPI-8 (VET); the 10-ring structures AlPO-11 (AEL), AlPO-41 (AFO), AlPO-H2 (AHT), Co-Ga-Phosphate-5 (CGF), Co-Ga-Phosphate-6 (CGS), Dachiardite (DAC), Epistilbite (EPI), EU-1 (EUO), Ferrierite (FER), Heulandite (HEU), Laumontite (LAU), ZSM-11 (MEL), ZSM-5 (MFI), ZSM-57 (MFS), ZSM-23 (MTT), MCM-22 (MWW), NU-87 (NES), Partheite (PAR), SSZ-44 (SFF), SSZ-35 (STF), Stilbite (STI), Terranovaite (TER), Theta-1 (TON), Weinebenite (WEI), Wenkite (WEN). The specific zeolite isotypic groups considered to be useful in the wide spectrum of heavy metal intoxication also include the 9-ring structures designated by the terms and abbreviations: Chiavennite (CHI), Lovdarite (LOV), Natrolite (NAT), RUB-17 (RSN), SSZ-23 (STT), VPT-7 (VSV). The specific zeolite isotypic groups considered to be useful in the wide spectrum of heavy metal intoxication also include the 8-ring structures designated by the terms and abbreviations: Li-A (ABW), ACP-1 (ACO), AlPO-18 (AEI), AlPO-EN3 (AEN), AlPO-14 (AFN), AlPO-52 (AFT), SAPO-56 (AFX), Analcime (ANA), AlPO-C (APC), AlPO-D (APD), MAPO-39 (ATN), AlPO-12-TAMU (ATT), AlPO-25 (ATV), AlPO-21 (AWO), AlPO-22 (AWW), Bikitaite (BIK), Brewsterite (BRE), Cesium Aluminosilicate (CAS), Chabazite (CHA), Deca-dodecasil 3R (DDR), DAF-2 (DFT), TMA-E (EAB), Edingtonite (EDI), Erionite (ER1), ERS-7 (ESV), Gismondine (GIS), Goosecreekite (GOO), ITQ-3 (ITE), NaJ (JBW), ZK-5 (KFI), Levyne (LEV), Linde Type A (LTA), Merlinoite (MER), Montesommaite (MON), MCM-35 (MTF), Paulingite (PAU), Phillipsite (PHI), Rho (RHO), RUB-3 (RTE), RUB-13 (RTH), STA-6 (SAS), STA-2 (SAT), Mg-STA-7 (SAV), Thomsonite (THO), Tschortnerite (TSC), VPI-9 (VNI), Yugawaralite (YUG), ZAPO-MI (ZON). These zeolites are described by Baerlocher and colleagues (Baerlocher Ch., Meier, W M and D H Olson. Atlas of Zeolite Framework Types, 5^threvised ed., Elsevier, 2001, pp. 3-18).
One related mineral, magnesium aluminum silicate [1327-43-1] also termed aluminum magnesium silicate [12511-31-8] is available commercially as a pharmaceutical excipient. It is used in a range concentrations in the pharmaceutical industry and functioning as an absorbent, a binding agent, a disintegrant, an oral or topical emulsion stabilizer, an oral or topical suspending agent, a stabilizing agent and a viscosity modifier. It is obtained from the silicate ores of the montmorillonite group and occurs as an off-white to creamy white, odorless, tasteless, soft, slippery small flakes or as fine micronized powder. It is practically insoluble in alcohols, water and organic solvents. It can swell to many times its original volume in water and may be dried and rehydrated many times. It is stable indefinitely when stored under dry conditions and is stable over a wide pH range. It absorbs some organic substances but appears to be compatible with organic solvents. It is generally regarded as nontoxic and nonirritating at levels employed as a pharmaceutical excipient. Subacute animal feeding studies in rats and dogs fed magnesium aluminum silicate at 10% of their diet for 90 days were negative including autopsy and histopathological examination. The oral LD₅₀for the rat is 16 g/kg. Magnesium aluminum silicate is included in the Food and Drug Administration's (FDA) Inactive Ingredients Guide.
The present invention relates to the use of zeolites, both natural and artificial, in the treatment of diseases related to heavy metals and ammonia in humans. Based on the relative affinities and diameters of the metallic ions, certain metals will bind preferentially to certain zeolites, thus creating the ability to design lattice structures of precise dimensions for each of the heavy metals that are known poisons in man. The specific metals known to cause human disease in elevated quantities include lead, copper, tin, arsenic, antimony, beryllium, bismuth, boron, cadmium, chromium, cobalt, copper, iron, lead, lithium, magnesium, nickel, selenium, silver, strontium, thallium, tin, titanium, vanadium, zinc, mercury. It is envisioned that the zeolite would be administered orally in the form of a capsule, tablet, powder or slurry daily or multiple times daily for weeks' to months' duration. Zeolites are generally insoluble in the aqueous environments present in the human gastrointestinal tract such as acid pH in the stomach, alkaline pH of the duodenum for the few hours of normal transit time. Dealuminization is known to occur in acidic environments with some zeolites. The neutral pH of the jejunum, ileum, cecum, colon and rectum do not pose a dealuminization or solubility risk. It is known to bind lead and copper when administered orally in an in vivo system.
Although zeolites and similar ion exchange, inorganic, relatively insoluble materials are claimed, the specific zeolite to be employed is the sodium aluminum silicate, CAS [12141-46-7]. As shown in the Material Safety Data Sheet (Material Safety Data Sheet for sodium aluminum silicate, CAS [12141-46-7] manufactured by Mineral-Right, Inc., Phillipsburg, Kans. Revised Mar. 22, 1995) it consists in its physical state as a solid in the form of granular crystals, which are white-opaque in color. The specific gravity of sodium aluminum silicate is 0.80. It is insoluble in pH neutral aqueous solution. It is formed from two ingredients: hydrated alumina [1344-28-1] 21% and sodium silicate [134409-8] 68%. It is known to be non-toxic to ingestion. It is subject to the following environmental protection procedures: conventional housekeeping methods. It is to be handled similar to earth. This material demonstrates temperature-dependent weight loss upon heating which appears to be unchanged in the temperature range between approximately 350° F. and 1200° F. (Research Report Covering High Temperature Tests on the MR-1 Synthetic Zeolite, Baumbach Labs, Appleton, Wis.; Dec. 30, 1993). At higher temperatures, the “Zeolite Reflection Phenomenon” has been observed.

Examples of zeolites useful in the present invention include zeolite Li-A (Barrer and White) (Barrer R M, et al., J. Chem. Soc. 1267-1278, 1951; Kerr I S, Z. Kristallogr. 139:186-195, 1974; Krogh Anderson E, et al. Z. Kristallogr. 176:67-73, 1986); [Be—As—O]-ABW (Gier T E, et al. Nature 349:508-510, 1991; Harrison W T A, et al., Acta Crystallogr. C51:181-183, 1995); [Be—P—O]-ABW (Gier T E, et al., Nature 349:508-510, 1991; Harrison W T A, et al., Acta Crystallogr. C51:181-183, 1995; Robl C, et al. J. Chem. Soc. Dalton Trans. 1911-1912; 1993); [Ga—Si—O]-ABW (Newsam J M, J. Phys. Chem. 92:445-452; 1988); [Zn—As—O]-ABW (Gier T E, et al. Nature 349:508-510; 1991); [Zn—P—O]-ABW (Gier T E, et al. Nature 349:508-510; 1991); |Cs—|[Mg—P—O]-ABW (Rakotomahanina Raloisoa E L, Ph.D. Thesis, U. Grenoble; 1972); |Cs—|[Al—Si—O]-ABW (Klaska R, et al. Naturwiss. 60:299, 1973; Klaska R, et al. Z. Kristallogr. 142:225-238, 1975); |Cs—|[Al—Ti—O]-ABW (Gatehouse B M, et al. Acta Crystallogr. C45:1674-1677, 1989); |Li—|[Al—Si—O]-ABW (Ghorbarkar H, Cryst. Res. Technol. 27:1071-1075, 1992); |Li—|[Zn—P—O]-ABW (Harrison W T A, et al. J. Solid State Chem. 114:249-257, 1995); |Li—|[Al—Ge—O]-ABW (Tripathi A, et al., Microporous and Mesoporous Materials, 34:273-279, 2000); |Na—|[Co—P—O]-ABW (Chippindale A M, et al., Acta Crystallogr., C55: 845-847, 1999); |Rb—|[Co—P—O]-ABW (Rakotomahanina Raloisoa E L, Ph.D. Thesis, U. Grenoble, 1972); |Rb—|[Al—Si—O]-ABW (Klaska R, et al., Naturwiss., 60: 299, 1973; Klaska R, et al., Z. Kristallogr. 142:225-238, 1975); |Tl—|[Al—Si—O]-ABW (Krogh Anderson E, et al., Zeolites, 11: 149-154, 1991); ACP-1 (Feng P Y, et al., Nature, 388: 735-741, 1997); AlPO-18 (Simmen A, et al., Zeolites, 11:654-661, 1991; U.S. Pat. No. 4,310,440, 1982); AlPO-11 (Bennett J M, et al., Zeolites, 7: 160-162, 1987; Richardson Jr J W, et al., Acta Crystallogr., B44: 367-373, 1988; Wilson S T, et al., U.S. Pat. No. 4,310,440, 1982); MnAPO-1 (Pluth J J, et al., J. Phys. Chem., 92: 2734-2738, 1988); SAPO-11 and compositional variants (Flanigen E M, et al., Pure Appl. Chem., 58: 1351-1358, 1986; Flanigen E M, et al., In Proc. 7^th Int. Zeolite Conf., Japan, 103-112, 1986); AlPO-EN3 (Parise J B, Stud. Surf Sci. Catal., 24: 271-278, 1985); [Ga—P—O]-AEN (Glasser F P, et al., Acta Crystallogr., C50:848-850, 1994); AlPO-53(A) (Kirchner R M, et al., Microporous and Mesoporous Materials, 39: 319-332, 2000); AlPO-53(B) (Kirchner R M, et al., Microporous and Mesoporous Materials, 39: 319-332, 2000); CFSAPO-1A (He H, et al., J Incl. Phenom., 5: 591-599, 1987); JDF-2 (Chippindale A M, et al., Acta Crystallogr., C50: 1537-1540, 1994); MSC-1 (Simmen A, et al., Ph.D. Thesis, ETH Zurich, Switzerland, 1992); UiO-12-500 (Kongshaug K O, et al., Microporous and Mesoporous Materials, 39: 333-339, 2000); UiO-12-as (Kongshaug K O, et al., Microporous and Mesoporous Materials, 39: 333-339, 2000); AlPO-8 (Dessau R M, et al., Zeolites, 10: 522-524, 1990; Richardson Jr J W, Zeolites, 12: 13-19, 1992); MCM-37 (Chu C T W, U.S. Pat. No. 5,091,073, 1992); Afghanite (Barian P, et al. Bull. Soc. Fr. Mineral. Cristallogr. 91: 34-42, 1968; Merlino S, et al. Zeolite 1976, Program and Abstracts, Tucson Ariz., 1976; Pobedimskaya E A, et al. Dokl. Akad. Nauk SSSR 320: 882-886, 1991; Ballirano P, et al. Eur. J. Mineral 9: 21-31, 1997); AlPO-5 (Bennett J M, et al. ACS Sym. Ser.218: 109-118, 1983; U.S. Pat. No. 4,310,440, 1982); CoAPO-5 (Chao K J, et al. J. Chem. Soc., Faraday Trans. 88: 2949-2954, 1992); CrAPO-5 (Radaev S, et al. J Mater. Chem. 6:1413-1418, 1996); SAPO-5 and its compositional variants (Flanigen E M, et al. Pure Appl. Chem 58: 1351-1358, 1986; Flanigen EM, et al. In Proc. 7^th Int. Zeolite Conf., Japan, pp. 103-112, 1986); SSZ-24 (Bialek R, et al., Zeolites 11: 438-442, 1991); TPAF AlPO-5 (Qiu S, et al. Zeolites 9:440 -444, 1989); AlPO-14 (Broach R W, et al. In Proc. 12^th Int. Zeolite Conf., USA, pp. 1715-1722, 1999); GaPO-14 (Parise J B, et al. Acta Crystallogr. C42: 670-673, 1986); AlPO-41 (Kirchner R M, et al. Zeolites 14:523-528, 1994); SAPO-40 (Estermann M A, et al. J. Appl. Crystallogr. 25:539-543, 1992; Dumont N, et al. Microporous Materials 1: 149-160, 1993; McCusker L B, et al. Microporous Materials 6:51-54, 1996); AlPO-40 (Ramaswamy V, et al. Microporous and Mesoporous Materials 31:1-8, 1999); CoAPSO-40 and ZnAPSO-40 (Lourence J P, et al. ??Journal?? 38:267-278, 2000); MAPSO-46 (Bennett J M, et al. Stud. Surf. Sci. Catal. 37:269-279, 1988); AlPO-52 (Bennett J M, et al. Stud. Surf. Sci. Catal. 49:731-739, 1989; McGuire N K, et al. Zeolites 15:460-469, 1995); SAPO-56 (Wilson S T, et al. Microporous and Mesoporous Materials 28:125-137, 1999); SSZ-16 (Lobo R F, et al. Chem. Mater. 8:2409-2411, 1996); CoAPO-50 (Bennett J M, et al. Stud. Surf Sci. Catal. 37: 269-279, 1988); MgAPO-50 (Akolekar D B, et al. Zeolites 15: 583-590, 1995); AlPO-H2 (Li H X, et al. Chem. Commun. ??Vol??: 403-405, 1993; Kennedy G J, et al., Solid State Nuc. Mag. Res 4: 173-178, 1995); Analcime (Taylor W H Z Z. Kristallogr 74:1-19, 1930; Knowles C R, et al. Indian Mineral. 6:127-, 1965; Ferraris G, et al. Z. Kristallogr. 135: 240-252, 1972); [Al—Co—P—O]-ANA (Feng P Y, et al. Nature 388: 735-741, 1997); [Al—Si—P—O]-ANA (Artioli G, et al. Acta Crystallogr. C40:214-217, 1984); [Ga—Ge—O]-ANA (Bu X, et al. J. Am. Chem. Soc. 120:13389-13397, 1998); |Cs—Na—(H₂O)|[Ga—Si—O]-ANA (Yelon W B, et al. Zeolites 10:553-558, 1990); |Cs₁₆|[Cu₈Si₄₀O₉₆]-ANA (Heinrich A R, et al. Acta Crystallogr. C47:237-241, 1991); |K—|[B—Si—O]-ANA (Millini R, et al. Microporous Materials 1:9-15, 1993); AlPO-24 (Wilson S T, et al. J. Am. Chem. Soc. 104:1146-1147, 1982); AlPO₄-pollucite (Keller E B, Ph.D. Thesis, ETH Zurich, Switzerland, 1987); Ammonioleucite (Hori H, et al. Am. Mineral. 71:1022-1027, 1986); Ca-D (Ames L L, et al. Am. Mineral. 43:476-480, 1958); Cs beryllosilicate pollucite (Torres-Martines L M, et al., J Solid State Chem. 51: 100-103, 1984); Cs, Fe silicate pollucite (Kopp O C, et al. Am. Mineral.48:100-109, 1963); Hsianghualite (Wen-Hui H, et al. Am. Mineral. 44:1327-1328, 1959); Kehoeite (McConnell D, et al. Can. Mines. 12:352-, 1974); Leucite (Peacor D R, Z. Kristallogr. 127: 213-224, 1968); Na—B (Barrer R M, et al. J. Chem. Soc. ??vol??: 1561-1571, 1952); Pollucite (Nel H J, Am. Mineral. 29: 443-451, 1944); Synthetic analcime (Ghobarker H, et al. Cryst. Res. Technol. 1071-1075, 1986); Synthetic hsinghualite (Ghobarker H, et al. Annal. Chemie, Science Materiaux 24:209-215, 1999); Synthetic wairakite (Ghobarker H, et al. Cryst. Res. Technol. K90-92, 1985); Wairakite and additional compositional variants (Takeuchi Y. et al. Am. Mineral., 64: 993-1001, 1979); AilPO-C (Bennett J M, et al. Zeolites 6:349-359, 1986; Keller E B, et al. Solid State Ionics 43: 93-103(?), 1990; AlPO-H3 (Pluth J J, et al. Acta Crystallogr. C42:1118-1120, 1986); AlPO-D (Keller E B, et al. Solid State Ionics 43:93-103, 1990); AlPO-16 (Bennett J M, et al., Zeolites 11:502-506, 1991); Octadecasil (Caullet P, et al. Eur. J. Solid State Inorg. Chem. 28:345-361, 1991); ASU-7 (Li H, et al. J. Am. Chem. Soc. 120:10569-10570, 1998); MAPO-39 (McCusker L B, et al. Acta Crystallogr. A46:C59(?), 1990; Baur W H, et al. Z. Kristallogr. 214:154-159, 1999); AlPO-31 (Bennett J M, et al. Zeolites 12:338-342, 1992; Baur W H, et al. Acta Crystallogr. B50: 290-294, 1994); SAPO-31 (Flanigen E M, et al. Pure Appl. Chem. 58:1351-1358, 1986; Flanigen E M, et al. In Proc. 7^th Int. Zeolite Conf, Japan, pp. 103-112, 1986; Baur W H, et al. Acta Crystallogr. B50:290-294, 1994); MAPO-36 (Smith J V, et al. Zeolites 13: 166-169, 1993); AlPO-12-TAMU (Rudolf PR, et al. J Phys. Chem. 90:6122-6125, 1986); AlPO-33 (Smith J V, et al. PRIVATE COMMUNIC; Patton R L, et al. U.S. Pat. No. 4,473,663, 1984); AlPO-25 (Richardson Jr J W, et al., J Phys. Chem. 94: 3365-3367, 1990); [Ga—P—O]-ATV (Parise J B, Chem. Communic. ??vol??:606-607, 1985); AlPO-21 (Bennett J M, et al. Inorg. Chem. 24:188-193, 1985; Parise J B, et al. Acta Crystallogr. C41:515-520, 1985); [Ga—P—O]-ATV (Parise J B, Chem. Communic. 606-607, 1985); AlPO-22 (Richardson Jr J W, et al. Naturwiss. 76:467-469, 1989); Beta (Higgins J B, et al. Zeolites 8:446-452, 1988; Newsam J M, et al. Proc. R. Soc. Lond. A 420: 375-405, 1988); [B—Si—O]-*BEA (Marler B, et al. In Proc. 9^th Int. Zeolite Conf., pp. 425-432, 1993; Reddy K S N, et al. J Incl. Phenom. Mol. Recogn. Chem. 20:197-210, 1994); [Ga—Si—O]-*BEA (Reddy K S N, et al. J Incl. Phenom. Mol. Recogn. Chem. 20:197-210, 1994); CIT-6 (Takewaki T, et al. Topics in Catalysis 9:35-42, 1999); Tschernichite (Boggs R C, et al. Am. Mineral. 78:822-826, 1993); Bikitaite (Kocman V, et al., Am. Mineral. 59:71-78, 1974; St{dot over (a)}hl K, et al. Zeolites 9:303-311, 1989); |Ca—|[Al—Si—O]-BIK (Annehed H, et al. Z. Kristallogr. 166:301-306, 1984); Triclinic bikitaite (Bissert G, et al. N. Jb. Miner. Mh. ??vol??:241-252, 1986); Boggsite (Pluth J J, et al. Am. Mineral. 75:501-507, 1990); Beryllophosphate-H (Harvey G, Z. Kristallogr. 182:123-124, 1988; Harvey G, et al. Z. Kristallogr. 201:113-123, 1992); Linde Q (Andries K J, et al. Zeolites 11:124-141, 1991); STA-5 (Patinec V, et al. Chem. Mater. 11:2456-2462, 1999); Brewsterite (Perrotta A J, et al. Acta Crystallogr. 17:857-862, 1964; Schlenker J L, et al. Acta Crystallogr. B33:2907-2910, 1977); Ba-dominant brewsterite (Cabella R, et al. Eur. J. Mineral. 5:353-360, 1993); CIT-4 (Khodabandeh S, et al. Microporous and Mesoporous Materials 11: 87-95, 1997); Synthetic bewsterite (Ghobarker H, et al. German Patent AZ 198 24 184.4-41, 1997); Cancrinite (Pauling L, Proc. Natl. Acad. Sci. 16:453-459, 1930; Jarchow O, Z. Kristallogr. 122:407-422, 1965); [Al—Ge—O]-CAN (Belokoneva E L, et al. Sov. Phys. Crystallogr. 31:516-519, 1986); [Ga—Si—O]-CAN (Newsam J M, et al. Zeolites 7:569-573, 1987); [Zn—P—O]-CAN (Yakubovich O V, et al. Crystallogr. Reports 39:564-568, 1994); Basic cancrinite (Barrer R M, et al. J. Chem. Soc. 1561-1571, 1952; Bresciana Pahor N, et al. Acta Crystallogr. B38:893-895, 1982); Cancrinite hydrate (Wyart J, et al. Compt. Rend. 229:131-, 1949); Davyne (Hassan I, et al. Can. Mineral. 28:341-349, 1990); ECR-5 (Vaughn D E W, E. Patent A-190,90; 1986); Microsommite (Bonaccorsi E, et al. Phys. Chem. Mineral. 22:367-374, 1995); Synthetic cancrinite (Smolin Y I, et al. Kristallografiya 26:63-66, 1981); Tiptopite (Peacor D R, et al., Am. Mineral., 72:816-820, 1987); Vishnevite (Hassan I, et al. Can. Mineral. 22:333-340, 1984); Cesium aluminosilicate (Araki T Z, Z. Kristallogr. 152:207-213, 1980); CIT-5 (Wagner P, et al. Chem. Commun. 2179-2180, 1997; Yoshikawa M, et al. J Phys. Chem. B 102:7139-7147, 1998); C-Ga-Phosphate-5 (Chippindale A M, et al. Zeolites 18:176-181, 1997); C-Ga-Phosphate-6 (Cowley A R, et al. Microporous and Mesoporous Materials 28:163-172, 1999); [Zn—Ga—P—O]-CGS (Cowley A R, et al. Microporous and Mesoporous Materials 28:163-172, 1999); TNU-1 (Hong S B, et al. J. Mater. Chem. 9:2287-2289, 1999); [Ga—Si—O]-CGS (Hong S B, et al. J Mater. Chem. 9:2287-2289, 1999); TsG-1 (Lee Y J, et al. J Mater. Chem. 11:879-880, 1999); [Ga—Si—O]-CGS (Lee Y J, et al. J Mater. Chem. 11:879-880, 1999); Chabazite (Dent L S, et al. Nature 181:1794-1796, 1958; Smith J V, et al. Acta Crystallogr. 16:45-53, 1963); [Al—Co—P—O]-CHA (Feng P Y, et al. Nature 388:735-741, 1997); [Co—Al—P—O]-CHA (Feng P Y, et al. Nature 388:735-741, 1997; Feng P, et al. Microporous and Mesoporous Materials 23:221-229, 1998); [Mg—Al—P—O]-CHA (Feng P, et al. Microporous and Mesoporous Materials 23:221-229, 1998); AlPO-34 (Harding M M, et al. Acta Crystallogr.C50:852-854, 1994); CoAPO-44 (Bennett J M, et al. Stud. Surf. Sci. Catal 37:269-279, 1988); CoAPO-47 (Bennett J M, et al. Stud. Surf. Sci. Catal. 37:269-279, 1988); Dehydrated Na-Chabazite (Mortier W J, et al. Mater. Res. Bull. 12:241-250, 1977); GaPO-34 (Schott-Darie C, et al. Stud. Surf. Sci. Catal. 84:101-108, 1994); LZ-218 (Breck D W, et al. U.S. Pat. No. 4,333,859, 1982); Linde D (Breck D W, et al. U.S. Pat. No. 2,950,952, 1960; Lillerud K P, et al. J. Chem. Soc., Faraday Transactions 90:1547-1551, 1994); and/or the other framework minerals, both natural and synthetic, a table of which appears below.

TABLE 4


				Page or
Name of Zeolite	First Author Cited	Citation	Vol.	Number	Year

Linde R	Milton R M	British Patent		841,812	1960
MeAPO-47	Bennett J M, et al.	Stud. Surf. Sci. Catal.	37:	269-279	1988
	Flanigen E M, et al.	Pure Appl. Chem.	58:	1351-1358	1986
	Flanigen E M, et al.	In Proc. 7^thInt. Zeolite		103-112	1986
		Conf., Japan
MeAPSO-47	Bennett J M, et al.	Stud. Surf. Sci. Catal.	37:	269-279	1988
	Flanigen E M, et al.	Pure Appl. Chem.	58:	1351-1358	1986
	Flanigen E M, et al.	In Proc. 7^thInt. Zeolite		103-112	1986
		Conf., Japan
Phi	Lillerud K P, et al.	J. Chem. Soc., Faraday	90:	1547-1551	1994
		Transactions
	Grose R W, et al.	U.S. Pat. No.		4,124,686	1978
SAPO-34	Lok, B M, et al.	J. Am. Chem. Soc.	106:	6092-6093	1984
SAPO-37	Pluth J J, et al.	J. Phys. Chem.	93:	6516-6520	1989
Si-CHA	Díaz-Cabañas M J, et	Chem. Commun.		1881-1882	1998
	al.
Willhendersonite	Tillmanns E, et al.	N. J.. Miner. Mh.		547-558	1984
ZK-14	Kuehl G H	PRIVATE
		COMMUNICATION
	Kuehl G H	In Molecular Sieves,		85-91	1968
		(ed. R. M. Barrer)
ZYT-6	Ito M, et al.	Acta Crystallogr.	C41:	1698-1700	1985
Herschelite	Discredited
Chiavennite	Tazzoli V, et al.	Eur. J. Mineral.	7:	1339-1344	1995
Cloverite	Esterman M, et al.	Nature	352:	320-323	1991
CIT-1	Lobo R F, et al.	J. Am. Chem. Soc.	117:	3764-3779	1995
SSZ-26	Lobo R F, et al.	J. Am. Chem. Soc.	117:	3764-3779	1995
	Lobo R F, et al.	Science	262:	1543-1546	1993
SSZ-33	Lobo R F, et al.	J. Am. Chem. Soc.	117:	3764-3779	1995
	Lobo R F, et al.	Science	262:	1543-1546	1993
Chiral	Rajic N, et al.	Zeolites	15:	672-678	1995
Zincophosphate
	Harrision W T A, et al.	Chem. Mater.	8:	145-151	1996
Dachiardite	Gottardi G, et al.	Z. Kristallogr.	119:	53-64	1963
	Vezzalini G Z	Z. Kristallogr.	166:	63-71	1984
Svetlozarite	Discredited
	Gellens L R, et al.	Mineral. Mag.	45:	157-161	1982
Deca-dodecasil 3R	Gies H	Z. Kristallogr.	175:	93-104	1986
Sigma-1	Stewart A, et al.	Stud. Surf. Sci. Catal.	37:	57-64	1988
ZSM-58	Valyocsik E W	U.S. Pat. No.		4,698,217	1987
	Ernst S, et al.	In Zeolites for the	8^thIZC	55-56	1989
		Nineties, Recent Progress
		Reports - Abstracts
DAF-1	Wright P A, et al.	Chem. Commun.		633-635	1993
DAF-2	Chen J, et al.	Angew. Chem., Int. Ed.	33:	639-640	1994
ACP-3	Bu X, et al.	J. Solid State Chem.	136:	210-215	1998
UCSB-3GaGe	Bu X, et al.	J. Am. Chem. Soc.	120:	13389-13397	1998
UCSB-3ZnAs	Bu X, et al.	J. Solid State Chem.	136:	210-215	1998
UiO-20	Kongshuang K O, et al.	Chem. Mater.	12:	1095-1099	2000
Dodecasil 1H	Gerke H, et al.	Z. Kristallogr.	166:	11-22	1984
UTD-1F	Wessels T, et al.	J. Am. Chem. Soc.	121:	6242-6247	1999
UTD-1	Lobo R F, et al.	J. Am. Chem. Soc.	119:	8474-8484	1997
TMA-E (Aiello and	Aiello R, et al.	J. Chem. Soc. (A).		1470-1475	1970
Barrer)
	Meier W M, et al.	J. Solid State Chem.	37:	204-218	1981
Bellbergite	Rüdinger B, et al.	Miner. Petrol.	48:	147-152	1993
Edingtonite	Taylor W H, et al.	Z. Kristallogr.	86:	53-64	1933
	Galli E	Acta Crystallogr.	B32:	1623-1627	1976
	Kvick Å, et al.	J. Chem. Phys.	79:	2356-2362	1983
[Co—Al—P—O]-EDI	Bu X, et al.	Chem. Mater.	10:	2546-2551	1998
[Co—Ga—P—O]-EDI	Bu X, et al.	Chem. Mater.	10:	2546-2551	1998
K—F	Barrer R M, et al.	J. Chem. Soc.		2882-2891	1956
	Baerlocher Ch, et al.	Z. Kristallogr.	140:	10-26	1974
Linde F	Sherman J D	ACS Sym. Ser.	40:	30-42	1977
Synthetic	Ghobarker H, et al.	Cryst. Res. Technol.	32:	653-657	1997
edingtonite
Tetragonal	Mazzi F, et al.	N. Jb. Miner. Mh.		373-382	1984
edingtonite
Zeolite N	Christensen A N, et al.	Acta Chemica Scand.	51:	969-973	1997
EMC-2	Delprato F, et al.	Zeolites	10:	546-552	1990
	Baerlocher Ch, et al.	Microporous Materials	2:	269-280	1994
CSZ-1	Barrett M G, et al.	UK Patent		GB 2,076,793	1981
ECR-30	Vaughn D E W	E Patent		0,351,461	1989
ZSM-20	Newsam J M, et al.	Chem. Commun.		493-495	1989
ZSM-3	Kokotailo G T, et al.	Adv. Chem. Ser.	101:	109-121	1971
Epistilbite	Kerr I S	Nature	202:	589	1964
	Perrotta A J	Mineral. Mag.	36:	480-490	1967
	Alberti A, et al.	Z. Kristallogr.	173:	257-265	1985
	Yang P, et al.	Eur. J. Mineral.	8:	263-271	1996
Synthetic	Ghobarkar H	Cryst. Res. Technol.		151-1573(?)	1984
epistilbite
Erionite	Staples L W, et al.	Mineral. Mag.	32:	261-281	1959
	Kawahara A, et al.	Bull. Soc. Fr. Minéral.	92:	250-256	1969
		Cristallogr.
	Gard J A, et al.	In Proc. 3rd Int. Cong.		94-99	1973
		Molecular Sieves
AlPO-17	Pluth J J, et al.	Acta Crystallogr.	C42:	283-286	1986
	Flanigen E M, et al.	Pure Appl. Chem.	58:	1351-1358	1986
	Flanigen E M, et al.	In Proc. 7^thInt. Zeolite		103-112	1986
		Conf.
LZ-220	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
Linde T	Breck D W	Zeolite Molecular		173	1974
		Sieves
ERS-7	Campbell B J, et al.	Chem. Commun.		1725-1726	1998
	Millini R, et al.	In Proc. 12^thInt. Zeolite		541-548	1999
		Conf.
EU-1	Casci J L, et al.	U.S. Pat. No.		4,537,754	1985
	Briscoe N A, et al.	Zeolites	8:	74-76	1988
TPZ-3	Sumitani K, et al.	E Patent		EP 51318	1982
ZSM-50	Rohrbaugh W J	Private communication
Faujasite	Bergerhoff G, et al.	N. Jb. Miner. Mh.		193-200	1958
	Baur W H	Am. Mineral.	49:	697-704	1964
[Al—Ge—O]-FAU	Barrer R M, et al.	J. Chem. Soc.		195-208	1959
[Co—Al—P—O]-FAU	Feng P Y, et al.	Nature	388:	735-741	1997
[Ga—Ge—O]-FAU	Barrer R M, et al.	J. Chem. Soc.		195-208	1959
Beryllophosphate	Gier T E, et al.	Zeolites	12:	770-775	1992
X
CSZ-1	Barrett M G, et al.	UK Patent		BG 2,076,793	1981
ECR-30	Vaughn D E W	E Patent		0,351,461	1989
LZ-210	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
Linde X	Milton R M	U.S. Pat. No.		2,882,244	1959
	Olson D H, et al.	J. Phys. Chem.	74:	2758-2764	1970
Linde Y	Breck D W	U.S. Pat. No.		3,130,007	1964
	Costenoble M L, et al.	J. Chem. Soc., Faraday	72:	1877-1883	1976
		Trans. I
SAPO-37	Lok B M, et al.	J. Am Chem. Soc.	106:	6092-6093	1984
Siliceous Na—Y	Hriljac J J, et al.	J. Solid State Chem.	106:	66-72	1993
ZSM-20	Newsam J M, et al.	Chem. Commun.		493-495	1989
ZSM-3	Kokotailo G T, et al.	Adv. Chem. Ser.	101:	109-121	1971
Zincophosphate X	Gier T E, et al.	Zeolites	12:	770-775	1992
Ferrierite	Vaughn P A	Acta Crystallogr.	21:	983-990	1966
[Ga—Si—O]-FER	Jacob N E, et al.	Zeolites	13:	430-434	1993
[Si—O]-FER	Gies H, et al.	Zeolites	7:	442-445	1987
	Morris R E, et al.	J. Am. Chem. Soc.	116:	11849-11855	1994
FU-9	Seddon D, et al.	E Patent		B-55,529	1985
ISI-6	Morimoto N, et al.	U.S. Pat. No.		4,578,259	1986
Monoclinic	Gramlich-Meier R, et	Am. Mineral.	70:	619-623	1985
ferrierite	al.
NU-23	Whittam T V	E Patent		A-103-981	1984
Sr-D	Barrer R M, et al.	J. Chem. Soc.		2296-2305	1964
ZSM-35	Plank C J, et al.	U.S. Pat. No.		4,016,245	1977
Franzinite	Ballirano P, et al.	Can. Mineral.	38:	657-668	2000
Gismondine	Fischer K, et al.	Adv. Chem. Ser.	101:	250-258	1971
[Al—Co—P—O]-GIS	Feng P Y, et al.	Nature	388:	735-741	1997
[Co—Al—P—O]-GIS	Feng P, et al.	Microporous and	23:	221-229	1998
		Mesoporous Materials
[Co—Ga—P—O]-GIS	Cowley A R, et al.	Chem. Commun.		673-674	1996
[Co—P—O]-GIS	Yuan H M, et al.	Inorg. Chem.	39:	1476-1479	2000
[Ga—Si—O]-GIS	Cho H H, et al.	Chem. Mater.	12:	2292-2300	2000
[Mg—Al—P—O]-GIS	Feng P, et al.	Microporous and	23:	221-229	1998
		Mesoporous Materials
[Zn—Ga—P—O]-GIS	Chippindale A M, et al.	Microporous and	24:	133-141	1998
		Mesoporous Materials
\|(NH₄)₄\|[Zn₄B₄P₈O₃₂]-GIS	Kniep R, et al.	Angew. Chem. Int. Ed.	38:	3642-3644	1999
\|Cs₄\|[Zn₄B₄P₈O₃₂]-GIS	Kniep R, et al.	Angew. Chem. Int. Ed.	38:	3642-3644	1999
\|Rb₄\|[Zn₄B₄P₈O₃₂]-GIS	Kniep R, et al.	Angew. Chem. Int. Ed.	38:	3642-3644	1999
Amicite	Alberti A, et al.	Acta Crystallogr.	B35:	2866-2869	1979
Garronite	Artioli G	Am. Mineral.	77:	189-196	1992
	Artioli G, et al.	Powder Diffraction	14:	190-194	1999
Gobbinsite	McCusker L B, et al.	Z. Kristallogr.	171:	281-289	1985
High-silica Na—P	Hakansson U, et al.	Acta Crystallogr.	C46:	1361-1362	1990
Low-silica Na—P	Albert B R, et al.	Microporous and	21:	133-142	1998
(MAP)		Mesoporous Materials
MAPO-43	Pluth J J, et al.	J. Am. Chem. Soc.	111:	1692-1698	1989
MAPSO-43	Flanigen E M, et al.	Pure Appl. Chem.	58:	1351-1358	1986
	Flanigen E M, et al.	In Proc. 7^thInt. Zeolite		103-112	1986
		Conf.
Na—P1	Baerlocher Ch, et al.	Z. Kristallogr.	135:	339-354	1972
Na—P2	Hansen S, et al.	Acta Crystallogr.	C46:	1361-1362	1990
SAPO-43	Helliwell M, et al.	Acta Crystallogr.	B49:	413-420	1993
Synthetic Ca-	Schropfer L, et al.	Eur. J. Mineral.	9:	53-65	1997
garronite
Synthetic amicite	Ghobarkar H, et al.	Mater. Res. Bull	34:	517-525	1999
Synthetic garronite	Ghobarkar H, et al.	Mater. Res. Bull	34:	517-525	1999
Synthetic	Ghobarkar H, et al.	Mater. Res. Bull	34:	517-525	1999
gobbinsite
TMA-gismondine	Baerlocher Ch, et al.	Helv. Chim. Acta	53:	1285-1293	1970
Gismondite	discredited
Synthetic zeolite B	disused
Gmelinite	Fischer K	N. Jb. Miner. Mh.		1-13	1966
K-rich gmelinite	Vezzalini G, et al.	N. Jb. Miner. Mh.		504-516	1990
Synthetic fault-free	Daniels R H, et al.	J. Am. Chem Soc	100:	3097-3100	1978
gmelinite
Sarcolite	Discredited
GUS-1	Plévert J, et al.	Chem. Commun.		2363-2364	2000
Goosecreekite	Rouse R C, et al.	Am. Mineral.	71:	1494-1501	1986
Heulandite	Merkle A B, et al.	Am. Mineral.	52:	273-276	1967
	Alberti A	Tschermarks Min. Petr.	18:	129-146	1972
		Min.
Clinoptilolite	Koyama K, et al.	Z. Kristallogr.	145:	216-239	1977
Dehydrated	Mortier W J, et al.	Am. Mineral.	66:	309-314	1981
Ca, NH₄-Heulandite
LZ-219	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
ITQ-4	Barrett P A, et al.	Chem. Mater.	9:	1713-1715	1997
MCM-58	Valyo, E W	WOP		9511196	1995
SSZ-42	Chen C Y, et al.	Chem. Commun.		1775-1776	1997
ITQ-7	Villaescusa L A, et al.	Angew. Chem. Int. Ed.	38:	1997-2000	1999
ITQ-3	Camblor, M A, et al.	Angew. Chem. Int. Ed.	36:	2659-2661	1997
Na-J (Barrer and	Hansen S, et al.	Zeolites	2:	162-166	1982
White)
Nepheline hydrate	Rheinhardt A, et al.	Fortsch. Mineral.	60:	175-176	1982
Synthetic \|Na—\|[Al—Si—O]-JBW	Ragimov K G, et al.	Sov. Phys. Dokl.	23:	697-698	1978
ZK-5	Meier W M, et al.	Z. Kristallogr.	121:	211-219	1965
(Cs, K)-ZK-5	Robson H E	U.S. Pat. No.		3,270,753	1973
	Parise J B, et al.	Z. Kristallogr.	165:	175-190	1983
P	Barrer R M, et al.	Z. Kristallogr.	135:	374-390	1972
Q	Barrer R M, et al.	Z. Kristallogr.	135:	374-390	1972
Laumontite	Bartl H, et al.	Jb. Miner. Mh.		33-42	1967
	Amirov S T, et al.	Dokl. Akad. Nauk SSSR	174:	667-	1967
	Schramm V, et al.	Adv. Chem. Ser.	101:	259-265	1971
	Artioli G, et al.	Zeolites	17:	249-255	1993
[Co—Ga—P—O]-LAU	Chippindale A M, et al.	Chem. Commun.		2453-2454	1994
	Bond A D, et al.	Zeolites	19:	326-333	1997
[Fe—Ga—P—O]-LAU	Bond A D, et al.	Zeolites	19:	326-333	1997
[Mn—Ga—P—O]-LAU	Bond A D, et al.	Zeolites	19:	326-333	1997
Synthetic	Ghorbarkar H, et al.	Microporous and	23:	55-60	1998
laumontite		Mesoporous Materials
Leonhardite	Lapham D L	Am. Mineral.	48:	683-689	1963
(discredited)
Levyne	Barrer R M, et al.	Trans. Faraday Soc.	55:	1915-1923	1959
	Merlino S, et al.	Min. Petr. Mitt.	22:	117-129	1975
AlPO-35	Zhu G S, et al.	Microporous Materials	11:	269-273	1997
CoDAF-4	Barrett P A, et al.	Phys. Chem. Chem.	2:	407-412	2000
		Phys.
LZ-132	Tvaruzkova Z, et al.	Int. Zeolite Sym.,			1988
		Wurzburg, Extended
		Abstracts
NU-3	McCusker L B	Mater. Sci. Forum	133-136:	423-433	1993
SAPO-35	Lok B M, et al.	J. Am. Chem. Soc.	106:	6092-6093	1984
ZK-20	Kerr G T	U.S. Pat. No.		3,459,676	1969
Liottite	Merlino S, et al.	Am. Mineral.	62:	321-326	1977
	Ballirano P, et al.	Can. Mineral.	34:	1021-1030	1996
Losod	Sieber W, et al.	Helv. Chim. Acta	57:	1533-1549	1974
	Schicker P	Ph. D. Thesis, ETH			1988
		Zürich, Switzerland
[Al—Ge—O]-LOS	Sokolov Yu. A., et al.	Sov. Phys. Dokl.	23:	789-791	1978
\|Li—\|[Be—P—O]-LOS	Harrison W T A, et al.	Zeolites	13:	242-248	1993
Bystrite	Pobedimskaya E A, et	Sov. Phys. Dokl.	36:	553-555	1991
	al.
Lovdarite	Merlino S	Acta Crystallogr.	A37:	C189	1981
		(Suppl.)
	Merlino S	Eur. J. Mineral.	2:	809-817	1990
Synthetic lovdarite	Ueda S, et al.	Preprints of Poster			1986
		Papers, 7^thInt. Zeolite
		Conf.
Linde Type A	Reed T B, et al.	J. Am. Chem. Soc.	78:	5972-5977	1956
	Gramlich V, et al.	Z. Kristallogr.	133:	134-149	1971
[Al—Ge—O]-LTA	Barrer R M, et al.	J. Chem. Soc.		195-208	1959
[Ga—P—O]-LTA	Simmen A, et al.	In Proc. 9^thInt. Zeolite		433-440	1993
		Conf.
Alpha	Wadlinger R L, et al.	U.S. Pat. No.		3,375,205	1968
LZ-215	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
N-A	Barrer R M, et al.	J. Chem. Soc.		971-982	1961
SAPO-42	Lok B M, et al.	J. Am. Chem. Soc.	106:	6092-6093	1984
ZK-21	Kuehl G H	Inorg. Chem.	10:	2488-2495	1971
ZK-22	Kuehl G H	Inorg. Chem.	10:	2488-2495	1971
ZK-4	Kerr G T	Inorg. Chem.	5:	1537-1539	1966
Linde Type L	Barrer R M, et al.	Z. Kristallogr.	128:	352-370	1969
(K,Ba)-G, L	Baerlocher Ch., et al.	Z. Kristallogr.	136:	245-254	1972
Gallosilicate L	Wright P A, et al.	Nature	318:	611-614	1985
	Newsam J M, et al.	Mater. Res. Bull.	21:	661-672	1986
LZ-212	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
Perlialite	Menshikov Y P	Vses. Mineral. O-va	113:	607-612	1984
	Artioli G, et al.	Eur. J. Mineral.	2:	749-759	1990
Linde Type N	Fälth L, et al.	Z. Kristallogr.	160:	313-316	1982
NaZ-21	Sheplev Yu F, et al.	Dokl. Akad. Nauk SSSR	272:	1133-1137	1983
Mazzite	Galli E	Cryst. Struct. Comm.	3:	339-344	1974
	Galli E	Rend. Ital. Mineral.	31:	599-612	1975
		Petrol.
[Ga—Si—O]-MAZ	Newsam J M, et al.	Mater. Res. Bull.	20:	125-136	1985
LZ-202	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
Omega	Galli E	Cryst. Struct. Comm.	3:	339-344	1974
ZSM-4	Rubin M K, et al.	U.S. Pat. No.		4,021,447	1977
ZSM-18	Lawton S L, et al.	Science	247:	1319-1321	1990
ZSM-11	Kokotailo G T, et al.	Nature	275:	119-120	1978
	Fyfe C A, et al.	J. Am. Chem. Soc.	111:	2470-2474	1989
	Van Koningveld H, et	In Proc. 12^thInt. Zeolite		2419-2424	1999
	al.	Conf.
Bor-D (MFI/MEL	Perego G, et al.	J. Appl. Crystallogr.	17:	403-410	1984
intergrowth)
Boralite D	Taramasso M, et al.	GB Patent		2,024,790	1980
SSZ-46	Terasaki O, et al.	Chem. Mater.	8:	463-468	1996
	Nakagawa Y, et al.	U.S. Pat. No.		5,968,474	1999
Silicalite 2	Bibby D M, et al.	Nature	280:	664-665	1979
TS-2	Reddy J S, et al.	Zeolites	12:	95-100	1992
Melanophlogite	Gies H	Z. Kristallogr.	164:	247-257	1983
	Gies H, et al.	N. Jb. Miner. Mh.		119-124	1982
Merlinoite	Passaglia E, et al.	N. Jb. Miner. Mh.		355-364	1977
		N. Jb. Miner. Mh.		1-9	1979
[Al—Co—P—O]-MER	Feng P Y, et al.	Nature	388:	735-741	1997
\|Ba—\|[Al—Si—O]-	Gottardi G, et al.	Natural Zeolites (book)		157	1985
MER
\|Ba—Cl-\|[Al—Si—O]-	Solov'eva L P, et al.	Sov. Phys. Crystallogr.	16:	1035-1038	1972
MER
\|NH4-\|[Be—P—O]-	Bu X, et al.	Microporous and	26:	61-66	1998
MER		Mesoporous Materials
K-M	Gottardi G, et al.	Natural Zeolites (book)		157	1985
	Barrer R M, et al.	J. Chem. Soc.		2882-2891	1956
Linde W	Gottardi G, et al.	Natural Zeolites (book)		157	1985
	Sherman J D	ACS Sym. Ser.	40:	30-42	1977
Synthetic	Barrett P A, et al.	J. Mater. Chem.	8:	2263-2268	1998
Merlinoite
Zeolite W	Bieniok A, et al.	J. Mater Chem.	6:	271-275	1996
ZSM-5	Kokotailo G T, et al.	Nature	272:	437-438	1978
	Olson D H, et al.	J. Phys. Chem.	85:	2238-2243	1981
	Van Koningsveld H, et	Acta Crystallogr.	B43:	127-132	1987
	al.
[As—Si—O]-MFI	Bhaumik A, et al.	Chem. Commun.		869-870	1995
[Fe—Si—O]-MFI	Patarin J, et al.	Zeolites	10:	674-679	1990
[Ga—Si—O]-MFI	Awate S V, et al.	J. Incl. Phenom.	13:	207-218	1992
AMS-1B	Klotz M R	U.S. Pat. No.		4,269,813	1981
AZ-1	Chono M, et al.	E. Patent		B-113,116	1984
Bor-C	Taramasso M, et al.	In Proc. 5^thInt. Zeolite		40-48	1980
		Conf.
Boralite C	Taramasso M, et al.	GB Patent		2,024,790	1980
Encilite	Ratnasamy P, et al.	E. Patent		A-160,136	1985
FZ-1	Suzuki T, et al.	E. Patent		B-31,255	1981
LZ-105	Grose R W, et al.	U.S. Pat. No.		4,257,885	1981
Monoclinic H-	Van Koningsveld H, et	Zeolites	10:	235-242	1990
ZSM-5	al.
Mutinaite	Vezzalini G, et al.	Zeolites	19:	323-325	1997
NU-4	Whittam T V	E. Patent		B-65,401	1986
NU-5	Whittam T V	E. Patent		B-54,386	1982
Silicalite	Flanigen E M, et al.	Nature	271:	512-516	1978
TS-1	Taramasso M, et al.	U.S. Pat. No.		4,410,501	1983
TSZ	Ashibe K, et al.	E. Patent		A-101,232	1984
TSZ-III	Sakurada S, et al.	E. Patent		A-170,751	1986
TZ-01	Iwayama K, et al.	E. Patent		A-57,016	1982
USC-4	Young D A	U.S. Pat. No.		4,325,929	1982
USI-108	Hinnenkamp J A, et al.	U.S. Pat. No.		4,423,020	1983
ZBH	Holderich W, et al.	E. Patent		B-77,946	1986
ZKQ-1B	Kee Kwee L S L	E. Patent		A-148,038	1984
ZMQ-TB	Kee Kwee L S L	E. Patent		A-104,107	1983
ZSM-57	Schlenker J L, et al.	Zeolites	10:	293-296	1990
Montesommaite	Rouse R C, et al.	Am. Mineral.	75:	1415-1420	1990
Mordenite	Meier W M	Z. Kristallogr.	115:	439-450	1961
[Ga—Si—O]-MOR	Eapen M J, et al.	J. Incl. Phenom.	14:	119-129	1992
Ca-Q	Koizumi M, et al.	J. Geol.	68:	41-53	1960
LZ-211	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
Large pore	Sand L B	In Molecular Sieves		71-77	1968
mordenite		(ed. R M Barrer)
Maricopaite	Rouse R C, et al.	Am. Mineral.	79:	175-184	1994
(interrupted
framework)
Na-D	Barrer R M, et al.	J. Chem. Soc.		1561-1571	1952
Ptilolite	Discredited
Arduinite	Discredited
Flokite	Discredited
MCM-61	Valyosik E W	U.S. Pat. No.		5,670,131	1997
	Shantz D F, et al.	Microporous and	31:	61-73	1999
		Mesoporous Materials
MCM-35	Barrett P A, et al.	Chem. Mater.	11:	2919-2927	1999
UTM-1	Plevert J, et al.	J. Phys. Chem. B	103:	8647-8649	1999
ZSM-39	Schlenker J L, et al.	Nature	294:	340-342	1981
CF-4	Long Y, et al.	J. Incl. Phenom.	5:	355-362	1987
Dodecasil-3C	Gies H	Z. Kristallogr.	167:	73-82	1984
Holdstite	Smith J V, et al.	Nature	303:	223-225	1983
ZSM-23	Schlenker J L, et al.	Private communication
	Rohrman Jr. A C, et al.	Zeolites	5:	352-354	1985
	Marler B, et al.	J. Appl. Crystallogr.	26:	636-644	1993
EU-13	Araya A, et al.	U.S. Pat. No.		4,581,211	1986
ISI-4	Kakatsu K, et al.	Eur. Pat. Appl.		EPA 102,497	1984
KZ-1	Parker L M, et al.	Zeolites	3:	8-11	1983
ZSM-12	LaPierre R B, et al.	Zeolites	5:	346-348	1985
	Fyfe C A, et al.	J. Phys. Chem.	94:	3718-3721	1990
[Ga—Si—O]-MTW	Zhi Y X, et al.	Zeolites	12:	138-141	1992
CZH-5	Hickson D A, et al.	UK Pat. Appl.		GB2079735A	1981
NU-13	Whittam T V	Eur. Pat. Appl.		EPA0059059	1982
TPZ-12	Sumitani K, et al.	U.S. Pat. No.		4,557,919	1985
Theta-3	Barlow T M	E. Patent		A-162,719	1985
VS-12	Reddy K M, et al.	Chem. Commun.		1491-1492	1994
MCM-22	Leonowicz M E, et al.	Science	264:	1910-1913	1994
ERB-1	Belussi G, et al.	Eur. Pat. Appl.		EPA293032	1988
ITQ-1	Camblor M A, et al.	Chem. Mater.	8:	2415-2417	1996
	Camblor M A, et al.	J. Phys. Chem. B	102:	44-51	1998
PSH-3	Puppe L, et al.	U.S. Pat. No.		4,439,409	1984
SSZ-25	Zones S I	E. Patent		231,860	1987
Natrolite	Pauling L	Proc. Nat. Acad. Sci.	16:	453-459	1930
	Meier W M	Z. Kristallogr.	113:	430-444	1960
[Al—Ge—O]-NAT	Tripathi A, et al.	J. Mater. Chem.	10:	451-455	2000
[Ga—Si—O]-NAT	Xie D, et al.	In MRS Sym. Proc.	111:	147-154	1988
		(Materials Res. Soc.)
\|Rb—\|[Ga—Ge—O]-NAT	Klaska K H, et al.	Z. Kristallogr.	172:	167-174	1985
Gonnardite	Mazzi F, et al.	N. Jb. Miner. Mh.		219-228	1986
High natrolite	Baur W H, et al.	N. Jb. Miner. Mh.		171-187	1996
Mesolite	Artioli G, et al.	Acta Crystallogr.	C42:	937-942	1986
Metanatrolite	Joswig W, et al.	N. Jb. Miner. Mh.		26-38	1995
Scolecite	Taylor W H, et al.	Z. Kristallogr.	86:	53-64	1933
	Fälth L, et al.	Acta Crystallogr.	B35:	1877-1880	1979
	Smith J V, et al.	In Proc. 6^thInt. Zeolite		842-850	1984
		Conf.
Synthetic	Ghorbarkar H, et al.	Zeolites	19:	259-261	1997
gonnardite
Synthetic mesolite	Ghorbarkar H, et al.	Cryst. Res. Technol.	31:	K67-69	1996
Synthetic natrolite	Ghorbarkar H, et al.	Cryst. Res. Technol.	31:	K67-69	1996
Synthetic scolecite	Ghorbarkar H, et al.	Cryst. Res. Technol.	31:	K67-69	1996
NU-87	Shannon M D, et al.	Nature	353:	417-420	1991
Gottardite	Alberti A, et al.	Eur. J. Mineral.	8:	69-75	1996
Nonasil	Marler B, et al.	J. Incl. Phenom.	4:	339-349	1986
[B—Si—O]-NON	Marler B, et al.	Zeolites	15:	517-525	1995
\|(Co(C₅H₅)₂)₄F4\|	Vandegoor G, et al.	Z. Anorg. Allg. Chemie	621:	311-322	1999
[Si₈₈O₁₇₆]-NON
CF-3	Long Y-C, et al.	J. Incl. Phenom.	4:	121-127	1986
ZSM-51	Rohrbaugh W J	Private communication
Offretite	Bennett J M, et al.	Nature	214:	1005-1006	1967
	Gard J A, et al.	Acta Crystallogr.	B28:	825-834	1972
LZ-217	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
Linde T (ERI-OFF	Breck D W, et al.	Zeolite Molecular		173	1974
structural		Sieves (book)
intermediate)
Synthetic offretite	Ghobarkar H, et al.	Cryst. Res. Technol	31:	K29-31	1996
TMA-O	Aiello R, et al.	Trans. Faraday Soc.	66:	1610-1617	1970
UiO-6	Akporiaye D E, et al.	Chem. Commun.		1553-1554	1996
OSB-1	Kongshaug K O, et al.	Private communication
Parthetite	Engel N, et al.	Z. Kristallogr.	169:	165-175	1984
Paulingite	Gordon E K, et al.	Science	154:	1004-1007	1966
ECR-18	Vaughn D E W, et al.	U.S. Pat. No.		4,661,332	1987
Phillipsite	Steinfink H	Acta Crystallogr.	15:	644-651	1962
	Rinaldi R, et al.	Acta Crystallogr.	B30:	2426-2433	1974
[Al—Co—P—O]-PHI	Feng P Y, et al.	Nature	388:	735-741	1997
Harmotome	Rinaldi R, et al.	Acta Crystallogr.	B30:	2426-2433	1974
	Sadanaga R, et al.	Acta Crystallogr.	14:	1153-1163	1961
ZK-19	Kuehl G H, et al.	Am. Mineral.	54:	1607-1612	1969
Wellsite	Cerny P, et al.	N. Jb. Miner. Abh.	128:	312-330	1977
(discredited)
Rho	Robson H E, et al.	Adv. Chem. Ser.	121:	106-115	1973
	McCusker L B, et al.	In Proc. 6^thInt. Zeolite		812-822	1984
		Conf.
[Be—As—O]-RHO	Gier T E, et al.	Nature	349:	508-510	1991
[Be—P—O]-RHO	Harvey G, et al.	Stud. Surf. Sci. Catal.	49:	411-420	1989
[Co—Al—P—O]-RHO	Feng P, et al.	Microporous and	23:	315-322	1998
		Mesoporous Materials
[Mg—Al—P—O]-RHO	Feng P, et al.	Microporous and	23:	315-322	1998
		Mesoporous Materials
[Mn—Al—P—O]-RHO	Feng P, et al.	Microporous and	23:	315-322	1998
		Mesoporous Materials
Deuterated	Parise J B, et al.	J. Phys. Chem.	88:	1635-1640	1984
Gallosilicate ECR-10	Newsam J M, et al.	J. Phys. Chem.	99:	9924-9932	1995
LZ-214	Breck D W, et al.	U.S. Pat. No.		4,503,023	1985
Pahasapaite	Rouse R C, et al.	N. Jb. Miner. Mh.		433-440	1987
	Rouse R C, et al.	Am. Mineral.	74:	1195-1202	1989
Roggianite	Giuseppetti G, et al.	N. Jb. Miner. Mh.		307-314	1991
RUB-17	Röhrig C, et al.	Angew. Chem. Int. Ed.	34:	63-65	1995
RUB-3	Marler B, et al.	Zeolites	15:	388-399	1995
	Marler B, et al.	Microporous and	26:	49-59	1998
		Mesoporous Materials
RUB-13	Vortmann S, et al.	Microporous Materials	4:	111-121	1995
RUB-10	Gies H, et al.	U.S. Pat. No.		4,060,590	1977
\|TMA-\|[Si—O]-RUT	Broach R W, et al.	J. Phys. Chem. Solids	56:	1363-1368	1995
B—NU-1	Belluse G, et al.	Zeolites	10:	642-649	1990
Fe—NU-1	Belluse G, et al.	Zeolites	10:	642-649	1990
Ga—NU-1	Belluse G, et al.	Zeolites	10:	642-649	1990
NU-1	Whittam T V, et al.	U.S. Pat. No.		4,060,590	1977
STA-1	Noble G W, et al.	Angew. Chem. Int. Ed.	36:	81-83	1997
STA-6	Patinec V, et al.	J. Chem. Soc. Dalton		3909-3911	1999
		Trans.
STA-2	Noble G W, et al.	J. Chem. Soc. Dalton		4485-4490	1997
		Trans.
Mg—STA-7	Wright P A, et al.	J. Chem. Soc. Dalton		1243-1248	2000
		Trans.
Co—STA-7	Wright P A, et al.	J. Chem. Soc. Dalton		1243-1248	2000
		Trans.
Zn—STA-7	Wright P A, et al.	J. Chem. Soc. Dalton		1243-1248	2000
		Trans.
UCSB-8Co	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-8Mg	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-8Mn	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-8Zn	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-6GaCo	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-6Co	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-6GaMg	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-6GaZn	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-6Mg	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-6Mn	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-6Zn	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-10GaZn	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-10Co	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-10Mg	Bu X H, et al.	Science	278:	2080-2085	1997
UCSB-10Zn	Bu X H, et al.	Science	278:	2080-2085	1997
SSZ-48	Wagner P, et al.	J. Phys. Chem. B.	103:	8245-8250	1999
SSZ-48	Wagner P, et al.	Angew. Chem. Int. Ed.	38:	1269-1272	1999
Sigma-2	McCusker L B, et al.	J. Appl. Crystallogr.	21:	305-310	1988
Sodalite	Pauling L	Z. Kristallogr.	74:	213-223	1930
	Loens J, et al.	Acta Crystallogr.	23:	434-436	1967
[Al—Co—P—O]-SOD	Feng P Y, et al.	Nature	388:	735-741	1997
[Al—Ge—O]-SOD	Bu X, et al.	J. Am. Chem. Soc.	120:	13389-13397	1998
[Be—As—O]-SOD	Gier T E, et al.	Angew. Chem., Int. Ed.	30:	1169-1171	1991
[Be—P—O]-SOD	Gier T E, et al.	Angew. Chem., Int. Ed.	30:	1169-1171	1991
[Be—Si—O]-SOD	Dann S E, et al.	Inorg. Chem.	35:	555-558	1996
[Co—Ga—P—O]-SOD	Bu X, et al.	Microporous and	20:	371-379	1998
		Mesoporous Materials
[Ga—Co—P—O]-SOD	Feng P Y, et al.	Nature	388:	735-741	1997
[Ga—Ge—O]-SOD	Bu X, et al.	J. Am. Chem. Soc.	120:	13389-13397	1998
[Ga—Si—O]-SOD	McCusker L B, et al.	Zeolites	6:	388-391	1986
[Zn—As—O]-SOD	Nenoff T M, et al.	J. Am. Chem. Soc.	113:	378-378	1991
[Zn—Ga—As—O]-SOD	Bu X, et al.	Microporous and	20:	371-379	1998
		Mesoporous Materials
[Zn—Ga—P—O]-SOD	Bu X, et al.	Microporous and	20:	371-379	1998
		Mesoporous Materials
[Zn—P—O]-SOD	Nenoff T M, et al.	J. Am. Chem. Soc.	113:	378-378	1991
\|Ca₈(WO₄)₂\|[Al₁₂O₂₄]—SOD	Depmeier W	Acta Crystallogr.	C40:	226-231	1984
AlPO-20 +	Wilson S T, et al.	J. Am. Chem. Soc.	104:	1146-1147	1982
compositional variants
	Flanigen E M, et al.	In Proc. 7^thInt. Zeolite			1986
		Conf.
Basic sodalite	Barrer R M, et al.	J. Chem. Soc.		1267-1278	1951
	Hassan I, et al.	Acta Crystallogr.	C39:	3-5	1983
Bicchulite	Sahl K, et al.	Z. Kristallogr.	146:	35-41	1977
Danalite	Glass J J, et al.	Am. Mineral.	29:	163-191	1944
G	Shishakova T N, et al.	Izv. Akad. Nauk SSSR		1303-	1965
Genthelvite	Merlino S	In Feldspars and		435-470	1983
		Feldspathoids (ed. W L
		Brown)
Hauyn	Loehn J, et al.	N. Jb. Miner. Abh.	109:	201-210	1968
Helvin	Glass J J, et al.	Am. Mineral.	29:	163-191	1944
Hydroxo sodalite	Felsche J, et al.	Zeolites	6:	367-372	1986
Nosean	Schulz H, et al.	Tschermaks Min. Petr.	10:	225-232	1965
		Mitt.
Silica sodalite	Bibby D M, et al.	Nature	317:	157-158	1985
TMA sodalite	Baerlocher Ch, et al.	Helv. Chim. Acta		1853-1860	1969
Tugtupite	Sorensen H	Am. Mineral.	48:	1178	1963
	Hassan I, et al.	Can. Mineral.	29:	385-390	1991
SSZ-35	Wagner P, et al.	Angew. Chem., Int. Ed.	38:	1269-1272	1999
ITQ-9	Villaescusa L A, et al.	Chem. Commun.	21:	2329-2330	1998
Stilbite	Galli E, et al.	Miner. Petrogr. Acta	12:	1-10	1966
	Slaughter M	Am. Mineral.	55:	387-397	1970
	Galli E	Acta Crystallogr.	B27:	833-841	1971
Barrerite	Galli E, et al.	Bull. Soc. Fr. Minéral.	98:	331-340	1975
		Cristallogr.
Stellerite	Galli E, et al.	Bull. Soc. Fr. Minéral.	98:	11-18	1975
		Cristallogr.
Synthetic barrerite	Ghobarkar H, et al.	J. Solid State Chem.	142:	451-454	1999
Synthetic stellerite	Ghobarkar H, et al.	J. Solid State Chem.	142:	451-454	1999
Synthetic stilbite	Ghobarkar H, et al.	J. Phys D: Appl. Phys.	31:	3172-3176	1998
Desmine
(discredited)
Epidesmine
(obsolete)
SSZ-23	Camblor M A, et al.	Angew. Chem. Int. Ed.	37:	2122-2126	1998
Terranovaite	Galli E, et al.	Am. Mineral.	82:	423-429	1997
Thomsonite	Taylor W H, et al.	Z. Kristallogr.	84:	373-398	1933
	Alberti A, et al.	Zeolites	1:	91-97	1981
	Pluth J J, et al.	Zeolites	5:	74-80	1985
[Al—Co—P—O]-THO	Feng P Y, et al.	Nature	388:	735-741	1997
[Ga—Co—P—O]-THO	Feng P Y, et al.	Nature	388:	735-741	1997
Na—V	Barrer R M, et al.	J. Chem. Soc.		195-208	1959
Synthetic	Ghobarkar, et al.	Cryst. Res. Technol.	32:	653-657	1997
thomsonite
Theta-1	Barri S A I, et al.	Nature	312:	533-534	1984
	Highcock R M, et al.	Acta Crystallogr.	C41:	1391-1394	1985
ISI-1	Kozo T, et al.	E Patent		A-170,003	1986
KZ-2	Parker L M, et al.	Zeolites	3:	8-11	1983
NU-10	Araya A, et al.	Zeolites	4:	280-286	1984
ZSM-22	Kokotailo G T, et al.	Zeolites	5:	349-351	1985
	Marler B	Zeolites	7:	393-397	1987
Tscöhrtnerite	Effenberger H, et al.	Am. Mineral.	83:	607-617	1998
VPI-8	Freyhardt C C, et a.	J. Am. Chem. Soc.	118:	7299-7310	1996
VPI-5	Davis M E, et al.	Nature	331:	698-699	1988
	Richardson Jr. J W, et	J. Phys. Chem.	93:	8212-8219	1989
	al.
	McCusker L B, et al.	Zeolites	11:	308-313	1991
AlPO-54	Richardson Jr. J W, et	J. Phys. Chem.	93:	8212-8219	1989
	al.
H1	d'Yvoire F	Bull. Soc. Chim. France		1762-1776	1961
MCM-9	Derouane E G, et al.	Appl. Catal.	51:	L13-20	1989
VPI-9	McCusker L B, et al.	Microporous Materials	6:	295-309	1996
VPI-7	Annen M J, et al.	Chem. Commun.		1175-1176	1991
	Röhrig C, et al.	Zeolites	14:	498-503	1994
Gaultite	Ercit T S, et al.	Can. Mineral.	32:	855-863	1994
VSV-7#	Röhrig C, et al.	J. Phys. Chem. Solids	56:	1369-1376	1995
Weinebeneite	Walter F	Eur. J. Mineral.	4:	1275-1283	1992
Wenkite	Wenk H-R	Z. Kristallogr.	137:	113-126	1973
	Merlino S	Acta Crystallogr.	B30:	1262-1266	1974
Yugawaralite	Kerr I S, et al.	Z. Kristallogr.	125:	220-225	1967
	Kerr I S, et al.	Acta Crystallogr.	B25:	1183-1190	1969
	Leimer HW, et al.	Z. Kristallogr.	130:	88-111	1969
Sr-Q	Hawkins DB	Mater. Res. Bull.	2:	951-958	1967
	Kvick Å	Z. Kristallogr.	174:	265-281	1986
ZAPO-M1	Marler B, et al.	Microporous Materials	5:	151-159	1995
GaPO-DAB-2	Meden A, et al.	Z. Kristallogr.	212:	801-807	1997
UiO-7	Akporiaye D E, et al.	Chem. Commun.		601-602	1996
	Akporiaye D E, et al.	J. Phys. Chem.	100:	16641-16646	1996
CSZ-3	Vaughn D E W, et al.	U.S. Pat. No.		4,333,859	1982

The zeolites may be used for oral chelation therapy for heavy metal poisoning, either by natural means such as Wilson's disease and primary biliary cirrhosis, or from environmental exposure such as lead poisoning and intoxication by other various heavy metals such as arsenic, chromium, cesium and strontium including also ammonia, mercaptans and other plant-, marine organism- and nuclear-derived toxins and involving multiple administrations during a single day, single daily, or sequential daily administrations for months to years to slowly remove tissue-bound toxins from the bodies of humans.
The zeolites may be used for therapy for hepatic encephalopathy as an adjunct or alternative to other therapies currently used by binding up chemical mediators of hepatic encephalopathy, which include at least ammonia and mercaptans which are elevated due to poor function of the liver because of its diseased state, which are bound to the zeolite in the gastrointestinal tract and are then removed from the body by fecal elimination. Examples of mercaptans include hydrogen sulfide and alkyl sulfides.
The zeolites may be used in the event of radioactive contamination of food (specifically strontium or cesium, but also other contaminating radionuclides) such that the zeolite is ingested and the radionuclide is adsorbed by the zeolite and carried out of the body (the radionuclide thereby not being absorbed and finding its way into bone or soft tissue where the half-life is substantially prolonged).
The zeolites may be used for treating potassium depletion for patients with elevated potassium in the outpatient or hospital by exploiting their ion-exchange properties in the intestinal juices whereby excess potassium is eliminated with the zeolite in the feces.
The zeolites may be used for oral drug delievery in which the specific framework structure, or mixture of structures chosen, or size of particles, to provide a temporally predictable gastrointestinal absorption profile whereby the zeolite acts a carrier of an active pharmaceutcal ingridient which is either slowly or rapidly desorbed out of the zeolite and absorbed by the gastointestinal tract on a predictable customizable basis.
The zeolites may be used for treating osteoporosis based on the observation that eggshell thickness increases in hens fed a small percentage of their diet as zeolite.
The use of zeolites as the active component for a hemoperfusion device in which blood-borne toxins, whether from an endogenous or exogenous source, are selectively depleted based on the relative affinity of certain zeolites for certain toxins may be used to advantage in a similar way as charcoal is currently used in the hemoperfusion devices.
The zeolites may be used to mitigate against toxic consequences of acrolein exposure in humans.
The zeolites may be used for mitigation, minimization, treatment and prevention of noxious and odoriferous flatulence exploiting the properties of zeolites to selectively absorb hydrogen sulfide, the most odoriferous component of flatulence.
The zeolites may be used for treating hemachromatosis alone or in combination with complementary therapies including therapeutic phlebotomy, erythropoietin administration, desferroxamine, and other experimental oral and intravenously administered chelating agents.
The zeolites may be used to remove arsenic and decrease toxicity from therapeutic arsenic-containing medications used in the treatment of cancer and infections specifically the cardiac arrhythmia-inducing effects of arsenic.

The zeolites may be used for therapy of acute poisonings from a wide variety of plant, animal, industrial and environmental toxins. These include the mitigation, minimization and elimination of toxin-induced clinical syndromes affecting the cardiovascular, respiratory, gastrointestinal, hepatic, renal, hematopoietic and nervous systems from the following list of plants by their common name, scientific name, toxic part and specific poison:

TABLE 5


Plants, toxic parts, and specific poison

Common	Scientific
Name	Name	Toxic part	Toxin	Symtoms/syndrome

Akee	Blighia sapida	Fruit	Hypoglycins A, B	“Jamaica vomiting sickness”
				with hypoglycemia,
				convulstions, coma, lethal
Apricot,	Prunus species	Pit/seed,	Amygdalin	Cyanide liberation in gut and
peach, etc		foliage	glycoside	cyanide poisoning
Autumn	Colchicum autumnale	All parts of	Colchicine alkaloid	Vomiting, diarrhea, shock,
crocus		plant		death
Meadow	Colchicum autumnale	All parts of	Colchicine alkaloid	Vomiting, diarrhea, shock,
saffron		plant		death
Bird of	Casealpinia gilliesii	Pods	Unidentified	Vertigo, vomiting,
paradise				diarrhea, dehydration
Black locust	Robinia pseudoacacia	Inner bark,	Robin (phytotoxin),	Vomiting, diarrhea,
		young leaves,	robitin (glycoside)	shock, CNS depression
		seeds
Bleeding-heart	Dicentra formosa	Foliage, roots	Apomorphine,	Tremors, staggering gait,
			protoberberine,	labored breathing, salivation,
			protopine, other	convulsions, death due to
			isoquinoline-type	paralysis
			alkaloids
Buckeye	Aesculus species	Leaves,	Esculin (glycoside)	Vomiting, diarrhea,
		flowers, seeds		pupillary dilatation, ms.
				Twitching, weakness, ataxia,
				CNS depression, paralysis
Castor bean	Ricinus communis	All parts, esp.	Ricin, ricinine	Nausea, vomiting, violent
		seeds	(phytotoxins,	purging, hemolysis, renal
			toxalbumins)	failure, oral burning
				sensation
Century plant	Agave americana	Sap	Unknown	Skin exposure causes
				dermatitis associated with
				leukocytosis and fever
Chinaberry	Melia azedarach	Fruit	Probably a resinoid	Severe gastroenteritis
Christmas rose	Helleborus niger	Rootstock and	Helleborin,	Numbing sensation in
		leaves	belleborein	mouth, vomiting, diarrhea,
			(glycosides)	convulsions, CNS effects
Daphne	Daphne mezereum	Berries, bark,	Daphnin, mezerenic	Burning oral sensation,
		leaves	acid anhydride	vomiting, blood and mucus
				in diarrhea, renal failure,
				weakness, convulsions,
				death
Desert potato	Jatropha macrorhiza	Plant root	Phytotoxins	Nausea, vomiting,
				abdominal cramps, watery
				diarrhea
Dumb cane	Dieffenbachia seguine	All parts of	Calcium oxalate	Burning sensation of
	or picta	plant induing	crystals, toxic	tongue, mouth, larynx;
		sap	protein	breathing affected
Fava bean	Vicia faba	Bean, plant	(G6PD	Headache, nausea, vomiting,
		pollen	deficiencient	abdominal pain, icterus
			individuals)	hyperthermia, hemolytic
				anemia, hemogloinuria
Four o'clock	Mirabilis jalapa	Root, seeds	Trigonelline	Skin, mouth, throat
			alkaloid	irritant causing purgation
Foxglove	Digitalis purpurea	Leaves and	Digitoxin, digitalin,	Cardiac arrhythmia
		seeds	digitonin glycosides
Golden chain	Laburnum anagyroides	Beanlike	Quinolizidine	Dysphagia, incoordination,
		capsules in	alkaloid cytisine	vomiting, renalr failure,
		which seeds		convulsions, coma, death by
		are suspended		asphyxiation
Holly	Ilex species	Berries	Ilicin	Nausea, abdominal pain,
				severe vomiting, diarrhea
Hyacinth	Hyacinthus orientalis	Bulb	Narcissine-like	Digestive upset,
			alkaloid(s)	vomiting, diarrhea
Hydrangea	Hydrangea species	All parts of	Hydrangin (a	Cyanide liberation in gut and
		plant	cyanogenic glycoside)	cyanide poisoning
Indian tobacco	Loebelia inflata	All parts of	Lobeline and	Nausea, vomiting,
		plant	lobelamine	weakness, tremors,
			alkaloids	convulsions, coma, death
Iris (blue flag)	Iris versicolor	Leaves and	Irisin, inidin,	GI tract, liver, pancreas;
		root stalks	irigenin	purging and congestion of
				GI tract
Jack-in-the-	Arisaema triphyllium	Rhizome	Calcium oxalate	Burning sensation of
pulpit (Indian			crystals	tongue, mouth, larynx;
turnip)				breathing affected
Jerusalem	Solanium pseudocapsicum	Berries	Solanine and related	Headache, abdominal pain,
cherry			alkaloids	vomiting, diarrhea,
				circulatory collapase,
				convulsions; CNS, resp.
				depression
Jimson weed	Datura stramonium,	All parts of	Atropine,	Intense thirst, urinary
	metel, inoxia,	plants,	hyoscyamine,	retention, xerostomia,
	suaveolens, other species	especially	scopolamine	tachycardia, delirium,
		seeds	(solanaceous	incoherence, pyrexia,
			alkaloids)	confulsions, coma, death
Lantana	Lantana camara	Berries	Lantadene A	Extreme muscular
		(unripe)	(a polycyclic	weakness, GI irritation,
			triterpinoid)	lethargy, cyanosis,
				circulatory collapse
Larkspur	Delphinium ajacis,	Young plant,	Delphinine (?other	Digestive upset, respiratory
	other species	seeds	poisonous	depression, parestieias,
			alkaloids)	salivation, headache,
				hypotension, cardie
				arrhythmias
Lilly of the	Convallaria majalis	Leaves,	Convallarin,	Dizziness, vomiting,
valley		flowers, roots	convallamarin,	Cardiac arrhythmias
			convallatoxin
			(cardiac glycosides)
Mistletoe	Phoradendron species	Berries	b-	Acute gastroenteritis,
			phenylethylamine,	circulatory collapse, nausea,
			tyramine, choline	vomiting, diarrhea,
				respiratory difficulties,
				bradycardia, delirium,
				hallucinations, coma
Monkshood	Aconitum napellus	Roots, seeds,	Aconitine (a	Vagal stimulation,
		leaves	polycyclic diterpene	bradycardia, irregular pulse,
			and other alkaloids)	dimness of vision, nausea,
				vomiting, diarrhea,
				respiratory failure,
				tingling/numbing of lips,
				tongue
Morning glory	Ipomoea violacea	Seeds	Ergine, isoergine,	Pychotomimetic effects,
			elymoclavine (other	hallucinations, euphoria,
			olavine alkaloids	nausea, uterine
			related to LSD)	stimulation
Mountain	Kalmia latifolia	All parts of	Andromedotoxin	Stimulation then paralysis of
laurel	and augustifolia	plant		skeletal muscle (curare-like
				effects), cardiac tissue
				inhibition, CNS depression,
				respiratory depression, death
Narcissus/daffodil	Narcissus species	Bulb	narcissine, lycorine	Severe gastroenteritis,
			(other alkaloids)	vomiting, purging,
				trembline, convulsions,
				hypotension, hepatic
				degeneration
Nightshade	Solanum species	Varies with	Solanine alkaloids	See Jerusalem cherry
family		specie
Oleander	Nerium oleander	All parts	oleandroside,	Local irritation to mucous
			oleandrin nerioside	membranes, mouth,
			(cardiac glycosides)	stomach; nausea, vomiting,
				diarrhea, slow and irregular
				pulse changing to
				rapid/thready pulse,
				ventricular fibrillation, death
Pencil tree	Euphorbia tirucalli	Leaves, stems,	Unidentified irritant	Irritation to lips, tongue,
		milky sap	in sap	mouth; skin blisters
Peyote	Lophophora williamsii	All parts	Mescaline and other	Sensory distortion, visual
	and diffusa	especially	alkaloids	hallucinations
		cactus
		“button”
Philodendron	Philodendron species	Entire plant	Calcium oxalate	Local irritation to mucous
				membranes, swelling of lips,
				tongue, excessive salivation,
				difficulty with swallowing;
				swelling of tongue, pharynx,
				inhibits respiration
Caladium	Caladium bicolor	Entire plant	Calcium oxalate	Local irritation to mucous
				membranes, swelling of lips,
				tongue, excessive salivation,
				difficulty with swallowing;
				swelling of tongue, pharynx,
				inhibits respiration
Elephant ear	Colocasia antiquorum	Entire plant	Calcium oxalate	Local irritation to mucous
				membranes, swelling of lips,
				tongue, excessive salivation,
				difficulty with swallowing;
				swelling of tongue, pharynx,
				inhibits respiration
Hemlock	Conium maculatum	All parts of	Coniium (alkaloid)	Nausea, vomiting, early
(poison)		plant		CNS stimulation followed
				by severe CNS depression,
				assoc. muscle paralysis,
				repiratory failure
Poison ivy	Toxicodendron radicans	All parts of	Urushiol (comprised	Severe dermatitis with
(erroneously	or Rhus toxicodendron	plant	of phenolic substances	inflammation, vesicles,
called poison		including	including 3-N-	blistering
oak)		smoke from	pentadecylcatechol
		burning
Pokeweed	Phytolacca amnericana	Roots, leaves	Saponin, a	Burning sensation in mouth,
(also called	and decandra	and fruit	glycoprotein,	GI cramps, vomiting,
pigeonberry,			phytolaccine,	diarrhea; visual disturbance,
inkberry)			phytolaccotoxin	amblyopia, perspiration,
			(alkaloids)	salivation, lassitude,
				prostration, weakend
				respiration and pulse, death
Privet	Ligustrum japonicum	All parts	Possible	Vomiting, colic, diarrhea,
			andromedotoxin,	death
			probably unknown
Red squill	Urginea maritima	Bulb	Cardiac glycosides	(see Oleander)
Rhododendron	Rhododendron	All parts	Andromedotoxin	Salivation, nasal discharge,
(azaela)	species			nausea, vomiting, diarrhea,
				muscle weakness, labored
				breathing, coma; dullness of
				vision, paralysis,
				hypotension, lacrimation,
				anorexia
Rhubarb	Rheum rhaponticum	Leaf blade	Oxalic acid	Severe intermittent
		(not petiole)		abdominal pains, vomiting,
				diarrhea, headache,
				weakness, hemorrhages;
				hypocalcemia causing
				muscular cramps, tetany;
				convulsions, coma, death by
				renal failure
Rosary pea	Abrus precatorius	Seeds	Abrin (phytotoxin),	Burns to mouth, esophagus;
(crabseye,			abric acid (tetanic	like castor bean; nausea,
precatory			glycoside)	vomiting, severe diarrhea,
bean, jequirity				weakness, shock, trembling
bean, Indiian				hands, oliguria, hemolytic
licorice)				anemia, hallucinations, fatal
				uremia
Star-of-	Ornithogalum umbrellatum	All parts	Colchicine-related	Nausea, nervous
Bethlehem			alkaloids	symptoms, general
(snowdrop)				disturbances of GI tract
Sweet pea	Lathyrus odoratus	Seeds	Aminopropionitrile	Skeletal deformity and
				growth suppression;
				muscle paralysis
Texas	Sophora secundiflora	Entire plant	Cytisine	Increased salivation, nausea,
mountain				vomiting, headache, vertigo,
laurel				confusion, hallucinations,
				excessive thirst, muscle
				fasciculation, convulsion,
				respiratory stimulation then
				failure
Threadleaf	Senecio longilobus	Entire plant	Pyrrolizidine	Chronic ingestion causes
groundsel		(ingested as	alkaloids	enlarged liver, ascites,
		herbal tea)		abdominal pain,
				headache, apathy,
				emaciation; major cause
				of veno-occlusive disease
Tobacco	Nicotiana species	Possibly all	Nicotine and related	Nausea, vomiting,
		parts	alkaloids	muscular fasciculations,
				early CNS stimulation
				followed by severe CNS
				depression assoc. with
				muscle paralysis and
				respiratory failure
Water	Cicuta maculata	All parts,	Cicutoxin	Severe stomach pain,
hemlock	and other species	mostly the		great mental excitation
(cowbane)		roots		and frenzy, vomiting,
				salivation, violent
				spasmodic convulsions
				alternating with periods
				of relaxation, dilated
				pupils, delirium, death
Wisteria	Wisteria floribunda	Seeds or pods	Wisterin (glucoside)	Mild to severe
	(Japanese); W. sinensis			gastroenteritis, vomiting,
	(Chinese)			abdominal pain, diarrhea
Yellow	Gelsmium semperviren	Whole plant,	Gelsemine and	Depress and paralyze
jessamine		berries	gelseminine	nerve motor endings in
(Carolina			(alkaloids)	brain and spinal cord,
jessamine)				respiratory arrest
Yellow	Thevetia peruviana	All parts; fruit	Thevetin A, B;	Similar to Oleander; Local
oleander		“lucky nut”	thevetoxin (cardiac	irritation to mucous
			glycosides)	membranes, mouth,
				stomach; nausea, vomiting,
				diarrhea, slow and irregular
				pulse changing to
				rapid/thready pulse,
				ventricular fibrillation, death
Yew	Taxus beccata	All parts, esp.	Taxine (alkaloid)	Nausea, vomiting, diarrhea,
	and T. canadensis	seeds		abdominal pain, circulatory
				failure, difficulty breathing;
				depresses heart function;
				dermatitis

The zeolites may be used for treating the following food-borne toxin-induced diseases: cholera, botulism and food poisoning due to Bacillus cereus and staphylococcal poisons and Escherecia coli; the followng toxic marine ingestions: (1) paralytic shellfish poisoning from the ingestion of mussels (Mytilus edulis and Mytilus californianus), clams (Saxidomus gigantus [the Alaskan butter clam] and Mya arenaria [the “soft-shell clam”]), scallops (Placopecten magellanicus), oysters which had previous fed upon certain Gonyaulux species (which comprise the so-called “red tide”) and elaborate saxitoxin 1, neosaxitoxin 2, gonyautoxin 3, gonyautoxin 4 and gonyautoxin 5; (2) pufferfish poisoning (“fugu” in Japan, tambore puffer in China); and (3) ciguatera, from certain fish (such as barracuda, amberjack, kingfish and dolfin) exposed to the benthic dinoflagellate Gambierdiscus toxicus; and minimization, mitigation and treatment of any one of the several sydromes arising from the ingestion of toxic mushrooms including stages I, II and III gastroenteritis and hepatorenal syndrome, the anti-cholinergic syndrome, delayed gastroenteritis with CNS abnormalities, cholinergic syndrome, the disulfiram-like reaction with alcohol, hallucinations, delayed gastritis and renal failure and the general gastroenteritis syndromes of nausea, vomiting, abdominal cramping and diarrhea; binding of one or more of the following mushroom poisonous substances including the cyclopeptides amatoxins and phallotoxins, muscimol, ibotenic acid [2552-55-8], gyromitrin monomethyl hydrazine, muscarine, coprine, indole species, orelline, orellanine, psilocin, psilocybin; for one or more of several different mushroom species including Amanita muscaria (also known as “fly agaric”),pantherina, gemata, cokeri, cothurnata, phalloides (also known as the “death cap”), verna (also known as the “death angel”), virosa (also known as the “destroying angel”), bisporigera, ocreata, suballiacae, tenuifolia; Galerina autumnaluis, marginata, venerata; Lepiota helveola, vosse-randii, Conocybe filaris, Gyromitra esculenta (also known as the “false morel”), gigas, ambigua, infula, cardiniana, brunnea; Paxina species; Sarcosphera coronaria; Boletus calopus, luridus, pulcherimus, satanas; Clitocybe clavipes, cerrusata, dealbata, illudens, riuulosa; Inocybe fastigiata, geophylla, lilocina, patuoillaridi, purica, rimosis; Psilocybe cubensis, caerulescens, cyanescens, baeocystis, fimentaria, mexicana, pellulolosa, semilanceata, silvatica; Conocybe cyanopus; Gymnopilus aeruginosa, spectabilis, validipes; Panaeolus subbalteatus andfoenisecii (also known as the “mowers' mushroom”); Stropharis coronillal; Cortinarius orellanus, speciosissimus, splendoma, gentilis; Chlorophyllum molybdites; and Orphalates illudens (also known as the “jack-o-lantern” mushroom).
Dosage and Administration
Preferred dosages are 100-1000 mg sodium aluminosilicate zeolite to a 5-20 kg weight of the human for treating lead poisoning. If the drug is administered to children, the preferred formulation would be as a gelatin capsule with minimal to no water. The number of times it would be administered could be up to 4× per day and could go on daily for more than 1 year. Actual dosage amounts could vary substantially depending on conventional criteria.
For treating excess ammonia, preferred dosages may be about 10 grams to a 70 kg human. This could be up to 4× per day and would be used for up to about 7 days per episode of ammonia-induced encephalopathy. Actual dosage amounts could vary substantially depending on conventional criteria. Preferably, a zeolite formulation would be administered between meals.
The particle size graphs of FIGS. 1-2 show the binding of ammonia using the same mass of sodium aluminosilicate, but with different particle size distributions. It shows that the smaller the particle, the poorer the ammonia binding. Hence, the larger the particle, the more active the drug in binding ammonia. However, there is a practical upper limit for particle size, and that upper limit is palatability. One must strike the right balance that optimizes the trade-off between ammonia binding palatibility. Preferably, at least 90% of the particles are of particle size from about 90 μm to about 150 μm. More preferably, at least 95% of the particles are in that range.

The following table present toxicology data on sodium aluminosilicates.

TABLE 6


Toxicology Studies by Oral Gavage Performed with Sodium Aluminosilicate

Study	Animal
Author/	Toxico-
Company	logy		Dose
Report	Model	Schedule	Range	Findings	Notes	References

Degussa,	Rat	Single	5,000	mg/kg to	No		Degussa A G - US IT No. 78-0012-
1978		dose	31,800	mg/kg	Mortality		DKT (unpublished data, 1978)
					observed
Gloxhuber,	Rat						Gloxhuber Ch, Potokar M,
1983							Pittermann W, et al. Food Chem.
							Toxic. 21: 209-220 (1983)
Gaynor,	Rat						Gaynor T, Klusman L. Procter &
1973							Gamble Company; Human Safety
							Appendices on Sodium
							Aluminosilicate, A.2 (1973)
Thomas,	Rat						Thomas J, Ballantyne B; J. of Am.
1992							Coll. Of Tox. 11(3): 259-273 (1992)
Moore,	Rat						Moore G E, Huntingdon Research
1974							Center, Project No. 747-129 in:
							Procter & Gamble Company;
							Human Safety Appendices on
							Sodium Aluminosilicate, A.2
							(1974)
Moulton,	Rat						Moulton R H, Scientific Associates,
1974							Inc., S. A. No. 201935 in: Procter
							& Gamble Company; Human
							Safety Appendices on Sodium
							Aluminosilicate, A.2 (1973)
Degussa,	Rat						Degussa A G - US IT No. 88-0207-
1988							DKT (unpublished data, 1988 A)
Litton,	Rat						Litton Bionetics, Inc.“Mutagenic
1974							evaluation of compound FDA 71-
							45, synthetic sodium
							silicoaluminate,” prep, for FDA;
							NTIS, US Dept. of Commerce,
							Springfield, VA; PB 245 468
							(1974)
Huber,	Rat						J. M. Huber Corporation; Report
1973							date January 12, 1973
							(unpublished data)
Degussa,	Rat		5,110	mg/kg			Degussa A G - US IT No. 90-0146-
1990A	(GLP)						DGT (unpublished data, 1990 A)
Degussa,							Degussa A G - US IT No. 90-0149-
1990B							DGT (unpublished data, 1990 D)
Litton,	Rat	Single			LD₅₀> 5000	Identical	BgVV (Bundesinstitut für gesund-
1974a		dose			mg/kg	protocol and	heitlichen Verbraucherschutz und
						laboratory as	Veterinärmedizin), Ärtzliche
						study below	Mitteilung bei Vergiftungen 1999,
							ISBN 3-931675-59-9
Litton,	Rat	Single			LD₅₀	Results	BgVV (Bundesinstitut für gesund-
1974b		dose			1050	deemed NOT	heitlichen Verbraucherschutz und
					mg/kg	RELIABLE by	Veterinärmedizin), Ärtzliche
						HERA Panel	Mitteilung bei Vergiftungen 1999,
							ISBN 3-931675-59-9
Litton,	Rat	D × 5	5,000	mg/kg/d	No signs		Reference not provided in HERA
1974c					of toxicity		documentation
					or abnormal
					behavior
Henkel,	Mouse	Single	10,000	mg/kg	n/a		Henkel KgaA, Archive-No. TBD
1978		dose					780104 (Akute Toxizität an der
							Maus, 11/1978)
							Sturm RN, Procter & Gamble
Sturm,	Dog	Single			n/a		Company; Human Safety
1973		dose					Appendices on Sodium
							Aluminosilicate, A.3 (1973)
Henkel,	Rat	D × 14	0.000%	(w/w)	No change in		Henkel KgaA, Archive-No. R
1979a	(Fischer		0.625%	(w/w)	food consump-		0100197 (External Report, Tracor-
	344)		1.25%	(w/w)	tion, no marked		Jitco, Inc., June 28, 1979,
			2.5%	(w/w)	signs of		unpublished data)
			5.0%	(w/w)	toxicity on
			10.0%	(w/w)	gross necropsy
Henkel,	Mouse	D × 14	0.000%	(w/w)	No change in		Henkel KgaA, Archive-No. R
1979b	(B6C3F1)		0.625%	(w/w)	food		0100196 (External Report, Tracor-
			1.25%	(w/w)	consumption, no		Jitco, Inc., June 28, 1979,
			2.5%	(w/w)	marked signs of		unpublished data)
			5.0%	(w/w)	toxicity on
			10.0%	(w/w)	gross necropsy
Henkel,	Rat	D × 90	0	ppm	High dose group:		Henkel KgaA, Archive-No. TBD
1977	(Wistar)			(w/w)	hyperplastic		770012 Subacute orale Toxizität an
			1,000	ppm	reaction of		Ratten, 90-Tage-Test, Jan. 1977,
				(w/w)	tranansitional		unpublished data).
			5,000	ppm	epithelium with
				(w/w)	calculi; kidneys
			10,000	ppm	of male higher
				(w/w)	silicate content
					vs. ctrls; NOAEL
					5,000 ppm (250-300
					mg/kg/d; 1500-1800
					mg/m²/d)
Henkel,	Rat	D × 163	0.0%	(w/w)	D28 sac: no Δ;		Henkel KgaA, Archive-No. TBD
1975	(COX-SD)		0.5%	(w/w)	D84, D85: 1		EX 0143 (External Report, Procter &
			1.0%	(w/w)	death/day: bladder		Gamble, Sept., 1975,
			2.0%	(w/w)	tox, stones; D91		unpublished data)
					sac: bladder
					stones; high dose
					only; D163 sac
					bladder stones
1
					animal each in
					1.0% and 0.5%
					groups
Henkel,	Rat	D × 160	0.0%	(w/w)	UA: No Δ treated		Henkel KgaA, Archive-No. TBD
1976a	(COX-SD)	or	0.125%	(w/w)	vs. Ctrl; bladder		EX 0127 (External Report, Procter &
		D × 200	2.0%	(w/w)	tox, stones, xtals		Gamble; June, 1976,
					in high dose		unpublished data)
					group; no Δ in
					urine parameter or
					kidney function;
					Histopath: ↑
					interstitial
					nephritis,
					regenerative
					epithelium and
					[renal]
					pelvic epithelial
					hyperplasia;
					bladder: ↑
					transitional
					epithelium
					hyperplasia in
					high dose group.
					No histopath Δ
					in low dose group;
					NOAEL 0.125%
					(˜69 mg/kg/d;
					˜420 mg/m²/d)
Henkel,	Rat	D × 168	0.0%	(w/w)	Regarding		Two citations for this study:
1976b			0.125%	(w/w)	mortality, physical		(1) Henkel KgaA, Archive-No.
	(Long-	(24 wk)	0.5%	(w/w)	appearance, feed		TBD EX 0129 (External Report,
	Evans)		2.0%	(w/w)	efficiency, body		Procter & Gamble, May, 1976,
					weights, organ		unpublished data);
					weights and		(2) Henkel KgaA, Archive-No.
					organ/body ratios		TBD EX 0137 (External Pathology
					no toxic effects		Report [13 weeks], Procter &
					observed.		Gamble, March, 1976,
					Histopath:		unpublished data)
					microscopic
					alternations in
					the kidneys at 0.5%
					and 2.0% groups;
					NOAEL 0.125%
					(˜69 mg/kg/d;
					˜420 mg/m²/d)
Henkel,	Rat	D × 728	0	ppm	Mortality, feed &	Same study as	Henkel KgaA, Archive-No. SAS
1979c	(Wistar)	(104 wk)	10	ppm	water consumption,	below, this is	7900017 (Prüfung auf
			100	ppm	BW monitored;	part 2 with	chronischtoxische und
			1000	ppm	Ophth, blood,	part 1 below.	tumorerzeugende Wirking von
					urinary, bio-		Sasil bei einer Versuchsdauer von
					chemical params
		2 Jahren Teil II, Sept., 1979,
					eval.; 104 wk sac:		unpublished data)
					all organs
					gross/micro
					eval. No significant
					test ariticle related
					effects were
					observed on
					histolopath; no Δ in
					types or incid.of
					neoplasms. NOEL
					60 mg/kg/d (360
					mg/m²/d)
Henkel,	Rat	D × 728	0	ppm	Mortality, feed &		Henkel KgaA, Archive-No. SAS
1979d	(Wistar)	(104 wk)	10	ppm	water consumption,		7900016 (Prüfung auf
			100	ppm	BW monitored;		chronischtoxische und
			1000	ppm	Ophth, blood,		tumorerzeugende Wirking von
					urinary, bio-		Sasil bei einer Versuchsdauer von
					chemical params
		2 Jahren Teil I, Sept., 1979,
					eval.; 104 wk		unpublished data)
					sac: all organs
					gross/micro eval.
					No significant
					test ariticle
					related effects
					were observed on
					histolopath; no Δ
					in types or incid.
					of neoplasms. NOEL
					60 mg/kg/d (360
					mg/m²/d)

TABLE 7


Table of Genotoxicity Studies Performed with Sodium Aluminosilicate

Study Author/
Company Report	Test	Schedule	Strains	Findings	Notes	References

Zeiger, 1987	Ames	w/ & w/o S9	S. typhimurium	No mutagenicity	Zeiger E, Anderson B, Haworth S,
		activation	TA 98	detected in any	et al. Environmental Mutagenesis 9
			TA 100	strain	(suppl. 9): 1-110 (1987)
			TA 1535
			TA 1537
			TA 1538
Prival, 1991	Ames		S. typhimurium	No mutagenicity	Two sources cited
			TA 98	detected in any	(1) Prival M J, Simmon V F,
			TA 100	strain	Mortelmans K E, Mutat. Res
			TA 1535		260: 321-329 (1991);
			TA 1537		(2) Simmon V F and Eckford S L
			TA 1538		Microbial mutagenesis testing of
					substances. Compound report: F76-
					001, sodium aluminum silicate.
					prep. for FDA; NTIS, US Dept. of
					Commerce, Springfield, VA; PB89-
					193650 (1989)
Prival, 1991	Reverse	w/ & w/o S9	E. coli WP2		Two sources cited
	mutation	activation			(1) Prival M J, Simmon V F,
					Mortelmans K E, Mutat. Res
					260: 321-329 (1991);
					(2) Simmon V F and Eckford S L
					Microbial mutagenesis testing of
					substances. Compound report: F76-
					001, sodium aluminum silicate.
					prep. for FDA; NTIS, US Dept. of
					Commerce, Springfield, VA; PB89-
					193650 (1989)
Litton, 1974			S. cerevisiae	Mutagenic	Litton Bionetics, Inc.”Mutagenic
				potential not	evaluation of compound FDA 71-
				reported	45, synthetic sodium
					silicoaluminate,” prep, for FDA;
					NTIS, US Dept. of Commerce,
					Springfield, VA; PB 245 468 (1974)
Litton, 1974			H. sapiens	No clastogeic	Litton Bionetics, Inc.”Mutagenic
			embryonic lung	potential observed	evaluation of compound FDA 71-
			cell cultures		45, synthetic sodium
			W 38		silicoaluminate,” prep. for FDA;
					NTIS, US Dept. of Commerce,
					Springfield, VA; PB 245 468 (1974)
FASEB, 1977			DNA-repair	Negative	Federation of American Societies of
			assay		Experimental Biology (FASEB),
					“Tentative evaluatin of the health
					aspects of certain silicates as food
					ingredients” (1977), cited in How M
					and Solbe J, Unilever Research,
					Document ref. D/93/021 (1993)

Litton, 1974	Male albino	4.25	mg/kg	Single dose &	No mutagenic	Observation	Litton Bionetics, Inc.”Mutagenic
	rat (10-12	42.5	mg/kg	D × 5	potential observed	time points:	evaluation of compound FDA 71-
	wk old)	425	mg/kg &			6, 24, 48 hrs;	45, synthetic sodium
		5000	mg/kg			No Δ in type	silicoaluminate,” prep, for FDA;
						or number of	NTIS, US Dept. of Commerce,

TABLE 8


Table of Developmental Toxicology and Teratogenicity Studies Performed with Sodium Aluminosilicate

Study Author/
Company Report	Model	Schedule	Dose Levels	Findings	Notes	References

Henkel, 1978	Rat	D × 10 on	0	mg/kg	D20 sac: high	Henkel KgaA, Archive-No. R
	(Charles	gestational	74	mg/kg	conception rates;	0100168 (External Report, Procter
	River;	days 6-15	1600	mg/kg	no maternal,	& Gamble, May, 1978 unpublished

pregnant)

(gavage)

embryo or fetal tox

data)

					noted; no diff in
					incidence of soft
					tissue
					malformations or
					skeletal defects vs.
					ctrl
					NOAEL 1,600
					mg/kg (9,600
					mg/m²)
FDRL, 1973	Rat	D × 10 on	0	mg/kg	D20 sac: no effect	Food and Drug Research
	(Wistar,	gestational	16	mg/kg	on nidation,	Laboratories, Inc. Teratologic
	pregnant)	days 6-15	74	mg/kg	maternal, or fetal	Evaluation of FDA 71-45 (sodium
			345	mg/kg	survival noted; no	silicoaluminate) prep. for FDA,
			1,600	mg/kg	diff in incidence of	NTIS, US Dept. of Commerce,
					soft tissue	USA, PB 223 810 (1973)
					malformations or

(gavage)

					skeletal defects vs.
					ctrl
					NOAEL 1,600
					mg/kg (9,600
					mg/m²)
FDRL, 1973a	Mouse	D × 10 on	0	mg/kg	D17 sac: no effect	Food and Drug Research
	(CD-1,	gestational	16	mg/kg	on nidation,	Laboratories, Inc. Teratologic
	pregnant)	days 6-15	74	mg/kg	maternal, or fetal	Evaluation of FDA 71-45 (sodium
			345	mg/kg	survival noted; no	silicoaluminate) prep. for FDA,
			1,600	mg/kg	diff in incidence of	NTIS, US Dept. of Commerce,

(gavage)

soft tissue

USA, PB 223 810 (1973)

					malformations or
					skeletal defects vs.
					ctrl
					NOAEL 1,600
					mg/kg (4,800
					mg/m²)
FDRL, 1973b	Rabbit (Dutch;	D × 14 on	0	mg/kg	D29 sac: no effect	Food and Drug Research
	pregnant)	gestational	16	mg/kg	on nidation,	Laboratories, Inc. Teratologic
		days 6-18	74	mg/kg	maternal, or fetal	Evaluation of FDA 71-45 (sodium
			345	mg/kg	survival noted; no	silicoaluminate) prep. for FDA,
			1,600	mg/kg	diff in incidence of	NTIS, US Dept. of Commerce,

(gavage)

soft tissue

USA, PB 223 810 (1973)

					malformations or
					skeletal defects vs.
					ctrl
					NOAEL 1,600
					mg/kg (???
					conversion mg/m²)
Henkel, 1978	Rabbit (New	D × 14 on	0	mg/kg	D29 sac: no effect	Henkel KgaA, Archive-No. R
	Zealand;	gestational	16	mg/kg	on maternal	0100169 (External Report, Procter &
	pregnant)	days 6-18	74	mg/kg	toxicity or effect on	Gamble, June, 1978 unpublished
			345	mg/kg	survival noted; no	data)
			1,600	mg/kg	diff in incidence of

(gavage)

soft tissue

					malforma-tions or
					skeletal defects vs.
					ctrl; NOAEL 1,600
					mg/kg (???
					conversion mg/m²)
FDRL, 1973c	Hamster	D × 5 on	0	mg/kg	D14 sac: no effect	Food and Drug Research
	(Syrian;	gestational	16	mg/kg	on nidation,	Laboratories, Inc. Teratologic
	pregnant)	days 6-10	74	mg/kg	maternal, or fetal	Evaluation of FDA 71-45 (sodium
			345	mg/kg	survival noted; no	silicoaluminate) prep. for FDA,
			1,600	mg/kg	diff in incidence of	NTIS, US Dept. of Commerce,

(gavage)

soft tissue

USA, PB 223 810 (1973)

					malformations or
					skeletal defects vs.
					ctrl
					NOAEL 1,600
					mg/kg (???
					conversion mg/m²)

The following examples are offered by way of illustration and not by way of limitation to the scope of the claims.

EXAMPLES

Example 1

General Manufacturing Process

The synthesis of sodium aluminosilicate consists of one synthetic reaction of aluminum oxide (Al₂O₃) (which is dissolved in hot sodium hydroxide in Step I) with liquid sodium silicate (Na₄SiO₄) at ambient temperature, to yield the crude sodium aluminosilicate crystalline substance (Step II). The crude crystals are then size reduced by conventional roller milling and size selected (Step III) yielding a uniform granular material. The material is collected in 40 cu. ft. bulk bags (Step IV) and manually transferred to a second size selection step for final size selection (Step V). The resulting size selection process yields a still more uniform particle size distribution of ca. 95% of the crystalline material ranging between 90 and 150 micrometers (μm).
The properly size selected material is washed in a clarification step in which an optimized retrograde flow rate of reverse osmosis (RO) water partially purifies and pH adjusts the crystalline material (Step VI). The material is then gravity-drained and dried with vacuum assistance. The partially purified, pH adjusted, and moist sodium aluminosilicate crystalline material is rehydrated with a saturated saline solution for additional removal of residual alkali and alkaline-earth cations (Step VII). The material is re-dried (Step VIII), and temporarily packaged and stored in fiber drums (Step IX) as the bulk investigational drug substance for shipment to the selected contractor for manufacture of the drug product.

Example 2

The following table provides summary and manufacturing capacity for each synthetic and production step.

TABLE 9


Step	Process

Step I	Dissolution of Aluminum into Sodium Hydroxide
Step Ia	Transfer Truck Tank Filling and Reaction Process
Step II	Synthesis of Crude Crystalline Substance
Step IIa	Maturation and Drying of the Sodium Aluminosilicate
Step III	Size Reduction and Selection of the Sodium Aluminosilicate
Step IV	Temporary Packaging and Transfer for Second Size Selection
Step V	Second Size Selection of Sodium Aluminosilicate
Step VI	Clarification of Sodium Aluminosilicate
Step VII	Regeneration into the Sodium form of Aluminosilicate
Step VIII	Drying of the Regenerated Sodium Aluminosilicate
Step IX	Temporary Packaging and Storage of Bulk Drug Substance

Example 3

Three particle size analyses were performed on the CR-100 zeolite manufactured by Mineral-Right, Inc. The raw data are shown in the table below. FIG. 1 shows a graphic representation of the data.

TABLE 10


US Std.	Pre-	Post-
Sieve Size	regeneration (%)	regeneration (%)

Bed #7	80	0.525	1.24
	100	4.65	12.36
	120	43.81	44.57
	140	37.15	30.52
	170	11.79	8.65
	230	0.9	1.21
	325	0.22	0.37
	Pan	0.43	0.12
Bed #10	80	1.17	2.34
	100	4.24	18.12
	120	41.4	38.6
	140	38.1	29.73
	170	12.11	8.83
	230	1.05	1.06
	325	0.34	0.3
	Pan	0.62	0.04
Bed #11	80	0.64	0.72
	100	9.38	5.37
	120	35.33	39.22
	140	34.7	36.57
	170	15.4	16.28
	230	2.45	3.42
	325	0.67	0.31
	Pan	0.64	0.1

“Pan” in the table refers to the bottommost item in the vertical series of sieves which is a solid bottom designed to collect all particles, regardless of size, that pass through the smallest sieve, which is generally the sieve second to the bottom. Pre- and post-regeneration refers to the particle size distribution before and after exposure to a saturated brine solution of USP salt. Only the post-regeneration product is envisioned to be used clinically. Particle size distributions may change minimally or substantially with use of other counterions such as potassium, calcium and others cited above.

Example 3

An experiment was performed to measure sodium aluminosilicate binding of undesirable ions, especially heavy metals, from man. The sodium aluminosilicate was manufactured according to the previously described manufacturing process. A man, weighing approximately 90 kilograms, orally self-administered a size 0 conventional pharmaceutical-grade hard gelatin capsule containing approximately 500 milligrams of sodium aluminosilicate (CR-100, manufactured by Mineral-Right, Inc., Phillipsburg, Kans.). The capsule was ingested with approximately 200 milliliters of tap water and was immediately swallowed. The subject did not complain of any adverse gastrointestinal effects such as constipation, diarrhea, pain, bloating, nausea, vomiting, or bloody stools. The sodium aluminosilicate remained in the subject for approximately 24 hours until the subject spontaneously experienced a bowel movement and produced a well-formed brown stool. This material was collected (before it was deposited into toilet and flushed) manually with clean, washed rubber gloves and was visually inspected for small white specks of sodium aluminosilicate material.
Specks of white, granular material that was observed in the stool was carefully teased out by the use of fine plastic tweezers, briefly dipped in deionized water to wash off any potentially contaminating fecal material, and placed in a plastic container that had been previously washed with deionized water and air dried. The amount of sodium aluminosilicate that was recovered was approximately 50 mg. The sodium aluminosilicate collected from the stool (designated “After” in the table below) and sodium aluminosilicate from the same manufacturing process that had not been administered to the subject (designated “Before” in the table below) were analyzed for metallic ion content with atomic absorption spectrophotometry.

The following tabulated results were noted for sodium aluminosilicate manufactured by the method described above with the exception that the material was not fully regenerated with sodium and extensively clarified with deionized water. The table thus reflects analysis of sodium aluminosilicate following passage through the human gastrointestinal tract.

	TABLE 11


	mg/kg (ppm)

	Practical			Difference
	quantification			between new
Cation/Anion	limit*	“new”	“used”	and used

aluminum	2,400	540,000	420,000
antimony	0.7	nd	nd
arsenic	7.0	nd	nd
barium	3.5	9.3	5.8
beryllium	0.7	0.8	nd
bismuth	1.1	nd	nd
boron
	50	nd	nd
cadmium	0.8	nd	nd
calcium	560	14,000	2,800
chromium	1.5	nd	nd
cobalt	1.0	nd	nd
copper	2.7	10	13
iron	1,300	nd	nd
lead	1.8	nd	4.7
lithium	3.4	3.7	nd
magnesium	350	3,200	1,405
manganese	14.0	nd	nd
mercury	0.3	nd	nd
molybdenum	0.4	nd	nd
nickel	2.4	nd	nd
ammonia nitrogen
	5	nd	nd
(mg/L)
potassium	150	3,300	16,000
selenium	12	nd	nd
silicon	8.4	730	1,900
silver	0.3	nd	nd
sodium	410	63,000	290,000
strontium	8.4	170	72
thallium	1.3	nd	nd
tin	0.1	0.2	0.4
titanium	5.1	18	19
vanadium	1	nd	nd
zinc	21	nd	41

*(lowest quantifiable limit of the instrument)

Lead was found in greater concentration after the aluminosilicate had transited the gastrointestinal tract. The sodium aluminosilicate manufactured by Mineral-Right, Inc. may therefore be used as a therapeutic agent for removal of lead in patients with abnormally high levels or toxic burdens of lead. The subject of this experiment was tested for elevated blood lead level. The subject's blood lead level was 7.5 μg/dL which is within normal limits of <10 μg/dL. Sodium aluminosilicate thus possesses utility in treating lead poisoning, and other metals with toxic effects, given that the sodium aluminosilicate was able to extract the toxic metal from an individual who was not suffering from lead poisoning. The same conclusion applies to copper poisoning, which occurs spontaneously though rarely as a clinical entity known as Wilson's disease or hepatolenticular degeneration.

Example 4

Sorbitol Verses Sorbitol+Zeolite Ammonia Removal Study

CR-100 is used through out this study. The study compares Sorbitol effect on ammonia to Sorbitol with 2 Zeolite partical sizes, pan, and standard fines. Ammonia challenge solution is approx. 100 Mg/L (100 P.P.M.).



Sample # 1	Sample # 2	Sample # 3	Sample # 4	Sample # 5

10 Gr. Pan	10 Gr. Fines	20 Gr. Pan	20 Cr. Fines	Control; no
				crystal
100 ML.	Same	Same	Same	Same
Sorbitol

100 ML. 95	Same	Same	Same	Same
P.P.M. NH4

Each sample is weighed dry, then wetted and added to the 100 mL sorbitol solution spiked with 95 ppm ammonia. The experiment took place in a 250 mL Erlenmeyer flask that was shaken overnight and tested for ammonia the next morning. The concentration of the ammonia in the solution is shown below for each sample.

Sample # 1 Sample # 2 Sample # 3 Sample # 4 Sample # 5

2 P.P.M 2 P.P.M 1 P.P.M 2 P.P.M 90 P.P.M.
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
The invention has been described in some detail by way of illustration and example for purposes of clarity of understanding. However the description is not meant to limit the scope of the claims. The invention being thus described, it will be apparent to those skilled in the art that the same may be varied in many ways without departing from the spirit and scope of the invention. Such variations are included within the scope of the following claims.

chromosomal

Springfield, VA; PB 245 468 (1974)

aberrations

observed; (+)

ctrl → (+)

1. A method of treating, preventing, or palliating elevated human blood lead levels, comprising administering to a human in need thereof a pharmaceutical formulation comprising a synthetic sodium aluminosilicate zeolite and a pharmaceutically acceptable adjuvant, wherein:

(a) the synthetic sodium aluminosilicate is particulate and at least 90% of the particles are of particle size from about 90 μm to about 150 μm;

(b) the formulation is administered in doses of about 10 mg to about 1000 mg sodium aluminosilicate.

2. The method of claim 1, wherein at least about 95% of the particles are of particle size from about 90 μm to about 150 μm.

3. The method of claim 1, wherein the formulation is from about 50% (w/w) to about 95% (w/w) water.

4. The method of claim 1, wherein the formulation is a capsule or tablet administered enterally.

5. The method of claim 1, wherein the human is suffering from chronic lead poisoning.

6. The method of claim 1, wherein the human has an elevated blood lead level.

7. The method of claim 1, wherein the human has a blood lead level of at least about 10 μg/L.

8. The method of claim 1, wherein the human is between about 2 and about 15 years of age.

9. The method of claim 1, wherein the human is about 6 years of age or younger.

10. The method of claim 1, wherein the formulation further comprises a bacteriostat.

11. A method of treating, preventing, or palliating elevated human blood ammonia levels, comprising administering to a human in need thereof a pharmaceutical formulation comprising a synthetic sodium aluminosilicate zeolite and a pharmaceutically acceptable adjuvant, wherein:

(b) the formulation is from about 50% (w/w) to about 95% (w/w) water; and

(c) the formulation is administered in doses of about 2 g to about 15 g sodium aluminosilicate.

12. The method of claim 11, wherein at least about 95% of the particles are of particle size from about 90 μm to about 150 μm.

13. The method of claim 11, wherein the human is suffering from hepatic encephalopathy or cirrhosis of the liver.

14. The method of claim 11, wherein the human has a history of liver failure.

15. The method of claim 11, wherein the formulation is a liquid gel administered enterally.

16. The method of claim 11, wherein the human's blood ammonia level is above normal.

17. A method, comprising administering to a human in need thereof a pharmaceutical formulation comprising a synthetic sodium aluminosilicate zeolite and a pharmaceutically acceptable adjuvant, wherein:

(a) the synthetic sodium aluminosilicate is particulate and at least about 95% of the particles are of particle size from about 90 μm to about 150 μm;

(b) the formulation is administered in doses of from about 5 g to about 12 g sodium aluminosilicate; and

(c) the human has a higher than normal risk of elevated blood levels of a toxic metal or has a higher than normal risk of hepatic encephalopathy.

18. The method of claim 17, wherein the human is a hospital in-patient.

19. A pharmaceutical formulation, comprising:

(a) a particulate synthetic sodium aluminosilicate zeolite wherein at least about 90% of the particles are of particle size from about 90 μm to about 150 μm,

(b) from about 50% (w/w) to about 80% (w/w) water; and

(c) a microbial preservative; and

(d) a pharmaceutically acceptable adjuvant;

wherein the formulation contains from about 100 mg to about 10,000 mg by weight of sodium aluminosilicate.