US20070026066A1 - Oral pharmaceutical delivery system with improved sustained release - Google Patents
Oral pharmaceutical delivery system with improved sustained release Download PDFInfo
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- US20070026066A1 US20070026066A1 US11/490,594 US49059406A US2007026066A1 US 20070026066 A1 US20070026066 A1 US 20070026066A1 US 49059406 A US49059406 A US 49059406A US 2007026066 A1 US2007026066 A1 US 2007026066A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
Definitions
- the present invention relates to a pharmaceutical delivery system that increases the sustained release properties of drugs.
- Said delivery system includes both human and veterinary applications. More specifically, the present invention relates to an orally ingested pharmaceutical delivery system that is a solid lipid suspension that provides improved sustained release.
- Drug efficacy generally depends upon the ability of the drug to reach its target in sufficient quantity to maintain therapeutic levels for the desired time period. Orally ingested drugs must overcome several obstacles to reach their desired targets. Before orally ingested drugs enter the general circulation of the human body, they are absorbed into the capillaries and veins of the upper gastrointestinal tract and are transported by the portal vein to the liver. The pH and enzymatic activities found in gastrointestinal fluids may inactivate the drug or cause the drug to dissolve poorly and not be absorbed. In addition, following their absorption in the intestine, orally ingested drugs are often subject to a “first pass” clearance by the liver and excreted into bile or converted into pharmacologically inactive metabolites.
- Testosterone is administered for oral ingestion in a bonded form as testosterone undecanoate, methyltestosterone, or testosterone cyclodextrin, to avoid the first pass effect.
- testosterone undecanoate methyltestosterone
- testosterone cyclodextrin testosterone cyclodextrin
- the unbonded form of testosterone is more stable than its bonded predecessors. More of the active ingredient is delivered in a smaller dosage.
- the unbonded form is a simpler and less expensive manufacturing process in that the additional step of bonding the testosterone is eliminated. Further, the unbonded testosterone is administered with or without food, unlike the bonded form which is administered with food consumption.
- “Sustained Release” generally refers to release of a drug whereby the drug concentration in the serum of the patient is maintained at the desired level over a period of time. The longer the drug is at the desired level, the better the sustained release properties are. It is desirable to have the desired level be maintained for 12 h or more, so that only one to two doses of a drug need to be taken daily.
- a second indicator of sustained release properties is the t max of the drug, which is the time after administration of the drug that the serum concentration reaches its maximum level. A larger t max may indicate a slower and more sustained release of the drug into the blood.
- a variety of methods and formulations are used to provide sustained release of drugs. Some of the methods are disclosed in U.S. Pat. No. 5,567,439, which is hereby incorporated by reference, which discloses controlled release systems using a shearform matrix.
- U.S. Pat. No. 5,229,131 discloses a sustained release system that uses one or more individual drug-containing subunits in a unitary drug depot, such as a tablet or capsule.
- coatings on pharmaceuticals to provide sustained release properties, taste and odor masking, and delayed release are known in the art.
- One line of products commercially available for the coating of pharmaceuticals is EUDRAGIT® polymers marketed by Pharma Polymers. Polymer coatings are prepared that release at the desired pH to deliver drugs to targeted portions of the gastrointestinal system.
- the present invention comprises a solid orally ingested delivery system comprising at least one lipid, dry particles including at least one pharmaceutical, and at least one filler, wherein the dry particles are continuously coated by the lipid and form a homogeneous suspension with the lipid.
- At least part of the pharmaceutical is microencapsulated with a polymer that releases in the pH range of from about 5.0 to 7.0.
- the suspension when melted, exhibits thixotropic and/or pseudoplastic properties.
- the suspension is formed into the desired dose by molding or pouring the suspension when in a liquid or semi-liquid state.
- the process for preparing the present delivery system comprises melting the lipid, blending the dry particles which include the pharmaceutical, at least one filler and, optionally, flavorings with the melted lipid, and pouring or molding the suspension to provide the solid dose.
- the suspension when melted, exhibits thixotropic and pseudoplastic flow properties.
- FIG. 1 is a graph demonstrating the serum concentration of various doses of testosterone over time when administered in a lipid formulation to dogs by oral ingestion.
- FIG. 2 is a graph demonstrating the serum concentration of various doses of testosterone over time when administered in a micronized formulation to dogs by oral ingestion.
- FIG. 3 is a graph demonstrating the serum concentration of 250 mg dose of testosterone with various amounts of rupturing agent over time when administered in a lipid formulation to dogs by oral ingestion.
- FIG. 4 is a graph demonstrating the serum concentration of 250 mg dose of testosterone with various types of surfactant over time when administered in a lipid formulation to dogs by oral ingestion.
- FIG. 5 is a graph demonstrating the serum concentration of 250 mg dose of testosterone with 100 mg microencapsulated with various coatings and 250 mg micronized, over time when administered in a lipid formulation to dogs by oral ingestion.
- the lipids of the present invention may be of animal, vegetable or mineral origin, which are substantially water-insoluble, inert, non-toxic hydrocarbon fats and oils and derivatives thereof, and may comprise any of the commonly commercially available fats or oils approved by the Food & Drug Administration, having melting points in the range of about 90 to 160° F. (32 to 71° C.).
- the lipid may comprise a vegetable oil base commonly known as hard butter.
- Hard butters are hydrogenated, press fractionated, or other processed oils that are processed or recombined to have a solid fat index (percent solid fat vs. temperature) similar to that of cocoa butter.
- lipids may be used that are relatively hard or solid at room temperature, but melt rapidly in the mouth at a temperature of about 92° to 98° F. (29 to 32° C., mouth temperature).
- the lipid is employed in the amounts within the range of from about 20 to 50%. Above about 50%, the suspension flows too readily and does not exhibit thixotropic or pseudoplastic flow properties. When present below about 20%, the amount of lipid is not sufficient to completely coat the dry particles.
- the lipid formulation would have improved sustained release properties over that of granulated pharmaceuticals alone, since the lipids may hinder the solubilizing of the pharmaceutical in the gastrointestinal tract and retard absorption.
- lipids examples include tallow, hydrogenated tallow, hydrogenated vegetable oil, almond oil, coconut oil, corn oil, cottonseed oil, light liquid petrolatum, heavy liquid petrolatum, olein, olive oil, palm oil, peanut oil, persic oil, sesame oil, soybean oil or safflower oil.
- stearines can be used as a lipid in the present invention. The addition of stearines to the product provides the favorable property of mold-release. Further, the addition of stearines raises the melting point of the composition as high as about 100° F. (38° C.), which is particularly beneficial when the product is shipped or stored in unrefrigerated compartments.
- the fillers of the present invention are pharmacologically inert and optionally nutritionally beneficial to humans and animals.
- Such fillers include cellulose such as microcrystalline cellulose, grain starches such as cornstarch, tapioca, dextrin, sugars and sugar alcohols such as sucrose sorbitol, xylitol, mannitol and the like.
- Preferred fillers include non-fat milk powder, whey, grain brans such as oat bran, and fruit and vegetable pulps.
- Preferred fillers are finely divided and have a preferred average particle size in the range of about 0.10 to 500 microns. More preferred fillers are from about 50 to 500 microns. Particles less than about 50 microns tend to cause difficulty in controlling dust when handling.
- the fillers are present in the drug delivery device in a concentration of about 50 to 80%.
- the pharmaceutical particles can also serve as filler in the delivery system.
- the filler may include an emulsifier or surfactant.
- an emulsifier or surfactant approved for use in foods by the Food and Drug Administration and having a relatively low HLB value, in the range of about 1 to 3, is suitable for use in the present invention.
- the appropriate surfactant minimizes the surface tension of the lipid, allowing it to oil wet and encapsulate the non-oil solid particles.
- the surfactant is present in the delivery system in the concentration of about 0.1 to 1.0%.
- Suitable surfactants include alkyl aryl sulfonate, alkyl sulfonates, sulfonated amides or amines, sulfated or sulfonated esters or ethers, alkyl sulfonates, of dioctyl sulfonosuccinate and the like, a hydrated aluminum silicate such as bentonite or kaolin, triglycerol monostearate, triglycerol monoshortening, monodiglyceride propylene glycol, octaglycerol monooleate, octaglyceron monostearate, and decaglycerol decaoleate.
- the preferred surfactant is lecithin.
- At least part of the pharmaceutical is microencapsulated. Any known method of encapsulation is suitable in the present invention. A preferred method involves slowly blending the drug with a filming agent solution to form granulated particles. The granulated particles are allowed to dry on a tray and are sieved to the desired size, typically in the range of from about 200 to 500 microns.
- the pharmaceutical is a mixture of encapsulated and non-encapsulated pharmaceutical.
- the mixture of encapsulated to non-encapsulated can be in the range of about 1:10 to 10:1. More preferably, the mixture is in the range of 2:3 to 3:2 encapsulated to non-encapsulated.
- the three types of methylcellulose tested were: (1) EUDRAGIT L100-55, designed to release in the duodenum with a pH in the range of 5.5 to 6.0, (2) EUDRAGIT L 100, designed to release in the jejunum at a pH of about 6.0 to 7.0, and (3) EUDRAGIT S 100, designed to release in the ileum at a pH of >6.5. Since the ingested pharmaceutical would proceed down the digestive tract in the order of (1) duodenum, (2) jejunum and (3) ileum, it was expected that the t max for each composition would increase as the pH range would increase, thereby providing improved sustained release properties.
- the t max would increase in the order of the EUDRAGIT L100-55 to the EUDRAGIT L100 to EUDRAGIT S 100. Further, the t max of each microencapsuled composition was expected to exceed that of the non-microencapsulated composition. Surprisingly, it was discovered that the EUDRAGIT L100-55 gave the greatest t max of 12 h, and demonstrated the best sustained release properties, with a serum concentration in the desired range for at least 12 h. The EUDRAGIT S 100 gave the poorest sustained release properties with a t max of 9 and 6 h of serum concentration in the desired range. The EUDRAGIT L 100 gave an acceptable t max of 9 h with 12 h of serum concentration in the desired range.
- the preferred pH values for controlled release are in the range of pH 4.0 to 7.0, more preferably, 5.5 to 7.0.
- EUDRAGIT® polymers marketed by Pharma Polymers. Polymer coatings are prepared that release at the desired pH to deliver drugs to targeted portions of the gastrointestinal system. Of particular interest are EUDRAGIT® L100 and EUDRAGIT® L 100-55. These polymers release at a pH in the range of about 5.5 to 7.0, and have been found to be surprisingly superior to similar polymers that release at greater than pH 6.5 (EUDRAGIT® S100).
- the pharmaceutical is present in the delivery device in a concentration of 30% or less.
- the pharmaceutical can comprise all of the dried particles, acting as a filler, to provide the necessary dose.
- the pharmaceuticals contemplated in the present invention are administered by oral ingestion.
- the pharmaceuticals include drugs that have reduced bioavailability when administered orally, and drugs that do not have reduced bioavailability.
- Drugs that have reduced bioavailability include drugs such as analgesics, anti-inflammatory agents, gastrointestinal medications, hormone products, cardiovascular preparations, anticoagulants and antibiotics. Specific drugs include insulin, heparin, oligosaccharides, aspirin, testosterone and prednisolone. Pharmaceuticals further includes vitamins and minerals. Pharmaceuticals also includes synthetic and natural food supplements, such as glucosamine, chondroitin, bee pollen, St. John's wort, echninaecia, etc. Additional pharmaceuticals are contemplated for the present invention, and are disclosed in U.S. Pat. No. 4,880,634, and U.S. Pat. No. 5,965,164, which are hereby incorporated by reference.
- the dry particles include flavorings that make the device taste and smell appealing to humans or animals.
- the flavorings can be natural or synthetic, and can include fruit, citrus, meat, chocolate, vanilla, fish, butter, milk, cream, egg or cheese flavorings.
- the flavorings are typically present in the device in the range of about 0.05 to 50.0%.
- the delivery device may also include other pharmaceutically acceptable agents, such as sweetening agents, including hydrogenated starch hydrolysates, synthetic sweeteners such as sorbitol, xylitol, saccharin salts, L-aspartyl-L-phenylalanine methyl ester, as well as coloring agents, other binding agents, lubricants, such as calcium stearate, stearic acid, magnesium stearate, antioxidants such as butylated hydroxy toluene, antiflatuants such as simethicone and the like.
- sweetening agents including hydrogenated starch hydrolysates, synthetic sweeteners such as sorbitol, xylitol, saccharin salts, L-aspartyl-L-phenylalanine methyl ester, as well as coloring agents, other binding agents, lubricants, such as calcium stearate, stearic acid, magnesium stearate, antioxidants such as butylated hydroxy toluene, antiflatuants
- rupturing agents are used to rapidly deliver the pharmaceutical into the recipient's system.
- a typical rupturing agent is a starch that swells in the presence of water.
- Various modified starches, such as carboxymethyl starch, currently marketed under the trade name EXPLOTAB or PRIMOGEL are used as rupturing agents.
- a preferred rupturing agent is sodium starch glycolate.
- the capsule or pellet swells in the presence of gastric juices and ruptures.
- the rupturing agent is present in the delivery system from about 1 to 5%.
- the rupturing agent is present inside the microcapsule. As water penetrates the microcapsule, it swells the starch and ruptures the capsule, rapidly delivering the pharmaceutical to the system. Additional rupturing agents are disclosed in U.S. Pat. No. 5,567,439, which is hereby incorporated by reference.
- the rupturing agent is present in the lipid suspension, which ruptures the pellet, but leaves the microcapsules intact. This allows the delayed delivery of the drug farther along in the digestive system, or in the intestines.
- the present invention is particularly effective in this embodiment, in that the ingested pellet may be chewable, where the pellet cleaves in the lipid suspension when chewed, but leaves the microcapsules intact. Tablets or gel capsules, when chewed, typically result in damage to or rupturing of the microcapsules defeating the effectiveness of the microcapsules.
- the process for preparing the above delivery system comprises melting the lipid and mixing with the surfactant.
- the dry particles are mixed with the melted lipid mixture to form a suspension exhibiting pseudoplastic and/or thixotropic flow properties, and poured or molded to provide solid dosage forms.
- the dry particles which include the pharmaceutical, filler and optional flavorings and additives, are pre-blended and typically have a particle size in the range of from about 50 to 150 microns.
- the pre-blended particles are gradually added to the heated lipid base until a high solid suspension is obtained, typically in the range of about 50 to 80% particles and from about 50 to 20% lipid.
- the mixing step is accomplished in a heated mixing device that insures thorough mixing of all materials with minimal shear, such as a planetary mixer or a scrape surface mixer.
- a heated mixing device that insures thorough mixing of all materials with minimal shear, such as a planetary mixer or a scrape surface mixer.
- the product is poured into molds and allowed to cool. De-molding and packaging are then performed.
- the suspension can be super-cooled and sheeted in a semi-soft format. The sheet is processed through forming rolls containing a design or configuration that embosses and forms the final shape.
- Example I was prepared according to the following procedure. This data was taken to determine the dosage range needed to achieve the desired blood serum level above about 300 ng/dl for 12 h or more. Additionally, the t max was determined as another indicator for sustained release, i.e., increasing t max indicates increased delivery time for the pharmaceutical, or increased sustained release properties.
- the lipid (hydrogenated vegetable oil sold under the trademark KLX®) was heated in a HOBART 5 Quart planetary mixer jacketed with a heating mantle in the range of about 140 to 150° F. (60 to 66° C.) and melted.
- the surfactant, lecithin was added to the lipid with mixing, and the mixture was allowed to cool to about 135° F. (° C.).
- the dry particles including the pharmaceutical (micronized, i.e., 3 to 5 microns, testosterone), the rupturing agent (sodium starch glycolate, sold under the trademark EXPLOTAB), and fillers (microcrystalline cellulose, sold under the trademark EUDRAGIT S100, dry milk, salt and powdered sugar) were screened to a particle size in the range of about 200 and 500 microns and dry-blended.
- the dry particles were slowly added incrementally to the lipid/surfactant mixture with mixing over a period of about 1 hour, to provide a smooth suspension with no lumps or agglomerations.
- the suspension exhibited thixotropic and pseudoplastic flow properties. It was molded and cooled to about 70° F. (21° C.). The suspension shrank as it cooled, and easily released from the mold when inverted.
- a study using six dogs was made to obtain preliminary pharmacokinetic data following a single oral dose of the delivery system.
- the dogs were 13-24 months old, and weighed in the range of 10.4 to 13.2 kg.
- the dosing was done in four sequential one day intervals with a minimum two day rest period in between each interval. Blood was drawn immediately before the dose was administered. The results revealed minimal levels of testosterone.
- the animals were given the placebo or test article, as described above, at approximately the same time each day, immediately prior to being fed. The dog ate its food within 30 minutes of the dose being administered.
- Blood samples were collected pre-dose and at 0.5, 1, 2, 4, 5, 6, 8 and 24 hours post dosing. At each time point, a minimum of 3 mL whole blood (or minimum volume determined by assay requirement) were collected by venipuncture of the jugular vein into non-heparinized Vacutainer tubes. The blood was centrifuged to obtain serum, which was kept on ice until placed into an appropriately sized vial, and frozen at ⁇ 70° C. The samples remained frozen until delivered on dry ice to the lab for analysis. The lab used radioimmunoassay to analyse for testosterone.
- Testosterone Dose 25 50 100 250 Testosterone Testosterone Testosterone Testosterone Testosterone Time (h) (ng/dl) (ng/dl) (ng/dl) (ng/dl) 0 0 1 0 26 0.5 286 154 270 264 1 390 286 309 555 2 425 376 450 835 4 118 288 522 1032 5 35 215 618 829 6 53 107 357 980 8 23 54 422 757 24 1 7 2 8 t max 2 h 2 h 5 h 4 h
- the data from Table 2 is plotted in FIG. 1 , Graph 1 .
- the t max time to maximum concentration
- Testosterone Dose 25 50 100 250 Testosterone Testosterone Testosterone Testosterone Testosterone Time (h) (ng/dl) (ng/dl) (ng/dl) (ng/dl) 0 49 0 0 7 0.5 253 150 772 1315 1 664 204 916 1306 2 238 324 703 1786 4 123 266 372 1009 5 109 293 332 775 6 57 295 278 542 8 20 165 143 412 24 1 3 2 16 t max 1 h 2 h 1 h 2 h
- Table 3 The results of Table 3 are plotted in FIG. 2 , Graph 2 .
- the t max for the samples ranged from 1 to 2. Increasing the dosage level did not increase the t max as it did for the lipid suspension of Example 1.
- Table 4 provides the sustained release properties of Example 1 and Control 1 by comparing t max for each sample.
- the lipid suspension (Example 1) provides improved sustained release properties at doses of 100 mg and 250 mg, as indicated by increased t max when compared to Control 1, the granulated testosterone. Smaller doses fail to display increased t max . It is important to note that the present data is taken using dogs as test animals. It is generally recognized that the metabolism of dogs is higher than that of humans, and that humans will typically display higher blood serum levels for a greater period of time under similar test conditions. It is expected that humans will experience even greater sustained release levels than those shown in the dogs.
- the lipid formulation provided improved sustained release properties when compared to the micronized testosterone, the testosterone was delivered in a sharp spike at 4 h, which then tapered off.
- a study using four dogs was made to obtain preliminary pharmacokinetic data following a single oral dose of the delivery system.
- the dogs were 13-24 months old, and weighed in the range of 11.1 to 12.6 kg.
- the dosing was done in four sequential one day intervals with a minimum four day rest period in between each interval. Blood was drawn immediately before the dose was administered. The results revealed minimal levels of testosterone.
- the animals were given the placebo or test article, as described above, at approximately the same time each day, immediately prior to being fed. The dog ate its food within 30 minutes of the dose being administered.
- Blood samples were collected pre-dose and at 3, 6, 8, 10, 12, 16, 20 and 24 hours post dosing. At each time point, a minimum of 3 mL whole blood (or minimum volume determined by assay requirement) were collected by venipuncture of the jugular vein into non-heparinized Vacutainer tubes. The blood was centrifuged to obtain serum, which was kept on ice until placed into an appropriately sized vial, and frozen at ⁇ 70° C. The samples remained frozen until delivered on dry ice to the lab for analysis. The lab used radioimmunoassay to analyse for testosterone.
- the results given in Table 6 are plotted in FIG. 4 , Graph 4 .
- the least favorable surfactant, in terms of t max is DUREM 300, with a t max of 2 h.
- the preferred composition having a combination of 100 mg microencapsulated testosterone with 150 mg micronized testosterone was prepared.
- the micronized testosterone was expected to give a quick release of testosterone in the stomach.
- the microencapsulated testosterone was expected to give delayed delivery of testosterone.
- Three samples were microencapsulated with three types of methylcellulose designed to release at different pH values. The fourth sample was prepared with all micronized testosterone (250 mg).
- the three types of methylcellulose tested were: (1) EUDRAGIT L100-55, designed to release in the duodenum with a pH in the range of 5.5 to 6.0, (2) EUDRAGIT L 100, designed to release in the jejunum at a pH of about 6.0 to 7.0, and (3) EUDRAGIT S 100, designed to release in the ileum at a pH of >6.5. Since the ingested pharmaceutical would proceed down the digestive tract in the order of (1) duodenum, (2) jejunum and (3) ileum, it was expected that the t max for each composition would increase as the pH range would increase.
- the t max would increase from the EUDRAGIT L100-55 having the lowest t max , then to the EUDRAGIT L100 to the EUDRAGIT S 100 having the highest t max . Further, the t max of each microencapsuled composition was expected to exceed that of the non-microencapsulated composition.
- Example 1 The four samples were formulated into a lipid suspension as disclosed in Example 1 and given to four dogs. Serum levels of testosterone were measured as in Example 1. TABLE 7 Serum Levels of Testosterone (ng/dl) pH 5.5-6.0 pH 6.0-7.0 pH > 6.5 Release, Release, Release, Time (h) Un-encapsulated L100-55 L100 S 100 0 79 5 12 15 1.5 438 166 314 254 3 649 179 333 290 6 603 426 487 271 9 302 438 599 348 12 147 576 377 344 15 52 351 266 195 18 25 86 90 173 21 18 55 75 190 24 16 30 112 117 tmax 3 12 9 9 9
Abstract
A solid orally ingested delivery system having at least one lipid, dry particles including at least one pharmaceutical, and at least one filler, where the dry particles are continuously coated by the lipid and form a homogeneous suspension with the lipid, and at least part of the pharmaceutical is microencapsulated with a polymer that releases in the pH range of about 5.0 to 7.0.
Description
- The application is a continuation-in-part of pending U.S. patent application Ser. No. 10/348,372, filed Jan. 21, 2003, which is a continuation-in-part of pending U.S. patent application Ser. No. 09/656,297, issued as U.S. Pat. No. 6,541,025, filed Sep. 6, 2000, which is a continuation-in-part of U.S. patent application Ser. No. 09/476,483 issued as U.S. Pat. No. 6,340,471B1, filed Dec. 30, 1999, all of which are hereby incorporated in their entirety by reference.
- The present invention relates to a pharmaceutical delivery system that increases the sustained release properties of drugs. Said delivery system includes both human and veterinary applications. More specifically, the present invention relates to an orally ingested pharmaceutical delivery system that is a solid lipid suspension that provides improved sustained release.
- Drug efficacy generally depends upon the ability of the drug to reach its target in sufficient quantity to maintain therapeutic levels for the desired time period. Orally ingested drugs must overcome several obstacles to reach their desired targets. Before orally ingested drugs enter the general circulation of the human body, they are absorbed into the capillaries and veins of the upper gastrointestinal tract and are transported by the portal vein to the liver. The pH and enzymatic activities found in gastrointestinal fluids may inactivate the drug or cause the drug to dissolve poorly and not be absorbed. In addition, following their absorption in the intestine, orally ingested drugs are often subject to a “first pass” clearance by the liver and excreted into bile or converted into pharmacologically inactive metabolites.
- The oral ingestion of hormones, such as testosterone or estrogen, has proven challenging. Testosterone is administered for oral ingestion in a bonded form as testosterone undecanoate, methyltestosterone, or testosterone cyclodextrin, to avoid the first pass effect. When it is administered in a regiment of hormone replacement therapy, it is desired to have sustained release properties, yet these forms of testosterone must be taken multiple times daily.
- Of particular interest is the delivery of testosterone in the unbonded form. The unbonded form of testosterone is more stable than its bonded predecessors. More of the active ingredient is delivered in a smaller dosage. The unbonded form is a simpler and less expensive manufacturing process in that the additional step of bonding the testosterone is eliminated. Further, the unbonded testosterone is administered with or without food, unlike the bonded form which is administered with food consumption.
- “Sustained Release” generally refers to release of a drug whereby the drug concentration in the serum of the patient is maintained at the desired level over a period of time. The longer the drug is at the desired level, the better the sustained release properties are. It is desirable to have the desired level be maintained for 12 h or more, so that only one to two doses of a drug need to be taken daily. A second indicator of sustained release properties is the tmax of the drug, which is the time after administration of the drug that the serum concentration reaches its maximum level. A larger tmax may indicate a slower and more sustained release of the drug into the blood. A variety of methods and formulations are used to provide sustained release of drugs. Some of the methods are disclosed in U.S. Pat. No. 5,567,439, which is hereby incorporated by reference, which discloses controlled release systems using a shearform matrix.
- The use of a lipid-based solid oral delivery system with improved taste masking is disclosed in U.S. Pat. No. 6,340,471B1. U.S. Pat. No. 5,229,131 discloses a sustained release system that uses one or more individual drug-containing subunits in a unitary drug depot, such as a tablet or capsule.
- The use of coatings on pharmaceuticals to provide sustained release properties, taste and odor masking, and delayed release are known in the art. One line of products commercially available for the coating of pharmaceuticals is EUDRAGIT® polymers marketed by Pharma Polymers. Polymer coatings are prepared that release at the desired pH to deliver drugs to targeted portions of the gastrointestinal system.
- None of the above-referenced patents describe the present invention as disclosed and claimed herein.
- The present invention comprises a solid orally ingested delivery system comprising at least one lipid, dry particles including at least one pharmaceutical, and at least one filler, wherein the dry particles are continuously coated by the lipid and form a homogeneous suspension with the lipid. At least part of the pharmaceutical is microencapsulated with a polymer that releases in the pH range of from about 5.0 to 7.0. The suspension, when melted, exhibits thixotropic and/or pseudoplastic properties. The suspension is formed into the desired dose by molding or pouring the suspension when in a liquid or semi-liquid state. The process for preparing the present delivery system comprises melting the lipid, blending the dry particles which include the pharmaceutical, at least one filler and, optionally, flavorings with the melted lipid, and pouring or molding the suspension to provide the solid dose. The suspension, when melted, exhibits thixotropic and pseudoplastic flow properties.
-
FIG. 1 is a graph demonstrating the serum concentration of various doses of testosterone over time when administered in a lipid formulation to dogs by oral ingestion. -
FIG. 2 is a graph demonstrating the serum concentration of various doses of testosterone over time when administered in a micronized formulation to dogs by oral ingestion. -
FIG. 3 is a graph demonstrating the serum concentration of 250 mg dose of testosterone with various amounts of rupturing agent over time when administered in a lipid formulation to dogs by oral ingestion. -
FIG. 4 is a graph demonstrating the serum concentration of 250 mg dose of testosterone with various types of surfactant over time when administered in a lipid formulation to dogs by oral ingestion. -
FIG. 5 is a graph demonstrating the serum concentration of 250 mg dose of testosterone with 100 mg microencapsulated with various coatings and 250 mg micronized, over time when administered in a lipid formulation to dogs by oral ingestion. - The lipids of the present invention may be of animal, vegetable or mineral origin, which are substantially water-insoluble, inert, non-toxic hydrocarbon fats and oils and derivatives thereof, and may comprise any of the commonly commercially available fats or oils approved by the Food & Drug Administration, having melting points in the range of about 90 to 160° F. (32 to 71° C.). The lipid may comprise a vegetable oil base commonly known as hard butter. Hard butters are hydrogenated, press fractionated, or other processed oils that are processed or recombined to have a solid fat index (percent solid fat vs. temperature) similar to that of cocoa butter. However, other lipids may be used that are relatively hard or solid at room temperature, but melt rapidly in the mouth at a temperature of about 92° to 98° F. (29 to 32° C., mouth temperature). The lipid is employed in the amounts within the range of from about 20 to 50%. Above about 50%, the suspension flows too readily and does not exhibit thixotropic or pseudoplastic flow properties. When present below about 20%, the amount of lipid is not sufficient to completely coat the dry particles.
- It is expected that the lipid formulation would have improved sustained release properties over that of granulated pharmaceuticals alone, since the lipids may hinder the solubilizing of the pharmaceutical in the gastrointestinal tract and retard absorption.
- Examples of suitable lipids include tallow, hydrogenated tallow, hydrogenated vegetable oil, almond oil, coconut oil, corn oil, cottonseed oil, light liquid petrolatum, heavy liquid petrolatum, olein, olive oil, palm oil, peanut oil, persic oil, sesame oil, soybean oil or safflower oil. Additionally, stearines can be used as a lipid in the present invention. The addition of stearines to the product provides the favorable property of mold-release. Further, the addition of stearines raises the melting point of the composition as high as about 100° F. (38° C.), which is particularly beneficial when the product is shipped or stored in unrefrigerated compartments.
- The fillers of the present invention are pharmacologically inert and optionally nutritionally beneficial to humans and animals. Such fillers include cellulose such as microcrystalline cellulose, grain starches such as cornstarch, tapioca, dextrin, sugars and sugar alcohols such as sucrose sorbitol, xylitol, mannitol and the like. Preferred fillers include non-fat milk powder, whey, grain brans such as oat bran, and fruit and vegetable pulps. Preferred fillers are finely divided and have a preferred average particle size in the range of about 0.10 to 500 microns. More preferred fillers are from about 50 to 500 microns. Particles less than about 50 microns tend to cause difficulty in controlling dust when handling. The fillers are present in the drug delivery device in a concentration of about 50 to 80%. Optionally, the pharmaceutical particles can also serve as filler in the delivery system.
- Optionally, the filler may include an emulsifier or surfactant. Any emulsifier or surfactant approved for use in foods by the Food and Drug Administration and having a relatively low HLB value, in the range of about 1 to 3, is suitable for use in the present invention. The appropriate surfactant minimizes the surface tension of the lipid, allowing it to oil wet and encapsulate the non-oil solid particles. Typically, the surfactant is present in the delivery system in the concentration of about 0.1 to 1.0%. Suitable surfactants include alkyl aryl sulfonate, alkyl sulfonates, sulfonated amides or amines, sulfated or sulfonated esters or ethers, alkyl sulfonates, of dioctyl sulfonosuccinate and the like, a hydrated aluminum silicate such as bentonite or kaolin, triglycerol monostearate, triglycerol monoshortening, monodiglyceride propylene glycol, octaglycerol monooleate, octaglyceron monostearate, and decaglycerol decaoleate. The preferred surfactant is lecithin.
- At least part of the pharmaceutical is microencapsulated. Any known method of encapsulation is suitable in the present invention. A preferred method involves slowly blending the drug with a filming agent solution to form granulated particles. The granulated particles are allowed to dry on a tray and are sieved to the desired size, typically in the range of from about 200 to 500 microns. In a preferred embodiment, the pharmaceutical is a mixture of encapsulated and non-encapsulated pharmaceutical. The mixture of encapsulated to non-encapsulated can be in the range of about 1:10 to 10:1. More preferably, the mixture is in the range of 2:3 to 3:2 encapsulated to non-encapsulated.
- The three types of methylcellulose tested were: (1) EUDRAGIT L100-55, designed to release in the duodenum with a pH in the range of 5.5 to 6.0, (2)
EUDRAGIT L 100, designed to release in the jejunum at a pH of about 6.0 to 7.0, and (3)EUDRAGIT S 100, designed to release in the ileum at a pH of >6.5. Since the ingested pharmaceutical would proceed down the digestive tract in the order of (1) duodenum, (2) jejunum and (3) ileum, it was expected that the tmax for each composition would increase as the pH range would increase, thereby providing improved sustained release properties. Therefore, the tmax would increase in the order of the EUDRAGIT L100-55 to the EUDRAGIT L100 toEUDRAGIT S 100. Further, the tmax of each microencapsuled composition was expected to exceed that of the non-microencapsulated composition. Surprisingly, it was discovered that the EUDRAGIT L100-55 gave the greatest tmax of 12 h, and demonstrated the best sustained release properties, with a serum concentration in the desired range for at least 12 h. TheEUDRAGIT S 100 gave the poorest sustained release properties with a tmax of 9 and 6 h of serum concentration in the desired range. TheEUDRAGIT L 100 gave an acceptable tmax of 9 h with 12 h of serum concentration in the desired range. - The preferred pH values for controlled release are in the range of pH 4.0 to 7.0, more preferably, 5.5 to 7.0. One line of products commercially available for the coating of pharmaceuticals is EUDRAGIT® polymers marketed by Pharma Polymers. Polymer coatings are prepared that release at the desired pH to deliver drugs to targeted portions of the gastrointestinal system. Of particular interest are EUDRAGIT® L100 and EUDRAGIT® L 100-55. These polymers release at a pH in the range of about 5.5 to 7.0, and have been found to be surprisingly superior to similar polymers that release at greater than pH 6.5 (EUDRAGIT® S100).
- Typically the pharmaceutical is present in the delivery device in a concentration of 30% or less. However, the pharmaceutical can comprise all of the dried particles, acting as a filler, to provide the necessary dose.
- The pharmaceuticals contemplated in the present invention are administered by oral ingestion. The pharmaceuticals include drugs that have reduced bioavailability when administered orally, and drugs that do not have reduced bioavailability. Drugs that have reduced bioavailability include drugs such as analgesics, anti-inflammatory agents, gastrointestinal medications, hormone products, cardiovascular preparations, anticoagulants and antibiotics. Specific drugs include insulin, heparin, oligosaccharides, aspirin, testosterone and prednisolone. Pharmaceuticals further includes vitamins and minerals. Pharmaceuticals also includes synthetic and natural food supplements, such as glucosamine, chondroitin, bee pollen, St. John's wort, echninaecia, etc. Additional pharmaceuticals are contemplated for the present invention, and are disclosed in U.S. Pat. No. 4,880,634, and U.S. Pat. No. 5,965,164, which are hereby incorporated by reference.
- Optionally, the dry particles include flavorings that make the device taste and smell appealing to humans or animals. The flavorings can be natural or synthetic, and can include fruit, citrus, meat, chocolate, vanilla, fish, butter, milk, cream, egg or cheese flavorings. The flavorings are typically present in the device in the range of about 0.05 to 50.0%.
- The delivery device may also include other pharmaceutically acceptable agents, such as sweetening agents, including hydrogenated starch hydrolysates, synthetic sweeteners such as sorbitol, xylitol, saccharin salts, L-aspartyl-L-phenylalanine methyl ester, as well as coloring agents, other binding agents, lubricants, such as calcium stearate, stearic acid, magnesium stearate, antioxidants such as butylated hydroxy toluene, antiflatuants such as simethicone and the like.
- Optionally, rupturing agents are used to rapidly deliver the pharmaceutical into the recipient's system. A typical rupturing agent is a starch that swells in the presence of water. Various modified starches, such as carboxymethyl starch, currently marketed under the trade name EXPLOTAB or PRIMOGEL are used as rupturing agents. A preferred rupturing agent is sodium starch glycolate. When ingested, the capsule or pellet swells in the presence of gastric juices and ruptures. Preferably, the rupturing agent is present in the delivery system from about 1 to 5%.
- In one embodiment of the present invention, the rupturing agent is present inside the microcapsule. As water penetrates the microcapsule, it swells the starch and ruptures the capsule, rapidly delivering the pharmaceutical to the system. Additional rupturing agents are disclosed in U.S. Pat. No. 5,567,439, which is hereby incorporated by reference.
- In another embodiment, the rupturing agent is present in the lipid suspension, which ruptures the pellet, but leaves the microcapsules intact. This allows the delayed delivery of the drug farther along in the digestive system, or in the intestines. The present invention is particularly effective in this embodiment, in that the ingested pellet may be chewable, where the pellet cleaves in the lipid suspension when chewed, but leaves the microcapsules intact. Tablets or gel capsules, when chewed, typically result in damage to or rupturing of the microcapsules defeating the effectiveness of the microcapsules.
- The process for preparing the above delivery system comprises melting the lipid and mixing with the surfactant. The dry particles are mixed with the melted lipid mixture to form a suspension exhibiting pseudoplastic and/or thixotropic flow properties, and poured or molded to provide solid dosage forms.
- The dry particles, which include the pharmaceutical, filler and optional flavorings and additives, are pre-blended and typically have a particle size in the range of from about 50 to 150 microns. The pre-blended particles are gradually added to the heated lipid base until a high solid suspension is obtained, typically in the range of about 50 to 80% particles and from about 50 to 20% lipid.
- Slow addition of the dry particles is critical in the production of the device, to insure that the particles are suspended in their micronized state and not as agglomerated clumps. Moreover, rapid addition can cause the mixing process to fail in that the melted suspension will not have the desired flow properties, but instead will be a granular oily mass (a sign of product failure). The mixing step is accomplished in a heated mixing device that insures thorough mixing of all materials with minimal shear, such as a planetary mixer or a scrape surface mixer. After the suspension is formed, the product is poured into molds and allowed to cool. De-molding and packaging are then performed. Alternatively, the suspension can be super-cooled and sheeted in a semi-soft format. The sheet is processed through forming rolls containing a design or configuration that embosses and forms the final shape.
- The following examples are to illustrate the claimed invention and are not intended to limit the claims in any way. All of the percentages are by weight unless otherwise indicated.
- Example I was prepared according to the following procedure. This data was taken to determine the dosage range needed to achieve the desired blood serum level above about 300 ng/dl for 12 h or more. Additionally, the tmax was determined as another indicator for sustained release, i.e., increasing tmax indicates increased delivery time for the pharmaceutical, or increased sustained release properties.
- Forming the Suspension
- The lipid (hydrogenated vegetable oil sold under the trademark KLX®) was heated in a
HOBART 5 Quart planetary mixer jacketed with a heating mantle in the range of about 140 to 150° F. (60 to 66° C.) and melted. The surfactant, lecithin, was added to the lipid with mixing, and the mixture was allowed to cool to about 135° F. (° C.). - The dry particles, including the pharmaceutical (micronized, i.e., 3 to 5 microns, testosterone), the rupturing agent (sodium starch glycolate, sold under the trademark EXPLOTAB), and fillers (microcrystalline cellulose, sold under the trademark EUDRAGIT S100, dry milk, salt and powdered sugar) were screened to a particle size in the range of about 200 and 500 microns and dry-blended. The dry particles were slowly added incrementally to the lipid/surfactant mixture with mixing over a period of about 1 hour, to provide a smooth suspension with no lumps or agglomerations. The suspension exhibited thixotropic and pseudoplastic flow properties. It was molded and cooled to about 70° F. (21° C.). The suspension shrank as it cooled, and easily released from the mold when inverted.
-
TABLE 1 BATCH FORMULA Ingredient Weight (grams) % KLX (lipid) 36.100 38.00 EXPLOTAB (rupturing agent) 4.750 5.00 EUDRAGIT S100 (cellulose) 4.750 5.00 Dry milk, low heat (filler) 9.500 10.00 Powdered sugar (filler) 14.250 15.00 Lecithin (surfactant) 0.950 1.00 Salt 0.190 0.20 Testosterone 24.938 26.25 Totals 95 100.45 - In vivo Evaluation
- A study using six dogs (female beagles) was made to obtain preliminary pharmacokinetic data following a single oral dose of the delivery system. The dogs were 13-24 months old, and weighed in the range of 10.4 to 13.2 kg.
- The dosing was done in four sequential one day intervals with a minimum two day rest period in between each interval. Blood was drawn immediately before the dose was administered. The results revealed minimal levels of testosterone. The animals were given the placebo or test article, as described above, at approximately the same time each day, immediately prior to being fed. The dog ate its food within 30 minutes of the dose being administered.
- Blood samples were collected pre-dose and at 0.5, 1, 2, 4, 5, 6, 8 and 24 hours post dosing. At each time point, a minimum of 3 mL whole blood (or minimum volume determined by assay requirement) were collected by venipuncture of the jugular vein into non-heparinized Vacutainer tubes. The blood was centrifuged to obtain serum, which was kept on ice until placed into an appropriately sized vial, and frozen at −70° C. The samples remained frozen until delivered on dry ice to the lab for analysis. The lab used radioimmunoassay to analyse for testosterone.
- Example 1 Results
-
TABLE 2 Testosterone Dose (mg) 25 50 100 250 Testosterone Testosterone Testosterone Testosterone Time (h) (ng/dl) (ng/dl) (ng/dl) (ng/dl) 0 0 1 0 26 0.5 286 154 270 264 1 390 286 309 555 2 425 376 450 835 4 118 288 522 1032 5 35 215 618 829 6 53 107 357 980 8 23 54 422 757 24 1 7 2 8 tmax 2 h 2 h 5 h 4 h - The data from Table 2 is plotted in
FIG. 1 ,Graph 1. The tmax (time to maximum concentration) increased with increasing dosage up to the 100 mg dosage, where it plateaued out. - Samples of micronized testosterone, not in a lipid suspension, was placed in a gelatin capsule and administered to dogs as described in Example 1. This test was run to compare the sustained release properties of a lipid suspension to those of a micronized pharmaceutical. The results are summarized in Table 3.
-
Control 1 Results -
TABLE 3 Testosterone Dose (mg) 25 50 100 250 Testosterone Testosterone Testosterone Testosterone Time (h) (ng/dl) (ng/dl) (ng/dl) (ng/dl) 0 49 0 0 7 0.5 253 150 772 1315 1 664 204 916 1306 2 238 324 703 1786 4 123 266 372 1009 5 109 293 332 775 6 57 295 278 542 8 20 165 143 412 24 1 3 2 16 tmax 1 h 2 h 1 h 2 h - The results of Table 3 are plotted in
FIG. 2 ,Graph 2. The tmax for the samples ranged from 1 to 2. Increasing the dosage level did not increase the tmax as it did for the lipid suspension of Example 1. Table 4 provides the sustained release properties of Example 1 andControl 1 by comparing tmax for each sample. -
TABLE 4 Testosterone Dose Example 1, Control 1,(mg) lipid tmax (h) granulated tmax (h) 25 2 1 50 2 2 100 5 1 250 4 2 - The lipid suspension (Example 1) provides improved sustained release properties at doses of 100 mg and 250 mg, as indicated by increased tmax when compared to
Control 1, the granulated testosterone. Smaller doses fail to display increased tmax. It is important to note that the present data is taken using dogs as test animals. It is generally recognized that the metabolism of dogs is higher than that of humans, and that humans will typically display higher blood serum levels for a greater period of time under similar test conditions. It is expected that humans will experience even greater sustained release levels than those shown in the dogs. - Although the lipid formulation provided improved sustained release properties when compared to the micronized testosterone, the testosterone was delivered in a sharp spike at 4 h, which then tapered off.
- Example 2
- This study was made to determine the effect of the amount of rupturing agent on sustained release properties. Samples of a lipid suspension were prepared as in Example 1, wherein the amount of testosterone administered was 250 mg, and the amount of rupturing agent was varied as follows: 0, 1, 2 and 5%.
- In vivo Evaluation
- A study using four dogs (female beagles) was made to obtain preliminary pharmacokinetic data following a single oral dose of the delivery system. The dogs were 13-24 months old, and weighed in the range of 11.1 to 12.6 kg.
- The dosing was done in four sequential one day intervals with a minimum four day rest period in between each interval. Blood was drawn immediately before the dose was administered. The results revealed minimal levels of testosterone. The animals were given the placebo or test article, as described above, at approximately the same time each day, immediately prior to being fed. The dog ate its food within 30 minutes of the dose being administered.
- Blood samples were collected pre-dose and at 3, 6, 8, 10, 12, 16, 20 and 24 hours post dosing. At each time point, a minimum of 3 mL whole blood (or minimum volume determined by assay requirement) were collected by venipuncture of the jugular vein into non-heparinized Vacutainer tubes. The blood was centrifuged to obtain serum, which was kept on ice until placed into an appropriately sized vial, and frozen at −70° C. The samples remained frozen until delivered on dry ice to the lab for analysis. The lab used radioimmunoassay to analyse for testosterone.
- Test Results
-
TABLE 5 % EXPLOTAB* Time (h) 5 0 1 2 0 2.0 0.0 2.5 0.3 3 433.5 485.8 274.0 690.8 6 1257.0 537.3 561.3 920.0 8 479.8 520.8 772.5 776.0 10 330.3 410.5 553.3 840.0 12 224.5 243.5 449.3 293.8 16 31.5 213.0 212.8 61.3 20 12.0 72.3 88.0 29.0 24 6.8 48.3 54.5 27.3 tmax 6 6 8 6
*The rupturing agent.
- The results shown in Table 5 are plotted in
FIG. 3 ,Graph 3.Graph 3 indicates that 5% EXPLOTAB releases more testosterone at once with Cmax (maximum concentration) of 1257 ng/dl. However, varying the rupturing agent concentration did not increase the tmax, except at the concentration level of 1%. - An in vivo evaluation, of the present invention was made, using the formulation from Table 1, but varying the surfactant as follows to determine the impact of varying the surfactant on sustained release properties. The same procedure was followed as described in Example 3, except that three dogs were used and there was a two day washout.
-
TABLE 6 Surfactant Time (h) Lecithin No Surfactant DUREM 300* 0 1.1 0.0 0.0 0.5 51.3 94.3 104.7 1.0 397.7 277.3 217.7 2.0 929.3 609.7 1136.7 4.0 1558.0 1410.0 581.0 5.0 1561.3 702.3 591.0 6.0 1039.3 632.7 688.7 8.0 502.0 375.0 576.3 24.0 10.0 48.0 59.3 tmax 5 h 4 h 2 h
*Monodiglyceride propylene glycol surfactant.
- The results given in Table 6 are plotted in
FIG. 4 ,Graph 4. The least favorable surfactant, in terms of tmax isDUREM 300, with a tmax of 2 h. - The preferred composition, having a combination of 100 mg microencapsulated testosterone with 150 mg micronized testosterone was prepared. The micronized testosterone was expected to give a quick release of testosterone in the stomach. The microencapsulated testosterone was expected to give delayed delivery of testosterone. Three samples were microencapsulated with three types of methylcellulose designed to release at different pH values. The fourth sample was prepared with all micronized testosterone (250 mg).
- The three types of methylcellulose tested were: (1) EUDRAGIT L100-55, designed to release in the duodenum with a pH in the range of 5.5 to 6.0, (2)
EUDRAGIT L 100, designed to release in the jejunum at a pH of about 6.0 to 7.0, and (3)EUDRAGIT S 100, designed to release in the ileum at a pH of >6.5. Since the ingested pharmaceutical would proceed down the digestive tract in the order of (1) duodenum, (2) jejunum and (3) ileum, it was expected that the tmax for each composition would increase as the pH range would increase. Therefore, the tmax would increase from the EUDRAGIT L100-55 having the lowest tmax, then to the EUDRAGIT L100 to theEUDRAGIT S 100 having the highest tmax. Further, the tmax of each microencapsuled composition was expected to exceed that of the non-microencapsulated composition. - The four samples were formulated into a lipid suspension as disclosed in Example 1 and given to four dogs. Serum levels of testosterone were measured as in Example 1.
TABLE 7 Serum Levels of Testosterone (ng/dl) pH 5.5-6.0 pH 6.0-7.0 pH > 6.5 Release, Release, Release, Time (h) Un-encapsulated L100-55 L100 S 100 0 79 5 12 15 1.5 438 166 314 254 3 649 179 333 290 6 603 426 487 271 9 302 438 599 348 12 147 576 377 344 15 52 351 266 195 18 25 86 90 173 21 18 55 75 190 24 16 30 112 117 tmax 3 12 9 9 - The date of Table 7 is plotted in
FIG. 5 ,Graph 5. A clear increase in sustained release is indicated with the increase in the tmax. Surprisingly, the greatest increase is not in the >6.5 pH, as expected, but in the 5.5-6.0 pH cellulose coating (EUDRAGIT L 100-55), which gave a four fold increase of unencapsulated testosterone, and a 33% increase over that of EUDRAGIT L100 orEUDRAGIT S 100. When the delivery time for serum concentration above 300 ng/dl is taken into account, both EUDRAGIT L100-55 andEUDRAGIT L 100 show sustained release properties of at least 12 h. TheEUDRAGIT S 100 showed unacceptable sustained release time of 6 h of serum concentration above 300 ng/dl.
Claims (20)
1. A sustained release solid orally ingested delivery system comprising at least one lipid and dry particles having a particle size greater than about 50 microns, wherein the dry particles contain at least one pharmaceutical,
wherein the dry particles are continuously coated with the lipid and form a homogeneous suspension with the lipid;
wherein the suspension, when melted exhibits pseudoplastic and/or thixotropic properties;
wherein at least part of the pharmaceutical is encapsulated with a polymer that dissolves at a pH in the range of from about 4.0 to about 7.0, and the ratio of unencapsulated to encapsulated pharmaceutical is in the range of about 1:10 to 10:1; and
wherein the suspension is formed or shaped into the appropriate solid dosage form by molding or pouring the suspension when in a liquid or semi-liquid state.
2. The delivery system of claim 1 wherein the system contains a rupturing agent.
3. The delivery system of claim 1 wherein the system contains a surfactant.
4. The delivery system of claim 1 wherein ratio of unencapsulated to encapsulated is in the range of about 3:2 to 2:3.
5. The delivery system of claim 1 wherein the polymer dissolves at a pH in the range of about 5.0 to 7.0.
6. The delivery system of claim 1 , wherein the pharmaceutical is selected from the group consisting of analgesics, antibodies, anti-inflammatory agents, cardiovascular drugs, gastrointestinal medicines, hormones and laxatives.
7. A sustained release solid orally ingested delivery system comprising at least one lipid and dry particles having a particle size greater than about 50 microns, wherein the dry particles contain at least one pharmaceutical, a surfactant and a rupturing agent,
wherein the dry particles are continuously coated with the lipid and form a homogeneous suspension with the lipid;
wherein the suspension, when melted exhibits pseudoplastic and/or thixotropic properties;
wherein at least part of the pharmaceutical is encapsulated with a polymer that dissolves at a pH in the range of from about 5.0 to about 7.0, and the ratio of unencapsulated to encapsulated pharmaceutical is in the range of about 2:3 to 3:2; and
wherein the suspension is formed or shaped into the appropriate solid dosage form by molding or pouring the suspension when in a liquid or semi-liquid state.
8. The delivery system of claim 7 , wherein the pharmaceutical is selected from the group consisting of analgesics, antibodies, anti-inflammatory agents, cardiovascular drugs, gastrointestinal medicines, hormones and laxatives.
9. A method of preparing a sustained release solid orally ingested delivery system comprising melting at least one lipid, blending dry particles which include at least one pharmaceutical and at least one filler to form a suspension, and pouring or molding the suspension to provide a solid oral delivery system;
wherein the pharmaceutical is encapsulated and unencapsulated in a ratio of 1:10 to 10:1 encapsulated to unencapsulated;
wherein the pharmaceutical is encapsulated with a polymer that dissolves at a pH in the range of from 4.0 to 7.0; and
wherein the system, when melted, exhibits thixotropic and pseudoplastic flow properties.
10. The method of claim 9 , wherein the delivery system includes a rupturing agent.
11. The method of claim 9 , wherein the ratio of encapsulated to non-encapsulated is in the range of 2:3 to 3:2.
12. The method of claim 9 , wherein the microencapsulating film releases at a pH in the range of about 5.0 to 7.0.
13. The method of claim 9 , wherein the microencapsulating film releases at a pH in the range of about 5.5 to 7.0.
14. The method of claim 9 , wherein the delivery system includes a surfactant.
15. A method of preparing a sustained release solid oral delivery system comprising
a) microencapsulating at least part of a pharmaceutical,
b) melting at least one lipid,
c) dry-mixing dry particles including the pharmaceutical, and at least one filler,
d) mixing the dry particle mixture with the melted lipid to form a suspension,
wherein the dry particles are continuously coated by the lipid and form a homogeneous suspension with the lipid;
wherein at least part of the pharmaceutical is encapsulated with a polymer that dissolves at a pH in the range of from about 4.0 to about 7.0, and the ratio of unencapsulated to encapsulated pharmaceutical is in the range of about 1:10 to 10:1;
wherein the suspension, when melted, exhibits thixotropic and/or pseudoplastic properties,
wherein the suspension is formed into the desired dose by molding or pouring the suspension when in a liquid or semi-liquid state.
16. The method of claim 15 , wherein said pharmaceutical is selected form the group consisting of analgesics, antibodies, anti-inflammatory agents, cardiovascular drugs, gastrointestinal medicines, hormones and laxatives.
17. A method of administering a pharmaceutical to a human or animal comprising administering by oral ingestion to the human or animal a therapeutic amount of a delivery system comprising at least one lipid and dry particles having a particle size greater than about 50 microns, wherein the dry particles contain at least one pharmaceutical,
wherein the dry particles are continuously coated with the lipid and form a homogeneous suspension with the lipid;
wherein the suspension, when melted exhibits pseudoplastic and/or thixotropic properties;
wherein at least part of the pharmaceutical is encapsulated with a polymer that dissolves at a pH in the range of from about 4.0 to about 7.0, and the ratio of unencapsulated to encapsulated pharmaceutical is in the range of about 1:10 to 10:1; and
wherein the suspension is formed or shaped into the appropriate solid dosage form by molding or pouring the suspension when in a liquid or semi-liquid state.
18. The delivery system of claim 1 wherein the pharmaceutical is testosterone.
19. The method of claim 9 , wherein the pharmaceutical is testosterone.
20. The method of claim 17 , wherein the pharmaceutical is testosterone.
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US09/476,483 US6340471B1 (en) | 1999-12-30 | 1999-12-30 | Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals |
US09/656,297 US6541025B1 (en) | 1999-12-30 | 2000-09-06 | Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals |
US34837203A | 2003-01-21 | 2003-01-21 | |
US11/490,594 US20070026066A1 (en) | 1999-12-30 | 2006-07-21 | Oral pharmaceutical delivery system with improved sustained release |
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US09/656,297 Expired - Lifetime US6541025B1 (en) | 1999-12-30 | 2000-09-06 | Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals |
US11/490,594 Abandoned US20070026066A1 (en) | 1999-12-30 | 2006-07-21 | Oral pharmaceutical delivery system with improved sustained release |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/656,297 Expired - Lifetime US6541025B1 (en) | 1999-12-30 | 2000-09-06 | Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals |
Country Status (6)
Country | Link |
---|---|
US (2) | US6541025B1 (en) |
EP (1) | EP1246615B1 (en) |
JP (1) | JP2003523959A (en) |
AU (1) | AU780136B2 (en) |
CA (1) | CA2392621C (en) |
WO (1) | WO2001049272A2 (en) |
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WO2021156043A1 (en) | 2020-02-05 | 2021-08-12 | Diurnal Limited | Testosterone containing pharmaceutical composition |
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US20060067954A1 (en) * | 2004-09-24 | 2006-03-30 | Cottrell Ian W | Lipid stabilized formulations |
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US8318210B2 (en) * | 2005-02-28 | 2012-11-27 | Neos Therapeutics, Lp | Compositions and methods of making sustained release liquid formulations |
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JP6255474B2 (en) | 2013-03-15 | 2017-12-27 | マリンクロッド エルエルシー | Abuse deterrent solid dosage form for immediate release with functional secant |
US10420729B2 (en) | 2013-03-15 | 2019-09-24 | R.P. Scherer Technologies, Llc | Abuse resistant capsule |
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EP3164117B1 (en) | 2014-07-03 | 2023-09-06 | SpecGx LLC | Abuse deterrent immediate release formulations comprising non-cellulose polysaccharides |
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- 2000-12-20 JP JP2001549640A patent/JP2003523959A/en active Pending
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US20150216806A1 (en) * | 2012-08-29 | 2015-08-06 | Salix Pharmaceuticals, Inc. | Laxative compositions and methods for treating constipation and related gastrointestinal diseases and conditions |
WO2021156043A1 (en) | 2020-02-05 | 2021-08-12 | Diurnal Limited | Testosterone containing pharmaceutical composition |
Also Published As
Publication number | Publication date |
---|---|
JP2003523959A (en) | 2003-08-12 |
AU780136B2 (en) | 2005-03-03 |
EP1246615A2 (en) | 2002-10-09 |
WO2001049272A2 (en) | 2001-07-12 |
AU2446301A (en) | 2001-07-16 |
EP1246615B1 (en) | 2010-04-21 |
CA2392621A1 (en) | 2001-07-12 |
WO2001049272A3 (en) | 2002-01-31 |
CA2392621C (en) | 2010-11-02 |
US6541025B1 (en) | 2003-04-01 |
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