US20040086570A1 - Antidepressant dosage form - Google Patents

Antidepressant dosage form Download PDF

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US20040086570A1
US20040086570A1 US10/696,370 US69637003A US2004086570A1 US 20040086570 A1 US20040086570 A1 US 20040086570A1 US 69637003 A US69637003 A US 69637003A US 2004086570 A1 US2004086570 A1 US 2004086570A1
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carbon atoms
drug
group
dosage form
alkyl
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David Edgren
Gurdish Bhatti
Zahedeh Hatamkhani
Patrick Wong
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Individual
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Application filed by Individual filed Critical Individual
Priority to US10/696,370 priority Critical patent/US20040086570A1/en
Publication of US20040086570A1 publication Critical patent/US20040086570A1/en
Priority to US11/522,014 priority patent/US8084059B2/en
Priority to US12/820,671 priority patent/US20100260810A1/en
Priority to US13/303,244 priority patent/US20120070496A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/26Psychostimulants, e.g. nicotine, cocaine

Definitions

  • This invention pertains to a controlled-release dosage form comprising a compound of the following structural formula:
  • the invention concerns also a method useful for antidepressant therapy by administering the controlled-release dosage form comprising the compound of the formula.
  • the primary goal of drug administration is to provide a therapeutic dose of drug in the body to achieve a desired blood concentration, and then maintain the desired drug blood concentration.
  • the prior art in attempts to obtain the desired therapeutic effect, often used different dosage forms or programs.
  • One dosage program consists of a single dosing of the drug from a conventional capsule or tablet that produced a rapid rise followed by an immediate decline of the drug blood level versus time. The single dosing does not maintain the drug within a therapeutic range for an extended period of time, but exhibits of a short duration of action due to the inability of the conventional dosage form to provide drug delivery over time.
  • Another prior art dosing program used to obtain and to achieve drug blood levels consists in administering the drug repetitively using conventional dosage forms at various dosing intervals, as in multiple-dose therapy.
  • the drug blood level reached and the time required to reach that level depends on the dose and the dosing interval.
  • the dosing interval is not appropriate for the biological half-life of the drug, large peaks and valleys may result in the drug blood levels.
  • the drug blood level may not be within the therapeutic range at sufficiently early times, an important consideration for many disease states.
  • a graph of drug in circulation following a dosage program of several doses has an appearance of a series of peaks, which may surpass the toxic threshold. Then, each time the blood levels decreases into valleys, below a critical level needed to achieve a desired therapeutic effect, that effect may not be obtainable in the blood and body.
  • the prior art provided controlled-release dosage forms that can continuously over time administer a drug for controlled-rate therapy.
  • the dosage forms disclosed in these patents provide a drug at a constant rate for effecting a therapeutic range for preferred therapy.
  • the dosage forms of the patents provide a therapeutic range and avoids delivering the drug in excess in a toxic range with its accompanying side-effects.
  • the dosage forms of the patents in providing a controlled dose in a therapeutic range also avoids delivering the drug in an ineffective dose in an ineffective range.
  • the dosage forms presented immediately above operate successfully for their intended use and they can deliver many drugs indicated for good therapy.
  • the drugs of the above structural formula possess properties such as a high solubility of 570 mg per ml at a body temperature of 37° C. that can lead to a premature release of the drug from the dosage form.
  • the convection motion of the imbibed fluid, and the hydrostatic pressure of the,imbibed fluid coupled with the high solubility can result in the premature release of the drugs of the formula.
  • Another object of the present invention is to provide a dosage form for administering the drug of the formula in a controlled-rate dose in a therapeutic range over a prolonged period of time.
  • Another object of the present invention is to provide a dosage form that can deliver the drug of the formula essentially-free of a premature release from the dosage form.
  • Another object of the present invention is to provide a drug delivery controlled-release system that can deliver a drug for maintaining constant drug levels in the blood thereby functioning as a prolonged release system.
  • Another object of the present invention is to provide drug delivery sustained-release system that provides slow release of the drug over an extended period of time optionally in a therapeutic range.
  • Another object of the present invention is to provide a dosage form that substantially reduces and/or substantially eliminates the unwanted influences of a gastrointestinal environment of use and still provides controlled drug administration.
  • Another object of the present invention is to provide an improvement in a dosage form for administering a drug embraced by the structural formula and its pharmaceutically acceptable salt, wherein the improvement comprises delivering the drug in a controlled-release rate from the dosage form for improved and known therapy.
  • Another object of the invention is to provide a once-a-day controlled-release dosage form to deliver the drug of the structural formula orally to a patent in need of therapy.
  • Another object of the invention is to provide a method for administering a drug of the formula by orally administering the drug in a controlled rate dose per unit dose over an extended time to an animal in need of therapy.
  • Another object of the present invention is to provide a method for administering a drug of the formula in a therapeutic range while simultaneously substantially-avoiding a toxic range and an infective range.
  • Another object of the present invention is to provide a therapeutic composition comprising a drug of the structural formula blended with a drug-composition forming polymer.
  • Another object of the invention is to provide a therapeutic composition
  • a therapeutic composition comprising a member selected from the group consisting of venlafaxine and its pharmaceutically acceptable additional salt and a pharmaceutically acceptable polymer carrier for venlafaxine and its acceptable salts.
  • FIG. 1 is a general view of a dosage form provided by the invention, which dosage form is designed and shaped for oral administration, and for a drug delivery in a controlled-rate dose in the gastrointestinal tract;
  • Drawing FIG. 2 is an opened view of the dosage form of drawing FIG. 1 for depicting the structure of the dosage form and the composition member contained inside the dosage form;
  • Drawing FIG. 3 is a view of a dosage form that depicts an external, instant-release of drug of the structural formula coated on the exterior surface of the dosage form.
  • FIG. 1 a dosage form 10 is seen comprising a body member 11 , which body 11 comprises wall 12 , that surrounds and forms an internal area, not seen in drawing FIG. 1.
  • Dosage form 10 comprises at least one exit port 13 for connecting the exterior with the interior of dosage form 10 .
  • the dosage form 10 of drawing FIG. 1 illustrates a controlled-release dosage form manufactured as an osmotic dosage form that delivers a drug by osmotic action over an extended period of time.
  • the dosage form comprising controlled-release properties embraced by this invention are successful at maintaining substantially constant drug levels in the blood or in a tissue.
  • the dosage forms within the mode and manner of this invention comprises also sustained-release dosage forms.
  • the sustained-release dosage forms releases the drug and provide drug levels in the blood or target tissue within a therapeutic range over an extended period of time.
  • the invention embraces additionally prolonged release dosage forms.
  • the prolonged release dosage form denotes extended duration of drug delivery action over that achieved by conventional drug delivery.
  • dosage form 10 of FIG. 1 is seen in opened section.
  • dosage form 10 comprises a body 11 , a wall 12 that surrounds and defines an internal compartment 14 .
  • internal compartment 14 communicates through an exit passageway 13 with the exterior of dosage form 10 .
  • Wall 12 of dosage form 10 comprises totally or in at least a part of a composition that is permeable to the passage of an exterior fluid present in an environment of use, such as aqueous and biological fluids.
  • Wall 12 is formed of nontoxic ingredients, is substantially impermeable to the passage of a drug and other ingredients present in compartment 14 .
  • Wall 12 comprises a composition that is substantially inert, that is, wall 12 maintains its physical and chemical integrity during the drug dispensing life of a drug from dosage form 10 .
  • wall 12 does not lose its structure and it does not change during the dispensing life of dosage form 10 , except for possible leaching of one or more exit 13 passageway formed during operation of dosage form 10 or for leaching a water-soluble flux enhancers blended into wall 12 .
  • Wall 12 comprises a material that does not adversely affect an animal, a human or any other components comprising the dosage form.
  • Representative materials for forming wall 12 are in one embodiment, a cellulose ester polymer, a cellulose ether polymer and a cellulose esterether polymer. These cellulosic polymers have a degree of substitution. D.S., on the anhydroglucose unit, from greater than 0 up to 3 inclusive.
  • degree of substitution is meant the average number of hydroxyl groups originally present on the anhydroglucose unit comprising the cellulose polymer that are replaced by a substituting group.
  • Representative materials include a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanylates, mono-,di-, and tricellulose aroylates, and the like.
  • Exemplary polymers include cellulose acetate having a D.S. up to 1 and an acetyl content up to 21%; cellulose acetate having a D.S.
  • More specific cellulosic polymers include cellulose propionate having a D.S. of 1.8 and a propyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a D.S.
  • cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7
  • cellulose triacylates having a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripolmitate, cellulose trisuccinate, and cellulose trioctanoate
  • cellulose diacylates having a D.S.
  • cellulose disuccinate such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, co-esters of cellulose such as cellulose acetate butyrate and cellulose acetate propionate, and the like.
  • Additional polymers include ethyl cellulose of various degree of etherification with ethoxy content of from 40% to 55%, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose acetate diethyl aminoacetate, semipermeable polyamides; semipermeable polyurethanes; semipermeable sulfonated polystyrenes; semipermeable cross-linked selective polymers formed by the coprecipitation of a polyanion and a polycation as disclosed in U.S. Pat Nos.
  • Compartment 14 comprises a drug composition, identified as drug layer 15 which contains drug 16 , identified by dots.
  • Drug 16 comprises a drug of the following structural formula:
  • R 1 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms
  • R 2 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms
  • R 4 is a member selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms
  • R 5 and R 6 are independently a member selected from the group consisting of hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms in which each alkyl group comprises 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms,
  • the formula embraces also the pharmaceutically acceptable addition salts including a member selected from the group consisting of inorganic, organic, hydrochloric, hydrobromic, gluconic, fumaric, maleric, sulfonic, succinic, sulfuric, phosphoric, tartaric, acetic, proponic, citric, oxalic and similar pharmaceutically acceptable addition salts.
  • the compounds are known in U.S. Pat. Nos. 4,535,186; 4,611,078; 4,761,501; and 5,190,765.
  • the drugs of the structural formula are represented by the drug 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol of the structural formula:
  • the drug embraced by the formula possesses antidepressant properties.
  • the drug in vitro prevents the neuronal uptake of seroton in, morepinephrine, and dopamine and it does not inhibit monoamine oxidase.
  • the drug antagonizes reserpine-induced hypothermia and potentiates the effects of levodopa, and reduces histamine-induced corticotropin release and induces cyclicadenosine monophosphate subsensitivity after both acute and chronic administration.
  • the drug possesses excellent antidepressant activity in humans.
  • the therapeutic amount of drug 16 in dosage form 10 is 0.5 mg to 750 mg, with individual dosage forms comprising 2, 5, 10, 25, 40, 50, 75, 100, 150, 250, 300, 500, and 600 mg of drug 16 for administering in a single dose or in more then one dose over an extended period of 24 hours.
  • the therapeutic properties of the drug embraced by the structural formula are reported in Current Therapeutic Research , Vol. 42, No. 5, pages 901 to 909 (1987).
  • Composition 15 comprising drug 16 may comprise a drug dispensing carrier and composition formulating member consisting of a member selected from the group consisting of 0 wt % to 25 wt % of a hydroxypropylalkylcellulose where alkyl consists of 1 to 7 carbons selected from the group consisting of methyl, ethyl, isopropyl, butyl, pentyl, and hexyl which cellulose member comprises a 9,000 to 1,250,000 molecular weight and is exemplified by hydroxypropylmethylcelluose, hydroxypropylethylcellulose, hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose and hydroxypropylhexylcellulose represented by dashes 17; a member selected from the group consisting of 0 wt % to 20 wt % hydroxylalkylcellulose where alkyl is 1 to 6 carbons including methyl, ethyl, propyl, but
  • Composition 15 optionally comprises from 0 to 4.5 wt % of a lubricant represented by magnesium stearate, calcium stearate or stearic acid.
  • the total weight of all ingredients in composition 15 is equal to 100 wt %, weight percent.
  • Compartment 14 comprises a displacement composition or push layer 21 .
  • Displacement composition 21 comprises a polymer member selected from the group consisting of a polymer possessing a repeating molecular unit (—0—CH 2 CH 2 —) n wherein n is a positive whole number of 50,000 to 300,000 as represented by a poly(alkylene oxide) comprising poly(ethylene oxide) seen as wavy line 22 ; a maltodextrin polymer of the formula (C 6 H 12 O 5 ) n H 2 O wherein n is 50 to 62,000 and comprises a 9,000 to 10,000,000 molecular weight and represented by triangle 23 ; a carboxymethylcellulose polymer comprising a 10,000 to 5,000,000 molecular weight represented by alkali carboxymethylcellulose, sodium carboxymethylcellulose and potassium carboxymethylcellulose, ammonium carboxymethylcellulose, sodium carboxymethyl-2-hydroxyethylcellulose, sodium carboxymethyl-methylcellulose, alkali carboxymethyl-hydroxypropyl-methylcellulose, alkali carb
  • the polymers in push layer 21 provide unforeseen operating advantages as the polymer maintains its chemical composition during operation as it imbibes an external aqueous fluid including biological fluid while simultaneously pushing the drug from the dosage form essentially-free of substantially mixing the drug composition with the push composition.
  • the displacement composition 21 comprises optionally from 4 to 35 wt % of an osmotically active compound, also known as osmagent and represented by vertical line 24 .
  • osmotically effective compounds comprises salts, oxides, esters that exhibit imbibition properties, carbohydrates and acids including a member selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium chloride, potassium sulfate, sodium sulfate, sodium sulfite, lithium sulfate, ammonium chloride, potassium lactate, mannitol, urea, magnesium succinate, tartaric acid, raffinose, sorbitol, sucrose, fructose, and glucose.
  • Displacement layer 21 optionally comprises 0.5 wt % to 30 wt % of a cellulose polymer 25 represented by the letter v.
  • cellulose polymer 25 comprise a member selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, and hydroxypropylhexylcellulose comprising a 9,000 to 225,000 molecular weight.
  • the displacement composition optionally comprises 0 wt % to 5 wt % of lubricant stearic acid and, magnesium stearate, calcium oleate, oleic acid, and caprylic acid.
  • the polymers are known in U.S. Pat Nos. 3,845,770; and 4,160,020; in Handbook of Common Polymers by Scott, J. R., and Roff, W. J., published by CRC Press, Cleveland, Ohio.
  • Dosage form 10 a seen in drawing FIG. 3 depicts another preferred manufacture provided by the invention.
  • Dosage form 10 in drawing FIG. 3, comprises an external coat on a the exterior surface of dosage form 10 .
  • Coat 26 is a therapeutic composition comprising 10 mg to 150 mg of drug 16 , represented by dots 16 .
  • Exterior coat 26 provides instant drug 16 for instant therapy.
  • Drug 16 is blended with an aqueous-soluble composition comprising a carrier methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and blends of hydroxypropylcellulose and hydroxypropylmethylcellulose.
  • Coat 26 optionally comprises polyethylene glycol or acetylated triglycerides.
  • Coat 26 provides instant therapy as coat 26 dissolves or undergoes dissolution in the presence of a biological fluid and concurrently therewith delivers drug 16 to a drug receiving patient. Coat 26 provides instant therapy and it essentially overcomes the time required for the drug to be delivered from the dosage form.
  • Dosage form 10 can be manufactured for administering drug 16 by the oral route, and in another embodiment, dosage form 10 comprising exterior and interior drug 16 can be sized and shaped for administering drug 16 by the sublingual and buccal routes.
  • the sublingual and buccal routes can be used for quicker therapy and they can be used when a smaller dose of drug 16 is needed for therapy.
  • the buccal and sublingual routes can be used as a by-pass of the first pass of hepatic metabolism of drug 16 .
  • the sublingual or buccal routes can be used for administering the first dose of drug, followed by permitting dosage form 10 to enter the gastrointestinal tract for subsequent drug delivery.
  • Dosage form 10 when manufactured as an osmotic, controlled-release dosage form, comprises at least one passageway 13 , or more than one passageway 13 .
  • the expression “at least one passageway” includes aperture, orifice, bore, pore, porous element through which the drug can be pumped, diffuse, travel or migrate, hollow fiber, capillary tube, porous overlay, porous insert, microporous member, porous composition, and the like.
  • the expression also includes a material that erodes or is leached from wall 12 in the fluid environment of use to produce at least one passageway in dosage form 10 .
  • Representative material suitable for forming at least one passageway, or a multiplicity of passageways includes an erodible poly(glycolic) acid or poly(lactic) acid member in the wall; a gelatinous filament; poly(vinyl alcohol); leachable materials such as fluid removable pore forming polysaccharides, salts, or oxides, and the like.
  • a passageway or a plurality of passageways can be formed by leaching a material such as sorbitol, sucrose, lactose, fructose, or the like, from the wall to provide an osmotic dimensioned pore-passageway.
  • the passageway can have any shape such as round, triangular, square, elliptical, and the like, for assisting in the metered release of drug from dosage form 10 .
  • Dosage form 10 can be constructed with one or passageways in spaced apart relation on one or more than a single surface of a dosage form. Passageways and equipment for forming passages are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899 by Theeuwes and Higuchi; in U.S. Pat No. 4,063,064 by Saunders et al; and in U.S. Pat. No. 4,088,864 by Theeuwes et al.
  • Osmotic passageways comprising controlled-drug releasing dimension, sized, shaped and adapted as a drug releasing pore formed by aqueous leaching to provide a drug-releasing pore of controlled osmotic release rate are disclosed in U.S. Pat. No. 4,200,098 by Ayer and Theeuwes; and in U.S. Pat. No. 4,285,987 by Ayer and Theeuwes.
  • Wall 12 of osmotic dosage form 10 can be formed in one technique using the air suspension procedure. This procedure consists in suspending and tumbling the compressed drug-push core laminate in a current of air and wall forming composition until a wall is applied to the drug-push compartment.
  • the air suspension procedure is well-suited for independently forming the wall. The air suspension procedure is described in U.S. Pat. No. 2,799,241 ; J. Am. Pharm. Assoc ., Volume 48, pages 451 to 454, (1959); and ibid, Volume 49, pages 82 to 84, (196).
  • Osmotic dosage forms can also be coated with a wall forming composition in a Wurster® air suspension coater, using methylene dichloride-methanol cosolvent, 80:20, wt:wt, an ethanol-water, or acetone-water cosolvent, 95:5 wt:wt using 2.5 to 4% solids.
  • the Aeromatic® air suspension coater using a methylene dichloride-methanol cosolvent, 80:20 wt:wt also can be used for applying the wall.
  • Other wall forming techniques such as pan coating system, where wall forming compositions are deposited by successive spraying of the composition on the drug-push compartment, accompanied by tumbling in a rotating pan.
  • the wall coated compartments are dried in a forced air over at 30° C. to 50° C. for up to a week to free dosage form 10 of solvent.
  • the walls formed by these techniques have a thickness of 2 to 30 mils with a presently preferred thickness of 4 to 10 mils.
  • Dosage form 10 of the invention is manufactured by standard manufacturing techniques.
  • the beneficial drug and other ingredients comprising the drug layer facing the exit means are blended and pressed into a solid layer.
  • the drug and other ingredients can be blended with a solvent and mixed into a solid or semisolid formed by conventional methods such a ball-milling, calendering, stirring or rollmilling and then pressed into a preselected shape.
  • the layer possesses dimensions that correspond to the internal dimensions of the area the layer is to occupy in the dosage form and it also possesses dimensions corresponding to the second layer for forming a contacting arrangement therewith.
  • the push layer is placed in contact with the drug layer.
  • the push layer is manufactured using techniques for providing the drug layer.
  • the layering of the drug layer and the push layer can be fabricated by conventional press-layering techniques.
  • the two layer compartment forming members are surrounded and coated with an outer wall.
  • a passageway is laser, leached, or mechanically drilled through the wall to contact the drug layer, with the dosage form optically oriented automatically by the laser equipment for forming the passageway on the preselected surface when a laser is used for forming the passageway.
  • the dosage form is manufactured by the wet granulation technique.
  • the drug and the ingredients comprising the drug layer are blended using an organic solvent, such as isopropyl alcohol-ethylene dichloride 80:20 v:v (volume:volume) as the granulation fluid.
  • Other granulating fluid such as denatured alcohol 100% can be used for this purpose.
  • the ingredients forming the drug layer are individually passed through a 40 mesh screen and then thoroughly blended in a mixer. Next, other ingredients comprising the drug layer are dissolved in a portion of the granulation fluid, such as the cosolvent described above. Then the latter prepared wet blend is slowly added to the drug blend with continual mixing in the blender.
  • the granulating fluid is added until a wet blend is produced, which wet mass then is forced through a 20 mesh screen onto oven trays.
  • the blend is dried for 18 to 24 hours at 30° C. to 50° C.
  • the dry granules are sized then with a 20 mesh screen.
  • a lubricant is passed through an 80 mesh screen and added to the dry screen granule blend.
  • the granulation is put into milling jars and mixed on a jar mill for 1 to 15 minutes.
  • the push layer is made by the same wet granulation techniques.
  • the compositions are pressed into their individual layers in a Manesty ® press-layer press.
  • Another manufacturing process that can be used for providing the compartment-forming composition layers comprises blending the powered ingredients for each layer independently in a fluid bed granulator. After the powered ingredients are dry blended in the granulator, a granulating fluid, for example, poly(vinyl-pyrrolidone) in water, or in denatured alcohol, or in 95:5 ethyl alcohol water, or in blends of ethanol and water is sprayed onto the powders.
  • the ingredients can be dissolved or suspended in the granulating fluid.
  • the coated powders are then dried in a granulator. This process granulates all the ingredients present therein while adding the granulating fluid. After the granules are dried, a lubricant such as stearic acid or magnesium stearate is added to the granulator.
  • a lubricant such as stearic acid or magnesium stearate is added to the granulator.
  • the granules for each separate layer are pressed then in
  • the dosage form of the invention is manufactured in another manufacture by mixing a drug with composition forming ingredients and pressing the composition into a solid lamina possessing dimensions that correspond to the internal dimensions of the compartment.
  • the drug and other drug composition-forming ingredients and a solvent are mixed into a solid, or a semisolid, by conventional methods such as ballmilling, calendering, stirring or rollmilling, and then pressed into a preselected layer forming shape.
  • a layer of a composition comprising an osmopolymer and an optional osmagent are placed in contact with the layer comprising the drug.
  • the layering of the first layer comprising the drug and the second layer comprising the osmopolymer and optional osmagent composition can be accomplished by using a conventional layer press technique.
  • the wall can be applied by molding, spraying or dipping the pressed bilayer's shapes into wall forming materials.
  • Another and presently preferred technique that can be used for applying the wall is the air suspension coating procedure.
  • the procedure consists in suspending and tumbling the two layers in current of air until the wall forming composition surrounds the layers.
  • the air suspension procedure is described in U.S. Pat. No. 2,799,241 ; J. Am. Pharm. Assoc ., Vol. 48 pp 451-454 (1979); and, ibid, Vol. 49, pp 82-84 (1960).
  • Other standard manufacturing procedures are described in Modern Plastics Encyclopedia , Vol 46, pp 62-70 (1969); and in Pharmaceutical Science , by Remington, 14th Ed., pp 1626-1678 (1970), published by Mack Publishing Co
  • Exemplary solvents suitable for manufacturing the wall, the laminates and laminae include inert inorganic and organic solvents final laminated wall.
  • the solvents broadly include members selected for the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cyclaliphatics, aromatics, heterocyclic solvents and mixtures thereof.
  • Typical solvents include acetone, diacetone, alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptaene ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachoroethan, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, tetrahydrofuran, diglyme, aqueous and nonaqueous
  • a dosage form adapted for delivering a drug in a therapeutic range is manufactured as follows: first a displacement or push layer is prepared by blending and passing through a stainless steel sizing screen having a mesh opening of 420 microns 587.5 grams of sodium carboxymethylcellulose having a degree of polymerization of approximately 3,200 and a degree of substitution of 0.7 carboxymethyl groups per anhydroglucose unit, 300 grams of powdered sodium chloride, 50 grams of hydroxypropylcellulose having a molecular weight of approximately 60,000 grams per mole, and 50 grams of hydroxypropylmethylcellulose having an average methoxyl content of 29 weight percent and an average hydroxypropyl content of 10 weight percent and an average molecular weight of approximately 11,300 grams per mole.
  • a composition comprising a drug of the structural formula was prepared as follows: first, a drug composition was prepared by passing 840 grams of venlafaxine hydrochloride, 100 grams of hydroxypropylcellulose having a molecular weight of approximately 60,000 grams per mole, and 50 grams of polyvinylpyrrolidone having a molecular weight of approximately 40,000 grams per mole, were passed through a sizing having openings of approximately 420 microns, and mixed in a planetary mixer to yield a uniform blend. Then, anhydrous ethyl alcohol was added to the mixture with stirring to produce a cohesive damp mass.
  • the resulting damp mass was sized through a sieve having an opening of 840 microns, producing coated venlafaxine drug, which was air dried overnight.
  • the resulting dried coated venlafaxine drug was passed again through the sizing screen having an 840 micron opening.
  • the displacement-push composition and the drug composition were formed into a bilayer core as follows: first, 87 mg of the drug composition was placed in a ⁇ fraction (9/32) ⁇ inch round die cavity and lightly tamped with a standard concave round tooling to form a slightly cohesive layer. Then, 70 mg of push composition was added to die and the and the resulting fill was compressed with a final force of 2 tons, thereby forming a two layer cores.
  • the bilayer cores were placed next in a coating pan having a 12 inch diameter and they were coated with a wall-forming solution.
  • the wall-forming solution was prepared by dissolving 380 grams of cellulose acetate having an acetyl content of 39.8 weight percent in 7,220 grams of acetone. In a separate mixing vessel, 20 grams of polyethylene glycol having a molecular weight of approximately 3,350 grams per mole were dissolved in approximately 380 grams of purified water. The two solutions were mixed to form the wall-coating solution which was spray coated onto the cores until about 20 mg of wall composition was deposited on the surfaces of the bilayer core.
  • a delivery exit port was formed across the wall by drilling an exit port, centered on the face of the dosage form on the drug composition side of the dosage form.
  • the resulting dosage form was placed in simulated physiological fluid at 37° C., and the dosage form delivered a dose of 73 mg of venlafaxine hydrochloride at a controlled, zero rate over an extended duration of 15 hours.
  • Example 1 The procedure of Example 1 was followed with the manufacturing procedures as set forth, except that the drug composition comprises 890 grams of venlafaxine hydrochloride, 100 grams of hydroxypropylcellulose, and 10 grams of magnesium stearate. The resulting dosage form released in simulated intestinal fluid 77 mg of venlafaxine hydrochloride at a zero-order rate over an extended duration of 16 hours.
  • Example 1 The procedure of Example 1 was followed with all manufacturing steps as described, except that the drug composition consists of 650.0 grams of venlafaxine hydrochloride, 240.0 grams of maltodextrin having an average molecular weight of approximately 1800 grams per mole and an average degree of polymerization of 11.1, 80.0 grams of hydroxypropyl cellulose, 20.0 grams of polyvinyl pyrrolidone, and 10.0 grams of magnesium stearate.
  • the resulting dosage form was tested in artificial intestinal fluid, the dosage form delivered a dose of 57 mg of venlafaxine hydrochloride at zero order rate over a period of 15 hours.
  • Example 1 The procedure of Example 1 was repeated with the manufacture as previously set-forth, except that the drug composition consists of 840.0 grams of venlafaxine hydrochloride, 150.0 grams of polyethylene oxide having an average molecular weight of approximately 100,000 grams per mole, and 10.0 grams of magnesium stearate. The wall weight weighed approximately 25 mg. The resulting dosage forms were tested in simulated intestinal fluid, and they released a dose of 73 mg of venlafaxine hydrochloride at controlled rate over an extended period of 20 hours.
  • the drug composition consists of 840.0 grams of venlafaxine hydrochloride, 150.0 grams of polyethylene oxide having an average molecular weight of approximately 100,000 grams per mole, and 10.0 grams of magnesium stearate.
  • the wall weight weighed approximately 25 mg.
  • the resulting dosage forms were tested in simulated intestinal fluid, and they released a dose of 73 mg of venlafaxine hydrochloride at controlled rate over an extended period of 20 hours.
  • compositions were manufactured as in Example 1.
  • the process of manufacture was the same except that the push layer manufactured was prepared in a fluid bed aqueous-based granulation process. This was accomplished by sizing the sodium carboxymethyl cellulose, the sodium chloride, the hydroxypropyl cellulose, and red ferric oxide through a screen having openings of 420 microns.
  • the resulting powders were charged into a fluid bed granulation column and binder solution consisting of the hydroxypropyl methylcellulose at a 5 percent solids concentration in water was sprayed on, thereby forming the granules for the push layer.
  • compositions and processes followed in this example were the same as in Example 1 except the push consisted of 740.0 grams polyethylene oxide with an average molecular weight of approximately 5 million grams per mole, 200.0 grams of sodium chloride, 50.0 grams of hydroxypropyl methyl cellulose having average molecular weight of approximately 11,300 per mole, 5.0 grams of red ferric oxide, and 5.0 grams of magnesium stearate.
  • Additional embodiments of the invention pertains to a method for delivering a drug embraced by the structural formula of this invention for its intended therapy.
  • One embodiment pertains to a method for delivering a drug of the formula by administering a dosage form comprising 0.5 mg to 750 mg of the drug from a dosage form selected from sustained-release and controlled-release dosage forms in a therapeutically responsive dose over an extended period of time.
  • Another embodiment of the invention pertains to a method for delivering a drug of the formula disclosed in this invention, to the gastrointestinal tract of a human in need of this therapy, wherein the method comprises the steps of: (A) admitting orally into the gastrointestinal tract of the human a dosage form comprising: (1) a non-toxic wall composition comprising means for imbibing an external aqueous fluid through the wall into the dosage form, which wall surrounds and defines; (2) an internal compartment; (3) a drug composition comprising a drug of the formula in the compartment comprising a dosage unit amount of said drug; (4) a push composition in the compartment for pushing the drug composition from the compartment; (5) at least one exit means in the wall for delivering the drug from the dosage form; (B) imbibing fluid through the wall into the compartment thereby causing the composition to form a deliverable dosage form and concomitantly causing the push composition to expand and push the drug composition through the exit means from the dosage form; and (C) deliver the therapeutic drug in a therapeutically effective amount at a controlled rate over an

Abstract

The invention pertains to a dosage form 10 and to administering an antidepressant medicament 16 for an extended period of time in a rate-known dose.

Description

    FIELD OF THE INVENTION
  • This invention pertains to a controlled-release dosage form comprising a compound of the following structural formula: [0001]
    Figure US20040086570A1-20040506-C00001
  • useful for antidepressant therapy. The invention concerns also a method useful for antidepressant therapy by administering the controlled-release dosage form comprising the compound of the formula. [0002]
  • BACKGROUND OF THE INVENTION
  • The primary goal of drug administration is to provide a therapeutic dose of drug in the body to achieve a desired blood concentration, and then maintain the desired drug blood concentration. The prior art, in attempts to obtain the desired therapeutic effect, often used different dosage forms or programs. One dosage program consists of a single dosing of the drug from a conventional capsule or tablet that produced a rapid rise followed by an immediate decline of the drug blood level versus time. The single dosing does not maintain the drug within a therapeutic range for an extended period of time, but exhibits of a short duration of action due to the inability of the conventional dosage form to provide drug delivery over time. [0003]
  • Another prior art dosing program used to obtain and to achieve drug blood levels consists in administering the drug repetitively using conventional dosage forms at various dosing intervals, as in multiple-dose therapy. In administering a drug according to the multiple-dose therapy, the drug blood level reached and the time required to reach that level depends on the dose and the dosing interval. There are, however, several potential problems inherent in multiple dose therapy. For example, if the dosing interval is not appropriate for the biological half-life of the drug, large peaks and valleys may result in the drug blood levels. Also, the drug blood level may not be within the therapeutic range at sufficiently early times, an important consideration for many disease states. And too, patient noncompliance with the multiple dosing regimen can result in a failure of this approach, especially as a drug in circulation surges to a high each time the drug is administered followed by a decline in drug concentration in the blood and in body compartments. Thus, a graph of drug in circulation following a dosage program of several doses, has an appearance of a series of peaks, which may surpass the toxic threshold. Then, each time the blood levels decreases into valleys, below a critical level needed to achieve a desired therapeutic effect, that effect may not be obtainable in the blood and body. Conventional dosage forms and their mode of operation are discussed in [0004] Remington's Pharmaceutical Sciences, 18th Edition, pages 1676 to 1686, (1990), Mack Publishing Co.; The Pharmacological Basis of Therapeutics, 7th Edition, page 7 (1985) published by MacMillian Publishing Co., and in U.S. Pat. Nos. 3,598,122 and 3,598,123 both issued to Zaffaroni.
  • A critical need exists for a controlled-rate dosage form for administering the drug of the formula: [0005]
    Figure US20040086570A1-20040506-C00002
  • which drug is presently administered in conventional dosage forms including tablets, capsules, elixirs and suspensions. These conventional dosage forms produce the peaks and valleys drug pattern presented above and they do not provide for controlled-rate therapy over an extended period of time. The drug of the formula is dosed twice or thrice a day now because of its elimination half-life of three to five hours. This pattern of dosing indicates the need for a controlled-release dosage form that can administer the drug at a controlled rate over an extended time to provide constant therapy and thereby eliminate the need for multiple dosing. The drugs of the structural formula are known in U.S. Pat. Nos. 4,535,186; 4,611,078; and 4,761,501 all issued to Husbands, Yardley and Muth. [0006]
  • The prior art provided controlled-release dosage forms that can continuously over time administer a drug for controlled-rate therapy. For example, in U.S. Pat. No. 4,327,725 issued to Cortese and Theeuwes and in U.S. Pat. Nos. 4,612,008; 4,765,989; and 4,783,337 issued to Wong, Barclay, Deters, and Theeuwes. The dosage forms disclosed in these patents provide a drug at a constant rate for effecting a therapeutic range for preferred therapy. The dosage forms of the patents provide a therapeutic range and avoids delivering the drug in excess in a toxic range with its accompanying side-effects. The dosage forms of the patents in providing a controlled dose in a therapeutic range also avoids delivering the drug in an ineffective dose in an ineffective range. [0007]
  • The dosage forms presented immediately above operate successfully for their intended use and they can deliver many drugs indicated for good therapy. The drugs of the above structural formula, however, possess properties such as a high solubility of 570 mg per ml at a body temperature of 37° C. that can lead to a premature release of the drug from the dosage form. During operation of the dosage forms, the convection motion of the imbibed fluid, and the hydrostatic pressure of the,imbibed fluid coupled with the high solubility can result in the premature release of the drugs of the formula. [0008]
  • It is immediately apparent in the light of the above presentation that an urgent need exists for a dosage form endowed with controlled-release delivery for delivering the drugs embraced by the structural formula. The need exists for the dosage form for delivering the drug at a controlled dose in a therapeutic range while simultaneously providing the intended therapy. It will be appreciated by those versed in the dispensing art, that such a dosage form that can administer the drug in a controlled-rate dose over time, would, represent an advancement and a valuable contribution to the art. [0009]
  • OBJECTS OF THE INVENTION
  • Accordingly, in view of the above presentation, it is an immediate object of this invention to provide a dosage from that possesses controlled-release delivery for providing a dosage form for administering a drug of the structural formula. [0010]
  • Another object of the present invention is to provide a dosage form for administering the drug of the formula in a controlled-rate dose in a therapeutic range over a prolonged period of time. [0011]
  • Another object of the present invention is to provide a dosage form that can deliver the drug of the formula essentially-free of a premature release from the dosage form. [0012]
  • Another object of the present invention is to provide a drug delivery controlled-release system that can deliver a drug for maintaining constant drug levels in the blood thereby functioning as a prolonged release system. [0013]
  • Another object of the present invention is to provide drug delivery sustained-release system that provides slow release of the drug over an extended period of time optionally in a therapeutic range. [0014]
  • Another object of the present invention is to provide a dosage form that substantially reduces and/or substantially eliminates the unwanted influences of a gastrointestinal environment of use and still provides controlled drug administration. [0015]
  • Another object of the present invention is to provide an improvement in a dosage form for administering a drug embraced by the structural formula and its pharmaceutically acceptable salt, wherein the improvement comprises delivering the drug in a controlled-release rate from the dosage form for improved and known therapy. [0016]
  • Another object of the invention is to provide a once-a-day controlled-release dosage form to deliver the drug of the structural formula orally to a patent in need of therapy. [0017]
  • Another object of the invention is to provide a method for administering a drug of the formula by orally administering the drug in a controlled rate dose per unit dose over an extended time to an animal in need of therapy. [0018]
  • Another object of the present invention is to provide a method for administering a drug of the formula in a therapeutic range while simultaneously substantially-avoiding a toxic range and an infective range. [0019]
  • Another object of the present invention is to provide a therapeutic composition comprising a drug of the structural formula blended with a drug-composition forming polymer. [0020]
  • Another object of the invention is to provide a therapeutic composition comprising a member selected from the group consisting of venlafaxine and its pharmaceutically acceptable additional salt and a pharmaceutically acceptable polymer carrier for venlafaxine and its acceptable salts. [0021]
  • Other objects, feature, and advantages of the invention will more apparent to those versed in the dispensing arts from the following detailed specification, taken in conjunction with the drawings and the accompanying claims.[0022]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • In the drawing figures, which are not drawn to scale, but are set forth to illustrate various embodiments of the invention, the drawing figures are as follows: [0023]
  • Drawing FIG. 1 is a general view of a dosage form provided by the invention, which dosage form is designed and shaped for oral administration, and for a drug delivery in a controlled-rate dose in the gastrointestinal tract; [0024]
  • Drawing FIG. 2 is an opened view of the dosage form of drawing FIG. 1 for depicting the structure of the dosage form and the composition member contained inside the dosage form; and [0025]
  • Drawing FIG. 3 is a view of a dosage form that depicts an external, instant-release of drug of the structural formula coated on the exterior surface of the dosage form. [0026]
  • In the drawing figures, and in the specification, like parts in related figures are identified by like numbers. The terms appearing earlier in the specification and in the description of the drawing figures, as well as embodiments thereof, are further described elsewhere in the disclosure.[0027]
  • DETAILED DESCRIPTION OF THE DRAWINGS
  • Turning now to the drawing figures in detail, which drawing figures are examples of dosage forms provided by this invention, and which examples are not to be construed as limiting, one example of a dosage form is seen in drawing FIG. 1. In drawing FIG. 1, a [0028] dosage form 10 is seen comprising a body member 11, which body 11 comprises wall 12, that surrounds and forms an internal area, not seen in drawing FIG. 1. Dosage form 10 comprises at least one exit port 13 for connecting the exterior with the interior of dosage form 10.
  • The [0029] dosage form 10 of drawing FIG. 1 illustrates a controlled-release dosage form manufactured as an osmotic dosage form that delivers a drug by osmotic action over an extended period of time. The dosage form comprising controlled-release properties embraced by this invention are successful at maintaining substantially constant drug levels in the blood or in a tissue. The dosage forms within the mode and manner of this invention comprises also sustained-release dosage forms. The sustained-release dosage forms releases the drug and provide drug levels in the blood or target tissue within a therapeutic range over an extended period of time. The invention embraces additionally prolonged release dosage forms. The prolonged release dosage form denotes extended duration of drug delivery action over that achieved by conventional drug delivery.
  • In drawing FIG. 2, [0030] dosage form 10 of FIG. 1 is seen in opened section. In drawing FIG. 2, dosage form 10 comprises a body 11, a wall 12 that surrounds and defines an internal compartment 14. In drawing FIG. 2, internal compartment 14 communicates through an exit passageway 13 with the exterior of dosage form 10.
  • [0031] Wall 12 of dosage form 10 comprises totally or in at least a part of a composition that is permeable to the passage of an exterior fluid present in an environment of use, such as aqueous and biological fluids. Wall 12 is formed of nontoxic ingredients, is substantially impermeable to the passage of a drug and other ingredients present in compartment 14. Wall 12 comprises a composition that is substantially inert, that is, wall 12 maintains its physical and chemical integrity during the drug dispensing life of a drug from dosage form 10. The phrase, “maintaining its physical and chemical integrity,” means wall 12 does not lose its structure and it does not change during the dispensing life of dosage form 10, except for possible leaching of one or more exit 13 passageway formed during operation of dosage form 10 or for leaching a water-soluble flux enhancers blended into wall 12. Wall 12 comprises a material that does not adversely affect an animal, a human or any other components comprising the dosage form. Representative materials for forming wall 12, are in one embodiment, a cellulose ester polymer, a cellulose ether polymer and a cellulose esterether polymer. These cellulosic polymers have a degree of substitution. D.S., on the anhydroglucose unit, from greater than 0 up to 3 inclusive. By degree of substitution is meant the average number of hydroxyl groups originally present on the anhydroglucose unit comprising the cellulose polymer that are replaced by a substituting group. Representative materials include a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanylates, mono-,di-, and tricellulose aroylates, and the like. Exemplary polymers include cellulose acetate having a D.S. up to 1 and an acetyl content up to 21%; cellulose acetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35 %; cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 35 to 44.8%, and the like. More specific cellulosic polymers include cellulose propionate having a D.S. of 1.8 and a propyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7; cellulose triacylates having a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripolmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, co-esters of cellulose such as cellulose acetate butyrate and cellulose acetate propionate, and the like.
  • Additional polymers include ethyl cellulose of various degree of etherification with ethoxy content of from 40% to 55%, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose acetate diethyl aminoacetate, semipermeable polyamides; semipermeable polyurethanes; semipermeable sulfonated polystyrenes; semipermeable cross-linked selective polymers formed by the coprecipitation of a polyanion and a polycation as disclosed in U.S. Pat Nos. 3,173,876, 3,276,586, 3,541,005; 3,541,006, and 3,546,142; semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132; semipermeable lightly cross-linked polystyrene derivatives, semipermeable cross-linked poly(sodium styrene sulfonate); semipermeable cross-linked poly(vinylbenzyltrimethyl ammonium chloride); semipermeable polymers exhibiting a fluid permeability of 2.5×10[0032] −8 to 2.5×10−4(cm2/hr.atm) expressed per atmosphere of hydrostatic or osmotic pressure difference across the semipermeable wall. The polymers are known to the art in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020; and in Handbook of Common Polymers by Scott, J. R. and Roff, W. J., 1971 published by CRC Press, Cleveland, Ohio.
  • [0033] Compartment 14 comprises a drug composition, identified as drug layer 15 which contains drug 16, identified by dots. Drug 16 comprises a drug of the following structural formula:
    Figure US20040086570A1-20040506-C00003
  • wherein the dotted line represents optional unsaturation or a cycloalkenyl moiety; R[0034] 1 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R2 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R4 is a member selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms; R5 and R6 are independently a member selected from the group consisting of hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms in which each alkyl group comprises 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo, and trifluoroethyl, R7 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbons, and n is one of the integers 0, 1, 2, 3, and 4. The formula embraces also the pharmaceutically acceptable addition salts including a member selected from the group consisting of inorganic, organic, hydrochloric, hydrobromic, gluconic, fumaric, maleric, sulfonic, succinic, sulfuric, phosphoric, tartaric, acetic, proponic, citric, oxalic and similar pharmaceutically acceptable addition salts. The compounds are known in U.S. Pat. Nos. 4,535,186; 4,611,078; 4,761,501; and 5,190,765.
  • The drugs of the structural formula are represented by the drug 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol of the structural formula: [0035]
    Figure US20040086570A1-20040506-C00004
  • The drug embraced by the formula possesses antidepressant properties. The drug in vitro prevents the neuronal uptake of seroton in, morepinephrine, and dopamine and it does not inhibit monoamine oxidase. The drug antagonizes reserpine-induced hypothermia and potentiates the effects of levodopa, and reduces histamine-induced corticotropin release and induces cyclicadenosine monophosphate subsensitivity after both acute and chronic administration. The drug possesses excellent antidepressant activity in humans. The therapeutic amount of [0036] drug 16 in dosage form 10 is 0.5 mg to 750 mg, with individual dosage forms comprising 2, 5, 10, 25, 40, 50, 75, 100, 150, 250, 300, 500, and 600 mg of drug 16 for administering in a single dose or in more then one dose over an extended period of 24 hours. The therapeutic properties of the drug embraced by the structural formula are reported in Current Therapeutic Research, Vol. 42, No. 5, pages 901 to 909 (1987).
  • Composition [0037] 15 comprising drug 16 may comprise a drug dispensing carrier and composition formulating member consisting of a member selected from the group consisting of 0 wt % to 25 wt % of a hydroxypropylalkylcellulose where alkyl consists of 1 to 7 carbons selected from the group consisting of methyl, ethyl, isopropyl, butyl, pentyl, and hexyl which cellulose member comprises a 9,000 to 1,250,000 molecular weight and is exemplified by hydroxypropylmethylcelluose, hydroxypropylethylcellulose, hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose and hydroxypropylhexylcellulose represented by dashes 17; a member selected from the group consisting of 0 wt % to 20 wt % hydroxylalkylcellulose where alkyl is 1 to 6 carbons including methyl, ethyl, propyl, butyl, pentyl, and hexyl which cellulose member comprises a 7,500 to 750,000 molecular weight and is exemplified by hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyisopropylcellulose and hydroxybutylcellulose as represented by slanted line 18; a member selected from the group consisting of 0 wt % to 35 wt % of a vinyl-polymer having a 3,500 to 750,000 molecular weight represented by poly-n-vinylamide, poly-n-vinlycetamide, poly-n-vinylethylacetamide, poly-n-vinylmethylpropionamide, poly-n-vinyl ethylpropionamide, poly-n-vinylmethylisobutyramide, poly-n-vinyl-2-pyrrolidone, poly-n-vinypiperidone also known as polyvinylpyrrolidone and as poly-n-vinylpyrroledone, poly-n-vinylcaprolactam, poly-n-vinyl-5-methyl-2-pyrrolidone and poly-n-vinyl-3-methyl-2-pyrrolidone, and poly-n-vinylpyrrolidone copolymer with a member selected from the group consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl laurate and vinyl stearate represented by small circles 19; and 0 wt %, where wt % is weight percent, 35 wt % of a maltodextrin polymer composition comprising the formula (C6H12O5)n H2O wherein n is 3 to 7,500 and the maltodextrin polymer comprises a 500 to 1,250,000 number average molecular weight represented by a small square 20; as member selected from the group consisting of 0 wt % to 40 wt % of poly(etheylen oxide) having a molecular weight of 100,000 to 600,000 grams per mole, represented by half-circles 20 a. Composition 15 optionally comprises from 0 to 4.5 wt % of a lubricant represented by magnesium stearate, calcium stearate or stearic acid. The total weight of all ingredients in composition 15 is equal to 100 wt %, weight percent.
  • [0038] Compartment 14 comprises a displacement composition or push layer 21. Displacement composition 21 comprises a polymer member selected from the group consisting of a polymer possessing a repeating molecular unit (—0—CH2CH2—)n wherein n is a positive whole number of 50,000 to 300,000 as represented by a poly(alkylene oxide) comprising poly(ethylene oxide) seen as wavy line 22; a maltodextrin polymer of the formula (C6H12O5)n H2O wherein n is 50 to 62,000 and comprises a 9,000 to 10,000,000 molecular weight and represented by triangle 23; a carboxymethylcellulose polymer comprising a 10,000 to 5,000,000 molecular weight represented by alkali carboxymethylcellulose, sodium carboxymethylcellulose and potassium carboxymethylcellulose, ammonium carboxymethylcellulose, sodium carboxymethyl-2-hydroxyethylcellulose, sodium carboxymethyl-methylcellulose, alkali carboxymethyl-hydroxypropyl-methylcellulose, alkali carboxymethyl-2-hydroxyethylmethylcellulose, alkali carboxymethyl-2-hydroxybutylmethylcellulose, alkali carboxymethyl-2-hydroxyethyl-ethylcellulose and alkali carboxymethyl-2-hydroxypropylcellulose, where alkali is sodium and potassium and seen in drawing FIG. 2 as hexagonal 23 a. The polymers in push layer 21 provide unforeseen operating advantages as the polymer maintains its chemical composition during operation as it imbibes an external aqueous fluid including biological fluid while simultaneously pushing the drug from the dosage form essentially-free of substantially mixing the drug composition with the push composition. The displacement composition 21 comprises optionally from 4 to 35 wt % of an osmotically active compound, also known as osmagent and represented by vertical line 24. Representative of osmotically effective compounds comprises salts, oxides, esters that exhibit imbibition properties, carbohydrates and acids including a member selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium chloride, potassium sulfate, sodium sulfate, sodium sulfite, lithium sulfate, ammonium chloride, potassium lactate, mannitol, urea, magnesium succinate, tartaric acid, raffinose, sorbitol, sucrose, fructose, and glucose. Displacement layer 21 optionally comprises 0.5 wt % to 30 wt % of a cellulose polymer 25 represented by the letter v. Representative of cellulose polymer 25 comprise a member selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, and hydroxypropylhexylcellulose comprising a 9,000 to 225,000 molecular weight. The displacement composition optionally comprises 0 wt % to 5 wt % of lubricant stearic acid and, magnesium stearate, calcium oleate, oleic acid, and caprylic acid. The polymers are known in U.S. Pat Nos. 3,845,770; and 4,160,020; in Handbook of Common Polymers by Scott, J. R., and Roff, W. J., published by CRC Press, Cleveland, Ohio.
  • [0039] Dosage form 10, a seen in drawing FIG. 3 depicts another preferred manufacture provided by the invention. Dosage form 10, in drawing FIG. 3, comprises an external coat on a the exterior surface of dosage form 10. Coat 26 is a therapeutic composition comprising 10 mg to 150 mg of drug 16, represented by dots 16. Exterior coat 26 provides instant drug 16 for instant therapy. Drug 16 is blended with an aqueous-soluble composition comprising a carrier methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and blends of hydroxypropylcellulose and hydroxypropylmethylcellulose. Coat 26 optionally comprises polyethylene glycol or acetylated triglycerides. Coat 26 provides instant therapy as coat 26 dissolves or undergoes dissolution in the presence of a biological fluid and concurrently therewith delivers drug 16 to a drug receiving patient. Coat 26 provides instant therapy and it essentially overcomes the time required for the drug to be delivered from the dosage form.
  • [0040] Dosage form 10, as provided by this invention, and as seen in the above drawing figures can be manufactured for administering drug 16 by the oral route, and in another embodiment, dosage form 10 comprising exterior and interior drug 16 can be sized and shaped for administering drug 16 by the sublingual and buccal routes. The sublingual and buccal routes can be used for quicker therapy and they can be used when a smaller dose of drug 16 is needed for therapy. The buccal and sublingual routes can be used as a by-pass of the first pass of hepatic metabolism of drug 16. The sublingual or buccal routes can be used for administering the first dose of drug, followed by permitting dosage form 10 to enter the gastrointestinal tract for subsequent drug delivery.
  • [0041] Dosage form 10, when manufactured as an osmotic, controlled-release dosage form, comprises at least one passageway 13, or more than one passageway 13. The expression “at least one passageway” includes aperture, orifice, bore, pore, porous element through which the drug can be pumped, diffuse, travel or migrate, hollow fiber, capillary tube, porous overlay, porous insert, microporous member, porous composition, and the like. The expression also includes a material that erodes or is leached from wall 12 in the fluid environment of use to produce at least one passageway in dosage form 10. Representative material suitable for forming at least one passageway, or a multiplicity of passageways, includes an erodible poly(glycolic) acid or poly(lactic) acid member in the wall; a gelatinous filament; poly(vinyl alcohol); leachable materials such as fluid removable pore forming polysaccharides, salts, or oxides, and the like. A passageway or a plurality of passageways can be formed by leaching a material such as sorbitol, sucrose, lactose, fructose, or the like, from the wall to provide an osmotic dimensioned pore-passageway. The passageway can have any shape such as round, triangular, square, elliptical, and the like, for assisting in the metered release of drug from dosage form 10. Dosage form 10 can be constructed with one or passageways in spaced apart relation on one or more than a single surface of a dosage form. Passageways and equipment for forming passages are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899 by Theeuwes and Higuchi; in U.S. Pat No. 4,063,064 by Saunders et al; and in U.S. Pat. No. 4,088,864 by Theeuwes et al. Osmotic passageways comprising controlled-drug releasing dimension, sized, shaped and adapted as a drug releasing pore formed by aqueous leaching to provide a drug-releasing pore of controlled osmotic release rate are disclosed in U.S. Pat. No. 4,200,098 by Ayer and Theeuwes; and in U.S. Pat. No. 4,285,987 by Ayer and Theeuwes.
  • [0042] Wall 12 of osmotic dosage form 10 can be formed in one technique using the air suspension procedure. This procedure consists in suspending and tumbling the compressed drug-push core laminate in a current of air and wall forming composition until a wall is applied to the drug-push compartment. The air suspension procedure is well-suited for independently forming the wall. The air suspension procedure is described in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Volume 48, pages 451 to 454, (1959); and ibid, Volume 49, pages 82 to 84, (196). Osmotic dosage forms can also be coated with a wall forming composition in a Wurster® air suspension coater, using methylene dichloride-methanol cosolvent, 80:20, wt:wt, an ethanol-water, or acetone-water cosolvent, 95:5 wt:wt using 2.5 to 4% solids. The Aeromatic® air suspension coater using a methylene dichloride-methanol cosolvent, 80:20 wt:wt, also can be used for applying the wall. Other wall forming techniques such as pan coating system, where wall forming compositions are deposited by successive spraying of the composition on the drug-push compartment, accompanied by tumbling in a rotating pan. Finally, the wall coated compartments are dried in a forced air over at 30° C. to 50° C. for up to a week to free dosage form 10 of solvent. Generally, the walls formed by these techniques have a thickness of 2 to 30 mils with a presently preferred thickness of 4 to 10 mils.
  • [0043] Dosage form 10 of the invention is manufactured by standard manufacturing techniques. For example, in one manufacture the beneficial drug and other ingredients comprising the drug layer facing the exit means are blended and pressed into a solid layer. The drug and other ingredients can be blended with a solvent and mixed into a solid or semisolid formed by conventional methods such a ball-milling, calendering, stirring or rollmilling and then pressed into a preselected shape. The layer possesses dimensions that correspond to the internal dimensions of the area the layer is to occupy in the dosage form and it also possesses dimensions corresponding to the second layer for forming a contacting arrangement therewith. Next, the push layer, is placed in contact with the drug layer. The push layer is manufactured using techniques for providing the drug layer. The layering of the drug layer and the push layer can be fabricated by conventional press-layering techniques. Finally, the two layer compartment forming members are surrounded and coated with an outer wall. A passageway is laser, leached, or mechanically drilled through the wall to contact the drug layer, with the dosage form optically oriented automatically by the laser equipment for forming the passageway on the preselected surface when a laser is used for forming the passageway.
  • In another manufacture, the dosage form is manufactured by the wet granulation technique. In the wet granulation technique, for example, the drug and the ingredients comprising the drug layer are blended using an organic solvent, such as isopropyl alcohol-ethylene dichloride 80:20 v:v (volume:volume) as the granulation fluid. Other granulating fluid such as denatured alcohol 100% can be used for this purpose. The ingredients forming the drug layer are individually passed through a 40 mesh screen and then thoroughly blended in a mixer. Next, other ingredients comprising the drug layer are dissolved in a portion of the granulation fluid, such as the cosolvent described above. Then the latter prepared wet blend is slowly added to the drug blend with continual mixing in the blender. The granulating fluid is added until a wet blend is produced, which wet mass then is forced through a 20 mesh screen onto oven trays. The blend is dried for 18 to 24 hours at 30° C. to 50° C. The dry granules are sized then with a 20 mesh screen. Next, a lubricant is passed through an 80 mesh screen and added to the dry screen granule blend. The granulation is put into milling jars and mixed on a jar mill for 1 to 15 minutes. The push layer is made by the same wet granulation techniques. The compositions are pressed into their individual layers in a Manesty ® press-layer press. [0044]
  • Another manufacturing process that can be used for providing the compartment-forming composition layers comprises blending the powered ingredients for each layer independently in a fluid bed granulator. After the powered ingredients are dry blended in the granulator, a granulating fluid, for example, poly(vinyl-pyrrolidone) in water, or in denatured alcohol, or in 95:5 ethyl alcohol water, or in blends of ethanol and water is sprayed onto the powders. Optionally, the ingredients can be dissolved or suspended in the granulating fluid. The coated powders are then dried in a granulator. This process granulates all the ingredients present therein while adding the granulating fluid. After the granules are dried, a lubricant such as stearic acid or magnesium stearate is added to the granulator. The granules for each separate layer are pressed then in the manner described above. [0045]
  • The dosage form of the invention is manufactured in another manufacture by mixing a drug with composition forming ingredients and pressing the composition into a solid lamina possessing dimensions that correspond to the internal dimensions of the compartment. In another manufacture the drug and other drug composition-forming ingredients and a solvent are mixed into a solid, or a semisolid, by conventional methods such as ballmilling, calendering, stirring or rollmilling, and then pressed into a preselected layer forming shape. Next, a layer of a composition comprising an osmopolymer and an optional osmagent are placed in contact with the layer comprising the drug. The layering of the first layer comprising the drug and the second layer comprising the osmopolymer and optional osmagent composition can be accomplished by using a conventional layer press technique. The wall can be applied by molding, spraying or dipping the pressed bilayer's shapes into wall forming materials. Another and presently preferred technique that can be used for applying the wall is the air suspension coating procedure. The procedure consists in suspending and tumbling the two layers in current of air until the wall forming composition surrounds the layers. The air suspension procedure is described in U.S. Pat. No. 2,799,241[0046] ; J. Am. Pharm. Assoc., Vol. 48 pp 451-454 (1979); and, ibid, Vol. 49, pp 82-84 (1960). Other standard manufacturing procedures are described in Modern Plastics Encyclopedia, Vol 46, pp 62-70 (1969); and in Pharmaceutical Science, by Remington, 14th Ed., pp 1626-1678 (1970), published by Mack Publishing Co., Easton, Pa.
  • Exemplary solvents suitable for manufacturing the wall, the laminates and laminae include inert inorganic and organic solvents final laminated wall. The solvents broadly include members selected for the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cyclaliphatics, aromatics, heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone, alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptaene ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachoroethan, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, tetrahydrofuran, diglyme, aqueous and nonaqueous mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol. [0047]
  • DETAILED DISCLOSURE OF EXAMPLES OF THE INVENTION
  • The following examples are merely illustrative of the present invention and they should not be considered as limiting thscope of the invention in any way as these examples and other equivalents thereof will become apparent to those versed in the art in the light of the present disclosure, the drawings and accompanying claims. [0048]
  • EXAMPLE 1
  • A dosage form adapted for delivering a drug in a therapeutic range is manufactured as follows: first a displacement or push layer is prepared by blending and passing through a stainless steel sizing screen having a mesh opening of 420 microns 587.5 grams of sodium carboxymethylcellulose having a degree of polymerization of approximately 3,200 and a degree of substitution of 0.7 carboxymethyl groups per anhydroglucose unit, 300 grams of powdered sodium chloride, 50 grams of hydroxypropylcellulose having a molecular weight of approximately 60,000 grams per mole, and 50 grams of hydroxypropylmethylcellulose having an average methoxyl content of 29 weight percent and an average hydroxypropyl content of 10 weight percent and an average molecular weight of approximately 11,300 grams per mole. Next 10 grams of red ferric oxide were passed through a sizing screen having openings of approximately 250 microns. The resulting powders were mixed in a planetary mixer to a uniform blend. The resulting blend was wet granulated by adding with stirring anhydrous ethyl alcohol until, a cohesive mass was formed. This mass was passed through a sizing screen having openings of approximately 840 microns, forming coated displacement particles, which were an dried overnight at ambient temperature and humidity. The dried particles were then passed again through the 840 micron sizing screen. Next 2.5 grams of magnesium stearate, which had been previously sized through a mesh having 180 micron openings, were tumble mixed into the coated particles. [0049]
  • A composition comprising a drug of the structural formula was prepared as follows: first, a drug composition was prepared by passing 840 grams of venlafaxine hydrochloride, 100 grams of hydroxypropylcellulose having a molecular weight of approximately 60,000 grams per mole, and 50 grams of polyvinylpyrrolidone having a molecular weight of approximately 40,000 grams per mole, were passed through a sizing having openings of approximately 420 microns, and mixed in a planetary mixer to yield a uniform blend. Then, anhydrous ethyl alcohol was added to the mixture with stirring to produce a cohesive damp mass. The resulting damp mass was sized through a sieve having an opening of 840 microns, producing coated venlafaxine drug, which was air dried overnight. The resulting dried coated venlafaxine drug was passed again through the sizing screen having an 840 micron opening. Next, 10 grams of magnesium stearate, sized to 180 microns, was tumble mixed into the blend. [0050]
  • Next, the displacement-push composition and the drug composition were formed into a bilayer core as follows: first, 87 mg of the drug composition was placed in a {fraction (9/32)} inch round die cavity and lightly tamped with a standard concave round tooling to form a slightly cohesive layer. Then, 70 mg of push composition was added to die and the and the resulting fill was compressed with a final force of 2 tons, thereby forming a two layer cores. [0051]
  • The bilayer cores were placed next in a coating pan having a 12 inch diameter and they were coated with a wall-forming solution. The wall-forming solution was prepared by dissolving 380 grams of cellulose acetate having an acetyl content of 39.8 weight percent in 7,220 grams of acetone. In a separate mixing vessel, 20 grams of polyethylene glycol having a molecular weight of approximately 3,350 grams per mole were dissolved in approximately 380 grams of purified water. The two solutions were mixed to form the wall-coating solution which was spray coated onto the cores until about 20 mg of wall composition was deposited on the surfaces of the bilayer core. [0052]
  • A delivery exit port was formed across the wall by drilling an exit port, centered on the face of the dosage form on the drug composition side of the dosage form. The resulting dosage form was placed in simulated physiological fluid at 37° C., and the dosage form delivered a dose of 73 mg of venlafaxine hydrochloride at a controlled, zero rate over an extended duration of 15 hours. [0053]
  • EXAMPLE 2
  • The procedure of Example 1 was followed with the manufacturing procedures as set forth, except that the drug composition comprises 890 grams of venlafaxine hydrochloride, 100 grams of hydroxypropylcellulose, and 10 grams of magnesium stearate. The resulting dosage form released in simulated intestinal fluid 77 mg of venlafaxine hydrochloride at a zero-order rate over an extended duration of 16 hours. [0054]
  • EXAMPLE 3
  • The procedure of Example 1 was followed with all manufacturing steps as described, except that the drug composition consists of 650.0 grams of venlafaxine hydrochloride, 240.0 grams of maltodextrin having an average molecular weight of approximately 1800 grams per mole and an average degree of polymerization of 11.1, 80.0 grams of hydroxypropyl cellulose, 20.0 grams of polyvinyl pyrrolidone, and 10.0 grams of magnesium stearate. The resulting dosage form was tested in artificial intestinal fluid, the dosage form delivered a dose of 57 mg of venlafaxine hydrochloride at zero order rate over a period of 15 hours. [0055]
  • EXAMPLE 4
  • The procedure of Example 1 was repeated with the manufacture as previously set-forth, except that the drug composition consists of 840.0 grams of venlafaxine hydrochloride, 150.0 grams of polyethylene oxide having an average molecular weight of approximately 100,000 grams per mole, and 10.0 grams of magnesium stearate. The wall weight weighed approximately 25 mg. The resulting dosage forms were tested in simulated intestinal fluid, and they released a dose of 73 mg of venlafaxine hydrochloride at controlled rate over an extended period of 20 hours. [0056]
  • EXAMPLE 5
  • The compositions were manufactured as in Example 1. The process of manufacture was the same except that the push layer manufactured was prepared in a fluid bed aqueous-based granulation process. This was accomplished by sizing the sodium carboxymethyl cellulose, the sodium chloride, the hydroxypropyl cellulose, and red ferric oxide through a screen having openings of 420 microns. The resulting powders were charged into a fluid bed granulation column and binder solution consisting of the hydroxypropyl methylcellulose at a 5 percent solids concentration in water was sprayed on, thereby forming the granules for the push layer. [0057]
  • EXAMPLE 6
  • The compositions and processes followed in this example were the same as in Example 1 except the push consisted of 740.0 grams polyethylene oxide with an average molecular weight of approximately 5 million grams per mole, 200.0 grams of sodium chloride, 50.0 grams of hydroxypropyl methyl cellulose having average molecular weight of approximately 11,300 per mole, 5.0 grams of red ferric oxide, and 5.0 grams of magnesium stearate. [0058]
  • DESCRIPTION OF METHOD OF PERFORMING THE INVENTION
  • Additional embodiments of the invention pertains to a method for delivering a drug embraced by the structural formula of this invention for its intended therapy. One embodiment pertains to a method for delivering a drug of the formula by administering a dosage form comprising 0.5 mg to 750 mg of the drug from a dosage form selected from sustained-release and controlled-release dosage forms in a therapeutically responsive dose over an extended period of time. Another embodiment of the invention pertains to a method for delivering a drug of the formula disclosed in this invention, to the gastrointestinal tract of a human in need of this therapy, wherein the method comprises the steps of: (A) admitting orally into the gastrointestinal tract of the human a dosage form comprising: (1) a non-toxic wall composition comprising means for imbibing an external aqueous fluid through the wall into the dosage form, which wall surrounds and defines; (2) an internal compartment; (3) a drug composition comprising a drug of the formula in the compartment comprising a dosage unit amount of said drug; (4) a push composition in the compartment for pushing the drug composition from the compartment; (5) at least one exit means in the wall for delivering the drug from the dosage form; (B) imbibing fluid through the wall into the compartment thereby causing the composition to form a deliverable dosage form and concomitantly causing the push composition to expand and push the drug composition through the exit means from the dosage form; and (C) deliver the therapeutic drug in a therapeutically effective amount at a controlled rate over an extended period of time to the patient in need of said therapy. The method also comprising dispensing a dose amount of said drug from an instant release exterior dosage amount of drug to the patient for providing instant anti-depressant therapy. [0059]
  • Inasmuch as the foregoing specification comprises preferred embodiments of the invention, it is understood that variations and modifications may be made herein, in accordance with the inventive principles disclosed, without departing from the scope of the invention. [0060]

Claims (7)

We claim:
1. A therapeutic composition comprising 0.5 mg to 750 mg of a drug of the formula:
Figure US20040086570A1-20040506-C00005
wherein the dotted line represents an unsaturation or a cycloalkenyl group; R1 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R2 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R4 is a member selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms; R5 and R6 are independently a member selected from the group consisting of hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms in which each alkyl group comprises 1 to 6 carbon atoms, alkanamide of 2 to 7 carbon atoms, halo, and trifluoroethyl, R7 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbons, and n is one of the integers 0, 1, 2, 3, and 4, and a pharmaceutically acceptable addition salt; and wherein the drug of the formula is blended with a poly(alkylene oxide) polymer.
2. A therapeutic composition comprising 0.5 mg to 750 mg of a drug of the formula;
Figure US20040086570A1-20040506-C00006
wherein the dotted line represents an unsaturation or a cycloalkenyl group; R1 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R2 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R4 is a member selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms; R5 and R6 are independently a member selected from the group consisting of hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms in which each alkyl group comprises 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo, and trifluoroethyl; R7 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbons and n is one of the integers 0, 1, 2, 3, 4, and a pharmaceutically acceptable addition salt; and wherein the drug of the formula is blended with a cellulose polymer.
3. A therapeutic composition comprising 0.5 mg to 750 mg of a drug of the formula:
Figure US20040086570A1-20040506-C00007
wherein the dotted line represents an unsaturation or a cycloalkenyl group; R1 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R2 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R4 is a member selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms; R5 and R6 are independently a member selected from the group consisting of hydrogen, hydroxyl, an alkyl of 1 to 6 carbon atoms, an alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms in which each alkyl group comprises 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo, and trifluoroethyl, R7 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbons, and n is one of the integers 0, 1, 2, 3, and 4; and a pharmaceutically acceptable addition salt; and wherein the drug of the formula is blended with a maltodextrin polymer.
4. A method for administering a drug to the gastrointestinal tract of an animal, wherein the method comprises:
(a) admitting orally into the animal a dosage form comprising a drug of the formula:
Figure US20040086570A1-20040506-C00008
which drug possesses antidepressant therapy and the dosage form comprises a member selected from the group consisting of a sustained-release dosage form and a controlled-release dosage form; and,
(b) administering the drug from the dosage form over an extended period of time in a therapeutically responsive dose to produce the antidepressant therapy.
5. A dosage form for administering a drug to an environment of use, wherein the dosage form comprises a drug of the formula:
Figure US20040086570A1-20040506-C00009
which dosage form comprises a member selected from the group consisting of a sustained-release dosage form and a controlled release dosage form, and wherein said dosage form comprises means for storing the drug and means for releasing the drug over an extended period of time.
6. A dosage form for the oral delivery of a drug to an environment of use, wherein the dosage form comprises:
(a) a wall comprising at least in part a composition permeable to the passage of fluid, which wall surrounds:
(b) a compartment;
(c) a drug composition in the compartment comprising a drug of the formula:
Figure US20040086570A1-20040506-C00010
wherein the dotted line represents a member selected from the group consisting of an unsaturation and cycloalkenyl group; R1 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R2 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms; R4 is a member selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, formyl, and alkanoyl of 2 to 7 carbon atoms; R5 and R6 are independently a member selected from the group consisting of hydrogen, hydroxyl and alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alknaoyloxy of 2 to 7 carbon atoms, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo and trifluoroethyl; R7 is a member selected from the group consisting of hydrogen and alkyl of 1 to 6 carbons; an n is 0 to 4; and
(d) a displacement in the compartment comprising a composition comprising an osmotically active compound; and,
(e) an exit passageway in the dosage form for delivering the drug composition from the dosage form.
7. A dosage form for the oral delivery of the drug to an environment of use according to claim 6, wherein the drug is 1-[2-(dimethylamino)-1(4-methoxeyphenyl)ethyl]-cyclohexanol.
US10/696,370 1993-05-27 2003-10-28 Antidepressant dosage form Abandoned US20040086570A1 (en)

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US11/522,014 US8084059B2 (en) 1993-05-27 2006-09-15 Antidepressant dosage form
US12/820,671 US20100260810A1 (en) 1993-05-27 2010-06-22 Antidepressant dosage form
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US11/522,014 Expired - Fee Related US8084059B2 (en) 1993-05-27 2006-09-15 Antidepressant dosage form
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070077301A1 (en) * 2002-12-23 2007-04-05 Meyer Glenn A Venlafaxine osmotic device formulation

Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6440457B1 (en) * 1993-05-27 2002-08-27 Alza Corporation Method of administering antidepressant dosage form
ES2273764T3 (en) * 1993-06-28 2007-05-16 Wyeth NEW TREATMENTS THAT USE FENETILAMINE DERIVATIVES.
PE57198A1 (en) * 1996-03-25 1998-10-10 American Home Prod PROLONGED RELEASE FORMULA
US6274171B1 (en) 1996-03-25 2001-08-14 American Home Products Corporation Extended release formulation of venlafaxine hydrochloride
EP1331003B1 (en) * 1996-03-25 2015-08-26 Wyeth LLC Extended release formulation containing venlafaxine
GB9609094D0 (en) * 1996-05-01 1996-07-03 Univ Strathclyde Delivery device
US6517866B1 (en) 1997-07-01 2003-02-11 Pfizer Inc. Sertraline salts and sustained-release dosage forms of sertraline
UA77145C2 (en) * 1997-11-05 2006-11-15 Wyeth Corp Extended release dosage formulation
CA2320900C (en) 1998-03-19 2009-10-27 Bristol-Myers Squibb Company Biphasic controlled release delivery system for high solubility pharmaceuticals and method
US6596776B2 (en) * 1999-06-21 2003-07-22 Hauser, Inc. High molecular weight primary aliphatic alcohols obtained from natural products and uses thereof
US6572890B2 (en) * 2000-01-13 2003-06-03 Osmotica Corp. Osmotic device containing venlafaxine and an anti-psychotic agent
IL146462A (en) 2001-11-13 2015-02-26 Lycored Bio Ltd Extended release compositions comprising as active compound venlafaxine hydrochloride
EP1451145A1 (en) 2001-12-05 2004-09-01 Wyeth Novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof
AU2002217373A1 (en) * 2002-01-03 2003-07-15 Lek Pharmaceutical And Chemical Company D.D. Controlled release pharmaceutical formulation containing venlafaxine
AU2003229408A1 (en) * 2002-06-10 2003-12-22 Philippe Kriwin Oral antidepressant formulation comprising a selective serotonin_reuptake inhibitor
GB2392385A (en) * 2002-09-02 2004-03-03 Cipla Ltd Pharmaceutical preparations comprising a 5HT uptake inhibitor and a homopolymer or copolymer of N-vinyl pyrrolidone
ZA200505180B (en) * 2002-11-28 2006-10-25 Themis Lab Private Ltd Process for manufacturing sustained release microbeads containing venlafaxine HCI
US8293799B2 (en) * 2003-12-29 2012-10-23 Osmotica Keresleedelmo és Szolgáltató KFT Osmotic device containing a venlafaxine salt and a salt having an ion in common
EP1596837A2 (en) * 2003-02-07 2005-11-23 Omega Farma Ehf Sustained release formulations of venlafaxine
RS51934B (en) * 2003-08-08 2012-02-29 Biovail Laboratories International Srl. Modified-release tablet of bupropion hydrochloride
GB0322859D0 (en) * 2003-09-30 2003-10-29 British Telecomm Communication
US7667849B2 (en) * 2003-09-30 2010-02-23 British Telecommunications Public Limited Company Optical sensor with interferometer for sensing external physical disturbance of optical communications link
PT1711169E (en) 2004-02-04 2007-07-23 Alembic Ltd Extended release coated minitablets of venlafaxine hydrochloride
GB0407386D0 (en) * 2004-03-31 2004-05-05 British Telecomm Monitoring a communications link
EP1794904A1 (en) 2004-09-30 2007-06-13 British Telecommunications Public Limited Company Identifying or locating waveguides
GB0421747D0 (en) * 2004-09-30 2004-11-03 British Telecomm Distributed backscattering
GB0427733D0 (en) * 2004-12-17 2005-01-19 British Telecomm Optical system
US8045174B2 (en) 2004-12-17 2011-10-25 British Telecommunications Public Limited Company Assessing a network
GB0504579D0 (en) * 2005-03-04 2005-04-13 British Telecomm Communications system
US7697795B2 (en) * 2005-03-04 2010-04-13 British Telecommunications Public Limited Company Acoustic modulation
EP1708388A1 (en) 2005-03-31 2006-10-04 British Telecommunications Public Limited Company Communicating information
EP1867973A1 (en) * 2005-04-08 2007-12-19 Eisai R&D Management Co., Ltd. Sampling device for viscous sample, homogenization method for spatum and method of detecting microbe
EP1713301A1 (en) * 2005-04-14 2006-10-18 BRITISH TELECOMMUNICATIONS public limited company Method and apparatus for communicating sound over an optical link
US20080175873A1 (en) * 2005-06-02 2008-07-24 Biovail Laboratories International S.R.L. Modified release composition of at least one form of venlafaxine
EP1729096A1 (en) * 2005-06-02 2006-12-06 BRITISH TELECOMMUNICATIONS public limited company Method and apparatus for determining the position of a disturbance in an optical fibre
PT1954669E (en) * 2005-12-01 2015-10-23 Auspex Pharmaceuticals Inc Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity
EP1989797B1 (en) * 2006-02-24 2011-04-13 BRITISH TELECOMMUNICATIONS public limited company Sensing a disturbance
EP1987317B1 (en) * 2006-02-24 2013-07-17 BRITISH TELECOMMUNICATIONS public limited company Sensing a disturbance
EP1826924A1 (en) * 2006-02-24 2007-08-29 BRITISH TELECOMMUNICATIONS public limited company Sensing a disturbance
CA2647173A1 (en) * 2006-04-03 2007-10-11 British Telecommunications Public Company Limited Evaluating the position of a disturbance
US7538652B2 (en) * 2006-08-29 2009-05-26 International Business Machines Corporation Electrical component tuned by conductive layer deletion
CA2680912C (en) * 2007-03-15 2017-11-14 Auspex Pharmaceuticals, Inc. Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity
EP2296634A1 (en) * 2008-06-02 2011-03-23 Dexcel Pharma Technologies Ltd. Process for manufacture of a medicament with granulation and pan coating
CN107080846A (en) 2010-07-09 2017-08-22 詹姆斯.特林卡.格林 For the combination including short-half-life medicine net Rui Gelie immediately/sustained release delivery system
US9205089B2 (en) 2011-04-29 2015-12-08 Massachusetts Institute Of Technology Layer processing for pharmaceuticals
US10213960B2 (en) 2014-05-20 2019-02-26 Massachusetts Institute Of Technology Plasticity induced bonding

Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2799241A (en) * 1949-01-21 1957-07-16 Wisconsin Alumni Res Found Means for applying coatings to tablets or the like
US3133132A (en) * 1960-11-29 1964-05-12 Univ California High flow porous membranes for separating water from saline solutions
US3173876A (en) * 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
US3276586A (en) * 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
US3541005A (en) * 1969-02-05 1970-11-17 Amicon Corp Continuous ultrafiltration of macromolecular solutions
US3541006A (en) * 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
US3546142A (en) * 1967-01-19 1970-12-08 Amicon Corp Polyelectrolyte structures
US3589123A (en) * 1967-08-21 1971-06-29 Messers Gebruder Junghans Gmbh Signal device for electric alarm clocks
US3589122A (en) * 1968-03-20 1971-06-29 Kienzle Uhrenfabriken Gmbh Electrodynamic oscillator
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4063064A (en) * 1976-02-23 1977-12-13 Coherent Radiation Apparatus for tracking moving workpiece by a laser beam
US4088864A (en) * 1974-11-18 1978-05-09 Alza Corporation Process for forming outlet passageways in pills using a laser
US4111201A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for delivering selected beneficial agents having varying degrees of solubility
US4160020A (en) * 1975-11-24 1979-07-03 Alza Corporation Therapeutic device for osmotically dosing at controlled rate
US4200098A (en) * 1978-10-23 1980-04-29 Alza Corporation Osmotic system with distribution zone for dispensing beneficial agent
US4285987A (en) * 1978-10-23 1981-08-25 Alza Corporation Process for manufacturing device with dispersion zone
US4327725A (en) * 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4535189A (en) * 1984-03-21 1985-08-13 Texaco Inc. Polyol purification process
US4611078A (en) * 1983-10-26 1986-09-09 American Home Products Corporation Substituted phenylacetonitriles
US4612008A (en) * 1983-05-11 1986-09-16 Alza Corporation Osmotic device with dual thermodynamic activity
US4761501A (en) * 1983-10-26 1988-08-02 American Home Products Corporation Substituted phenylacetamides
US4765989A (en) * 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
US4783337A (en) * 1983-05-11 1988-11-08 Alza Corporation Osmotic system comprising plurality of members for dispensing drug
US4842867A (en) * 1986-05-09 1989-06-27 Alza Corporation Pulsed drug delivery of doxylamine
US4863744A (en) * 1984-09-17 1989-09-05 Alza Corporation Intestine drug delivery
US4946687A (en) * 1987-10-02 1990-08-07 Alza Corporation Dosage form for treating cardiovascular diseases
US4948592A (en) * 1986-05-09 1990-08-14 Alza Corporation Pulsed drug delivery
US4950486A (en) * 1987-10-02 1990-08-21 Alza Corporation Dosage form for treating cardiovascular diseases
US4966769A (en) * 1988-06-02 1990-10-30 Alza Corporation Method for delivering dosage form for diltiazem
US5190765A (en) * 1991-06-27 1993-03-02 Alza Corporation Therapy delayed
US5407676A (en) * 1990-12-14 1995-04-18 Fuisz Technologies Ltd. Hydrophilic form of perfluoro compounds and a method of manufacture
US6440457B1 (en) * 1993-05-27 2002-08-27 Alza Corporation Method of administering antidepressant dosage form

Family Cites Families (175)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2738303A (en) 1952-07-18 1956-03-13 Smith Kline French Lab Sympathomimetic preparation
US2996431A (en) 1953-12-16 1961-08-15 Barry Richard Henry Friable tablet and process for manufacturing same
US2921883A (en) * 1957-05-03 1960-01-19 Smith Kline French Lab Novel coating material for medicaments
US2928770A (en) * 1958-11-28 1960-03-15 Frank M Bardani Sustained action pill
NL265428A (en) * 1960-06-06
US3139383A (en) 1961-06-26 1964-06-30 Norton Co Encapsulated time release pellets and method for encapsulating the same
US3634584A (en) * 1969-02-13 1972-01-11 American Home Prod Sustained action dosage form
US3598122A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3554905A (en) * 1969-04-01 1971-01-12 Dow Chemical Co Process for treating water with a polyhalide resin using a semipermeable membrane barrier
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US3870790A (en) * 1970-01-22 1975-03-11 Forest Laboratories Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose
US3625214A (en) 1970-05-18 1971-12-07 Alza Corp Drug-delivery device
US3865108A (en) 1971-05-17 1975-02-11 Ortho Pharma Corp Expandable drug delivery device
US3962414A (en) 1972-04-27 1976-06-08 Alza Corporation Structured bioerodible drug delivery device
DE2254043C2 (en) 1972-11-04 1985-01-24 Hoechst Ag, 6230 Frankfurt LH-releasing hormone for nasal application
US3811444A (en) 1972-12-27 1974-05-21 Alza Corp Bioerodible ocular device
US4138474A (en) * 1973-05-01 1979-02-06 Wisconsin Alumni Research Foundation Method and device for immunoassay
DE2336218C3 (en) 1973-07-17 1985-11-14 Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Oral dosage form
US3992518A (en) 1974-10-24 1976-11-16 G. D. Searle & Co. Method for making a microsealed delivery device
US4093708A (en) * 1974-12-23 1978-06-06 Alza Corporation Osmotic releasing device having a plurality of release rate patterns
US4093709A (en) 1975-01-28 1978-06-06 Alza Corporation Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates)
US4036228A (en) 1975-09-11 1977-07-19 Alza Corporation Osmotic dispenser with gas generating means
US4029757A (en) 1975-12-15 1977-06-14 Hoffmann-La Roche Inc. Manufacture of pharmaceutical unit dosage forms
US4197289A (en) 1975-12-15 1980-04-08 Hoffmann-La Roche Inc. Novel dosage forms
US4008719A (en) * 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4014334A (en) * 1976-02-02 1977-03-29 Alza Corporation Laminated osmotic system for dispensing beneficial agent
US4140755A (en) * 1976-02-13 1979-02-20 Hoffmann-La Roche Inc. Sustained release tablet formulations
US4066747A (en) 1976-04-08 1978-01-03 Alza Corporation Polymeric orthoesters housing beneficial drug for controlled release therefrom
US4138471A (en) * 1976-06-01 1979-02-06 J. M. Huber Corporation Process for reducing the polycyclic aromatic hydrocarbon content of carbon black
US4140756A (en) * 1976-06-10 1979-02-20 Mead Johnson & Company Film-coated matrix core tablet
US4070347A (en) 1976-08-16 1978-01-24 Alza Corporation Poly(orthoester) co- and homopolymers and poly(orthocarbonate) co- and homopolymers having carbonyloxy functionality
US4137300A (en) 1976-08-20 1979-01-30 Ciba-Geigy Corporation Sustained action dosage forms
US4138472A (en) * 1976-11-10 1979-02-06 Basf Aktiengesellschaft Process for obtaining coarsely crystalline pure ammonium sulfate
US4256108A (en) * 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
AU520409B2 (en) * 1977-05-25 1982-01-28 Commonwealth Scientific And Industrial Research Organisation Controlled release composition
GB1561204A (en) * 1977-06-01 1980-02-13 Ici Ltd Sustained release pharmaceutical composition
US4138473A (en) * 1977-10-31 1979-02-06 Gieck Joseph F Process for recovering sulfur from sour gas
US4277582A (en) 1978-03-03 1981-07-07 Ciba-Geigy Corporation Water-insoluble hydrophilic copolymers
US4250611A (en) * 1979-04-19 1981-02-17 Alza Corporation Process for making drug delivery device with reservoir
JPS55153715A (en) * 1979-05-18 1980-11-29 Nikken Kagaku Kk Prolonged granule of theophylline
US4248858A (en) * 1979-08-09 1981-02-03 American Home Products Corporation Sustained release pharmaceutical compositions
US4309405A (en) * 1979-08-09 1982-01-05 American Home Products Corporation Sustained release pharmaceutical compositions
US4248857A (en) * 1979-08-09 1981-02-03 American Home Products Corporation Sustained release pharmaceutical compositions
US4259314A (en) * 1979-12-10 1981-03-31 Hans Lowey Method and composition for the preparation of controlled long-acting pharmaceuticals
US4320759A (en) * 1980-04-28 1982-03-23 Alza Corporation Dispenser with diffuser
US4259315A (en) * 1980-06-13 1981-03-31 A. H. Robins Company, Inc. Controlled release potassium dosage form
US4423099A (en) 1980-07-28 1983-12-27 Ciba-Geigy Corporation Membrane modified hydrogels
PH19942A (en) 1980-11-18 1986-08-14 Sintex Inc Microencapsulation of water soluble polypeptides
IE52535B1 (en) 1981-02-16 1987-12-09 Ici Plc Continuous release pharmaceutical compositions
DE3125178A1 (en) 1981-06-26 1983-01-13 Gödecke AG, 1000 Berlin METHOD FOR THE TIMED CONTROL OF THE RELEASE OF ACTIVE SUBSTANCES FROM ACTIVE SUBSTANCE PREPARATIONS, IN PARTICULAR DRUG PREPARATIONS
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4439196A (en) * 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4649043A (en) * 1982-03-22 1987-03-10 Alza Corporation Drug delivery system for delivering a plurality of tiny pills in the gastrointestinal tract
US4434153A (en) * 1982-03-22 1984-02-28 Alza Corporation Drug delivery system comprising a reservoir containing a plurality of tiny pills
US4642233A (en) * 1982-03-22 1987-02-10 Alza Corporation Gastrointestinal drug delivery system comprising a hydrogel reservoir containing a plurality of tiny pills
US4659558A (en) * 1982-03-22 1987-04-21 Alza Corporation Oral delivery system comprising a plurality of tiny pills for delivering drug in the stomach and intestine
EP0094123A3 (en) 1982-05-06 1984-07-25 THE PROCTER & GAMBLE COMPANY Therapeutic granules
IE56324B1 (en) * 1982-12-13 1991-06-19 American Home Prod Phenethylamine derivatives and intermediates therefor
US4535186A (en) 1983-04-19 1985-08-13 American Home Products Corporation 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives
US4721613A (en) 1982-12-13 1988-01-26 Alza Corporation Delivery system comprising means for shielding a multiplicity of reservoirs in selected environment of use
US4576604A (en) * 1983-03-04 1986-03-18 Alza Corporation Osmotic system with instant drug availability
FI831096L (en) 1983-03-30 1984-10-01 Merck & Co Inc BIOLOGISKT LOESLIGT OKULAERT FAST AEMNE.
US5082668A (en) * 1983-05-11 1992-01-21 Alza Corporation Controlled-release system with constant pushing source
NZ206600A (en) * 1983-05-11 1987-01-23 Alza Corp Osmotic drug delivery device
GB8319766D0 (en) * 1983-07-22 1983-08-24 Graham N B Controlled release device
US4732915A (en) * 1983-11-02 1988-03-22 Alza Corporation Process for increasing solubility of drug
US4624945A (en) 1984-03-19 1986-11-25 Alza Corporation Dispensing system with means for increasing delivery of beneficial agent from the system
WO1985004100A1 (en) * 1984-03-21 1985-09-26 American Home Products Corporation Sustained release pharmaceutical capsules
US4749576A (en) 1984-05-10 1988-06-07 Ciba-Geigy Corporation Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use
US4624848A (en) 1984-05-10 1986-11-25 Ciba-Geigy Corporation Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use
DE3419129A1 (en) 1984-05-23 1985-11-28 Bayer Ag, 5090 Leverkusen NIFEDIPINE PREPARATIONS AND METHOD FOR THE PRODUCTION THEREOF
US5182207A (en) * 1984-09-14 1993-01-26 American Cyanamid Company Strains of streptomyces thermoarchaensis
IE58110B1 (en) 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
US5204356A (en) * 1985-07-24 1993-04-20 Glaxo Group Limited Treatment of anxiety
ES8704080A1 (en) 1985-08-23 1987-03-16 Leo Ab Method for producing a pharmaceutical tablet essentially coated with a terpolymer of poly(vinyl chloride), poly(vinyl acetate) and poly(vinyl alcohol)
NL194822C (en) 1985-10-01 2003-04-03 Novartis Ag Preparation for oral administration with controlled release and method for its preparation.
FR2588188B1 (en) 1985-10-04 1988-01-08 Delalande Sa PROGRAMMED RELEASE CINEPAZIDE HYDROSOLUBLE SALT (S) TABLET AND PROCESS FOR PREPARING SAME
US5185456A (en) * 1986-03-12 1993-02-09 American Cyanamid Company Macrolide compounds
US4986987A (en) * 1986-05-09 1991-01-22 Alza Corporation Pulsed drug delivery
GB8613688D0 (en) 1986-06-05 1986-07-09 Euro Celtique Sa Pharmaceutical composition
US4798725A (en) * 1986-06-16 1989-01-17 Norwich Eaton Pharmaceuticals, Inc. Sustained release capsule
US5198447A (en) * 1986-11-21 1993-03-30 Glaxo Group Limited Medicaments
US5202343A (en) * 1986-11-28 1993-04-13 Glaxo Group Limited Tricyclic ketones useful as HT3 -receptor antagonists
US5200414A (en) * 1986-12-17 1993-04-06 Glaxo Group Limited Methods for the treatment of cognitive disorders
US5190954A (en) * 1986-12-17 1993-03-02 Glaxo Group Limited Methods for the treatment of cognitive disorders
US4786503A (en) 1987-04-06 1988-11-22 Alza Corporation Dosage form comprising parallel lamine
US5200193A (en) * 1987-04-22 1993-04-06 Mcneilab, Inc. Pharmaceutical sustained release matrix and process
US4892778A (en) * 1987-05-27 1990-01-09 Alza Corporation Juxtaposed laminated arrangement
US5499979A (en) * 1987-06-25 1996-03-19 Alza Corporation Delivery system comprising kinetic forces
US4874388A (en) 1987-06-25 1989-10-17 Alza Corporation Multi-layer delivery system
US5391381A (en) * 1987-06-25 1995-02-21 Alza Corporation Dispenser capable of delivering plurality of drug units
GB2206046B (en) 1987-06-25 1991-04-03 Alza Corp Multi-unit delivery system
US4915949A (en) * 1987-07-13 1990-04-10 Alza Corporation Dispenser with movable matrix comprising a plurality of tiny pills
US4824675A (en) * 1987-07-13 1989-04-25 Alza Corporation Dispenser with movable matrix comprising a plurality of tiny pills
US4915954A (en) * 1987-09-03 1990-04-10 Alza Corporation Dosage form for delivering a drug at two different rates
US4915953A (en) * 1987-09-03 1990-04-10 Alza Corporation Dosage form for delivering acetaminophen or phenylpropanolamine
US4814181A (en) * 1987-09-03 1989-03-21 Alza Corporation Dosage form comprising fast agent delivery followed by slow agent delivery
US5192777A (en) * 1987-09-11 1993-03-09 American Cyanamid Company Macrolide compounds
CH672887A5 (en) 1987-10-14 1990-01-15 Debiopharm Sa
US4853229A (en) 1987-10-26 1989-08-01 Alza Corporation Method for adminstering tiny pills
US5194407A (en) * 1987-12-16 1993-03-16 Stemcor Corporation Molten metal-resistant ceramic fiber-containing composition
US4904474A (en) * 1988-01-25 1990-02-27 Alza Corporation Delivery of drug to colon by oral disage form
DE3822095A1 (en) 1988-06-30 1990-01-04 Klinge Co Chem Pharm Fab NEW MEDICAMENT FORMULATION AND METHOD FOR THE PRODUCTION THEREOF
US5194464A (en) * 1988-09-27 1993-03-16 Takeda Chemical Industries, Ltd. Enteric film and preparatoin thereof
US5030456A (en) 1988-11-07 1991-07-09 Alza Corporation Dosage form for treating cardiovascular diseases
US5728088A (en) * 1988-12-13 1998-03-17 Alza Corporation Osmotic system for delivery of fluid-sensitive somatotropins to bovine animals
US5196203A (en) * 1989-01-06 1993-03-23 F. H. Faulding & Co. Limited Theophylline dosage form
US5202128A (en) * 1989-01-06 1993-04-13 F. H. Faulding & Co. Limited Sustained release pharmaceutical composition
IL92966A (en) 1989-01-12 1995-07-31 Pfizer Dispensing devices powered by hydrogel
US5019396A (en) * 1989-05-12 1991-05-28 Alza Corporation Delivery dispenser for treating cardiac arrhythmias
JPH035421A (en) * 1989-05-31 1991-01-11 A Baisuke Donald Administering deprenyl drug so as to decrease risk of side effect
US5009895A (en) * 1990-02-02 1991-04-23 Merck & Co., Inc. Sustained release with high and low viscosity HPMC
US5182299A (en) * 1990-03-19 1993-01-26 Brigham And Women's Hospital Treatment of osmotic disturbance with organic osmolytes
US5178866A (en) 1990-03-23 1993-01-12 Alza Corporation Dosage form for delivering drug to the intestine
US5324280A (en) 1990-04-02 1994-06-28 Alza Corporation Osmotic dosage system for delivering a formulation comprising liquid carrier and drug
US5017381A (en) 1990-05-02 1991-05-21 Alza Corporation Multi-unit pulsatile delivery system
GB9012469D0 (en) * 1990-06-05 1990-07-25 Glaxo Group Ltd Medicaments
US5057321A (en) * 1990-06-13 1991-10-15 Alza Corporation Dosage form comprising drug and maltodextrin
US5464631A (en) 1990-06-27 1995-11-07 Warner-Lambert Company Encapsulated dosage forms
US5156850A (en) * 1990-08-31 1992-10-20 Alza Corporation Dosage form for time-varying patterns of drug delivery
US5284662A (en) * 1990-10-01 1994-02-08 Ciba-Geigy Corp. Oral osmotic system for slightly soluble active agents
US5208037A (en) 1991-04-22 1993-05-04 Alza Corporation Dosage forms comprising polymers comprising different molecular weights
US5204116A (en) * 1991-05-01 1993-04-20 Alza Corporation Dosage form providing immediate therapy followed by prolonged therapy
US5160744A (en) * 1991-06-27 1992-11-03 Alza Corporation Verapmil therapy
US5326570A (en) 1991-07-23 1994-07-05 Pharmavene, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US5178867A (en) * 1991-08-19 1993-01-12 Alza Corporation Dosage form for delivering drug in short-time period
US5200194A (en) * 1991-12-18 1993-04-06 Alza Corporation Oral osmotic device
US5294770A (en) 1992-01-14 1994-03-15 Alza Corporation Laser tablet treatment system with dual access to tablet
IT1255522B (en) * 1992-09-24 1995-11-09 Ubaldo Conte COMPRESSED FOR THERAPEUTIC USE SUITABLE FOR SELLING ONE OR MORE ACTIVE SUBSTANCES WITH DIFFERENT SPEEDS
US5869097A (en) * 1992-11-02 1999-02-09 Alza Corporation Method of therapy comprising an osmotic caplet
ATE188375T1 (en) * 1992-11-17 2000-01-15 Yoshitomi Pharmaceutical A SUSTAINED RELEASE MICROBLADE CONTAINING AN ANTIPSYCHOTIC AND METHOD FOR THE PRODUCTION THEREOF
US5512593A (en) 1993-03-02 1996-04-30 John S. Nagle Composition and method of treating depression using natoxone or naltrexone in combination with a serotonin reuptake inhibitor
DE69425453T2 (en) 1993-04-23 2001-04-12 Novartis Ag Drug delivery device with controlled release
US5613958A (en) 1993-05-12 1997-03-25 Pp Holdings Inc. Transdermal delivery systems for the modulated administration of drugs
US6287598B1 (en) 1993-05-28 2001-09-11 Alza Corporation Method for providing sustained antiepileptic therapy
ES2273764T3 (en) 1993-06-28 2007-05-16 Wyeth NEW TREATMENTS THAT USE FENETILAMINE DERIVATIVES.
US5532003A (en) * 1994-01-18 1996-07-02 Alza Corporation Pentoxifylline therapy
US5434631A (en) * 1994-07-21 1995-07-18 Lieberman; Phillip L. Collapsible large screen audiovisual display system
US5718700A (en) 1994-09-20 1998-02-17 Alza Corporation Exit means in dosage form
FR2725623A1 (en) 1994-10-18 1996-04-19 Flamel Tech Sa MEDICINAL AND / OR NUTRITION MICROCAPSULES FOR PER OS ADMINISTRATION
US5513293A (en) 1994-11-29 1996-04-30 At&T Corp. Optical backplane for a telecommunication distribution frame
IL139728A (en) * 1995-01-09 2003-06-24 Penwest Pharmaceuticals Compan Aqueous slurry composition containing microcrystalline cellulose for preparing a pharmaceutical excipient
JP3113793B2 (en) * 1995-05-02 2000-12-04 株式会社エヌ・ティ・ティ ファシリティーズ Air conditioning system
GB9514451D0 (en) 1995-07-14 1995-09-13 Chiroscience Ltd Sustained-release formulation
US5837284A (en) 1995-12-04 1998-11-17 Mehta; Atul M. Delivery of multiple doses of medications
US6274171B1 (en) * 1996-03-25 2001-08-14 American Home Products Corporation Extended release formulation of venlafaxine hydrochloride
US6096339A (en) * 1997-04-04 2000-08-01 Alza Corporation Dosage form, process of making and using same
TW506836B (en) 1996-06-14 2002-10-21 Janssen Pharmaceutica Nv Fast-dissolving galanthamine hydrobromide tablet
JP4393587B2 (en) 1996-08-16 2010-01-06 アルザ コーポレイション Drug administration form for providing an ascending dose of a medicament
CA2264852C (en) 1996-09-30 2005-11-01 Alza Corporation Use of methylphenidate or a pharmaceutically acceptable salt thereof
US6919373B1 (en) 1996-11-12 2005-07-19 Alza Corporation Methods and devices for providing prolonged drug therapy
WO1998023263A1 (en) 1996-11-25 1998-06-04 Alza Corporation Ascending-dose dosage form
MY125870A (en) * 1997-07-25 2006-08-30 Alza Corp Osmotic delivery system flow modulator apparatus and method
EP1014951B1 (en) * 1997-09-09 2004-11-17 ALZA Corporation Pharmaceutical coating composition and method of use
US6039977A (en) * 1997-12-09 2000-03-21 Alza Corporation Pharmaceutical hydrogel formulations, and associated drug delivery devices and methods
JP4215188B2 (en) * 1997-12-22 2009-01-28 インターシア セラピューティクス,インコーポレイティド Rate-regulating membranes for devices that regulate drug delivery
US6551613B1 (en) * 1998-09-08 2003-04-22 Alza Corporation Dosage form comprising therapeutic formulation
US6174547B1 (en) * 1999-07-14 2001-01-16 Alza Corporation Dosage form comprising liquid formulation
HUP0104993A3 (en) * 1998-11-02 2003-02-28 Alza Corp Mountain View Method and device for controlled delivery of active agents
US20050048120A1 (en) * 1998-11-04 2005-03-03 Edgren David Emil Dosage form comprising self-destructive membrane
CA2356860C (en) * 1998-12-31 2006-11-07 Alza Corporation Osmotic delivery system having space efficient piston
US6348494B1 (en) 2000-11-21 2002-02-19 American Home Products Corporation Ethers of o-desmethyl venlafaxine
ATE290365T1 (en) * 1999-12-16 2005-03-15 Alza Corp DOSAGE FORMS WITH A BARRIER LAYER AGAINST LASER ABLATION
KR100734187B1 (en) * 1999-12-21 2007-07-02 알자 코포레이션 Valve for osmotic device
US6572890B2 (en) 2000-01-13 2003-06-03 Osmotica Corp. Osmotic device containing venlafaxine and an anti-psychotic agent
ES2233611T3 (en) * 2000-02-04 2005-06-16 Alza Corporation OSMOTIC DRIVE FLUID DISPENSER.
EP1339449A2 (en) * 2000-11-29 2003-09-03 Durect Corporation Devices and methods for controlled delivery from a drug delivery device
AR040301A1 (en) * 2002-06-28 2005-03-23 Alza Corp EXPANSIBLE OSMOTIC COMPOSITION AND SUSPENSION FOR IMPROVED COATING
US7014636B2 (en) * 2002-11-21 2006-03-21 Alza Corporation Osmotic delivery device having a two-way valve and a dynamically self-adjusting flow channel
CA2534920A1 (en) * 2003-08-06 2005-02-24 Alza Corporation Uniform delivery of topiramate over prolonged period of time with enhanced dispersion formulation
US20060057206A1 (en) * 2004-08-19 2006-03-16 Wong Patrick S Controlled release nanoparticle active agent formulation dosage forms and methods
EP1912622A2 (en) * 2005-08-04 2008-04-23 Alza Corporation Osmotic dosage forms comprising semipermeable membranes with polymer blends providing improved properties
US8852638B2 (en) * 2005-09-30 2014-10-07 Durect Corporation Sustained release small molecule drug formulation
WO2007041079A2 (en) * 2005-09-30 2007-04-12 Alza Corporation Banded controlled release nanoparticle active agent formulation dosage forms and methods

Patent Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2799241A (en) * 1949-01-21 1957-07-16 Wisconsin Alumni Res Found Means for applying coatings to tablets or the like
US3173876A (en) * 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
US3133132A (en) * 1960-11-29 1964-05-12 Univ California High flow porous membranes for separating water from saline solutions
US3276586A (en) * 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
US3546142A (en) * 1967-01-19 1970-12-08 Amicon Corp Polyelectrolyte structures
US3589123A (en) * 1967-08-21 1971-06-29 Messers Gebruder Junghans Gmbh Signal device for electric alarm clocks
US3589122A (en) * 1968-03-20 1971-06-29 Kienzle Uhrenfabriken Gmbh Electrodynamic oscillator
US3541006A (en) * 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
US3541005A (en) * 1969-02-05 1970-11-17 Amicon Corp Continuous ultrafiltration of macromolecular solutions
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4088864A (en) * 1974-11-18 1978-05-09 Alza Corporation Process for forming outlet passageways in pills using a laser
US4160020A (en) * 1975-11-24 1979-07-03 Alza Corporation Therapeutic device for osmotically dosing at controlled rate
US4063064A (en) * 1976-02-23 1977-12-13 Coherent Radiation Apparatus for tracking moving workpiece by a laser beam
US4111201A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for delivering selected beneficial agents having varying degrees of solubility
US4285987A (en) * 1978-10-23 1981-08-25 Alza Corporation Process for manufacturing device with dispersion zone
US4200098A (en) * 1978-10-23 1980-04-29 Alza Corporation Osmotic system with distribution zone for dispensing beneficial agent
US4327725A (en) * 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4612008A (en) * 1983-05-11 1986-09-16 Alza Corporation Osmotic device with dual thermodynamic activity
US4765989A (en) * 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
US4783337A (en) * 1983-05-11 1988-11-08 Alza Corporation Osmotic system comprising plurality of members for dispensing drug
US4611078A (en) * 1983-10-26 1986-09-09 American Home Products Corporation Substituted phenylacetonitriles
US4761501A (en) * 1983-10-26 1988-08-02 American Home Products Corporation Substituted phenylacetamides
US4535189A (en) * 1984-03-21 1985-08-13 Texaco Inc. Polyol purification process
US4863744A (en) * 1984-09-17 1989-09-05 Alza Corporation Intestine drug delivery
US4842867A (en) * 1986-05-09 1989-06-27 Alza Corporation Pulsed drug delivery of doxylamine
US4948592A (en) * 1986-05-09 1990-08-14 Alza Corporation Pulsed drug delivery
US4946687A (en) * 1987-10-02 1990-08-07 Alza Corporation Dosage form for treating cardiovascular diseases
US4950486A (en) * 1987-10-02 1990-08-21 Alza Corporation Dosage form for treating cardiovascular diseases
US4966769A (en) * 1988-06-02 1990-10-30 Alza Corporation Method for delivering dosage form for diltiazem
US5407676A (en) * 1990-12-14 1995-04-18 Fuisz Technologies Ltd. Hydrophilic form of perfluoro compounds and a method of manufacture
US5190765A (en) * 1991-06-27 1993-03-02 Alza Corporation Therapy delayed
US6440457B1 (en) * 1993-05-27 2002-08-27 Alza Corporation Method of administering antidepressant dosage form

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070077301A1 (en) * 2002-12-23 2007-04-05 Meyer Glenn A Venlafaxine osmotic device formulation

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US20120070496A1 (en) 2012-03-22
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KR960702303A (en) 1996-04-27
CA2157186A1 (en) 1994-12-08
US6440457B1 (en) 2002-08-27
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WO1994027589A2 (en) 1994-12-08
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US20060099263A1 (en) 2006-05-11
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FI955681A (en) 1995-11-24
US20100260810A1 (en) 2010-10-14

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