CA2301042A1 - Micro-osmotic controlled drug delivery systems - Google Patents
Micro-osmotic controlled drug delivery systems Download PDFInfo
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- CA2301042A1 CA2301042A1 CA002301042A CA2301042A CA2301042A1 CA 2301042 A1 CA2301042 A1 CA 2301042A1 CA 002301042 A CA002301042 A CA 002301042A CA 2301042 A CA2301042 A CA 2301042A CA 2301042 A1 CA2301042 A1 CA 2301042A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Abstract
Disclosed herein are compositions and methods related to pharmaceutical compositions that employ a micro-osmotic core for the controlled delivery of a therapeutic agent. The invention particularly relates to therapeutic agents which are present in some portion in a solid state solution in the composition.
Description
WO 99/63971 PCT/US99/132?.3 MICRO-OSMOTIC CONTROLLED DRUG DELIVERY SYSTEMS
BACKGROUND OF THE INVENTION
The invention relates to the field of osmotic release systems for the controlled release of a'therapeutic agent. Osmotic release systems facilitate the controlled release of a medicament from a dosage form based on a change in osmotic pressure in the dosage form. Osmotic release systems are useful for the delivery of both poorly soluble and highly soluble therapeutic agents.
SUMMARY OF THE INVENTION
In accordance with the current invention, a micro-osmotic controlled drug delivery system has been developed. The micro-osmotic system contains the following components: a micro-osmotic core, a drug component, and, optionally, a controlled release matrix and/or coating.
The micro-osmotic core contains at least one osmotic agent and, optionally, a swelling agent and/or a gelling agent. Osmotic agents facilitate the penetration of aqueous biological fluids into the micro-osmotic core. Osmotic agents include, for example, sorbitol, mannitol, xylitol, sodium chloride or any other such highly soluble and pharmaceutically acceptable excipient. Preferred osmotic agents include, for example, the following osmotic agents: spray dried sorbitol, particularly Sorbitol Instant (EM
Industries, Hawthorne, New York), which has a surface area of ~lmZ/g; spray dried mannitol; mannitol with a polymorphic composition (dry state) that contains not less than about 85% of the "8" form of mannitol; a combination of sorbitol-mannitol-xylitol, preferably with sorbitol z 90%, mannitol Z 4%, and xylitol z4%, such as described in DE
. 196 47 282 A1, P96 47 282 - DE and WO 44 39 858, PCTJEP95/04059.
The micro-osmotic core may also optionally comprise a swelling agent. The ' swelling agent expands in volume when contacted by aqueous biological fluids, thereby changing the volume of the micro-osmotic core. A swelling agent preferably is capable
BACKGROUND OF THE INVENTION
The invention relates to the field of osmotic release systems for the controlled release of a'therapeutic agent. Osmotic release systems facilitate the controlled release of a medicament from a dosage form based on a change in osmotic pressure in the dosage form. Osmotic release systems are useful for the delivery of both poorly soluble and highly soluble therapeutic agents.
SUMMARY OF THE INVENTION
In accordance with the current invention, a micro-osmotic controlled drug delivery system has been developed. The micro-osmotic system contains the following components: a micro-osmotic core, a drug component, and, optionally, a controlled release matrix and/or coating.
The micro-osmotic core contains at least one osmotic agent and, optionally, a swelling agent and/or a gelling agent. Osmotic agents facilitate the penetration of aqueous biological fluids into the micro-osmotic core. Osmotic agents include, for example, sorbitol, mannitol, xylitol, sodium chloride or any other such highly soluble and pharmaceutically acceptable excipient. Preferred osmotic agents include, for example, the following osmotic agents: spray dried sorbitol, particularly Sorbitol Instant (EM
Industries, Hawthorne, New York), which has a surface area of ~lmZ/g; spray dried mannitol; mannitol with a polymorphic composition (dry state) that contains not less than about 85% of the "8" form of mannitol; a combination of sorbitol-mannitol-xylitol, preferably with sorbitol z 90%, mannitol Z 4%, and xylitol z4%, such as described in DE
. 196 47 282 A1, P96 47 282 - DE and WO 44 39 858, PCTJEP95/04059.
The micro-osmotic core may also optionally comprise a swelling agent. The ' swelling agent expands in volume when contacted by aqueous biological fluids, thereby changing the volume of the micro-osmotic core. A swelling agent preferably is capable
-2-of swelling to a volume that is many times its volume in the dry state.
Preferred swelling agents include, for example, sodium starch glycollate, crosscarmellose sodium, cellulose, and microcrystalline cellulose.
The micro-osmotic core may also optionally comprise a gelling agent. The S gelling agent functions to maintain the integrity of the swelling agent and thereby functions to maintain the integrity of the micro-osmotic core. The gelling agent is preferably a water soluble polymer. Preferred gelling agents include, for example, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) and its derivatives, gums - tragacanth, accacia, guar, carageenan, and other carbohydrate derived gums, alginic acid and its derivatives, and carbomers.
The micro-osmotic core is in the form of small particles, with diameter ranges of between about 2 ~cm to about 3000 ~cm, preferably 200 ~m about to about 3000 Vim, and more preferably about 200 ~cm to about 1500 ~cm. The particles may be miniature tablets such as, for example, may be formed using a water soluble lubricant such as.PEG 8000.
The micro-osmotic core may also be extruded and spheronized into small spheres and/ or spray agglomerated into particles. The osmotic agent/swelling agent/gelling agent may be combined in weight ratios ranging from 10010/0 to 0.05/99.9/0.05 to 99.9/0.05/0.05 to 0.05/0.05/99.9. Preferred ratios of osmotic agent/swelling agent/gelling agent are the following: 1/8/1, 217/1, 3/6/1, 4/5/1, 6/212, 7/1/2, 8/1/1, 9/0.5/0.5, and 5/4/1.
The micro-osmotic cores of the invention are coated with a drug component to obtain loaded cores. Coated, as used herein, refers to any physical contact between the drug component and the micro-osmotic core. For example, micro-osmotic cores may be fully coated with the drug component, partially coated with the drug component, or impregnated with the drug component. Loaded cores preferably have diameter ranges of between about 2 ~m to about 3000 ~cm, more preferably about 200 ~m to about 3000 Vim, and most preferably about 200 ~cm to about 1500 ~cm. The drug component comprises at least one therapeutic agent. The therapeutic agent in the drug component rnay be, for example, in the form of a solid, a solid-state solution, a solid-state solution-dispersion, a
Preferred swelling agents include, for example, sodium starch glycollate, crosscarmellose sodium, cellulose, and microcrystalline cellulose.
The micro-osmotic core may also optionally comprise a gelling agent. The S gelling agent functions to maintain the integrity of the swelling agent and thereby functions to maintain the integrity of the micro-osmotic core. The gelling agent is preferably a water soluble polymer. Preferred gelling agents include, for example, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) and its derivatives, gums - tragacanth, accacia, guar, carageenan, and other carbohydrate derived gums, alginic acid and its derivatives, and carbomers.
The micro-osmotic core is in the form of small particles, with diameter ranges of between about 2 ~cm to about 3000 ~cm, preferably 200 ~m about to about 3000 Vim, and more preferably about 200 ~cm to about 1500 ~cm. The particles may be miniature tablets such as, for example, may be formed using a water soluble lubricant such as.PEG 8000.
The micro-osmotic core may also be extruded and spheronized into small spheres and/ or spray agglomerated into particles. The osmotic agent/swelling agent/gelling agent may be combined in weight ratios ranging from 10010/0 to 0.05/99.9/0.05 to 99.9/0.05/0.05 to 0.05/0.05/99.9. Preferred ratios of osmotic agent/swelling agent/gelling agent are the following: 1/8/1, 217/1, 3/6/1, 4/5/1, 6/212, 7/1/2, 8/1/1, 9/0.5/0.5, and 5/4/1.
The micro-osmotic cores of the invention are coated with a drug component to obtain loaded cores. Coated, as used herein, refers to any physical contact between the drug component and the micro-osmotic core. For example, micro-osmotic cores may be fully coated with the drug component, partially coated with the drug component, or impregnated with the drug component. Loaded cores preferably have diameter ranges of between about 2 ~m to about 3000 ~cm, more preferably about 200 ~m to about 3000 Vim, and most preferably about 200 ~cm to about 1500 ~cm. The drug component comprises at least one therapeutic agent. The therapeutic agent in the drug component rnay be, for example, in the form of a solid, a solid-state solution, a solid-state solution-dispersion, a
-3-microdisperse system, a solution-suspension (e.g. aqueous, alcoholic, or hydroalcoholic), or any combination thereof. The therapeutic agents may be combined with select excipients andlor binders. The solution-suspension form of the therapeutic agent may optionally include a hydrophilic agent such as HPMC, HPC, PVP, sorbitol, and/or natural gums (for example, accacia) in addition to water, alcohol, or a hydroalcoholic system.
A solid-state solution, as used herein, refers to a solution of the therapeutic agent in solid form. A solid-state solution of the therapeutic agent is characterized by the lack of a melting point peak at the melting point of the therapeutic agent, indicating the absence of the solid state of the therapeutic agent. A solid state solution-dispersion, as used herein, is a system in which part of the therapeutic agent is in the form of a solid-state solution and part of the therapeutic agent is in the form of a finely dispersed solid.
Preferably, greater than 1 % of the total therapeutic agent content exists in solution in the system, in either the solid, semi-solid, or liquid phases. The system is also characterized in that at least one therapeutic agent can exist as a solid dispersion. Any portion of the therapeutic agent which exists as a solid dispersion preferably has a panicle size distribution wherein the diameter of about 90% of the particles is less than aboutl0~.
For a solid-state solution-dispersion, the solubilized therapeutic agent/dispersed therapeutic agent ratio is in a range from 1/99 to 100/0. Preferably, about 30% to about 100 % of the therapeutic agent exists in solution, and more preferably, about 60 %
to about 90 % of the therapeutic agent exists in solution. The ratio of the amount of therapeutic agent present in the form of a solid-state solution to the amount present in the form of solid dispersion can be easily ascertained by the use of techniques in thermal analysis such as Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), and Differential Scanning Microcalorimetry. The crystallinity of the therapeutic agent is easily determined by X-ray diffraction.
One example of a solid-state solution-dispersion system, particularly for therapeutic agents having poor water solubility, comprises a mixture of saturated polyglycolyzed glycerides (for example, Gelucire~, available from Gattefosse),
A solid-state solution, as used herein, refers to a solution of the therapeutic agent in solid form. A solid-state solution of the therapeutic agent is characterized by the lack of a melting point peak at the melting point of the therapeutic agent, indicating the absence of the solid state of the therapeutic agent. A solid state solution-dispersion, as used herein, is a system in which part of the therapeutic agent is in the form of a solid-state solution and part of the therapeutic agent is in the form of a finely dispersed solid.
Preferably, greater than 1 % of the total therapeutic agent content exists in solution in the system, in either the solid, semi-solid, or liquid phases. The system is also characterized in that at least one therapeutic agent can exist as a solid dispersion. Any portion of the therapeutic agent which exists as a solid dispersion preferably has a panicle size distribution wherein the diameter of about 90% of the particles is less than aboutl0~.
For a solid-state solution-dispersion, the solubilized therapeutic agent/dispersed therapeutic agent ratio is in a range from 1/99 to 100/0. Preferably, about 30% to about 100 % of the therapeutic agent exists in solution, and more preferably, about 60 %
to about 90 % of the therapeutic agent exists in solution. The ratio of the amount of therapeutic agent present in the form of a solid-state solution to the amount present in the form of solid dispersion can be easily ascertained by the use of techniques in thermal analysis such as Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), and Differential Scanning Microcalorimetry. The crystallinity of the therapeutic agent is easily determined by X-ray diffraction.
One example of a solid-state solution-dispersion system, particularly for therapeutic agents having poor water solubility, comprises a mixture of saturated polyglycolyzed glycerides (for example, Gelucire~, available from Gattefosse),
-4-polyoxypropylene-polyoxyethylene block copolymer (for example, Pluronic~NF
surfactants, available from BASF), and a therapeutic agent, as described, for example, in U.S. Patent Application No. 09/050913 and in U.S. Provisional Patent Application Nos.
60/080163, 60/085417,60/085333, and 60/092767. The polyglycolyzed glycerides component of the pharmaceutical carrier composition may include all grades of the saturated and unsaturated polyglycolyzed glycerides, preferably polyglycolyzed glycerides with a hydrophilic-lipophilic balance (HLB) > 10. Preferred polyglycolyzed glycerides include, for example, Gelucire ~ 44/13 and Gelucire 50/13. The mixture may also include all grades of polyoxypropylene-polyoxyethylene block co-polymer, preferably polyoxypropylene-polyoxyethylene block co-polymers with a HLB > 10. Preferred polyoxypropylene-polyoxyethylene block co-polymers include, for example, Pluronic~ L44, Pluronic~ F68, Pluronic~ F108, and Pluronic~
F127. The polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer may be combined in weight ratios ranging from about 0.10/99.9 to about 99.9/0.10. The preferred ratios are 1/9, 2/8, 3/7, 4/6, 6/4, 7/3, 8/2, 9/1 and
surfactants, available from BASF), and a therapeutic agent, as described, for example, in U.S. Patent Application No. 09/050913 and in U.S. Provisional Patent Application Nos.
60/080163, 60/085417,60/085333, and 60/092767. The polyglycolyzed glycerides component of the pharmaceutical carrier composition may include all grades of the saturated and unsaturated polyglycolyzed glycerides, preferably polyglycolyzed glycerides with a hydrophilic-lipophilic balance (HLB) > 10. Preferred polyglycolyzed glycerides include, for example, Gelucire ~ 44/13 and Gelucire 50/13. The mixture may also include all grades of polyoxypropylene-polyoxyethylene block co-polymer, preferably polyoxypropylene-polyoxyethylene block co-polymers with a HLB > 10. Preferred polyoxypropylene-polyoxyethylene block co-polymers include, for example, Pluronic~ L44, Pluronic~ F68, Pluronic~ F108, and Pluronic~
F127. The polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer may be combined in weight ratios ranging from about 0.10/99.9 to about 99.9/0.10. The preferred ratios are 1/9, 2/8, 3/7, 4/6, 6/4, 7/3, 8/2, 9/1 and
5/5. The combination of saturated polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer preferably has a melting point in the range of about 30°C to about 70°C, and more preferably about 50°C to about 70°C. When a polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer combination is employed, the combination is present in the final composition of the drug component in an amount of about 0.10% to about 99.9%, and preferably about 5% to about 75%.
Therapeutic agents are present in the final composition of the drug component in an amount of about 0.10% to about 99.9%, preferably about 5% to about 75%.
Examples of therapeutic agents that may be used in conjunction with this invention include the following: dihydropyridine compounds, including for example, nifedepine, felodipine, nicardipine; cyclopeptides, including for example cyclosporine;
omperazol; spironolactone; furosemide; terbutaline; riboflavin; gemfibrozi;
indomethacin; ibuprofen; phenytoin; and glyburide. Additionally, any therapeutic agent with an intrinsic solubility of less than about 10.0 g/L and having therapeutic activity in any of the following areas are contemplated as part of this invention: activity in the cardiovascular system; immunosuppressive activity; cholesterol lowering activity; anti-hypertensive activity; anti-epileptic activity; hormonal activity;
hypoglycemic activity; anti-viral activity; anti-histaminic activity; nasal decongestant activity; anti-microbial activity; anti-arrthrytic activity; analgesic activity, anti-mycobacterial, anti-cancer activity, diuretic activity, anti-fungal activity, anti-parasitic activity, activity as a central nervous system (CNS) stimulant, activity as a CNS
depressant, activity as a 5-HT inhibitor, anti-schizophrenia activity, anti-alzheimer activity, anti-psoriatic activity, anti-ulcer activity, activity as a proton pump inhibitor, anti-asthmatic activity, activity as a bronchodialator, and thrombolytic activity. The therapeutic agent may be, for example, a protein, a peptide, a cyclopeptide, a steroid molecule, a vitamin, an oligonucleotide, or any small or large molecule, or any combination of the foregoing.
In addition to the therapeutic agent or agents, the drug component may optionally comprise excipients. Excipients preferably comprise about 5 % to about 95 % by weight of the final composition of the drug component, and more preferably about 10%o to about 70%. Examples of suitable excipients include, but are not limited to, the following: ascorbyl palmitate; tocopheryl acetate; glycerol; glyceryl monooleate; glyceryl monosterate; glyceryl palmitosterate; triglycerides;
diglycerides;
monoglycerides; stearic acid; magnesium stearate, talc, diesters of polyethylene glycol (PEG); monoesters of PEG; polyethylene glycol; glyceryl polyoxyethylene fatty acid esters; glyceryl polyoxyethylene polyethylene glycol fatty acid esters and ethers;
polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives;
polyoxyethylene sorbitan fatty acid esters; polyoxyethylene sterates; polyvinyl alcohol;
sodium starch glycollate; sorbitan fatty acid esters; polyoxyl sterates; polyethylene glycol hydroxysterate; polyoxyethylene alcohols; anionic; cationic; amphiphilic compounds;
lecithins; phospholipids; carbohydrates, including for example, lactose, maltodextrins, sucrose, and starch; polyols, including for example, sorbitol, mannitol, and xylitol;
microcrystalline cellulose; vitamins, including for example, ascorbic acid and
Therapeutic agents are present in the final composition of the drug component in an amount of about 0.10% to about 99.9%, preferably about 5% to about 75%.
Examples of therapeutic agents that may be used in conjunction with this invention include the following: dihydropyridine compounds, including for example, nifedepine, felodipine, nicardipine; cyclopeptides, including for example cyclosporine;
omperazol; spironolactone; furosemide; terbutaline; riboflavin; gemfibrozi;
indomethacin; ibuprofen; phenytoin; and glyburide. Additionally, any therapeutic agent with an intrinsic solubility of less than about 10.0 g/L and having therapeutic activity in any of the following areas are contemplated as part of this invention: activity in the cardiovascular system; immunosuppressive activity; cholesterol lowering activity; anti-hypertensive activity; anti-epileptic activity; hormonal activity;
hypoglycemic activity; anti-viral activity; anti-histaminic activity; nasal decongestant activity; anti-microbial activity; anti-arrthrytic activity; analgesic activity, anti-mycobacterial, anti-cancer activity, diuretic activity, anti-fungal activity, anti-parasitic activity, activity as a central nervous system (CNS) stimulant, activity as a CNS
depressant, activity as a 5-HT inhibitor, anti-schizophrenia activity, anti-alzheimer activity, anti-psoriatic activity, anti-ulcer activity, activity as a proton pump inhibitor, anti-asthmatic activity, activity as a bronchodialator, and thrombolytic activity. The therapeutic agent may be, for example, a protein, a peptide, a cyclopeptide, a steroid molecule, a vitamin, an oligonucleotide, or any small or large molecule, or any combination of the foregoing.
In addition to the therapeutic agent or agents, the drug component may optionally comprise excipients. Excipients preferably comprise about 5 % to about 95 % by weight of the final composition of the drug component, and more preferably about 10%o to about 70%. Examples of suitable excipients include, but are not limited to, the following: ascorbyl palmitate; tocopheryl acetate; glycerol; glyceryl monooleate; glyceryl monosterate; glyceryl palmitosterate; triglycerides;
diglycerides;
monoglycerides; stearic acid; magnesium stearate, talc, diesters of polyethylene glycol (PEG); monoesters of PEG; polyethylene glycol; glyceryl polyoxyethylene fatty acid esters; glyceryl polyoxyethylene polyethylene glycol fatty acid esters and ethers;
polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives;
polyoxyethylene sorbitan fatty acid esters; polyoxyethylene sterates; polyvinyl alcohol;
sodium starch glycollate; sorbitan fatty acid esters; polyoxyl sterates; polyethylene glycol hydroxysterate; polyoxyethylene alcohols; anionic; cationic; amphiphilic compounds;
lecithins; phospholipids; carbohydrates, including for example, lactose, maltodextrins, sucrose, and starch; polyols, including for example, sorbitol, mannitol, and xylitol;
microcrystalline cellulose; vitamins, including for example, ascorbic acid and
-6-niacinamide; bioflavonoids, including for example, quercetin, isoquercetin, naringin, rutin, etc.; and inorganic compounds, including for example, calcium carbonate, dicalcium phosphate, and any combinations of the above mentioned materials.
The micro-osmotic cores that are coated with a drug component (loaded cores), can be either coated with a suitable polymeric coating and/or combined with a polymer matrix system. The polymer coating or the polymer matrix may serve to modify the .
release profile of the therapeutic agent from the loaded cores. The polymer coating may comprise, for example, the following: hydrophilic polymers such as, for example HPMC, HPC, derivatives of cellulose, derivatives of starch, PVP and PVP derivatives, and carbomers; water insoluble polymers such as, for example, ethyl cellulose, cellulose acetate, polymethacrylate polymers (for example, Eudragit~ polymers, ) and pseudolatex dispersions of the above; enteric polymers such as, for example, shellac, cellulose acetate phthalate; plasticizers such as, for example, dibutyl sebecate, triacetin, acetyl tributyl phthalate; and pearlescent pigments such as, for example, the CandurinTM line of pigments (EM Industries, Hawthorne, New York). Coating of the loaded cores can be performed using pharmaceutical techniques that are well known in the art, including techniques such as wurster coating, rotor coating, and/or pan coating.
The polymer matrix comprises at least one hydrophilic polymer such as, for example, cellulose and its derivatives, including, for example, HPMC, HEC, Carbomers (e.g. Carbopol P934, Carbopol P974), and alginic acid and its derivatives. The hydrophilic polymers of the polymer matrix preferably have molecular weights of between about 100 to about 4,000,000. The hydrophilic polymers are also preferably combined with at least one hydration enhancer which allows for faster hydration of the hydrophilic polymer. Hydration enhancers include, for example, sorbitol, mannitol, xylitol, and microcrystalline cellulose, and any combination thereof. A
preferred hydrating enhancer is a specialized spray agglomerated form of sorbitol (commercially available as Sorbitol Instant, EM Industries, Hawthorne, New York) which has a surface area of 1m2/g. Hydrophilic polymers of different molecular weights and different _7_ chemical natures may be combined to achieve the desired release profile for the therapeutic agent.
The loaded cores and the polymer matrix may be dry blended and then granulated by using a suitable solvent (e.g. aqueous and/or organic) and/or processed to form beads or spheres, or compressed into tablets using suitable lubricants. Suitable lubricants for compressing the dry blended mixture of the loaded cores and the polymer matrix include, for example, sodium stearyl fumarate, magnesium sterate, PEG 8000. A flow promoter such as, colloidal silicon dioxide, may also be employed as part of the compression step.
The product from the above processes, which comprises loaded cores, both coated and uncoated, optionally blended with a polymeric matrix to form a dry blend, and optionally further processed to form granules, beads, spheres or tablets, may be further processed into final dosage forms as follows. As one example, granules, spheres, beads or the dry blend may be compressed into tablets, and the tablets may optionally be coated with a polymeric coating to modify the release profile of the therapeutic agent. The polymeric coating is essentially as described above. As another example, beads, spheres, or granules may be coated with a polymeric coating essentially as described above. The coated beads, spheres or granules may then be encapsulated into capsules or compressed into tablets, with the use of suitable pharmaceutical excipients.
It is also contemplated as part of this invention that a final dosage form rnay comprise more than one type of loaded core. For example, loaded cores containing same therapeutic agent but having different release profiles may be incorporated into the final dosage formulation. Different release profiles for loaded cores containing the same therapeutic agent may be obtained, for example, by varying the content of the micro-osmotic core or the polymeric coating of the loaded cored.
Alternatively, loaded cores having different therapeutic agents may also be incorporated into the same final dosage formulation.
The invention also relates to a method of manufacturing a pharmaceutical composition. The method comprises the steps of providing a micro-osmotic core;
_g_ coating the micro-osmotic core with a drug component to form loaded cores, and optionally, formulating the loaded cores into final dosage forms as described above.
The invention also relates to a method for delivering one or more therapeutic agents to a physiologic target site. The method comprises the steps of providing a pharmaceutical composition according to the invention and introducing a pharmaceutically effective amount of the pharmaceutical composition to a physiologic target site. The introduction of the pharmaceutical composition to the physiologic target site may be accomplished, for example, by administration topically, subcutaneously, intramuscularly, intraperitoneally, nasally, pulmonarily, vaginally, rectally, aurally, orally or ocularly. A preferred method for delivering at least one therapeutic agent to a physiologic target site that is contemplated by this invention is through oral delivery.
g~FF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 17.
Figure 2 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 18.
Figure 3 is a graph showing the in vitro release profile of felodipine from tablets f4rmed according to example 19.
Figure 4 i's a graph showing the in vitro release profile of felodipine from tablets formed according to example 20.
Figure S is a graph showing the in vitro release profile of felodipine from tablets formed according to example 21.
Figure 6 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 22.
Figure 7 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 23.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The following ' prefer ed specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure.
EXAMPLES
In the following examples, all parts and percentages are by weight unless otherwise indicated.
For examples 17-23 below, the following components were employed.
1. PruvTM - (sodium stearyl fumarate) (available from Mendell).
2. AvicelT"' PH200 - (microcrystalline cellulose NF) (available from FMC).
3. Sorbitol Instant P300 - (Sorbitol NF) (available from Merck KGaA).
4. MethocelT"s E4M Premium CR - (hydroxypropylmethyl cellulose NF) (available from Dow Chemical).
5. MethocelTM K100 M - (hydroxypropylmethyl cellulose NF) (available from Dow Chemical).
6. TriacetinT"' - (glyceroltriacetate) (available from Spectrum Quality Products).
The micro-osmotic cores that are coated with a drug component (loaded cores), can be either coated with a suitable polymeric coating and/or combined with a polymer matrix system. The polymer coating or the polymer matrix may serve to modify the .
release profile of the therapeutic agent from the loaded cores. The polymer coating may comprise, for example, the following: hydrophilic polymers such as, for example HPMC, HPC, derivatives of cellulose, derivatives of starch, PVP and PVP derivatives, and carbomers; water insoluble polymers such as, for example, ethyl cellulose, cellulose acetate, polymethacrylate polymers (for example, Eudragit~ polymers, ) and pseudolatex dispersions of the above; enteric polymers such as, for example, shellac, cellulose acetate phthalate; plasticizers such as, for example, dibutyl sebecate, triacetin, acetyl tributyl phthalate; and pearlescent pigments such as, for example, the CandurinTM line of pigments (EM Industries, Hawthorne, New York). Coating of the loaded cores can be performed using pharmaceutical techniques that are well known in the art, including techniques such as wurster coating, rotor coating, and/or pan coating.
The polymer matrix comprises at least one hydrophilic polymer such as, for example, cellulose and its derivatives, including, for example, HPMC, HEC, Carbomers (e.g. Carbopol P934, Carbopol P974), and alginic acid and its derivatives. The hydrophilic polymers of the polymer matrix preferably have molecular weights of between about 100 to about 4,000,000. The hydrophilic polymers are also preferably combined with at least one hydration enhancer which allows for faster hydration of the hydrophilic polymer. Hydration enhancers include, for example, sorbitol, mannitol, xylitol, and microcrystalline cellulose, and any combination thereof. A
preferred hydrating enhancer is a specialized spray agglomerated form of sorbitol (commercially available as Sorbitol Instant, EM Industries, Hawthorne, New York) which has a surface area of 1m2/g. Hydrophilic polymers of different molecular weights and different _7_ chemical natures may be combined to achieve the desired release profile for the therapeutic agent.
The loaded cores and the polymer matrix may be dry blended and then granulated by using a suitable solvent (e.g. aqueous and/or organic) and/or processed to form beads or spheres, or compressed into tablets using suitable lubricants. Suitable lubricants for compressing the dry blended mixture of the loaded cores and the polymer matrix include, for example, sodium stearyl fumarate, magnesium sterate, PEG 8000. A flow promoter such as, colloidal silicon dioxide, may also be employed as part of the compression step.
The product from the above processes, which comprises loaded cores, both coated and uncoated, optionally blended with a polymeric matrix to form a dry blend, and optionally further processed to form granules, beads, spheres or tablets, may be further processed into final dosage forms as follows. As one example, granules, spheres, beads or the dry blend may be compressed into tablets, and the tablets may optionally be coated with a polymeric coating to modify the release profile of the therapeutic agent. The polymeric coating is essentially as described above. As another example, beads, spheres, or granules may be coated with a polymeric coating essentially as described above. The coated beads, spheres or granules may then be encapsulated into capsules or compressed into tablets, with the use of suitable pharmaceutical excipients.
It is also contemplated as part of this invention that a final dosage form rnay comprise more than one type of loaded core. For example, loaded cores containing same therapeutic agent but having different release profiles may be incorporated into the final dosage formulation. Different release profiles for loaded cores containing the same therapeutic agent may be obtained, for example, by varying the content of the micro-osmotic core or the polymeric coating of the loaded cored.
Alternatively, loaded cores having different therapeutic agents may also be incorporated into the same final dosage formulation.
The invention also relates to a method of manufacturing a pharmaceutical composition. The method comprises the steps of providing a micro-osmotic core;
_g_ coating the micro-osmotic core with a drug component to form loaded cores, and optionally, formulating the loaded cores into final dosage forms as described above.
The invention also relates to a method for delivering one or more therapeutic agents to a physiologic target site. The method comprises the steps of providing a pharmaceutical composition according to the invention and introducing a pharmaceutically effective amount of the pharmaceutical composition to a physiologic target site. The introduction of the pharmaceutical composition to the physiologic target site may be accomplished, for example, by administration topically, subcutaneously, intramuscularly, intraperitoneally, nasally, pulmonarily, vaginally, rectally, aurally, orally or ocularly. A preferred method for delivering at least one therapeutic agent to a physiologic target site that is contemplated by this invention is through oral delivery.
g~FF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 17.
Figure 2 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 18.
Figure 3 is a graph showing the in vitro release profile of felodipine from tablets f4rmed according to example 19.
Figure 4 i's a graph showing the in vitro release profile of felodipine from tablets formed according to example 20.
Figure S is a graph showing the in vitro release profile of felodipine from tablets formed according to example 21.
Figure 6 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 22.
Figure 7 is a graph showing the in vitro release profile of felodipine from tablets formed according to example 23.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The following ' prefer ed specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure.
EXAMPLES
In the following examples, all parts and percentages are by weight unless otherwise indicated.
For examples 17-23 below, the following components were employed.
1. PruvTM - (sodium stearyl fumarate) (available from Mendell).
2. AvicelT"' PH200 - (microcrystalline cellulose NF) (available from FMC).
3. Sorbitol Instant P300 - (Sorbitol NF) (available from Merck KGaA).
4. MethocelT"s E4M Premium CR - (hydroxypropylmethyl cellulose NF) (available from Dow Chemical).
5. MethocelTM K100 M - (hydroxypropylmethyl cellulose NF) (available from Dow Chemical).
6. TriacetinT"' - (glyceroltriacetate) (available from Spectrum Quality Products).
7. Eudragit~ NE 30 D - (30% aqueous dispersion of polyacrylate copolymers) (available from Roehm).
8. Eudragit~ L 30 D - (30% aqueous dispersion of methacrylic acid/methacrylate copolymers) (available from Roehm).
9. PVP 30 - (polyvinylpyrrolidone, MW: 44,000-54,000) (available as Kollidon~
from BASF)
from BASF)
10. Gelucire~ 50/13 - (saturated polyglycolized glycerides of hydrogenated vegetable oil consisting glycerides and PEG-esters) (available from Gattefosse).
11. Pluronic~ F 68 - (polyoxy propylene-polyoxy ethylene block copolymers) (available from BASF) Example 1: Manufacture of the micro-osmotic cores.
Micro-osmotic cores may be manufactured by any number of techniques known in the art, using a variety of materials. A few of these techniques and materials are as follows:
( 1 ) crystalline or spray agglomerated sorbitol are employed as the micro-osmotic core;
(2) sorbitol, sodium starch glycollate, and HPMC are combined and compressed into miniature tablets (for example, a diameter < 1 mm) using PEG 8000 as a lubricant;
(3) sorbitol powder and sodium starch glycollate are combined, and the mixture is extruded and spheronized into spheres;
(4) sodium starch glycollate is spray agglomerated onto sorbitol.
Micro-osmotic cores may be made using any of the above methods or using any other techniques that are well known in the art, including granulation.
Example 2: Manufacture of the therapeutic agent component as a solid state solution-dispersion.
A mixture of polyglycolyzed glycerides and polyoxypropylene-polyoxyethylene block copolymer are heated to 20°C above the melting point (~50°C). The therapeutic agent is added gradually to the molten mixture. The therapeutic agent is preferably milled to a particle size range such that the diameter of at least about 90%
of the particles is less than about 75 microns. The mixture is maintained at 20°C above the melting point of the polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer mixture. The ratio of the polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer is selected to facilitate solubilization of > 1% and preferably 30-100%
of the therapeutic agent in the mixture.
Example 3: Controlled release tablets containing I~Tifedepine.
_ Ingredients: Quantities {mg/Tab): Application 1. Sorbitol Instant P300 50 osmotic core 2. Nifedepine, USP 90 active 3. Gelucire 50// 3 90 excipient 4. Pluronic F68 90 excipient 5. HPMC E4M CR Grade 300 hydrophillic polymer 6. Sorbitol Instant P30075 hydration enhancer 7. Microcrystalline Cellulose7~ hydration enhancer 8. Magnesium Stearate 6.8 lubricant Sorbitol Instant was used as an osmotic core. Gelucire 50/13, Pluronic F68, and Nifedepine were processed together to yield a drug component having IvTifedepine as the therapeutic agent in a solid state solution-dispersion. The drug component was then spray congealed onto Sorbitol Instant. The loaded cores as manufactured above were blended with a polymeric matrix containing Sorbitol Instant P300, HPMC E4M CR
Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets were obtained by compression of the mixture of the loaded cores with the polymeric formulation.
Example 4: Controlled release tablets containing Felodipine.
Ingredients: Quantities (mglTab):Application:
1. Sorbitol Instant P300SO osmotic agent 2. Sodium starch glycollate20 swelling agent 3. Felodipine, USP 90 active 4. Gelucire SO/13 90 excipient 5. Pluronic F68 90 excipient 6. HPMC E4M CR Grade 300 hydrophillic polymer 7. Sorbitol Instant P30075 hydration enhancer 8. Microcrystalline Cellulose75 hydration enhancer 9. Magnesium Stearate 6.8 lubricant
Micro-osmotic cores may be manufactured by any number of techniques known in the art, using a variety of materials. A few of these techniques and materials are as follows:
( 1 ) crystalline or spray agglomerated sorbitol are employed as the micro-osmotic core;
(2) sorbitol, sodium starch glycollate, and HPMC are combined and compressed into miniature tablets (for example, a diameter < 1 mm) using PEG 8000 as a lubricant;
(3) sorbitol powder and sodium starch glycollate are combined, and the mixture is extruded and spheronized into spheres;
(4) sodium starch glycollate is spray agglomerated onto sorbitol.
Micro-osmotic cores may be made using any of the above methods or using any other techniques that are well known in the art, including granulation.
Example 2: Manufacture of the therapeutic agent component as a solid state solution-dispersion.
A mixture of polyglycolyzed glycerides and polyoxypropylene-polyoxyethylene block copolymer are heated to 20°C above the melting point (~50°C). The therapeutic agent is added gradually to the molten mixture. The therapeutic agent is preferably milled to a particle size range such that the diameter of at least about 90%
of the particles is less than about 75 microns. The mixture is maintained at 20°C above the melting point of the polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer mixture. The ratio of the polyglycolyzed glycerides/polyoxypropylene-polyoxyethylene block co-polymer is selected to facilitate solubilization of > 1% and preferably 30-100%
of the therapeutic agent in the mixture.
Example 3: Controlled release tablets containing I~Tifedepine.
_ Ingredients: Quantities {mg/Tab): Application 1. Sorbitol Instant P300 50 osmotic core 2. Nifedepine, USP 90 active 3. Gelucire 50// 3 90 excipient 4. Pluronic F68 90 excipient 5. HPMC E4M CR Grade 300 hydrophillic polymer 6. Sorbitol Instant P30075 hydration enhancer 7. Microcrystalline Cellulose7~ hydration enhancer 8. Magnesium Stearate 6.8 lubricant Sorbitol Instant was used as an osmotic core. Gelucire 50/13, Pluronic F68, and Nifedepine were processed together to yield a drug component having IvTifedepine as the therapeutic agent in a solid state solution-dispersion. The drug component was then spray congealed onto Sorbitol Instant. The loaded cores as manufactured above were blended with a polymeric matrix containing Sorbitol Instant P300, HPMC E4M CR
Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets were obtained by compression of the mixture of the loaded cores with the polymeric formulation.
Example 4: Controlled release tablets containing Felodipine.
Ingredients: Quantities (mglTab):Application:
1. Sorbitol Instant P300SO osmotic agent 2. Sodium starch glycollate20 swelling agent 3. Felodipine, USP 90 active 4. Gelucire SO/13 90 excipient 5. Pluronic F68 90 excipient 6. HPMC E4M CR Grade 300 hydrophillic polymer 7. Sorbitol Instant P30075 hydration enhancer 8. Microcrystalline Cellulose75 hydration enhancer 9. Magnesium Stearate 6.8 lubricant
-12-Sorbitol Instant P300 and sodium starch glycollate were combined into a micro-osmotic core. Gelucire 50/13, Pluronic F68, and felodipine were combined to yield drug component having felodipine in a solid-state solution. The drug component was then spray congealed onto the micro-osmotic core. The loaded cores as manufactured above S were then blended with Sorbitol Instant P300, HPMC E4M CR Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets were obtained by compression of the mixture of the loaded cores with the polymeric formulation.
Example 5: Controlled release tablets containing Phenytoin.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Phenytoin, USP 95 active 5. Gelucire 50/13 90 excipient 6. Pluronic F68 90 excipient 7. HPMC K100 Grade 300 hydrophillic polymer 8. Sorbitol Instant 150 hydration enhancer 9. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. Gelucire SO/13, Pluronic F68, and Phenytoin are processed together to yield a solid state solution of Phenytoin in the matrix.
This drug system is spray congealed onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC E4M
CR
Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets are , compressed with the above formulation.
Example 6: Controlled release tablets containing indomethacin.
Example 5: Controlled release tablets containing Phenytoin.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Phenytoin, USP 95 active 5. Gelucire 50/13 90 excipient 6. Pluronic F68 90 excipient 7. HPMC K100 Grade 300 hydrophillic polymer 8. Sorbitol Instant 150 hydration enhancer 9. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. Gelucire SO/13, Pluronic F68, and Phenytoin are processed together to yield a solid state solution of Phenytoin in the matrix.
This drug system is spray congealed onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC E4M
CR
Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets are , compressed with the above formulation.
Example 6: Controlled release tablets containing indomethacin.
-13-Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant SO osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Indomethacin, USP 100 active 5. PVP 90 excipient, binder.
6. HPMC K100 Grade 300 hydrophillic polymer 7. Sorbitol Instant 150 hydration enhancer 8. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. PVP, and Indomethacin are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC E4M CR Grade, microcrystalline cellulose, and magnesium IS stearate. Controlled release tablets are compressed with the above formulation.
Example 7: Controlled release tablets containing Chlorpheniramine maleate.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Chlorpheniramine 10 . active maleate 5. PVP 20 excipient, binder 6 HPMC K100 Grade 300 hydrophillic polymer 7. Sorbitol Instant 150 hydration enhancer 8. Microcrystalline 6.8 lubricant Stearate ~
1. Sorbitol Instant SO osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Indomethacin, USP 100 active 5. PVP 90 excipient, binder.
6. HPMC K100 Grade 300 hydrophillic polymer 7. Sorbitol Instant 150 hydration enhancer 8. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. PVP, and Indomethacin are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC E4M CR Grade, microcrystalline cellulose, and magnesium IS stearate. Controlled release tablets are compressed with the above formulation.
Example 7: Controlled release tablets containing Chlorpheniramine maleate.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Chlorpheniramine 10 . active maleate 5. PVP 20 excipient, binder 6 HPMC K100 Grade 300 hydrophillic polymer 7. Sorbitol Instant 150 hydration enhancer 8. Microcrystalline 6.8 lubricant Stearate ~
-14-Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. PVP and chlorpheniramine maleate are processed together to yield a solution in water. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC E4M CR Grade, microcrystalline cellulose, and magnesium stearate. Controlled release tablets are compressed with the above formulation.
Example 8: Controlled release tablets containing Diltiazem hydrochloride.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P300160 osmotic agent 2. Sodium starch glycollate40 swelling agent 3. HPMC E4M 20 gelling agent 4. Diltiazem hydrochloride300 active p~rp 60 excipient, binder 6 Ethyl Cellulose dispersionq.s. hydrophobic polymer 7. Dibutyl sebecate q.s. plasticizer 8. Talc q.s. anti-caking agent Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. PVP and diltiazem hydrochloride are processed together to yield a solution in water. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are coated with ethyl cellulose dispersion plasticized with dibutyl sebecate. Controlled release tablets are compressed with the above formulation.
Example 9: Capsules containing controlled release pellets containing Chlorpheniramine maleate.
Ingredients: Quantities (mg/Tab): Application:
Example 8: Controlled release tablets containing Diltiazem hydrochloride.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P300160 osmotic agent 2. Sodium starch glycollate40 swelling agent 3. HPMC E4M 20 gelling agent 4. Diltiazem hydrochloride300 active p~rp 60 excipient, binder 6 Ethyl Cellulose dispersionq.s. hydrophobic polymer 7. Dibutyl sebecate q.s. plasticizer 8. Talc q.s. anti-caking agent Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. PVP and diltiazem hydrochloride are processed together to yield a solution in water. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are coated with ethyl cellulose dispersion plasticized with dibutyl sebecate. Controlled release tablets are compressed with the above formulation.
Example 9: Capsules containing controlled release pellets containing Chlorpheniramine maleate.
Ingredients: Quantities (mg/Tab): Application:
-15-1. Sorbitol Instant P300SO osmotic agent 2. Sodium starch glycollate20 swelling agent . 3. pVp 10 gelling agent 4. Chlorpheniramine maleate10 active S S. PVP 20 excipient, binder 6 Eudragit RS 30D dispersionq.s. hydrophobic polymer 7. Dibutyl sebacate q.s. plasticizes 8. Talc q.s. anti-caking agent Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together PVP and chlorpheniramine maleate into are processed a micro-osmotic core.
together This drug system is spray coated to onto the micro-yield a solution in water.
osmo tic core. The drug system micro-osmotic cores as manufactured above are coated with Eudragit RS
(polymethacrylate copolymer) dispersion plasticized with dibutyl sebecate. are encapsulated into capsules.
Controlled release pellets Example 10: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab): Application:
1. Sorbitol Instant P30050 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Nifedepine, USP 90 active 5. PVP 90 excipient, binder 6 Locust bean gum - 175 hydrophillic polymer 7. Xanthan Gum 175 hydrophillic polymer 8. Sorbitol Instant P3001 SO hydration enhances 9. Calcium Chloride 25 crosslinking agent 10. Magnesium Stearate 6.8 lubricant
together This drug system is spray coated to onto the micro-yield a solution in water.
osmo tic core. The drug system micro-osmotic cores as manufactured above are coated with Eudragit RS
(polymethacrylate copolymer) dispersion plasticized with dibutyl sebecate. are encapsulated into capsules.
Controlled release pellets Example 10: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab): Application:
1. Sorbitol Instant P30050 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. HPMC E4M 10 gelling agent 4. Nifedepine, USP 90 active 5. PVP 90 excipient, binder 6 Locust bean gum - 175 hydrophillic polymer 7. Xanthan Gum 175 hydrophillic polymer 8. Sorbitol Instant P3001 SO hydration enhances 9. Calcium Chloride 25 crosslinking agent 10. Magnesium Stearate 6.8 lubricant
-16-Sorbitol Instant P300, HPMC E4M and sodium starch glycollate are processed together into a micro-osmotic core. PVP and Nifedepine are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core.
The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, locust bean gum, Xanthan gum, calcium chloride, and finally with magnesium stearate. Controlled release tablets are compressed with the above formulation.
Example 11: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab): Application:
1. Sorbitol Instant P300 50 osmotic agent 2. Sodium starch glycollate 20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P300 150 hydration enhances 7. Ethyl cellulose 100 hydrophobic polymer 8. Triacetin 25 plasticizes 9. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and Nifedepine are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of ethyl cellulose and Triacetin, dried, delumped and finally combined with magnesium stearate.
Controlled release tablets are compressed with the above formulation.
Example 12: Controlled release tablets containing Nifedepine.
The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, locust bean gum, Xanthan gum, calcium chloride, and finally with magnesium stearate. Controlled release tablets are compressed with the above formulation.
Example 11: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab): Application:
1. Sorbitol Instant P300 50 osmotic agent 2. Sodium starch glycollate 20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P300 150 hydration enhances 7. Ethyl cellulose 100 hydrophobic polymer 8. Triacetin 25 plasticizes 9. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and Nifedepine are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of ethyl cellulose and Triacetin, dried, delumped and finally combined with magnesium stearate.
Controlled release tablets are compressed with the above formulation.
Example 12: Controlled release tablets containing Nifedepine.
-17-Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P30050 osmotic agent ' 2. Sodium starch glycollate20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder S. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P300150 hydration enhances 7. Ethyl cellulose 100 hydrophobic polymer 8. Triacetin 25 plasticizes 9. HPMC E4M 10 hydrophillic polymer 10 Magnesium Stearate 6.8 lubricant Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and Nifedepine are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of ethyl cellulose; HPMC E4M, and triacetin, dried, delumped and finally combined with magnesium stearate. Controlled release tablets are compressed with the above formulation.
Example 13: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P30050 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder S. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P3001 SO hydration enhances ~'O 99!63971 PCT/US99/13223
1. Sorbitol Instant P30050 osmotic agent ' 2. Sodium starch glycollate20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder S. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P300150 hydration enhances 7. Ethyl cellulose 100 hydrophobic polymer 8. Triacetin 25 plasticizes 9. HPMC E4M 10 hydrophillic polymer 10 Magnesium Stearate 6.8 lubricant Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and Nifedepine are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of ethyl cellulose; HPMC E4M, and triacetin, dried, delumped and finally combined with magnesium stearate. Controlled release tablets are compressed with the above formulation.
Example 13: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant P30050 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder S. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P3001 SO hydration enhances ~'O 99!63971 PCT/US99/13223
-18-7. Ethyl cellulose 100 hydrophobic polymer 8. Triacetin 25 plasticizer 9. HPMC E4M 10 hydrophillic polymer 10. Magnesium Stearate 6.8 lubricant S Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and Nifedepine are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of ethyl cellulose and triacetin, dried, delumped and finally combined with magnesium stearate.
Controlled release tablets are compressed with the above formulation. These tablets are coated with a semi-permeable polymer coating system composed of ethyl cellulose, HPMC E4M, and triacetin.
Example 14: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant 150 hydration enhancer 7. Eudragit NE 30D 100 hydrophobic polymer 8. Dibutyl sebecate 25 plasticizer 9. HPMC E4M 10 hydrophillic polymer 10. Magnesium Stearate 6.8 lubricant
Controlled release tablets are compressed with the above formulation. These tablets are coated with a semi-permeable polymer coating system composed of ethyl cellulose, HPMC E4M, and triacetin.
Example 14: Controlled release tablets containing Nifedepine.
Ingredients: Quantities (mg/Tab):Application:
1. Sorbitol Instant 50 osmotic agent 2. Sodium starch glycollate20 swelling agent 3. Nifedepine, USP 90 active 4. PVP 90 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant 150 hydration enhancer 7. Eudragit NE 30D 100 hydrophobic polymer 8. Dibutyl sebecate 25 plasticizer 9. HPMC E4M 10 hydrophillic polymer 10. Magnesium Stearate 6.8 lubricant
-19-Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and Nifedepine are processed together to yield a suspension in ethanol. This drug system is spray coated onto the micro-osmotic core. The drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit NE
30D (polymethacrylate copolymer dispersion) and triacetin, dried, delumped and finally combined with magnesium stearate. Controlled release tablets are compressed with the above formulation. These tablets are coated with a semi-permeable polyner coating system composed of Eudragit NE 30D (polymethacrylate copolymer dispersion), HPMC
E4M and Triacetin.
Example 15: Controlled release tablets containing Verapamil hydrochloride.
Ingredients: Quantities (mg/Tab):
Application:
1. Sorbitol Instant P300 220 osmotic agent 2. Sodium starch glycollate 40 swelling agent 3. Verapamil hydrochloride 240 active 4. PVP 60 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P300 50 hydration enhancer 7. Eudragit NE 30D 150 hydrophobic polymer 8. Eudragit L30D . 100 hydrophobic polymer 9 Dibutyl sebecate 75 plasticizer 10. HPMC E4M 10 hydrophillic polymer 11. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300 and sodium late are combined to starch glycol form a micro-osmotic core.
PVP and verapamil hydrochloride are processed together to yield a - solut ion in water. This drug system to the micro-osmotic is spray coated on core. The drug micro-osmotic cores are divided One portion of the drug in two portions. system
30D (polymethacrylate copolymer dispersion) and triacetin, dried, delumped and finally combined with magnesium stearate. Controlled release tablets are compressed with the above formulation. These tablets are coated with a semi-permeable polyner coating system composed of Eudragit NE 30D (polymethacrylate copolymer dispersion), HPMC
E4M and Triacetin.
Example 15: Controlled release tablets containing Verapamil hydrochloride.
Ingredients: Quantities (mg/Tab):
Application:
1. Sorbitol Instant P300 220 osmotic agent 2. Sodium starch glycollate 40 swelling agent 3. Verapamil hydrochloride 240 active 4. PVP 60 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant P300 50 hydration enhancer 7. Eudragit NE 30D 150 hydrophobic polymer 8. Eudragit L30D . 100 hydrophobic polymer 9 Dibutyl sebecate 75 plasticizer 10. HPMC E4M 10 hydrophillic polymer 11. Magnesium Stearate 6.8 lubricant Sorbitol Instant P300 and sodium late are combined to starch glycol form a micro-osmotic core.
PVP and verapamil hydrochloride are processed together to yield a - solut ion in water. This drug system to the micro-osmotic is spray coated on core. The drug micro-osmotic cores are divided One portion of the drug in two portions. system
-20-micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit NE
30D (polymethacrylate copolymer dispersion) and triacetin, dried, and delumped. One portion of the drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit L 30D (polymethacrylate copolymer dispersion) and triacetin, dried, and delumped. Material obtained in steps c and d are combined, blended with magnesium stearate. Controlled Release Tablets are compressed with the above formulation. These tablets are coated with a semi-permeable polymer coating system composed of Eudragit NE 30D (polymethacrylate copolymer dispersion), HPMC E4M, and triacetin.
Example 16: Capsules containing Verapamil hydrochloride.
Ingredients: Quantities (mglTab):Application:
1. Sorbitol Instant 220 osmotic agent 2. Sodium starch glycollate40 swelling agent 3. Verapamil hydrochloride240 active 4, pZrp 6 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant 50 hydration enhancer 7. Eudragit NE 30D 100 hydrophobic polymer 8. Eudragit L30D 150 hydrophobic polymer 9. Dibutyl sebecate 75 plasticizer 10. Talc q.s. anti-caking agent Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and verapamil hydrochloride are processed together to yield a solution in water. This drug system is spray coated onto the micro-osmotic core. The drug micro-osmotic cores are divided into two portions. One portion of the drug system
30D (polymethacrylate copolymer dispersion) and triacetin, dried, and delumped. One portion of the drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit L 30D (polymethacrylate copolymer dispersion) and triacetin, dried, and delumped. Material obtained in steps c and d are combined, blended with magnesium stearate. Controlled Release Tablets are compressed with the above formulation. These tablets are coated with a semi-permeable polymer coating system composed of Eudragit NE 30D (polymethacrylate copolymer dispersion), HPMC E4M, and triacetin.
Example 16: Capsules containing Verapamil hydrochloride.
Ingredients: Quantities (mglTab):Application:
1. Sorbitol Instant 220 osmotic agent 2. Sodium starch glycollate40 swelling agent 3. Verapamil hydrochloride240 active 4, pZrp 6 excipient, binder 5. HPMC K100 Grade 300 hydrophillic polymer 6. Sorbitol Instant 50 hydration enhancer 7. Eudragit NE 30D 100 hydrophobic polymer 8. Eudragit L30D 150 hydrophobic polymer 9. Dibutyl sebecate 75 plasticizer 10. Talc q.s. anti-caking agent Sorbitol Instant P300 and sodium starch glycollate are processed together into a micro-osmotic core. PVP and verapamil hydrochloride are processed together to yield a solution in water. This drug system is spray coated onto the micro-osmotic core. The drug micro-osmotic cores are divided into two portions. One portion of the drug system
-21 -micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade and granulated with a granulating solvent composed of Eudragit NE
' 30D (polymethacrylate copolymer dispersion) and triacetin, dried, and delumped. These granules are then coated with Eudragit L30D (polymethacrylate copolymer) system plasticized with dibutyl sebecate. One portion of the drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade, pelletized and granulated with a granulating solvent composed of Eudragit L
(poIymethacrylate copolymer dispersion) and triacetin, dried, and delumped.
Material obtained in steps c and d are combined, blended with talc and encapsulated into capsules.
For examples 17-23 below, the following Felodipine Matrix component was employed:
Felodipine USP 1.5 g Gelucire 50/I3 1.5 g Pluronic F 68 1.5 g Sorbitol Instant P300 4.Og The Gelucire and Pluronic were melted together. Felodipine was dissolved in the mixture, and the solution was added to Sorbitol Instant P300 while stirring.
The mixture was mixed well and allowed to congeal. The congealed mixture was then passed through a ~ 20 mesh.
Example 17: In vitro release profile of felodipine tablets having a micro-osmotic core.
Excipients mg/tablet Supplier HPMC E4M 112.5 Dow Chemical Sorbitol P300 66 EMI
Avicel PH200 209.48 FMC
' 30D (polymethacrylate copolymer dispersion) and triacetin, dried, and delumped. These granules are then coated with Eudragit L30D (polymethacrylate copolymer) system plasticized with dibutyl sebecate. One portion of the drug system micro-osmotic cores as manufactured above are blended with Sorbitol Instant P300, HPMC K100 Grade, pelletized and granulated with a granulating solvent composed of Eudragit L
(poIymethacrylate copolymer dispersion) and triacetin, dried, and delumped.
Material obtained in steps c and d are combined, blended with talc and encapsulated into capsules.
For examples 17-23 below, the following Felodipine Matrix component was employed:
Felodipine USP 1.5 g Gelucire 50/I3 1.5 g Pluronic F 68 1.5 g Sorbitol Instant P300 4.Og The Gelucire and Pluronic were melted together. Felodipine was dissolved in the mixture, and the solution was added to Sorbitol Instant P300 while stirring.
The mixture was mixed well and allowed to congeal. The congealed mixture was then passed through a ~ 20 mesh.
Example 17: In vitro release profile of felodipine tablets having a micro-osmotic core.
Excipients mg/tablet Supplier HPMC E4M 112.5 Dow Chemical Sorbitol P300 66 EMI
Avicel PH200 209.48 FMC
- 22 -Felodipine Matrix 60.98 EMI
Pruv 1 Mendell The HPMC, SorbitoI Instant, Avicel and the Felodipine Matrix were combined.
Pruv was added to the mixture and the mixture was mixed well. Samples of the mixture (450 mg) were compressed into a tablet using Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized water, with paddle agitation at SO rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 1.
Time (h) t'~' % release s.d.
2 1.41421356 20.43 3.07 4 2 38.56 3.24 6 2.44948974 55.3 3.03 8 2.82842712 70.51 4.22 10 3.16227766 86.79 6.54 12 3.4641 O 162 95.24 1.4 According to the Higuchi Equation: %=Kt"~ + constant:
Tablet r slope intercept felodipine 0.9739667 28.60726 -10.1986 According to the Zero Order Release:
SU8ST1TUTE SHEET (RULE 26)
Pruv 1 Mendell The HPMC, SorbitoI Instant, Avicel and the Felodipine Matrix were combined.
Pruv was added to the mixture and the mixture was mixed well. Samples of the mixture (450 mg) were compressed into a tablet using Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized water, with paddle agitation at SO rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 1.
Time (h) t'~' % release s.d.
2 1.41421356 20.43 3.07 4 2 38.56 3.24 6 2.44948974 55.3 3.03 8 2.82842712 70.51 4.22 10 3.16227766 86.79 6.54 12 3.4641 O 162 95.24 1.4 According to the Higuchi Equation: %=Kt"~ + constant:
Tablet r slope intercept felodipine 0.9739667 28.60726 -10.1986 According to the Zero Order Release:
SU8ST1TUTE SHEET (RULE 26)
- 23 -Tablet r slope intercept felodipine 0.9952701 8.042679 4.148214 Example 18: In vitro release profile of felodipine tablets having a micro-osmotic core.
S Excipients mg/tablet Supplier HPMC E4M Premium I 12.5 Dow Chemical CR
Sorbitol P300 67.5 EMI
Avicel PH200 212.3 FMC
Felodipine Matrix 56.7 EMI
Pruv 1 Mendell The procedures were the same as described for Example 17 above. The results of the measurements are presented in the tables below and in Figure 2.
Time (h) t'n 7-8 KP s.d. 6-7 KP s.d.
release % released 1 ~ 2 1.41 66.59 13.5 59.88 5.33 4 2 88.9 8.13 85.88 2.27 6 2.45 95.87 2.88 99.47 2.57 8 2.83 97.79 3.64 102.06 3.38 10 3.I6 97.46 3.08 101.72 3.42 12 3.46 According to the Higuchi Equation: %=Kt's'- + constant:
SUBSTITUTE SHEET (RULE 26)
S Excipients mg/tablet Supplier HPMC E4M Premium I 12.5 Dow Chemical CR
Sorbitol P300 67.5 EMI
Avicel PH200 212.3 FMC
Felodipine Matrix 56.7 EMI
Pruv 1 Mendell The procedures were the same as described for Example 17 above. The results of the measurements are presented in the tables below and in Figure 2.
Time (h) t'n 7-8 KP s.d. 6-7 KP s.d.
release % released 1 ~ 2 1.41 66.59 13.5 59.88 5.33 4 2 88.9 8.13 85.88 2.27 6 2.45 95.87 2.88 99.47 2.57 8 2.83 97.79 3.64 102.06 3.38 10 3.I6 97.46 3.08 101.72 3.42 12 3.46 According to the Higuchi Equation: %=Kt's'- + constant:
SUBSTITUTE SHEET (RULE 26)
-24-Tablet r slope intercept 7-8 KP 0.98997 40.6174942 3.335371 6-7 KP 0.99881 41.2926417 0.81378 According to the Zero Order Release:
Tablet r slope intercept 7-8 KP 0.91526 15.496 16.352 6-7 KP 0.95079 16.2205 12.646 Example 19: In vitro release profile of felodipine tablets.
Excipients mg/tablet Supplier E4M & K100M formulation:
HPMC E4M 106.88 Dow Chemical HPMC K 1 OOM 5.62 Dow Chemical Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
I S Felodipine Matrix30.36 EMI
Pruv .99 Mendell E4M formulation:
HPMC E4M 112.5 Dow Chemical Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
Felodipine Matrix30.36 EMI
Pruv .99 Mendell SUBSTITUTE SHEET (RULE 26) WO 99/63971 PCT/US991i3223
Tablet r slope intercept 7-8 KP 0.91526 15.496 16.352 6-7 KP 0.95079 16.2205 12.646 Example 19: In vitro release profile of felodipine tablets.
Excipients mg/tablet Supplier E4M & K100M formulation:
HPMC E4M 106.88 Dow Chemical HPMC K 1 OOM 5.62 Dow Chemical Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
I S Felodipine Matrix30.36 EMI
Pruv .99 Mendell E4M formulation:
HPMC E4M 112.5 Dow Chemical Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
Felodipine Matrix30.36 EMI
Pruv .99 Mendell SUBSTITUTE SHEET (RULE 26) WO 99/63971 PCT/US991i3223
- 25 -The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well.
' Samples of the mixture (445 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized water, with paddle agitation at 50 lpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 3.
Time (h) t'n 95% E4M K100 M 100% E4M
&
released s.d % released s.d.
2 1.41 14.63 2.13 15.99 6.15 4 2 41.5 3.86 42.52 7.24 6 2.45 63.26 6.21 64.29 5.4 g 2.83 75.85 6.79 78.23 5.23 IO 3.16 90.14 6.24 88.78 4.66 12 3.46 96.6 6.56 95.92 3.06 According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept E4M & K100M 0.95949 29.55133836 -10.80056 E4M 0.96362 29.5771156 -10.11314 According to the Zero Order Release:
Tablet r slope intercept E4M & K100M 0.99329 10.1065 -1.018
' Samples of the mixture (445 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized water, with paddle agitation at 50 lpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 3.
Time (h) t'n 95% E4M K100 M 100% E4M
&
released s.d % released s.d.
2 1.41 14.63 2.13 15.99 6.15 4 2 41.5 3.86 42.52 7.24 6 2.45 63.26 6.21 64.29 5.4 g 2.83 75.85 6.79 78.23 5.23 IO 3.16 90.14 6.24 88.78 4.66 12 3.46 96.6 6.56 95.92 3.06 According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept E4M & K100M 0.95949 29.55133836 -10.80056 E4M 0.96362 29.5771156 -10.11314 According to the Zero Order Release:
Tablet r slope intercept E4M & K100M 0.99329 10.1065 -1.018
-26-I E4M I 0.99509 ~ 10.238 I -0.746 Example 20: In vitro release profile of felodipine tablets. ' Excipients mg/tablet Supplier HPMC E4M 101.25 Dow Chemical S HPMC K100M 11.25 Dow Chemical Sorbitol P300 73.39 EMI
Avicel PH200 227.76 FMC
Felodipine Matrix30.36 EMI
Pruv .99 Mendell The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (445 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized water, with paddle agitation at 50 rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 4.
Time (h) t'n HydroSolve s.d.
release p 0 0 2 1.41 19.6 3.54 4 2 36.96 2.46 6 2.45 54.39 0 8 2.83 68.86 0.62
Avicel PH200 227.76 FMC
Felodipine Matrix30.36 EMI
Pruv .99 Mendell The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (445 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized water, with paddle agitation at 50 rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 4.
Time (h) t'n HydroSolve s.d.
release p 0 0 2 1.41 19.6 3.54 4 2 36.96 2.46 6 2.45 54.39 0 8 2.83 68.86 0.62
-27-3.16 79.83 3.73 12 3.46 89.04 10.54 According to the Higuchi Equation: %=Kt'a + constant:
Tablet r slope intercept 5 felodipine 0.977973256626.8444051 -8.90112 According to the Zero Order Release:
Tablet r slope intercept tg felodipine 0.9922566 7.49071429 4.8671429 11.3651187 Example 21: In vitro release profile of felodipine tablets.
10 Excipients mg/tablet Supplier K100M formulation:
HPMC K100M 50.75 Dow Chemical Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv .45 Mendell E4M & K100M formulation:
HPMC E4M 40.6 Dow Chemical HPMC K100M 10.15 Dow Chemical Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv .45 Mendell 1v0 99/63971 PCT/US99/13223
Tablet r slope intercept 5 felodipine 0.977973256626.8444051 -8.90112 According to the Zero Order Release:
Tablet r slope intercept tg felodipine 0.9922566 7.49071429 4.8671429 11.3651187 Example 21: In vitro release profile of felodipine tablets.
10 Excipients mg/tablet Supplier K100M formulation:
HPMC K100M 50.75 Dow Chemical Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv .45 Mendell E4M & K100M formulation:
HPMC E4M 40.6 Dow Chemical HPMC K100M 10.15 Dow Chemical Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv .45 Mendell 1v0 99/63971 PCT/US99/13223
-28-The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well. ' Samples of the mixture (203 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile S was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized water, with paddle agitation at 50 rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure S.
Time (h) t'~ K100M E4M & K100M
release s.d % released s.d.
2 1.41421 15.82 2.59 18.64 2.94 4 2 34.46 2.59 46.89 7.64 6 2.44949 57.63 10.31 71.75 5.45 8 2.82843 72.32 9.79 86.44 7.38 1 S 10 3.16228 79.82 10.66 89.83 11.11 According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept KIOOM 0.9598 26.6965209 -9.402476 E4M & K100M I 0.9655 I 31.1539762 I -9.293658 According to the Zero Order Release:
Tablet r slope intercept K100M 0/9977 9.3225 -1.244 '
Time (h) t'~ K100M E4M & K100M
release s.d % released s.d.
2 1.41421 15.82 2.59 18.64 2.94 4 2 34.46 2.59 46.89 7.64 6 2.44949 57.63 10.31 71.75 5.45 8 2.82843 72.32 9.79 86.44 7.38 1 S 10 3.16228 79.82 10.66 89.83 11.11 According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept KIOOM 0.9598 26.6965209 -9.402476 E4M & K100M I 0.9655 I 31.1539762 I -9.293658 According to the Zero Order Release:
Tablet r slope intercept K100M 0/9977 9.3225 -1.244 '
-29-~ E4M & K100M ~ 0.9953 ~ 11.2995 ~ -0.454 Example 22: In vitro release profile of tablets made from hydrosolve.
Formula I (10% Sorbitol) Excipients mg/tablet Supplier HPMC E4M 50.75 Dow Chemical Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv 0.45 Mendell The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (203 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized water, with paddle agitation at 50 rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 6.
Time (h) t'n HydroSolve s.d.
release 2 1.414213562 53.41 3.89 4 2 85.31 6.06 6 2.449489743 98.33 1.76 g 2.828427125 101.75 1.76 ' 9 3 101.75 1.76
Formula I (10% Sorbitol) Excipients mg/tablet Supplier HPMC E4M 50.75 Dow Chemical Sorbitol P300 33.2 EMI
Avicel PH200 103.3 FMC
Felodipine Matrix15.18 EMI
Pruv 0.45 Mendell The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (203 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1 % sodium lauryl sulfate in deionized water, with paddle agitation at 50 rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 6.
Time (h) t'n HydroSolve s.d.
release 2 1.414213562 53.41 3.89 4 2 85.31 6.06 6 2.449489743 98.33 1.76 g 2.828427125 101.75 1.76 ' 9 3 101.75 1.76
-30-I 10 I 3.15227766 I I I
According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept .
Felodipine 0.9907336 38.00593 1.6895071 According to the Zero Order Release:
Tablet r slope intercept Felodipine 0.9261162 12.421 18.076 Example 23: In vitro release profile of felodipine tablets.
Excipients mg/tablet Supplier HPMC E4M 62.19 Dow Chemical Sorbitol P300 30.45 EMI
Avicel PH200 94.73 FMC
Felodipine Matrix15.18 EMI
Pruv 0.45 Mendell The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (203 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized water, with paddle agitation at 50 rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 7.
According to the Higuchi Equation: %=Kt'n + constant:
Tablet r slope intercept .
Felodipine 0.9907336 38.00593 1.6895071 According to the Zero Order Release:
Tablet r slope intercept Felodipine 0.9261162 12.421 18.076 Example 23: In vitro release profile of felodipine tablets.
Excipients mg/tablet Supplier HPMC E4M 62.19 Dow Chemical Sorbitol P300 30.45 EMI
Avicel PH200 94.73 FMC
Felodipine Matrix15.18 EMI
Pruv 0.45 Mendell The HPMCs, Sorbitol Instant, Avicel and the Hydrosolve-Felodipine component were combined. Pruv was added to the mixture and the mixture was mixed well.
Samples of the mixture (203 mg) were compressed into tablets using a Carver Press, with compression at 2 Ton. Each tablet was placed in a basket and the in vitro release profile was measured in a 900 ml solution of 1% sodium lauryl sulfate in deionized water, with paddle agitation at 50 rpm. Samples of the solution were taken at different time points and the absorbence at 362 nm was measured. The results of the measurements are presented in the tables below and in Figure 7.
-31 -Time (h) t'n HydroSolve release 2 I .41421356 20.27 4 2 48.65 6 2.4494897 67.12 According to the Higuchi Equation: %=Kt"~ + constant:
Tablet r slope intercept Felodipine 0.9723567 31.17882739 -9.19942 According to the Zero Order Release:
Tablet r slope intercept Felodipine 0.9897404 9.729285714 3.755238 The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The entire disclosure of all patent applications, patents, and publications cited herein are hereby incorporated by reference.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope WO 99/63971 PCT/iJS99/13223
Tablet r slope intercept Felodipine 0.9723567 31.17882739 -9.19942 According to the Zero Order Release:
Tablet r slope intercept Felodipine 0.9897404 9.729285714 3.755238 The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.
The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The entire disclosure of all patent applications, patents, and publications cited herein are hereby incorporated by reference.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope WO 99/63971 PCT/iJS99/13223
-32-thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions.
Claims (21)
1. A pharmaceutical composition comprising loaded cores comprising micro-osmotic cores having a coating of a drug component thereon, wherein the micro-osmotic cores comprise at least one micro-osmotic agent and, wherein the drug component comprises at least one therapeutic agent.
2. A pharmaceutical composition according to claim 1, wherein at least one micro-osmotic agent is sorbitol, mannitol, xylitol, or sodium chloride.
3. A pharmaceutical composition according to claim 1, wherein the micro-osmotic core further comprises at least one swelling agent or at least one gelling agent.
4. A pharmaceutical composition according to claim 1, wherein the drug component comprises at least a portion of at least one therapeutic agent in a solid-state solution.
5. A pharmaceutical composition according to claim 4, wherein the drug component comprises a polyglycolyzed glycerides component and a polyoxypropylene polyoxyethylene block copolymer component.
6. A pharmaceutical composition according to claim 5, wherein at least portion of at least one therapeutic agent is in a solid state solution in a mixture comprising the polyglycolyzed glycerides component and the polyoxypropylene-polyoxyethylene block co-polymer component.
7. A pharmaceutical composition according to claim 6, wherein the portion of the therapeutic agent in a solid state solution comprises between 30% to 100% of the therapeutic agent in the drug component.
8. A pharmaceutical composition according to claim 6, wherein the loaded cores are coated with a polymeric coating.
9. A pharmaceutical composition according to claim 6, wherein the loaded cores are combined with a polymer matrix.
10. A pharmaceutical composition according to claim 6, wherein the loaded cores are coated with polymeric coating and combined with a polymer matrix.
11. A pharmaceutical composition according to claim 1, wherein the diameter of the loaded cores ranges from 2 µ to 3 mm.
12. A pharmaceutical composition according to claim 6, wherein the therapeutic agent is a dihydropyridine compound.
13. A method of delivering at least one therapeutic agent to a physiologic target site comprising the steps of providing a pharmaceutical composition according to claim 6; and introducing a pharmaceutically effective amount of the pharmaceutical composition to physiologic target site.
14. A method according to claim 13, wherein the physiologic target site is the gastrointestinal tract.
15. A method of delivering at least one therapeutic agent to a physiologic target site comprising the steps of providing a pharmaceutical composition according to claim 7; and introducing a pharmaceutically effective amount of the pharmaceutical composition to physiologic target site.
16. A method according to claim 1, wherein the physiologic target site is the gastrointestinal tract.
17. A method of delivering at least one therapeutic agent to a physiologic target site comprising the steps of providing a pharmaceutical composition according to claim 1; and introducing a pharmaceutically effective amount of the pharmaceutical composition to physiologic target site.
18. A method of formulating a pharmaceutical composition comprising the steps of providing a micro-osmotic core, coating the micro-osmotic core with a drug component.
19. A method according to claim 18, wherein the drug component comprises a mixture of a polyglycolyzed glycerides component and the polyoxypropylene-polyoxyethylene block co-polymer component.
20. A method according to claim 19, wherein at least a portion of at least one therapeutic agent exists in a solid state solution in the mixture.
21. A method according to claim 20, wherein the portion of at least one therapeutic agent comprises 30% to 100%.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8885598P | 1998-06-11 | 1998-06-11 | |
| US60/088,855 | 1998-06-11 | ||
| PCT/US1999/013223 WO1999063971A1 (en) | 1998-06-11 | 1999-06-11 | Micro-osmotic controlled drug delivery systems |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2301042A1 true CA2301042A1 (en) | 1999-12-16 |
Family
ID=22213892
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002301042A Abandoned CA2301042A1 (en) | 1998-06-11 | 1999-06-11 | Micro-osmotic controlled drug delivery systems |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1003485A1 (en) |
| JP (1) | JP2002517431A (en) |
| CN (1) | CN1272785A (en) |
| AU (1) | AU4679999A (en) |
| CA (1) | CA2301042A1 (en) |
| DE (1) | DE1003485T1 (en) |
| WO (1) | WO1999063971A1 (en) |
| ZA (1) | ZA200000610B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10026698A1 (en) | 2000-05-30 | 2001-12-06 | Basf Ag | Self-emulsifying active ingredient formulation and use of this formulation |
| CN101961317A (en) * | 2001-07-06 | 2011-02-02 | 生命周期药物公司 | Controlled agglomeration |
| AR039744A1 (en) * | 2002-06-26 | 2005-03-09 | Alza Corp | METHODS AND DOSAGE FORMS TO INCREASE THE SOLUBILITY OF PHARMACOS COMPOSITIONS FOR CONTROLLED ADMINISTRATION |
| GB0222612D0 (en) * | 2002-09-30 | 2002-11-06 | Univ Gent | Controlled delivery system for bioactive substances |
| US8377952B2 (en) | 2003-08-28 | 2013-02-19 | Abbott Laboratories | Solid pharmaceutical dosage formulation |
| US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
| AU2004291080A1 (en) * | 2003-11-13 | 2005-06-02 | Alza Corporation | Melt blend dispersions comprising a low water solubility drug and an ethylene oxide-propylene oxide block copolymer |
| EP1765292B1 (en) | 2004-06-12 | 2017-10-04 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
| JP2006327943A (en) * | 2005-05-23 | 2006-12-07 | Towa Yakuhin Kk | Taste-masked tablet suppressed with delay of elution over time |
| ES2406939T3 (en) * | 2007-10-19 | 2013-06-10 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutical solid matrix preparation |
| CA2728215A1 (en) | 2008-06-18 | 2010-06-24 | Innovative Biotherapies, Inc. | Methods for enhanced propagation of cells |
| US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
| US20190060325A1 (en) * | 2016-04-08 | 2019-02-28 | Shionogi & Co., Ltd. | Stabilized solid dosage form |
| WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758437A (en) * | 1981-12-23 | 1988-07-19 | Yamanouchi Pharmaceutical Co., Ltd. | Composition for long acting nicardipine preparation and process of producing the composition |
| US5260068A (en) * | 1992-05-04 | 1993-11-09 | Anda Sr Pharmaceuticals Inc. | Multiparticulate pulsatile drug delivery system |
| IE80467B1 (en) * | 1995-07-03 | 1998-07-29 | Elan Corp Plc | Controlled release formulations for poorly soluble drugs |
| HUP9903869A3 (en) * | 1996-06-28 | 2000-07-28 | Schering Corp | Oral composition comprising a triazole antifungal compound |
-
1999
- 1999-06-11 JP JP2000553040A patent/JP2002517431A/en active Pending
- 1999-06-11 AU AU46799/99A patent/AU4679999A/en not_active Abandoned
- 1999-06-11 DE DE1003485T patent/DE1003485T1/en active Pending
- 1999-06-11 WO PCT/US1999/013223 patent/WO1999063971A1/en not_active Application Discontinuation
- 1999-06-11 CN CN99800925A patent/CN1272785A/en active Pending
- 1999-06-11 CA CA002301042A patent/CA2301042A1/en not_active Abandoned
- 1999-06-11 EP EP99930217A patent/EP1003485A1/en not_active Withdrawn
-
2000
- 2000-02-09 ZA ZA200000610A patent/ZA200000610B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1272785A (en) | 2000-11-08 |
| AU4679999A (en) | 1999-12-30 |
| EP1003485A1 (en) | 2000-05-31 |
| JP2002517431A (en) | 2002-06-18 |
| DE1003485T1 (en) | 2000-11-02 |
| WO1999063971B1 (en) | 2000-02-10 |
| ZA200000610B (en) | 2001-06-11 |
| WO1999063971A1 (en) | 1999-12-16 |
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