US5330766A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Sustained release pharmaceutical composition
Assignee: Alpharma Pharmaceuticals LLC
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Filing: 1993-01-21
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Granted: 1994-07-19
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Expires: 2013-01-21
Abstract
Abstract The present invention relates to a pharmaceutical pellet composition having a core element including at least one highly soluble active ingredient and a core coating which is partially soluble at a highly acidic pH. The pharmaceutical composition provides a slow release of active ingredient at a highly acidic pH and provides a constant, relatively faster rate of release at a more alkaline pH such as that of the intestine. Oral administration of the pharmaceutical pellet composition of the present invention to a patient is effective to deliver to the blood levels of active ingredient within the therapeutic range and to maintain such levels over an extended period of time.
Inventors
- 👤 Angelo M. Morella
- 👤 Mark C. Fisher
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-03 10:21
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/48; A61K9/50; A61K9/5005; A61K9/5021; A61K9/5026; A61K9/5031; A61K9/5036; A61K9/5042; A61K9/5047; A61K9/5073; A61K9/5078
Claims Analysis
Total Claims: 24
Claim 1
Independent Claim
286 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing a therapeutically effective amount of at least one active ingredient having an aqueous solubility of at least 1 in 30 and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and contributes to the control of the rate of release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 2
Independent Claim
286 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing a therapeutically effective amount of at least one active ingredient having an aqueous solubility of at least 1 in 30 and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and contributes to the control of the rate of release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 3
Dependent Claim
61 words
The method of claim 1 wherein the active ingredient of high solubility is selected from the group consisting of antihistamines, antibiotics, antituberculosis agents, cholinergic agents, antimuscarinics, sympathomimetics, sympatholytic agents, autonomic drugs, iron preparations, haemostatics, cardiac drugs, antihypertensive agents, non-steroidal antiinflammatory agents, opiate agonists, anticonvulsants, stimulants, sedatives, expectorants, antiemetics, gastrointestinal drugs, heavy metal antagonists, antithyroid agents, genitourinary smooth muscle relaxants and vitamins
Claim 4
Dependent Claim
31 words
The method of claim 2 wherein the active ingredient is an opiate agonist selected from the group consisting of the salts of codeine, dextromoramide, hydrocodone, hydromorphine, pethidine, methadone, morphine and propoxyphene.
Claim 5
Dependent Claim
23 words
The method of claim 3 wherein the composition, in use, minimized fluctuations in the plasma concentration of the active ingredient in said patient.
Claim 6
Dependent Claim
117 words
The method of claim 1 wherein the coating contains: as component (a), a compound selected from the group consisting of ethyl cellulose, a quaternary ammonium acrylic polymer, a quaternary ammonium methacrylic polymer, an acrylic ester copolymer, a methacrylic ester copolymer, and a mixture thereof; as component (b), a compound selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid: acrylic acid ester copolymer, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate and mixtures thereof; and as component (c), a compound selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol having a molecular weight of from 1700 to 20,000, polyvinyl alcohol and monomers therefor and mixtures thereof.
Claim 7
Dependent Claim
30 words
The method of claim 5 wherein the coating comprises: 35 to 75% by weight of component (a); 2-20% by weight of component (b); and 15-40% by weight of component (c).
Claim 8
Dependent Claim
81 words
The method of claim 5 wherein the coating also includes up to 50% of plasticizer selected from diethyl phthalate, triethyl citrate, triethyl acetyl citrate, triethyl acetin, tributyl citrate, polyethylene glycol having a molecular weight of from 200 to less than 1700 or glycerol and up to 75% of a filler selected from silicon dioxide, titanium dioxide, talc, alumina, starch, kaolin, polacrilin potassium, powdered cellulose and microcrystalline cellulose and mixtures thereof, said percentages being based on the total weight of the coating.
Claim 9
Dependent Claim
30 words
The method of claim 7 wherein the coating contains: ______________________________________
component (a) 35 to 70%
component (b) 4 to 20%
component (c) 15 to 35%
plasticizer 4 to 30%.
______________________________________
Claim 10
Independent Claim
281 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing as an active ingredient a therapeutically effective amount of an acid addition salt of morphine and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and contributes to the control of the rate of release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 11
Independent Claim
281 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing as an active ingredient a therapeutically effective amount of an acid addition salt of morphine and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and contributes to the control of the rate of release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 12
Dependent Claim
15 words
The method of claim 9 wherein said acid addition salt of morphine is morphine sulphate.
Claim 13
Dependent Claim
23 words
The method of claim 9 wherein the composition, in use, minimizes fluctuations in the morphine compound concentration in the plasma of said patient.
Claim 14
Dependent Claim
38 words
The method of claim 11 wherein, in use, the time during which the concentration of the morphine compound is greater than or equivalent to 75% of maximum morphine compound concentration in the plasma is at least 3 hours.
Claim 15
Dependent Claim
27 words
The method of claim 9 wherein the rate of release in the intestine is 1.2 to 3 times greater than the rate of release in the stomach.
Claim 16
Dependent Claim
111 words
The method of claim 9 wherein the coating contains: as component (a), a compound selected from the group consisting of ethyl cellulose, a quaternary ammonium acrylic or methacrylic polymer, an acrylic or a methacrylic ester copolymer and a mixture thereof; as component (b), a compound selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid ester copolymer, hydroxypropyl methylcellulose acetate succinate, shellac, cellulose acetate trimellitate and mixtures thereof; and as component (c), a compound selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol having a molecular weight of from 1700 to 20,000, polyvinyl alcohol and monomers therefor and mixtures thereof.
Claim 17
Dependent Claim
30 words
The method of claim 14 wherein the coating comprises: 35 to 75% by weight of component (a); 2-20% by weight of component (b); and 15-40% by weight of component (c).
Claim 18
Dependent Claim
39 words
The method of claim 14 wherein the coating comprises: ______________________________________
polyethylene glycol having a molecular
15 to 40%
weight of from 1700 to 20,000
ethylcellulose 45 to 65%
methacrylic acid: acrylic acid
4 to 20%.
ethylester 1:1 copolymer
______________________________________
Claim 19
Independent Claim
308 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing a therapeutically effective amount of at least one active ingredient having an aqueous solubility of at least 1 in 30 and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and is composed of ethyl cellulose, a quaternary ammonium acrylic or methacrylic polymer, an acrylic or a methacrylic ester copolymer or a mixture thereof which contributes to the control of the release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 20
Independent Claim
308 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing a therapeutically effective amount of at least one active ingredient having an aqueous solubility of at least 1 in 30 and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and is composed of ethyl cellulose, a quaternary ammonium acrylic or methacrylic polymer, an acrylic or a methacrylic ester copolymer or a mixture thereof which contributes to the control of the release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 21
Independent Claim
303 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing as an active ingredient a therapeutically effective amount of an acid addition salt of morphine and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and is composed of ethyl cellulose, a quaternary ammonium acrylic or methacrylic polymer, an acrylic or a methacrylic ester copolymer or a mixture thereof which contributes to the control of the release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 22
Independent Claim
303 words
A method for the preparation of a sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: forming a core element containing as an active ingredient a therapeutically effective amount of an acid addition salt of morphine and coating said core element with an admixture of the following components: (a) from 1 to 85% by weight of a matrix polymer which is insoluble at a pH of from 1 to 7.5 and is composed of ethyl cellulose, a quaternary ammonium acrylic or methacrylic polymer, an acrylic or a methacrylic ester copolymer or a mixture thereof which contributes to the control of the release of the active ingredient in the stomach and intestines; (b) from 1 to 30% of an enteric polymer which is substantially insoluble at a pH of from 1 to 4, sufficient to delay the release of the active ingredient in the stomach, but which is soluble at a pH of from 6 to 7.5 so as not to substantially delay release in the intestines; (c) from 1 to 60% of a compound soluble at a pH of from 1 to 4, sufficient to enable initiation of release of the active ingredient in the stomach; said percentages being by weight based on the total weight of components (a), (b), and (c); the ratio of the components (a), (b), and (c) in said coating being such that a dose of the pellet composition delivers to the patient a therapeutically effective amount of said active ingredient over the course of said predetermined interval, the active ingredient blood level at steady state being at least 75% of maximum blood level for more than approximately 4 hours, and the time for reaching the maximum concentration of the active ingredient being between about 4 and about 30 hours.
Claim 23
Dependent Claim
32 words
The method of claim 1 wherein said core element is coated with said admixture by introducing said core element into a fluidized bed reactor and spraying said admixture on the core element.
Claim 24
Dependent Claim
32 words
The method of claim 9 wherein said core element is coated with said admixture by introducing said core element into a fluidized bed reactor and spraying said admixture on the core element.
References Cited (Backward Citations)
US4806361A
Cited
US5068112A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1997-07-18 | 1998-01-17 | 1998-07-19 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2001-07-18 | 2002-01-17 | 2002-07-19 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2005-07-18 | 2006-01-17 | 2006-07-19 | $7700.00 | Window Closed / Lapsed |