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Claims for Patent: 5,378,474

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Claims for Patent: 5,378,474

Title: Sustained release pharmaceutical composition
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.
Inventor(s): Morella; Angelo M. (Campbelltown, AU), Fisher; Mark C. (Birkenhead, AU)
Assignee: F. H. Faulding & Co. Limited (Parkside, AU)
Application Number:08/021,276
Patent Claims: 1. A sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: 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 a coating on said core element which comprises 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, so as to maintain an active ingredient blood level at steady state of at least 75% of maximum blood level for more than approximately 4 hours and so that the time at which the active ingredient reaches its maximum concentration is between about 4 and about 30 hours.

2. The sustained release pharmaceutical pellet composition of claim 1 wherein the time at which the active ingredient reaches its maximum concentration is between about 4 and about 12 hours.

3. The sustained release pharmaceutical pellet composition 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, vasodilators, non-steroidal antiinflammatory agents, opiate agonists, anticonvulsants, tranquilizers, stimulants, barbiturates, sedatives, expectorants, antiemetics, gastrointestinal drugs, heavy metal antagonists, antithyroid agents, genitourinary smooth muscle relaxants and vitamins.

4. The sustained release pharmaceutical pellet composition of claim 3 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.

5. The sustained release pharmaceutical pellet composition of claim 1 wherein the active ingredient has a first dissolution profile measured at a pH of from 1 to 4, and a second dissolution profile measured at a pH of about 7.5 and wherein said first and second dissolution profile are each at least equal to the minimum dissolution required to provide substantially the same bio-availability as with an immediate release oral dosage form.

6. The sustained release pharmaceutical pellet composition of claim 5 wherein the composition, in use, minimizes fluctuations in the plasma concentration of the active ingredient in said patient.

7. The sustained release pharmaceutical pellet composition of claim 1 wherein the coating contains:

as component (a), ethyl cellulose, a quaternary ammonium acrylic or methacrylic polymer, an acrylic or a methacrylic ester copolymer or a mixture thereof;

as component (b), 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), 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.

8. The sustained release pharmaceutical pellet composition of claim 7 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).

9. The sustained release pharmaceutical pellet composition of claim 7 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.

10. The sustained release pharmaceutical pellet composition of claim 9 wherein the coating contains:

component (a) 35 to 70%

component (b) 4 to 20%

component (c) 15 to 35%

plasticizer 4 to 30%.

11. A sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: a core element containing as the active ingredient a therapeutically effective amount of an acid addition salt of morphine and a coating on said core element which comprises 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, so as to maintain an active ingredient blood level at steady state of at least 75% of maximum blood level for more than approximately 4 hours and so that the time at which the active ingredient reaches its maximum concentration is between about 4 and about 30 hours.

12. The sustained release pharmaceutical pellet composition of claim 11 wherein the time at which the active ingredient reaches its maximum concentration is between about 4 and about 12 hours.

13. The sustained release pharmaceutical pellet composition of claim 11 wherein said acid addition salt of morphine is morphine sulphate.

14. The sustained release pharmaceutical pellet composition of claim 11 wherein the composition, in use, minimizes fluctuations in the morphine compound concentration in the plasma of said patient.

15. The sustained release pharmaceutical pellet composition of claim 11 wherein the coating contains:

as component (a), ethyl cellulose, a quaternary ammonium acrylic or methacrylic polymer, an acrylic or a methacrylic ester copolymer or a mixture thereof;

as component (b), 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), polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol having a molecular weight of from 1700 to 20,000, polyvinyl alcohol and monomers therefore and mixtures thereof.

16. The sustained release pharmaceutical pellet composition of claim 15 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).

17. The sustained release pharmaceutical pellet composition of claim 15 wherein the coating comprises:

polyethylene glycol having a molecular weight of from 1700 to 20,000 15 to 40%

ethylcellulose 45 to 65%

methacrylic acid: acrylic

acid ethylester 1:1 copolymer 4 to 20%.

18. A sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: 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 a coating on said core element which comprises the following components:

(a) at least 35% 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, so as to maintain an active ingredient blood level at steady state of at least 75% of maximum blood level for more than approximately 4 hours and so that the time at which the active ingredient reaches its maximum concentration is between about 4 and about 30 hours.

19. The sustained release pharmaceutical pellet composition of claim 18 wherein the time at which the active ingredient reaches its maximum concentration is between about 4 and about 12 hours.

20. A sustained release pharmaceutical pellet composition for administration to a patient at a predetermined dosage and interval which comprises: a core element containing as the active ingredient a therapeutically effective amount of an acid addition salt of morphine and a coating on said core element which comprises the following components:

(a) at least 35% 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, so as to maintain an active ingredient blood level at steady state of at least 75% of maximum blood level for more than approximately 4 hours and so that the time at which the active ingredient reaches its maximum concentration is between about 4 and about 30 hours.

21. The sustained release pharmaceutical pellet composition of claim 20 wherein the time at which the active ingredient reaches its maximum concentration is between about 4 and about 12 hours.
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