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Claims for Patent: 5,370,879

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Claims for Patent: 5,370,879

Title: Formulations and their use in the treatment of neurological diseases
Abstract:Pharmaceutical formulations comprise a mono- or di-aminopyridine active agent for administration on a once- or twice-daily basis for use in the treatment of neurological diseases, in particular multiple sclerosis and Alzheimer's disease. The formulations, which are suitable for oral or percutaneous administration of the active agent, include the active agent in a carrier effective to permit release of the mono- or di-aminopyridine at a rate allowing controlled absorption thereof over, on the average, not less than a 12 hour period and at a rate sufficient to achieve therapeutically effective blood levels over a period of 12-24 hours following administration.
Inventor(s): Masterson; Joseph G. (London, GB), Myers; Michael (Athlone, IE)
Assignee: Elan Corporation, plc (Athlone, IE)
Application Number:08/073,651
Patent Claims: 1. A sustained release pharmaceutical formulation comprising a therapeutically effective amount of a monoaminopyridine for administration on a once- or twice-daily basis, said formulation including the monoaminopyridine in a carrier effective to permit sustained release of said monoaminopyridine at a rate allowing controlled absorption thereof over, on the average, not less than a 12 hour period and at a rate sufficient to ameliorate a neurological disease characterized by a slowing of nerve impulse transmission by achieving therapeutically effective blood levels over a period of 12-24 hours following administration.

2. A pharmaceutical formulation according to claim 1, which comprises a pellet for oral administration, each pellet comprising a core of monoaminopyridine or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable excipient(s), the monoaminopyridine component and the pharmaceutically acceptable excipient(s) being present in a ratio of from 10:1 to 1:20, and a multi-layer membrane surrounding said core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water soluble polymer, the number of layers in said membrane and the ratio of said water soluble to water insoluble polymer, when said water soluble polymer is present, being effective to permit release of said monoaminopyridine from said pellet at a rate allowing controlled absorption thereof over, on the average, not less than a 12 hour period following oral administration, said rate being measured in vitro as a dissolution rate of said pellet, which when measured in a type II dissolution apparatus according to U.S. Pharmacopoeia XXII in water at 50 r.p.m. substantially corresponds to the following:

a) no more than 50% of the total monoaminopyridine is released after 1 hour of measurement in said apparatus;

b) no more than 75% of the total monoaminopyridine is released after 4 hours of measurement in said apparatus; and

c) 100% of the monoaminopyridine is released no earlier than after 8 hours of measurement in said apparatus.

3. A pharmaceutical formulation according to claim 2, wherein the release of monoaminopyridine from said pellet is at a rate allowing controlled absorption thereof over a 24 hour period following oral administration, said rate being measured in a type II dissolution apparatus according to U.S. Pharmacopoeia XXII in water at r.p.m. which substantially corresponds to the following dissolution pattern:

a) from 0 to 40% of the total monoaminopyridine is released after 1 hour of measurement in said apparatus;

b) from 20 to 60% of the total monoaminopyridine is released after 4 hours of measurement in said apparatus;

c) from 30 to 80% of the total monoaminopyridine is released after 8 hours of measurement in said apparatus;

d) from 50 to 90% of the total monoaminopyridine is released after 12 hours of measurement in said apparatus: and

e) not less than 75% of the total monoaminopyridine is released after 24 hours of measurement in said apparatus.

4. A pharmaceutical formulation according to claim 2, wherein the release of monoaminopyridine from said pellet is at a rate allowing controlled absorption thereof over a 12 hour period following oral administration, said rate being measured in a type II dissolution apparatus according to U.S. Pharmacopoeia XXII in water at 50 r.p.m. which substantially corresponds to the following dissolution pattern:

a) from 0 to 40% of the total monoaminopyridine is released after 1 hour of measurement in said apparatus;

b) from 20 to 60% of the total monoaminopyridine is released after 4 hours of measurement in said apparatus;

c) from 30 to 80% of the total monoaminopyridine is released after 8 hours of measurement in said apparatus; and

d) not less than 75% of the total monoaminopyridine is released after 12 hours of measurement in said apparatus.

5. A pharmaceutical formulation according to claim 2, wherein the core comprises:

a) a powder mixture containing a monoaminopyridine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and

b) a polymeric material containing a major proportion of a pharmaceutically acceptable water soluble polymer and a minor proportion of a pharmaceutically acceptable water insoluble polymer,

said core comprising layers of said powder mixture and said polymeric material superimposed one upon the other and said polymeric material being present in an amount effective to ensure that all of said powder mixture is coated into said core.

6. A pharmaceutical formulation according to claim 5, wherein the water soluble polymer in the core or membrane is the same or different and is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, agar, carrageenan, xanthan and polyethylene glycol and mixtures thereof.

7. A pharmaceutical formulation according to claim 5, wherein the water soluble polymer in the core or membrane is replaced by a polymeric material which is freely permeable to monoaminopyridine and water and comprises a copolymer of acrylic and methacrylic acid esters.

8. A pharmaceutical formulation according to claim 5, wherein the water insoluble polymer in the core or membrane is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene oxide), poly(ethylene terephtalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) and polyurethane and mixtures thereof.

9. A pharmaceutical formulation according to claim 5, wherein the water insoluble polymer of the core or membrane is selected from a naturally occurring polymer selected from the group consisting of shellac, chitosan and gum juniper and mixtures thereof.

10. A pharmaceutical formulation according to claim 5, wherein the water insoluble polymer in the core or membrane is replaced by a polymeric material which is slightly permeable to monoaminopyridine and water and comprises a copolymer of acrylic and methacrylic acid esters.

11. A pharmaceutical formulation according to claim 5, wherein the pharmaceutically acceptable excipient(s) and polymeric material are built up on an inert core.

12. A pharmaceutical formulation according to claim 5, wherein the monoaminopyridine, pharmaceutically acceptable excipient(s) and polymeric material are built up on a non-pareil seed of sugar/starch having an average diameter in the range 0.2-1.4 mm.

13. A pharmaceutical formulation according to claim 5, wherein the monoaminopyridine, pharmaceutically acceptable excipient(s) and polymeric material are built up on a central active core.

14. A pharmaceutical formulation according to claim 5, wherein the monoaminopyridine, pharmaceutically acceptable excipient(s) and polymeric material are built up on a central active core formed by blending the monoaminopyridine, pharmaceutically acceptable excipient(s) and polymeric material to form a homogeneous powder, shaping a portion of said blend to form a central core and applying the remainder of said blend alternately or simultaneously with a polymer binding solution to form a layered structure on said central core.

15. A pharmaceutical formulation according to claim 14, wherein the completed cores have an average diameter in the range 0.4-1.6 mm.

16. A controlled absorption monoaminopyridine formulation for oral administration, comprising pellets according to claim 2, said formulation including a sufficient quantity of a rapid release form of monoaminopyridine to ensure prompt achievement of therapeutically effective blood levels together with therapeutically effective blood levels over a 12 to 24 hour period following each oral administration.

17. A controlled absorption monoaminopyridine formulation for oral administration, comprising pellets according to claim 2 and a sufficient quantity of a rapid release form of a monoaminopyridine to ensure prompt achievement of therapeutically effective blood levels together with therapeutically effective blood levels over a 12 to 24 hour period following each oral administration, said formulation having a dissolution rate which when measured in a type II dissolution apparatus according to U.S. Pharmacopoeia XXII in water at 50 r.p.m. substantially corresponds to the following dissolution pattern:

a) from 20 to 60% of the total monoaminopyridine is released after 2 hours of measurement in said apparatus;

b) from 30 to 70% of the total monoaminopyridine is released after 4 hours of measurement in said apparatus;

c) from 50 to 90% of the total monoaminopyridine is released after 8 hours of measurement in said apparatus; and

d) not less than 75% of the total monoaminopyridine is released after 12 hours of measurement in said apparatus.

18. A controlled absorption monoaminopyridine formulation for oral administration, comprising pellets according to claim 2 and a sufficient quantity of a rapid release form of a monoaminopyridine to ensure prompt achievement of therapeutically effective blood levels together with therapeutically effective blood levels over a 24 hour period following each oral administration, said formulation having a dissolution rate which when measured in a type II dissolution apparatus according to U.S. Pharmacopoeia XXII in water and at 50 r.p.m. substantially corresponds to the following dissolution pattern:

a) from 10 to 40% of the total monoaminopyridine is released after 1 hour of measurement in said apparatus;

b) from 25 to 65% of the total monoaminopyridine is released after 4 hours of measurement in said apparatus;

c) from 40 to 80% of the total monoaminopyridine is released after 8 hours of measurement in said apparatus;

d) from 50 to 90% of the total monoaminopyridine is released after 12 hours of measurement in said apparatus; and

e) not less than 75% of the total monoaminopyridine is released after 24 hours of measurement in said apparatus.

19. A controlled absorption monoaminopyridine formulation for oral administration, comprising pellets according to claim 2 and a sufficient quantity of a rapid release form of a monoaminopyridine to ensure prompt achievement of therapeutically effective blood levels together with therapeutically effective blood levels over a 12 hour period following each oral administration, said formulation having a dissolution rate which when measured in a type II dissolution apparatus according to U.S. Pharmacopoeia XXII in water and at 50 r.p.m. substantially corresponds to the following dissolution pattern:

a) from 20 to 50% of the total monoaminopyridine is released after 1 hour of measurement in said apparatus;

b) from 30 to 70% of the total monoaminopyridine is released after 4 hours of measurement in said apparatus;

c) from 40 to 80% of the total monoaminopyridine is released after 8 hours of measurement in said apparatus; and

d) not less than 75% of the total monoaminopyridine is released after 12 hours in said apparatus.

20. A controlled absorption monoaminopyridine formulation, which comprises a blend of pellets according to claim 2, together with up to 60% by weight of a rapid release form of monoaminopyridine.

21. A controlled absorption monoaminopyridine formulation according to claim 2, together with up to 60% by weight of rapid release pellets of a monoaminopyridine.

22. A controlled absorption monoaminopyridine formulation according to claim 2, together with up to 60% by weight of rapid release pellets of a monoaminopyridine, said rapid release pellets comprising a core of monoaminopyridine, or pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable excipient(s), the component and the pharmaceutically acceptable excipient(s) being present in a ratio of from 10:1 to 1:20 and a multi-layer membrane surrounding said core and containing a major proportion of a pharmaceutically acceptable film-forming, water soluble polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water insoluble polymer, the number of layers in said membrane and the ratio of said water soluble to water insoluble polymer being effective to allow relatively immediate release of the active agent from said pellet.

23. A controlled absorption monoaminopyridine formulation according to claim 2, together with up to 60% by weight of rapid release pellets of a monoaminopyridine, said rapid release pellets comprising a core of a monoaminopyridine or pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable excipient(s), the monoaminopyridine component and the pharmaceutically acceptable excipient(s) being present in a ratio of from 10:1 to 1:20 and a multi-layer membrane surrounding said core and containing a major proportion of a pharmaceutically acceptable film-forming, water soluble polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water insoluble polymer, the number of layers in said membrane and the ratio of said water soluble to water insoluble polymer being effective to allow relatively immediate release of the active agent from said pellet, said rapid release pellets having a dissolution rate, which when measured in vitro in a type II dissolution apparatus according to US Pharmacopoeia XXII in water at 50 r.p.m. substantially corresponds to the following dissolution pattern:

a) not less than 70% of the total monoaminopyridine is released after 1 hour of measurement in said apparatus; and

b) not less than 85% of the monoaminopyridine is released after 2 hours of measurement in said apparatus.

24. A formulation according to claim 1, from which the monoaminopyridine active agent is released at a rate allowing controlled absorption thereof over a twenty-four hour period following oral administration, said rate being measured in vivo and having a Tmax between 2 and 16 hours and achieving minimum effective blood levels from 12 to 20 hours over a 24 hour period.

25. A capsule comprising pellets according to claim 2.

26. A tablet formulation comprising pellets according to claim 2.

27. A pharmaceutical formulation according to claim 2, wherein the mono-aminopyridine is 4-aminopyridine.
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