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发表于 2004-7-21 22:51
Low dose entecavir formulation and use
Abstract
Compositions containing a low dose of entecavir are administered on a daily basis to treat hepatitis B virus infection and/or co-infections. Formulations for the oral administration of a low dose of entecavir are provided. Other pharmaceutically active substances can be included in the entecavir composition or can be separately administered for the treatment of hepatitis B virus infection or for the treatment of co-infected patients.
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Inventors: Colonno; Richard J. (Farmington, CT); Sprockel; Omar L. (Bridgewater, NJ); Harianawala; Abizer (North Brunswick, NJ); Desai; Divyakant (West Windsor, NJ); Fakes; Michael G. (Belle Mead, NJ)
Assignee: Bristol-Myers Squibb Co. (Princeton, NJ)
Appl. No.: 792576
Filed: February 23, 2001
Current U.S. Class: 424/480; 424/451; 424/464; 424/474; 424/482; 424/489; 424/490; 514/770; 514/772.3; 514/774; 514/777; 514/778; 514/781; 514/782; 514/784
Intern'l Class: A61K 009/16; A61K 009/20; A61K 009/28; A61K 009/48
Field of Search: 424/464,465,451,474,475,480,482,489,490
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References Cited [Referenced By]
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U.S. Patent Documents
4489026 Dec., 1984 Yalkowsky 264/123.
4513008 Apr., 1985 Revici et al. 514/560.
4631284 Dec., 1986 Salpekar et al. 514/227.
5206244 Apr., 1993 Zahler et al. 514/262.
5997905 Dec., 1999 McTeigue et al. 424/490.
Foreign Patent Documents
97/37638 Oct., 1997 WO.
98/09964 Mar., 1998 WO.
00/16754 Mar., 2000 WO.
00/16755 Mar., 2000 WO.
00/16779 Mar., 2000 WO.
WO 01/30329 May., 2001 WO.
Other References
Innaimo et al., Antimicrobial Agents and Chemotherapy, vol. 41, No. 7, p. 1444-1448, Jul. 1997.
Seifer et al., Antimicrobial Agents and Chemotherapy, vol. 42, No. 12, p. 3200-3208, Dec. 1998.
Genovesi et al., Antimicrobial Agents and Chemotherapy, vol. 42, No. 12, p. 3209-3217, Dec. 1998.
Yamanaka et al., Antimicrobial Agents And Chemotherapy, vol. 43, No. 1, p. 190-193, Jan. 1999.
Torresi et al., Gastroenterology vol. 118, p. S83-S103, Feb. 2000.
Marion et al., Antiviral Research, vol. 41, No. 2, p. A55, Mar. 1999.
Marion et al., 38.sup.th Interscience Conference on Antimicrobial Agents and Chemotherapy, p. 329, Sep. 24, 1998.
Grasela et al., 37.sup.th Interscience Conference on Antimicrobial Agents and Chemotherapy, p. 219, Sep. 28, 1997.
Goodhart, Journal of Pharmaceutical Sciences, vol. 59, No. 4, p. 540-547, Apr. 1970.
Colonno et al., Hepatology, p. 488A, Oct. 1998.
Bisacchi et al., Bioorganic & Medicinal Chemistry Letters, vol. 7, No. 2, p. 127-132 1997.
Graul et al., Drugs of the Future, vol. 24, No. 11, p. 1173-1177 1999.
DeClercq, International Jour. of Antimicrobial Agents, vol. 12, page 81-95 1999.
Primary Examiner: Spear; James M.
Attorney, Agent or Firm: Davis; Stephen B.
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Parent Case Text
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This application claims priority from Ser. No. 60/185,672 filed Feb. 29, 2000 and Ser. No. 60/221,313 filed Jul. 28, 2000.
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Claims
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What is claimed is:
1. A pharmaceutical composition effective for once a day oral administration to treat hepatitis B virus infection in a human adult patient comprising a pharmaceutically acceptable carrier and from about 0.01 mg to about 5 mg of entecavir.
2. The composition of claim 1 wherein said entecavir is present at about 0.01 mg.
3. The composition of claim 1 wherein said entecavir is present at about 0.05 mg.
4. The composition of claim 1 wherein said entecavir is present at about 0.1 mg.
5. The composition of claim 1 wherein said entecavir is present at about 0.5 mg.
6. The composition of claim 1 wherein said entecavir is present at about 1.0 mg.
7. The composition of claim 1 wherein the form of a tablet or capsule.
8. The composition of claim 1 containing one or more other pharmaceutically active substances.
9. A phramaceutical composition for oral administration of a low dose of entecavir comprising:
from about 0.001 mg to about 10 mg of entecavir adhered to a carrier substrate wherein said carrier substrate is selected from lactose, microcrystalline cellulose, calcium phosphate, dextrin, dextrose, dextrates, mannitol, sorbitol and sucrose, and mixture thereof, and
said entecavir is adhered to said substrate by an adhesive substance which is a polymeric material possessing sufficient tack.
10. The composition of claim 9 wherein:
said adhesive substance is selected from povidone, methylcellulose, hydroxymethylcellulose, hydroxypropyl-methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, and xanthan gum and mixtures thereof.
11. The composition of claim 9 including a lubricant and a disintegrant.
12. The composition of claim 11 wherein:
said lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium lauryl sulfate, and mixtures thereof and said disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, and corn starch and mixtures thereof.
13. A pharmaceutical composition effective for once a day oral administration to treat hepatitis B virus infection in a human patient comprising a pharmaceutically acceptable carrier and about 0.01 mg of entecavir.
14. The composition of claim 13 in the form of a tablet or capsule.
15. The composition of claim 13 containing one or more other pharmaceutically active substances.
16. A pharmaceutical composition for oral administration of a low dose of entecavir comprising entecavir coated by means of an adhesive substance to a carrier substrate, a lubricant, and a disintegrant wherein:
said entecavir is present at from about 0.001 to about 10% by weight of said composition,
said adhesive substance is present at from about 0.01 to about 10% by weight of said composition,
said carrier substrate is present at from about 80 to about 95% by weight of said composition,
said disintegrant is present at from about 1 to about 7% by weight of said composition, and
said lubricant is present at from about 0.1 to about 5% by weight of said composition.
17. A composition of claim 16 wherein:
said adhesive substance is selected from povidone, methylcellulose, hydroxymethylcellulose, hydroxypropyl-methylcellulose, hydroxypropylcellulose, hydroxyethyl-cellulose, gelatin, guar gum, and xanthan gum and mixtures thereof,
said carrier substrate is selected from lactose, microcrystalline cellulose, calcium phosphate, dextrin, dextrose, dextrates, mannitol, sorbitol, and sucrose and mixtures thereof,
said disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, and corn starch, and mixtures thereof, and
said lubricant is selected from magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium lauryl sulfate, and mixtures thereof.
18. A composition of claim 17 wherein:
said adhesive substance is povidone.
19. A composition of claim 17 wherein:
said carrier substrate is microcrystalline cellulose or lactose or mixtures thereof.
20. A composition of claim 17 wherein:
said disintegrant is crospovidone.
21. A composition of claim 17 wherein:
said lubricant is magnesium stearate.
22. The low dose entecavir tablet composition comprising:
about 0.01% entecavir,
about 93.24% microcrystalline cellulose,
about 4.0% crospovidone,
about 2.50% povidone, and
about 0.25% magnesium stearate, said percentages being on a weight/weight basis.
23. The low dose entecavir tablet composition comprising:
about 1.0% entecavir,
about 90.0% mannitol,
about 4.0% croscarmellose sodium,
about 2.50% methyl cellulose, and
about 2.50% stearic acid, said percentages being on a weight/weight basis.
24. The low dose entecavir tablet composition comprising:
about 0.5% entecavir,
about 60.00% lactose monohydrate,
about 32.50% microcrystalline cellulose,
about 4.0% crospovidone,
about 2.50% povidone, and
about 0.50% magnesium stearate, said percentages being on a weight/weight basis.
25. The low dose entecavir tablet composition comprising:
about 0.1% entecavir,
about 60.00% lactose monohydrate,
about 35.39% microcrystalline cellulose,
about 4.0% crospovidone,
about 0.01% povidone, and
about 0.5% magnesium stearate, said percentage being on a weight/weight basis.
26. The low dose entecavir tablet composition comprising:
about 0.25% entecavir,
about 60.25% lactose monohydrate,
about 32.50% microcrystalline cellulose,
about 4.0% crospovidone,
about 2.50% povidone, and
about 0.5% magnesium stearate, said percentages being on a weight/weight basis.
27. The low dose entecavir tablet composition of claim 22 having an outer film coating.
28. The low dose entecavir tablet composition of claim 23 having an outer film coating.
29. The low dose entecavir tablet composition of claim 24 having an outer film coating.
30. The low dose entecavir tablet composition of claim 25 having an outer film coating.
31. The low dose entecavir tablet composition of claim 26 having an outer film coating.
32. The low dose entecavir capsule composition comprising:
about 10.0% entecavir,
about 82.03% microcrystalline cellulose,
about 4.00% crospovidone,
about 2.50% povidone,
about 0.25% magnesium stearate, and about 1.22% hydrochloric acid, said percentages being on a weight/weight basis.
33. The low dose entecavir capsule composition comprising:
about 0.05% entecavir,
about 93.20% dicalcium phosphate,
about 4.00% crospovidone,
about 2.50% hydroxypropyl cellulose, and
about 0.25% magnesium stearate, said percentages being on a weight/weight basis.
34. A pharmaceutical composition effective for once a day oral administration to treat hepatitis B virus infection in a human patient comprising a pharmaceutically acceptable carrier and about 0.05 mg of entecavir.
35. The composition of claim 34 in the form of a tablet or capsule.
36. The composition of claim 34 containing one or more other pharmaceutically active substances.
37. A pharmaceutical composition effective for once a day oral administration to treat hepatitis B virus in a human patient comprising a pharmaceutically acceptable carrier and about 0.1 mg of entecavir.
38. The composition of claim 37 in the form of a tablet or capsule.
39. The method of treating a patient infected with hepatitis B virus infection or co-infected with hepatitis B and another viral or non-viral disease comprising administering a pharmaceutical composition containing from about 0.001 mg to about 25 mg of entecavir on a daily basis.
40. The method of claim 39 wherein:
said pharmaceutical composition administered on a daily basis contains from about 0.01 mg to about 10 mg of entecavir.
41. The method of claim 39 wherein said pharmaceutical composition administered on a daily basis contains from about 0.01 mg to about 5 mg of entecavir.
42. The method of claim 39 wherein said entecavir composition is administered along with a second composition containing one or more antiviral agents and/or one or more immunomodulators.
43. The method of claim 42 wherein said entecavir composition and said second composition are combined into a single dosage form for co-administration.
44. The method of claim 42 wherein said entecavir composition and said second composition are separate dosage forms for a co-administration or sequential administration according to a prescribed schedule.
45. The method of treating a patient infected with hepatitis B virus infection comprising orally administering a pharmaceutical composition containing from about 0.001 mg to about 25 mg of entecavir on a daily basis until the infection is no longer active and then orally administering a pharmaceutical composition containing from about 0.01 mg to about 25 mg of entecavir on a less than daily regimen.
46. A method of preparing a pharmaceutical composition of entecavir for oral administration containing from about 0.001 to about 10% on a weight/weight basis of entecavir comprising:
(a) dissolving said entecavir and an adhesive substance in a solvent wherein said solvent is water or water having an acidic or basic pH,
(b) spraying said solution form step (a) onto a carrier substrate while said carrier substrate is in motion,
(c) drying said coated carrier substrate from step (b) to remove said solvent, and
(d) combining said dried coated carrier substrate from step (c) with other desired ingredients to form said pharmaceutical composition.
47. The method of claim 46 wherein:
said carrier substrate is kept in motion during spraying step (b) by mechanical agitation, and said coated carrier substrate is dried in step (c) in a tray drier or fluidbed drier.
48. The method of claim 46 wherein:
said carrier substrate is kept in motion during spraying step b) by air stream, and said coated carrier substrate is dried in step (c) also by means of air stream agitation.
49. The method of claim 46 wherein said adhesive substance in step (a) is selected from the group consisting of povidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum and mixtures thereof.
50. The composition of claim 37 containing one or more other pharmaceutically active substances.
51. A pharmaceutical composition effective for once a day oral administration to treat hepatitis B virus infection in a human patient comprising a pharmaceutically acceptable carrier and about 0.5 m of entecavir.
52. The composition of claim 51 in the form of a tablet or capsule.
53. The composition of claim 51 containing one or more other pharmaceutically active substances.
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