Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-02-23
2003-09-30
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S464000, C424S474000, C424S482000, C424S489000, C424S490000, C514S770000, C514S772300, C514S774000, C514S777000, C514S778000, C514S781000, C514S782000, C514S784000
Reexamination Certificate
active
06627224
ABSTRACT:
BACKGROUND OF THE INVENTION
Entecavir, [1S-(1&agr;,3&agr;,4&bgr;)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one
is an antiviral agent currently undergoing clinical evaluation for the treatment of hepatitis B virus infection.
Entecavir and its use in treating hepatitis B are disclosed by Zahler et al. in U.S. Pat. No. 5,206,244. This patent discloses that an effective antiviral dose for oral or parenteral administration will likely be in the range of about 1.0 to 50 mg/kg of body weight and that the desired dose may be administered several times daily at appropriate intervals.
Improved methods for the synthesis of entecavir are disclosed by Bisacchi et al. in WO 98/09964.
BRIEF SUMMARY OF THE INVENTION
This invention is directed to pharmaceutical compositions containing a low dose of entecavir and the use of such low dose composition to safely and effectively treat hepatitis B virus infection.
This invention is also directed to the treatment of hepatitis B virus infection with a low dose of entecavir in combination with other pharmaceutically active agents. Suitable agents for this purpose include other antiviral agents and/or immunomodulators. The entecavir and the other pharmaceutically active agent or agents can be combined into a single dose form or can be administered from separate dose forms at the same time or sequentially according to a prescribed schedule.
This invention is also directed to pharmaceutical compositions for oral administration containing low doses of a pharmaceutically active substance. This result is achieved by adhering particles of the pharmaceutically active substance to the surface of a carrier substrate. The process of depositing the active substance on the carrier substrate is controlled to minimize the agglomeration of the active substance/carrier substrate particles.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to pharmaceutical compositions containing a low dose of from about 0.001 mg to about 25 mg of the active antiviral agent entecavir for once daily administration to treat hepatitis B virus infection in an adult human patient. Preferred pharmaceutical compositions contain from about 0.01 mg to about 10 mg of entecavir and most preferred pharmaceutical compositions contain from about 0.01 to about 5 mg of entecavir. Such preferred and most preferred pharmaceutical compositions are also administered once daily to treat hepatitis B virus infection in an adult patient.
The term adult human patient is defined as a patient of about 16 years or more of age and a weight equal to or greater than about 50 kilograms. Pharmaceutical compositions containing entecavir at the lower end of the above ranges are suitable for administration to pediatric patients or adult patients weighing less than about 50 kilograms.
The low dose entecavir pharmaceutical compositions described above for daily administration may also be administered to certain patients less often. For example, patients who have been treated by daily administration of the low dose entecavir pharmaceutical compositions so that their hepatitis B virus infection is now under control may be placed on a maintenance regimen to protect against further infection. Such maintenance therapy may involve the administration of the low dose entecavir composition on a less than daily basis. For example, a single dose administered every three or four days or administered on a weekly basis may be sufficient.
The low dose entecavir pharmaceutical compositions of this invention can be formulated for administration by any suitable means. For example, compositions for oral administration, which are preferred, can be in the form of tablets, capsules, granules or powders or in the form of elixirs, solutions or suspensions. The low dose entecavir pharmaceutical compositions may also be formulated for parenteral, rectal, transdermal or nasal administration according to methods well known in the art. Such formulations can include pharmaceutically acceptable excipients including bulking agents, lubricants, disintegrants, binding agents, etc. as commonly employed in such compositions. Sustained release formulations are also within the scope of this invention.
Surprisingly, it has been found that once daily administration of the low dose entecavir pharmaceutical compositions of this invention are effective in treating hepatitis B virus infection without undesirable side effects that can result from administration of the high dose regimen described in U.S. Pat. No. 5,206,244.
This invention is also directed to the treatment of hepatitis B virus infection with low dose entecavir compositions as described above in combination with one or more other pharmaceutically active agents. Suitable pharmaceutically active agents for this purpose include one or more antiviral agents, for example, didanosine, lamivudine, abacavir, adefovir, adefovir dipivoxil, famciclovir, (2R,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-hydroxymethyl-1,3-dioxolane (DAPD), hepatitis B immunomodulating proteins (EHT 899 from Enzo Biochem), emtricitabine, 1-(2-deoxy-2-fluoro-&bgr;-D-arabinofuranosyl) thymine(FMAU), GLQ-223 (Compound A, alpha-trichosanthin), epavudine (L-dT), epcitabine (L-dC), ribavirin, tenofovir (PMPA), 2′,3′-dideoxy-2′,3′-didehydro-beta-L(−)-5-fluorocytidine [L (−)Fd4C], as well as other fluoro L- and D-nucleosides. Suitable pharmaceutically active agents for this purpose also include one or more immunomodulators, for example, alpha interferon, beta interferon, pegylated interferon, thymosin alpha, and hepatitis B vaccines such as HBV/MF59, Hepagene and Theradigm-HBV.
When the other pharmaceutically active agent or agents are suitable for oral administration, they can be combined with the low dose of entecavir into a single tablet or capsule. If the other pharmaceutically active agent or agents are not compatable with entecavir for co-administration from a single dosage form, for example, if the mode of administration is different or if the frequency of administration is different, then the other pharmaceutically active agent or agents will be administered separately. The amount of the other agent or agents administered is that conventionally employed in mono therapy or a reduced amount as determined by the treating physician. The separate dose forms can be administered at the same time or sequentially according to a prescribed schedule.
This invention also includes the treatment of co-infected patients with the low dose entecavir compositions described above. A co-infected patient is one infected with other viral or non-viral diseases in addition to hepatitis B. In particular, such treatment is possible for hepatitis B patients co-infected with hepatitis C or HIV. Such co-infected patients are preferably treated with the low dose entecavir compositions as described above in combination with one or more other pharmaceutically active agents as described above. For example, a patient co-infected with hepatitis B and hepatitis C can be treated with the low dose entecavir composition in addition to being treated with a regimen of ribavirin and an interferon.
Another aspect of this invention is the preparation of pharmaceutical compositions, particularly tablets and capsules, containing entecavir in an amount of less than or equal to about 10 mg. Such compositions cannot be prepared with good content uniformity by simply mixing the active substance and the excipients. The traditional methods of granulation are also not suitable for products active at such low doses.
Tablet and capsule formulations containing from about 0.001 mg to about 10 mg of entecavir are prepared according to the following procedures that ensure high potency and good uniformity of the product. The compositions are prepared by first carefully depositing the entecavir on the surface of carrier substrate particles. This step is accomplished by forming a solution of the entecavir in a solvent along with an adhesive substance at temperatures ranging fro
Colonno Richard J.
Desai Divyakant
Fakes Michael G.
Harianawala Abizer
Sprockel Omar L.
Bristol-Myers Squibb Co.
Davis Stephen B.
Spear James M.
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