Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-03-02
2001-07-03
Page, Thurman K. (Department: 1615)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C424S489000, C514S220000
Reexamination Certificate
active
06255481
ABSTRACT:
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The invention relates to a novel composition of matter which is a pharmaceutical suspension comprising nevirapine hemihydrate.
(2) Description of the Related Art
Nevirapine, or 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e] [1,4] diazepin-6-one, is a known agent for the treatment of infection by HIV-1 (human immunodeficiency virus, type 1), which acts through specific inhibition of HIV-1 reverse transcriptase. Its synthesis and use are described in various publications including, inter alia, U.S. Pat. No. 5,366,972; European Patent Application No. 0 429 987, U.S. patent application Ser. No. 08/515,093 U.S. Pat. No. 5,571,912 and U.S. patent application Ser. No. 08/371,622 U.S. Pat. No. 5,569,760. Viramune® tablets, a pharmaceutical comprising nevirapine in tablet form, has recently been approved by the U.S. Food and Drug Administration for use in the treatment of HIV-1 infection.
Angel et al. [Proc. 50th Annual Meeting of the Electron Microscopy Society of America, pp. 1326-1327 (1992)] have disclosed that nevirapine exists as the hemihydrate stable form and as the anhydrous metastable form. This same reference describes an attempt to make an aqueous suspension of nevirapine, suitable for pediatric use, from the anhydrous form of the compound. The attempt was unsuccessful because, when formulated in aqueous suspension, the anhydrous nevirapine slowly converted to the hemihydrate form, yielding crystals of the hemihydrate which, over time, grew so large as to adversely affect drug dissolution and pharmaceutical performance.
SUMMARY OF THE INVENTION
The invention is an aqueous suspension of the hemihydrate form of nevirapine. It has been found, unexpectedly, that, when placed in aqueous suspension, the crystal size of the hemihydrate remains stable over time. For this reason, aqueous suspensions of nevirapine hemihydrate are pharmaceutically acceptable.
DETAILED DESCRIPTION OF THE INVENTION
Anhydrous nevirapine can be made by any of several known methods, including those described in the references mentioned above.
The hemihydrate is conveniently produced by recrystallization of the anhydrous material from an aqueous medium. This can be accomplished by treating an aqueous suspension of the anhydrous material, which is a free base, with a strong acid, such as HCl, to yield the acid addition salt. The salt is, in turn, treated with a strong base, such as NaOH, to yield the free base as a precipitate, in the hemihydrate form. The precipitate is removed from the aqueous medium by filtration, washed with water and dried until the water content is between about 3.1 and 3.9% by weight. Further drying, which would convert the hemihydrate to the anhydrous form is to be avoided. The term hemihydrate is intended to refer to nevirapine which contains about 0.5 mole of water.
For use in a pharmaceutically acceptable aqueous suspension, the particle size of the hemihydrate should be between about 1 and 150 microns in diameter. The hemihydrate produced as described above can be milled, if necessary, so that particle size will fall within this range.
A pharmaceutically acceptable aqueous suspension of nevirapine hemihydrate can be made by adding the hemihydrate to purified water, in ratios from 1 to 50 mg nevirapine hemihydrate to 1 mL of water, followed by agitation. The formulation can additionally comprise conventional pharmaceutical additives, such as, but not limited to, suspending agents and/or viscosity thickening agents such as, for example cellulose-based polymers or synthetic polymers, preferably cross-linked polymers such as the carbomers; wetting agents such as, for example, polyethylene oxides or polyoxyethylene sorbitan fatty acid esters (polysorbates); sweetening or flavoring agents, such as sucrose; and preservatives, such as, for example, the parabens.
By way of non-limiting description, a typical formulation in accordance with the invention would be one as described in the following table.
Range of Amount
Constituent
(g/100 mL)
Nevirapine Hemihydrate
0.1-50
Carbomer 934P, NF
0.17-0.22
Polysorbate 80, NF
0.01-0.2
Sorbitol Solution, USP
5-30
Sucrose, NF
5-30
Methylparaben, NF
0.15-0.2
Propylparaben, NF
0.02-0.24
Sodium Hydroxide, N.F.*
q.s. to pH 5.5-6.0
Purified Water, USP
q.s. ad 100.0 mL
*20% solution prepared
REFERENCES:
patent: 5366972 (1994-11-01), Hargrave et al.
Angel, et al; Proc. 50th Annual Meeting of the Electron Microscopy Society of America; pp. 1326-1327; 1992.
Grozinger Karl G.
Hawi Amale A.
Boehringer Ingelheim Pharmaceuticals Inc.
Devlin Mary-Ellen M.
Page Thurman K.
Pulliam Amy E
Raymond Robert P.
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