Crystalline Efavirenz

Details Crystalline Efavirenz Crystalline Efavirenz

1999-06-10

2004-01-06

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S464000

Reexamination Certificate

active

06673372

ABSTRACT:

FIELD OF THE INVENTION
The potent reverse transcriptase inhibitor Efavirenz is produced in crystalline form. Crystalline Efavirenz exists in several physical forms which are designated Forms 1, 2, 3, 4, and 5 and are characterized by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions and methods are useful for the treatment of the human immunodeficiency virus (HIV).
BACKGROUND OF THE INVENTION
Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication.
Efavirenz is a compound which is effective in the treatment of the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase has been shown for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones such as Efavirenz have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. Efavirenz is known by its chemical name, (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one represented in formula (I):
Efavirenz is not only a highly potent reverse transcriptase inhibitor, but is also efficacious against HIV reverse transcriptase resistance. Due to the importance of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a reverse transcriptase inhibitor, crystalline forms which exhibit chemical and physical advantages for manufacture, purification and formulation are necessary.
Treatment or prevention of the foregoing disorders is accomplished by administering a therapeutically effective amount of Efavirenz to a human or animal subject in need of such treatment or prevention. The treatment with Efavirenz may be accomplished by its use as a single compound, as a pharmaceutical composition ingredient, or in combination with other antivirals, immunomodulators, antibiotics and vaccines. The compound may be administered enterally or parenterally in solid or liquid dosage forms.
Efavirenz has not been known previously to exist in stable crystalline polymorphic forms. Accordingly, a need exists for stable crystalline forms of the drug and reliable and reproducible procedures for their manufacture.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to crystalline Efavirenz. A related aspect resides in novel crystalline forms of Efavirenz, designated as Form 1, Form 2, Form 3, Form 4, and Form 5. These forms have been characterized and distinguished from one another by differential scanning calorimetry (DSC) and x-ray powder diffraction analysis.
Further aspects of the invention involve pharmaceutical compositions of crystalline Efavirenz and its five forms. The crystalline products of this invention may be formulated into conventional solid pharmaceutical dosage forms or used for the preparation of liquid dosage forms by combining a therapeutically effective amount of the crystalline drug with a pharmaceutically acceptable carrier. The crystalline products may be administered in pharmaceutical compositions which may combine other antivirals, immunomodulators, antibiotics or vaccines.
In another aspect, the present invention involves a method for inhibiting reverse transcriptase which comprises administering an amount of crystalline Efavirenz sufficient to result in reverse transcriptase being contacted with an effective inhibitory amount of the active drug substance.
In particular aspects, the invention involves methods for treating retroviral infections such as human immunodeficiency virus and disorders involving viral replication, which comprise administering a therapeutically effective amount of a pharmaceutical composition comprising the novel crystalline forms of Efavirenz of this invention.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of Form 1, 2, 3, 4, or 5 Efavirenz with and one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.


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PGPUB US 20020115664 A1, App. No. 10/000,537, filed Oct. 19, 2001.

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