Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-03-04
2003-11-11
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252010, C514S255030, C514S311000
Reexamination Certificate
active
06645961
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to solid dosage formulations, and process for manufacture, of an HIV protease inhibitor. More specifically, the invention relates to a dry granulation formulation of the HIV protease inhibitor, indinavir.
BACKGROUND OF THE INVENTION
The pharmaceutical industry employs various methods for compounding pharmaceutical agents in oral formulations. In particular, wet granulation is one of the more prevalent methods for preparing tablets and/or capsules. When tablet (capsule) ingredients are sensitive to moisture or are unable to withstand elevated temperatures during drying, and when tablet (capsule) ingredients have sufficient inherent binding or cohesive properties, slugging may be used to form granules. This method is also known as dry granulation. The encapsulation of medicinal agents provides a popular alternative to the tablet for administering drugs. The hard gelatin capsule, available in a large variety of sizes, consists of two sections one slipping over the other to completely surround the drug formulation.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. Recently, a number of HIV protease inhibitor compounds have been disclosed as being useful in the treatment of infection by HIV and in the treatment of AIDS. These HIV protease inhibitor compounds and their utility in treating HIV and AIDS is described in U.S. Pat. No. 5,413,999 and EP 541,168, published May 12, 1993. More particularly, the compound disclosed and referred to as “Compound J” in U.S. Pat. No. 5,413,999 and EP 541,168, is a potent inhibitor of HIV protease and is useful in the treatment of infection by HIV and in the treatment of AIDS or ARC (AIDS related complex), without significant side effects or toxicity.
Compound J, i.e., N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide, now also known as indinavir, is prepared according to the procedure of Example 15 in U.S. Pat. No. 5,413,999 or according to the Vocesses disclosed in U.S. Pat. Nos. 5,420,353; 5,169,952; 5,463,067; 5,496,948; 5,491,238. The sulfate salt of Compound J (more specifically, the sulfate salt ethanolate) is currently marketed as CRIXVAN® (trademark of Merck & Co. Inc.), i.e., indinavir sulfate.
Devising an oral formulation of indinavir, in particular, indinavir sulfate, proved problematic for a number of reasons. The daily dose of indinavir sulfate is quite high, i.e., 2.4 g per day; therefore the formulation should contain a minimum number of excipients. Moreover, since indinavir sulfate does not possess good compaction properties, an excipient with good compaction properties was necessary. Additionally, indinavir sulfate is very moisture sensitive making formulation difficult. Furthermore, many HIV protease inhibitors, including indinavir sulfate, have bitter and unpleasant taste.
The present invention now provides a dry granulation formulation of indinavir sulfate and process therefore which solves all of the problems discussed above.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition which comprises by weight, about 50 to 90% by weight of an active ingredient which is indinavir, or a pharmaceutically acceptable salt thereof,.about 10 to 50% by weight of an excipient and about 0.5 to 2% by weight of a lubricant. Preferably, the active ingredient is indinavir sulfate. More preferably, the active ingredient is indinavir sulfate, the excipient is selected from anhydrous lactose, low moisture microcrystalline cellulose or anhydrous calcium phosphate dibasic, and the lubricant is selected from magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate or hydrogenated vegetable oil. Most preferably, the active ingredient is indinavir sulfate, the excipient is anhydrous lactose and the lubricant is magnesium stearate.
In one embodiment of the invention is the pharmaceutical composition which comprises by weight, about 70 to 80% by weight indinavir sulfate, about 20 to 30% by weight of the excipient and about 0.8% to 1.5% by weight of the lubricant. Preferably, the excipient is selected from anhydrous lactose, low moisture microcrystalline cellulose or anhydrous calcium phosphate dibasic, and the lubricant is selected from magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate or hydrogenated vegetable oil; most preferably, the excipient is anhydrous lactose and the lubricant is magnesium stearate.
In a class of the invention is the pharmaceutical composition which comprises by weight, about 75 to 78% by weight indinavir sulfate, about 22 to 25% by weight anhydrous lactose and about 0.9% to 1.1% by weight magnesium stearate.
In a subclass of the invention is the pharmaceutical composition which comprises by weight, about 76% by weight indinavir sulfate, about 23% by weight anhydrous lactose and about 1% by weight magnesium stearate.
Illustrative of the invention is the pharmaceutical composition in the form of a capsule.
An illustration of the invention is a process for making a pharmaceutical composition containing an active ingredient of indinavir, or a pharmaceutically acceptable salt thereof, comprising the steps of:
(a) mixing about 50 to 90% by weight of the active ingredient with about 10 to 50% by weight of an excipient and about 0.25 to 1% by weight of a first lubricant;
(b) compacting the mix from step (a) to form compacts;
(c) milling the compacts from step (b) to form granules;
(d) lubricating the granules from step (c) with about 0.25 to 1% by weight of a second lubricant; and
(e) forming the lubricated granules from step (d) into the pharmaceutical composition.
In a preferred embodiment of this process, the pharmaceutical composition is formed by encapsulating the lubricated granules from step (d) to form a capsule.
Exemplifying the invention is the process further comprising, the steps of:
(f) sieving the compacts discharged from the compactor in step (b) prior to milling;
(g) collecting the uncompacted material from step (f); and
(h) recycling the collected material back to the compactor.
An example of the invention is the process wherein the active ingredient is indinavir sulfate.
Further illustrating the invention is the process wherein the excipient is selected from anhydrous lactose, low moisture microcrystalline cellulose or anhydrous calcium phosphate dibasic, and the first and second lubricants are each independently selected from magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate or hydrogenated vegetable oil. Preferably, the first and second lubricant are the same. Most preferably, the first and second lubricants are both magnesium stearate and the excipient is anhydrous lactose.
Further exemplifying the invention is the process wherein the capsule contains about 70 to 80% by weight indinavir sulfate, about 20 to 30% by weight anhydrous lactose and about 0.8% to 1.5% by weight magnesium stearate; preferably, about 75 to 78% by weight indinavir sulfate, about 22 to 25% by weight anhydrous lactose and about 0.9% to 1.1% by weight magnesium stearate.
More particularly illustrating the invention is the process comprising the steps of:
(a) mixing about 76% by weight indinavir sulfate, with about 23% by weight anhydrous lactose and about 0.5% by weight magnesium stearate;
(b) compacting the mix from step (a) in a roller compactor to form compacts;
(c) milling the compacts from step (b) to form granules;
(d) lubricating the granules from step (c) with about 0.5% by weight magnesium stearate; and
(e) encapsulating the lubricated granules from step (d) to form the capsule.
More specifically exemplifying the invention is the process comprising the steps of:
(a) mixing about 70 to 80% by weight indinavir sulfate, preferably about 76% by weight indinavir sulfate, with about 20 to 30% by weig
Katdare Ashok V.
Lui Chung Y.
Ostovic Drazen
Stelmach Christine
Camara Valerie J.
Merck & Co. , Inc.
Travers Russell
Walton Kenneth R.
Winokur Melvin
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