Delavirdine high strength tablet formulation

Details Delavirdine high strength tablet formulation Delavirdine high strength tablet formulation

1999-06-07

2001-01-23

Dudash, Diana (Department: 1619)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S465000, C424S474000, C514S253010, C514S253090

Reexamination Certificate

active

06177101

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a tablet formulation which reduces the rate of precipitation of a rapidly precipitating drug and improves dissolution.
2. Description of the Related Art
U.S. Pat. 5,563,142 (EXAMPLE 105) discloses delavirdine.
International Publication W095/28398 based on PCT patent application PCT/U.S.95/02166 discloses delavirdine mesylate in two crystal forms “S” and “T”.
U.S. Pat. 5,358,941 discloses a compressed tablet formulation comprising about 0.5 to 40% active ingredient, about 10-80% anhydrous lactose, about 5 to 50% by weight of microcrystalline cellulose, about 0.5 to 10% by weight of croscarmallose sodium and about 0.1 to 5% magnesium stearate. The pharmaceutical tablet formulation of the present invention does not require lactose.
Patent EP 283925 discloses utilization of solvent-based polymers under action of high shearing forces so that precipitation is divided into smallest particles to purify resorbable polyester products. The claimed invention does not co-precipitate polymers in any solvent system with the rapidly precipitating drug prior to formulation with other ingredients, but relies only on close proximity of the dry binder or superdisintegrant with the rapidly precipitating drug in a conventional compressed tablet dosage form.
International Journal of Pharmaceutics
, 154, 59-66 (1997) discloses the utilization of HPMC, HPC and PVP in a liquid system at various polymer ratios with intent to delay precipitation. Methods discussed include preparation of solid dispersions either by the co-precipitation method of grinding method to improve dissolution properties. The claimed invention utilizes conventional direct compression method of tablet formulation and does not utilize any solid dispersion techniques such as co-precipitation via solvent use or grinding to achieve co-precipitation.
The Handbook of Drug Excipients, 2
nd
. Ed., edited by A. Wade and P. J. Weller. 1994, page 141, and many other pharmaceutical references, describe the common use of superdisintegrants such as croscarmellose sodium are used to aid tablet disintegration typically in the amount of 1-2% and not more than 5% of the formulation. Higher amounts are not used or recommended due to gelation of the croscarmellose sodium forming a loose matrix which is known to impede dissolution of many drug compounds. The present invention uses greater than 6% croscarmellose sodium.
The Handbook of Drug Excipients, 2
nd
. Ed., edited by A. Wade and P. J. Weller. 1994, pages 223, 229 and 392, and many other pharmaceutical references, describe the common use of water soluble polymers such as HPMC, HPC-L, and PVP as binders, either as wet binders or dry binders, in immediate and sustained release tablet formulations. For non-sustained release applications, not more than 5% is used of these binders. Higher amounts are not recommended due to impedance of the dissolution rate for many drugs. Amounts higher than 5% of especially HPMC are commonly used only for sustained release dosage forms, and are generally of high molecular weight grades. In the present invention, however, the binder includes use at levels of greater than 5%.
U.S. Pat. 5,225,197 discloses a chewable tablet formulation. The present invention is not a chewable tablet.
JP 84-185584 discloses the utilization of HPC, PVP and other binders together with difficulty soluble drugs by use of heat. The instant invention does not use heat.
SUMMARY OF INVENTION
Disclosed is a non-sustained release pharmaceutical tablet composition which comprises: a rapidly precipitating drug in an amount from about 5 to about 60%, microcrystalline cellulose and at least one member selected from the group consisting of a binder in an amount of from about 2 to about 25% and a superdisintegrant in an amount from about 6 to about 40% where the rapidly precipitating drug, microcrystalline cellulose, binder and superdisintegrant are mixed and compressed into a tablet without heating, solvent or grinding.
Also disclosed is a non-sustained release pharmaceutical tablet composition which is:
Amount (from about to about)
Item
%
delavirdine mesylate
10-40
hydroxypropyl methylcellulose
 5-20
croscarmellose sodium
 6-35
microcrystalline cellulose
10-50
lactose
 0-15
colloidal silicon dioxide
0-5
magnesium stearate
0-5
where the delavirdine mesylate, microcrystalline cellulose, hydroxypropyl methylcellulose and croscarmellose sodium are mixed and compressed into a tablet without heating, solvent or grinding.
DETAILED DESCRIPTION OF THE INVENTION
The tablets of the present invention require a rapidly precipitating drug (5-60%), microcrystalline cellulose (10-50%), a binder (2-25%) and superdisintegrant (6-40%). While not required, it is often highly desirable to use one or more of the following pharmaceutical ingredients - microcrystalline cellulose (0-50%), lactose (0-80), a flow agent (0-5) and a lubricant (0-5%).
A rapidly precipitating drug is a pharmaceutical compound, or its salt form, which when introduced in water, or simulated physiological fluids at body temperature, begins to dissolve fairly rapidly and then begins to rapidly precipitate out of solution within 60 min to a less soluble form which provides a concentration that is less than therapeutic. This precipitation results in slow and incomplete dissolution. In most cases, the amount precipitating can be up to 90% or greater which leave about 10% or less available for therapeutic activity. It is preferred that the rapidly precipitating drug is a fairly soluble or highly soluble salt form of a poorly soluble free base or free acid drug or an anhydrous form of a poorly soluble free base or free acid drug. The rapidly precipitating drugs are prone to supersaturation as is known to those skilled in the art. It is preferred that the rapidly precipitating drug be selected from the group consisting of delavirdine mesylate, phenytoin, furosemide, pseudoephedrine, clindamycin hydrochloride, cloridine hydrochloride, diphenhydramine hydrochloride, fluphenazine hydrochloride, griseofulvin, hydromorphone hydrochloride, naloxone hydrochloride, oxytetracycline hydrochloride, phenylephrine hydrochloride, pheniramine maleate, tetracycline hydrochloride, verapamil hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate, hydrocodine bitartrate, acyclovir sodium, albuterol sulfate, ampicillin sodium, benztropine mesylate, benzphetamine hydrochloride, bupivacaine hydrochloride, bupropin hydrochloride, chlorphenamine maleate, chlorpromazine hydrochloride. It is most preferred that the rapidly precipitating drug is delavirdine mesylate. The rapidly precipitating drug should be present in an amount of about 5 to about 60%, preferably in an amount of about 10 to about 40%.
Delavirdine, 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethyl-amino)-2-pyridinyl]piperazine is known, see U.S. Pat. 5,563,142 (EXAMPLE 105). Delavirdine mesylate is also known in two different crystal forms “S” and “T”, see, International Publication W095/28398 based on PCT patent application PCT/U.S.95/02166.
The tablet formulation of the present invention is a non-sustained release pharmaceutical tablet composition which comprises a rapidly precipitating drug in an amount from about 5 to about 60%, microcrystalline cellulose (10-50%) and at least one member selected from the group consisting of a binder in an amount of from about 2 to about 25% and a superdisintegrant in an amount from about 6 to about 40% where the rapidly precipitating drug, microcrystalline cellulose, binder and superdisintegrant are mixed and compressed into a tablet without heating, solvent or grinding. It is preferred that the binder, microcrystalline cellulose and superdisintegrant all be present.
The tablet formulation of the present invention can use a binder. The binder is preferably selected from the group consisting of hydroxypropyl methylcellulose, PVP, hydroxypropyl cellulose, microcrystalline cellulose, hydroxymethylcellulose, carbopol and sodium carboxymethylcellulose

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