Title:  Cyclodextrin stabilized pharmaceutical compositions of bupropion hydrochloride

United States Patent:  6,462,237

Issued:  October 8, 2002

Inventors:  Gidwani; Suresh Kumar (Mumbai, IN); Singnurkar; Purushottam (Mumbai, IN); Tewari; Prashant Kumar (Mumbai, IN)

Assignee:  USV Limited (Mumbai, IN)

Appl. No.:  881582

Filed:  June 14, 2001

An inclusion complex of bupropion hydrochloride with beta cyclodextrin that stabilizes the bupropion hydrochloride against degradation. A method of preparing an inclusion complex of bupropion hydrochloride with beta cyclodextrin that stabilizes the bupropion hydrochloride against degradation. A novel stabilized sustained-release pharmaceutical composition of bupropion hydrochloride containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin. A method of preparing a novel stabilized sustained-release pharmaceutical composition containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel inclusion complex of (.+-.)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propane hydrochloride, commonly known as bupropion hydrochloride with beta-cyclodextrin, where the molar ratio of bupropion hydrochloride to beta cyclodextrin is 1:(0.25-4). The inclusion complex stabilizes the bupropion hydrochloride against degradation.

The present invention further provides a method for preparing a novel inclusion complex of bupropion hydrochloride with beta cyclodextrin, comprising the steps of:

1. wetting an amount of beta cyclodextrin with a pharmaceutically acceptable solvent such as water, acetone and/or a C1 to C4 aliphatic alcohol and mixtures thereof, at room temperature to form a semisolid mixture;

2. shear mixing the resulting semisolid mixture with bupropion hydrochloride to form an inclusion complex; and

3. drying the shear mixed inclusion complex at 40-80^oC.;

where the molar ratio of bupropion hydrochloride to beta cyclodextrin is 1:(0.25-4.0), and preferably is 1:(0.5-2.0).

In a preferred embodiment, the C1-C4 aliphatic alcohol is selected from the group consisting of isopropyl alcohol, ethanol, and their combinations. The shear mixed inclusion complex may be freeze dried or spray dried or dried by low temperature vacuum evaporation in a fluidized bed dryer or tray dryer. In a preferred embodiment, drying is carried out in a tray dryer at 40-60^oC.

The present invention also provides a novel stabilized sustained release pharmaceutical composition containing the novel inclusion complex of bupropion hydrochloride with beta cyclodextrin, that further contains drug release rate controlling materials selected from a combination of hydroxypropyl methyl cellulose with hydroxypropyl cellulose, sodium carboxymethyl cellulose or stearic acid, the molar ratio of bupropion hydrochloride to beta cyclodextrin being 1:(0.25-4.0). Where a mixture of the release rate controlling materials is employed, the weight ratio of one release rate controlling material to the other is within the range of about 1:0.1 to 0.1:1, and preferably is within the range of about 1:0.3 to 0.3:1.

In a preferred embodiment, the drug release rate controlling materials include hydroxypropyl methyl cellulose with average molecular weight of 20000 to 120000, preferably 86000 to 120000, and with a methoxy degree of substitution ranging from 1.36 to 1.90 and hydroxypropyl molar substitution ranging from 0.18 to 0.25.

Where hydroxypropyl cellulose is employed as a drug release rate controlling material, it preferably has molecular weight in the range of 370000 to 1150000, preferably from 850000 to 1150000. Where sodium carboxymethylcellulose is so employed, it has a molecular weight in the range of 90000 to 700000, preferably from 250000 to 700000, with degree of substitution ranging from 0.65 to 0.95.

The combination of hydroxypropyl methyl cellulose with hydroxypropyl cellulose, sodium carboxymethyl cellulose or stearic acid has been found to effectively control the release rate of bupropion hydrochloride from the pharmaceutical compositions containing the inclusion complex of bupropion hydrochloride with beta cyclodextrin.

The novel stabilized sustained release pharmaceutical composition of the present invention may further contain one or more conventional excipients, such as lactose, microcrystalline cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, colloidal silicone dioxide, titanium dioxide, propylene glycol, polyethylene glycol-6000, talc, magnesium stearate and other excipients known in the art.

The novel pharmaceutical compositions according to the present invention can be used to produce oral dosage forms as compressed tablets of any shape, preferably round, or can be formed into compressed compact slugs filled into capsules using modem capsule filling machines. Dosage forms of the novel pharmaceutical composition of the present invention generally contain 25 mg to 500 mg of bupropion hydrochloride, and preferably contain 50 mg, 75 mg, 100 mg, or 150 mg of active ingredient, bupropion hydrochloride.

The present invention also provides a method for preparing a novel stabilized sustained release pharmaceutical composition containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin, and further containing a combination of hydroxypropyl methyl cellulose with hydroxypropyl cellulose, sodium carboxymethyl cellulose or stearic acid, where the molar ratio of bupropion hydrochloride to beta cyclodextrin is 1:(0.25-4.0).

The pharmaceutical compositions of the present invention are prepared by following method:

a) The novel inclusion complex of bupropion hydrochloride with beta cyclodextrin is admixed with the excipients.

b) The mixture is granulated, dried, and milled. Solid dosage forms are prepared such as by compressing the milled granulation to form tablets or caplets. Alternatively capsules may be prepared by placing the compact slugs of milled granulation in, for example, a two part hard gelatin capsule.

c) Solid dosage forms such as tablets may optionally be film coated with aqueous or organic solvent solution of commonly known film coating materials such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, etc.

The method for preparing the pharmaceutical compositions of the present invention is described in greater detail in the examples that follow.

The in-vitro release rate of bupropion hydrochloride from the sustained release pharmaceutical compositions disclosed herein (whether or not film coated) in 0.1 N HCl up to the first hour and then continued in Phosphate buffer pH 6.8 USP, is preferably as follows:

The stability of the novel sustained release pharmaceutical compositions was tested in accordance with industry standards by storage for four to twelve weeks at various accelerated conditions such as 40^oC. with about 75% relative humidity; and also 50^oC. Sustained release pharmaceutical compositions containing the novel inclusion complex of bupropion hydrochloride with beta cyclodextrin of the present invention stored under these conditions retained at least 98% and at least 95% respectively, of the bupropion hydrochloride in the composition at the time of storage. The amount of bupropion hydrochloride remaining after storage may be determined through HPLC or other standard procedures.

A kinetic degradation study of the novel inclusion complex of bupropion hydrochloride with beta cyclodextrin of the present invention also showed excellent stabilization of bupropion hydrochloride when suspended in water and stored at 50 degrees. C. for four weeks.

Claim 1 of 15 Claims

We claim:

1. An inclusion complex of bupropion hydrochloride that is(.+-.)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propane hydrochloride with beta-cyclodextrin, where bupropion hydrochloride and beta cyclodextrin are present in a molar ratio of 1:(0.25-4).

 

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