Cyclodextrin stabilized pharmaceutical compositions of bupropion hydrochloride

1. Field of Invention

The present invention relates to a stabilized sustained-release pharmaceutical composition of bupropion hydrochloride containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin. The invention also relates to the preparation of a stabilized sustained release pharmaceutical compositions of bupropion hydrochloride containing the inclusion complex of bupropion hydrochloride with beta cyclodextrin.

The invention further relates to a method for preventing the degradation of bupropion hydrochloride by making an inclusion complex with beta cyclodextrin, thus allowing the preparation of acceptable pharmaceutical compositions for sustained release tablets and capsules.

2. Description of Related Art

Bupropion hydrochloride is an antidepressant of the aminoketone class. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propane hydrochloride. Bupropion hydrochloride has been shown to decompose in variety of pharmaceutical compositions formulated without the use of stabilizer.

In the present application the term stabilizer means a composition which prevents the decomposition of bupropion hydrochloride.

It has been found that by making an inclusion complex of bupropion hydrochloride with beta cyclodextrin, improved stability of the bupropion hydrochloride results. Accordingly, pharmaceutical compositions of bupropion hydrochloride that contain an inclusion complex of bupropion hydrochloride with beta cyclodextrin will decompose more slowly and maintain their effectiveness for longer periods of time.

It is thus desirable to provide an inclusion complex of bupropion hydrochloride with beta cyclodextrin that improves the stability of the bupropion hydrochloride. It is also desirable to provide a method for preparing an inclusion complex of bupropion hydrochloride with beta cyclodextrin that improves the stability of the bupropion hydrochloride. It is further desirable to provide a stabilized sustained-release pharmaceutical composition of bupropion hydrochloride that contains an inclusion complex of bupropion hydrochloride with beta cyclodextrin. It is still further desirable to provide a method of preparing a stabilized sustained-release pharmaceutical composition of bupropion hydrochloride that contains an inclusion complex of bupropion hydrochloride with beta cyclodextrin.

One aspect of the invention is to provide a method for preparing a composition of an inclusion complex of bupropion hydrochloride with beta cyclodextrin that stabilizes bupropion hydrochloride against degradation, is safe for use as a pharmaceutical composition, is efficient, economical and simple, and which is suitable for manufacture on a commercial scale.

Another aspect of the invention is to provide a method for preparing a stabilized sustained release pharmaceutical composition containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin, which is safe for use as a pharmaceutical composition and stabilizes bupropion hydrochloride against degradation.

FIG. 1A shows a DSC Thermogram of Bupropion hydrochloride.

FIG. 1B shows a DSC Thermogram of Beta cyclodextrin.

FIG. 1C shows a DSC Thermogram of a physical mixture of bupropion hydrochloride with beta cyclodextrin (1:1).

FIG. 1D shows a DSC Thermogram of an inclusion complex of bupropion hydrochloride with beta cyclodextrin.

FIG. 2A is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet (without an inclusion complex of bupropion hydrochloride with beta cyclodextrin) at 50° C. after 4 weeks. Assay of bupropion hydrochloride=99.998% w/w with respect to standard bupropion hydrochloride.

FIG. 2B is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin at 50° C. after 4 weeks. Assay of bupropion hydrochloride=99.998% w/w with respect to standard bupropion hydrochloride.

FIG. 2C is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet (without an inclusion complex of bupropion hydrochloride with beta cyclodextrin) at 37° C. temperature with 75% relative humidity after 4 weeks. Assay of bupropion hydrochloride=99.998% w/w with respect to standard bupropion hydrochloride.

FIG. 2D is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin at 37° C. temperature with 75% relative humidity after 4 weeks. Assay of bupropion hydrochloride=99.998% w/w with respect to standard bupropion hydrochloride.

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, of the following Formula 1

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. degrees. C.;

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. degrees. C.

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. degrees. C. with about 75% relative humidity; and also 50. degrees. C. 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.

FIG. 2A shows an HPLC chromatogram obtained for a bupropion hydrochloride sustained release tablet without a beta cyclodextrin inclusion complex, containing the same matrix material for a sustained release dosage form as the one for sustained release tablets of bupropion hydrochloride containing the inclusion complex, illustrated by FIG. 2 B. One can clearly see the difference in degradation products and assay percentage between the two formulations. The sustained release tablet without the inclusion complex showed the degradation as high as 45% as indicated by FIG. 2A, whereas there is hardly any degradation at 50° C. for over a period of 4 weeks with tablets made with the inclusion complex. FIGS. 2C and 2D further show the HPLC chromatograms illustrating the stability of sustained release tablets not containing the inclusion complex (FIG. 2C) versus those containing inclusion complex (FIG. 2D) at 37° C. with 75% relative humidity. It is clearly again seen that even at low temperature there is sizable degradation, to the extent of 7% over one month period, with a sustained release tablet containing bupropion hydrochloride without the inclusion complex, while hardly any degradation was found with the sustained release bupropion hydrochloride tablets containing the inclusion complex of the present invention.

The preparation of the inclusion complex of the present invention, and of the pharmaceutical compositions of the present invention, is described in greater detail in the following examples. The examples are illustrative, and are not meant to limit the present invention.