Controlled release formulation containing bupropion

This is a provisional application No. 60/061,121, filed Oct. 6, 1997.

The present invention relates to a controlled release formulation for administration of antidepressant drugs such as bupropion to a subject and to antidepressant formulations of improved stability.

Bupropion, or (±)-2-(tert-butylamino)3′-chloropropiophenone, is an aminoketone antidepressant. It may be administered in the form of a pharmaceutically acceptable salt, such as bupropion hydrochloride.

Bupropion is extensively metabolised in mammals and on oral administration, only a small portion of the administered dose reaches the systemic circulation intact. For example, the absolute bioavailability of bupropion in mammals such as rats and dogs ranges from 5% to 20%.

It would therefore be useful to employ a controlled release formulation of bupropion.

The stability of bupropion on storage has also been a cause for concern, the compound being subject to hydrolytic decomposition during storage ( Ther. Drug Monit . (1985), v. 7(y), pp. 447-458; GA (1985), v. 101, pp. 210748e of UX; and J. Pharm. Sci . (1980), v. 69, pp. 1206-1209).

Similar problems of active metabolism and storage instability are encountered with many antidepressant drugs.

It is an object of the present invention to ode a controlled release pharmaceutical formulation containing as active ingredient an antidepressant such as bupropion or a pharmaceutically acceptable bupropion salt, whereby the active ingredient is released over a period of time to provide improved availability of the drug.

It is a further object of the invention to provide controlled release pharmaceutical formulations whereby the active ingredient is released in either a continuous or a pulsatile manner.

In accordance with one embodiment, the invention provides a controlled release pharmaceutical formulation which comprises an effective amount of bupropion hydrochloride and from about 1% to about 70% by weight of a polymer selected from the group consisting of a) at least one uncrosslinked polymer selected from the group consisting of hydroxyethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose; b) at least one crosslinked insoluble polymer; and c) a mixture of (a) and (b).

The formulations of the invention may further comprise a stabilising agent, such as a saturated polyglycolised glyceride. The polyglycolised glyceride may consist of mono-, di- and triglycerides and of mono- and di- fatty acid esters of polyethylene glycol.

In accordance with one embodiment, the invention provides controlled release pharmaceutical formulations containing as active ingredient a monocyclic, bicyclic, tricyclic or heterocyclic antidepressant.

In a preferred embodiment, the active ingredient is bupropion or a pharmaceutically acceptable salt of bupropion. Bupropion hydrochloride is especially preferred as active ingredient

The controlled release formulations of the invention, in oral dosage form, are prepared by mixing a selected active ingredient with one or more uncrosslinked, linear polymers, or with one or more covalently crosslinked insoluble polymers or with a mixture of uncrosslinked, linear and crosslinked, insoluble polymers.

The present invention is simple in fabrication, permitting efficient and reproducible mass production by conventional techniques.

Suitable polymers for use in the controlled release formulations of the present invention are uncrosslinked, linear polymers including cellulosic polymers, preferably hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose and hydroxypropyl cellulose, or covalently crosslinked insoluble polymers such as high molecular weight crosslinked homopolymers and copolymers of acrylic acid (carbopol resins), or mixtures of these uncrosslinked and covalently crosslinked polymers.

In accordance with a further embodiment, the formulations of the invention also include at least one stabilising agent which improves the stability of bupropion hydrochloride on storage of the formulation.

Suitable stabilising agents for use in the formulations of the invention, to reduce the degradation of bupropion hydrochloride on storage, include shellac, any of its constituent aliphatic polyhydroxy acids presented as lactones, lactides and inter-esters, saturated polyglycolised glycerides containing C 8 to C 18 saturated fatty acids such as gelucire, ascorbic acid, benzoic acid and fumaric acid.

Gelucire serves a dual role, providing protective action against oxidation and hydrolysis of bupropion and, also, together with the polymer component, modulating the release of bupropion hydrochloride.

Pharmaceutically acceptable excipients and tablet lubricants may optionally be included in the formulations of the invention. Suitable excipients include sucrose, silicone dioxide, silicified microcrystalline cellulose, fatty acids, fatty acid salts such as metallic salts of stearate, including aluminum-, calcium-, magnesium-, sodium- and zinc stearate, fatty acid esters and talo.

The active ingredient content of the formulations of the invention will depend on the desired dosage and the time frame over which the formulations release the active ingredient For example, if the formulation releases active ingredient over twenty four hours such that one dosage is given daily, ear oral dosage form of the formulation will contain the desired daily dose of active ingredient If two dosages of formulation are to be given daily, each releasing drug over 12 hours, each oral dosage form of the formulation will contain half of a daily drug dose. For example, a controlled release formulation of bupropion hydrochloride should preferably provide 150-400 mg of drug per day.

The formulations of the invention may provide for continuous delivery of active ingredient or for pulsatile delivery. The rate of controlled release of active ingredient, and the pattern of release, for example continuous or pulsatile, is determined by the proportions and type of polymer incorporated into the formulation The polymer content is adjusted to give a desired rate of release, for example over 12 hours, 24 hours or 48 hours. For continuous release, one formulation of a desired rate of release is employed.

Pulsatile delivery is achieved by preparing an oral dosage form, such as a capsule, containing more than one type of tablet or more than one population of granules, each tablet type or granule population releasing the active ingredient at a different rate or at a different time interval; for example, one tablet type or granule population begins drug release first and when the drug level from that release has peaked and begun to decline, a second tablet type or granule population begins drug release, leading to a second peak of drug level. The controlled release formulations of the invention are prepared by mixing bupropion hydrochloride with an uncrosslinked linear polymer, a crosslinked polymer or a mixture of such polymer, wet granulating the mixture with a solution of a stabilising agent and drying the resulting granules, which can be processed into tablets or pellets.

In accordance with a further embodiment, there is provided a method of producing a wax matrix controlled delivery formulation comprising polyglycolised glyceride having the following types of fatty acids: C 8 to C 18 saturated fatty acids, for controlled delivery of bupropion hydrochloride which is stable during storage.

The sustained release characteristics of the formulations of the present invention can be predetermined and varied by adjusting the makeup of the composition as described and exemplified herein. For example, the duration, uniformity and continuity of release of bupropion hydrochloride can be suitably controlled by varying the relative amounts of gelucire and polymer. The finished tablet may be film coated

The following specific examples of the controlled release pharmaceutical formulations of the invention are for illustration and are not intended to be limiting in any way.