Title:  Pharmaceutical composition containing two active ingredients for smoking cessation

United States Patent:  6,582,737

Issued:  June 24, 2003

Inventors:  Hirsh; Mark (Wellesley, MA); Midha; Kamal K. (Hamilton HM, BM); Junginger; Hans E. (Wellesley, MA)

Assignee:  Peirce Management, LLC (Wellesley, MA)

Appl. No.:  962927

Filed:  September 25, 2001

Abstract

A kit to alleviate tobacco-smoking withdrawal symptoms in a patient is disclosed which comprises: (a) a therapeutically effective amount of nicotine, at least one active nicotine metabolite, a combination of nicotine and an active nicotine metabolite, or an azapirone, or a pharmaceutically acceptable salt thereof; (b) a transdermal delivery system consisting essentially of a bupropion base in a therapeutically effective amount; and (c) a packaging material surrounding (a) and (b).

SUMMARY OF THE INVENTION

Quitting smoking is hard. Smoking is a physical addiction as well as a habituation. The pharmaceutical composition according to the present invention is a treatment package that has been designed to assist in slowly weaning the patient, off of nicotine, while eliminating the depressive state associated with withdrawal from smoking. Because smoking is such a strong habit it is necessary to provide a well-contained therapy. The unit will assist the patient by allowing him/her to eliminate the habit of smoking over time as well as to provide relief of symptoms associated with withdrawal of smoking cigarettes.

The present invention is directed to a pharmaceutical composition in unit dosage form combining two pharmaceutically active ingredients to alleviate tobacco-smoking withdrawal symptoms which comprises:

(a) a therapeutically effective amount of nicotine, at least one active nicotine metabolite, a combination of nicotine and an active nicotine metabolite, or an azapirone, or a pharmaceutically acceptable salt thereof; and

(b) a transdermal delivery system consisting essentially of a bupropion base in a therapeutically effective amount.

Preferably the transdermal delivery system is a patch for transdermal delivery of bupropion to a mammalian subject, said patch comprising:

(i) a flexible, inert backing layer incapable of absorbing bupropion base;

(ii) a release liner through which bupropion base is not permeable; and

(iii) a reservoir located between the backing layer and the release liner, said reservoir having a bupropion-transfer surface adjacent to the release liner and adapted to contact the skin of the patient and sufficient to transfer an effective dosage of bupropion base through the skin of said patient into the bloodstream of said patient, which comprises:

(1) a therapeutically effective amount of bupropion base selected from the group which consists of (+)-bupropion base, (-)-bupropion base and racemic bupropion base and mixtures thereof; and

(2) means for securing the bupropion-transfer surface area of said reservoir to the skin of the patient.

The bupropion base contained in the reservoir in the transdermal patch may be stabilized with a stabilizer. Such stabilizers for stabilization of the bupropion base preferably include L-ascorbic acid palmitate, tocopherol solution in alcohol, butylated hydroxyanisole, vitamin E succinate, Vitamin E 700 acetate, or L-ascorbic acid G palmitate. Preferably the stabilizer is present in the reservoir containing the bupropion base in an amount of 2.7 to 27% by weight of the bupropion base.

Preparation of the transdermal delivery system containing the bupropion base and the transdermal patch containing the stabilized bupropion base may be found respectively in our copending U.S. patent applications Ser. No. 09/309,075 filed May 10, 1999 and Ser. No. 09/562,178 filed May 2, 2000, the entire contents of which are both expressly incorporated herein by reference.

The unit dosage form containing nicotine or the combination of nicotine and its active metabolite, the azapirone or a pharmaceutically acceptable salt thereof may be in an oral or intraoral dose as a tablet or capsule, may be in an oral dosage form dissolved in an aqueous solution, may be contained in a patch for transdermal delivery including location within the reservoir containing the bupropion base in the transdermal patch as well as location within a transdermal patch separate from the transdermal patch containing the bupropion base, may be in a nasal spray inhaler or nasal vapor inhaler for intranasal administration, and may be in the form of a lozenge or a chewing gum suitable for intraoral administration. Such transdermal patches containing the azapirone may be found for example in U.S. Pat. No. 5,837,280.

Preferred active nicotine metabolites include cotinine, nornicotine, norcotinine, nicotine N-oxide, cotinine N-oxide, 3-hydroxy-cotinine, 5-hydroxy-cotinine or a pharmaceutically acceptable salt thereof.

The azapirone is preferably buspirone, but may also include gepirone, ipsapirone, tandospirone, WY-47,846, MDL-73005 EF or BP-554.

The invention also includes a method of alleviating tobacco-smoking withdrawal symptoms in a patient who is refraining from smoking tobacco which comprises the step of administering to said patient a therapeutically effective amount of a pharmaceutical composition in unit dosage form combining two pharmaceutically active ingredients to alleviate tobacco-smoking withdrawal symptoms which comprises:

(a) a therapeutically effective amount of nicotine, at least one active nicotine metabolite, a combination of nicotine and an active nicotine metabolite, or an azapirone, or a pharmaceutically acceptable salt thereof; and

(b) a transdermal delivery system consisting essentially of a bupropion base in a therapeutically effective amount.

Preferably the transdermal delivery system is a patch for transdermal delivery of bupropion to a mammalian subject, said patch comprising:

(i) a flexible, inert backing layer incapable of absorbing bupropion base;

(ii) a release liner through which bupropion base is not permeable; and

(iii) a reservoir located between the backing layer and the release liner, said reservoir having a bupropion-transfer surface adjacent to the release liner and adapted to contact the skin of the patient and sufficient to transfer an effective dosage of bupropion base through the skin of said patient into the bloodstream of said patient, which comprises:

(1) a therapeutically effective amount of bupropion base selected from the group which consists of (+)-bupropion base, (-)-bupropion base and racemic bupropion base and mixtures thereof; and

(2) means for securing the bupropion-transfer surface area of said reservoir to the skin of the patient.

Preferably the therapeutically effective amount of nicotine, a combination of nicotine and its active metabolite, an azapirone, or a pharmaceutically acceptable salt thereof ranges from 1 to 100 mg/kg of body weight of the patient. Preferably the therapeutically effective amount of transdermally administered bupropion base selected from the group which consists of (+)-bupropion base, (-)-bupropion base and racemic bupropion base and mixtures thereof ranges between 40 and 300 mg/day.

The present invention also provides an article of manufacture in the form of a kit comprising packaging material, such as a bottle, box, tube, sprayer, insufflator, envelope and the like, and two units containing dosage units of pharmaceutical agents contained within said packaging material, wherein said pharmaceutical agents comprise nicotine, a nicotine metabolite, or a combination of nicotine metabolites, or pharmaceutically acceptable salts thereof in an amount effective to alleviate tobacco withdrawal syndrome. The other pharmaceutical agent will consist of a transdermal patch system containing bupropion in its base form and/or the isomers of bupropion in combination with bupropion. The invention also includes the combination of the transdermal bupropion patch and nicotine, at least one of its active metabolites, a combination of nicotine and one of its active metabolites, an azapirone or their pharmaceutically acceptable salts.

Preparation of the Transdermal Patch Containing Bupropion Base

In one embodiment, the transdermal system contains bupropion base either as the racemate or as the (+) isomer or as the (-) isomer in acrylic-based polymer pressure sensitive adhesives with a resinous cross-linking agent (either based on silicone polymers or polyacrylates and alcohol) to provide a continuous source of active ingredients. Each unit is sealed in a paper polyethylene-foil pouch. Isomers of bupropion can be separated by known methods. Stabilizers that may optionally be included in the reservoir of the patch include Vitamin E preferably as DL Tocopheral solution in alcohol, Vitamin E succinate or Vitamin E 700 acetate and butylated hydroxy anisole.

The reservoir may include a carrier or vehicle. The "Carriers" or "vehicles" refer to carrier materials suitable for transdermal drug administration and include any such materials known in the art, such as any liquid, gel solvent, liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner. Examples of suitable carriers for use herein include water, silicone, liquid sugars, waxes, petroleum jelly, and a variety of other materials. The term "carrier" or "vehicle" can also refer to crystallization inhibitors, or other types of additives useful for facilitating transdermal drug delivery. Suitable materials for this layer include, for example, polysiloxanes, polyisobutylenes, polyurethanes, plasticized ethylenevinyl acetate copolymers, low molecular weight polyether amide block polymers (e.g., PEBAX), tacky rubbers, such as polyisobutene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and mixtures thereof. Presently preferred adhesive materials for use as reservoir layer are polyisobutylenes, silicones, polyurethanes and polyacrylates, with polyisobutylenes particularly preferred. The carrier will be composed of these materials in such a way to achieve a controlled occlusion of the skin achieving optimal enhancement of drug penetration across the skin with minimal skin irritation (which may be caused by complete occlusivity of the system).

In a preferred embodiment, the reservoir matrix may include a dispersing agent which aids in maintaining the particulate phase dispersed in the continuous phase. In other embodiments, non-ionic excipients, such as lauric alcohol, propylene glycol monolaurate, myristyl lactate, lauryl lactate, or the like, facilitate dispersion.

The cold flow properties of the polymer adhesives of the bupropion delivery system are considered acceptable when adhesion of the transdermal patch to the skin of the user remains high throughout the drug delivery period and the adhesive does not extend beyond the boundary of the patch.

The release liner is a disposable element which protects the device prior to application. Typically, the release liner is formed form a material impermeable to the drug, vehicle and adhesive, and which is easily stripped from the contact adhesive. Release liners are typically treated with silicone or fluorocarbons. Silicone-coated polyester is a preferred embodiment. Another material may be silicone-coated aluminum.

The backing layer functions as the primary structural element of the device and provides the device with much of its flexibility, drape and, preferably, controlled occlusivity. The material used for the backing layer should be inert and incapable of absorbing drug, enhancer or other components of the pharmaceutical composition contained within the device. The backing is preferably made of one or more sheets or films of a flexible material that serves as a protective covering to prevent loss of drug or vehicle or both by transmission through the upper surface of the device, and imparts a desired degree of occlusivity to the device, such that the area of the skin covered on application becomes hydrated. The material used for the backing layer may permit the device to follow the contours of the skin and be worn comfortably on areas of the skin, such as at joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device. Examples of materials useful for the backing layer are polyesters, polyethylene, polypropylene, polyurethanes and polyether amides. The layer is preferably in the range of about 15 micrometers to about 20 micrometers in thickness.

The bupropion transdermal infusion system is a flat unit designed to provide continuous controlled release of bupropion base as racemate or its isomers through the intact skin. The rate of release of bupropion base or its isomers is linearly dependent upon the area of the applied system; each square cm of the applied system delivers approximately 2 mg to 7.5 mg/cm². In one embodiment, the patch size can range from about five to forty square centimeters. The rate of delivery of the bupropion from a forty square centimeter patch can range from about 10 mg/day to 300 mg/day for all methods of treatment.

Bupropion hydrochloride is commercially available under the name Welbutrin and Welbutrin from Burroughs Wellcome. For bupropion (1-(3-chlorophenyl-Z-[(1,1-dimethylethyl)amino]-1-propanone, its preparation is described in U.S. Pat. Nos. 3,819,706 and 3,885,046, wherein the teachings of each patent are incorporated by reference.

Preparation of bupropion base can be carried out by a suitable method. In one embodiment, 1.2 g bupropion HCl is dissolved in 20 ml of distilled water to which 0.1 N NaOH is added until the pH is about 12. Then this mixture is extracted with 50 ml of diethylether by shaking followed by centrifugation. The ether phase containing the bupropion base is separated and the remaining watery phase is treated three times with 80 ml diethylether. The unified ether phases are dried (removal of residual water) by adding 15 g anhydrous K₂ CO₃, filtrated and the ether is evaporated at 50^oC. under vacuum (rotavapor). The residual phase (bupropion base) (1.0 g) is dissolved in 6 ml propylene glycol and stored until further use under nitrogen gas in a tight bottle in the dark. Bupropion base can be prepared by other procedures that are known as state of the art.

Claim 1 of 22 Claims

What is claimed is:

1. A pharmaceutical composition in unit dosage form to alleviate tobacco-smoking withdrawal symptoms which consists essentially of:

(a) a therapeutically effective amount of nicotine, at least one active nicotine metabolite, a combination of nicotine and an active nicotine metabolite, or an azapirone, or a pharmaceutically acceptable salt thereof; and

(b) a transdermal delivery system comprising bupropion base in a therapeutically effective amount.

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