Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-04-28
2001-10-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S465000, C424S474000, C424S488000, C514S772300, C514S781000
Reexamination Certificate
active
06306436
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to sustained release bupropion hydrochloride compositions, and more specifically relates to such compositions in which the drug is stabilized without added acid. The invention additionally relates to methods for administering bupropion using the novel formulations. The invention finds utility in the fields of drug delivery, pharmacology and medicine.
BACKGROUND
Bupropion is an antidepressant agent that is chemically distinct from tricyclic, tetracyclic and other commercially available antidepressants, e.g., selective serotonin-reuptake inhibitors, or “SSRIs.” Bupropion, described in U.S. Pat. Nos. 3,819,706 and 3,885,046, is currently available as the hydrochloride salt, i.e., as m-chloro-&agr;-(t-butylamino)propiophenone (amfebutamone) hydrochloride,
and is used as both an antidepressant and a smoking cessation aid. Utility in treating attention deficit hyperactivity disorder (ADHD) has also been evaluated. Bupropion hydrochloride is a water-soluble, crystalline solid having a melting point of 233-234° C., and is highly hygroscopic and susceptible to decomposition. Because of the drug's instability, the shelf-life of bupropion formulations has proved to be problematic, and those working in the field have tried a number of different approaches to improving the storage stability of the drug.
For example, U.S. Pat. Nos. 5,541,231, 5,763,493, 5,358,970, and 5,731,000 to Ruff et al. describe bupropion hydrochloride formulations that use an organic acid, a carboxylic acid, an amino acid salt (e.g., cysteine hydrochloride, glycine hydrochloride, and cysteine dihydrochloride), or sodium metabisulfite as a stabilizer. PCT Publication No. WO 99/33457 to Kulkani et al. describes bupropion hydrochloride formulations containing dicarboxylic acids as stabilizing agents. U.S. Pat. No. 5,968,553 to Maitra et al. describes bupropion hydrochloride formulations containing dilute inorganic acids as stabilizers including hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid. Acid stabilization of the related compound diethylpropion hydrochloride has also been described by Walters (1980)
J. Pharm. Sci
. 69(10):1206-1209. Placing bupropion HCl in a relatively low pH environment has proven effective in stabilizing bupropion and its major metabolites in human plasma; see Laizure et al. (1985)
Ther. Drug Monit
. 7(4): 447-450. Unfortunately, the use of acidic materials in pharmaceutical formulations requires costly production procedures and equipment. Therefore, it would be desirable to produce a stabilized bupropion hydrochloride formulation without the use of acid stabilizers.
Pharmaceutical dosage forms are known which provide a variety of drug release profiles, including immediate release, delayed release, and sustained release. An immediate release formulation provides for drug release immediately following drug administration, while delayed release (also termed “site-specific release”) formulations prevent drug release until a certain point in the body is reached, and “sustained release” formulations provide substantially continuous release over a predetermined time period (so-called “sustained release”). As the incidence of seizures is reduced by use of sustained release bupropion hydrochloride formulations, (See Physicians Desk Reference, 1999 Edition, page 1279), sustained release formulations are particularly preferred for administration of the drug. Sustained release formulations have been described, for example, in U.S. Pat. No. 5,427,798 to Ludwig et al. These formulations control drug release by varying the surface area to volume ratio of the tablet. Unfortunately, the Ludwig et al. formulations rely on the inclusion of acids to stabilize the bupropion hydrochloride.
The present invention is directed to a novel means for stabilizing bupropion hydrochloride in a sustained release formulation without having to incorporate an added acid in the formulation. Accordingly, the present invention provides novel bupropion hydrochloride formulations that are sustained release and have substantially improved storage stability but are acid-free. No art of which applicants are aware describes sustained release bupropion hydrochloride formulations as now provided herein.
To the best of applicants' knowledge, the pharmaceutical formulations of the invention are previously unknown and completely unsuggested by the art.
SUMMARY OF THE INVENTION
It is a primary object of the invention to provide a bupropion hydrochloride pharmaceutical composition for oral administration that is free of added acid, provides for sustained release of the active agent from the dosage form, and contains at least about 80 wt. % of undegraded bupropion hydrochloride after storage for three months at about 40° C. and 75% relative humidity.
It is another object of the invention to provide a bupropion hydrochloride pharmaceutical composition for oral administration in the form of a compressed tablet containing bupropion hydrochloride crystals coated with a cellulosic polymer that is free of added acid, provides for sustained release of the active agent from the dosage form, and contains at least about 90 wt. % of undegraded bupropion hydrochloride after storage for three months at about 40° C. and 75% relative humidity.
It is another object of the invention to provide a method for preparing a stabilized bupropion hydrochloride composition for oral administration without addition of acid by admixing bupropion hydrochloride with a pharmaceutically acceptable carrier and compressing the admixture into a tablet, wherein the bupropion hydrochloride has a particle size in the range of 75&mgr; to 900&mgr;.
It is a still further object of the invention to provide a method for preparing a bupropion hydrochloride pharmaceutical composition for oral administration without addition of acid by coating particulate bupropion hydrochloride with an amount of a cellulosic polymer, admixing the coated bupropion hydrochloride with a suitable amount of a pharmaceutically acceptable carrier and compressing the resulting admixture into a tablet.
In one aspect of the invention, then, a sustained release bupropion hydrochloride pharmaceutical composition is provided that is free of acid additives. The composition provides for sustained release of the bupropion hydrochloride from the dosage form and contains at least about 80 wt. % of undegraded bupropion hydrochloride after storage for three months at about 40° C. and 75% relative humidity. The bupropion hydrochloride may be in the form of crystals and may be coated with a cellulosic polymer.
In another aspect of the invention, a method for preparing the pharmaceutical composition is provided, comprising the steps of admixing particulate bupropion hydrochloride with a pharmaceutically acceptable carrier and compressing the admixture into a tablet. The bupropion hydrochloride may be in a crystalline form that is coated with a cellulosic polymer prior to admixture with the pharmaceutically acceptable carrier.
In another aspect of the invention, a method of treating a patient suffering from depression or nicotine addiction is provided. The method comprises orally administering to the patient the pharmaceutical composition of the present invention, within the context of a dosing regimen effective to treat the particular condition. When used to treat nicotine addiction, the pharmaceutical composition may be administered in combination with an effective amount of nicotine.
DETAILED DESCRIPTION OF THE INVENTION
D
EFINTIONS AND
N
OMENCLATURE:
Before the present formulations and methods of use are disclosed and described, it is to be understood that unless otherwise indicated this invention is not limited to specific pharmaceutical carriers, other formulation components, or particular administration regimens, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specificatio
Chungi Shubha
Lin Kangwen
Fubara Blessing
Hartrum J. Elin
Page Thurman K.
Reed Dianne E.
Reed & Associates
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