Title of Invention	PHARMACEUTICAL FORMULATION COMPRISING ANTI-OBESITY AGENT AND ACIDULANT
Abstract	Pharmaceutical Formulation Comprising Anti-Obesity Agent and Acidulant The present invention relates to a pharmaceutical composition comprising an anti-obesity agent present as the free base in an amount ranging from about 1% to 10 wt% and at least one acidulant 5.0 wt% to 25.0 wt% along with pharmaceutically acceptable carrier, diluents or excipient thereof.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) "PHARMACEUTICAL FORMULATION COMPRISING ANTI-OBESITY AGENT AND ACIDULANT" CIPLA LIMITED, 289 Bellasis Road, Mumbai Central, Mumbai 400 008, India, The following specification particularly describes the invention and the manner in which it is to be performed. Field of the Invention The present invention relates to pharmaceutical formulations comprising an anti-obesity agent useful in the management and treatment of obesity and related conditions. Obesity can be defined as a condition occurring as a result of environmental, emotional and / or familial factors that have as the lowest common denominator an abnormal energy balance, usually resulting from excessive caloric intake and inadequate caloric loss. In simple terms, obesity exists when there is excess energy stored as body fat. In man, moderate obesity is present when fat accounts for more than 25% of ideal weight. The upper limit in females is about 30%. Difference in racial background and socioeconomic status appear to influence body fat, but it is often difficult to accurately distinguish the individual effects that each of the factors have. Obesity is the most prevalent and serious nutritional disease among western countries. Approximately 300,000 deaths a year are currently associated with overweight and obesity. Obesity affects many organ systems and is a risk factor for gastrooesophageal reflux disease, nonalcoholic fatty liver disease, cholelithiasis, and colon cancer. Chronic obesity is also associated with various cardiovascular disorders, including diabetes, dyslipidemia and hypertension. Medication for the treatment of obesity act through one or more of three mechanisms: 1. Appetite suppression (eg. treatment with sibutramine, orlistat or the like); . 2. Increased metabolic activity; 3. Decreased absorption of caloric load. Pharmacotherapy with anti-obesity agents is an important management strategy, in conjunction with lifestyle interventions. For mild to moderate obesity, medications can be beneficial. Two medications approved by USFDA for long term obesity management are sibutramine and orlistat Both drugs are reported to modestly reduce weight. Orlistat, N-formyl-L-leucine (1S)-l-[[(2S,3S)-3-hexyl-4-oxo-2- oxetanyl]methyl]dodecyl ester, has the following structural formula Orlistat is a pancreatic lipase inhibitor and as such is useful as an anti-obesity agent. Sibutramine, N- {1 -[ 1 -(4-chlorophenyl)cyclobutyl]-3-methylbutyl} -N,N-dimethyl-amine, has the following structural formula Sibutramine is an orally administered agent for the treatment of obesity and chemically the active ingredient is a racemic mixture of its enantiomers. Sibutramine is a serotonin - norepinephrine reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. For example, sibutramine produces its therapeutic effects by norepinephrine serotonin and dopamine reuptake inhibition. Sibutramine is an orally administered agent that primarily acts to promote a sense of satiety; this is the result of serotonin (5-hydroxytryptamine) and noradrenaline reuptake inhibition effected by the drug. Sibutramine also has a moderate effect on energy expenditure by attenuating the decrease in energy output during rest. Increased satiety (i.e. decreased energy intake) combined with increased physical activity (i.e. increased energy output), which is encouraged during therapy, should lead to an overall decrease in body weight. Sibutramine is a centrally acting agent that dose-dependently inhibits serotonin and noradrenaline reuptake. The effect of sibutramine is largely attributable to its active primary and secondary amine metabolites. The pharmacological activity of sibutramine does not appear to be a result of increased serotonin release; this differentiates it from the actions of dexfenfluramine, which predominantly releases serotonin, and dexamphetamine, which predominantly releases dopamine and noradrenaline. Hence, the pharmacological mechanisms by which sibutramine exerts its weight loss effect are likely due to a combination of reduced appetite, feelings of satiety, and possibly the induction of thermogenesis. It's efficacy for inducing an initial-weight loss and the subsequent maintenance of the weight loss is well proven in short- and long-term clinical trials. Sibutramine is thus an established and well-proven agent for obesity, is available for use and should be considered effective in the management of patients requiring pharmacotherapy as part of the multi-modal approach to weight-loss. The literature reports formulations of sibutramine hydrochloride and orlistat for use in the treatment of obesity and related conditions. For example, prior art sibutramine hydrochloride formulations are described in US 6162831, US 6426096, WO 01/34140, WO 01/00187, WO 01/00205 and BG106180. More particularly, BG106180 describes pharmaceutical compositions of sibutramine hydrochloride and orlistat for the treatment of co-morbid conditions associated with obesity in a human in need of such treatment, which comprises administration to the human a therapeutically effective amount of the drug. WO 01/00187, WO 01/00205, US 6162831 and US 6426096 describe pharmaceutical compositions of sibutramine hydrochloride alone or with other active agents for the treatment of obesity and related disorders. WO01/34140 describes pharmaceutical formulations comprising sibutramine hydrochloride and a bulking agent for the treatment of obesity and related disorders. The bulking agent not only works as the excipient and / or aid in the formulation but also helps to have a synergistic action with the drug. This is because, when the bulk-forming agent is taken with water, this swells in a patient's stomach, giving rise to a sense of satiety and thus reducing food intake and acting as an anti-obesity agent. Despite a large number of known formulations of sibutramine hydrochloride, for example as discussed above, there continues to exist a need for improved stable formulations of an anti-obesity agent, such as sibutramine and orlistat. To this end, it has surprisingly been found that use of sibutramine or orlistat as the free base, with acidulants (to prepare salt in situ) provides good therapeutic effect for treatment of obesity and related disorders. Additionally, the free base is more stable compared to prior art salts, such as the hydrochloride salt, with respect to accelerated conditions of temperature and humidity. According to the present invention, therefore, there is provided a pharmaceutical formulation comprising an anti-obesity agent, and at least one acidulant, together with a phannaceutically acceptable carrier, diluent or excipient therefor. Suitably, an anti-obesity agent for use in a pharmaceutical formulation according to the present invention is selected from the group consisting of sibutramine, orlistat, phannaceutically acceptable salts, solvates or physiologically functional derivatives thereof. In a preferred embodiment according to the present invention, there is provided a pharmaceutical formulation which is prepared from an admixture of an anti-obesity agent, present as the free base, and at least one acidulant, together with a phannaceutically acceptable carrier, diluent or excipient therefor. Preferably, the anti-obesity agent comprises sibutramine or orlistat, especially sibutramine. In this way a salt of the anti-obesity agent and the acidulant, such as for example sibutramine fumarate, is formed in situ in the formulation. There is further provided by the present invention, therefore, a pharmaceutical formulation which comprises an anti-obesity agent present in salt form, wherein said salt is formed from said anti-obesity agent and an acidulant, together with a phannaceutically acceptable carrier, diluent or excipient therefor. Preferably, the anti-obesity agent comprises sibutramine or orlistat, especially sibutramine, as referred to above. The acidulant employed in a pharmaceutical formulation according to the present invention is suitably selected to react with an anti-obesity agent, such as sibutramine or orlistat, when present as the free base, thereby forming a salt of the anti-obesity agent with the acidulant. This resulting salt form of the anti-obesity agent is stable and is substantially equivalent to prior art hydrochloride salts of anti-obesity agents, such as sibutramine hydrochloride, in terms of in vitro performance of respective formulations thereof. An acidulant as present in a pharmaceutical formulation according to the present invention is suitably selected from the group consisting of acetic acid, citric acid anhydrous, citric acid monohydrate, fumaric acid, DL-malic acid, L-malic acid, phosphoric acid, sorbic acid, DL-tartaric acid, L-tartaric acid, succinic acid and the like. Most preferred is fumaric acid and analogues thereof. Pharmaceutical formulations according to the present invention are preferably in the form of capsules, but it is possible to use other preparations, such as tablets, oral solution, or the like. Suitably, 5-50 mg of an anti-obesity agent, as present in a formulation according to the present invention, when administered once daily generally provides effective therapy for obesity and related disorders. In particular, the present invention provides capsule formulations comprising at least one anti-obesity agent together with at least one acidulant. A preferred anti-obesity agent for use in a capsule formulation according to the present invention is sibutramine, or analogues thereof, and substantially as hereinbefore described the acidulant is suitably selected from the group consisting of acetic acid, citric acid anhydrous, citric acid monohydrate, fumaric acid, DL-malic acid, L-malic acid, phosphoric acid, sorbic acid, DL-tartaric acid, L-tartaric acid, succinic acid and the like. Most preferred is fumaric acid and analogues thereof. Suitably, a diluent or bulking agent is present in a capsule formulation according to the present invention and typically can provide an increase in capsule size. The artisan can utilize known methods to select the diluent, which provides good flow, better compressibility and good homogeneity as required for pharmaceutical usage. A preferred diluent is lactose or microcrystalline cellulose. Various forms of lactose are appropriate for such formulations, including anhydrous, hydrous and spray dried forms. The most desired form of lactose for use according to the present invention can be selected based on desired dissolution, content uniformity, flowability and disintegration time. The artisan can use known techniques to achieve the desired physical properties. The artisan may further select appropriate dry binders and disintegrants using known methods. Most preferably, dry binders and disintegrants are starch and microcrystalline cellulose; however, other appropriate dry binders and disintegrants may be selected. Further suitable binders for use in capsule formulations according to the present invention include a hydroalcoholic solution, an aqueous binder or a non-aqueous binder. A particular binder described in the Examples is isopropyl alcohol together with methylene chloride. A capsule formulation according to the present invention may also include a hydrophobic lubricant and a suitable glidant. The artisan can select an appropriate lubricant and glidant in combination to impart good flowability to the blend to enable filling into the capsule shells. Suitable agents include talc, colloidal silicon dioxide and derivatives thereof, fatty acids and salts of fatty acids, mineral oil, and hydrogenated vegetable oils. An example of a suitable fatty acid material is stearic acid or its magnesium salt The most preferred combination is colloidal silicon dioxide and magnesium stearate. The present invention further comprises a process of preparing a pharmaceutical formulation substantially as herein before described, which process comprises providing an anti-obesity agent substantially as hereinbefore described, and at least one acidulant substantially as hereinbefore described, together with one or more pharmaceutically acceptable carriers, diluents or excipients therefor, in a pharmaceutical formulation. More particularly, a process of preparing a pharmaceutical formulation substantially as herein before described comprises mixing an anti-obesity agent, typically sibutramine, present as the free base, with a portion of acidulant, and at least one pharmaceutically acceptable carrier, diluent or excipient therefor, to obtain a dry mix, dissolving the remaining portion of acidulant in substantially purified water to obtain an aqueous acidulant solution, granulating the dry mix with the aqueous acidulant solution, to obtain a mass of required consistency, drying, sizing and filtering the resulting granules, and filling the granules in an appropriate capsule size. There is also provided by the present invention sibutramine fumarate suitable for use in a pharmaceutical formulation substantially as hereinbefore described. There is also provided by the present invention sibutramine fumarate, for use in the manufacture of a medicament for the treatment of obesity and related conditions. There is also provided by the present invention, use of sibutramine free base, together with an acidulant substantially as hereinbefore described, for the manufacture of a medicament for the treatment of obesity and related conditions. There is still further provided by the present invention a method of treating obesity and related conditions, which method comprises administering to a patient in need of such treatment sibutramine fumarate, or a pharmaceutical formulation, substantially as hereinbefore described. The present invention will now be further illustrated by the following examples, which do not limit the scope of the invention in anyway. While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims. The pharmaceutical formulation comprising an intimate admixture of an anti-obesity agent present as the free base, and at least one solid acidulant, together with a pharmaceutically acceptable carrier, diluent or excipient therefore is synergistic and exhibits surprising results. We Claim; I. A pharmaceutical composition useful for the treatment of obesity and related conditions, said composition comprising an anti-obesity agent present as the free base in an amount ranging from about 1% to 10 wt% and at least one acidulant in an amount in the range of 5.0 wt% to 25.0 wt% along with pharmaceutically acceptable carrier, diluents or excipient thereof, wherein said acidulant is selected to react with the anti-obesity agent to form a salt of the anti-obesity agent in situ. . 2. A pharmaceutical composition as claimed in claim 1, wherein said acidulant is selected from the group consisting of citric acid anhydrous, citric acid monohydrate, fumaric acid, DL-malic acid, L-malic acid, sorbic acid, DL-tartaric acid, L-tartaric acid and succinic acid. 3. A pharmaceutical composition as claimed in claim 2, wherein said acidulant is fumaric acid. 4. A pharmaceutical composition as claimed in claim 2, wherein said acidulant is succinic acid. .5. A pharmaceutical composition as claimed in claim 1, wherein said anti-obesity agent is selected from the group consisting of sibutramine, orlistat, solvates or physiologically functional derivatives thereof. 6. A pharmaceutical composition as claimed in claim 5, wherein said anti-obesity agent is sibutramine or orlistat free base. 7. A pharmaceutical composition as claimed in claim 6, wherein said anti-obesity agent is sibutramine free base. 8. A pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of oral preparation, wherein oral preparation is a capsule or tablet. 9. A pharmaceutical composition as claimed in claim 8, which is a capsule. 10. A pharmaceutical composition as claimed in claim 1, wherein said diluent comprises lactose and / or microcrystalline cellulose. II. A pharmaceutical composition as claimed in claim 1, wherein excipient comprises a glidant. 12. A pharmaceutical composition as claimed in claim 11, wherein said glidant is selected from the group consisting of talc, colloidal silicon dioxide and derivatives thereof, fatty acids and salts of fatty acids, mineral oil, and hydrogenated vegetable oils. 13. A pharmaceutical composition as claimed in claim 12, wherein said glidant comprises colloidal silicon dioxide and magnesium stearate. 14. A process of preparing a pharmaceutical formulation as claimed in any of claims 1 to 13, which process comprises providing an intimate admixture of said anti-obesity agent present as the free base and said at least one acidulant, together with said one or more pharmaceutically acceptable carriers, diluents or excipients thereof, in a pharmaceutical formulation according to any of claims 1 to 13. 15. A process as claimed in claim 14, which comprises mixing said anti-obesity agent, present as the free base, with a portion of said acidulant, and at least one pharmaceutically acceptable carrier, diluent or excipient thereof, to obtain a dry mix, dissolving the remaining portion of acidulant in substantially purified water to obtain an aqueous acidulant solution, granulating the dry mix with said aqueous acidulant solution, to obtain a mass of required consistency, drying, sizing and filtering the resulting granules, and filling the granules in an appropriate capsule size. Dated this 10th day of November, 2005 ABSTRACT Pharmaceutical Formulation Comprising Anti-Obesity Agent and Acidulant The present invention relates to a pharmaceutical composition comprising an anti-obesity agent present as the free base in an amount ranging from about 1% to 10 wt% and at least one acidulant 5.0 wt% to 25.0 wt% along with pharmaceutically acceptable carrier, diluents or excipient thereof.

Documents:

1255-mumnp-2005-abstract(03-02-2006).doc

1255-mumnp-2005-abstract(03-02-2006).pdf

1255-MUMNP-2005-ABSTRACT(AMENDED)-(2-5-2008).pdf

1255-MUMNP-2005-ABSTRACT(GRANTED)-(7-1-2009).pdf

1255-mumnp-2005-cancelled pages(03-02-2006).pdf

1255-MUMNP-2005-CANCELLED PAGES(2-5-2008).pdf

1255-MUMNP-2005-CLAIMS(10-11-2005).pdf

1255-MUMNP-2005-CLAIMS(AMENDED)-(2-5-2008).pdf

1255-mumnp-2005-claims(granted)-(03-02-2006).doc

1255-mumnp-2005-claims(granted)-(03-02-2006).pdf

1255-MUMNP-2005-CLAIMS(GRANTED)-(7-1-2009).pdf

1255-mumnp-2005-correspondence(02-05-2008).pdf

1255-MUMNP-2005-CORRESPONDENCE(9-11-2005).pdf

1255-mumnp-2005-correspondence(ipo)-(14-11-2008).pdf

1255-MUMNP-2005-CORRESPONDENCE(IPO)-(25-2-2009).pdf

1255-MUMNP-2005-DESCRIPTION(COMPLETE)-(10-11-2005).pdf

1255-MUMNP-2005-DESCRIPTION(GRANTED)-(7-1-2009).pdf

1255-mumnp-2005-form 1(03-02-2006).pdf

1255-mumnp-2005-form 1(10-11-2005).pdf

1255-mumnp-2005-form 18(17-04-2006).pdf

1255-MUMNP-2005-FORM 2(COMPLETE)-(10-11-2005).pdf

1255-mumnp-2005-form 2(granted)-(03-02-2006).doc

1255-mumnp-2005-form 2(granted)-(03-02-2006).pdf

1255-MUMNP-2005-FORM 2(GRANTED)-(7-1-2009).pdf

1255-MUMNP-2005-FORM 2(TITLE PAGE)-(10-11-2005).pdf

1255-MUMNP-2005-FORM 2(TITLE PAGE)-(GRANTED)-(7-1-2009).pdf

1255-mumnp-2005-form 26(01-02-2006).pdf

1255-mumnp-2005-form 26(03-02-2006).pdf

1255-MUMNP-2005-FORM 26(3-2-2006).pdf

1255-MUMNP-2005-FORM 3(10-11-2005).pdf

1255-mumnp-2005-form 3(20-02-2006).pdf

1255-mumnp-2005-form 5(09-11-2005).pdf

1255-MUMNP-2005-FORM 5(10-11-2005).pdf

1255-mumnp-2005-form-pct-isa-210(03-02-2006).pdf

1255-MUMNP-2005-SPECIFICATION(AMENDED)-(2-5-2008).pdf

1255-MUMNP-2005-WO INTERNATIONAL PUBLICATION REPORT(10-11-2005).pdf