WO2007007971A1

WO2007007971A1 - Pharmaceutical compositions comprising sibutramine

Info

Publication number: WO2007007971A1
Application number: PCT/KR2006/002618
Authority: WO
Inventors: Young-Joon Park; Yoen-Ju Son; Hyun-Jun Kim
Original assignee: Yuhan Corp
Current assignee: Yuhan Corp
Priority date: 2005-07-12
Filing date: 2006-07-05
Publication date: 2007-01-18
Anticipated expiration: 2008-01-12
Also published as: KR20070008787A; KR100781882B1

Abstract

The present invention provides a pharmaceutical composition for oral administration comprising: sibutramine in a free base form; an acidifying agent selected from the group consisting of citric acid, succinic acid, malic acid, maleic acid, and a mixture thereof; and a surfactant. Further, the present invention provides a pharmaceutical composition with improved stability comprising a sibutramine salt and an alkaline earth metal-free pharmaceutically acceptable additive.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING

SIBUTRAMINE

Technical Field

[1] The present invention relates to a pharmaceutical composition comprising sibutramine or a salt thereof as an active ingredient. Background Art

[2] Sibutramine is known as an inhibitor of 5 -hydroxy tryptamine (5-HT) and noradrenaline reuptake in vivo {Prog. Neuro-Psychopharmacol. Biol. Psychiast. 12, 575-584, Neuropharmacology, 28, 129-134). Sibutramine is also known to have a therapeutic effect against a Parkinson's disease, obesity, or depression (WO 88/06444, U.S. Pat. No. 4,814,352, and WO 90/06110] and to reduce insulin resistance or improve glucose tolerance (U.S. Pat. No. 6,174,925 and No. 6,187,820).

[3] Sibutramine in a free base form is hardly soluble in water or a basic solvent. In order to enhance the solubility of sibutramine, the use of sibutramine as an acid addition salt form, e.g., hydrochloride, methanesulfonate, or a monno- or hemi-hydrate thereof is disclosed (EP0230742 and U.S. Pat. Laid-Open Pub. No. 20040068018). For example, sibutramine hydrochloride monohydrate is used as an active ingredient of

Meridia or Reductil that has been widely known as an anti-obesity drug (WO 90/06110).

[4] Although commercially available Reductil exhibits a markedly improved dissolution property in water, it still shows a dissolution pattern of a poorly soluble drug, i.e., less than 50% initial release (within 15 minutes) and about 70% subsequent release (within one hour after the initial release).

[5] Furthermore, the preparation of an acid addition salt of sibutramine involves a separate process for the conversion of sibutramine to its acid addition salt. At this time, there may arise a problem that an organic solvent used is left in the product. In addition, sibutramine-containing formulations are not stable in long-term storage due to increased impurities. Therefore, it is necessary to improve storage stability of sibutramine-containing formulations. Disclosure of Invention

Technical Problem

[6] The present invention provides a pharmaceutical composition for enhancing a dissolution rate of sibutramine in an aqueous medium, comprising sibutramine in a free base form as an active ingredient, and a pharmaceutical composition with improved stability, comprising sibutramine or its salt. [7] That is, the present invention provides a pharmaceutical composition comprising sibutramine in a free base form as an active ingredient.

[8] The present invention also provides a pharmaceutical composition with improved stability, including sibutramine or its salt. Technical Solution

[9] In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for oral administration comprising: sibutramine in a free base form; an acidifying agent selected from the group consisting of citric acid, succinic acid, malic acid, maleic acid, and a mixture thereof; and a surfactant.

[10] In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising a sibutramine salt and an alkaline earth metal-free pharmaceutically acceptable additive. Mode for the Invention

[11] The present invention provides a pharmaceutical composition including sibutramine in a free base form. In the pharmaceutical composition of the present invention, the sibutramine in the free base form is formulated together with an acidifying agent and a surfactant. Therefore, it is possible to solve the problem of a residual solvent caused in a separate process for the conversion of sibutramine to an acid addition salt form, and to achieve a satisfactory dissolution rate of sibutramine in an aqueous medium.

[12] In the pharmaceutical composition of the present invention, the sibutramine in the free base form is used as an active ingredient. The sibutramine in the free base form can be used in a therapeutically effective amount. A unit dosage form may include 5 - 50 mg, preferably about 8 - 20 mg of the sibutramine in the free base form. The content of the sibutramine in the free base form may be 1 - 10 wt%, preferably 1 - 5 wt%, based on the total weight of the composition.

[13] The acidifying agent included in the pharmaceutical composition of the present invention is selected from the group consisting of citric acid, succinic acid, malic acid, maleic acid, and a mixture thereof. The content of the acidifying agent may be 1 - 20 wt%, preferably 2 - 5 wt%, based on the total weight of the composition.

[14] The surfactant may be selected from the group consisting of polyoxyethylene castor oil derivatives, polyoxyethylene-polyoxypropylene block copolymers, sucrose fatty acid esters, sodium dioctyl sulfosuccinate, metal salts of alkyl sulfate, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. The metal salts of alkyl sulfate may include sodium lauryl sulfate, sodium dodecyl sulfate, etc., the sorbitan fatty acid esters may include commercially available Span series surfactants, and the polyoxyethylene sorbitan fatty acid esters may include commercially available Tween series surfactants. The content of the surfactant may be 1 - 30 wt%, preferably 1 - 10 wt%, based on the total weight of the composition.

[15] The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive. Surprisingly, the present inventor found that inte raction of sibutramine or its salt with an alkaline earth metal (e.g., magnesium, barium, strontium, or calcium) produced impurities (e.g., desmethyl-sibutramine (Ml) produced in the presence of an alkaline earth metal-containing excipient), thereby resulting in a significant reduction in stability.

[16] Thus, the pharmaceutically acceptable additive may be an alkaline earth metal-free pharmaceutically acceptable additive.

[17] The pharmaceutically acceptable additive may be a diluent selected from the group consisting of lactose (including hydrous lactose, anhydrous lactose, and direct compression lactose), microcrystalline cellulose, starch, sodium starch glycolate, mannitol, and a mixture thereof; and/or a lubricant selected from the group consisting of silicon dioxide, talc, sodium stearyl fumarate, stearic acid, sugar esters (Ryoto esters, Tokyo), hydrogenated castor oil, and a mixture thereof. The content of the diluent may be 5 - 80 wt%, preferably 10 - 60 wt%, based on the total weight of the composition, and the content of the lubricant may be 0.1 - 5 wt%, preferably 0.1 - 1 wt%, based on the total weight of the composition. The pharmaceutical composition of the present invention may further include a disintegrating agent, a flavoring agent, or a sweetener, when needed.

[18] The pharmaceutical composition of the present invention can be formulated into various oral dosage forms, preferably tablets or capsules.

[19] The present invention also provides a pharmaceutical composition with improved stability, including a sibutramine salt and an alkaline earth metal-free pharmaceutically acceptable additive. The sibutramine salt may be selected from all known salts, e.g., hydrochlorides, methanesulfonates, and mono- or hemi-hydrates thereof.

[20] The alkaline earth metal-free pharmaceutically acceptable additive may be the above-illustrated diluent and/or lubricant, and when needed, may further include a disintegrating agent, a flavoring agent, a sweetener, etc.

[21] The above-described pharmaceutical compositions of the present invention can be prepared according to conventional preparation methods of oral formulations, e.g., direct tableting, wet granulation, or dry granulation.

[22] Hereinafter, the present invention will be described more specifically by the following working examples. However, the following working examples are provided only for illustrations and thus the present invention is not limited to or by them.

[23]

[24] Examples 1 - 3

[25] Capsules were prepared with components and contents presented in Table 1 below. Sibutramine in a free base form, colloidal silicon dioxide, starch, and microcrystalline cellulose were mixed, and the other additives (except for talc) were added thereto. The resultant mixture was mixed with talc and filled in No. 2 hard capsules to give capsules.

[26] Table 1

[27] [28] Examples 4 - 6 [29] Capsules were prepared with components and contents presented in Table 2 below. Sibutramine in a free base form, colloidal silicon dioxide, and microcrystalline cellulose were mixed, and the other additives (except for talc) were added thereto. The resultant mixture was mixed with talc and filled in No. 2 hard capsules to give capsules.

[30] Table 2

[31] [32] Examples 7 and 8 [33] Tablets were prepared with components and contents presented in Table 3 below. Sibutramine in a free base form, colloidal silicon dioxide, and microcrystalline cellulose were mixed, and the other additives (except for talc or sodium stearyl fumarate) were added thereto. The resultant mixture was mixed with talc (or sodium stearyl fumarate) and compressed to give tablets.

[34] Table 3

[35] [36] Example 9 [37] Capsules were prepared with components and contents presented in Table 4 below. Sibutramine hydrochloride monohydrate, colloidal silicon dioxide, and micro- crystalline cellulose were mixed, and the other additives (except for talc) were added thereto. The resultant mixture was mixed with talc and filled in No. 2 hard capsules to give capsules.

[38] Table 4

[39] [40] Comparative Examples 1 - 3 [41] Capsules were prepared with components and contents presented in Table 5 below. Sibutramine in a free base form, colloidal silicon dioxide, starch, and microcrystalline cellulose were mixed, and the other additives (except for talc) were added thereto. The resultant mixture was mixed with talc and filled in No. 2 hard capsules to give capsules.

[42] Table 5

[43] [44] [45] Comparative Examples 4 and 5 [46] Capsules were prepared with components and contents presented in Table 6 below. Sibutramine in a free base form, colloidal silicon dioxide, and microcrystalline cellulose were mixed, and the other additives (except for magnesium stearate or magnesium trisilicate) were added thereto. The resultant mixture was mixed with magnesium stearate or magnesium trisilicate and filled in No. 2 hard capsules to give capsules.

[47] Table 6

[48] [49] Comparative Example 6 [50] Capsules were prepared with components and contents presented in Table 7 below. Sibutramine hydrochloride monohydrate, colloidal silicon dioxide, and micro- crystalline cellulose were mixed, and the other additives (except for magnesium stearate) were added thereto. The resultant mixture was mixed with magnesium stearate and filled in No. 2 hard capsules to give capsules.

[51] Table 7

[52] [53] Test Example 1: Dissolution tests [54] The dissolution tests of the capsules prepared in Examples 1, 2, 5, and 6 and the comparative capsules prepared in Comparative Examples 1 - 3, and commercially available capsules (control capsules: Reductil ™, Abbott) were performed according to Dissolution Test Method II (paddle method) described in the General Tests chapter of the Korean pharmacopoeia under the following conditions. The results are summarized in Table 8 below.

[55] Dissolution medium: deionized purified water [56] Temperature of dissolution medium: 37 + 0.5 ⁰C [57] Rotation speed: 50 rpm [58] Analytical method: liquid chromatography [59] Column - YMC-Pack pro C

8 [60] Mobile phase - Buffer: acetonitrile: methanol (30:40:30, v/v/v) [61] Injection volume - 20 ul [62] Flow rate - 1 ml/min [63] Detector - UV 225 nm [64] [65] Table 8

[66] As seen from Table 8 above, the capsules of the present invention exhibited a significantly improved dissolution rate in an aqueous medium, relative to the comparative capsules. Furthermore, the capsules of the present invention exhibited about 10% higher dissolution rate than the control capsules (Reductil ).

[67] [68] Experimental Example 2: Stability tests [69] The capsules prepared in Examples 1, 2, 5, 8, and 9 and the comparative capsules prepared in Comparative Examples 4 - 6 were stored under acceleration conditions (40 ⁰C/ 75 RH) for 10 days, and the contents of impurities (including desmethyl- sibutramine (Ml)) were measured. The results are summarized in Table 9 below.

[70] Table 9

[71] As seen from Table 9 above, the contents of impurities (desmethyl-sibutramine (Ml)) in the capsules of the present invention were not increased significantly, whereas the contents of impurities (desmethyl-sibutramine (Ml)) in the comparative capsules were increased significantly.

[72] [73] Experimental Example 3: Interaction tests between active ingredients and additives

[74] Sibutramine was mixed with each component presented in Table 10 below with a mixture ratio of 1 to 1. The resultant mixtures were stored under acceleration conditions (40 ⁰C / 75 RH) for 15 days, and the contents of impurities (including desmethyl-sibutramine (Ml)) were measured. The results are summarized in Table 10 below.

[75] Table 10

[76] [77] As seen from Table 10 above, with respect to the mixtures of sibutramine with alkaline earth metal-containing compounds, i.e., magnesium stearate and magnesium trisilicate, the concentration of desmethyl-sibutramine (Ml) was increased significantly.

Industrial Applicability [78] A pharmaceutical composition of the present invention exhibits a markedly improved dissolution rate of sibutramine in an aqueous medium while it includes sibutramine in a free base form as an active ingredient. Furthermore, the pharmaceutical composition of the present invention can maintain good stability during long-term storage.

Claims

[I] A pharmaceutical composition for oral administration comprising: sibutramine in a free base form; an acidifying agent selected from the group consisting of citric acid, succinic acid, malic acid, maleic acid, and a mixture thereof; and a surfactant.

[2] The pharmaceutical composition of claim 1, wherein the content of the sibutramine in the free base form is 1 to 10 wt% based on the total weight of the composition.

[3] The pharmaceutical composition of claim 1, wherein the content of the acidifying agent is 1 to 20 wt% based on the total weight of the composition.

[4] The pharmaceutical composition of claim 1, wherein the surfactant is selected from the group consisting of polyoxyethylene castor oil derivatives, poly- oxyethylene-polyoxypropylene block copolymers, sucrose fatty acid esters, sodium dioctyl sulfosuccinates, metal salts of alkyl sulfate, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters and a mixture thereof.

[5] The pharmaceutical composition of claim 1, wherein the content of the surfactant is 1 to 30 wt% based on the total weight of the composition.

[6] The pharmaceutical composition of any one of claims 1 through 5, further comprising an alkaline earth metal-free pharmaceutically acceptable additive.

[7] The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable additive is a diluent selected from the group consisting of lactose, mi- crocrystalline cellulose, starch, sodium starch glycolate, mannitol, and a mixture thereof; and/or a lubricant selected from the group consisting of silicon dioxide, talc, sodium stearyl fumarate, stearic acid, sugar esters, hydrogenated castor oil, and a mixture thereof.

[8] The pharmaceutical composition of claim 6, which is formulated into tablets or capsules.

[9] The pharmaceutical composition of claim 8, which comprises a diluent selected from the group consisting of lactose, microcrystalline cellulose, starch, sodium starch glycolate, mannitol, and a mixture thereof; and/or a lubricant selected from the group consisting of silicon dioxide, talc, sodium stearyl fumarate, stearic acid, sugar esters, hydrogenated castor oil, and a mixture thereof.

[10] A pharmaceutical composition comprising a sibutramine salt and an alkaline earth metal-free pharmaceutically acceptable additive.

[I I] The pharmaceutical composition of claim 10, wherein the sibutramine salt is sibutramine hydrochloride, sibutramine methanesulfonate, or a mono- or hemi- hydrate thereof. [12] The pharmaceutical composition of claim 10 or 11, wherein the pharmaceutically acceptable additive is a diluent selected from the group consisting of lactose, mi- crocrystalline cellulose, starch, sodium starch glycolate, mannitol, and a mixture thereof; and/or a lubricant selected from the group consisting of silicon dioxide, talc, sodium stearyl fumarate, stearic acid, sugar esters, hydrogenated castor oil, and a mixture thereof.