KR100781882B1 - A pharmaceutical composition containing sibutramine - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing sibutramine as an active ingredient, and provides a composition in which the dissolution rate of sibutramine free base in water is significantly improved. The present invention also provides compositions with improved storage stability of sibutramine.

Sibutramine

Description

Pharmaceutical composition containing sibutramine {A PHARMACEUTICAL COMPOSITION CONTAINING SIBUTRAMINE}

The present invention relates to a pharmaceutical composition containing sibutramine as an active ingredient.

Sibutramine is known in vivo as 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitors (Prog. Neuro-Psychopharmacol. Biol. Psychiast. 12, 575-584, Neuropharmacology, 28, 129-134) . In addition, sibutramine is known to have Parkinson's disease or antidepressant effects (Inter. J. Obesity, 1995, 19,145, WO 88/06444, Korean Patent Nos. 0032617 and 0164435) and reduce insulin resistance. Or to enhance sugar resistance (US Pat. Nos. 6,174,925 and 6,187,820).

However, sibutramine in freebase form is a poorly soluble drug in water or basic solvents. Therefore, in order to solve this solubility problem of sibutramine free base, it is mainly developed by converting it into the form of acid addition salt of sibutramine, for example, hydrochloride, methanesulfonate, or hydrate thereof.

Typically, sibutramine hydrochloride monohydrate is used as an active ingredient of the well-known Meridia ^(TM Meridia) or rideoktil (Reductil ^TM) in obesity treatment (Republic of Korea Patent No. 0164435 No.). However, even though the dissolution rate in commercially available reductil is significantly improved, the release rate of the drug is still less than 50% in the initial 15 minutes, and the release rate in the first hour is also 70%. Therefore, it becomes a problem.

Therefore, in recent years, attempts have been made to develop various acid addition salts in addition to sibutramine hydrochloride monohydrate (Korean Patent Registration No. 0081418 and Korean Patent Publication No. 2004-0031574). However, such acid addition salt has to go through a separate synthesis process in order to introduce a salt at the end of sibutramine, and there is a troublesome process such as the problem of residual organic solvent used during the synthesis process.

In addition, in the case of the formulation containing the sibutramine of the prior art there is a problem in terms of stability due to increased impurity (impurity) during long-term storage. In particular, the inventors have found that sibutramine reacts with certain excipients to significantly increase its metabolite desmethyl-sibutramine (M1) content, and selection of excipients that can minimize such impurity increases is required.

Accordingly, an object of the present invention is to provide a composition containing sibutramine free base as an active ingredient with improved dissolution rate in water, and another object to provide a sibutramine-containing composition in which stability is maintained during long-term storage.

According to one embodiment of the invention, the invention provides a composition comprising sibutramine free base, an acidifying agent, a surfactant and a pharmaceutically acceptable excipient as an active ingredient.

According to another embodiment of the invention, the present invention provides a composition comprising sibutramine or a salt thereof and a pharmaceutically acceptable excipient and no excipients containing alkaline earth metals.

The composition of the present invention contains sibutramine free base as an active ingredient, and includes an acidulant, a surfactant, and a pharmaceutically acceptable excipient.

Sibutramine, the active ingredient included in the composition of the present invention, is in free base form, and the content of the active ingredient is included in an amount of 1 to 10% based on the total weight of the composition, and preferably in an amount of 1 to 5% based on the total weight of the composition. Do.

In the present invention, citric acid, citric acid, malic acid, maleic acid or maleic acid may be used. The acidifier may be included in an amount of 1 to 20% based on the total weight of the composition, and preferably in an amount of 2 to 5% based on the total weight of the composition.

In the present invention, the surfactant is polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, sucrose fatty acid ester, sodium dioxylsulfo succinate, sodium lauryl sulfate, alkyl sulfate or mono Sorbitan sorbate and the like can be used. The amount of the surfactant may be 1 to 30% based on the total weight of the composition, and preferably 1 to 10% based on the total weight of the composition.

In addition, the composition of the present invention may further include optionally one or more pharmaceutically acceptable excipients, if necessary, for example, may further include diluents, lubricants, disintegrants, flavoring or sweetening agents.

For example, lactose, anhydrous lactose, straight lactose, microcrystalline cellulose, starch or mannitol may be used, and the content may include 5 to 80% of the total weight of the composition, and the total weight of the composition It is preferably included in 10 to 60%.

As the lubricant, colloidal silicon dioxide, talc, sodium stearyl fumarate, rotoester, stearic acid, rotoester or hydrogenated castor oil and the like can be used, of which colloidal silicon dioxide or talc is preferable. The lubricant may be included in an amount of 0.1 to 5% based on the total weight of the composition, and preferably in an amount of 0.1 to 1% based on the total weight of the composition.

The composition of the present invention may further include a disintegrant, a flavoring agent and a sweetening agent in an appropriate range in addition to the additives mentioned above by those skilled in the art.

In addition, the inventors of the present invention, when an excipient containing an alkaline earth metal such as magnesium, barium, strontium, calcium, etc. are included in the composition containing sibutramine or a salt thereof, the excipient interacts with sibutramine to form impurities (M1). It was found for the first time that it was significantly increased.

Accordingly, the present invention provides a composition comprising sibutramine or a salt thereof as an active ingredient and no excipient containing an alkaline earth metal as a pharmaceutically acceptable excipient. For example, excipients containing alkaline earth metals include magnesium stearate or magnesium trisilicate and the like.

The composition according to the present invention can be prepared variously by a conventional tablet or capsule manufacturing method such as direct mixing, wet granulation, dry granulation method, there is no particular limitation on the preparation method.

As described above, the composition prepared according to the present invention improves dissolution rate in water while containing sibutramine free base as an active ingredient. In addition, the composition prepared according to the present invention does not increase impurities even during long-term storage is maintained stability.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the present invention.

Examples 1 to 3

According to the content shown in Table 1, the sibutramine free base, colloidal silicon dioxide, starch and microcrystalline cellulose are mixed and then mixed again with the excipients except for talc. The mixture was mixed with talc and then filled into capsules (2 hard capsules).

Ingredient Name Content (mg) Example 1 Example 2 Example 3 Lactose 180.5 180.5 180.5 Starch 15.9 15.9 15.9 Microcrystalline cellulose 31.8 31.8 31.8 Sodium starch glycolate 5.2 5.2 5.2 Talc 1.3 1.3 1.3 Colloidal silicon dioxide 1.3 1.3 1.3 Citric acid 13 - - Succinic acid - 13 - Malic acid - - 13 Polyoxyethylene-Polyoxypropylene Block Copolymer 2.6 2.6 2.6 Citratramine freebase 8.4 8.4 8.4 Total 260 260 260

Examples 4-6

According to the content shown in Table 2, the sibutramine free base, colloidal silicon dioxide and microcrystalline cellulose are mixed and then mixed with the other excipients except talc. The mixture was mixed with talc and then filled into capsules (2 hard capsules).

Ingredient Name Content (mg) Example 4 Example 5 Example 6 Lactose 155.4 158.0 155.4 Microcrystalline cellulose 78.0 78.0 78.0 Sodium starch glycolate 5.2 5.2 5.2 Talc 1.3 1.3 1.3 Colloidal silicon dioxide 1.3 1.3 1.3 Citric acid 5.2 5.2 5.2 Polyoxyethylene-Polyoxypropylene Block Copolymer 5.2 - - Sodium Lauryl Sulfate - 2.6 - Sucrose fatty acid ester - - 5.2 Sibutramine freebase 8.4 8.4 8.4 Total 260 260 260

Examples 7 and 8

Sibutramine free base, colloidal silicon dioxide, and microcrystalline cellulose are mixed according to the contents shown in Table 3, and then mixed again with the excipients except for talc (or sodium stearyl fumarate). The mixture was mixed with talc (or sodium stearyl fumarate) and then compressed.

Ingredient Name Content (mg) Example 7 Example 8 Lactose 155.4 155.4 Microcrystalline cellulose 78.0 78.0 Starch Gly Sodium A 5.2 5.2 Talc 1.3 - Sodium stearyl fumarate - 1.3 Colloidal silicon dioxide 1.3 1.3 Citric acid 5.2 5.2 Polyoxyethylene-Polyoxypropylene Block Copolymer 5.2 5.2 Sibutramine freebase 8.4 8.4 Total 260 260

Example  9

Sibutramine hydrochloride monohydrate, colloidal silicon dioxide and microcrystalline cellulose were mixed according to the contents shown in Table 4, and then mixed again with the excipients except for talc. The mixture was mixed with talc and then filled into capsules (2 hard capsules).

Ingredient Name Content (mg) Lactose 164.2 Microcrystalline cellulose 78.0 Sodium starch glycolate 5.2 Talc 1.3 Colloidal silicon dioxide 1.3 Sibutramine Hydrochloride Monohydrate 10 Total 260

Comparative Examples 1 to 3

According to the content shown in Table 5, sibutramine free base, colloidal silicon dioxide, starch and microcrystalline cellulose are mixed and then mixed again with the excipients except for talc. The mixture was mixed with talc and then filled into capsules (2 hard capsules).

Ingredient Name Content (mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Lactose 190.9 190.9 183.1 Starch 15.9 15.9 15.9 Microcrystalline cellulose 31.8 31.8 31.8 Starch Gly Sodium A 5.2 5.2 5.2 Talc 1.3 1.3 1.3 Colloidal silicon dioxide 1.3 1.3 1.3 Polyoxyethylene-Polyoxypropylene Block Copolymer 5.2 - - Sodium Lauryl Sulfate - 5.2 - Sucrose fatty acid ester - - 13 Sibutramine freebase 8.4 8.4 8.4 Total 260 260 260

Comparative example  4 and 5

Sibutramine free base, colloidal silicon dioxide, and microcrystalline cellulose are mixed according to the contents shown in Table 6, and then mixed again with the excipients except magnesium stearate (or magnesium trisilicate). The mixture was mixed with magnesium stearate (or magnesium trisilicate) and filled into capsules (2 hard capsules).

Ingredient Name Content (mg) Comparative Example 4 Comparative Example 5 Lactose 155.4 155.4 Microcrystalline cellulose 78.0 78.0 Sodium starch glycolate 5.2 5.2 Magnesium Stearate 1.3 - Magnesium trisilicate - 1.3 Colloidal silicon dioxide 1.3 1.3 Citric acid 5.2 5.2 Polyoxyethylene-Polyoxypropylene Block Copolymer 5.2 5.2 Sibutramine freebase 8.4 8.4 Total 260 260

Comparative example  6

Sibutramine hydrochloride monohydrate, colloidal silicon dioxide, and microcrystalline cellulose were mixed according to the contents shown in Table 7, and then mixed again with the excipients except magnesium stearate. The mixture was mixed with magnesium stearate and filled into capsules (2 hard capsules).

Ingredient Name Content (mg) Lactose 177.0 Sodium starch glycolate 2.0 Colloidal silicon dioxide 0.5 Microcrystalline cellulose 70.0 Magnesium Stearate 0.5 Sibutramine Hydrochloride Monohydrate 10.0 Total 260

Test Example 1: Comparative Dissolution Experiment

Example 1, 2, 5 and 6, Comparative Examples 1 to 3 capsules and commercial preparations (control: Reductil ^TM capsules, Abbott) dissolution test method 2 (paddle) Method), and the elution rate was confirmed over time. The test results are shown in Table 8 below.

Eluent: deionized purified water

Eluent temperature: 37 ± 0.5 ℃

Rotational Speed: 50 rpm

Method: Liquid Chromatography

Column-ymc-pack pro c ₈

 Mobile phase-Buffer: Acetonitrile: Methanol (30: 40: 30 v / v)

Injection volume-20 μl

Flow rate-1 ml / min

Detector-UV 225 nm

Elution time Dissolution rate (%) Reference Example 1 Example 2 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 minutes 32.8 42.2 37.7 37.6 35.1 17.8 15.2 21.3 15 minutes passed 47.8 64.0 77.9 67.4 74.1 26.3 28.1 38.6 30 minutes passed 60.0 70.5 89.3 79.3 86.0 32.0 29.8 38.8 15 minutes passed 69.6 77.7 91.8 84.2 89.9 36.6 32.6 39.2 Elapsed 60 minutes 71.2 82.3 92.4 88.6 91.3 38.7 35.8 43.1

As can be seen in Table 8, in the embodiment of the present invention, not only the dissolution rate in water was significantly improved compared to the comparative example, but also showed a dissolution rate of about 10% higher than that of the reference drug (Reductil ^TM capsule).

Test Example  2: stability test

The capsules prepared according to Examples 1, 2, 5, 8 and 9 and Comparative Examples 4 to 6 were stored for 10 days under accelerated conditions (40 ° C./75 RH), and the increase in each impurity (M1) was confirmed. The test results are shown in Table 9 below.

Early 10 days M1 unknown M1 unknown Example 1 0.02 0.01 0.06 0.03 Example 2 0.02 0.02 0.08 0.03 Example 5 0.01 0.02 0.06 0.03 Example 8 0.02 0.01 0.04 0.03 Example 9 0.02 0.02 0.06 0.04 Comparative Example 4 0.02 0.03 0.36 0.18 Comparative Example 5 0.02 0.02 0.53 0.20 Comparative Example 6 0.02 0.02 0.25 0.51

 As can be seen in Table 9, the impurity M1 did not increase much in the case of the example, but it was confirmed that the impurity M1 increased greatly in the comparative example.

Test Example  3: Test of interaction between active ingredient and excipient

After mixing cibutramine and each component of Table 10 in a 1: 1 ratio, an increase of each impurity (M1) was observed after storing for 15 days in an open and closed state under accelerated conditions (40 ° C./75 RH). . The test results are shown in Table 10 below.

Ingredient Name Early 15th M1 unknown M1 unknown Lactose 0.03 0.02 0.07 0.05 Microcrystalline cellulose 0.02 0.02 0.05 0.03 Sodium starch glycolate 0.03 0.02 0.06 0.03 Colloidal silicon dioxide 0.02 0.02 0.06 0.05 Polyoxy Ethylene-Polyoxy Propylene Block Copolymer 0.02 0.02 0.04 0.03 Magnesium Stearate 0.02 0.02 0.18 0.06 Magnesium trisilicate 0.02 0.02 0.11 0.05 Talc 0.02 0.03 0.06 0.03 Sodium stearyl fumarate 0.02 0.02 0.04 0.03 Citric acid 0.02 - 0.04 0.03 Succinic acid 0.02 0.02 0.05 0.02

As can be seen in Table 10, in the case of magnesium stearate and magnesium trisilicate as an excipient containing an alkaline earth metal, it can be seen that the impurities (M1) increased significantly.

The composition of the present invention significantly improves dissolution rate in water while containing sibutramine free base as an active ingredient. In addition, the compositions prepared according to the present invention maintain stability even during long term storage.

Claims (13)

Sibutramine free base as an active ingredient; Acidifying agents selected from the group consisting of citric acid, succinic acid, malic acid and maleic acid; From the group consisting of polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, sucrose fatty acid ester, sodium dioxylsulfo succinate, sodium lauryl sulfate, alkyl sulfate and monosorbitan sorbate Surfactant selected; And one or more excipients that do not contain magnesium, barium, strontium, or calcium. The composition of claim 1, wherein the content of the active ingredient is included in an amount of 1 to 10% based on the total weight of the composition. delete delete The composition of claim 1 wherein the content of acidifying agent comprises 1-20% of the total weight of the composition. The composition of claim 1 wherein the content of surfactant comprises 1-30% of the total weight of the composition. The composition of claim 1, wherein the excipient comprises a diluent, a lubricant, a perfume and / or a sweetener. 8. The composition of claim 7, wherein the diluent is at least one selected from the group consisting of lactose, anhydrous lactose, straight lactose, microcrystalline cellulose, starch and mannitol. 8. The composition of claim 7, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, sodium stearyl fumarate, stearic acid, rotoesters and hydrogenated castor oils. delete Tablets or capsules prepared from the composition according to claim 1, 2, 5 to 9. delete delete