KR20060059022A - Pharmaceutical formulations containing sumatriptan succinate - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing succinate sumatriptan, which masks the unpleasant taste of succinate sumatriptan optionally used for the treatment and prevention of migraine headache, and improves the release rate of the drug. The present invention relates to a succinate sumatriptan-containing pharmaceutical composition, which masks the unpleasant taste of succinate sumatriptan and improves the release rate of the drug by mixing the tableting agent.

Succinate sumatriptan, gasoline polymer, disintegration accelerator

Description

Pharmaceutical formulations containing sumatriptan succinate}

1 is a graph showing the dissolution rate test results of succinate sumatriptan-containing tablets prepared in Examples 1-2 and Comparative Examples 1-3 and 7.

The present invention relates to a pharmaceutical composition containing succinate sumatriptan, which masks the unpleasant taste of succinate sumatriptan optionally used for the treatment and prevention of migraine headache, and improves the release rate of the drug. The present invention relates to a succinate sumatriptan-containing pharmaceutical composition, which masks the unpleasant taste of succinate sumatriptan and improves the release rate of the drug by mixing the tableting agent.

Sumatriptan having the above structure has the chemical name 3- [2- (dimethylamino) ethyl] -N-1H-indole-5-methanesulfonamide, and may exist in the form of various organic acids and salts. It is a structural compound similar to serotonin, an endogenous delivery material in the cerebrovascular vessel, which selectively activates the receptor by acting on the 5-HT _1D receptor present in cerebrovascular smooth muscle, thereby constricting intracranial blood vessels, By reducing the secretion of vascular functional peptides involved in inflammation, migraines are alleviated and improved.

Forms of sumatriptan hydrochloride that are effective in treating migraines include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, methylsulfonate, citrate, benzoate, malate, maleate, tartarate and succinate. Korean Patent Registration No. 202042 proposes a tablet composition in which a 1: 1 salt with succinic acid is the active ingredient among several salt compounds of sumatriptan in the treatment of migraine symptoms. However, this only blocks the unpleasant taste of the active ingredient through a simple film coating process, and in adult patients and children who cannot swallow tablets, the nausea caused by the unpleasant taste when chewed or ground in powder form , It can cause side effects such as vomiting, and if the tablets are to be taken separately, there is a disadvantage that the unpleasant taste can not be avoided.

In order to solve this problem, a method of coating the active ingredient with a suitable polymer may be used, in which the coating ingredient should not affect the release rate of the active ingredient in that the active ingredient should have a rapid migraine treatment effect. Therefore, care must be taken in selecting the appropriate concentration of polymer to be used as the coating substrate. In addition, in order to quickly reduce the migraine headache should be a rapid drug release, the drug release of the film-coated tablets proposed in the patent has the disadvantage that it is difficult to obtain a rapid migraine treatment effect. In order to solve this problem, by using a suitable disintegration accelerator in succinate sumatriptan can be increased the release rate of succinate sumatriptan without a complicated process.

The present invention is to solve the above problems, an object of the present invention is to cover the unpleasant taste of succinate sumatriptan by coating the succinate sumatriptan with a gas-soluble polymer, and by mixing and disintegrating the disintegration accelerator and to block the rate of drug release An improved succinate sumatriptan-containing pharmaceutical composition is provided.

The succinic sumatriptan-containing pharmaceutical composition of the present invention is coated with an effective amount of succinic sumatriptan with 5 to 20% by weight relative to the weight of succinic sumatriptan with a gastric solubility polymer, and 3 to 10 weight with respect to the total weight of the formulation on the succinate sumatriptan coated with the gastric solubilizing polymer. After mixing and tableting the disintegration accelerator of%, it is characterized in that the coating was prepared in the form of a coated tablet.

The succinic acid sumatriptan-containing pharmaceutical composition of the present invention is characterized by including the process of coating the active ingredient to mask unpleasant taste and the process of adding a disintegration accelerator to achieve a more rapid migraine treatment effect.

Hereinafter, a method for preparing the succinate sumatriptan-containing pharmaceutical composition of the present invention will be described in detail.

1) sheath of succinate sumatriptan

In the present invention, in order to mask the unpleasant taste of succinate sumatriptan, an effective amount of succinate sumatriptan is coated with 5 to 20% by weight of succinate sumatriptan with a gastric polymer.

The gasosoluble polymer used to coat succinate sumatriptan is preferably contained 5 to 20% by weight based on the weight of succinate sumatriptan. If the gasosoluble polymer is used in less than 5% by weight of the active ingredient succinate sumatriptan, the unpleasant taste of succinate sumatriptan is not completely shielded, and if it is used in excess of 20% by weight, the release of the active ingredient is not preferable. .

In the present invention, Eudragit E-100, Carbopol 934P and the like can be used as the gasosoluble polymer. Use of Eudragit E-100 among the above materials is most preferred in view of the unpleasant taste masking effect of succinate sumatriptan.

In a preferred embodiment of the present invention, a coating solution is prepared by using Eudragit E-100, a gasosoluble polymer, in acetone / ethanol mixed solvent at a concentration of 5% (w / w), and then adding succinate sumatriptan to a fluidized bed coater. After fluidizing, the coating liquid may be sprayed such that Eudragit E-100 is in a ratio of 5 to 20% by weight, preferably 7 to 15% by weight, based on the active ingredient, thereby preparing succinate sumatriptan shielded with an unpleasant taste.

2) addition of disintegration accelerators

In the present invention, in order to improve the drug release rate of succinate sumatriptan, the tableting by mixing the disintegration accelerator of 3 to 10% by weight relative to the total weight of the formulation in the succinate sumatriptan coated with the gastric solubilizing polymer. If the disintegration accelerator is contained in less than 3% by weight of the total weight of the formulation can not be expected to promote the tablet disintegration effect, when contained in excess of 10% by weight is not preferable because the disintegration rate is constant regardless of the amount of the disintegration accelerator.

As the disintegration accelerator in the present invention, crospovidone, calcium carboxymethyl cellulose (Ca-CMC), sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), and the like can be used. Among the above materials, low-substituted hydroxypropyl cellulose is most preferred in view of improving the release rate of the active ingredient.

In a preferred embodiment of the present invention, 30 to 55 weight of microcrystalline cellulose relative to the total weight of the formulation as a disintegration accelerator and excipient of 3 to 10% by weight, preferably 5% by weight, of succinic sumatriptan coated with a gastric polymer. %, 20-30% by weight lactose and 0.1-1% by weight of lubricant can be mixed and then coated with an appropriate substrate to prepare a formulation in the form of a coated tablet.

Hereinafter, the structure and effect of the present invention will be described in more detail with specific examples and comparative examples, but these examples are only intended to more clearly understand the present invention, and are not intended to limit the scope of the present invention.

In Examples and Comparative Examples, the operating conditions of the fluidized bed coater used for the coating of succinate sumatriptan are shown in Table 1 below, and the composition of the tablet coating solution used in the prepared tablet coating is shown in Table 2 below.

TABLE 1

 Inlet air temperature 50 ??  Product bed temperature 42 ??  Feeding rate   5 g / min  Injection air velocity   5 m / sec  Spray nozzle pressure   1.5 bar  Spray nozzle diameter   0.8 mm

TABLE 2

Ingredient Name weight% Hydroxypropylmethylcellulose 2910 1.0 Hydroxypropyl cellulose 0.6 Polyethylene Glycol 6000 0.1 Talc 0.1 Titanium oxide 0.1 Yellow iron oxide 0.05 Red iron oxide 0.05 ethanol 49.0 Methylene chloride 49.0 system 100.0

(Examples 1-2 and Comparative Examples 1-2)

Ingredient Name Example 1 Example 2 Comparative Example 1 Comparative Example 2 Content (mg) weight% Content (mg) weight% Content (mg) weight% Content (mg) weight% Succinate Sumatriptan 70 17.5 70 17.5 70 17.5 70 17.5 Eudragit E-100 7 1.75 7 1.75 7 1.75 17 4.25 Microcrystalline cellulose 180 45.0 200 50.0 216 54.0 205 51.25 Lactose 100 25.0 100 25.0 100 25.0 100 25.0 L-HPC 40 10.0 20 5.0 4 1.0 20 5.0 Magnesium stearate 3 0.75 3 0.75 3 0.75 3 0.75 system 400 100.0 400 100.0 400 100.0 400 100.0

* L-HPC; Low Substituted Hydroxypropyl Cellulose (Shin-Etsu Chemical, Co, Japan)

Coating solution was prepared using Eudragit E-100 (R ?? hm Pharma GmbH, Germany) in acetone / ethanol mixed solvent at a concentration of 5% (w / w), followed by a fluidized bed coater (UniGlatt, Glatt GmbH, Germany). After adding succinate sumatriptan in the fluidized solution, the coating liquid is sprayed, and the remaining substances are mixed thereto to prepare tablets by direct tableting. This was coated with a tablet coating solution of Table 2 to prepare a tablet having a weight of 405 mg.

(Comparative Examples 3 to 6)

Ingredient Name Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Content (mg) weight% Content (mg) weight% Content (mg) weight% Content (mg) weight% Succinate Sumatriptan 70 17.5 70 17.5 70 17.5 70 17.5 Eudragit E-100 7 1.75 17 4.25 2 0.5 - - Microcrystalline cellulose 200 50.0 205 51.25 190 47.5 207 51.75 Lactose 120 30.0 100 25.0 100 25.0 100 25.0 Crospovidone - - 20 5.0 - - - - Carboxymethylcellulose Calcium - - - - 20 5.0 - - Sodium starch glycolate - - - - - - 20 5.0 Magnesium stearate 3 0.75 3 0.75 3 0.75 3 0.75 system 400 100.0 400 100.0 400 100.0 400 100.0

Coating solution was prepared using Eudragit E-100 (R ?? hm Pharma GmbH, Germany) in acetone / ethanol mixed solvent at a concentration of 5% (w / w), followed by a fluidized bed coater (UniGlatt, Glatt GmbH, Germany). After adding succinate sumatriptan in the fluidized solution, the coating liquid is sprayed, and the remaining substances are mixed thereto to prepare tablets by direct tableting. This was coated with the tablet coating solution of Table 2 to prepare a tablet having a weight of 405 mg.

(Comparative Example 7)

50 mg of the imiran tablet manufactured and sold by GlaxoSmithKline was used.

(Evaluation of the Unpleasant Taste According to the Amount of Gasolyte Polymer Used in Coating of Test Example 1-Succimatantan)

Coated tablets prepared according to the formulations of Examples 1 to 2 and Comparative Examples 3 to 6, and the products of Comparative Example 7, their tablet grounds and tablets without their coated skin were orally administered to 20 healthy adults. After a second, the unpleasant taste was evaluated. Evaluation criteria were evaluated by the following six grades. The results are shown in Table 3 below.

0: no unpleasant taste at all

1: 있음 has an unpleasant taste

2: taste slightly unpleasant

3: There is an unpleasant taste.

4: unpleasant taste but tolerable

5: unpleasant taste unbearable

TABLE 3

Example 1 Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Coated tablets 0 0 0 0 0 0 0 Refined powder 0 0 0 0 4 5 5 Uncoated tablet 0 0 0 0 3 5 5

As can be seen from the table, the coated tablets of Examples 1-2 and Comparative Examples 3-7 were masked of the unpleasant taste of sumatriptan. However, in these tablet mills and tablets from which the coated skin was removed, Examples 1 and 2 and Comparative Examples 3 and 4, in which an appropriate amount of Eudragit E-100, a gas-soluble polymer, were used or a little more than the appropriate amount, were unpleasant of sumatriptan. Although the taste was completely masked, Comparative Examples 5-6, with or without very little Eudragit E-100, did not mask the unpleasant taste of sumatriptan.

(Test Example 2- disintegration comparison test)

In order to confirm the drug release rate of succinate sumatriptan, the disintegration test was evaluated to predict the drug release rate. The disintegration test was carried out in Examples 1 to 2 and Comparative Examples 1 to 3 and 7 according to the disintegration test method of the Korean Pharmacopoeia. That is, put the auxiliary plate with 37 ㅁ 2 ?? of purified water as a test solution, take 6 tablets each time in a tester that reciprocates 29 to 32 times for 1 minute, put them in a glass tube, and then move them up and down for a certain period of time. The time was measured. The results are shown in Table 4 below.

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 7 Disintegration time (seconds) 60 60 340 60 570 300

(Test Example 3-Dissolution rate comparison test)

In order to confirm the release rate of succinate sumatriptan, using the coated tablets prepared with the compositions of Examples 1 and 2 and Comparative Examples 1 to 3 and the product of Comparative Example 7, dissolution using the dissolution test method of USP 27 for each time period Cumulative percentage (%) was evaluated. The paddle was rotated at 30 rpm while maintaining 37 W 0.2 ?? with 900 mL of 0.01 M HCl solution, and a certain amount of the eluate was filtered for each time period, and the content was analyzed by high performance liquid chromatography. The results are shown in Table 5 and FIG. 1.

Table 5

Minutes Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 7 0.5 17.2 14.2 13.5 8.2 0.1 0.2 One 49.4 48.5 21.4 12.4 0.3 0.8 1.5 84.3 81.1 38.4 28.4 1.8 2.5 2 94.2 92.5 49.6 45.6 3.8 14.8 2.5 98.3 97.4 64.8 62.4 7.2 24.4 3 100.0 100.0 74.6 74.5 19.5 58.2 5 100.0 100.0 82.4 84.2 42.8 71.4 10 100.0 100.0 93.8 97.8 74.6 98.0 20 100.0 100.0 100.0 100.0 94.6 100.0 30 100.0 100.0 100.0 100.0 100.0 100.0

According to the present invention, adult patients and children who are unable to swallow tablets by coating succinate sumatriptan having an unpleasant taste with gastric polymers, such as nausea and vomiting due to unpleasant taste when chewed or pulverized in powder form Side effects can be reduced, and the need to split the tablets can also mask the unpleasant taste. In addition, by adding an appropriate disintegration accelerator to succinate sumatriptan can significantly improve the drug release rate to improve the ease of taking and medication compliance of migraine patients compared to conventional formulations and to obtain a faster migraine treatment effect.

Claims (4)

After coating an effective amount of succinate sumatriptan with 5 to 20% by weight relative to the weight of succinate sumatriptan with a gasoline polymer, and mixing and mixing 3 to 10 wt. , Succinate sumatriptan-containing pharmaceutical composition, characterized in that the coated with a substrate prepared in the form of a coated tablet. The succinate sumatriptan-containing pharmaceutical composition according to claim 1, wherein the gasosoluble polymer is selected from Eudragit E-100 or Carbopol 934P. The succinic acid sumatriptan-containing drug according to claim 1, wherein the disintegration accelerator is one or two or more selected from the group consisting of crospovidone, calcium carboxymethyl cellulose, sodium starch glycolate and low-substituted hydroxypropyl cellulose. Pharmaceutical composition. The succinic acid sumatriptan-containing pharmaceutical composition according to claim 1, wherein the disintegration accelerator contains 5% by weight of low-substituted hydroxypropyl cellulose relative to the total weight of the preparation.

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