KR100572411B1 - Thermodynamic stable amorphous torasemide solid dispersions and pharmaceutical composition comprising same and method for the preparation thereof - Google Patents

Abstract

The present invention relates to a thermodynamically stable amorphous torasemide solid dispersion, a pharmaceutical composition comprising the same and a method for preparing the same. The amorphous torasemide solid dispersion according to the present invention is thermodynamically stable under the influence of heat and moisture, and has excellent solubility. In addition, the pharmaceutical composition comprising the amorphous torasemide solid dispersion according to the present invention has a high dissolution rate, the method of preparing the amorphous torasemide solid dispersion according to the present invention is thermodynamically stable amorphous solid dispersion with no crystallinity Provide a sieve.

Description

Thermodynamically stable amorphous torasemide solid dispersion, a pharmaceutical composition comprising the same, and a method for preparing the same, and a method for preparing the same.             

1 shows a thermogram of a differential scanning calorimeter (DSC) at the initial conditions of torasemide variant I, comparative examples 1 and 2, examples 1 and 5;

FIG. 2 is a thermogram of a differential scanning calorimeter (DSC) after storage for 50 days in a high density polyethylene container at 40 ° C. and 75% relative humidity conditions of Torasemide Variation I, Comparative Examples 1 and 2, and Examples 1 and 5; FIG. Indicates.

Figure 3 shows the differential scanning calorimetry (DSC) of the differential scanning calorimetry (DSC) at the initial conditions of Comparative Examples 3 and 7 and the differential scanning calorimetry (DSC) after storage for 50 days in a high density polyethylene container at 40 ℃, 75% relative humidity conditions It shows the temperature record of.

4 shows the solubility test results of torasemide variant I, comparative example 2, examples 2 and 6;

Figure 5 shows the results of X-ray powder diffraction analysis at the initial conditions of the control formulation (torem tablet), torasemide modified I, modified II, Comparative Example 1, Example 1 and Example 8.

FIG. 6 shows the results of X-ray powder diffraction analysis after storage for 50 days in a high-density polyethylene container at 40 ° C. and 75% relative humidity conditions of Comparative Example 1, Example 1, and Example 8. FIG.

7 shows the results of Fourier transformed Raman analysis of torasemide modified I, modified II, comparative example 1 and comparative example 4. FIG.

Figure 8 shows the results of the dissolution test in water of the control formulation (torem tablet), Preparation Examples 1, 2 and 3.

The present invention relates to a thermodynamically stable amorphous torasemide solid dispersion, a pharmaceutical composition comprising the same and a method for preparing the same.

Toracemide is a 1-isopropyl-3-[(4-m-toloidino-3-pyridyl) sulfonyl] urea having a structure of Formula 1 below (generally referred to as torsemide or torasemide, The generic name "toracemide" in the specification of the application) is a loop diuretic:

Loop diuretics act as a diuretic that acts on the Henle's loop, and is a preventive agent for cardiac or heart tissue damage induced by metabolic or ionic abnormalities associated with ischemia. Treatment of primary and secondary aldosteroneism or Bartter's syndrome; Treatment of cancer or glaucoma; Reduction of intraocular pressure, acute or chronic bronchitis; Treatment of cerebral edema induced by trauma, ischemia, concussion, metastasis or epileptic seizures; And in the treatment of nasal infections induced by allergens. In particular, the drug trade names of edema and hypertension drugs for related epilepsy in the US Food and Drug Administration Demas index; was approved (DEMADEX ^R Roche, USA), Torah Deer (Toradiur ^R), torem (Torem ^R) and oil naeteu It is marketed under brand names, such as (Unat ^R ).

The ability of a substance to exist in one or more crystalline forms is defined as polymorphism, and the different crystalline forms are called polymorph variants or polymorphs. Generally, homogeneity is induced by the ability of molecules of a substance to change their structure, or to form different intermolecular or intramolecular interactions, especially hydrogen bonds, and to different atomic arrangements among the crystal lattice of different polymorphs. Is reflected. Different polymorphs of a substance have different crystal lattice energies, so that density, melting point, color, stability, dissolution rate, milling equipment, granulation, compaction can affect the manufacturability, solubility and bioavailability in pharmaceutical formulations. Different physical properties of the solid state, and the like.

Torasemide can exist in two or more different crystalline variants for the variables of a single cell, identified by X-ray diffraction on a single crystal. Acta Cryst., B34 (1978), pp. 2659-2662 and Acta Cryst., B34 (1978), pp. 1304-1310 refer to Dupont Type I and Dupont Type II. According to this document, Dupont type I shows a melting point of 169 ° C. as P 2 ₁ / C (prism) of crystallized monoclinic system, and DuPont type II shows P 2 / n (foil, foil) of crystallized monoclinic system. The melting point of 162 ° C is shown.

In European Patent No. 0212537 (1986) Topfmeyer discloses a problem that is at the same time a torasemide crystalline variant present at the same time. The two variants present at the same time correspond to Dupont Type I and Dupont Type II when the melting points are compared. U.S. Patent No. 4,822,807, reissued by Beringer Manheim, U.S. Pat.No.34,672, has two melting forms of torasemide, designated variants I and II, with a melting point of 159-161 ° C. The melting point of II was corrected to a relatively low melting point of 157.5 to 160 ° C.

In addition, US Pat. No. 5,914,336 discloses torasemide crystalline form ('336 variant III'), designated as variant III in Tevasa International Publication No. WO 01/10441. International Publication No. WO 00/20395 also discloses torasemide crystalline form (" pliba strain III "), designated variant III, which is unstable in torasemide under conditions of increased humidity as well as normal storage conditions. It did not change into strain III or stable strain I, and showed higher solubility in water and artificial intestinal fluids than torasemide stable strain I. In addition, specific X-ray powder patterns have been presented, and variants I and II disclosed in US Reissue Patent 34,672 are described in Acta Cryst., B34 (1978), pp. 2659-2662 and Acta Cryst., B34 (1978), pp. 1304-1310, contrary to what is disclosed.

International Publication No. WO 01/10441 discloses torasemide crystalline and amorphous variants named novel 'toracemide variant V' and 'amorphous torasemide', which are described herein as' theva variant V 'and' Teva amorphous amorphous torasemide.

Tevasa U.S. Pat.No. 6,482,417 claims a composition comprising at least about 99.7% high purity torasemide II and a composition comprising the same, wherein the composition comprises high purity torasemide variant II. In the dissolution test using the paddle method of the dissolution method of the US Pharmacopoeia, it is described that more than 80% is eluted in 30 minutes under the conditions of 50 to 90 revolutions per minute, it does not rearrange to the stable strain I in the process Doing.

The Teva amorphous torasemide has the advantage of being soluble compared to the '336 modified III', but the suspension of the torasemide solution to about -50 to 80 ℃ to be dissolved and lyophilized by treatment with ammonium gas or ammonium hydroxide after suspension in water After cooling, the torasemide solution should be cooled to a low temperature and subjected to a long drying process such as drying for 80 hours at a pressure of about 0.1 Torr or less. In addition, high purity torasemide modified II has a disadvantage that rearranged to stable strain I of torasemide unless maintaining high purity.

Accordingly, an object of the present invention is an amorphous torasemide solid dispersion which is superior in solubility, thermodynamically stable, and more physically and chemically stable to temperature and humidity from crystalline or amorphous torasemide than to torasemide stable strain I and It is to provide a pharmaceutical composition containing.

Another object of the present invention is to provide a method for preparing the amorphous torasemide solid dispersion.

In order to achieve the above object, the present invention provides an amorphous torasemide solid dispersion containing torasemide and a water-soluble high molecular material as an active ingredient.

The present invention also provides an amorphous torasemide solid dispersion-containing pharmaceutical composition comprising an amorphous torasemide solid dispersion and optionally a pharmaceutically acceptable additive such as a surfactant or a water-insoluble inorganic carrier.

In order to achieve another object of the present invention, the present invention comprises the steps of: iii) dissolving a water-soluble polymer in an organic solvent; Ii) finely dispersing crystalline or amorphous torasemide in the resulting solution; Iii) dissolving torasemide by mixing a basic substance with the resulting dispersion; And iii) removing the organic solvent of the resultant torasemide solution, to provide a method for preparing the amorphous torasemide solid dispersion.

Hereinafter, the components of the torasemide solid dispersion constituting the present invention will be described in more detail.

(1) active ingredient

The active ingredient used in the preparation of the torasemide solid dispersion in the present invention is crystalline or amorphous torasemide.

(2) water soluble high molecular substance

The water-soluble polymer used in the present invention is essential for the torasemide to form a completely amorphous solid dispersion. That is, the water-soluble polymer material is a water-soluble carrier to form a homogeneous distribution with the torasemide hydrophobicity to the hydrophobic torasemide by improving the solubility, and also by minimizing the thermodynamic deformation of the torasemide by external temperature and moisture It ensures the stability of the amorphous crystal form. Thus, this water-soluble polymer forms a complete solid dispersion with torasemide, which shows little endothermic peaks in the differential scanning calorimeter (DSC), contributing to the complete amorphous solid dispersion. In addition, X-ray powder diffraction analysis does not characterize diffraction peaks.

The water-soluble high molecular material is preferably selected from the group consisting of hydroxypropyl methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyvinyl acetal diethylamino acetate, polyethylene glycol and mixtures thereof.

(3) pharmaceutically acceptable additives

The amorphous torasemide solid dispersion-containing oral pharmaceutical composition of the present invention may optionally contain a pharmaceutically acceptable additive in addition to containing crystalline or amorphous torasemide and a water-soluble high molecular material as active ingredients. Such pharmaceutically acceptable additives include surfactants and water-insoluble inorganic carriers. These pharmaceutically acceptable additives contribute to reducing the adhesion of the solid dispersion, improving the flowability and yield and the like and facilitating handling.

Surfactants used in the present invention include polyoxyethylene-sorbitan-fatty acid esters such as esters of mono or trilauryl, palmityl, stearyl or oleyl (trade names: Tween, ICI) and the like; Sorbitan fatty acid esters such as sorbitan monolauryl, sorbitan mono palmityl or sorbitan monostearyl (trade name: Span); Polyoxyethylene-polyoxypropylene block copolymers (trade name: Poloxamer); Reaction products of ethylene glycol with natural or hydrogenated vegetable oils such as polyoxyethylene glycolated natural or hydrogenated castor oil (trade names: Cremophor, BASF) and the like; Polyoxyethylene fatty acid esters such as polyoxyethylene stearic acid ester (trade name: Myrj) and the like; Sodium dioctylsulfosuccinate or sodium lauryl sulfate; Phospholipids; Propylene Glycol Dicaprylate, Propylene Glycol Dilaurate, Propylene Glycol Isostearate, Propylene Glycol Laurate, Propylene Glycol Licinolate or Propylene Glycol Caprylic-Capric Acid Diester (Product Name: Miglyol) 840 Propylene glycol mono-fatty acid esters or propylene glycol di-fatty acid esters; Trans-esterification reaction products of natural vegetable oil triglycerides and poly alkylene polyols (trade name: Labrafil M); And mono-, di- or mono / di-glycerides (Immitor) and the like. In particular, double polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sodium dioctylsulfosuccinate, sodium lauryl sulfate and sorbitan fatty acid esters are preferred, most preferably Polyoxyethylene-sorbitan-fatty acid esters.

The water-insoluble inorganic carrier used in the present invention may be selected from the group consisting of silicon dioxide, hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, titanium dioxide, talc, aluminum silicate, magnesium aluminum metasilicate, bentonite and mixtures thereof. Can be. In particular, silicon dioxide is most preferred.

Each component of the torasemide solid dispersion of the present invention is a pharmacologically active component of torasemide: water-soluble polymer: surfactant: water-insoluble inorganic carrier 1: 0.1 to 10: 0 to 5: It exists in the ratio of 0-5, Preferably it exists in the ratio of 1: 0.5-7: 0-3: 0-3. When the content of the water-soluble polymer material exceeds 10 weight ratio, the stability of amorphous torasemide by temperature and moisture is improved, but the disintegration time may be delayed during the dissolution test of the formulation after the formulation process. Excessive increase in formulation weight due to the use of disintegrants and additives is inevitable. In addition, when the content of the water-soluble polymer material is less than 0.1 weight ratio, it is difficult to secure the thermodynamic stability in maintaining the amorphous crystal form of torasemide may be easily transformed into a crystalline form by temperature and moisture.

In the present invention, the pharmaceutical composition comprising the amorphous torasemide solid dispersion as an active ingredient may be formulated as a powder, granules, tablets, capsules or coating agents. That is, lubricants and other pharmaceutically acceptable additives may be added to the torasemide solid dispersion, and then filled into hard capsules in the form of powder or granules, or pharmaceutically acceptable additives required for tableting may be used as tablets. It can be formulated by a compression method and a conventional coating method.

The present invention also provides a process for producing the amorphous torasemide solid dispersion.

First, the above-mentioned water-soluble high molecular material is dissolved in a suitable organic solvent, for example, alcohols such as acetone, methanol or ethanol, acetonitrile, tetrahydrofuran, dichloromethane, chloroform or a mixture thereof, and are crystalline or amorphous thereto. The torasemide is dispersed evenly and then the basic material is mixed to dissolve the torasemide. The basic material used to dissolve the torasemide increases the pH of the torasemide solution to facilitate dissolution of the torasemide. The basic substance may be ammonium bicarbonate or a solution thereof; N-methyl-D-glucamine or a solution thereof; Ammonium hydroxide or a solution thereof; And ammonia gas and the like, and ammonium bicarbonate is most preferred.

If necessary, surfactants or other pharmaceutically acceptable additives are added to the torasemide solution to dissolve or disperse homogeneously.

The torasemide solid dispersion can be prepared by removing the organic solvent from the resulting torasemide solution according to a conventional method. Spray drying or reduced pressure evaporation is preferred as a method of removing the organic solvent.

Hereinafter, the present invention will be described in more detail with reference to the following Comparative Examples and Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Comparative Example 1

를 사용하여 분무 건조시켜 무정형의 토라세미드 고체분산체를 제조하였다. 이 때 분무 건조의 조건은 입구 온도 75℃, 출구 온도 50 내지 55℃였다. 이 후 잔류 유 기 용매를 제거하기 위해 30 내지 40℃에서 약 2 시간 동안 건조시켰다.After dispersing 5 g of Torasemide variant I (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form I, China) in a mixture of 100 g of methylene chloride and 100 g of ethanol, 10 g of 10% ammonium bicarbonate solution was added and the solution became clear. Stir until dark. Tooth spray dryer

Spray drying was carried out to prepare an amorphous torasemide solid dispersion. The conditions of spray drying at this time were the inlet temperature of 75 degreeC, and the outlet temperature of 50-55 degreeC. This was followed by drying at 30 to 40 ° C. for about 2 hours to remove residual organic solvents.

Comparative Example 2

After dispersing 5 g of Torasemide variant I (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form I, China) in a mixture of 200 g of methylene chloride and 200 g of ethanol, 10 g of 10% ammonium bicarbonate solution was added and the solution became clear. Stir until dark. To this, 5 g of silicon dioxide, an inorganic carrier, was added and dispersed uniformly, and then spray dried using a spray dryer to prepare an amorphous torasemide solid dispersion. At this time, the conditions of spray drying are the same as that of the comparative example 1.

Comparative Example 3

After dispersing 5 g of Torasemide variant I (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form I, China) in a mixture of 100 g of methylene chloride and 100 g of ethanol, 10 g of 10% ammonium bicarbonate solution was added and the solution became clear. Stir until dark. The torasemide solution was immersed in liquid nitrogen to freeze, and then freeze-dried at -80 ° C. for 48 hours using a freeze dryer (EYELA, Freeze Dryer, FDU-810, Japan) to disperse amorphous torasemide solid. Sieve was prepared.

Comparative Example 4

Amorphous torasemide solid dispersion was prepared in the same manner as in Comparative Example 1 except that 5 g of torasemide modified II (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form II, China) was used.

The contents of the components of the solid dispersions prepared in Comparative Examples 1, 2, 3, and 4 are shown in Table 1 below.

ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Unit (g) Unit (g) Unit (g) Unit (g) Torasemide 5 5 5 5 Silicon dioxide - 5 - - Methylene chloride 100 200 100 100 ethanol 100 200 100 100 10% Ammonium Bicarbonate Solution 10 10 10 10

Example 1

를 사용하여 분무 건조시켜 무정형의 토라세미드 고체분산체를 제조하였다. 이 때 분무 건조의 조건은 비교예 1과 동일하다. 15 g of hydroxypropylmethylcellulose 2910 (ShinEtsu, HPMC 2910 P645W, Japan) was dissolved in a mixed solution of 150 g of methylene chloride and 150 g of ethanol. While stirring the resulting solution, 5 g of Torasemide strain I (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form I, China) was dispersed well, and then 10 g of 10% ammonium bicarbonate solution was added and stirred until the solution became clear. It was. Tooth spray dryer

Spray drying was carried out to prepare an amorphous torasemide solid dispersion. At this time, the conditions of spray drying are the same as that of the comparative example 1.

Example 2

Amorphous torasemide solid dispersion was prepared in the same manner as in Example 1, except that 10 g of hydroxypropylmethylcellulose 2910 (ShinEtsu, HPMC 2910 P645W, Japan) was used.

Example 3

Amorphous torasemide solid dispersion was prepared in the same manner as in Example 1, except that 5 g of hydroxypropylmethylcellulose 2910 (ShinEtsu, HPMC 2910 P645W, Japan) was used.

Example 4

15 g of hydroxypropylmethylcellulose 2910 (ShinEtsu, HPMC 2910 P645W, Japan) was dissolved in a mixed solution of 150 g of methylene chloride and 150 g of ethanol. While stirring the resulting solution, 5 g of Torasemide strain I (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form I, China) was dispersed well, and then 10 g of 10% ammonium bicarbonate solution was added and stirred until the solution became clear. It was. After dissolving 2 g of Tween 80, spray drying was carried out using a spray dryer to prepare an amorphous torasemide solid dispersion. At this time, the conditions of spray drying are the same as that of the comparative example 1.

Example 5

10 g of hydroxypropylmethylcellulose 2910 (ShinEtsu, HPMC 2910 P645W, Japan) was dissolved in a mixed solution of 100 g of methylene chloride and 100 g of ethanol. While stirring the resulting solution, 5 g of Torasemide strain I (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form I, China) was dispersed well, and then 10 g of 10% ammonium bicarbonate solution was added and stirred until the solution became clear. It was. 2.5 g of silicon dioxide was uniformly dispersed while continuously stirring the solution, followed by spray drying using a spray dryer to prepare an amorphous torasemide solid dispersion. At this time, the conditions of spray drying are the same as that of the comparative example 1.

Example 6

Amorphous torasemide solid dispersion was prepared in the same manner as in Example 2, except that 10 g of povidone K-30 (ShinEtsu, Japan) was used as the water-soluble polymer.

Example 7

10 g of hydroxypropylmethylcellulose 2910 (ShinEtsu, HPMC 2910 P645W, Japan) was dissolved in a mixed solution of 100 g of methylene chloride and 100 g of ethanol. While stirring the resulting solution, 5 g of Torasemide strain I (Taizhou DongDong Pharmachem Co., Ltd., Torasemide Form I, China) was dispersed well, and then 10 g of 10% ammonium bicarbonate solution was added and stirred until the solution became clear. It was. The torasemide solution was immersed in liquid nitrogen to freeze, and then freeze-dried at -80 ° C. for 48 hours using a freeze dryer (EYELA, Freeze Dryer, FDU-810, Japan) to disperse amorphous torasemide solid. Sieve was prepared.

Example 8

Amorphous torasemide solid dispersion was prepared in the same manner as in Example 1, except that torasemide modified II was used.

The components and contents of the solid dispersions prepared in Examples 1 to 8 are shown in Table 2 below.

ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Unit (g) Unit (g) Unit (g) Unit (g) Unit (g) Unit (g) Unit (g) Unit (g) Torasemide 5 5 5 5 5 5 5 5 Hydroxypropylmethylcellulose 2910 15 10 5 15 10 - 10 15 Povidone, K-30 - - - - - 10 - - Twin 80 - - - 2 - - - - Silicon dioxide - - - - 2.5 - - - Methylene chloride 150 100 100 150 100 100 100 150 ethanol 150 100 100 150 100 100 100 150 10% Ammonium Bicarbonate Solution 10 10 10 10 10 10 10 10

Test Example 1 Thermodynamic Stability Test of Amorphous Torasemide

On the differential scanning calorimeter (DSC), the torasemide solid dispersion and the crystalline torasemide variant I (Taizhou DongDong Pharmachem Co., Ltd., China) of Comparative Examples 1 and 2 and Examples 1 and 5 were prepared at room temperature and After exposing for 50 days in a high-density polyethylene container at 40 ° C. and 75% relative humidity, the endothermic peak was observed on DSC. Temperatures showing endothermic peaks after 50 days are shown in Table 3 below, and the results of DSC are shown in FIGS. 1 and 2.

Temperature (℃) indicating the endothermic peak of the start date Temperature indicating endothermic peak after 50 days Room temperature 40 ℃, relative humidity 75% Comparative Example 1 none none 159.4 Comparative Example 2 none none 151.4 Example 1 none none none Example 5 none none none  Crystalline Torasemide Modification I 160.9 160.8 161.4

As shown in Figs. 1 and 2, the amorphous torasemide solid dispersion obtained in the present invention is a torasemi solid dispersion having no crystallinity, showing no thermodynamic change such as an endothermic peak on a differential scanning calorimeter (DSC). Could confirm.

In addition, the torasemide solid dispersion of Comparative Example 3 and Example 7 was exposed to a high-density polyethylene container under conditions of 75% at room temperature and 40 ° C relative humidity for 50 days, and then the endothermic peak was observed on DSC. The results of the DSC are shown in FIG.

As a result, as shown in Figure 3, it is possible to obtain an amorphous torasemide solid dispersion by lyophilization, it can be obtained by spray drying with a water-soluble polymer material to obtain a torasemi solid dispersion with no crystallinity at all Could confirm. In Comparative Example 3, the endothermic peak was observed when exposed to a high-density polyethylene container at a temperature of 40 ° C. and a relative humidity of 75% for 50 days, thereby changing from amorphous to crystalline form during the exposure period. As the sieve did not show endothermic peaks under the same conditions, it was confirmed that the sieve remained amorphous without the thermodynamic change during the exposure period.

Test Example 2: Solubility Test of Amorphous Torasemide

About 500 mg of Comparative Example 2, Examples 2 and 6, and crystalline torasemide variant I were taken as torasemide and placed in 900 ml of purified water, and the conditions as shown in Table 4 below in an Erweka DT 80 solubility test apparatus. And the results are shown in FIG.

Condition Test solution (water) 900 ml Temperature of test liquid 37 ± 0.5 ℃ Rotational Speed (Rotational Sample Method) 100 ± 2 rpm

As shown in FIG. 4, it was confirmed that the amorphous torasemide solid dispersion obtained in the present invention showed superior solubility as compared to the crystalline torasemide modification I.

Test Example 3: X-ray powder diffraction analysis of amorphous torasemide

Comparative Example 1, Example 1, Example 8, crystalline torasemide variant I, variant II and commercial control formulation (Torem tablet, Roche, Korea; ground in Judo) were prepared under X-ray powder diffractometer MAC- at initial conditions. Using 18CHF, measured by Cu X-ray, 40kV, 300mA, and also after 50 days exposed to 40% relative humidity 75% in a high-density polyethylene container was measured. The results of X-ray powder diffraction analysis at both conditions are shown in FIGS. 5 and 6. FIG. 5 shows the results of X-ray powder diffraction analysis at the initial conditions of torasemide modified I, modified II, a commercial control formulation, Torem tablet, Comparative Examples 1, 1 and 8, and FIG. The result of X-ray powder diffraction analysis of Comparative Example 1, Example 1, and Example 8 after exposure to 50 degreeC on the conditions of 40 degreeC relative humidity 75% in a container is shown.

As shown in Figures 5 and 6, Comparative Example 1 in which torasamide solid dispersion was prepared by spray drying only the crystalline torasemide without using a water-soluble polymer material, but initially exhibits an amorphous tendency, but the temperature is 40 ℃ After 50 days of exposure at 75% relative humidity, it was confirmed that the crystalline form was changed. On the other hand, in the case of Examples 1 and 8 where the torasemide solid dispersion by spray-drying the torasemide and the water-soluble polymer material together, even after exposure for 50 days at a temperature of 40 ℃ relative humidity 75% in a high-density polyethylene container It could be confirmed that it did not change into a crystalline form.

Therefore, the amorphous torasemide solid dispersion of the present invention is changed from the crystalline form to the amorphous form through the spray drying process, even if stored in a high-density polyethylene container at a temperature of 40 ℃ relative humidity 75% 50 days for 50 days By keeping the amorphous rather than arranged, it could be confirmed that it has a thermodynamically stable characteristic.

Test Example 4: Raman analysis of amorphous torasemide

The change in crystal form was measured with a Raman beam of 200 mW using a Fourier transformed Raman analyzer (Brucker, FT-Raman RFS 100 / S) at torasemide strain I, variant II, comparative example 1 and comparative example 4 under initial conditions. It was. Raman analysis results are shown in FIG.

As shown in Fig. 7, the torasemide has a unique peak pattern of strains I and II, and the amorphous torasemide obtained through the spray drying process has a unique amorphous peak pattern that is completely different from the strains I and II. It can be seen that.

The pharmaceutical compositions of the present invention may be prepared in the following formulations, but the scope of the present invention is not limited thereto.

Formulation Example 1 Preparation of Tablet

20 g of the amorphous torasemide solid dispersion of Example 1 (5 g as torasemide), 5 g of crospovidone, and 15 g of lactose were mixed, tableted and ground to form granules. Here, pharmaceutically acceptable additives required for the manufacture of tablets, 16 g of Ludipress, 20 g of crospovidone, 3 g of silicon dioxide, and 1 g of magnesium stearate are mixed homogeneously, and then 5 mg equivalent (80 mg) of torasamide per unit formulation. ) Was compressed.

Formulation Example 2 Preparation of Tablet

Tablets were prepared in the same manner as in Formulation Example 1, except that 15 g of crospovidone was used and 5 g of crosscarboxymethyl cellulose sodium was added.

Formulation Example 3 Preparation of Tablet

A tablet was prepared in the same manner as in Formulation Example 1, except that 22 g of amorphous torasemide solid dispersion (5 g as torasemide) of Example 4 was used.

The components and contents per unit formulation of the tablets prepared in Preparation Examples 1 to 3 are shown in Table 5 below.

Formulation Example 1 Formulation Example 2 Formulation Example 3 mg / formulation mg / formulation mg / formulation Solid Dispersion of Example 1 (5 mg as torasemide) 20 20 - Solid dispersion of Example 4 (5 mg as torasemide) - - 22 Crospovidone 5 5 5 Lactose 15 15 15 Rudy Press 16 16 14 Cross Carboxymethyl Cellulose Sodium - 5 - Crospovidone 20 15 20 Silicon dioxide 3 3 3 Magnesium stearate One One One Tablet total weight 80 80 80

Test Example 5: Dissolution test of tablets containing amorphous torasemide solid dispersion

For the dissolution test of the tablet containing the amorphous torasemide solid dispersion obtained in Formulation Examples 1 to 3, 8 tablets of the Korean Pharmacopoeia, dissolution test method using a commercially available tablet (Torem tablet, Roche Korea) as a control formulation In the dissolution test apparatus Erweka DT 80 (Erweka DT 80), the dissolution test under the conditions as shown in Table 6, which was analyzed under the conditions as shown in Table 7 by the liquid chromatography method and the results are shown in FIG.

Condition Eluent (water) 900 ml Eluent temperature 37 ± 0.5 ℃ Rotational Speed (Paddle Method) 50 ± 2 rpm

Condition column Inertsil C18 (150mm × 4.6mm) Mobile phase 0.02M potassium phosphate buffer (pH 3.5): methanol (50:50) Injection volume 20 μl Flow rate 1.0 ml / min Detector 288 nm

As shown in FIG. 8, it was confirmed that the tablet containing the amorphous torasemide solid dispersion obtained in the present invention had a dissolution rate equivalent to that of the torem tablet as a control formulation.

Amorphous torasemide solid dispersion containing crystalline or amorphous torasemide and water-soluble high molecular materials as the active ingredient according to the present invention is thermodynamically stable and has excellent solubility under the influence of heat and moisture. In addition, the pharmaceutical composition comprising the amorphous torasemide solid dispersion has a high dissolution rate. In addition, the method for preparing amorphous torasemide solid dispersion according to the present invention provides a thermodynamically stable amorphous solid dispersion with no crystallinity.

Claims (25)

delete delete delete delete delete delete delete delete delete delete Iii) dissolving the water-soluble polymer in an organic solvent; Ii) finely dispersing torasemide in the solution produced in iii) above; Iii) dissolving torasemide by mixing a basic substance with the dispersion produced in ii); And Iii) removing the organic solvent of the torasemide solution produced in iii) above; A method for producing an amorphous torasemide solid dispersion comprising torasemide and a water-soluble high molecular material. The method of claim 11, Iii) dissolving or dispersing a pharmaceutically acceptable additive in the torasemide solution of step iii, wherein the amorphous torasemide solid dispersion is prepared. The method of claim 12, A method for producing an amorphous torasemide solid dispersion, wherein the pharmaceutically acceptable additive is a surfactant or a water insoluble inorganic carrier. The method of claim 11, Iii) the basic material of step is selected from the group consisting of ammonium bicarbonate, N-methyl-D-glucamine, ammonium hydroxide, solutions thereof and ammonia gas. The method of claim 11, A process for producing an amorphous torasemide solid dispersion, wherein the organic solvent of the torasemide solution in step iii) is removed by spray drying or reduced pressure evaporation. delete The method of claim 11, A method for producing an amorphous torasemide solid dispersion having a weight ratio of torasemide and a water-soluble high molecular material of 1: 0.1 to 10. The method of claim 11, A method for producing an amorphous torasemide solid dispersion having a weight ratio of torasemide and a water-soluble high molecular material of 1: 0.5 to 7. The method of claim 11, Wherein the water-soluble high molecular material is hydroxypropylmethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyvinyl acetal diethylamino acetate, polyethylene glycol and mixtures thereof. Manufacturing method. The method of claim 12, A method for producing an amorphous torasemide solid dispersion having a content of a pharmaceutically acceptable additive per 5 parts by weight of torasemide. The method of claim 12, A method for producing an amorphous torasemide solid dispersion having a pharmaceutically acceptable additive content of 3 parts by weight or less per 1 part by weight of torasemide. The method of claim 13, The surfactant is selected from the group consisting of polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sodium dioctylsulfosuccinate, sodium lauryl sulfate, sorbitan fatty acid esters and mixtures thereof Process for producing amorphous torasemide solid dispersion. The method of claim 13, An amorphous torasemi solid selected from the group consisting of silicon dioxide, hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, titanium dioxide, talc, aluminum silicate, magnesium aluminum metasilicate, bentonite and mixtures thereof Process for the preparation of the dispersion. Amorphous torasemide solid dispersion prepared by the method of any one of claims 11 to 15 and 17 to 23. A pharmaceutical composition for treating edema or hypertension associated with epilepsy comprising an amorphous torasemide solid dispersion prepared by the method of any one of claims 11 to 15 and 17 to 23 as an active ingredient.

Images