KR100711220B1 - Oral pharmaceutical composition comprising tarcrolimus and method thereof - Google Patents

Abstract

The present invention relates to an oral composition containing tacrolimus and a method for preparing the same, and more specifically, 0.1 to 10 parts by weight of tacrolimus, 0.1 to 50 parts by weight of copolymers or gastric polymers, and a residual amount of organic solvent. 0.1 to 50.0% by weight of a solid dispersion prepared amorphous by spray drying or coprecipitation using a speed mixer; And 50.0-99.9% by weight of at least one additive selected from the group consisting of excipients, binders, disintegrants and absorption aids.

Oral compositions of the present invention is convenient to manufacture and very easy to industrialize, has the advantage of high bioavailability as an amorphous solid dispersion.

Tacrolimus, oral compositions, immunosuppressants, solid dispersions.

Description

ORAL PHARMACEUTICAL COMPOSITION COMPRISING TARCROLIMUS AND METHOD THEREOF

Figure 1 shows the dissolution results of the compositions prepared in Examples 1 to 4 and Comparative Examples 1,2.

Figure 2 shows the dissolution results of the composition prepared in Examples 5 to 9 and commercially available.

Figure 3 shows the tacrolimus agent (A), copovidone copolymer (B), a mixture of tacrolimus and the copolymer (copovidone) agent (C), tacrolimus and the copolymer by X-ray diffraction analysis The amorphous form of the solid dispersion (D) composition of povidone is shown.

[Industrial use]

The present invention provides 17-allyl-1,14-dihydroxy-12- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -23,25-dimethoxy-13,19 Represented by the chemical name of, 21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraon The present invention relates to an oral composition containing tacrolimus and a method for preparing the same. More particularly, the present invention relates to an oral composition containing a solid dispersion having high bioavailability and convenient to manufacture and easy to industrialize.

[Private Technology]

Tacrolimus has pharmacological activities such as immunosuppressive activity and antimicrobial activity, as described in European Patent No. 184162, such as rejection of transplantation, graft versus host disease caused by bone marrow transplantation, autoimmune disease, infectious disease, etc. Useful for the treatment and prevention of However, tacrolimus is poorly soluble in water, so the rate of absorption into the blood during oral administration is low, resulting in low bioavailability.

According to Korean Patent Publication No. 1987-0010073, in order to increase the bioavailability of tacrolimus, it is dissolved in an organic solvent, suspended in hydroxypropylmethylcellulose in this solution, degassed, dried, and pulverized. Prepare a dispersion. However, the manufacturing method has a disadvantage that the manufacturing process such as drying time takes a long time. Further, according to WO95 / 001786, a pharmaceutical composition for oral administration using polyglycerol fatty acid esters or sorbitan fatty acid esters in combination with lipophilic excipients and nonionic surfactants as a solubilizer to increase the solubility of poorly water-soluble active substances is developed. However, this has the disadvantage of causing irritation in the gastrointestinal wall.

The present invention is to solve the above problems, it is an object of the present invention to provide an amorphous solid dispersion and a method for producing the same that the production time is short and the bioavailability is improved.

In order to achieve the above object, the present invention is obtained by mixing 1 to 10 parts by weight of tacrolimus, 0.1 to 50 parts by weight of a copolymer or gastric polymer and a residual amount of an organic solvent, followed by coprecipitation using spray drying or a speed mixer. It provides an oral composition comprising 0.1 to 50.0% by weight of the solid dispersion prepared in amorphous form and 50.0 to 99.9% by weight of one or more additives selected from the group consisting of excipients, binder disintegrating agents and absorption aids.

The present invention also comprises the steps of dissolving a tacrolimus copolymer and gastric polymer in an organic solvent to form a mixed solution, and preparing an amorphous solid dispersion by spray drying or speed mixer coprecipitation method, and Provided is a method for preparing an oral composition comprising adding at least one additive selected from the group consisting of disintegrants, excipient lubricants and absorption aids to the solid dispersion.

The present invention also provides a solid dispersion prepared amorphous by mixing 1 to 10 parts by weight of tacrolimus, 0.1 to 50 parts by weight of copolymers or gastric polymers, and a residual amount of organic solvent, followed by spray drying.

Hereinafter, the present invention will be described in more detail.

In order to improve bioavailability of poorly soluble tacrolimus, tacrolimus and copolymer or gastric polymer are dissolved in an organic solvent, mixed and spray-dried to amorphize tacrolimus and contain a disintegrant, excipient lubricant and absorption aid. Prepared as a brother, it effectively contributes to eluting tacrolimus.

Tacrolimus used in the present invention may be 0.1 to 50 parts by weight, preferably 1 to 10 parts by weight based on the solid dispersion. The tacrolimus content is not limited to the above range, but is preferably 0.1 to 50 parts by weight, considering the daily dosage for therapeutic purposes.

Examples of the copolymer mixed with tacrolimus include vinylpyrrolidone-vinylacetate copolymer (hereinafter referred to as 'copovidone', trade name: Kollidon VA64), carbomer (trade name: Cabopol), polyvinyl alcohol-polyethylene glycol fused air Coalescing (hereinafter referred to as 'collicoat', trade name: Kollicoat IR). The copolymer may be 0.05 to 50 parts by weight based on the solid dispersion, preferably 0.1 to 50 parts by weight based on the solid dispersion. If it is less than 0.05, there is a fear that the solubility is poor because tacrolimus is not completely changed to amorphous, and if it is more than 50, the elution may be delayed due to the large volume and high viscosity.

Examples of the gas soluble polymer may be an aminoalkyl methacrylate copolymer (hereinafter referred to as Eudragit, trade name: Eudragit E) and polyvinyl acetal diethylaminoacetate (trade name: AEA). The gasosoluble polymer may be 0.05 to 50 parts by weight, and preferably 0.1 to 50 parts by weight, based on the solid dispersion. If it is less than 0.05, the solubility may drop due to the problem that tacrolimus is not completely changed to amorphous, and if it is more than 50, the elution may be delayed due to the large volume and high viscosity.

Spray-drying is possible by mixing tacrolimus with a copolymer or gastric polymer so that the tacrolimus can be amorphous into a solid dispersion.

In addition, the speed coprecipitation method can be used when mixing tacrolimus and a copolymer or a gasosoluble polymer. In general, a final composition is obtained by applying a method of coprecipitation using a speed mixer to a composition including an additive. In the present invention, a mixture obtained by coprecipitating a mixture of tacrolimus with a copolymer or a gastric polymer using a speed mixer is used. The method of drying and obtaining a solid dispersion can be chosen. In this case, the effect of shortening the time and the process in the preparation of the oral composition can be obtained.

The solid dispersion comprises 0.1 to 50% by weight, preferably 15 to 40% by weight based on the total composition. If it is less than 0.1% by weight, solubility may be reduced due to the problem that tacrolimus is not completely changed to amorphous, and if it is more than 50% by weight, dissolution may be delayed due to the increase in the overall volume and high viscosity.

The solid dispersion may include one or more additives selected from the group consisting of excipients, binders, disintegrants and absorption aids.

The additive comprises 50 to 99.9% by weight, preferably 60 to 85% by weight based on the total composition. If it is out of the above range, excessive dosage of additives may increase the size and volume of the preparation, causing dose rejection.

Excipients in the additive may be included in 2 to 90% by weight based on the total composition, disintegrant may be included in 0.1 to 50% by weight based on the total composition, 0.1 to 40% by weight relative to the total composition. If the above range is exceeded, excessive excipients, disintegrants or binders may be added to increase the size and volume of the preparation, causing dose rejection.

Examples of the excipient include lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose, cellulose derivatives, dextrin, calcium dihydrogen phosphate, calcium dihydrogen phosphate, and carbonic acid. It can be calcium, potassium polyacrylic acid, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid, ascorbyl parmitate, etc. .

Examples of the disintegrant may be microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, crospovidone and the like. These excipients and disintegrants can be used simultaneously or separately.

Examples of the binder may be hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxy cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, dextrin, microcrystalline cellulose and the like. .

The oral composition may further comprise a lubricant. Examples of the lubricant may be magnesium stearate, sodium stearyl fumarate, stearic acid, talc, silicon dioxide, colloidal silicon dioxide and the like. At least one glidant selected from the glidants may be contained in an amount of 0.1 to 20 wt% based on the total composition. If it is less than 0.1% by weight, there is a concern that mass deviation or content unevenness may occur during filling, and when it exceeds 20% by weight, the dissolution rate may be reduced by preventing contact with moisture.

In addition, the oral composition may further include an absorption aid. Examples of the absorbent aid may be polyethylene glycol, sodium chloride, mannitol, sorbitol, polyethylene-propylene glycol copolymer (hereinafter referred to as 'poloxamer', trade name: Lutrol). At least one absorbent selected from the absorbents may be contained in an amount of 0.1 to 20% by weight based on the total composition. If it is less than 0.1% by weight, there is a fear that the role as an absorption aid may not appear, and if it exceeds 20% by weight, there is a fear that the variation between individuals due to rapid elution will increase.

The composition according to the present invention may be formulated into solid dosage forms for oral administration such as tablets, capsules, granules, powders, pills, dry syrups, and preferably, oral administration in the form of tablets or capsules.

The formulation composition according to the present invention may be used for the treatment of a disease by containing about 0.01 to 1000 mg, preferably 0.05 to 500 mg, more preferably 0.1 to 100 mg of tacrolimus as an active ingredient per day.

Hereinafter, preferred embodiments of the present invention are described. However, the following examples are only preferred embodiments of the present invention, and the present invention is not limited to the following examples.

EXAMPLE

Example 1-4 Preparation of Solid Dispersion with Tacrolimus Dispersed in Copolymer or Gasolyte Polymer

1.0 g of tacrolimus and 2.0 g of the copolymer or gasosoluble polymer shown in Table 1 were evenly dissolved in 10.0 g of ethanol (Korean Pharmacopoeia Standard, Purity: 95%). Thereafter, this solution was sprayed using a spray dryer (Model, B-191 Mini Spray Dryer, Buchi Co., Swiss) to make a solid dispersion in which tacrolimus was dispersed in a copolymer or a gas-soluble polymer. It was.

Example 1 Example 2 Example 3 Example 4 Tacrolimus 1.0 g 1.0 g 1.0 g 1.0 g Copovidone VA 64 2.0 g - - - Carbomer - 2.0 g - - Eudragit E PO - - 2.0 g - Collicoat IR - - - 2.0 g

Example 5 Preparation of Capsules Containing Tacrolimis Solid Dispersion

The tacrolimus solid dispersion obtained in Example 1 was well mixed with sodium croscarmellose and lactose in an amount as shown in Table 2, and then magnesium stearate as a lubricant was finally mixed and filled into capsules.

ingredient Example 1 Croscarmellose Sodium Lactose Magnesium stearate Content (mg) 3.0 5.0 100.0 1.0

Example 6 Preparation of Tablets Containing Tacrolimus Solid Dispersion

The tacrolimus solid dispersion obtained in Example 1 was mixed well with crospovidone and anhydrous lactose in an amount as shown in Table 3 below, followed by final mixing of a glidant magnesium stearate, which was compressed into tablets.

ingredient Example 1 Crospovidone Lactose free Magnesium stearate Content (mg) 3.0 15.0 65.0 1.0

Examples 7 and 8: Preparation of Capsules Containing Tacrolimus Using Coprecipitation Method

The mixture is prepared by first mixing croscarmellose sodium and lactose in a speed mixer, and dissolving the copolymer of Table 4 or gastric polymer in 10 ml of ethanol (KEPCO, 95% purity) in tacrolimus. Pour slowly into the mixture and mix and copulate. At this time, the speed mixer condition was set to an agitator speed of 50 rpm and a chopper speed of 3000 rpm to operate for 5 minutes. The mixture was placed in a plate dryer, dried at a temperature of 80 ° C. for 30 minutes, stipulated using a 35 mesh sieve, and finally mixed with 1 mg of magnesium stearate, a lubricant, and filled into capsules.

Example 7 Example 8 Tacrolimus 1.0mg Tacrolimus 1.0mg Copovidone 2.0mg Eudragit 2.0mg Croscarmellose Sodium 3.0mg Croscarmellose Sodium 3.0mg Lactose 65.0 mg Lactose 65.0 mg

Example 9 Preparation of Capsules Containing Tacrolimus Using Coprecipitation Method

In the same manner as in Example 7, except for preparing by mixing the croscarmellose sodium, lactose, and polyethylene glycol in the speed mixer and operating the speed mixer for 5 minutes, the materials of Table 5 were mixed to include tacrolimus. Capsules were prepared.

Tacrolimus 1.0mg Copovidone 2.0mg Croscarmellose Sodium 3.0mg Polyethylene glycol 0.2mg Lactose 65.0 mg

Comparative Example 1

Tacrolimus, croscarmellose sodium and lactose were mixed well as shown in Table 4, followed by final mixing of the glidant magnesium stearate to fill the capsules.

ingredient Tacrolimus Croscarmellose Sodium Lactose Magnesium stearate Content (mg) 1.0 5.0 100.0 1.0

Comparative Example 2

As shown in Table 5, tacrolimus and copovidone, which are copolymers, were simply mixed, croscarmellose sodium and lactose were well mixed, and magnesium stearate as a lubricant was finally mixed and filled into capsules.

ingredient Tacrolimus Original Copovidone VA64 Croscarmellose Sodium Lactose Magnesium stearate Content (mg) 1.0 2.0 5.0 100.0 1.0

Experimental Example 1: Dissolution Test

Examples 1 to 7, Comparative Examples 1 and 2, and a commercially available formulation (manufacturer: Fuji Fuji Korea Co., Ltd., product name: 1 mg Prograb capsule) were tested by the Korean Pharmaceutical Pharmacology Dissolution Test Method 2 (paddle method). The eluate was pH 1.2 liquid (artificial gastric juice, 8 tablets of KP), the paddle speed was 100 rpm, and the tacrolimus content was quantified by the high-performance liquid chromatography method, and is shown in Table 6 and FIGS. 1 and 2.

Item Dissolution rate (%) 5 minutes 15 minutes 30 minutes 45 minutes Example 1 67.3 100.4 101.4 101.2 Example 2 57.1 99.4 100.2 100.5 Example 3 53.3 87.2 100.5 101.1 Example 4 55.9 97.1 101.2 100.8 Example 5 53.4 83.1 102.5 100.7 Example 6 34.2 78.7 101.4 101.6 Example 7 60.2 84.8 100.0 100.2 Example 8 62.1 86.4 97.5 101.1 Example 9 69.3 89.7 99.2 99.9 Comparative Example 1 6.2 12.6 22.4 25.3 Comparative Example 2 5.3 10.1 17.3 22.7 Commercially available 45.8 79.9 98.7 101.1

Figure 1 shows the dissolution results of the compositions prepared in Examples 1 and Comparative Examples 1,2.

In addition, Figure 2 shows the dissolution results of the composition prepared in Examples 5 to 9 and commercially available formulations (manufacturer: Fuji Inc., Korea, trade name: 1 mg prograb capsule).

As shown in Table 6 and Figure 1, according to Comparative Examples 1 and 2 it can be confirmed that the dissolution rate is low only by the disintegrating agent except for the copolymer, the comparative example 2 was found to be difficult to dissolve even by simple mixing of the copolymer. .

It was found that the dissolution rate of the solid dispersion using the copolymer to the gas-soluble polymer in Examples 1 to 4 was much higher than that of the comparative example, which was not in the form of a solid dispersion.

From Table 6 and FIG. 2, the same or dissolution rates were observed in the case of preparing capsules or tablets as in Examples 5 and 6, compared to commercially available formulations.

In addition, the same or higher dissolution rates were observed in the case of preparing capsules or tablets using speed co-precipitation instead of spray drying as in Examples 7 to 9, compared to commercially available formulations.

Experimental Example 2: X-ray Diffraction Analysis

Copolymer with tacrolimus 1 g (A), copovidone copolymer formulation 1 g (B), tacroromus formulation and copolymer (copovidone) formulation 2C (C), and tacrolimus X-ray diffraction analysis was performed on the solid dispersion of chain copovidone (3) at a measurement angle of 5 to 90 degrees and a scanning speed of 10 degrees / minute. The result by this is shown in FIG.

The poorly soluble tacrolimus is dissolved in an organic solvent together with a copolymer such as copovidone, a water-soluble carrier, or a gas-soluble polymer such as Eudragit, and then spray-dried to dry the drug and the water-soluble carrier immediately after spraying, thereby shortening the manufacturing time and There is an advantage to obtain a high oral composition for utilization. In addition, by dissolving the drug and water-soluble carrier by coprecipitation method using a speed mixer by mixing and granulating the appropriate excipients, it is possible to apply the general granulation process as it is, the manufacturing method of oral composition with excellent economic efficiency with the advantages of convenient production and easy industrialization. Can be provided.

Claims (7)

a) 1 to 10 parts by weight of tacrolimus, and vinylpyrrolidone-vinylacetate copolymer, carbomer, polyvinyl alcohol-polyethyleneglycol fusion copolymer, aminoalkyl methacrylate copolymer, and polyvinyl acetal dimethylaminoacetate 0.1 to 50.0 wt% of an amorphous solid dispersion comprising 0.1 to 50 parts by weight of at least one polymer selected from the group consisting of b) 50.0 to 99.9% by weight of one or more additives selected from the group consisting of excipients, binders, disintegrants and lubricants Oral composition comprising a. The oral composition of claim 1, wherein the oral composition further comprises an absorption aid. The oral composition of claim 2, wherein the absorbent aid is one or more selected from the group consisting of polyethylene glycol, sodium chloride, mannitol, sorbitol, and polyethylene-propylene copolymers. The oral composition according to claim 2, wherein the absorbent aid is included in an amount of 0.1 to 20% by weight based on the total oral composition. The oral composition according to any one of claims 1 to 4, wherein the composition is a tablet, capsule, granule, powder, pill or dry syrup. At least one member selected from the group consisting of tacrolimus and vinylpyrrolidone-vinylacetate copolymers, carbomers, polyvinyl alcohol-polyethylene glycol fusion copolymers, aminoalkylmethacrylate copolymers, and polyvinyl acetal dimethylaminoacetate Dissolving the polymer in an organic solvent to form a mixed solution; Preparing an amorphous solid dispersion using the mixed solution by spray drying or speed coprecipitation; And Adding at least one additive selected from the group consisting of disintegrants, excipients, lubricants and absorption aids to the solid dispersion Method for producing an oral composition comprising a. 1-10 parts by weight of tacrolimus, and a group consisting of a vinylpyrrolidone-vinylacetate copolymer, a carbomer, a polyvinyl alcohol-polyethylene glycol fusion copolymer, an aminoalkyl methacrylate copolymer, and a polyvinyl acetal dimethylaminoacetate Amorphous solid dispersion containing 0.1 to 50 parts by weight of one or more polymers selected from

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