KR100670921B1 - Oral tacrolimus formulation and process - Google Patents

Abstract

The present invention relates to a preparation for oral administration of tacrolimus, and more particularly, containing tacrolimus as an effective drug, and caprylocaproyl macrogol-8 glycerides and macrogol as solubilizers. 15 A solid dispersion dissolved in ethanol using a macrogol surfactant mixed with a specific ratio of hydroxystearate to change the crystallinity of tacrolimus in the formulation, thereby increasing the solubility and dissolution rate, and having high wettability. The present invention relates to a preparation for oral administration of tacrolimus having such easy, reproducible, economical, and stable properties.

Tacrolimus, Caprylocaproyl macrogol-8 glycerides, Macrogol 15 hydroxystearate, solid dispersion

Description

Oral tacrolimus formulation and process

FIG. 1 compares the dissolution rate of Example 1 and a commercial formulation [Prograb capsule, Fujisa Korea].

Figure 2 compares the dissolution rates of Examples 1 to 3 and Comparative Example 1.

3 compares the dissolution rates of Examples 4 to 5 and Comparative Example 2.

The present invention relates to a preparation for oral administration of tacrolimus, and more particularly, containing tacrolimus as an effective drug, and caprylocaproyl macrogol-8 glycerides and macrogol as solubilizers. 15 A solid dispersion dissolved in ethanol using a macrogol surfactant mixed with a specific ratio of hydroxystearate to change the crystallinity of tacrolimus in the formulation, thereby increasing the solubility and dissolution rate, and having high wettability. The present invention relates to a preparation for oral administration of tacrolimus having such easy, reproducible, economical, and stable properties.

Tacrolimus is 17-allyl-1,14-dihydroxy-12- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -23,25-dimethoxy -13,19,21,27-Techlamethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone The drug known as FK506 has an immunosuppressive activity with a macrolide lactone compound having a molecular weight of 882.05, and has been commercialized as a transplant rejection inhibitor (Prograf ™) and an atopic eczema therapeutic agent (Protopic ™) in organ transplant patients. However, tacrolimus has a very low solubility in water of 1 to 2 μg / ml and thus has low absorption rate during oral administration, and changes between individuals are very severe.

Conventionally, as a method for increasing the solubility of Tacrolimus, a pharmaceutical composition in which Tacrolimus raw material is solubilized using two or more surfactants and a method for producing the same [Japanese Patent Laid-Open No. 1997-93715] Although it is known, in the case of using an organic solvent in the formation of a solid dispersion, a vacuum dryer must be used, and in the case of using two or more solubilizers, it must be heated to a temperature of 60 ° C. or higher, and the mill is formed to form particles. There is a problem that requires operation by special working conditions such as particle formation in the crushing furnace.

Therefore, there is a need for the development of formulations with equivalent drug release effects, such as tacrolimus-containing oral formulations currently on the market, while simplifying the composition.

Accordingly, the present inventors have made diligent efforts to solve the problems of the prior art, and as a result, caprylocaproyl macrogol-8 glycerides and macrogol 15 hydroxystearate are mixed at a specific ratio. Using a solid dispersion prepared by dissolving one macroroll-based surfactant in ethanol at 20 to 30 ° C., solubility and dissolution rate are improved even with a small amount of tacrolimus, and have high wettability without addition of other excipients. The present invention has been completed by developing a stable tacrolimus oral preparation, which is simple, simple, and reproducible, economical, and can be denatured by solubilization.

Accordingly, the present invention provides a tacrolimus-containing solid containing a surfactant in which tacrolimus is mixed with caprylocaproyl macrogol-8 glycerides and macrogol 15 hydroxystearate. It is an object to provide a dispersion composition and a preparation for oral administration using the same.

In addition, the present invention is added to tacrolimus, a surfactant mixed with caprylocaproyl macrogol-8 glyceride and macrogol 15 hydroxystearate, dissolved in ethanol at 20 ~ 30 ℃ to dissolve the solid dispersion Another object is to provide a method of preparation.

The present invention provides a tacrolimus-containing solid dispersion containing a surfactant in which tacrolimus is mixed with caprylocaproyl macrogol-8 glycerides and macrogol 15 hydroxystearate. It is characterized by a composition and a preparation for oral administration using the same.

In addition, the present invention is added to tacrolimus, a surfactant mixed with caprylocaproyl macrogol-8 glyceride and macrogol 15 hydroxystearate, dissolved in ethanol at 20 ~ 30 ℃ to dissolve the solid dispersion The manufacturing method is another feature.

The present invention will be described in more detail as follows.

The present invention is a macrogol surfactant containing tacrolimus as an effective drug, caprylocaproyl macrogol-8 glycerides and macrogol 15 hydroxystearate as a solubilizer It is a solid dispersion dissolved in ethanol to change the crystallinity of tacrolimus in the formulation to increase the solubility and dissolution rate, high wettability, easy and reproducible manufacturing process, economic and stable tacrolime It relates to a mousse oral preparation.

Tacrolimus, an effective drug of the present invention, is a poorly soluble substance having a solubility in water of 1 to 2 ㎍ / ml, and is mainly used for the cytokine gene which plays an important role in the immune response by acting at the initial stage of T cell activation. It is a drug that effectively suppresses immunity by inhibiting expression.

As a solubilizer for use in the solid dispersion composition of the present invention, Caprylocaproyl macrogol-8 glycerides is used, which is one of the macrogol surfactants, which is an effective drug of tacrolimus. It increases the absorption rate in the body.

In addition, as a solubilizer for use in the solid dispersion composition of the present invention is used macrogol 15 hydroxystearate, which is one of the macrogol surfactant, increases the solubility of the active drug tacrolimus, It increases the rate of absorption.

However, when applied to tacrolimus by using the surfactant alone as a solubilizer, the dissolution of tacrolimus was hardly achieved, but it was confirmed that the solubility increased when the two surfactants were mixed in a specific ratio. It was.

In other words, the present invention uses the macrogol surfactant, caprylocaproyl macrogol-8 glyceride, and macrogol 15 hydroxystearate in a weight ratio of 1: 4 to 1: 6 to solubilize tacrolimus. If it is less than this range, the solubilization effect, that is, the solubility and absorption in the body cannot be increased, and if it exceeds the range, the flowability of the granules becomes very bad, and the sticking phenomenon and the flowability decrease during production into the product. There is a problem that a severe deviation of the mass occurs.

Accordingly, the solubilizer of the present invention is a water-soluble surfactant in which a mixture of caprylocaproyl macrogol-8 glyceride and macrogol 15 hydroxystearate is applied to the body simultaneously with the drug to increase the body's utilization (absorption rate) of the drug. It is preferable to play a role, and it is preferable to use 300 to 800 parts by weight based on 100 parts by weight of tacrolimus, which is an effective drug. If less than 300 parts by weight of solubilizer is used, the elution effect is poor, and if it exceeds 800 parts by weight, the flowability of the granule is very bad, and the mass deviation due to the sticking phenomenon and the decrease in flowability during production into the product is severe. There is a problem that occurs.

A mixture of such tacrolimus and a solubilizer is dissolved in ethanol at 20 to 30 ° C. to prepare a solid melt. At this time, the amount of ethanol is used 250 to 400 parts by weight based on 100 parts by weight of tarcolimus, if outside the above range is not preferable because there is a problem in the formation of granules due to the excess solvent. In addition, since the process of melting at 20 ~ 30 ℃ proceeds because no separate device or process is required, the process is simplified and is expected to be very economical and excellent industrial availability.

On the other hand, it is possible to prepare a formulation for oral administration by mixing the pharmaceutically acceptable conventional excipients, binders, disintegrants, lubricants, sweeteners and the like to the solid dispersion. At this time, as an excipient, microcrystalline cellulose, lactose, etc. are preferable, as a binder, povidone, hydroxypropyl cellulose, etc. are preferable, and a disintegrant is croscarmellose sodium, sodium starch glycolate, carboxymethyl cellulose calcium, etc. The lubricant is preferably colloidal silicon dioxide, magnesium stearate, talc or the like. In addition, oral administration preparations may be tablets, capsules, solutions, suspension preparations, granules, and the like. The effective dose of tacrolimus varies depending on the patient's age, disease level, etc., but generally 0.001 to 1000 mg per day, Preferably from 0.01 to 500 mg, more preferably from 0.1 to 100 mg.

The present invention provides a solid dispersion composition prepared by dissolving a caprylocaproyl macrogol-8 glycerides and a macrogol 15 hydroxystearate surfactant in ethanol among tacrolimus and macrogol surfactants. By varying the crystallinity of tacrolimus in the formulation, the solubility and dissolution rate is increased, the wettability is high, and the fabrication process is generally used without expensive equipment such as fluid bed granulators. It is possible to provide a composition for oral administration of tacrolimus having easy, reproducible, economical, and stable characteristics by using a group and a mixer (mixing) group. In particular, the tacrolimus solid dispersion composition according to the present invention has the following effects.

First, there is an advantage to prevent the phenomenon that the main component is precipitated by performing solubilization.

Secondly, the solubilization method of the present invention does not require any special solubilization device or equipment because it uses conventional apparatuses and devices such as speed mixers which are generally used in the manufacture of medicines.

Third, the solubilizer used in the present invention serves to increase the utilization (absorption) of the drug as a water-soluble substance applied to the body at the same time as the drug.

Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Examples 1 to 3 and Comparative Example 1: Preparation of the capsule

division Usage (mg) Example 1 Example 2 Example 3 Comparative Example 1 Effective drug Tacrolimus  1.02 1.02 1.02 1.02 Solubilizer Caprylocaproyl Macrogol-8 Glyceride ¹⁾  1.00 1.00 1.00 0.80 Macrogol 15 hydroxy stearate ²⁾  4.00 5.00 6.00 3.50 Solvent ethanol  4.00  4.00  4.00  4.00 Excipient Microcrystalline cellulose 70.48 69.48 68.48 71.18 Lactose 15.50 15.50 15.50 15.50 Binder Povidone  3.00  3.00  3.00  3.00 Disintegrant Croscarmellose sodium  3.00  3.00  3.00  3.00 Lubricant Colloidal Silicon Oxide  1.00  1.00  1.00  1.00 Magnesium Stearate  1.00  1.00  1.00  1.00  1) Labrasol, GATTEFOSSE 2) Solutol HS15, BASF

[Manufacturing method]

1) A solid dispersion was prepared using a main component, a solubilizer and ethanol, and solubilized at 20 to 30 ° C.

2) A solubilized solid dispersion of 1) was introduced into an associative mixture of excipients, binders and disintegrants to form particles.

3) The resulting granules were dried at 50 ° C. for 6 hours or at 40 ° C. with a fluidized bed dryer for 30 minutes.

4) The dried granules were sized using a 30 mesh sizing machine.

5) The granulated granules were placed in a mixer and mixed with a lubricant.

6) The mixture was filled into capsules at a target weight of 100 mg using a capsule filling machine.

Examples 4-5 and Comparative Example 2: Preparation of Suspending Formulations

division Usage (mg) Example 4 Example 5 Comparative Example 2 Effective drug Tacrolimus  4.08 4.08 4.08 Solubilizer Caprylocaproyl Macrogol-8 Glyceride ¹⁾  4.00 4.00 3.20 Macrogol 15 hydroxy stearate ²⁾ 16.00 20.00 14.00 Solvent ethanol  4.00  4.00  4.00 Sweetener D-mannitol 83,475.92 83,471.92 83,478.72 Aspartame 1,000.00 1,000.00 1,000.00 Excipient Hydroxypropylmethylcellulose 12,500.00 12,500.00 12,500.00 Lubricant Colloidal Silicon Oxide 3,000.00 3,000.00 3,000.00  1) Labrasol, GATTEFOSSE 2) Solutol HS15, BASF

[Manufacturing method]

1) A solid dispersion was prepared using the main component, a solubilizer and ethanol, and solubilized at room temperature.

2) The solubilized solid dispersion of 1) was introduced into a coalescing agent mixed with an excipient and a sweetener to form particles.

3) The resulting granules were dried at 50 ° C. for 6 hours or at 40 ° C. with a fluidized bed dryer for 30 minutes.

4) The dried granules were sized using a 30 mesh sizing machine.

5) The granulated granules were placed in a mixer and mixed with a lubricant.

6) The mixture was charged to a container with a target weight of 100 g using a granule filling machine.

7) The formulation is a suspension formulation which can be taken by suspension in water when in use.

Test Example 1: Comparison of Dissolution Rates

900 mL of deionized water was used as the eluent, and the dissolution test was carried out for 60 minutes at 100 revolutions per minute in Method 2 of the Korean Pharmacopoeia Elution Test. The dissolution samples measured dissolution rates up to 60 minutes at intervals of 15 minutes. Analysis of the eluted samples was analyzed by HPLC using test solutions taken at 15 minute intervals.

Detector: ultraviolet absorbance photometer (wavelength: 230 nm)

Column: Shisheido CN, 5 ㎛, 150 mm × 4.6 mm

Mobile phase: 50% acetonitrile

Column temperature: 40 ℃

Flow rate: 1.0 mL / min

As a result of measuring the elution pattern in the aqueous solution of the tacrolimus solubilizing agent prepared according to Example 1, the elution pattern was almost equivalent to that of a commercially available product [Prograb capsule, Fujisa Korea]. [FIG. 1].

Test Example 2: Comparison of Melting Rate According to the Solubilizer Mixing Ratio

As a result of comparing the dissolution rates of the formulations of Examples 1 to 5 and Comparative Examples 1 and 2 as in Test Example 1, the mixing ratio of caprylocaproyl macrogol-8 glyceride and solutol HS 15 was 1: 4. In Comparative Examples 1 and 2 deviating from 1: 6, the dissolution rate was significantly lower than that of Examples 1 to 5 [Fig. 2 and 3].

As described above, the tacrolimus solid dispersion composition according to the present invention can be solubilized to prevent denaturation of the drug, using a conventional apparatus, such as a speed mixer that is generally used in the manufacture of medicines It is very economical because no special solubilizer or equipment is needed.

Claims (3)

An interface in which 100 parts by weight of Tacrolimus is mixed with caprylocaproyl macrogol-8 glycerides and macrogol 15 hydroxystearate in a weight ratio of 1: 4 to 1: 6. Tacrolimus-containing solid dispersion composition, characterized in that 300 to 800 parts by weight of the active agent is contained. A formulation for oral administration, comprising the solid dispersion composition of claim 1. To 100 parts by weight of tacrolimus, 300 to 800 parts by weight of a surfactant obtained by mixing caprylocaproyl macrogol-8 glyceride and macrogol 15 hydroxystearate in a weight ratio of 1: 4 to 1: 6 was added, and 20 Method for producing a tacrolimus-containing solid dispersion, characterized in that to produce a solid dispersion by dissolving in ethanol at ~ 30 ℃.

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