JP2012001487A - Tacrolimus-containing capsule - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral solid preparation containing tacrolimus in which bioavailability is improved, and further, the variation of concentration in blood is reduced.SOLUTION: A composition for filling into a capsule made of: (1) the tacrolimus; (2) propylene glycol; (3) propylene glycol fatty acid ester; and (4) polyoxyethylene castor oil is filled into a capsule by the conventional method.

Description

  The present invention relates to a tacrolimus-containing capsule with improved bioavailability and further stabilized absorption upon oral administration.

  Tacrolimus is an active substance having an immunosuppressive effect discovered as a metabolite of the actinomycete Streptomyces tsukubaensis. It is a macrolide compound different from cyclosporine and has a strong immunosuppressive action. In vitro experimental models such as lymphocyte mixed reaction show the same inhibitory effect at low concentrations of 1/100 of cyclosporine, and in organ transplantation models such as rats and dogs, 1/10 to 1/30 of cyclosporine. Suppression of rejection at dose and prolonged survival of transplanted organs was observed. In 1993, Prograf (registered trademark) was approved for the manufacture and sale of drugs for the suppression of rejection in liver transplantation. Indications such as drugs are expanding. Compared to cyclosporine, tacrolimus has a strong immunosuppressive activity but has a comparable or less proliferative inhibitory effect on bone marrow cells, and a high engraftment rate and survival rate can be obtained. Yes.

Tacrolimus is a therapeutic drug that requires a very difficult dose adjustment of immunosuppression. While it is ideal to maintain a minimum blood concentration that provides the expected drug efficacy, oral administration is desirable to improve the patient's QOL. Absorption at oral administration is not constant and varies from patient to patient, so side effects when blood concentration is high and rejection and graft versus host disease when blood concentration is low In order to prevent this, it is necessary to measure the blood concentration according to the situation and adjust the dose with reference to the blood concentration of the trough level. Furthermore, at the time of oral administration, it has been found that bioavailability remains in the 20% range due to the effects of the first-pass effect on the liver.

Among oral preparations containing tacrolimus, hard capsules, granules, and hard capsules with sustained release are commercially available. Granules are used as an adjustable form when the therapeutic range of blood drug concentration in children is narrow. Although hard capsules with sustained release are in a once-daily dosage form and contribute to improving the patient's QOL, absorption during oral administration varies, and the best formulation effect is not always obtained. There was no situation.

  Patent Documents 1 to 3 are prior art relating to an oral preparation containing tacrolimus. Patent Document 1 discloses that a solid solution composition is prepared by dispersing with tacrolimus and a water-soluble polymer in order to avoid the disadvantage of low bioavailability during oral administration because tacrolimus is insoluble in water. . However, the bioavailability of this technology has not always reached a satisfactory level. Patent Document 2 relates to a solution formulation including tacrolimus, not limited to oral. Although tacrolimus has a very low solubility in water, this report discloses the preparation of a solution form embodiment by specifying various additives and their composition ratios. However, it is merely intended to be in solution form, and no mention is made of suppressing bioavailability and variation in blood concentration. Patent Document 3 relates to a sustained-release preparation of a macrolide compound, which is also an object different from bioavailability and reduction in variation in blood concentration.

Japanese Patent Laid-Open No. 62-277321 Japanese Patent Laid-Open No. 4-211012 Japanese Patent Application No. 11-545641

  In view of the above, an object of the present invention is to provide an oral solid preparation containing tacrolimus with improved bioavailability and further reduced variation in blood concentration.

According to the present invention, the above-mentioned problems are solved by providing a capsule filling composition comprising (1) tacrolimus, (2) propylene glycol, (3) propylene glycol fatty acid ester, and (4) polyoxyethylene castor oil.
Tacrolimus can also use its hydrate.
Tacrolimus dissolves well in propylene glycol. However, since propylene glycol dissolves or swells the capsule skin, the amount that can be blended is limited. In the present invention, from various studies, it was possible to add up to 30% to the capsule filling composition. Further, when considering the improvement of bioavailability and the reduction in variation in blood concentration, which are the objects of the present invention, it is desirable that tacrolimus, which is sparingly soluble in water, be easily solubilized in the digestive tract.
As a result of intensive studies in the present invention, tacrolimus can be solubilized by blending propylene glycol fatty acid ester and polyoxyethylene castor oil together with propylene glycol as a solubilizer.
Propylene glycol fatty acid ester is a lipophilic surfactant of about HLB 3.4 that is synthesized by direct esterification of propylene glycol with a fatty acid lower alkyl ester or by transesterification of natural fat and oil with propylene glycol in the presence of a catalyst. Commercially available products include SEFSOL-218, SEFSOL-228 and PDD (Nippon Surfactant Industries), Deformer PS (Nippon Activator), Homotex PS-200V (Kao), Miglyol S40 (Mitsuba Trading) and the like.
Polyoxyethylene castor oil is also called polyoxyl 35 castor oil, and is a nonionic surfactant obtained by addition polymerization of castor oil with ethylene oxide. The average number of moles of ethylene oxide added is about 35. Commercially available products include Cremo Hall EL (BASF Japan).
Specifically, propylene glycol is 1 to 30 parts by weight, propylene glycol fatty acid ester is 30 to 300 parts by weight, and polyoxyethylene castor oil is 4 to 130 parts by weight with respect to 1 part by weight of tacrolimus. The specific gravity adjuster, disintegrant and stabilizer are not particularly defined, but up to 100 parts by weight can be added.
When the composition is released into a large amount of water, the effect can be observed by mixing with gentle stirring. “Mixing” refers to a state in which separation of components is not visually recognized, and includes emulsions with turbidity to microemulsions and nanoemulsions. The large amount of water here is assumed to be about 900 mL that can be used when a single dose of tacrolimus is orally administered.
In the present invention, convenience and stability can be further improved by using the pharmaceutical composition as a capsule.
The type of capsule may be a soft capsule or a hard capsule. Soft capsules can be manufactured by a rotary die method or a multi-nozzle dropping method, and hard capsules can be manufactured by encapsulating the composition of the present invention in a hard capsule such as gelatin by a conventional liquid filling method. can do.
In particular, the soft capsules produced by the multi-nozzle dropping method can further increase the added value by making the particles 1-5 mm in diameter. It is necessary to adjust the dosage of tacrolimus so that an effective therapeutic concentration range can be obtained for each individual patient. In general, it is desired to monitor the blood concentration at the time of the first administration, and it is desirable that the dose capable of maintaining a suitable concentration range is finely adjusted for each patient. Fine-grained capsules facilitate fine-tuning for each patient, and ease of administration, divided administration, and reduction of the packaging action for dispensing.
As specific gravity adjusters, pharmaceutically acceptable animal and vegetable oils, synthetic oils, mineral oils, sucrose acetate isobutyrate, and the like can be blended. Moreover, these can also be combined.
As the disintegrant, pharmaceutically acceptable ingredients can be blended. For example, povidone, crospovidone, hydroxypropylcellulose, hypromellose, hydroxypropyl starch, partially pregelatinized starch, methylcellulose and the like are applicable. Moreover, these can also be combined.
As the stabilizer, pharmaceutically acceptable ingredients can be blended. For example, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium edetate, dibutylhydroxytoluene, tocopherol, butylhydroxyanisole, β-carotene and the like are applicable. Moreover, these can also be combined.
It is also effective to impart functionality to the capsule of the capsule of the present invention. In the case of soft capsules manufactured by the soft capsule rotary die method, a method of applying a coating layer to soft capsules manufactured according to a conventional method, or a method of previously adding a polymer such as chitosan or hydroxypropylmethylcellulose phthalate to the capsule skin Is possible. Similarly, in the case of seamless capsules produced by the soft capsule multiple nozzle dropping method, a method of applying a coating layer after production, or a method of adding polysaccharides such as alginic acid and chitosan to the capsule skin in advance are also possible. In the case of a hard capsule, it can be easily changed by selecting the capsule type.

The graph which compared the result of the dissolution test of the capsule of this invention described in an Example, a control example, and a commercially available tacrolimus formulation.

〔Example〕
Examples of capsule filling compositions are given below as examples. Each component was mixed to form a liquid and filled in a capsule according to a conventional method to produce a soft capsule. In the examples, SEFSOL-218 manufactured by Nippon Surfactant Kogyo Co., Ltd. was used as the propylene glycol fatty acid ester, and Cremohol EL manufactured by BASF Japan Co., Ltd. was used as the polyoxyethylene castor oil.

[Test example]
The Japanese Pharmacopoeia dissolution test was carried out on the soft capsules produced according to the examples and control examples, and the commercial preparations containing tacrolimus. Specifically, one specimen was taken, and 900 mL of water was used as a test solution, and the test was performed at 50 revolutions per minute by the paddle method. 10 mL of the eluate was taken at the specified time, and the dissolution rate relative to the content of tacrolimus contained in the preparation was calculated by high performance liquid chromatography. As a result, in Examples, extremely good dissolution was obtained as compared with Comparative Examples and commercially available preparations (tacrolimus hard capsules). The results are shown in FIG.

Claims (5)

  (1) tacrolimus, (2) propylene glycol, (3) propylene glycol fatty acid ester, and (4) polyoxyethylene castor oil, 1 to 100 parts by weight of propylene glycol, propylene glycol fatty acid ester to 1 part by weight of tacrolimus A capsule filling composition comprising 5 to 300 parts by weight and 3 to 200 parts by weight of polyoxyethylene castor oil.   The capsule filling composition according to claim 1, wherein the tacrolimus is tacrolimus hydrate.   The capsule according to claim 1, further comprising a specific gravity adjusting agent, a disintegrant and / or a stabilizer.   The composition for filling capsules according to claim 1, wherein the composition for filling capsules is mixed by gentle stirring when released into a large amount of water.   The capsule formed by filling the composition for capsule filling of Claims 1-4.

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