JP2003055254A - Cyclosporin preparation for oral administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cyclosporin preparation for oral administration having excellent safety. SOLUTION: The cyclosporin preparation for oral administration is obtained by dissolving cyclosporin in a mixed liquid consisting of (a) 0.5-3 times by weight ratio of propylene glycol, (b) 0.5-3 times of a propylene glycol mono- or di-fatty acid ester, (c) 1-10 times of a surfactant selected from a polyoxyethylene sorbitan fatty acid ester and/or a polyglycerin fatty acid ester, and (d) 0.5-10 times of an extender/viscosity adjusting agent selected from the group consisting of a middle-chain fatty acid triglyceride, a vegetable oil, a polyethylene glycol, a polyvinyl pyrrolidone, a carbonyl vinyl polymer and a polyvinyl alcohol.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a preparation for oral administration of cyclosporine which is an immunosuppressant.

Cyclosporine is well soluble in organic solvents such as methanol and ethanol, but is hardly soluble in water. Therefore, even if cyclosporin in a crystalline state is orally administered in the form of a solid preparation, it is hardly absorbed from the digestive tract, and the bioavailability is very low.

A microemulsion concentrate is known as a preparation which enhances gastrointestinal absorption and bioavailability by oral administration of cyclosporine. This is a solution of cyclosporine dissolved in an oily liquid medium containing a surfactant, which disperses into fine emulsion particles in the digestive tract to help absorption of cyclosporine. The microemulsion concentrate contains a solvent that dissolves cyclosporine.

Japanese Patent Publication No. 62-7891 describes a microemulsion concentrate using ethanol as a solvent. Ethanol permeates and volatilizes through the gelatin film even after the formulation is filled into capsules, causing cyclosporin in the microemulsion concentrate to crystallize, thereby reducing the stability and absorbability of the formulation.

The use of propylene glycol as a solvent has been proposed in JP-A-2-121929. Propylene glycol does not evaporate as much as ethanol, but when the capsule filled with the microemulsion concentrate is dried, it evaporates by heat through the capsule membrane, and cyclosporine may crystallize.

Therefore, not only after being made into a soft capsule,
It is desired to develop a preparation for oral administration of cyclosporine containing a microemulsion concentrated liquid in which the medium for dissolving cyclosporine is less volatile even in the manufacturing process.

[0007]

DISCLOSURE OF THE INVENTION The present invention is based on the fact that cyclosporine is soluble in at least equal amounts of propylene glycol / propylene glycol fatty acid ester 1: 1 mixed systems. Since this mixed system does not volatilize significantly as compared with propylene glycol alone, it can be used to produce a cyclosporin solution having excellent stability.

Therefore, according to the present invention, cyclosporine comprises (a) 0.5 to 3 times the amount of propylene glycol, and (b) 0.5 to 3 times the amount of propylene glycol mono- or difatty acid ester, by weight ratio to cyclosporine. ,
(C) a surfactant selected from 1 to 10 times the amount of polyoxyethylene sorbitan fatty acid ester and / or polyglycerin fatty acid ester, and (d) 0.5 to 1
Cyclosporin preparation for oral administration dissolved in a mixture of a bulking agent / viscosity control agent selected from the group consisting of 0-fold amount of medium-chain fatty acid triglyceride, vegetable oil, polyethylene glycol, polyvinylpyrrolidone, carboxyvinyl polymer and polyvinyl alcohol I will provide a.

Although the preparation of the present invention can be administered as a liquid preparation, it is generally administered in the form of a capsule having a fixed dose, and the above-mentioned beneficial effects can be obtained.

As the fatty acid ester of propylene glycol for dissolving cyclosporine in combination with propylene glycol, monoesters such as propylene glycol monocaprylic acid ester can be used, but diesters with medium and long chain fatty acids are preferred. .

The surfactant used is polysorbate 80.
Or a polyglycerin fatty acid ester such as decaglycerate monolaurate. You may use both together. Surfactants are cyclosporin solubilizers and also emulsifiers when the formulation is emulsified in the digestive tract.

The extender / viscosity modifier is selected from medium chain fatty acid triglycerides or vegetable oils such as olive oil, or polyethylene glycol, polyvinylpyrrolidone, carboxyvinyl polymers or polyvinyl alcohol.

The weight ratio of each of the components (a) to (d) to cyclosporine is as described above.
The weight ratio is preferably as small as possible, unless the stability and workability are adversely affected. This is because the volume of the formulation of cyclosporine per unit dose is small, and thus the size of the capsule is preferably small.

The method for preparing the concentrated liquid is arbitrary. For example, cyclosporine is dissolved in a mixed solution of propylene glycol, propylene glycol fatty acid ester, and optionally a surfactant, and the remaining components are added to this solution to prepare a concentrated solution. A gelatin capsule is filled with this concentrated solution by a conventional method.

[0015]

EXAMPLES The following examples are formulation examples of formulations containing 50 mg of cyclosporine per capsule.

[0016] Example 1   Cyclosporine 50 mg   Propylene glycol 25mg   Propylene glycol fatty acid ester 25mg   Polysorbate 80 150mg   Medium chain fatty acid triglyceride 150mg ─────────────────────────────   400 mg in total

[0017] Example 2   Cyclosporine 50 mg   Propylene glycol 25mg   Propylene glycol fatty acid ester 25mg   Decaglyceryl monolaurate 50mg   Polysorbate 80 100mg   Medium chain fatty acid triglyceride 100mg ─────────────────────────────   350 mg in total

[0018] Example 3   Cyclosporine 50 mg   Propylene glycol 50mg   Propylene glycol fatty acid ester 25mg   Polyethylene glycol 400 50 mg   Decaglyceryl monolaurate 25mg   Polysorbate 80 100mg   Medium chain fatty acid triglyceride 100mg ─────────────────────────────   400 mg in total

[0019] Example 4   Cyclosporine 50 mg   Propylene glycol 25mg   Propylene glycol fatty acid ester 25mg   Polyvinylpyrrolidone 50 mg   Decaglyceryl monolaurate 50mg   Polyethylene glycol 400 200 mg ─────────────────────────────   400 mg in total

[0020] Example 5   Cyclosporine 50 mg   Propylene glycol 50mg   Propylene glycol fatty acid ester 50mg   Polysorbate 80 125 mg   Olive oil 125mg ─────────────────────────────   300 mg in total

In Vitro and In Vivo Tests The solubility of cyclosporine in soft capsules filled with the preparations of Examples 1 to 5 in water was determined by the Japanese Pharmacopoeia dissolution test method No. 2.
When tested according to the method (paddle method), 100% of cyclosporine was eluted from all capsules within 30 minutes. Elution amount is high performance liquid chromatography (HPL
Determined by C).

Next, the soft capsules filled with the preparation of Example 1 were administered to beagle dogs (n = 6), and the change in blood cyclosporine concentration was observed. The peak (about 700 ng / ml) was observed 2 hours after the administration. After reaching this level, the effective blood level was maintained for 12 hours.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/34 A61K 47/44 47/44 A61P 37/06 A61P 37/06 A61K 37/02 (72) Invention Takahiro Endo 560 Nakazatohigashi-cho, Fujinomiya-shi, Shizuoka Prefecture F-term in Toyo Capsule Co., Ltd. (reference) 4C076 AA55 AA56 BB01 CC07 DD08F DD38E DD38Q DD46A EE06A EE09A EE16A EE23 MA52 NA02 MA17 NA02 MA17 NA04MA4A04MA4AFFMA4A4MA04A4MA4AFFMA4A4MA4A4MA04A4MA4AFF3A4MA4A4MA04A4MA4A4A4MA4A4MA4A4A4A4MA4A4A4MA4A4MA4A4A4A4MA4A4A4A4MA4A4MA4A4A4MA4A4A4MA4A4A4MA4A5A4A4MA4A4A4MA4A4A4MA4A4A4MA4A4MA4A0A4MA4A4MAA3A02A17A4A4MAA4A4MA4A0A4A4MAA3A0 of 5 NA11 ZB082

Claims (3)

[Claims] 1. Cyclosporine is (a) 0.5 to 3 times the amount of propylene glycol, (b) 0.5 to 3 times the amount of propylene glycol mono- or difatty acid ester, and (c) by weight ratio to cyclosporine. ) 1 to 10 times the amount of polyoxyethylene sorbitan fatty acid ester and /
Or a surfactant selected from polyglycerin fatty acid ester, and (d) selected from the group consisting of 0.5 to 10-fold amount of medium chain fatty acid triglyceride, vegetable oil, polyethylene glycol, polyvinylpyrrolidone, carboxyvinyl polymer and polyvinyl alcohol. Extender /
A cyclosporin preparation for oral administration, which is dissolved in a mixed solution of a viscosity modifier. 2. The cyclosporin preparation for oral administration according to claim 1, wherein the dosage form is a soft capsule. 3. The cyclosporin preparation for oral administration according to claim 1, which is contained in a liquid-fillable hard capsule.