JPH07291865A - Stabilized composition of prostaglandin e1 - Google Patents

Abstract

PURPOSE:To obtain the subject readily handleable composition which is a freeze- dried substance containing a cyclodextrin clathrate compound of prostaglandin E1 and glucose as blending ingredients, excellent in stability at ambient temperature and having high safety. CONSTITUTION:This composition is a freeze-dried substance containing a cyclodextrin clathrate compound of prostaglandin E1 and glucose as blending ingredients. The blending ratio of the glucose is 25-150 pts.wt., preferably 35-100 pts.wt. based on 1 pt.wt. prostaglandin E1.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to stable prostaglandin E ₁ compositions for use in medicine.

[0002]

BACKGROUND ART Prostaglandin E ₁ (hereinafter abbreviated as PGE ₁ ) is a substance that is present in various animal tissues, is secreted in vivo, and has a small amount of potent peripheral vasodilatory action and platelet aggregation inhibitory action. . And this PGE ₁
It is used as a therapeutic drug for Buerger's disease and arteriosclerosis obliterans. However, PGE ₁ is a very unstable substance such that it is easily decomposed by heat and the like, and it is necessary to prepare a formulation in a stabilized state in order to use it for therapeutic purposes.

Conventionally, prostaglandins E (hereinafter PG
As a method of stabilizing PGEs), a method of encapsulating PGEs with cyclodextrin (hereinafter abbreviated as CD) has been proposed (see Japanese Patent Publication Nos. 50-3362 and 52-31404). ). Further, a method using etherified CD (see JP-A-59-10525), a method in which CD is further added to an aqueous solution of a clathrate compound by CD and freeze-dried (see JP-A-54-43569), CD A method of adding vitamin C or citric acid to an aqueous solution of a clathrate compound and freeze-drying it (Japanese Examined Patent Publication No.
No. 43570) is also known.

However, stabilization of PGEs by these methods cannot be said to be sufficient. Further, in order to obtain a more stable preparation, CD of PGEs, a method of adding an oligosaccharide to an aqueous citric acid solution and freeze-drying (see Japanese Patent Publication No. 60-54933), freeze the PGEs, the CD and the oligosaccharide together. A method of drying (see Japanese Patent Publication No. 61-52146) is also known. However, although these methods provide sufficient stability at room temperature, some of the oligosaccharides are difficult to be metabolized [Pharmacotherapy and treatment, 17 (Supl.
1) 21-30 (1989)], in preparations directly administered into an artery or vein, such as in the PGE ₁ preparation, it may be undesirable to contain such an oligosaccharide.

[0005]

DISCLOSURE OF THE INVENTION As a result of intensive studies conducted by the present inventors to overcome the drawbacks of conventional PGE ₁ preparations, P
The present invention has been completed by finding that a freeze-dried composition comprising a CD inclusion compound of GE ₁ and glucose is very excellent in terms of stability and safety. That is, the present invention provides a stabilized composition of prostaglandin E ₁ , which is a freeze-dried composition composed of a cyclodextrin inclusion compound of prostaglandin E ₁ and glucose.

The composition of the present invention can be produced by a method known in the art of formulation or a method analogous thereto. For example, a general method of freezing an aqueous solution in which a CD inclusion compound of PGE ₁ and glucose are dissolved, and then sublimating under reduced pressure while supplying heat of sublimation if necessary, or once thawing a frozen product A method in which the temperature is raised to a temperature that does not occur, the temperature is maintained for a certain period of time if necessary, and then cooled again, and sublimation is performed under reduced pressure while supplying heat of sublimation if necessary [JP-A-51-123813, Chemical Magazine, 104 966-97
2 (1984)] and the like.

The glucose used in the composition of the present invention is a commonly available glucose, which has a purity used for pharmaceuticals. As the CD used in the composition of the present invention, any of α-, β-, and γ-type CDs can be used.

C of PGE ₁ used in the composition of the present invention
D inclusion compound was lyophilized [Pharmacology, 46 (1) 58
-62 (1986)] or the saturated solution method (Japanese Patent Publication No. 50-
It can be manufactured by using a known manufacturing method such as 3362 and 52-31404.

The compounding ratio of each component in the composition of the present invention is usually 5 to 140 CD with respect to 1 part by weight of PGE _1.
Parts by weight, glucose is preferably 25 parts by weight or more,
More preferably 35 parts by weight or more, further preferably 40
The amount is not less than 100 parts by weight, preferably not more than 150 parts by weight, more preferably not more than 100 parts by weight, still more preferably not more than 80 parts by weight.

Conventionally, no freeze-dried preparation of PGE ₁ stabilized by adding glucose, which is a monosaccharide, has been known at all, and in terms of its stability, the ratio of glucose to 1 part by weight of PGE ₁ is compared. When the amount is 25 to 150 parts by weight, the residual rate of PGE ₁ after 30 days at 60 ° C. is about 80% or more, and the remaining rate after 30 days at 60 ° C. is relatively small within 35 to 100 parts by weight. Rate is 85%
The fact that a highly stable lyophilized preparation is obtained as described above is a surprising thing that cannot be predicted from the prior art.

The composition of the present invention is capable of maintaining sufficient stability at room temperature during the normal distribution period of pharmaceuticals. In general, glucose is a highly safe substance, which is often used as a nutrient for intravenous administration in a large amount, and is often used as a diluting solution for many injectables. Can be safely administered to. The present invention will be described below with reference to examples and test examples.

[0012]

【Example】

[Example 1] Inclusion compound of α-CD of PGE ₁
3 g (containing 100 mg as PGE ₁ ) and 5.0 g glucose were dissolved in water for injection, and then the total amount was 1000
Set to ml. According to the usual method, after sterile filtration, 1.0 ml
Each was filled in a vial, lyophilized, and sealed with a rubber stopper to obtain a lyophilized product composed of the inclusion compound of α-CD of PGE ₁ and glucose.

Example 2 Inclusion compound of PGE ₁ by α-CD 3.3 g (containing 100 mg as PGE ₁ )
And 10 g of glucose are dissolved in water for injection, and then the total amount is 200 ml. According to a conventional method, after sterile filtration, 0.
2 ml of each ampoule was filled and freeze-dried to seal the ampoule, thereby obtaining a freeze-dried product containing the inclusion compound of α-CD of PGE ₁ and glucose.

[Example 3] Inclusion compound of PGE ₁ with α-CD 6.6 g (containing 200 mg as PGE ₁ )
Glucose and 7.0 g are dissolved in water for injection, and then the total amount is 200 ml. According to the usual method, after sterile filtration,
Each 0.1 ml was filled in an ampoule, freeze-dried, and the ampoule was melt-sealed to obtain a freeze-dried product consisting of an inclusion compound of α-CD of PGE ₁ and glucose.

Example 4 Inclusion compound of PGE ₁ by α-CD 3.3 g (containing 100 mg as PGE ₁ )
And glucose (15 g) are dissolved in water for injection, and then the total amount is made 500 ml. According to a conventional method, after sterile filtration, 0.
The ampoule was filled with 5 ml each, and the ampoule was freeze-dried to seal the ampoule to obtain a freeze-dried product consisting of the inclusion compound of α-CD of PGE ₁ and glucose.

[0016]

Example 5 Inclusion Compound of PGE ₁ by α-CD 6.
6 g (containing 200 mg as PGE ₁ ) and 5.0 g glucose were dissolved in water for injection, and then the total amount was 500 m.
Let l. After aseptic filtration according to a conventional method, 0.5 ml each was filled in a vial, freeze-dried and sealed with a rubber stopper to obtain a freeze-dried product consisting of an inclusion compound of α-CD of PGE ₁ and glucose. It was

[0017]

TEST EXAMPLE Each sample of the freeze-dried preparation having the composition shown in Table 1 below was stored at 60 ° C. for 30 days, and the remaining PGE ₁
Was quantified by high performance liquid chromatography. That is, 2 ml of water was accurately added to each sample to completely dissolve it.
2 ml of an internal standard solution (dissolving 10.4 mg of prednisone in acetonitrile to make 500 ml) was accurately added to each sample solution to prepare each sample solution. Separately about 10 PGE ₁ standard products
Precisely weigh mg, add water to dissolve it, and total 200 m
It was set to l. 2 ml of this solution was accurately weighed, and 2 ml of the internal standard solution was accurately added to obtain a standard solution. High-performance liquid chromatography (Shimadzu LC) using a reversed-phase column under the following conditions for 25 μl of sample solution and standard solution.
-6A) separated, UV detector (Shimadzu SPD-
6AV) and data processor (C-R4 manufactured by Shimadzu Corporation)
Using A), a test was carried out by a conventional method, the ratio of the peak area of PGE _{1 to} the internal standard substance was determined, and the quantitative value and the residual rate were determined by the following formula.

[0018]

[Equation 1]

Condition column: M. Nagel Nucleosil 7C18 (inner diameter 4.6 mm, length 25 cm) Temperature: 40 ° C. Moving layer: 0.02 M potassium dihydrogen phosphate solution / acetonitrile mixture (29:21) Flow rate: 1.0 ml / min Measurement wavelength: 205 nm The results are shown in Table 1.

[0020]

[Table 1]

According to the above test, the composition of the present invention is
It was confirmed that the freeze-dried preparation was excellent in the stability of E ₁ and had a good finish.

[0022]

PGE ₁ in stabilizing composition according to the present invention consists of a simple composition comprising the high inclusion compound and safety by PGE ₁ of CD glucose, sufficiently maintain the stability at room temperature can do. Therefore, it is possible to provide a useful formulation of PGE _{1 which} is stable, easy to handle, and extremely safe therapeutically within a normal distribution period.

Claims (2)

[Claims] _1. A stabilized composition of prostaglandin E ₁ , which is a freeze-dried product containing a cyclodextrin inclusion compound of prostaglandin E ₁ and glucose as a blending component. 2. The stabilizing composition according to claim 1, wherein the content of glucose is 25 to 150 parts by weight, preferably 35 to 100 parts by weight, based on 1 part by weight of prostaglandin E ₁ .