JPS6150926A - Preparation of medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method for preparing a pharmaceutical composition. More specifically, the present invention relates to a method for producing IJ11, a pharmaceutical composition comprising a mixture of a steroid and a polymeric carrier, wherein when this pharmaceutical composition is administered into the body, the carrier absorbs the steroid. It is released into the body.

A pharmaceutical composition that is repeatedly administered over a long period of time,
Carriers are used in pharmaceutical compositions that release active ingredients in rapid succession, but when polymers are used as carriers, living organisms can easily metabolize these polymers without forming harmful substances. The question will arise as to whether it is possible to do so. in general,
In such compositions, polymers have never been used as carriers. This is because these readily available polymers were initially developed with the aim of being stable for non-medicinal uses, and were not easily metabolized. .

According to the present invention, there is provided a pharmaceutical composition comprising a mixture of an (al copolymer and a (bl steroid substance), the copolymer comprising a compound of the following formula, an OH group and a CO
Compounds having more than one group selected from OH groups,
It is a copolymer with at least one.

According to a preferred embodiment of the invention, the copolymer is cross-linked to form a matrix containing the steroid substance.

As the compound having two or more groups selected from the group 0) and the C0OH group, compounds that exist in nature and/or are benign to the human body are suitable. Compounds having two or more OH groups that can be used in the present invention are as follows: a) Compounds having two or more OH groups include glycerin, sorbitol, erythritol, inositol, glycols based on polyethylene oxide, 4′
-dihydroxyphenyl-2,2-pronozone, 1,2
-dihydroxy-benzene, 1゜3-dihydroxy-benzene, 1,4-dihydroxy-benzene, 1.2.3
-trihydroxy-benzene, 1.2.4-trihydroxy-benzene, 1.5.5-trihydroxy-benzene, etc.; b) at least one OH group, at least one C0
Compounds containing OH groups at the same time include lactic acid, malic acid, 2-hydroxy-isobutyric acid, 10-hydroxycapric acid, 12-hydroxystearic acid, 12-hydroxy-(cis)-9-octadecenoic acid, 2-hydroxy Cyclohexanecarboxylic acid (hexahydrosalicylic acid)
, 2-hydroxy-2-phenyl-(D)-flopion vRs) phenylhydroxyacetic acid, ascorbic acid, citric acid, tartaric acid, 2-hydroxy-6-methyl-
(D)-Succinic acid, 2-hydroxybenzoic acid, 6-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid%
2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 2.5.4-)dihydroxybenzoic acid, 2,
4.5-) Dihydroxybenzoic acid, 2,4.6. -trihydroxybenzoic acid, 5,4,5-) dihydroxybenzoic acid, others; a) Compounds having two or more C0OHj& include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, 1,2- Cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,a-cyclohexanedicarboxylic acid, phthalic acid, isophthalic acid, terephthalic acid, and others.

Mixtures of these compounds can also be used.

The steroid substance present in the pharmaceutical composition provided by the present invention can be one or more steroids whose release can be controlled. Preferably, steroids have proguste-9F activity such as: Nysteroid substances include all compounds having one or more tetracyclic cyclontafenanthrene skeletons. For example, examples of steroids include progesterone, norethisterone, norethisterone acetate, spirono2ct/, cortisone, and others. Further, preferred examples of the steroid in the present invention include norethisterone or norethisterone acetate.

The ratio of steroid to copolymer that can be present in the pharmaceutical compositions according to the invention can vary within wide limits. It is preferred that the weight of Steroid F is at least approximately equal to the weight of the copolymer, but it is possible to have a weight ratio of steroid to copolymer of up to 90:10. A particularly preferred ratio of steroid to copolymer is approximately 50 by weight.
:50-60 :40.

According to the method of the present invention, the pharmaceutical composition according to the present invention is produced as follows. That is, in the presence of an acidic catalyst and a steroid substance, the compound represented by the above formula I is
It is copolymerized with at least one compound having two or more groups selected from H and COOH groups.

The compounds of formula I mentioned above are stereoisomeric mixtures, but
It is a colorless liquid with a high boiling point, very low oral toxicity, and no known harmful effects on the skin. This compound can be prepared by the following reaction sequence: H,C=CH-CHO Acrolein The process of the invention can be carried out as follows. In other words,
In the presence of an acidic catalyst, preferably at a high temperature of about 60 to 100°C, particularly preferably at a temperature of 80°C, a compound of formula (1) and two or more groups selected from OH and COOR groups are combined. or a mixture of such compounds, and then to the mixture thus obtained is added the desired steroid in the appropriate amount to uniformly disperse the steroid in the mixture. The mixture thus obtained can be cured, preferably at elevated temperatures.

Optionally, a compound of formula I and a compound having two or more groups selected from OH and COOH groups,
or by first mixing with a mixture of such compounds.
It is possible that one may wish to stop the copolymerization during this period. In such a case, you can do as follows.

For example, adding a primary amine, a tertiary amine, a tertiary amine such as triethylamine, a quaternary ammonium hydroxide, a basic inorganic oxide or hydroxide in an amount sufficient to neutralize the activity of the acidic catalyst. All you have to do is do it. Therefore, a steroid can be added to uniformly distribute it in the mixture, and then an acidic catalyst can be further added to proceed and complete the copolymerization reaction.

Suitable acidic catalysts that can be used in this method include the following: Examples include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as para-toluenesulfonic acid, and Lewis acids such as zinc chloride, tin tetrachloride, aluminum chloride, and ferric chloride. A preferred acidic catalyst is ferric chloride. The amount of acidic catalyst used is not critical, but ranges from about 0.01% to 2% based on the total weight of the mixture.
．． A value of 0% is a good idea, and a value of about 0.0% is particularly preferred.
04% to 1.0ch.

The ratio of the compound of formula (1) to the compound having two or more groups selected from OH and COOH groups can be changed as appropriate. Although it is advantageous to use stoichiometric amounts, it is also possible to use oils that deviate considerably from stoichiometry.

The copolymerization can be carried out in the presence of a pharmaceutically acceptable inert M medium or a pharmaceutically acceptable inert oil,
In this case, the pharmaceutical composition obtained as a result of this copolymerization is
Its nature is changing.

An example of such an oil is olive oil. The pharmaceutically acceptable solvent or oil may be added by itself or may be used as a solvent or dispersant to dissolve or disperse other components in the polymerization mixture. good. Thus, for example, the steroid can be dissolved or dispersed in a pharmaceutically acceptable inert solvent or oil.

The following formula shows a simplified process for preparing a cross-linked copolymer using a compound of formula I and glycerin: for a certain period of time, e.g.
Over a period of several months to two years, the steroid is slowly released from the pharmaceutical composition, and at the same time the copolymer is biodegraded into a material that is easily disposed of by the human body. . As mentioned above, suitable copolymers are copolymers prepared between a compound of formula (1) and a compound that is naturally occurring and/or benign to the human body. . When such a copolymer is subjected to hydrolysis, particularly acid hydrolysis, the latter compound itself is overwhelmingly obtained. As mentioned above, in the case of a copolymer prepared using glycerin, the seven hydrolyzed fragments of the compound represented by Formula 1 are as follows: These seven fragments are It is also easily oxidized and disposed of within the body.

The rate of steroid release from the pharmaceutical compositions provided by the present invention can be controlled in a variety of ways. For example, in a copolymer produced using each given component, the density of cross-linking may be changed. Also, for example, regarding pharmaceutically acceptable inert solvents or oils that may be present in the composition,
You can change the type or the amount used.

Although pharmaceutical compositions are provided by the present invention based on cross-linked copolymers (i.e. matrices),
Its outstanding feature is that this copolymer has two states: a so-called glass state (in this state, the copolymer is hard and brittle) and a rubber state, and it changes from the glass state to the rubber state at the so-called glass transition temperature. It is to change. When a pharmaceutical composition in which the copolymer is in a glass state is administered into the body, the steroid is slowly released, and at the same time, the copolymer is also slowly biodegraded, resulting in a gradual decrease in the glass transition temperature. I will do it. When the glass transition temperature is reached, the copolymer becomes rubbery and completely disintegrates in vivo. Therefore, as soon as the glass transition temperature reaches body temperature, the copolymer begins to decompose within the body. From this it can be seen that pharmaceutical compositions based on cross-linked copolymers that initially have a glass transition temperature slightly above body temperature are highly desirable.

The pharmaceutical compositions provided by the invention can be administered, for example, by subcutaneous or intramuscular injection or subcutaneous implantation. When in the form of an injectable, the pharmaceutical composition having the appropriate particle size may be dispersed in a pharmaceutically acceptable carrier suitable for subcutaneous or intramuscular administration. The steroid release rate can be controlled by appropriately selecting the size of the particles or changing their distribution as appropriate. # as a drug form for subcutaneous implantation
-1-1 Examples include t-bar, lattice, film, disk, rod, etc. A solid drug in such a form for subcutaneous implantation can be manufactured by a conventional method.

The following examples serve to illustrate the invention: Example 1 The ratio of Compound I to glycerin was 6:2.

To produce a polymer matrix containing norethisterone by weight f%, the following components were used as raw materials: Glycerin 215.5■3.4-
Dihydro C: l-2H-bilan-2-methyl-(5,4-
Dihydro-2H-pyran-2-carboxylate) (Compound)) 790.0m9 Ferric chloride 1.0 TI9 Norethisterone 1006.5M! A solution of ferric chloride in glycerin is warmed to 80° C. and compound I is added dropwise. The heating and stirring process continues during this droplet process. Initially, Compound I and glycerin do not mix, but as Compound I is added little by little, and while heating, the mixture becomes one phase, and when Compound I is added, the glycerin mixture forms this even more easily. Uke is put in and reaches a stage where it becomes even.

When the amount of Compound I to glycerin reaches the stoichiometric bond, the heat source is removed from the mixture and norethisterone is added to form a homogeneous paste. Subsequently, the temperature of the paste is kept at 80° C. until the polymerization is complete and the desired polymerized matrix is obtained.

The nine-part star described in the above paragraph can be used to prepare discs for subcutaneous implantation as described below: Before entering the final polymerization step, this star can be used to prepare polythene ( (Polyth@ne) film, cover this with a polythene film, and place it in a press. When this press is closed, it does not close completely without any heat gaps;
There is a slight gap, and the size of the gap corresponds to the distance between the two polythene films described above, and corresponds to the thickness of the copolymer matrix, and the size of the gap corresponds to the thickness of the copolymer matrix, and the size of the gap corresponds to the distance between the two polythene films described above. It can be changed according to the thickness. Continue heating the tonoburst to 8°C until polymerization is complete. While still soft, punch the norethisterone/polymer matrix film to form flat disks, and after curing, polyethylene The lining is removed.

Example 2 The following ingredients were used to prepare a 45.33% norethisterone-containing polymer matrix according to the method described in Example 1: Glycerin
91.2Ql Compound I 5
52.9mg ferric chloride 0.5
q Norethisterone 382.8 Cape Example 6 26.2f of 1,2,6-hexandriol and 18
．． 4f K in glycerin, 0.42 p-toluenesulfonic anhydride was dissolved. The mixture was heated on a steam bath without stirring for over 1.5 hours. BY's 3°4-dihydro-2H-pyran-2-methyl-(6°4-dihydro-2H-pyran-2-carboxylate) (Compound Engineering) was slowly added. Heating was continued for an additional 20 minutes until a viscous, clear yellow prepolymer was formed. The prepolymer was collected and 0.22 of tert-butylamine was added followed by 89.6 f of 6,4-dihydro-2H-
Pyran-2-methyl-(6,4-dihydro-2H-pyran-2-carboxylate) was added.

This pressure gave a pale yellow syrup which could be stored for many weeks at room temperature.

Microcrystalline norethisterone 52 was mixed into the prepolymer 51 prepared as described in the above paragraph with stirring. Shake thoroughly to uniformly disperse norethisterone in this mixture, and
．． 0.0 in 225 tons of 1,2°6-hexanetriol.
025f of p-toluenesulfonic anhydride was added thereto with rapid stirring. Then the temperature rose to 100°C. Heating at this temperature for 4 hours resulted in a light brown opaque solid consisting of norethisterone dispersed in a polymeric matrix.

Example 4 0.021 to 922 anhydrous glycerin? A solution of anhydrous ferric chloride was heated to 80°C.

To this solution, 35.6 t of Compound I was slowly added with stirring. The addition operation was carried out drop by drop, and once the mixture became homogeneous, further addition operations were stopped. The addition of compound (1) was completed in 0.1 hour, and a pale yellow, transparent liquid was obtained.

3% by weight of cortisone was dissolved in the liquid obtained by the method described in paragraph &C above and the resulting mixture was heated to 80° C. overnight to obtain a hard and brittle solid polymer matrix.

Example 5 The same procedure as described in Example 4 was repeated, except that 8.4% by weight of spironolactone was introduced into the polymerization matrix. The product obtained was a friable solid.

Claims (1)

[Scope of Claims] 1. A compound represented by ▼Math formula, chemical formula, table, etc.▼ (I) and at least one compound having more than one group selected from OH group and COOH group, In the presence of an acidic catalyst and in the presence of a steroid substance,
A method for preparing a pharmaceutical composition, comprising copolymerization. 2. A compound represented by the formula, ▲Mathematical formula, chemical formula, table, etc.▼(II) and at least one compound having more than one group selected from OH group and COOH group in the presence of an acidic catalyst. 1. A method for preparing a pharmaceutical composition, which comprises copolymerizing in the presence of a steroid substance and a pharmaceutically acceptable inert solvent or a pharmaceutically acceptable inert oil. 3. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by (I) and at least one compound having more than one group selected from OH group and COOH group are combined in the presence of an acidic catalyst and In the presence of steroid substances,
Pharmaceutical compositions, characterized in that, after copolymerization, they are in the form of a dispersion in a pharmaceutically acceptable liquid carrier, adapted for subcutaneous or intramuscular administration, or in the form of a subcutaneous implant, adapted for subcutaneous administration. Preparation method. 4. Formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) A compound represented by (I) and at least one compound having more than one group selected from OH group and COOH group are combined in the presence of an acidic catalyst. A pharmaceutically acceptable liquid that is compatible with subcutaneous or intramuscular administration after copolymerization in the presence of a steroid substance and a pharmaceutically acceptable inert solvent or pharmaceutically acceptable inert oil. A method for preparing a pharmaceutical composition, which comprises dispersing it in a carrier. 5. Formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) A compound represented by (I) and at least one compound having more than one group selected from OH group and COOH group are combined in the presence of an acidic catalyst. After copolymerization in the presence of a steroid substance and in the presence of a pharmaceutically acceptable inert solvent or a pharmaceutically acceptable inert oil, the compound is prepared in the form of a subcutaneous implant suitable for subcutaneous administration. A method for preparing a characterized pharmaceutical composition. 6. In order to produce a cross-linked copolymer, OH groups and C
Claims 1, 2, 3, 4, or 3, characterized in that a compound having more than two groups selected from OOH groups is copolymerized with a compound of formula I. The method described in Section 5. 7. The method according to claim 1, 2, 3, 4 or 5, wherein the weight of the steroid substance present is at least approximately equal to the weight of the copolymer. . 8. The method according to claim 1, 2, 3, 4 or 5, characterized in that ferric chloride is used as the acidic catalyst. 9. Claims 1, 2, 3, 4, or 9, wherein the amount of the catalyst used is about 0.01% to 2.0% based on the total weight of the mixture. The method described in Section 5.