HK1081451B - Medicinal composition - Google Patents

Description

Pharmaceutical composition

Technical Field

The present invention relates to a pharmaceutical composition containing N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine dissolved in high concentration, which has improved pharmaceutical stability and constant quality.

Background

N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine is a compound disclosed in WO01/32164 and is believed to be capable of selectively inhibiting the 20-HETE-producing enzyme for the control of renal, cardiovascular and cerebrovascular diseases, in particular cerebral infarction.

Known methods for improving the water solubility of a sparingly water-soluble drug to obtain an injectable solution or the like are: salifying the raw materials, forming micelle, cosolvent, lipid emulsion preparation and beta-cyclodextrin inclusion method. For the solubilization of a sparingly water-soluble drug by inclusion with β -cyclodextrin, WO85/02767 discloses the solubilization of a sparingly water-soluble drug by inclusion with hydroxypropyl β -cyclodextrin, and USP 5134127 discloses the solubilization of a sparingly water-soluble drug by inclusion with thiobutyl ether β -cyclodextrin.

However, it is very difficult to obtain a suitable solubilization method due to the difference in characteristics between various drugs. Further, even if solubilization is possible, various problems occur in terms of solubility over a long period of time and safety.

Although N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine is preferably administered by the intravenous route, its solubility in water is very low, and it is not suitable for solubilization in the form of an acid salt because of its unstable nature in acidic solutions, and it is also unstable when exposed to light in the solution state. Therefore, there is a need for certain specific methods for preparing pharmaceutical compositions such as injectable solutions. In addition, for the preventive therapy of cerebral infarction, since prolonged intravenous infusion needs to be taken into consideration, it is necessary to take the safety of the organism into consideration in the production operation of the pharmaceutical preparation.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide a pharmaceutical composition containing N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine dissolved in high concentration. The pharmaceutical composition not only has excellent stability over time, heat and light, but also is safe to living bodies.

As a result of repeated experiments to achieve the above object, the present inventors found that by adding sulfobutyl ether β -cyclodextrin or a salt thereof to N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine, a formulation containing the drug dissolved in a high concentration can be obtained and has improved stability under heat and light exposure while causing no damage to an organism upon administration. The present invention has been completed based on this finding. The invention relates to a pharmaceutical composition containing pharmaceutically effective amounts of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine and sulfobutyl ether beta-cyclodextrin or a salt thereof. In the pharmaceutical composition of the present invention, further stability over time can be ensured by preparing it into a lyophilized preparation.

Best mode for carrying out the invention

The present invention is described in more detail below.

The invention relates to a pharmaceutical composition containing a pharmaceutically effective amount of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxy imidocarboxamidine and sulfobutyl ether beta-cyclodextrin or a salt thereof.

In the present invention, N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine can be synthesized, for example, by the method described in WO01/32164 (Compound 302), and the dosage varies depending on the disease and the administration form, and is usually 0.1 to 3000mg per day, preferably 1 to 300mg per day.

Sulfobutyl ether β -cyclodextrin or a salt thereof is available as a commercial product (e.g., Captisol ® manufactured by cydex. inc.) or can be synthesized by introducing a sulfobutyl group onto the OH group of β -cyclodextrin according to the method described in USP 5134127. The number of thiobutyl groups substituted on the OH of a single β -cyclodextrin molecule is referred to as the "degree of substitution". The average of the degrees of substitution of all β -cyclodextrin molecules is referred to as the "average degree of substitution". The average degree of substitution is preferably from about 5 to about 8, more preferably from about 6 to about 7, and most preferably about 7. Preferred salts of the sulfobutyl ether β -cyclodextrin are pharmaceutically acceptable salts, such as alkali metal salts. Particularly preferred is the sodium salt.

The thiobutyl ether beta-cyclodextrin or a salt thereof is contained in an amount of usually 1.18 to 35.45 mol, preferably 5.91 to 17.7 mol, per mol of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine.

For example, Captisol ® is generally present in an amount of 10 to 300 parts by weight, preferably 50 to 150 parts by weight, based on one part by weight of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine.

In addition, if necessary, a pharmaceutically acceptable carrier or other additives such as an isotonic agent (e.g., glycerol or glucose) and a pH adjusting agent may be further contained.

The pharmaceutical composition of the present invention may be formulated into various pharmaceutical forms such as injection solution, lyophilized injectable preparation, tablet, granule, powder, capsule, internal solution or dry syrup. In particular, injectable solutions and lyophilized injectable solutions are preferred. These injectable solutions, as well as lyophilized injectable formulations, can be administered in a single administration or by intravenous infusion.

The pharmaceutical composition of the present invention can be formulated by a conventional preparation method. For example, a common method for preparing injectable solutions involves mixing N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine, sulfobutyl ether beta-cyclodextrin or a salt thereof, water for injection with stirring and dissolving the mixture. Specifically, there is a method comprising adding water for injection to a powder of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine, sulfobutyl ether β -cyclodextrin or a salt thereof, and dissolving the mixture; yet another method comprises dissolving the sulfobutyl ether β -cyclodextrin or salt thereof in water for injection, adding N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyamidinidine to the resulting solution, and dissolving the mixture. Agitation is usually performed by an agitator, however, an emulsifier or homogenizer having a shearing force or a grinding force may also be used for the purpose such as shortening the dissolution time.

Conventional autoclaving and filter sterilization are sterilization methods in the preparation of injectable solutions, however, in the case of the pharmaceutical compositions of the present invention, autoclaving has the potential to reduce the drug content, and thus filter sterilization is preferred. In general, the filter sterilization can be carried out by using a filter having a pore size of about 0.2. mu.m. The material of the filter is not particularly limited except for problems such as adsorption.

For the preparation of the freeze-dried injectable preparation, a common freeze-dryer may be used. Further, in order to prevent the decomposition of the drug, the headspace of the vial or ampoule may preferably be replaced with nitrogen gas regardless of the solution state or the frozen state of the composition.

As shown in the test examples which follow, the pharmaceutical compositions of the present invention may contain N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine dissolved in very high concentrations. That is, in the case of a 10 w/v% aqueous solution of the sodium salt of β -cyclodextrin of thiobutyl ether, the solubility of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine in an aqueous solution of β -cyclodextrin of thiobutyl ether or a salt thereof is 3.57mg/mL at 25 ℃; whereas in the case of a 20 w/v% aqueous solution, the solubility of the drug was 7.67mg/mL at 25 ℃. In contrast, the solubility of the above drugs in 5% Tween 80, 10% polyethylene glycol, soybean oil and olive oil used to prepare them into micelle, co-solvent and lipid emulsion formulations was not higher than 0.5mg/mL at 25 ℃. Thus, the pharmaceutical composition of the present invention may contain the above-mentioned drug dissolved at a significantly higher concentration than conventional preparations.

Furthermore, in the solution of β -cyclodextrin, which is a sulfobutyl ether, N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine is also very stable under heat and light, and therefore, it is convenient for practical use.

The present invention will be illustrated in more detail by the following examples and test examples, which are not intended to limit the scope of the present invention. Various changes and modifications will become apparent to those skilled in the art from this detailed description, and such changes and modifications are intended to be within the scope of the invention.

Examples

Example 1

Weighing N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine (1g) and sulfobutyl ether beta-cyclodextrin sodium salt (Captisol ®; average degree of substitution about 7) (110g), and adding distilled water for injection (1L); after dispersion by the stirrer, the mixture was dissolved using a homogenizer. The solution was then sterilized by filtration using a filter (pore size 0.22 μm). The solution (10mL) was filled into a 20mL amber vial. Each vial headspace was replaced with nitrogen; the vial was stoppered to give an injectable solution containing 1mg/mL of the drug.

Example 2

Weighing N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine (1g) and sulfobutyl ether beta-cyclodextrin sodium salt (Captisol ®; average degree of substitution about 7) (110g), and adding distilled water for injection (1L); after dispersion by the stirrer, the mixture was dissolved using a homogenizer. The solution was then filter sterilized using a filter (pore size 0.22. mu.l). The solution (10mL) was filled into a 20 mL-amber vial and freeze dried with the shelf temperature set at-10 ℃. The top of each vial was replaced with nitrogen; the vials were capped to give lyophilized injectable formulations containing 10mg of drug per vial.

Comparative example 1

A saturated aqueous solution of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine was obtained in the same manner as in example 1, except that the sodium salt of β -cyclodextrin sulfobutylether was not used.

Comparative example 2

A lyophilized injectable solution of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine was obtained in the same manner as in example 2, except that 100g of hydroxypropyl β -cyclodextrin and 30g of dextromannitol as isotonic agents were used instead of 110g of sodium sulfobutylether β -cyclodextrin.

Test example 1[ solubilization test ]

Excess N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine was added to 10 w/v% and 20 w/v% aqueous solutions of the sodium salt of thiobutyl ether beta-cyclodextrin (Captisol ®; average degree of substitution about 7) and to purified water as a blank, respectively. The solubility of the drug was determined by shaking in a water bath adjusted to 25 ℃ for one day.

As a result, the blank solubility of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine in purified water was 0.08mg/mL, and it was found that the solubility increased after the addition of the sodium salt of sulfobutyl ether β -cyclodextrin to the solution, and the results are shown in Table 1. .

Accordingly, the results show that the thiobutyl ether β -cyclodextrin can be used to dissolve N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine.

TABLE 1

Concentration of Thiobutyl ether beta-Cyclodextrin	Solubility in water
		10w/v％20w/v％	3.57mg/mL7.67mg/mL

Test example 2[ light stability test ]

The solution of example 1 and the solution of comparative example 1 were placed in a colorless transparent glass tube with a cover and stored under a fluorescent condition of 3000lux, and the remaining rate of N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine was measured. As a result, as shown in Table 2, N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine in the solution of example 1 is more stable than in the solution of comparative example 1. Accordingly, the results show that the thiobutyl ether β -cyclodextrin is very useful for stabilizing N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine.

TABLE 2

	Example 1	Comparative example 1
			Remaining storage time (hrs)%	4897.8	2438.7

Test example 3[ stability test of lyophilized injectable preparation ]

After the lyophilized injectable preparation of example 2 and the lyophilized injectable preparation of comparative example 2 were stored at 60 ℃ for 7 days, the remaining rate of the drug was determined.

As shown in table 3, N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine in the lyophilized injectable formulation of example 2 is much more stable than in the lyophilized injectable formulation of comparative example 2. Accordingly, the results show that the thiobutyl ether β -cyclodextrin very effectively stabilizes N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine. As a result, the lyophilized injectable formulation of the pharmaceutical composition of the present invention was demonstrated to have excellent thermal stability and good convenience in practical storage and use.

TABLE 3

	Example 2	Comparative example 2
			Storage time (Tian)	7	7
Residual ratio (%)	99.4	97.8

Industrial applicability

The pharmaceutical composition of the present invention is very convenient for practical use because it can contain N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine dissolved in high concentration and can stabilize the drug over a period of time and under heat and light exposure.

Claims (3)

1. A pharmaceutical composition comprises N- (3-chloro-4-morpholin-4-yl) phenyl-N' -hydroxyiminocarboxamidine and β -cyclodextrin, or a salt thereof, thiobutylether.

2. The pharmaceutical composition of claim 1 which is lyophilized.

3. The pharmaceutical composition of claim 1 or 2, which is an injectable solution.