Pharmaceutical composition

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises N-(chloro-4-morpholin-4-yl)-phenyl-N'-hydroxyimidoformamide and β-cyclodextrin sulfobutyl ester or its salt. Invention provides stability of a drug in storage, heating and light effect and shows practice in using also.

EFFECT: improved and valuable properties of pharmaceutical composition.

3 cl, 3 tbl, 7 ex

 

The scope of the invention

The present invention relates to pharmaceutical compositions, which may contain a highly concentrated solution of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov with improved stability of the medicinal product uniformity and quality.

The level of technology

N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide is a compound which is disclosed in WO 01/32164, and in respect of which it was discovered that it has the ability to selectively inhibit 20-NET, producing the enzyme to monitor renal diseases, cardiovascular diseases and cerebrovascular diseases (in particular, cerebral infarction).

Known methods for improving the solubility of poorly soluble in water drug to obtain solutions for injection and so on., such as to redefine them in the form of salts, micelles, the use of auxiliary solvents and drugs in the form of fat emulsions and methods for incorporating β-cyclodextrin. In relation to solubilize poorly water medicines in WO 85/02767 disclosed solubilization of poorly soluble in water drug using hydroxypropyl β-cyclodextrin, and in U.S. patent 5134127 disclosed solubilization of poorly soluble in water medicines with Sul is outillage ether β -cyclodextrin.

However, there is no appropriate way solubilization, which can be easily achieved due to the differences of form or characteristics medicines. In addition, even if the drug can be solubilisation can receive thevarious problems in terms of stability over time and in relation to security.

Although N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxydopamine preferably be administered intravenously, by the way, it is poorly soluble in water, is not suitable for solubilization by the transferred in the form of acid salts due to the instability properties in acidic solutions and also instability in a state of solution when exposed to light. So needed some special tools to obtain pharmaceutical compositions, such as injection. In addition, as prolonged intravenous infusion should be considered for prevention or treatment of cerebral infarction, it is necessary to take into account the safety of the living organism in the production of pharmaceutical preparations.

Disclosure of invention

The object of the present invention is to provide a pharmaceutical composition, which may contain N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide dissolved in high concentrations. F the pharmaceutical composition has not only excellent stability during storage, when heated or when exposed to light, but also safe for the living body.

As a result of multiple studiesto obtain the above object, the inventors have found that by adding sulfobutyl ether β-cyclodextrin or its salt to N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide can be obtained the drug, which may contain a medicinal substance dissolved in a high concentration, stable when heated and exposed to light and safe,not causing damage to a living organism when introduced. The present invention was created based on these data. That is, the present invention is directed to a pharmaceutical composition that includes a pharmaceutically effective amount of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov and sulfobutyl ether β-cyclodextrin or its salts. In the pharmaceutical compositions of the present invention is its improved stability over time can be ensured by moving it in the dried product.

The preferred embodiment of the invention

The present invention can be further elaborated as follows.

The present invention relates to a pharmaceutical composition, which comprises N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroximino Ramadin and sulfobutyl ether β -cyclodextrin or its salt.

In the present invention N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide can be synthesized, for example, according to the method described in WO 01/32164 (revealed as the connection 302), and its dose is different depending on the disorders and forms of introduction, but it usually ranges from 0.1 to 3000 mg per day, and preferably from 1 to 300 mg per day.

Sulfobutyl ether β-cyclodextrin or its salt is available as a commercial product (e.g., Captisol®produced by CyDex, Inc.) or can be synthesized by the introduction sulfobutyl group (s) in the HE group(s) β-cyclodextrin according to the method described in U.S. patent 5134127. The number sulfobutyl groups substituted by an Oh group(s)in one molecule β-cyclodextrinreferred to as "degree of substitution". The average degree of substitution forall molecules β-cyclodextrinreferred to as a "medium " degree of substitution". The average degree of substitution is preferably from about 5 to about 8, more preferably from about 6 to about 7, most preferably about 7. The preferred salt sulfobutyl ether β-cyclodextrin is a pharmaceutically acceptable salt such as a salt of an alkali metal. Especially preferred is nutrie the AI Sol.

Sulfobutyl ether β-cyclodextrin or its salt is usually contained in an amount of from 1.18 to 35,45 mol, preferably from 5,91 to 17.7 mol, per mole of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov.

For example, Captisol® usually contained in an amount of from 10 to 300 moschata on the basis of one Mascali N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov.

In addition, if necessary, can be included pharmaceutically acceptable carriers or other additives, such as isotonic agents (e.g. glycerol or glucose) and pH modulators.

The pharmaceutical composition of the present invention may be formulated into various pharmaceutical forms, such as solutions for injection, lyophilized preparations for injections, tablets, granules, powders, capsules, solutions for indoor use or dry syrups. Particularly preferred solutions for injection and lyophilized preparations for injection. Data solutions for injection and lyophilized preparations for injection can be entered with a single introduction ofor intravenous infusion.

The pharmaceutical composition of the present invention can be prepared using conventional methods, for example, a conventional method for the production of drugs for injection, which comprises mixing N-(3-chloro-4-orfelin-4-yl)phenyl-N'-gidroksiaminopirimidinov, sulfobutyl ether β-cyclodextrin or its salt and water for injection with stirring and dissolving the mixture. In particular, there is a method that involves adding water for injection to the powders of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov and sulfobutyl ether β-cyclodextrin or its salt, and dissolving the mixture, or a method which comprises dissolving sulfobutyl ether β-cyclodextrin or its salts in water for injection pre, adding N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov to the obtained solution and the dissolution of the mixture.

Mixing is usually carried out by conventional agitators, however, for specific purposes, such as reducing the time of dissolution, can be applied emulsifier or a homogenizer, using shear force or crushing force.

Conventional steam sterilization under high pressure and sterilization by filtrationconsidered as a stage sterilization to obtain a solution for injection, but in the case of the pharmaceutical compositions of the present invention steam sterilization under high pressure leads to a decrease inthe content of the medicinal product, therefore, the preferred filtration sterilization. Usually filtration sterilization can be carried out using f is ltr with a pore size of about 0.2 μm. The filter material is not specifically limited, unless there is anyproblems, such as adsorption.

For the production of lyophilized preparations may be used a conventional freeze dryer. In addition, in order to prevent decomposition of the medicinal product, the free space of the vials or ampoules above product is preferably filled with nitrogen regardless of whether the composition is in a state of solution or in a lyophilized state.

As shown in the test example described below, the pharmaceutical composition of the present invention may contain N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide dissolved in very high concentrations. That is, in the case of 10 wt.%/about. an aqueous solution of salt sulfobutyl ether β-cyclodextrin, the solubility of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov in aqueous solution sulfobutyl ether β-cyclodextrin or its salt is of 3.57 mg/ml at 25°and in the case of 20 wt.%/about. aqueous solubility of drugs is to 7.67 mg/ml at 25°C. on the Contrary, the solubility of the above drugs in 5% tween - 80, 10% polyethylene glycol, soybean oil and olive oil, which are used to move theit micelles, the alcohol and the drug is x fat emulsion is not more than 0.5 mg/ml at 25° C. Thus, it is proved that the pharmaceutical composition of the present invention contains the above-mentioned drug, dissolved in significantly higher concentrations compared with conventional drugs.

Moreover, in the solution sulfobutyl ether β-cyclodextrin N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide also verystable when heated and exposed to light and, thus, it is convenient for practical application.

The present invention is illustrated in more detail using the following examples and test examples, which do not limit the scope of the invention. Based on a detailed description of the various changes and modifications will be obvious to experts in this field, and such changes and modifications arein the scope of the invention.

EXAMPLES

Example 1

N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide (1 g) and sodium salt sulfobutyl ether β-cyclodextrin (Captisol®; average degree of substitution of about 7) (110 g) is weighed and added distilled water (1 l) for injection; after dispersion stirrer, the mixture is dissolved using a homogenizer. Then the solution is sterilized by filtration using a filter (pore size: 0.22 μm). A solution (10 ml) fill the 20 ml vial a dark stack is and. The free space above the product each vial fillnitrogen; and the vial sealed and pressurized to obtain a solution for injection containing 1 mg/ml of the drug.

Example 2

N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide (1 g) and sodium salt sulfobutyl ether β-cyclodextrin (Captisol®; average degree of substitution of about 7) (110 g) is weighed and added distilled water (1 l) for injection; after dispersion stirrer, the mixture is dissolved using a homogenizer. Then the solution is sterilized by filtration using a filter (pore size: 0.22 μm). A solution (10 ml) is filled with 20-ml bottle of dark glass and subjected to freeze-drying, in which the set point temperature at -10°C. the Free space above the product each vial is filled with nitrogen, and the vials sealed and pressurized to obtain a lyophilized preparation for injection containing 10 mg/ml of drug in the vial.

Comparative example 1

A saturated aqueous solution of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov receive the same manner as in example 1, except that sodium salt sulfobutyl ether β-cyclodextrin is not used.

Comparative example 2

Liofilizarea the hydrated drug for the injection of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov get the same way as in example 2, except that 100 g of hydroxypropyl β-cyclodextrin and 30 g of d-mannitol was used as an isotonic agent instead of 110 g of sodium salt sulfobutyl ether β-cyclodextrin.

Test example 1 [Test to solubilize]

Excess amount of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov add 10 wt.%/about. and 20 wt.%/about. aqueous solutions of sodium salt sulfobutyl ether β-cyclodextrin (Captisol®; average degree of substitution of about 7) and purified water as a control, respectively. After shaking in a water bath set at 25°, 1 day measure the solubility of the drug.

As a result, the solubility of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov in purified water, ascontrol was 0.08 mg/ml, and it was found that it increases when you add sodium salt sulfobutyl ether β-cyclodextrin to the solutions, as shown in table 1.

Accordingly, it is shown that sulfobutyl ether β-cyclodextrin useful for dissolving N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov.

Table 1
Concentration sulfobutyl

ether β-cyclodextrin
Solubility
10 wt.%/about.

20 wt.%/about.
of 3.57 mg/ml

to 7.67 mg/ml

Test example 2 [Test photostability]

The solution of example 1 and the solution of comparative example 1, each, placed in colorless and transparent closed glass test tube and incubated under fluorescent lamp when the light 3000 Lux and measure the remaining amount of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov. As a result, N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymetabolites in the solution of example 1 is much more stable than in the solution of comparative example 1, as shown in table 2. Accordingly, it is shown that sulfobutyl ether β-cyclodextrin useful for the stabilization of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov.

Table 2
Example 1Comparative example 1
The term

keeping (h)

the remaining share(%)
4824
of 97.838,7

Test example 3 [Test on the stability of lyophilized for injection]

After keeping the lyophilized preparation for injectionp is the iMER 2 and lyophilized for injection of comparative example 2 at 60° C for 7 days to measure the remaining share of drugs.

As a result, N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymetabolites in dried preparation for injection of example 2 was more stable than that of the lyophilized preparation for injection of comparative example 2, as shown in table 3. Accordingly, it was shown that sulfobutyl ether β-cyclodextrin very useful for the stabilization of N-(3-chloro-4-morpholine-4-yl)phenyl-N'-gidroksiaminopirimidinov. In conclusion, therefore, it was proved thatfreeze-dried preparation for injection, the pharmaceutical compositions of the present invention has theexcellentthe heat resistance ofandconvenient for practical storage and use.

Table 3
Example 2Comparative example 2
The term

keeping (h)

the remaining share(%)
77
99,4of 97.8

Industrial applicability

Since the pharmaceutical composition of the present invention may contain N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide, Rast is Genny in high concentrations, and ensures the stability of the medicinal product during storage, when heated and exposed to light, it is convenient for practical use.

1. Pharmaceutical composition, which comprises N-(3-chloro-4-morpholine-4-yl)phenyl-N'-hydroxymaleimide and sulfobutyl ether β-cyclodextrin or its salt.

2. The pharmaceutical composition according to claim 1, which is freeze-dried.

3. The pharmaceutical composition according to claim 1 or 2, which is a solution for injection.



 

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