HU204700B - Process for producing aqueous compositions comprising piperidinyl cyclopentylheptenoic acid derivatives - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of aqueous compositions containing (1R [1a (2), 2 ^ 3R5y]) - (+) - 7- <5 - [(1,1'-biphenyl) -4-yl] methoxy] -3-hydroxy-2- (1-piperidinyl) cyclopentyl} -4-heptenoic acid (hereinafter referred to as Compound A). 5

Compound A is described in United Kingdom Patent 2,097,397 as a representative of aminocyclopentane derivatives having endoperoxide and thromboxane anagonist activity, and is described for the treatment of asthma and cathodicovascular disease. suitable. Recently, the hydrochloride salt of Compound A has been found to be superior to other salts and solvates of Compound A, both in terms of preparation and use as a medicament. The hydrochloride tube is described in British Patent No. 2,127,406.

Compound A is only slightly soluble in water, and the aqueous formulation of the hydrochloride salt of Compound A with conventional excipients and / or carriers has not been shown to be suitable for intravenous administration because the hydrochloride salt of Compound A is converted to substantially insoluble Compound A at physiological pH.

In our experiments, we have found that the water solubility of Compound A or its hydrochloride salt at physiological pH is significantly increased in the presence of unsubstituted or substituted α, β, or γ-cyclodextrin (or its hydrate). It has further been found that aqueous compositions containing Compound A or its hydrochloride salt and 30 unsubstituted or substituted α, β or γ-cyclodextrin (or hydrates thereof) may be used as medicaments, particularly for the treatment or prevention of thromboxane A ₂ mediated conditions by oral, e.g. or parenteral, especially for injection (e.g., intravenous) administration.

The present invention therefore relates to a process for the preparation of aqueous compositions containing Compound A or its hydrochloride salt as an active ingredient, and unsubstituted 40 or substituted α-, β- or γ-cyclodextrin (or hydrate thereof). The aqueous compositions thus prepared are useful as medicaments, in particular for the treatment or prevention of thromboxane A ₂ mediated conditions. 45

The aqueous compositions of the present invention are useful in the treatment of the conditions described in British Patent Nos. 2,097,397 and 2,127,406 for compositions containing Compounds A and their hydrochloride salts. The aqueous compositions of the present invention are particularly useful in the treatment or prevention of occlusive vascular disease, including myocardial infarction, cardiac death, and instability. angina, transient ischemic attacks, cerebral infarction 55, atherosclerosis and vascular disease, peripheral vascular disease, retinal haemorrhage, postoperative thrombosis and pulmonary embolism. These aqueous formulations may also be used to prevent organ transplantation (particularly cardiac and renal transplantation), coronary artery bypass grafting, peripheral arterial bypass and post-thrombolytic complications. Aqueous formulations are also potentially useful for relapse of gastric ulcer, especially from a cured gastric ulcer.

Preferably, Compound A in the aqueous compositions of the present invention is readily appreciated by those skilled in the art that the benefits of the present invention can be achieved using a variety of cyclodextrins, but it is generally preferred to use a single cyclodextrin.

When a substituted cyclodextrin is used, it may be any known substituted cyclodextrin. Suitable substituted cyclodextrins are, for example, sulfur-containing cyclodextrins, nitrogen-containing cyclodextrins, alkylated (e.g. hydroxyalkylcyclodextrins such as hydroxypropyl? -cyclodextrin and acylated derivatives thereof. Hydroxyalkylated cyclodextrins such as hydroxypropyl-β-cyclodexttin have been found to be particularly suitable in the process of the invention.

Preferably, the present invention utilizes a single unsubstituted cyclodextrin. Particularly preferred is β-cyclodextrin, preferably in its hydrated form.

In order to obtain an aqueous composition having the appropriate properties, it is important that the molar ratio of Compound A or its hydrochloride salt to cyclodextrin is properly adjusted. It has been found that the molar ratio of Compound A or its hydrochloride salt to cyclodexttin is 1: 1 to 1: 4.

One skilled in the art will recognize that the aqueous compositions of the present invention may also contain one or more pharmacologically acceptable carriers or other excipients. Suitable excipients are, for example, compositions which render the composition isotonic with blood plasma (e.g., sodium chloride, glucose or preferably mannitol) and buffering agents (e.g., phosphate buffer or a mixture of sodium dihydrogen phosphate and disodium phosphate).

The aqueous compositions of the present invention are particularly suitable for parenteral administration, particularly by injection (e.g., intravenous). For parenteral administration, it is desirable that the pH of the composition be around physiological pH. Therefore, it is convenient to adjust the pH to a physiological level using a conventional method, for example, using a suitable base such as an hydroxide (e.g., an alkali metal hydroxide, such as sodium hydroxide). Preferably, ApH is adjusted to about 6.0.

For parenteral administration, particularly for administration by injection (e.g., intravenous), it is highly desirable that the composition be in the form of a clear solution. The clear solution does not require any further treatment (for example, dissolving a dry powder) and can be added without further ado. The use of a clear solution further allows the particle to be present in the formulation2

Two or other visible impurities are easily noticed. In addition, intravenous administration of an aqueous solution of an active ingredient may produce an immediate physiological effect. It has been found that at least 1 mole of cyclodextrin is required to produce a clear solution of each mole of the hydrochloride of Compound A at a physiological pH under normal storage temperature and at least about 1.2 moles for β-cyclodextrin.

In a preferred embodiment of the process of the invention, a pure aqueous composition is prepared which contains the hydrochloride salt of Compound A and β-cyclodextrin (or its hydrate) at a physiological pH close to about ól of the β-cyclodextrin content per mole of the hydrochloride salt of Compound A. 1.2 moles (1.2-2 moles). The molar ratio is preferably about 1: 1.4.

In said aqueous compositions for parenteral administration, in particular for injection (e.g., intravenous) administration, the concentration of Compound A or its hydrochloride salt is preferably 0.1 to 10 mg / ml, for example 0.1 to 5 mg / ml, expressed as the free base. More preferably, the concentration is expressed as 1 mg / ml of free base when the aqueous composition is intended for intravenous injection. If desired, higher concentrations may be used and the solution may be diluted with, for example, isotonic saline or glucose or mannitol. Injectable solutions are conveniently prepared in a suitable dose volume (e.g., 1100 ml). In solutions for continuous infusion, the concentration of Compound A or its hydrochloride salt may be in the range of 0.01-0.2 mg / ml expressed as the free base. Formulations for continuous infusion are conveniently formulated, for example, in units of 50 to 100 µl or higher, and diluted prior to administration, for example, with isotonic saline or glucose or mannitol. Solutions of low volume and higher concentration (e.g. 0.1-5 mg / ml) may also be administered by continuous infusion (e.g. 0.5-9.9 ml / hour).

The aqueous compositions described above are conveniently prepared by mixing Compound A, or more preferably the hydrochloride salt thereof, with water with the other components. More preferably, the compound A or its hydrochloride salt is dissolved in water and the other components are added thereto. For parenteral administration, especially for injection (e.g., intravenous) administration, the reconstituted solution is preferably filtered, then filled into a suitable container and finally sterilized, for example by heating. Alternatively, the solution may be sterilized by filtration and then aseptically filled into suitable containers.

Water for injections is used for parenteral formulations for intravenous or continuous infusion administration.

Formulations for injection may be presented in unit dose containers such as ampoules, vials, or pre-filled syringes, or in multi-dose containers, using a preservative.

As mentioned above, the aqueous compositions of the present invention may be administered orally (e.g., in the form of a capsule, syrup or solution) or by inhalation (e.g., aerosol spray for nebulization).

British Patent Nos. 2,097,397 and 2,127,406 disclose suitable general methods for preparing oral and inhalation compositions which may be used without particular experimentation with the compositions of the present invention.

Aqueous formulations may also be prepared by dissolving the solid cyclodextrin complex of Compound A or its hydrochloride salt in water, optionally together with the other components.

The invention further relates to a process for the preparation of aqueous compositions comprising a complex of Compound A or its hydrochloride salt with cyclodextrin.

The invention further relates to a process for the preparation of Compound A or its hydrochloride salt and cyclodextrin complex. The ratio of the compound A or its hydrochloride salt to the cyclodextrin in the complex depends on the cyclodextrin used and the conditions of preparation of the complex. It has been found that the molar ratio of Compound A or its hydrochloride salt to cyclodextrin is 1: 1 to 1: 3.

The cyclodextrin used in the silicate complex may be unsubstituted or substituted α-, β- or γ-cyclodextrin as previously defined or may be a mixture thereof (e.g., a mixture of two cyclodextrins). Preferably, γ-cyclodextrin or, more preferably, β-cyclodextrin is used.

In a preferred embodiment of the process of the invention, a complex is prepared in which the molar ratio of Compound A to β-cyclodextrin is between 1: 1 and 1: 2, preferably about 1: 1.

In another preferred embodiment, a complex comprising Compound A and γ-cyclodextrin in a molar ratio of about 1: 1.5 is prepared.

Complexes containing Compound A or its hydrochloride salt and cyclodextrin are prepared by mixing Compound A or its hydrochloride salt and cyclodextrin or hydrate in a suitable solvent under conditions such that the desired complex is formed. Complexes are thus prepared, for example, by dissolving Compound A or its hydrochloride salt in water or in a water-miscible organic solvent (e.g., an alcohol such as methanol) and a solution of the corresponding cyclodextrin or hydrate thereof in water and / or water-miscible organic solvent. added. The reaction is carried out at a temperature of 0 to 80 ° C, but preferably the mixture is kept at room temperature and the desired complex is swallowed by concentrating the mixture under reduced pressure or allowing the mixture to cool. The mixing ratio of organic solvent to water depends on the solubility of the starting materials and the product. Preferably 1-4 moles of cyclodextrin are used per mole of Compound A or its hydrochloride salt. The resulting complex is a white solid which has high thermal stability and good water solubility. These physical properties make it particularly suitable for the production of ore derivatives. In addition to the aforementioned aqueous formulations containing Compound A or its hydrochloride salt complex with cyclodextrin, especially for parenteral administration, the complexes may also be used for oral, parenteral or inhalation administration, as described in British Patent Nos. 2,097,397 and 2,127,406. methods described in the literature

The daily dose of Compound A or its hydrochloride salt in said formulations will depend on the condition, age and condition of the subject being treated and the mode of administration. Generally, however, the dosage regimes set forth in British Patent Nos. Q97397 and 152127406 are suitable.

The invention is illustrated by the following non-limiting examples. In the following examples, the molar ratios were determined by 1 H NMR analysis.

Example 7 (a) {[IR-Ila (Z) 2 ', 3', 3', 5'-3'-methyl-4-ylmethoxy] -3-hydroxy-2- (1-piperidinyl) -cyclopentyl} -4-Heptenoal: $ -cyclodextrin (1: 1) Complex 0.954 g of β-crodextrin hydrate is almost completely dissolved in 35 ml of water. The suspension is filtered and the filtrate is added to a solution of 0.2 g of compound A (prepared according to Example 10 of British Patent No. 2,097,397) in 10 ml of methanol. The reaction mixture was stirred at 25 ° C for 26 hours until a clear solution was formed, which was evaporated to 12 ml, when slight crystallization began. After 1 h at 5 ° C, the resulting thick precipitate was filtered off and dried to give 0.273 g of the title compound, m.p.> 310 ° C, darkening above 230 ° C.

(b) The filtrate from the previous step further crystallizes on standing and is evaporated to give a white solid 40 which is dissolved in 3 mL of hot water, cooled to 5 ° C and allowed to crystallize to give 121 mg of white solid. (DMSO) analysis: (1Η- [1α (Ζ), 2β, 3β, 5α]) - (+) - 7- {5 - [((1, 4-biphenyl) -4-yl] methoxy] -3-hydroxy 2- (1-piperidinyl) cyclopentyl) -4-heptteoate: β-cyclodextrin (1: 1.5) complex.

EXAMPLE 2 {1R- [10of] (3S, 5S)} - (+) - 7- {5 - [((1,1'-Biphenyl) -4- (50-yl) methoxy] -3-hydroxy-2 - (1-piperidinyl) cyclopenyl} 4-hepenoate: γ-cyclodextrin (1: 1.5) complex

A solution of 1.09 g of γ-cyclodextrin in 25 ml of water was added to 0.20 g of compound A in 10 ml of methanol. added. The reaction mixture was stirred at 25 ° C for 26 hours until a thick white suspension was obtained. The precipitate was filtered off and dried in vacuo to give 0.612 g of the title product as a white solid, m.p.> 310 ° C, darkening above 250 ° C. 60

Parenteral Injection / Infusion Formulations (1) 50 mg of the base hydrochloride salt of β-cyclodextrin hydrate 143 mg 166 mg 238 mg Sodium hydroxide solution 7pH 7 pH 7pH Water for injections 50 ml 50 ml- to 50 ml

The hydrochloride salt of Compound A is dissolved in 35 ml of water for injections and β-cyclodextrin is added. The solution is titrated to pH 7 with 0.02 M sodium hydroxide solution and the volume is adjusted with water for injections. The solution can then be sterilized by filtration and filled into vials or ampoules.

(ii) 166 mg of β-cyclodextrin hydrate corresponding to 50 Irish bases of hydrochloride

Sodium chloride 450 mg

PH 7.0 Phosphate buffer 2.5 ml

Sodium hydroxide solution to pH 7

Water for injections up to 50 ml.

The hydrochloride salt of Compound A was ca. Dissolve in 25 ml water for injections. The β-cyclodextrin is dissolved therein, the resulting solution is titrated to pH 6 with 0.02 M sodium hydroxide solution and phosphate buffer is added. Sodium chloride is added to the solution and the pH is adjusted to 7 with sodium hydroxide. The volume of the solution is adjusted with water for injection, filled into glass vials, sealed with a rubber stopper and sealed with a metal stopper and sterilized.

(iiii) The compound is the hydrochloride salt corresponding to 50 mg of base

Hydroxypropyl [beta] -cyclodextrin 170 mg

Mannit 2.5 g

PH 6.0 phosphate buffer 5.0 ml

Sodium hydroxide solution up to pH 6

Water for injections up to 50 ml.

The hydrochloride salt of Compound A was ca. Dissolve in 25 ml of water for injection and add hydroxypropyl N-cyclodextrin. The mannitol is then added and the solution is titrated to pH 6 with 0.02 M sodium hydroxide. The phosphate buffer is added and the volume of the solution is adjusted with water for injection. The solution is then filled into glass vials, which are sealed with a rubber stopper and a metal cap and sterilized.

(iv) The hydrochloride salt of the compound corresponding to 50 mg of base

β-cyclodextrin hydrate 166 mg mannitol 2.5 mg Sodium dihydrogen phosphate 46 mg Disodium phosphate anhydrous 5 mg Sodium hydroxide To pH 6 Water for injections To 50 ml. The hydrochloride salt of Compound A was ca. 25 ml for injection

Dissolve in water and then dissolve β-cyclodextrin and mannitol and titrate the solution to pH 6 with 0.02 M sodium hydroxide. Sodium hydrogen phosphate and anhydrous disodium phosphate are dissolved in water for injection and added to the solution, and the volume is adjusted with water for injection. The solution is filtered and filled into glass vials, which are sealed and sterilized.

HU 204 700 B (V) Cyclodextrin

The compound is the hydrochloride salt corresponding to 50 mg of base the 7 Mix β + 7 cyclodextrin 143 mg 190 mg 119 mg 136 mg mannitol 2.5 g 2.5 g 2.5 g PH 6.0 phosphate buffer 5.0 ml 5.0 ml 5.0 ml Sodium hydroxide To pH 6 To pH 6 To pH 6 Water for injections To 50 ml To 50 ml • up to 50 ml

The hydrochloride salt of Compound A was ca. Dissolve in 25 ml of water for injections and add cyclodextrins. Add mannitol and titrate the solution to pH 6 with 0.02 15 M sodium hydroxide. The phosphate buffer solution is added and the volume of the solution is adjusted with water for injection. The solution is then nailed and filled into glass vials, which are sealed with rubber stoppers and metal caps. 20

Syrup for oral use

The compound is the hydrochloride salt corresponding to 2.5 mg of base

β-cyclodextrin hydrate 9 mg Citric acid To pH 4.5 Sodium methyl hydroxybenzoate 5 mg Sodium propyl hydroxybenzoate 2 mg orange Flavor qs saccharose 3.25 g Cleaned water To 5.0 ml. Dissolve sucrose in a minimum amount of water-

add the hydrochloride salt of Compound A and adjust the pH to 4.5 with citric acid while stirring with β-cyclodextrin. While stirring, a solution of the hydroxybenzoates was added and finally the aroma volume A was nearly filled with water and the mixture was stirred. Check the pH and adjust to pH 4.5 with citric acid if desired. Make up the volume with water. 40

Solution for Inhalation ml dose

The compound is the hydrochloride salt of 2 mg of base β-cyclodextrin hydrate 7 mg 45 NaCI 18 mg Sodium hydroxide To pH 7.2 7.2 pH phosphate buffer 0.2 ml Water for injections To 2 ml. The hydrochloride salt of Compound A is added to water for injection

solution, dissolve the β-cyclodextrin and titrate the resulting solution with sodium hydroxide solution to pH 6 and add the phosphate buffer. Sodium chloride is then added and the pH is adjusted to 7.2 with sodium hydroxide solution. The volume is adjusted with water for injection, the solution is nailed sterile and aseptically filled into nebuliser containers.

Claims (8)

PATIENT INDIVIDUAL POINTS Process 1: As active ingredient {1- [1α (Ζ), 2β, 3β, 5α]} (+) - 7- {5 - [(1,1'-biphenyl) -4-yl] methoxy] -3- for the preparation of aqueous pharmaceutical compositions containing hydroxy-2- (1-piperidinyl) cyclopentyl} -4-heptenoic acid or its hydrochloride salt, characterized in that the active ingredient is substituted or unsubstituted with α, β or γ cyclodextrin in a molar ratio of 1: 1 to 1: 4; its hydrate and the usual excipients used in the preparation of aqueous pharmaceutical compositions are mixed with water to form a pharmaceutical composition. (Priority: 22.2.1987) Method according to claim 1, characterized in that the active ingredient is dissolved in water and the other components are added, (22.12.1987). 3. The method of claim 1, wherein the active ingredient is a hydrochloride salt. (First of 22.12.1987) 4. The method of claim 1, wherein the cyclodextrin is β-cyclodextrin. (First of 22.12.1987) 5. A method for preparing injection preparations according to claim 1, wherein the appropriate starting materials are used. (First of 22.12.1987) 6. The method of claim 1, wherein the β-cyclodextrin is used in an amount of at least 1.2 moles per mole of active ingredient. (Aug. 25, 1988) 7. The method of claim 1, wherein the molar ratio of the drug to the β-cyclodextrin is 1: 1.4 (First of February, 1988). 8. The method of claim 1, wherein the pH is adjusted to 6.0. (First known: 1988-12-21)