JPH02210A - Aqueous recipe containing pyperidinylcyclopentylpentenic acid derivative - Google Patents

Abstract

PURPOSE: To obtain an aqueous prescription preparation containing α-, β-, or γ-cyclodextrin or its hydrate, and a specific compound as an active ingredient, improved in the solubility of the active ingredient in water, useful for treating embolic vascular diseases, and especially suitable for injection administration. CONSTITUTION: This aqueous prescription preparation contains [1 R-[1α(2),2β,3β,5α]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1- piperidinyl)cyclopentyl]-4-heptenoic acid or its hydrochloride as an active ingredient and non-substituted or substituted α-, β- or γ-cyclodextrin or a hydrate thereof. The active ingredient or its hydrochloride is used in a molar ratio of 1:1-1:4 per the dextrin. The aqueous prescription preparation is suitably parenterally administered, and is preferably adjusted to a pH near to approximately a physiological pH.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides active ingredients [1R-[lα(Z), 2β
, 3β, 5α))-(+)-7-(5-[((1,1'
-biphenyl)-4-yl]mei-xy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4
- Concerning an aqueous formulation containing heptenoic acid (hereinafter referred to as "compound A"), its preparation and its use in medicine.

[Conventional technology and issues to be solved]

Compound A is described in the Applicant's UK Patent No. 2097397 as one of a family of aminocyclopentane derivatives with endoperoxide and thromboxane antagonist activity, in which such compounds are shown to be effective against asthma and cardiac It has been reported to be important in the treatment of vascular diseases. More recently, the inventors have discovered that the hydrochloride salt of the compound has advantages over Compound A and its heterogeneous salts and solvates, both in terms of its preparation and use in medicine. This hydrochloride is known as British Patent No. 212.
No. 7406.

Unfortunately, Compound A is only sparingly soluble in water. It has also been found that aqueous formulations containing the hydrochloride salt of Compound A with standard binders and/or carriers are unsuitable for intravenous administration. This is because, near physiological pl+, the hydrochloride salt of Compound A is converted to Compound A, which is substantially insoluble.

The aqueous solubility of Compound A and its hydrochloride near physiological p)I is significantly improved in the presence of unsubstituted or substituted α-1β- or γ-cyclodex(~phosphorus (or its hydrate)). It was newly discovered that compound A or its hydrochloride and unsubstituted or substituted α
- Aqueous formulations consisting of 1β- or γ-cyclodextrins (or hydrates thereof) for use in medicine, more particularly in the treatment or prevention of conditions mediated by thromboxane A2, oral method,
It has also been found suitable when administered either by inhalation or parenterally, especially by injection (eg intravenous injection).

[Structure of the invention]

The present invention provides an aqueous formulation consisting of Compound A or its hydrochloride salt with an unsubstituted or substituted α-β- or γ-cyclodextrin (or hydrate thereof).

The invention also has use in medicine. More particularly, aqueous formulations as defined herein are provided for use in the treatment or prevention of conditions mediated by thromboxane A2.

The present invention also provides a method for treating conditions mediated by thromboxane A2, comprising administering to a human or animal patient an effective amount of Compound A by an aqueous formulation as defined herein.

Conditions amenable to treatment with the aqueous formulations of the invention include those described in GB 2097397 and GB 2127406. There, treatments were administered with different (eg, oral) formulations of Compound A and the hydrochloride salt of Compound A, respectively.

The aqueous formulations of the invention can be used in particular for the treatment or prevention of embolic vascular disease. Specifically, myocardial infarction, cardiac fatality, unstable angina, transient ischemic attack and cerebral infarction, atherosclerosis and vascular wall disease, peripheral vasculopathy, retinopathy, and postoperative thrombosis. and pulmonary embolism. This aqueous formulation also contains: It can also be used in the prevention of perioρerative and post-operative complications after organ transplantation (particularly cardiac and 'Ff Pm), coronary artery bypass, peripheral artery bypass and thrombolysis. The aqueous formulations also have potential for use in connection with peptic ulcers, more particularly in preventing recurrence of healed peptic ulcers.

Preferably, in the aqueous formulations of the invention, Compound A is used as its hydrochloride salt.

- Although the use of a single cyclodextrin is preferred for aggregation, those skilled in the art will appreciate that the effects of the invention may be achieved using more than one cyclodextrin.

When using substituted cyclodextrins, according to the invention any suitable cyclodextrins known to the person skilled in the art can be used. Substituted cyclodextrins suitable for use in accordance with the present invention will be readily appreciated by those skilled in the art, such as sulfur-containing cyclodextrins, nitrogen-containing cyclodextrins, mono-, di- or trimethylated derivatives of cyclodextrins. Alkylation (e.g. methylation)
cyclodextrin and hydroxypropyl β-
Includes hydroxyalkylated (eg hydroxypropylated) cyclodextrins such as cyclodextrins and acylated derivatives thereof. Hydroxyalkyl (such as hydroxypropyl β-cyclodextrin)
For example, hydroxypropyl) cyclodextrin
It has been found to be particularly suitable for use according to the invention.

According to the present disclosure, a single unsubstituted cyclodextrin is conveniently used. Particularly preferred is β-cyclodextrin, conveniently used in the form of its hydrate.

In order for the aqueous formulation to exhibit the desired properties, it is important to use the correct molar ratio of Compound A or its hydrochloride to cyclodextrin. It has been found that the molar ratio of Compound A or its hydrochloride to cyclodextrin is suitably within the range of 1:1 to 1:4.

It will be appreciated by those skilled in the art that the aqueous formulations of the present invention may, if desired, contain one or more pharmaceutical carriers or binders. Suitable binders that may be incorporated into the aqueous formulations include agents rendering the preparation isotonic with plasma (e.g. sodium chloride, dextrose or preferably mannitol) and buffers (e.g. phosphate buffer or acid phosphate). (a mixture of sodium and disodium phosphate).

The aqueous formulations of the invention are particularly suitable for parenteral administration, especially injection (eg intravenous injection). When intended for parenteral administration, it is desirable that the formulation be at about physiological pH. Therefore, conventional means such as hydroxide (
The pH may be adjusted to near physiological pi using a suitable base, such as an alkaline total hydroxide such as sodium hydroxide solution. Conveniently, the pH is about 6.
Adjust to 0.

For parenteral administration, particularly by injection (eg, intravenous), it is highly desirable to present the formulation as a clear solution. Unlike dry powders, clear solutions require no extra steps and can be administered immediately. The use of clarification solutions also ensures that the product can be easily tested for particulate or other visible contaminants.

Furthermore, intravenous injection of an aqueous drug solution produces instant physiological effects. In order to obtain a clear solution at near physiological pH and at normal storage temperatures, at least 1 mole of sifurobukis] phosphorus should be used for each mole of chloride of compound A; in the case of β-cyclodextrin, at least Approximately 1.2
It was found that moles should be used.

Accordingly, in a preferred embodiment of the invention, the hydrochloride salt of Compound A and β-cyclodextrin (or its hydrate) are comprised, at about physiological pH, at least about 1. A clear aqueous formulation containing 2 moles (eg, 1.2 to 2 moles) of β-cyclodextrin is provided. Preferably, this molar ratio is about 1:1.4.

The concentration of Compound A or its hydrochloride in said aqueous formulation suitable for parenteral administration, in particular administration by injection (e.g. intravenous injection), is conveniently between 0.1 and 1, expressed as free base.
When administered by intravenous injection, this concentration is 1 mg/mQ in the range of 0 mg/+nI2, eg, 0.1 to b. If desired, higher concentrations may be used and the formulation solution may be diluted with, for example, isotonic saline or dextrose or mannitol solutions prior to use. Conveniently, solutions suitable for injection are presented in appropriate dosages (eg, 1-100 mfl). In a diluted solution suitable for infusion, the concentration of Compound A or its hydrochloride is 0.01 to 0.2 mg/ml in terms of free base.

Solutions for continuous injection can be prepared in this form, e.g.
It may be provided in packs of 00n+Q, or it may be provided in a higher concentration form to be diluted before use.

For dilution, for example, isotonic saline or dextrose or mannitol solutions are used. Alternatively, some amount of a higher 1 degree (e.g. 0.1-5 mg/mQ) solution can be injected, conveniently from 0.5 to 9.9 mρ.
It may also be used to administer at a rate of /hour.

The aqueous formulations described herein can be conveniently prepared by mixing Compound A, or more preferably its hydrochloride salt, with the remaining components in water. Preferably, Compound A or its hydrochloride is dissolved in water.

Add the remaining ingredients to this. For parenteral administration, especially by injection (eg intravenous injection), the bulk solution is preferably filtered, filled into suitable containers and finally sterilized, eg by heating.

Alternatively, the solution may be sterilized by filtration and then aseptically filled into suitable containers.

It will be appreciated that if the parenterally administered formulation is to be administered by intravenous injection or infusion, water suitable for injection will be used.

Injectable formulations may be presented in single dose form in containers such as ampoules, vials or prefilled syringes;
It can be presented in multi-dose containers with an added preservative.

As previously mentioned, the aqueous formulations of the present invention.

Oral medicine (e.g. capsules, syrups or solutions)
It is also suitable for administration by inhalation (eg as an aerosol spray, conveniently as a nebulizer). British Patent Nos. 2097397 and 2127406 are
For this purpose, it provides a suitable general method for the preparation of oral and inhalation formulations that can be easily applied without resorting to unaided experimentation.9 Aqueous formulations may also be used for one or more of the above defined A cyclodextrin solid complex of Compound Δ or its hydrochloride salt may be dissolved in water, along with other ingredients.

Thus, one invention provides an aqueous formulation comprising a complex of Compound A or its hydrochloride and cyclodextrin.

The present invention also provides a complex of Compound A or its hydrochloride and cyclodextrin. The ratio of Compound A or the hydrochloride of Compound A to cyclodextrin in the complex will of course vary considerably depending on the cyclodextrin used and the conditions used to prepare the complex. However, it has been found that the molar ratio of Compound A or its hydrochloride to cyclodextrin is suitably within the range of 1:1 to 1:3.

The cyclodextrin used in the solid composite may be a non-converted or substituted α-1β- or γ-cyclodextrin as previously defined, or such a cyclodextrin
It may also be a mixture of phosphorus (eg a mixture of two such cyclodextrins). Preferably, γ-cyclodextrin is used, and β-cyclodextrin is more preferably used.

The present invention provides that the molar ratio of Compound A to β-cyclodextrin is within the range of 1:1 to 1:2, preferably about 1
Provided is a complex of Compound A and β-cyclodextrin where =1.

Further, the present invention particularly provides compound A and γ-cyclodextrin in which the molar ratio of compound A to γ-cyclodextrin is about 1:1.5.
- providing a complex with cyclodextrin;

The complex of Compound A or its hydrochloride and cyclodextrin is prepared by combining Compound A or its hydrochloride with one or more cyclodextrins or hydrates thereof in a suitable solvent under conditions that form the desired complex. It can be manufactured by mixing with. Thus, for example, compound A or its hydrochloride is dissolved in water or a water-miscible organic solvent (e.g. an alcohol such as methanol) and in this solution.

A complex can be prepared by adding a solution of one or more suitable cyclodextrins or hydrates thereof in water and/or a water-miscible organic solvent. The reaction can be carried out at temperatures ranging from 0°C to 80°C, but preferably the mixture is kept near room temperature and the mixture is concentrated under reduced pressure or allowed to cool to yield the desired conjugate. The mixing ratio of organic solvent to water varies considerably depending on the solubility of the starting materials and products. Preferably per mole of cyclodextrin or its hydrochloride.

4 to 4 moles of cyclodextrin are used.

The resulting complex is obtained as a white solid with high thermal stability and good water solubility. These physical characteristics make it particularly suitable for formulation into medical preparations.
Ru. Said aqueous formulation of a complex consisting of compound A or its hydrochloride and cyclodextrin is particularly suitable for parenteral administration, but this complex is described in British Patent No. 209739.
According to the general method described in No. 7 and No. 2127406,
It can also be formulated for oral or parenteral administration or for administration by inhalation.

[Specific disclosure of the invention]

The following examples are provided to illustrate the invention and are not intended to limit the invention. In addition, in the following examples, the molar ratio is determined by "H-N, M, R, analysis,
All temperatures were 0°C.

Lost garden history (6) [1R-(l α (Z), 2 β, 3β,
5 a ))-(+)-7-(5-[((1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-
2-(1-piperidinyl)cyclopentyl]-4-hebutenoic acid: β-cyclodextrin (1: L) complex β
S cyclodextrin hydrate (0,954 g) was dissolved in water (3
5mM) was almost completely dissolved. Filter this suspension and
The filtrate was mixed with compound A (0.2g) in methanol (10mM).
added to the solution. The reaction solution was stirred at 21"C for 26 hours to obtain a clear solution. When the solvent was distilled off to a volume of 12+aD, slight crystallization began to occur. The suspension was cooled to 5°C and kept for 1 hour. A thick precipitate was formed.

This was filtered off and dried to obtain the title compound (0,273 g). Melting point: 310℃, turns black above 230℃.

(b) When the filtrate obtained in the above experiment was allowed to stand still, more crystalline material began to precipitate. So, when the solvent was distilled off, the remaining white solid was heated. Dissolve in RI (3d), cool (5°C),
A white crystalline solid (121 mg) was obtained.

' +1-N, M, R, (DMSO) According to analysis, it contains the following substances.

(a) [1R-[1a (Z), 2β, 3β
, 5 α))-(+)-7-(5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-
2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid:β-cyclodextrin (1:1.5) complex.

01 elephant (a) (1 total [1α (su), 2β, 3β, 5α]] -
(÷)-7-(5-[[(1,1'-biphenyl)-4
-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid:γ-cyclodextrin (1:1,5) complex.

γ-Cyclodextrin (1,09g) was dissolved in water (25mM
) was added to a solution of Compound A (0.20 g) in methanol (10 mM). The reaction solution was stirred at 21° C. for 26 hours, resulting in a thick white suspension. When the precipitate was filtered and dried under vacuum, the title compound was obtained as a white solid (0
, 612g) To L 1" remaining ivy. Melting point >310'C1
Turns black from 250'C to E.

Salt β-cyclodextrin hydrate 143mg 166m
g 238mg sodium hydroxide solution pH7
Required amount of water suitable for injection to make a total volume of 50 mN Compound A hydrochloride was dissolved in 35 mfl of water suitable for injection, and β-cyclodextrin was added.

Add 0.02M sodium hydroxide solution dropwise to reduce the solution to p.
The total volume was adjusted to H7 and injection compatible water was added.

The solution may then be sterilized by filtration and filled into vials or ampoules.

(M) Compound A liquid salt β-cyclodextrin hydrate having an equivalent relationship with a base of 50 naH 166 mg Sodium chloride 450 mg p) 17.0 Phosphate buffer 2.5 ml 12 Solutonium hydroxide solution Adjust to p117 Required amount of water suitable for injection
The required amount of Compound A hydrochloride to make a total volume of 50 mQ was dissolved in approximately 25 mΩ injection compatible water. β to this
-Dissolve the cyclodextrin and add 0.0
2M sodium hydroxide solution was added dropwise to p116 and phosphate buffer was added. The entire volume was made up with injection-compatible water. Samples of this solution were filled into glass vials and sealed with rubber stoppers and metal overseals. Thereafter, it was sterilized by autoclaving.

(ff) Compound A hydrochloride hydroxypropyl-β-dicyclodextrin 1 F0 in equivalent relationship with 50 mg of base
Mannitol 2.5 g pH 6,0 phosphate buffer 5.0 mΩ Sodium hydroxide solution Required amount to adjust to pH 6.0 Water suitable for injection
Required amount of compound A to make the total amount 50mQ
hydrochloride was dissolved in approximately 25 injection compatible water and hydroxypropyl-β-cyclodextrin was added thereto. After this, mannitol was added and 0.02M sodium hydroxide solution was added dropwise to obtain P116.

Phosphate buffer solution was added and the total volume was made up with injection compatible water. The solution was then filtered, filled into glass vials, and sealed with rubber stoppers and metal overseals. This was then sterilized using an autoclave.

(~) 5 0 mg Hydrochloride of Compound A in equivalent relationship with the base β-cyclodextrin hydrate 1 66 mg Mannitol 2 , 5 mg Sodium acid phosphate 46 mg Disodium phosphate anhydrous 5 mg Sodium hydroxide solution pH 6
The required amount of water suitable for injection is adjusted to make the total volume 50 mQ.
injection-compatible water. β-Cyclodextrin and mannitol were dissolved in this, and 0.02M sodium hydroxide solution was added dropwise to give Pl (6). In addition to the above stock solution, the total volume was made up with water suitable for injection.The solution was filtered, filled into glass vials, sealed, and sterilized by autoclaving.

(1) Cyclodextrin α 1ml L Cyclodextrin, mg Mannitol, g pH 6, 0 phosphate buffer, mQ 143 190 119 13G2, 5
2.5 2.5 5,0 5.0 5.0 Sodium hydroxide solution Required amount of water suitable for injection to adjust pH to 6 Required amount to make a total volume of 50 d Dissolve Compound A hydrochloride in approximately 25 mfl of water suitable for injection, add cyclodextrin added. Then, mannitol was added, and 0.02M sodium hydroxide solution was added dropwise to adjust to p) 16. Phosphate buffer solution was added and made up to volume with injection compatible water. The solution was then filtered, filled into glass vials, and sealed with rubber stoppers and metal overseals.

Oral syrup" Compound A hydrochloride β-cyclodextrin hydrate 91 ■ Citric acid in equivalent relationship with 2.5 mg of base
Required amount to adjust to pH 4.5 Sodium methyl hydroxybenzoate 5 + ng Sodium propyl hydroxybenzoate 2 + ng Liquid orange flavor qs Cane sugar
3.25g pure water
Dissolve the required amount of sucrose in the minimum amount of water to make the total amount 5.0. The hydrochloride salt of the compound is then added with stirring to the β-cyclodextrin. Adjust to Ull4.5 with citric acid. While continuing to stir, add the hydroxybenzoate solution and finally the flavor. Add water to adjust almost the total volume to 5.0+aQ, and stir further.

Check the pH and adjust to 4.5 with citric acid if necessary. Total amount 5. with water. Make it OmQ.

Beta-Cyclodextrin Hydrate 7mg Sodium Chloride 18B Sodium Hydroxide Solution per 2 to 1 person dosage
Required amount to adjust pH to 7.2 pH 7.2 Phosphate buffer 0.2mM Injection-compatible water Required amount to bring total volume to 2 mg Dissolve Compound A hydrochloride in Injection-compatible water.

Dissolve β-cyclodextrin in this and titrate the resulting solution with sodium hydroxide solution to PI (6). Add phosphate buffer solution. Add common salt and adjust the pH to 7.2 with sodium hydroxide solution. Make up the solution with injection-compatible water and sterilize by filtration.

Fill aseptically into containers suitable for inhalation by nebulization.

The ultra-platelet aggregation performance of the composition of the present invention was evaluated using the method of Lumley and Illumpery (J.
Pharma-col, Methods, 198
1.6.153-166) was experimented and proven. U-46619 was used as a pro-aggregation agent. A concentration-effect curve of U-46619 was determined for each sample of human whole blood, and the amount of rightward shift of the curve in the presence of the test composition was evaluated.

Arunlakshana and the 5child method (Br
, J. Pharmacol, 14°48-58 (195
These data were analyzed according to 9)) to give the average PAz value for the test compositions. The experimental compositions described in the Examples have PAz values ranging from 8.0 to &3.

The compositions of the present invention are non-toxic at therapeutically useful doses. For example, when the compositions of the Examples were prescribed to dogs at a dose of 10 mg/kg, no significant adverse effects occurred.

Claims (1)

[Claims] 1. Unsubstituted or substituted α-, β- or γ-cyclodextrin or a hydrate thereof and [1\R\-[1
α(￥Z￥), 2β, 3β, 5α]]-(+)-7-[
Aqueous formulation consisting of 5-[[(1,1′-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (compound A) or its hydrochloride thing. 2. The formulation according to claim 1, which uses the hydrochloride of compound A. 3. The formulation according to claim 1 or 2, wherein the cyclodextrin is β-cyclodextrin. 4. The formulation according to any one of claims 1 to 3, which is in a form suitable for injection. 5. The formulation of claim 4, comprising the hydrochloride salt of Compound A and β-cyclodextrin or a hydrate thereof, at about physiological pH, at least about 1.2 moles of β per mole of Compound A. - A clear aqueous formulation containing cyclodextrin. 6. The formulation of claim 5, wherein the molar ratio of the hydrochloride of Compound A to β-cyclodextrin is about 1:1.
Something that is 4. 7. The formulation according to any one of claims 4 to 6, having a pH of about 6.0. 8. The formulation according to any one of claims 4 to 7, further comprising sodium hydroxide. 9. The formulation according to any one of claims 4 to 8, wherein the concentration of compound A or its hydrochloride is 0.1 to 5 mg/ml in terms of free base. 10. The formulation according to any one of claims 4 to 8, which is in a form suitable for infusion, and has a concentration of compound A or its hydrochloride of 0.01 to 0 in terms of free base. .2m
g/ml. 11. A process for preparing a formulation according to any of the preceding claims, comprising mixing Compound A or its hydrochloride salt with the remaining components in water. 12. Compound A or its hydrochloride and unsubstituted or substituted α
-, β-, or γ-cyclodextrin. 13. A complex of compound A and β-cyclodextrin, wherein the molar ratio of compound A to β-cyclodextrin is about 1:1.