HK1073078A1 - Injection solution comprising an lhrh antagonist - Google Patents

Abstract

The aqueous injection solution comprising an LHRH antagonist contains in addition to the LHRH antagonist, such as cetrorelix, an organic, physiologically compatible acid and optionally a surfactant and also a framework builder. The LHRH antagonist has significantly improved solubility and can be prepared in higher concentrations and with an improved bioavailability. The aggregation tendency of the LHRH antagonist is significantly reduced.

Description

Injection solution containing LHRH antagonist

The technical field is as follows:

the present invention relates to aqueous injection solutions for LHRH-antagonists with addition of an organic physiologically tolerated acid and/or surfactant for preventing aggregation of the LHRH-antagonists in solution, and their preparation. The injection solutions prepared according to the invention additionally lead to an increase in the bioavailability and make it possible to reduce the injection volume to be administered.

The prior art is as follows:

in controlled ovarian stimulation prior to egg removal and assisted reproduction techniques, LHRH antagonists (cetrorelix, ganirelix) are sometimes used in particular in addition to LHRH agonists (e.g. triptorelin, buserelin), since they avoid the initial increase in gonadotropin endocrine and immediately lead to competitive inhibition of gonadotropin-releasing hormone [ EP 0788799 a 2; EP 0299402B 1]. Currently ready-to-use injection form () The LHRH antagonist ganirelix was used in the formulation of 0.25 mg ganirelix in 0.5 ml aqueous solution containing mannitol. Currently the LHRH antagonist cetrorelix (b) is provided in two administration forms): lyophilizates containing 0.25 mg of cetrorelix in combination with a ready-to-use syringe containing 1 ml of water for reconstitution and lyophilizates containing 3 mg of cetrorelix in combination with a ready-to-use syringe containing 3 ml of water for reconstitution however LHRH antagonists are not exclusively usedControlled ovarian stimulation, but also for the treatment of hormone-dependent cancers such as prostate cancer. Like abarelix (abarelix) [ WO 98/25642]Or cetrorelix [ WO00/47234]Such substances can be used for this purpose in that LHRH antagonists may be a replacement for the major agonists (leuprolide, goserelin) on the market for this treatment. Noting the relatively poor solubility of Abarelix in water or physiological media, long-term effects must be achieved by using long-acting formulations (depot formulations) but it is pointed out that good solubility of LHRH antagonists can also lead to long-acting effects [ G.Jiang, J.Stakewski, R.Galyean, J.Dykert, C.Schteingart, P.Broqua, A.Aebi, M.L.Aubert, G.Semple, P.Robson, K.Akinsanya, R.Haigh, P.Riviere, J.Trojnar, J.L.Junien and J.E.Rivier, J.Med.m.2001, 44, 453-467]。

Description of the invention:

it is an object of the present invention to prepare an injection solution which, with its improved solubility, achieves a reduced injection volume and an increased injection concentration of the LHRH antagonist, at the same time as aggregation of the LHRH antagonist in the relatively highly concentrated injection solution is prevented.

It has surprisingly been found that an organic physiological tolerance to acids, in particular carboxylic acids, in particular hydroxycarboxylic acids, but preferably gluconic acid, alone or in combination with surfactants such as Tween, can significantly improve the solubility of LHRH antagonists and thus significantly reduce the aggregation tendency of these substances.

The invention thus makes it possible to prepare relatively high concentrations of aqueous solutions of LHRH antagonists for injection. LHRH antagonists which may be mentioned are, for example, cetrorelix, teverelix, D-63153 (Ac-D-Nal (2) -D-Cpa-D-Pal (3) -Ser-N-Me-Tyr-D-H-Cit-Nle-Arg-Pro-D-Ala-NH₂) Ganirelix, abarelix, anti-ovulation peptide, azaline B. It has been found necessary to use an excess of each carboxylic acid; apparently, by itself with the presence of basic amino acid residues such as arginine, pyridylalanine, prolysineThe formation of salts in the site cannot explain this effect. Also, it is not necessary to choose too high a surfactant concentration, since otherwise the solution foams too much, followed by surfactant-induced aggregation.

At the same time, these additives make it possible to increase the bioavailability, since they also significantly slow down the spontaneous aggregation in the body after injection or make it possible for substances to be absorbed more quickly from the site of action. It has been found that the reduced pH (e.g. pH 2.5-3) of such injections has no effect on the local tolerance of the injections. By increasing the concentration it is possible to reduce the volume administered, for example in the case of cetrorelix, from 3 ml to 1 ml for a 3 mg dosage form. It has also been found that with these additives good storage stability can be achieved (see example 1). Although storage at 25 ℃/60% for 6 months resulted in an increase in impurities, the value of the content was still undoubtedly above 90% in each case (as an example, the minimum value of the pharmaceutical product lifetime). Haze values of up to 8FTU (formazin haze units according to European pharmacopoeia) are fully tolerated.

Preservatives, such as, for example, phenol or p-chloro-m-cresol, do not interfere and can therefore additionally be used for preserving solutions. It is likewise possible to use conventional fillers such as mannitol, lactose, glucose and fructose.

Description of the routes for carrying out the invention:

example 1

500 mg cetrorelix

2 grams Tween80

2.4g glucono delta lactone

95 g mannitol

Mix with water for injection to 2 liters to obtain a homogeneous solution. The solution was then sterile filtered and dispensed into ampoules. The ampoules were analyzed initially and after 6 months of storage at 2-8 ℃ and 25 ℃/60% relative humidity to determine purity (HPLC), content (HPLC), pH and aggregation (turbidity).

And (3) analysis results:

	initial study	Study after 6 months at 2-8 deg.C	Study after 6 months at 25 ℃/60% relative humidity
				Purity [% ]]	0.37	0.69	2.32
Content [% ]]	100.0	98.7	95.4
				pH	3.12	3.16	3.16
Turbidity [ FTU]	1.88	2.62	3.92

Example 2

About 500 mg D-63153

About 100 mg Tween80

About 475 mg of mannitol in the form of mannitol,

the pH was adjusted to about 2.5 with a saturated aqueous glucono delta lactone solution. A volume of about 50 ml was obtained. The mixture was stirred until a clear solution was obtained.

And (3) analysis results:

the turbidity of the solution at the beginning was 2.4 FTU. After 24 hours, the turbidity was measured to be 2.1 FTU. The purity profile and content (HPLC) of the solution remained unchanged.

Structure of LHRH antagonist D-63153

Ac-D-Nal(2)-D-Cpa-D-Pal(3)-Ser-N-Me-Tyr-D-H-Cit-Nle-Arg-Pro-D-Ala-NH₂

Example 3

About 100 mg of teverelix

About 100 mg Tween80

About 475 mg mannitol

The pH was adjusted to about 2.5 with a saturated aqueous glucono delta lactone solution. A volume of about 10 ml was obtained. The mixture was stirred until a clear solution was obtained.

And (3) analysis results:

the turbidity of the solution at the beginning was 6.8 FTU. After 24 hours, the turbidity was measured to be 8.4 FTU. The purity profile and content (HPLC) of the solution remained unchanged.

Structure of LHRH antagonist teverelix

Ac-D-Nal-pCl-D-Phe-3-D-Pal-Ser-Tyr-D-H-Cit-Leu-iPr-Lys-Pro-D-Ala-NH2

Claims (6)

1. An aqueous injection solution of an LHRH antagonist containing gluconic acid, a bulking agent and optionally a surfactant, characterized in that the gluconic acid is present in an amount more than equimolar with respect to the amount of the LHRH antagonist and is added in the form of glucono delta lactone, mannose as bulking agent and optionally Tween80 as surfactant,

   the LHRH antagonist is selected from cetrorelix, teverelix and D-63153, namely Ac-D-Nal (2) -D-Cpa-D-Pal (3) -Ser-N-Me-Tyr-D-H-Cit-Nle-Arg-Pro-D-Ala-NH₂Ganirelix, abarelix, antithetical rankingEgg peptide and Azaline B.
2. 2. The aqueous injection solution according to claim 1, further comprising Tween80 as a surfactant.
3. 3. The aqueous injection solution according to claim 1, which contains in 2 liters of water for injection:

   500 mg cetrorelix

   2.4g glucono delta lactone

   2.0 grams Tween80

   95.0 g mannitol.
4. 4. An aqueous injection solution according to claim 1, which contains

   500 mg of D-63153

   100 mg Tween80

   475 mg of mannitol, which was added to the syrup,

   it was adjusted to 50 ml using a saturated glucono delta lactone solution.
5. 5. An aqueous injection solution according to claim 1, comprising

   100 mg of teverelix

   100 mg Tween80

   475 mg of mannitol, which was added to the syrup,

   it was adjusted to 10 ml using a saturated glucono delta lactone solution.
6. 6. Process for the preparation of an aqueous injection solution according to any one of claims 1 to 5, characterized in that alternatively

   -dissolving in the water for injection gluconic acid in the form of an LHRH antagonist, glucono delta lactone, wherein gluconic acid is present in more than equimolar amounts relative to the amount of LHRH antagonist, mannitol as a bulking agent, and optionally Tween80 as a surfactant, either for homogenization and treatment for injection purposes, or

   Homogenization and treatment for injection purposes using a saturated aqueous solution of glucono delta lactone to dissolve the LHRH antagonist, mannitol as bulking agent, and optionally Tween80 as surfactant.