Slightly soluble salt analogue wg-lh, slightly soluble salt analogue of bombezin, pharmaceutical composition, medicine

 

(57) Abstract:

The invention relates to medicine, in particular to the creation of analogues of hormonal preparations of a protein nature. The inventive as analogues releasing hormone/luteinizing hormone use a slightly soluble salt of cetrorelix, intraradices, ganirelix, antide or A-75998, as well as salt monowai acid. Another object of the invention is a pharmaceutical composition based on each of the named salts. The technical result of the invention is the expansion of the means for correcting hormonal regulation. 4 C. and 3 h.p. f-crystals, 4 Il.

The invention relates to injectable suspensions prolonged action, containing therapeutically active peptides in the form of poorly soluble, physiologically acceptable x-ray amorphous or crystalline salts, and also to the way they are received.

Prior art

In therapy, the peptides can often be used safely and only bioavailable when administered parenterally, because when oral administration they are decomposed by enzymes; natalina the introduction of absorbed only a small percentage of the dose, and for cutaneous introduction does not occur the body, parenteral administration of peptide drugs, for example, analogues releasing hormone luteinizing hormone (RH-LH), the so-called superagonist and antagonists WG-LH should be used daily to achieve the desired effect, consisting for both groups of substances in the suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

As a result, men decreases the formation of testosterone, and women a decrease in the number formed by estradiol. This is called chemical castration.

Analogues WG-LH considered and as superagonist, for example, goserelin (International nonproprietary name INN) or triptorelin (INNS), and as antagonists, for example, cetrorelix (INN), antic (INN) or ganirelix (INNS). Goserelin and its synthesis are described in Drugs of the Future, 5(4), (1980), p. 191. Buserelin and its synthesis - ibid, 4(3), (1979), page 173 and Drugs of Today, 21, (305), (1985). Decapeptyl and its synthetic Drugs of the Future, 3, (9), (1978), page 645. Leuprolide and its synthesis - ibid, 7(12), (1982), page 883.

Azalin B described on page 13-26 "GHRH-Analogues - The State of the Art" (1993), Parthenon Publishing Groups, Ed., B. Lunenfeld, V. lnsler.

Still no successful attempts to get prolonged pharmaceutical analogues Redlener releasing effect, which contains analogues of WG-LH injection in the form of a zinc salt of the peptide, sesame oil and aluminum stearate.

The difference between superagonistic and antagonists is that in the case of the use of superagonistic feedback mechanism leads to unwanted release of a large amount of hormones in the first few weeks of treatment, the so-called sudden aggravation of the disease, which must be overcome by additional treatment. In contrast, in the case of the use of antagonists, such as cetrorelix (INN), pharmacological effects are immediate and without aggravation. Continued lowering of the level of sex hormones in the blood is a standard therapy for palliative treatment of carcinoma of the prostate and breast cancer to reduce the growth of tumors that are dependent on sex hormones, as well as for treatment of endometriosis. From a chemical point of view superagonist WG-LH and antagonists are Nona - and Decapeptide. Effective antagonist WG-LH is cetrorelix, which is Decapeptide with the following amino acid sequence: Ac-DNal-DpCl-Phe-DPal-Ser-Tyr-DCit-Leu-Arg - Pro-D-Ala-NH2. Its synthesis and pharmacological properties are described in European patent EP 299402. what was installed, for decreasing hormonal levels of testosterone or estradiol to the desired extent, until the next injection, an aqueous solution of cetrorelix acetate should be entered daily. Duration cannot be increased due to reaching the threshold dose, although a one-week interval introduction instead of the daily would have been a major positive step for the chronically ill and rehospitalized patients.

Effective antagonist WG-LH is also entrelacs, which has the following amino acid sequence: Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Lys(iPr)-Pro-D-Ala-NH2. Its properties are described in the journal of Biomedical Pharmacotherapy, 1993 , N47(2-3), pp. 107-117, article Deghendhi R. et al. "Entrelacs (EP 24332), a new water-soluble antagonist WG-LH". In the above article provides data entrelacs on its in vitro and in vivo activity in several animal models. Emphasizes efficiency, reasonable histamine-releasing activity and high solubility.

In addition, an effective antagonist WG-LH is A-75998 with the following amino acid sequence: Ac-D-Nal-D-(pCl)Phe-D - Pal-Ser-N-MeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH2. Its properties are described in the journal Medical Chemistry, March 4, 1994, No. 37(5), pages 701-705, St was created on the basis of the structure of fragment (2-9) agonist RH and LH is octapeptide antagonist WG-LH. A systematic study of SAR was first allowed to improve activity in vitro and then in vivo suppression of luteinizing hormone. It suppresses luteinizing hormone in castrated rats for more than 80% within 4 h after a quick hypodermic injection in an amount of 30 μg/kg

Almost two decades of research antagonists WG-LH led to the creation of a number of Decapeptide, which are currently undergoing clinical study. The structure of these antagonists, in contrast to agonists, significantly different from the structure of the WG-LH. Five of the ten amino acids have the same origins and D-form. The structural combination of the hydrophobic N-Terminus (residues 1, 2 and 3) and the primary/hydrophilic C-Terminus (residues 6 and 8) was considered to be the cause of some HR reactions, with whom he had to deal when using the second generation of the WG-LH antagonists. This side effect was significantly reduced by substitution of amino acids at positions 5, 6 and 8 appropriate amino acids. The next obstacle to the development of antagonists of the WG-LH medicines was the solubility and aggregation. In the case of A-75998 the solubility was improved by 12 - to 25-fold folding by placing N-MeTyr position on the Itza, invisible to the naked eye. This formation of aggregated particles was removed immediately after formulation A-75998 in enkapsis. A single dose of A-75998 2 mg, injected subcutaneously, was lowered in men T to levels of alter on more than 30 Other antagonists WG-LH, including ganirelix and cetrorelix, are also in phase I/II clinical study. Reported information on clinical trials of cetrorelix for prostate cancer; in vitro fertilization and benign prostatic hypertrophy.

Physico-chemical properties of A-75998, synthetic antagonist releasing hormone, luteinizing hormone, have been investigated for the treatment of hormone-sensitive tumors and endometriosis. In accelerated stability studies in solution have shown that the compound is relatively stable, and revealed a U-shaped curve changes in pH, with maximum stability in the pH range between 5.5 and about 6.5. The nature of the acid dissociation, A-75998 were studied using spectrophotometry in the ultraviolet and visible rays at 25oC in the range of buffer solutions with pH from 1 to 13. Based on the research model was developed, according to which the dissociation of all four is able to break down into ions group is then: p beta 1 = 3,230 0,022, p beta 2 = 4,885 0,030, p beta 3 = 9,871 0,0322 beta 4 and p = 11,026 of) 0.157. The corresponding microscopic acid dissociation constants were as follows: DC1 = 3,24 (nicotinyl), PK2= 4,88 (pyridyl), RC = to 9.91 (tyrosyl) and RK = 10,99 (isopropylate). Experimental data of partition coefficients of n-octanol and water was measured at pH from 2 to 13, the curve of these data is consistent with the intended character of the acid dissociation. Despite the fact that at pH<5 was discovered pretty good solubility, dynamic light scattering, A-75998 in buffer solution at pH 4.5 showed the formation of aggregated particles (aggregation) with an uneven distribution of particle size. A-75998 expressed or reverse thermal gel, sodium chloride enhances this gel and coassociative. Surface activity was pH-dependent, but evidence of the formation of micelles were found. Based on these results, the creation of a parenteral composition with A-75998 seem feasible, provided that the aggregation will be minimized.

Up to the present time equivalents WG-LH used by daily single injection of a solution of soluble salts in the form of an injectable solution or multiple nasal centuries the s are only made in the USA. As described above, for such forms of medicines predetermined the need for frequent application. Injection can be carried out only by the doctor, nasal drops must be administered several times a day. Both dosage forms are not well suited for the treatment of chronic diseases.

Patent DE-OS 4223282.1 describes obtaining the microencapsulation dosage forms cetrorelix of embonate prolonged action. Implants are medical forms, allowing to increase the intervals of application. For example, being introduced under the skin, cylindrical capsule biodegradable copolymer poly(lactic-glycolic acid) containing gozlerin acetate, can effectively reduce the level of testosterone (Zoladex depot). Monthly injections of suspensions of biodegradable polymer particles containing as the active ingredient leiprorelina acetate, also effectively reduce the levels of the sex hormone during this period (Enatone Monatsdepot).

Both dosage forms with prolonged action are described in the following patents and patent applications. Their advantage lies in the interval between the introduction is accompanied by obvious drawbacks, which will be the th sign Zoladex. The disadvantage of this dosage form is in the expensive process of obtaining cylinders requiring extrusion equipment and devices for packaging, which insert cylinders in a specially designed syringes with very thick cannula. The cylinder diameter is 1 mm, and a length of several mm, which causes patients with the introduction of soreness and bruising. Preferably the receiving less painful dosage forms.

EP 0052510 describes a composition and method for producing microparticles containing, for example, nafarelin acetate. In the presence of chlorinated hydrocarbons active ingredient is introduced into the copolymers poly(lactic-glycolic acid). The use of this composition chlorinated hydrocarbons inevitably, because they only soluble biorstwami polymers required in vivo. High residual content of solvent in the dosage form obtained by the above method is about 1000 ppm, and is a disadvantage. In accordance with earlier representations of the chlorinated hydrocarbons are carcinogenic. The residual content of solvent in the dressing materials and medicines today is limited to the value of <50 RTCOM, the output of the active substance is enclosed in microcapsules, small due to the loss of the peptide in the aqueous phase, which is necessarily present in the process.

Reducing the residual content of the solvent is below the threshold for safety of medicines if possible, it is only in the application of labour intensive methods further processing. For example, the claimed method of reducing residual solvents using subcritical concentrations of CO2.

B DE 4023134 A1 used is similar to that described how the introduction of peptide in biorazlagaemykh polymers of the type copolymers poly(lactic-glycolic acid). According to the application, in this way to reduce the loss of active ingredient instead of the acetate of peptide embedded in polyester, used peptide salt, insoluble in water. Peptide salts, insoluble in water, are pamoate, tannate, stearates and palmitate. As already mentioned, the disadvantage of this method is the necessity of application of carcinogenic hydrocarbons that creates the problem physiologically acceptable residual solvents chloromethane or chloroform.

In EP 145240 offered another way of implementing a water-soluble coleago solution of the active ingredient in biorazlagaemykh copolymers poly (lactic-glycolic acid) through the multiple emulsion however, a disadvantage of the method is the use of chlorinated hydrocarbons.

In EP 505966 proposed introduction of buserelin acetate in the copolymer poly(lactic-glycolic acid) by spray drying of a solution: the active ingredient-polymer containing chlorohydrocarbons. The disadvantage of this method is the use of carcinogenic chlorohydrocarbons as solvents.

The lack of application of chlorohydrocarbons is not only a high content of residual solvent in finished dosage form, but also from an environmental point of view, the use of these solvents creates problems associated with waste production and safety.

In the International application WO 9214449 proposed introduction of soluble peptides, such as growth hormones, for example, lauric acid by mixing the active ingredient with the specified acid, further alloying and grinding the mixture after cooling in particle size of 100 μm. In the US 5137669 offered to acquire the same way prolonged dosage forms antagonists WG-LH for injectable suspensions with a gradual release of active the Ingram is giovannoli actions and only in the time-consuming process receive injectable drugs. So far, it was impossible to prove the tolerance of fatty media, their reliability and the reproducibility of the selection of the active substance. In the case of fatty membrane potential side effects in the form of encapsulation, which is unacceptable in long-term care for several years.

In DE 3430852 to bromkriptin nelfinavir, active ingredient, which is very difficult to obtain prolonged dosage form, synthesized polyester in the form of polyolefine, for example, glucose from lactic and glycolic acid to obtain the desired mode selection of the active substance. In this case, it was necessary to make an exhaustive and expensive study and Toxicological samples to obtain a dosage form with a long enough duration, because it was clear that no more simple and cheap dosage form will not be able to give the same effect.

The invention

Albanova acid (4,4'-methylene-bis-(3-hydroxy-2-naphthalene acid) is often used in pharmaceutical preparations to get slightly soluble salts drugs. These, the Tr. 1007).

It was found that the drug under item 1 of the formula of the invention shows unexpected prolonged action and superior effect without the use of biodegradable polymers or fats. Not only has there been a prolonged effect, measured by duration of suppression of hormones, but also suppressed tumor growth in a disproportionate degree.

The proposed remedy can also be used as agonist-WG LH, for example in leuprolide, buserelin, goserelin and triptorelin. It can also be used as antagonists bombezin and somatostatin and analogues G-Germany.

Experimental studies were conducted in accordance with the following methods: the Inhibitory effect on cancer of the breast caused by DMBA (7,12-dimethylbenz[a]-anthracene) in rats Spraque-Dawley.

Way:

Rats-female Spraque-Dawley at the age of 50 days (diet animals: Altromin R, water ad lib) was administered orally 20 mg DMBA dissolved in 1 ml of olive oil, via a stomach tube. Monitoring of tumor growth was performed weekly by palpation animals. Approximately 90% of the animals were observed tumor suitable for experimental experience, the 35-th - 70 th day after the e zum increasing the dose-Problem in der Krebs-Chemotherapie und zur Wirkungsweise von Endoxan [Experimental contributions to the study of problems of doses in hemoterapia cancer and the mechanism of action of endoksana], Dtsch. Med. Wschr. 88:651.

The method was confirmed by comparison of the weight of the tumor identified by palpation, with the data obtained by direct weighing (after removal of the tumor). The correlation coefficient amounted to 0.98. After the total weight of the tumors reached approximately 1 g, the animals were randomly divided into control group 7 animals each. Treatment was started immediately after subcutaneous injection of the tested substances. Hormonal status of the animals was determined by vaginal smear of cells stained with methylene blue, and examined in accordance with the method of Jones,T. S., Mohr U, Hunt, R. D (1972): The genital system, in: Monographs on pathology of laboratory animals sponsored by the International Life Science Institute (Springer, N. Y., London).

The experimental data shown in Fig. 1. Curve weight of the tumor to untreated control animals shows no slowdown. Curves 1(*and 2o) correspond to the treatment cetrorelix acetate in two different media. The long curve 3 shows a sharp decrease in the weight of the tumor after treatment with umbonata.

Since in this case the treatment was carried out only a single dose, the tumor continued to grow, because if one dose does not occur unichtojeni the peptide cetrorelix in the form of a salt monowai acid. Water suspension of this sludge, which may contain isotonic supplements, exhibits, in comparison with the aqueous solution of the peptide substantial prolongation of action in experimental animals. It was unexpectedly found that the renewal was about the same as when injection suspensions which contain the residue of embonate peptide in a biodegradable polymer, for example, copolymers of poly(lactic, glycolic acid). In particular, this result was unexpected because, as mentioned above, only very time consuming dosage forms, which generally contain active ingredient in biodegradable polymers, to date has shown significant long-term effect.

This result was unexpected because according to J. Pharm Pharmavol. 47, 878-883 (1985), pyrimethamine derived 2,4-diaminopirimidina, did not show differences compared to its salt monowai acid from the viewpoint of pharmacokinetics, changes in plasma levels and AUC (curve of concentration against time) after subcutaneous administration to mice.

Similarly, imipramine HCl did not show differences compared to imipramine-umbonatum after oral administration (Indian Jornal of Phisiology and Pha shall dnisolone or triamcinolone, are known preparations with prolonged action, as well as crystalline zinc suspension insulin used to treat diabetes. Insulin contains 51 amino acid. All of the latter drugs are crystalline, while the proposed remedy according to the XRD analysis is amorphous. The particle size of the proposed drug is 5 to 200 μm. Slightly soluble salt analogues WG-LH and bombezin with particle sizes less than 5 microns are prolonging effect is smaller than for the proposed drug. Similarly, slightly soluble salt analogues WG-LH and bombezin with particle sizes greater than 200 μm are weaker prolonging effect than the proposed drug.

Another advantage of the proposed drug is a higher degree of consistency: quality drugs from this drug, more stable.

According to the invention proposed slightly soluble salt analogue of bombezin, which, as mentioned above, the particle size is 5 to 200 μm, of the formula: pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His - Leu-Met-NH2.

In the journal Biochemistry, may 2, 1978, N 17(9), pp. 1766-1771, article Rivier JE and Br39 peptides associated with bombezin (structural analogs or other peptides found in nature), and biological evaluation of thermoregulation. This system biological assessment measures the ability of peptides introduced intracavitary injection, to lower the temperature in rats, placed in cold (4oC). Most potent analogues of bombezin were those who had changed positions from 1 to 5 (not inclusive), suggesting that C-terminal Decapeptide sufficient for full effectiveness. Gln at the 7th position and Gly at the 11th position it is possible to replace, respectively, D-Gln, D-Ala (but not D-Pro or D-Phe), without any changes in the efficiency. The methionine at the 14th position can be replaced by a D-isomer, keeping 10% of the biological activity. Any other change in the C-endpoint (remove free acid and except N-methylamide) dramatically reduces the biological activity of these peptides. It was found that among the peptides found in nature, efficiency, corresponding to 100% efficiency bombezin, has alicein, while the effectiveness of litorina, neurotensin, xenopedia, substance P, physalaemin and eledoisin was lower by four orders of magnitude. It is established that the shortest is asin.

As examples of bombezin and its analogues can cause the following:

1. The bombezin

Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met - NH2< / BR>
Is tetradecapeptide isolated from the skin of amphibians, biologically active both in the Central nervous system and gastrointestinal tract. It was also found that the bombezin weakens nutrition in rats. Biochemical characteristic of the bombezin-like peptides on the basis of research on the brain of rats (A. Anastasi et al., Experentia 27, (1971), G. Berlaccini et al., Br.J.Pharmacy, 52, 219 and 227 (1974).

2. (Leu13-()-Leu14-Bombezin

< / BR>
() - reduced peptide bond.

This peptide showed a specific and competitive antagonist bombezin, particularly in relation to cell growth T Swiss mice in vitro.

(A. Cowan, TIPS-9, 1 (1988), S. Mahinoual et al., Cancer Res.51, 1798, (1991)).

3. (Lys3-Bombezin

Pyr-Gln-Lys-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2< / BR>
4. (D-Phe12-Bombezin

Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-D-Phe-Leu-Met - NH2< / BR>
This peptide belongs to a new class of receptor antagonists bombezin that interact only with the receptor bombezin. Because of this specificity, this peptide may be., Am.J.Physicl. 252, G439 (1987)).

5. (D-Phe12, Leu14-Bombezin

Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-D-Phe-Leu-Leu - NH2< / BR>
This analog of bombezin is a specific receptor antagonist bombezin (H. Heinz-Erian et al., Am.J.Physicl. 252, G439 (1987)).

6. (Tyr4-Bombezin

Pyr-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met - NH2(J. E. Rivier and M. T. Brawn, Biochemistry, 17, 1766 (1978)).

7. (Tyr4,D-Phe12-Bombezin

Pyr-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-D-Phe-Leu-Met - NH2< / BR>
This analog of bombezin is a specific receptor antagonist bombezin (P. Heinz-Erian et al., Am.J.Phisicl. 252, G439 (1987)).

8. (D-Cys6, Asn7, D-Ala11, Cys14-Bombezin (6-14)

H-D-Cys-Asn-Trp-Ala-Val-D-Ala-His-Leu-Cys-NH2< / BR>
Acting as an agonist bombezin, it's (D-Ala11)-derived demonstrates significant efficacy in the values of EC50about 610-8M

(D. H. Coy et al., Peptides, Chemistry and Biology, Proceeding of the 12th American Peptide Symposium, Cambridge, MA, p.40, J. A. Smith and J. E. Rivier, eds, Escom, Leiden (1992)).

< / BR>
< / BR>
() - reduced peptide bond.

This highly effective antagonist of bombezin in submicromolar concentrations inhibited tumor development 41 cells with small cell lung cancer in vitro. (F. Thomas et al., Cancer Res. 52, 4872 (1992).

(J. E. Rivier and G. R. Marshall, eds., Escom, Leiden (1990)).

11. The bombezin (8-14)

H-Trp-Ala-Val-Gly-His-Leu-Met-NH2< / BR>
12. Cyclo-(D-Phe-His-Trp-Ala-Val-Gly-His-Leu-Leu)

Cyclo(-D-Phe-His-trp-Ala-Val-Gly-His-Leu-Leu)

The agonist bombezin, with a value of EC50equal to 310-7M (D. H. Coy et al., Peptides, Chemistry and Biology, Proceedings of the 12th American Peptide Symposium, Cambridge, MA, p.40, J. A. Smith and J. E. Rivier, eds, Escom, Leiden (1992)).

The list of analogues of bombezin are only as proof of their receipt and existence. This list can be continued, and the invention is not limited to the above list.

Example 1

An aqueous solution monowai acid containing an excess of alkali added to the acetate solution cetrorelix acetate. When this took equimolar amount of a peptide (for free base) in relation to monowai acid. This resulted in yellow crystals monowai acid. When adding a dilute solution of sodium hydroxide to a pH of 7-7,5 albanova acid dissolved and shoesadidas with decapeptides in aqueous salt embonate of cetrorelix. The molar ratio of peptide : albanova acid with which Alexa and amborovy acid in equimolar ratio were dissolved in dimethylacetamide, and the solution is added dropwise into the water. A white precipitate composition cetrorelix embonate peptide : albanova acid with a ratio of 2:1 (mol/mol) was filtered and dried.

Example 3

Cetrorelix and amborovy acid in a molar ratio of 1:1,6 dissolved in dimethylacetamide, with the possible water content, and the resulting solution was added dropwise into the water. The yellow precipitate was filtered and dried. The precipitate was transferred into a paste-like state with 70% ethanol, dried at 35oWith and sifted through a sieve with a size of 80-125 microns.

Example 4

The alkaline solution of embonate added to the aqueous ethanol solution of the acetate of peptide (cetrorelix, entrelacs, ganirelix, anted, A-75998 or similar bombezin) in a molar ratio of peptide : albanova acid is 2:1. White precipitate was filtered and dried. The dry residue was moistened with 50% ethanol, dried in a vacuum drying chamber and pass through a sieve.

The obtained white precipitate contains a peptide composition : umbonata salt in the ratio of 2:1 (mol/mol).

Example 5

The alkaline solution of embonate added to the water-ethanol solution of the acetate of peptide at a molar ratio of peptide : albanova acid is 1:1,6. Ultyimate 35oC and sifted through a sieve. The obtained yellow solution contained the peptide-salt embonate in a 2:1 ratio in excess monowai acid.

Experiments on the duration of action on animals:

The precipitation suspension was injected subcutaneously to rats-males at a dose of 0.5 mg cetrorelix per kg of body weight and measured after the introduction of the effect of the peptide on the levels of testosterone in the plasma. The effect of cetrorelix is to reduce the level of testosterone. Injectable suspension tested in accordance with DE 40232134 A1. This suspension contained embonate peptide copolymers poly(lactic-glycolic acid). The duration of the dosage forms cetrorelix without releasing effect identified in the study of an aqueous solution of acetate cetrorelix.

In Fig. 3 shows the level of testosterone that is defined after 300 h of rats-males aqueous solution of acetate cetrorelix (D-20761). The effect of suppression of testosterone was achieved within 6 h after injection. Suppression to values below 1 ng/ml could be noted in two animals after 24 h, and the other three in 48 hours or two days.

In Fig. 2 shows the levels of testosterone after 300 h in four animals (N 11-14) after introduction of the -20762). Suppression of testosterone was also achieved after 6 h after injection, the levels were increased above 1 ng/ml in one animal after 192 hours (eight days), the other three animals reliably lasted until the ninth day.

In Fig. 4 shows changes in the level of testosterone in rats in the treatment umbonatum according to the invention (particle size of 80-125 µm).

The comparison of Fig. 2-3 with Fig. 4 clearly shows the advantage of the proposed drug.

1. Slightly soluble salt analogue releasing hormone luteinizing hormone-WG LH, the size of the particles of which comprise from 5 to 200 μm, wherein the analog-WG LH is cetrorelix, entrelacs, ganirelix, antic or A-75998.

2. Salt p. 1, characterized in that the particle diameter is 10 to 150 μm.

3. Salt p. 1, characterized in that the particle diameter is 20 to 125 μm.

4. Slightly soluble salt analogue of bombezin, characterized in that the particle diameter is 5 to 200 μm.

5. Sol according to any one of paragraphs.1 to 4, characterized in that the salt is monowai acid.

6. A pharmaceutical composition comprising a salt according to any one of paragraphs.1 - 5.

7. The use of a salt according to any one of paragraphs.1 to 5 to obtain medicines is

 

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