MXPA99010936A - Compositions suitable for controlled release of the hormone gnrh and its analogs - Google Patents

Abstract

Se proporciona una composición líquida para la liberación controlada de la hormona de liberación de gonodotropina (GnRH) o sus análogos la cual incluye:(i) un material portador líquido no soluble en agua (HVLCM) o una viscosidad de al menos 5,000 cP a una temperatura de 37§C, la cual no cristaliza bajo condiciones ambientales o fisiológicas, y (ii) GnRHósus análogos.

Description

ADEQUATE COMPOSITIONS FOR THE CONTROLLED RELEASE OF GnRH HORMONE AND ITS ANALOGS BACKGROUND OF THE INVENTION The development in the horse industry of an economic and precise method for the exact control of ovulation in mares would be of great benefit for the reproduction of mares and stallions. The wide mating period of the mares, during which ovulation can occur at any time in a time that goes from 1 to 10 days, after beginning the heat, has made the management of the mares' reproduction very difficult in terms of time, costly and, most importantly, inefficient. In mares, the hormone GnRH and its analogs were used as alternative non-antigenic substitutes to replace hCG to advance ovulation in mares in the period prior to ovulation. This is because the repeated use of h-CG has been associated with a reduction in response [Sullivan, J., J Am Veterinary Medical Association. 63: 895 (1973)] and the formation of antibodies against hCG [Roser, J., J. S Supplement for Fertility in Reproduction. 173-179 (1974)]. Current information suggests that the induction of ovulation with potent GnRH analogs requires several injections of very low doses [Harrison, L. et al., J. Eq Veterinary Science 11: 163-166 (1991)] or a very high dose that is supplied in the form of a prolonged release implant [Jochle, W. et al., J. Eq Veterinary Science 44: 632 (1994)] . The selection of a system to deliver the drug that is appropriate should be based on the pharmacokinetic and pharmacodynamic properties of the drug. The importance of the pharmacodynamic properties of the drug is especially relevant in the case of hormones that target receptors with highly specific affinity for tene-effect. In the case of GnRH this relationship depends on several elements including the species, the reproductive status and the complex effects of concentration and presentation of the peptide and the response of the pituitary to it. Applicants have discovered that some compositions are suitable for the controlled release of GnRH analogues, particularly for the purpose of accelerating ovulation in mares. The composition includes a system based on sucrose acetate isobutyrate (SAIB) a completely esterified sucrose molecule. SAIB is a material with a low molecular weight that has many properties associated with polymeric materials. Since SAIB is a non-polymer, it It requires dilution only with small amounts of solvents to make it easy to inject. BRIEF DESCRIPTION OF THE INVENTION Applicants have discovered a particular adaptation of the system technology for the supply of the SAIB drug that is suitable for inducing ovulation in mares, with a composition that can be injected and sterilized. ABBREVIATIONS AND DEFINITIONS GnRH Gonadotropin releasing hormone HVLCM High viscosity liquid carrier material LH Luteinic hormone LH-RH LVLCM luteal hormone releasing hormone Low viscosity liquid carrier material BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the concentrations of LH in the Mares after treatment with experimental formulations. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a composition for the controlled release of GnRH or the like of the same in mares to induce ovulation, which comprises: (a) a non-water soluble, non-polymeric liquid carrier material having a viscosity of at least 5,000 cP at a temperature of 37 ° C, which does not crystallize low, environmental conditions or physiological conditions; (b) GnRH or its analogs, or combinations thereof. In one embodiment of the composition of the present invention, the soluble liquid carrier material in water is sucrose acetate isobutyrate. In another embodiment of the composition of the present invention the liquid carrier material not soluble in water is present in an amount from about 99.5 percent to about 10 percent by weight, in relation to the total weight of the composition. In another embodiment of the composition of the present invention the liquid carrier material not soluble in water is present in an amount from about 95 percent to about 25 percent, by weight, relative to the total composition but. In another embodiment of the composition of the present invention, said composition further comprises a solvent in which the liquid carrier not soluble in water is soluble.

In another embodiment of the composition of the present invention, the solvent is selected from a group consisting of ethanol, dimethyl sulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate and glycofurol. In another embodiment of the composition of the present invention, the solvent is ethanol. In another embodiment of the composition of the present invention, the solvent is present in an amount of from about 10 to about 50 percent by weight, based on the weight of the composition. In another embodiment of the composition of the present invention, the analogue is deslorelin. In another embodiment of the composition of the present invention, the analog is selected from deslorelin, avoreline, leuprolide and natural LHRH. The present invention also relates to a liquid composition for the controlled release of GnRH or analogs thereof in mares to induce ovulation, this having isobutyrate sucrose acetate and ethanol in a weight ratio of about 75:25 to about 60: 40, and GnRH or analogs thereof, as well as combinations thereof in a concentration of about 0.1 to about 5.0 mg / ml of the liquid composition, to provide a dose of about 0.3 mg to about 10 mg of GnRH or its analogues, as well as combinations thereof. ~~ The present invention also relates to a liquid composition for the controlled release of GnRH or its analogs in mares to induce ovulation, comprising sucrose acetate isobutyrate and ethanol at an average weight of between about 75:25 and about 60: 40, as well as GnRH or its analogues, or a combination thereof in a concentration of between about 1.0 to about 2.5 mg / ml of a liquid composition, to deliver a dose of between about 0.3 to about 10 mg of GnRH or its analogs , or a combination thereof. In one embodiment of the composition of the present invention, the GnRH analogue is Deslorelin. In another embodiment of the liquid composition of the present invention, the composition is sterilized before being administered to the mares. In another embodiment of the liquid compositions of the present invention, the composition is sterilized by filtration before being administered to the mares. The present invention also relates to a filtered sterile liquid composition for the controlled release of deslorelin in the mares, in order to induce the ovulation, this comprises sucrose acetate isobutyrate and ethanol at a weight-to-weight ratio of about 75:25, and deslorelin at a concentration between about 0.1 and about 5.0 mg / ml of the liquid composition, to deliver a dose between about , 1 mg to approximately 2 mg of deslorelin, this composition is administered by means of injections. The present invention also relates to a liquid composition sterilized by filtration for the controlled release of deslorelin in the mares in order to induce ovulation, this comprises sucrose acetate isobutyrate and ethanol in a weight-to-weight ratio of approximately 75:25 and deslorelin. in a concentration of about 1.0 and about 2.5 mg / ml of a liquid composition, to give a dose between about 1 mg to about 2 mg of deslorelin, this composition is administered by means of injections. I. High Viscosity Liquid Carrier Material (HVLCM) High viscosity liquid carrier material must be selected to be non-polymeric, non-water soluble, and have a viscosity of at least 5,000 cP (and optionally at least 10,000, 15,000, 20,000 25,000 or even 50,000 cP) at a temperature of 37 ° C, and that does not crystallize under ambient or physiological conditions. The term "water insoluble" refers to a material that is soluble in water to a degree of at least one percent by weight under ambient conditions. In a preferred embodiment of the invention, HVLCM significantly reduces its viscosity when mixed with a solvent to form LVLCM that can be mixed with a substrate for controlled delivery. Typically, the LVLCM / substrate composition is easily applied in the body to the HVLCM / substrate composition, since the former flows easier from the syringe or other implantation means, and can be easily formulated as an emulsion. The LVLCM can have any desired viscosity. It has been found that an average viscosity for the LVLCM of about 1000 cP, and more particularly less than 200 cP, is typically useful for in vivo applications. In the preferred embodiment of the invention, sucrose acetate isobutyrate (SAIB), a sucrose molecule esterified with two of acetic acid and six parts of isobutyric acid, is used as HVLCM. The structure of SAIB is specified below.

SAIB is not toxic for oral administration and is currently used to stabilize emulsions in the food industry. It is a very viscous liquid and has an unusual property as it undergoes a dramatic change in its viscosity with small additions of heat or solvents. It is soluble in a large number of biocompatible solvents. When it is in solution or in emulsion, SAIB can be applied through an injection. In other embodiments, the HVLCM may be ester stearates such as propylene glycol, glyceryl, diethylaminoethyl, and glycol, amide stearate, and other amides. long chain fats, such as N, N'-ethylene disteramide, stearamide MEA and DEA, ethylene bisteramide, cocoamine oxide, long chain fatty alcohols, such as cetyl alcohol and stearyl alcohol, long chain esters such as myristyl myristate, erucate behenium and glyceryl phosphate. In a particular embodiment, the HVLCM is an acetylated sucrose diskette (Crodesta A-10). The HVLCM is present in the composition in any amount that achieves the desired effect. Typically, HVLCM is present in controlled delivery compositions for GnRH or its analogues in an amount on average from about 99.5 percent to about 10 percent by weight, more typically, between 90 and about 25 percent, and more typically, between about 85 and about 65 percent, relative to the total weight of the composition. _ II. Substance to be provided _ A variety of hormone analogs releasing gonpdotropin are suitable for controlled release in the compositions of the present invention. Suitable analogs include, but are not limited to, those listed in Table I below.

Preferred GnRH analogues include deslorelin, avoreline, leuproide and natural LHRH. Other series of preferred GnRH analogs include triptorelin, nafrelin, goserelin, buserelin and fertirelin. The most preferred in deslorelin. GnRH analogs are synthesized by any of a variety of conventional techniques. In general, it can refer to Merrifield, B., Science 232: 342 (1986), Norman, A.. and collaborators, Hormones Academic Press New York 1987. Deslorelin is synthesized by the method of Ajayaghosh, A. et al., J. Org. Chem. 55: 2826 (1990); Néstor, J.J. and collaborators, Proc. Am. Pept Symp. 7,109 (1981); avorelin by the method of WO 91/18016; leuprolide by the methods of German Patent 2,446,005, U.S. Patent 4,005,063; Natural LHRH by the method of German Patent 2,213,737 and that of Coy et al., Methods Enzymol 3_7, 416 (1975); triptorelline by the methods of German Patent 2,625,843, U.S. Patent 4,010,125; goserelin by the method of German Patent 2,720,245; United States Patent 4,100,274; buserelin by the method of German Patent 2,438,352, U.S. Patent 4,024,248; fertireline by the method of German Patent 2,321,174; United States Patent 3,853,837.

III. Solvent When the composition is used as an LVLCM, it must contain a solvent in which the KVLCM is soluble. Preferably, the The substance to be supplied is also soluble in the solvent. The solvent must be non-toxic, soluble in water and mixable with water, as well as biocompatible. Solvents that are toxic should not be used for pharmaceutical or agricultural purposes. The solvents used to inject the composition into the animals should not cause significant tissue irritation or necrosis at the site of implantation. The solvent must be at least soluble in water, so that it spreads rapidly in body fluids or in another aqueous environment, causing the composition to coagulate or solidify. Examples of suitable solvents include ethanol, ethyl lactate, propylene carbonate, glycofurol, N-methylpyrrolidone, 2-pyrrolidone, propylene glycol, acetone, methyl acetate. Ethyl acetate Methyl ethyl ketone. Benzyl alcohol, triacetin, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid and I-dodecylazacycloheptan-2-one. The preferred solvent is ethanol. When SAIB is used as HVLCM, the preferred solvents are ethanol, dimethyl sulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate and glycofurol. SAIB is not mixed with glycerol, corn oil, peanut oil, 1,2-propanediol, polyethylene glycol (PEG200), sesame oil Very refined and very refined peanut oil. According to this, there is a large group of solvents that are not very preferred for use with SAIB. Typically, the solvent is added to the composition in an amount in a proportion from about 5 percent to about 55 percent by weight, relative to the total weight of the composition. Preferably, the solvent is present in the composition in an amount ranging from about 10 percent to about 50 percent by weight. Another preferred proportion ranges from about 10 percent to 30 percent by weight.

IV. Veterinary uses of the compositions LVLCM and LVLCM The composition described herein can be administered to a recipient by various methods that can vary depending on the results desired logxar. When the recipient is an animal, the composition can be administered, for example, topically, systematically " (for example, in the mucosa (oral, rectal, vaginal or nasal), or parenterally (intravenous, subcutaneous, intramuscular or intraperitoneal) in an appropriate carrier if desired, preferably, for veterinary purposes, the present compositions are administered as solutions or suspensions by means of an injection.When administered by means of an injection as an LVLCM, it is it uses a small amount of solvent in the composition reaching the receiver as an aqueous fluid, forming a highly viscous deposit for a controlled supply. See, for example, Ansel, H.C. and collaborators, Pharmaceutical Dosage Forms and Drugs Del. Systems, fifth edition, 1995.

EXAMPLE 1 A. Preparation of SAIB Formulation 1 A solution of deslorelin in DMSO (1.0 weight percent) is prepared. A concentrated solution is also prepared with a 95: 5 ratio by weight of SAIB: DMSO ^ A predetermined amount (2.1870 g) of deslorelin acetate (DA) / DMSO is added to 7.9230 g of a SAIB / ethanol solution in a proportion of 95. :5. The final formulation contains 2.4 mg / ml deslorelin and has a SAIB: DMSO ratio of 75:25. B. The preparation of SAIB Formula 2 A solution of deslorelin in ethanol (2.1 percent by weight) was prepared. A concentrated SAIB solution with a 95: 5 weight ratio was also prepared. A predetermined amount (1.0376 g) of deslorelin acetate / ethanol was added to 8.9917 g of a SAIB: 95: 5 ethanol solution. The final formula contains 2.3 mg / ml of deslorelin and a ratio of SAIB: ethanol of 85:15.

C. The preparation of SAIB Formula 3 A solution of deslorelin in ethanol (1.9 percent by weight) was prepared. A concentrated SAIB solution with a 95: 5 weight ratio was also prepared. A predetermined amount (1.0826 g) of deslorelin acetate / ethanol was added to 7.9085 g of a SAIB: 95: 5 ethanol solution. The final formula contains 2.2 mg / ml of deslorelin and a ratio of SAIB: ethanol of 75:25. D. The preparation of SAIB Formulas 4-8 with a 75:25 ratio of. SAIB: ethanol for the study of titration of the dose. The dose titration study was carried out using the SAIB: 75:25 ethanol formula, which evaluated deslorelin concentrations of 0.5, 1.0, 1.5 and 2.0 mg / ml. A concentrated solution of SAIB in ethanol (83.6 percent by weight) was prepared and filtered for sterilization using a 0.2μm hydrophobic filter. Pure ethanol and a solution of deslorelin in ethanol (21.0 mg / ml) were sterilized by filtration using sterile 0.22 μm syringe filters. The appropriate amounts of the sterile solutions of SAIB / EtOH and EtOH / deslorelin were combined with a predetermined amount of sterile ethanol to produce the final mixtures at the desired concentrations. The amounts of each component used and the compositions of the formulas prepared are shown in Table A, below. The lowest concentration of each formula produced a solution, while the remaining formulas were suspensions whose cloudy appearance was accentuated by increasing the concentration of deslorelin.

E. Preparation of formulas 9-12 of SAIB with SAIB: ethanol at 65:35 for the titration study of the dose. The dose titration study was carried out using the SAIB: ethanol formula of 65:25, which evaluated deslorelin concentrations of 0.5, 1.0, 1.5 and 2.0 mg / ml. A concentrated solution of SAIB was prepared in ethanol (83.6 percent by weight) and filtered for sterilization using a 0.2μm hydrophobic filter. Pure ethanol and a solution of deslorelin in ethanol (21.0 mg / ml) were sterilized by filtration using sterile 0.22 μm syringe filters. The appropriate amounts of the sterile solutions of SAIB / EtOH and EtOH / deslorelin were combined with a predetermined amount of sterile ethanol to produce the final mixtures at the desired concentrations. The amounts of each component used and the compositions of the prepared formulas are shown in Table B, below. The lowest concentration of each formula produced a solution, while the remaining formulas were suspensions whose cloudy appearance was accentuated by increasing the concentration of deslorelin.

EXAMPLE 2 The mares used in this experiment were from the herd resident in the LSU Agricultural Centrer Horse Farm and Quarter Horses, Pure Blood and Arabs. All the mares were in good health and kept on grazing on native summer pasture (predominantly berudagrass). Most of the mares in the herd did not cross the previous season, while six had 30-day-old foals and were breastfeeding. The mares underwent a heat detection regimen beginning on June 1 and they were tested for general health and reproduction during this month. Only mares with good health, conformation of the vulva and vagina, Satisfactory as well as apparently normal uterine and ovarian conformations were selected as possible candidates for treatment. Most of the mares were between 11 and 14 years old (average of 8 to 22 years old) and weighed between 400 and 650 kg. In this study, three experimental formulas were prepared by weighing and mixing SAIB (SABER, SBS Inc., Birmingham, AL), diluting in a solvent and adding deslorelin to obtain a final concentration of 2.1 mg / ml. The SAIB: dilute solvent compositions were 75:25 weight / weight of SAIB: DMSO of formula 1 (see example IA); 85:15 weight / weight of SAIB: ethanol of formula 2 (see example IB); and 75:25 weight / weight of SAIB: ethanol in formula 3 (see example 1C). The resulting experimental formulas had a low hydrophobic viscosity after injection i.m. as the solvent disintegrates, leaving behind the SAIB-DA matrix that released DA by diffusion through the high viscosity SAIB, accompanied by the degradation of the SAIB in sucrose and its corresponding aliphatic acids from which the ester was prepared of sucrose. In addition, a negative control was prepared (1 ml of 9% USP NaCl, injected i.m.). As mares entered their estrus period after July 1, their ovaries were evaluated daily by transrectal ultrasonography to verify follicular size and appearance of the uterus. Once the mare met the following two criteria, it was assigned to the treatment based on a predetermined randomization: 1) it was in heat, and 2) it had a follicle of at least 30 mm in diameter, but not greater than 40 mm in diameter. Ultrasound evaluations were carried out every morning, and the mares were usually treated before noon. To avoid any possible deviation in the data, the personnel that administered the treatments was different from the one that verified the follicle and the characteristics of the heat, as well as the places for the injection. In addition, the three SABER formulas had a color code and their actual content was unknown by the herd staff. Once the mares were treated, their ovaries were verified by means of an ultrasonography, every 2 hours, until the mare ovulated. The sizes of the follicles that can be measured in each ovary were recorded, and ovulation was determined by the various changes in size, softness and the predominant appearance of the follicle as described in the Ginther's detail (Ginther, OJ Image, Ultonic and Events reproductive effects in mares Equiservices Cross Plains, WI 1986). In addition, blood samples were taken 24 hours before treatment (-24h); immediately before treatment (time 0); in 1, 3, 6, 12, 24, 36 and 48 hours after treatment; and then every 24 hours until the day then to ovulation to measure progesterone and (or) luteinizing hormone (LH) concentrations. These blood samples were taken by means of jugular venipuncture in heparinized as well as empty tubes, and the tubes were placed in 5C until the plasma was collected by centrifugation. Progesterone was measured by radioimmunoassay with commercially available reagents (Diagnostic Systems Laboratories, Inc., Webster, TX) and LH was measured by radioimmunity test as described in Thompson et al., 1983. J. Anim. Sci ..- 56: 678-686. For each day, in a 7-day treatment, the place of injection in the mare was determined according to these three characteristics: 1) swelling, which was rated 0 = no swelling; 1 = slight swelling (1 c in diameter or less), 2 = slight (1 to 2.5 cm in diameter) and 3 = significant (greater than 3 cm in diameter); 2) sensitivity to touch, which was rated as yes or no, - and 3) elevation of skin temperature, which was also rated as yes or no. The concentrations of deslorelin were determined in the blood samples taken at -24, 0, 1, 3, 6, 12, 24, 36, 48 and 72 hours in relation to the treatment. Immediately after the jugular vein sample was taken, a 1-ml aliquot was removed and 4 ml of acetone was added to a disposable 12 x 75mm glass tube. This mixture was reversed several times and covered for storage at a temperature of -15C. At a later date, the extracts were centrifuged and the acetone was decanted in a second tube. The acetone was then dried under a jet of air, and the residual aqueous solution was diluted again to 1.0 ml with a test buffer. The deslorelin was measured in the extracts by radioimmunoassays using anti GnRH antiserum (Rabe et al., 1990. J. Anim. Sci. 68: 3322-3329) and radioiodinated deslorelin. Deslorelin was radioiodinated by the chloramine-T method and isolated by means of QAE-Sephadex chromatography as described for GnRH by Nett et al., Endocrinology 1Q_1: H35 (1977). Since the endogenous is not present in sufficient amounts in the blood taken from the jugular for detection, any immunoreactivity in the samples was assumed with deslorelin and not GnRH. During the course of the experiment, a mare had an unusually long period of estrus and did not ovulate until 216 hours after treatment. Since his responses were so different compared to the other mares, his ovulation time was compared with that of the rest of the mares receiving deslorelin and he was found to have a standard deviation of 3.82 out of his average (P < .01 ). Therefore, the data from this mare was removed from all the analyzes, and another mare was treated with a formulation of slow release (see example IA) to take the place of the other. The data for simple time points were analyzed by a one-way variant analysis using the SAS General Linear Models procedure. 1988. SAS / STAT® User's Guide (Publication 6.03). SAS Inst. Inc. Cary, NC. For each variable, the comparison between the mares with saline treatment and all the mares that received deslorelin was included in the analysis, as well as the individual comparisons between each group receiving deslorelin and the saline group; these comparisons were based on the LSD value calculated from the error variant. Of the percen of mares that ovulated within 48 hours, the mares were graded with one (1) if or (0) no and a one-way variant analysis was conducted on the data instead of using the method Chi squared . The data from the repeated sample (for example, LH concentrations) were analyzed by the variant spli t -plot test with which the effect of the treatment with the horse term (treatment) was determined and the interaction of time was evaluated x of the treatment with a variant of residual error. The net areas under the response curves were calculated for deslorelin concentrations from 0 hours to 24 hours after treatment, and for LH concentrations from 0 hours to 48 hours after the treatment. treatment; These areas were verified by a one-way analysis as described above. Ovulation was confirmed by ultrasound (US) and elevated levels of progesterone (P4). The final points studied included the hours for ovulation, percentage (%) of mares ovulating within 48 hours and the levels of LH, P and DA were measured by RIA. In addition, swelling at the site of injection (0 to 3, 0 = none, 1 = light, 2 = moderate, 3 = significant), sensitivity at the site of injection (Yes / No) and Elevation of the temperature at the injection site (Yes / No). The results showed that concentrations of DA in the plasma (deslorelin acetate) increased significantly after treatment with the three formulations of SAIB with peak levels of 1902 to 1699 pg / ml. The area under the response curve (AUC) for 24 hours after the injection confirmed a significant increase in SAIB in the treated mares compared to the control mares treated with saline (see Table II). II, a significant increase in% of mares was detected ovulating within 48 hours (when compared with saline) in the mares that were given formulations 2 and 3.

There was no effect of the treatment (P = .467) or relationship with the application time (P = .817) for the data about the swelling at the injection site, nor was there any type of sensitivity or increase in the temperature of the injection. the skin at the injection site for no treatment. The area under the LH response curve in the first 48 hours indicated that the mares that received formulation 3 (P = .01) and formulation 2 (P = 1) improved compared to those that received the treatment with saline solution. In addition, the concentration of LH in the plasma increased immediately (P <.003) with all treatments, except with saline, with a peak at 6 hours after injection, remaining elevated from 36 to 48 hours after treatment. as shown in Figure 1. The results showed that formulations 2 and 3 effectively released deslorelin that stimulates ovulation levels of LH and accelerates ovulation in mares, with 7 out of 8 mares ovulating within 48 hours after to the treatment. In addition, the data indicate that all 3 formulations of SAIB showed excellent blacompatibility in judging the minimal reactions at the injection site, which were similar to those of the control animals.

EXAMPLE 3 Ninety mares were used, in cycle, from 3 to 16 years of age weighing between 400 and 650 kg. The mares were randomly assigned to one of 9 groups of blind color (n = 10 (group) to avoid the deviation of the interpretation.The treatment consisted of 2 experimental groups that contained: 0.5, 1.0, 1.5 or 2.0 mg of acetate. deslorelin (DA) designed to release DA at different proportions for approximately 12 to 3-6 hours (h) after an intramuscular (i.m.) injection of 1 ml, using a 21 gauge needle; and a negative control that consisted of SAIB that had no medication, which was also administered as an injection of 1 mi, i.m. The experimental formulations were prepared by weighing and mixing SAIB (SABER, SBS Inc., Hirmingham, AL), diluting the solvent and adding DA to give the "appropriate final concentration of 0.5, 1.0, 1.5 or 2.0 mg / ml. SAIB: solvent to dilute was: 75:25 weight / weight of SAIB: Ethanol in formulations- 4 to 8 (see "ID example") and 65:35 weight / weight of SAIB: Ethanol in formulations 9 to 12 (see example 1E). The ovaries of the mares were examined daily by ultrasound (US) and treated once it was detected that the follicle was between 30mm and 40 mm. Then, it " examined the ovaries of the mares every 24 hours until ovulation was confirmed by US. The two most efficient variables in the study were (a) the interval in hours from treatment to ovulation, and (b) the percentage of mares that ovulated at 48 hours of treatment. This was analyzed "statistically using the Cox regression model, SAS® (proportional hazard), the last one was analyzed statistically using the logistic regression that investigates the effects of the formulation and the dose. study were 8a) the visible signs of swelling (b) the sensitivity to touch, and (c) the increase in skin temperature at the injection site.These variables were analyzed statistically by repeated measurement analysis for the data in categories using the SAS PROC CATMOD, however, since there was no swelling, sensitivity or temperature increase, the analysis was not carried out.Ovulation data were presented in Table III.Using the Cox model (linear) in the doses for both groups of formulations, the coefficient for the formulation of SAIB / ethanol at 75:25 was highly significant (p <0.01 using a two-sided test), but the coefficient for SAIB / ethanol formulations at 65:35 they did not indicate significantly superiority in relation to the SAF / Ethanol formulations at 75:25 (see example 1C). TABLE III *% Real (% predicted according to the linear model for Cox proportional hazards, predicted logistic model%) ~ en (p <0.01).

Using the logistic (linear) model in doses for both formulations, the effect of SAIB / Ethanol formulations at 75:25 was highly significant (p, 0.01 using a two-slope test), while the effect of SAIB formulations / Ethanol at 65:35 were highly significant (p <0.1 using a two-slope test). Furthermore, the inclination for the formulations of 75:25 was significantly higher than for the formulations of 65:35 (ß) (p = 0.025) indicating the superiority of the formulations "of 75:25." The quadratic terms were not significant in any analysis indicating that the linear models used provide sufficient representation for all nine groups.The predicted percentage of mares ovulating within 48 hours of using both types of analysis is presented in table III in parentheses following the actual observed data. of greater safety in the study were visible signs of swelling, sensitivity to touch and increased temperature at the injection site, none of which was detected in any of the 90 mares.The absence of any observable swelling, sensitivity or increase of skin temperature in the place where the injection of any treatment is applied strongly suggests the excellent e formulation compatibility SAIB herein, when produced using filter sterilization and administered using 21 Gauges needles (see Table IV). Table IV The present study clearly demonstrated the superiority of the SAIB / Ethanol formulation of 75:25 compared to the "SAIB / Ethanol" formulation at 65:35 in the acceleration of ovulation. In addition, both models of Cox proportional and logistic risk predicted an average positive response for ovulation stimulation at 48 hours of treatment greater than 70% for the dose of 1 mg, 80% for the dose of 1.5 mg and greater than 90% for the dose of 2 mg of DA, indicating that these treatments effectively stimulate the LH levels of ovulation and accelerate ovulation in the mares. Finally, the safety data indicated that the nine formulations have an excellent biocompatibility. It is considered that no reaction was observed that can be detected at the injection site. While the above specifications show the principles of the present invention, with the examples provided for illustration, it will be understood that the practice of the invention includes all customary variations, adaptations, or modifications, which are within the scope of the appended claims. and its equivalents.

Claims (20)

1. A composition for the controlled release of GnRH or its analogues in mares to induce ovulation, this composition comprises: (a) a water-soluble, non-polymeric liquid carrier material having a viscosity of at least 5,000 cP at a temperature of 37 ° C that does not crystallize under environmental or physiological conditions; (b) GnRH or its analogs, or combinations thereof.

2. The composition according to claim 1, wherein the liquid carrier material not soluble in water is sucrose acetate isobutyrate.

3. The composition according to claim 2, wherein the liquid carrier material not soluble in water is present in an amount ranging from 99.5 percent to about 10 percent by weight, relative to the total weight of the composition .

The composition according to claim 3, wherein the liquid carrier material not soluble in water is present in an amount ranging from about 95 percent to about 25 percent by weight, relative to the total weight of the composition.

5. The composition according to claim 2, wherein the composition further comprises a solvent in which the liquid carrier material not soluble in water is soluble.

6. The composition according to claim 5, wherein the solvent is selected from a group consisting of ethanol, dimethylsulfoxide, ethyl-lactate, ethyl acetate, benzyl alcohol, triacetin, N-methylpyrrolidone, propylene carbonate and glycofurol.

7. The composition according to claim 5, wherein the solvent is ethanol.

The composition according to claim 5, wherein the solvent is present in an amount ranging from about 10 to about 50 percent by weight, relative to the total weight of the composition.

9. The composition according to claim 1, wherein the analogue is deslorelin.

10. The composition according to claim 1, wherein the analog is selected from deslorelin, avorelin, leuprolide and natural LHRH.

11. A liquid composition for the controlled release of GnRH or analogs thereof in mares to induce ovulation, which has sucrose acetate isobutyrate and ethanol in a proportion - by weight of about 75:25 and about 60:40, and GnRH or analogs thereof, as well as combinations thereof in a concentration of about 0.1 to about 5.0 mg / ml of the liquid composition, to provide a dose of between about 0.3 mg to about 10 mg of GnRH or its analogs, as well as combinations thereof.

12. The liquid composition for controlled release of GnRH or analogs thereof in mares to induce ovulation, this having sucrose acetate isobutyrate and ethanol in a weight ratio of about 75:25 to about 60:40, and GnRH or analogs thereof, as well as combinations thereof in a concentration of about 1.0 to about 2.5 mg / ml of the liquid composition, to provide a dose of between about 0.3 mg to about 10 mg of GnRH or its analogues, as well as combinations of the same .

13. The liquid composition according to claim 11, wherein the GnRH analogue is deslorelin.

14. The liquid composition according to claim 12, wherein the GnRH analog is deslorelin.

15. The liquid composition according to claim 11, wherein the composition is sterilized before being administered to the mares.

16. The liquid composition according to claim 12, wherein the composition is sterilized before being administered to the mares.

17. The liquid composition according to claim 11, wherein it is sterilized by filtration before being administered to the mares. ~~

18. The liquid composition according to claim 12, wherein it is sterilized by filtration before being administered to the mares.

19. A filtered sterile liquid composition for the controlled release of deslorelin in mares, in order to induce ovulation, it comprises isobutyrate of sucrose acetate and ethanol in a weight-to-weight ratio of about 75:25, and deslorelin in a concentration of between about 0.1 and about 5.0 mg / ml of the liquid composition, to supply a dose between about 1 mg to about 2 mg of deslorelin, this composition is administered by means of injections.

20. A sterile filtered liquid composition for the controlled release of deslorelin in the mares, in order to induce ovulation, this comprises sucrose acetate isobutyrate and ethanol in a weight-to-weight ratio of approximately 75:25, and deslorelin in a concentration of between about 1.0 and about 2.5 mg / ml of the liquid composition, to deliver a dose between about 1 mg to about 2 mg of deslorelin, this composition is administered by means of injections.