WO2006128266A2

WO2006128266A2 - Pharmaceutical compositions of the peptide angiotensin-(1 -7) [ang-(i -7)] and its analogues, agonists and antagonists, for use in controlling the functions of the reproductive system

Info

Publication number: WO2006128266A2
Application number: PCT/BR2006/000105
Authority: WO
Inventors: Adelina Martha Dos Reis; Rubén Dario Sinisterra MILLÁN; Robson Augusto Souza Dos Santos; Gregório Elias Nunes VIANA; Virginia Mara Pereira
Original assignee: Universidade Federal De Minas Gerais
Priority date: 2005-05-30
Filing date: 2006-05-30
Publication date: 2006-12-07
Also published as: BRPI0503122A; WO2006128266A3

Abstract

The present invention relates to the use of pharmaceutical compositions of the peptide Ang-(1-7) and its analogues, agonists and antagonists, prepared by using the cyclodextrins, its derivatives, liposomes and biodegradable polymers and/or mixtures thereof and/or the derived products, mixtures thereof with excipients, as well as mixed or not mixed with other pharmaceutically or pharmacologically active principles, in controlling the functions of the human or animal reproductive system and its pathologies.lt was not found any prior art technology claiming the use of Ang- (1-7) as well as its pharmaceutical compositions, in encapsulated or non- encapsulated form, its mixtures with pharmaceutically and pharmacologically active excipients, as well as mixed or non-mixed with other pharmaceutically or pharmacologically active principles, in controlling diseases associated to the male or female reproductive system. The invention is also characterized by the use of the receptor- ligand interaction between the MAS receptor and Ang-(1 -7) and its analogues, its pharmaceutical compositions, either encapsulated or not, as a target for study and therapeutics of the reproductive functions.

Description

Title: "PHARMACEUTICAL COMPOSITIONS OF THE PEPTIDE ANGIOTENSIN-(1 -7) [ANG-(I -7)] AND ITS ANALOGUES, AGONISTS AND ANTAGONISTS, FOR USE IN CONTROLLING THE FUNCTIONS OF THE REPRODUCTIVE SYSTEM" The present invention relates to the use of pharmaceutical compositions of the peptide Ang-(1-7) and its analogues, agonists and antagonists, prepared by using cyclodextrins, its derivatives, liposomes and biodegradable polymers and/or mixtures thereof and/or the derived products, mixtures thereof with excipients, as well as admixed or not mixed with other pharmaceutically or pharmacologically active principles, in controlling the functions of the human or animal reproductive system and its pathologies.

It also relates to the use of the receptor-ligand interaction between the MAS receptor and Ang-(1-7) and its analogues, its pharmaceutical compositions in encapsulated or non-encapsulated form, as a target for the study and therapeutic treatment of reproductive functions.

Infertility, as well as birth control, has been the focus of intense basic and applied research. The statistics referring to infertility show that in the USA about 15-20% of the couples (or 4.5 million men and women) fail to get pregnant in the first year trying to achieve the first pregnancy (Associated Urologists, P. C. http://mo-urology.com/services/index.asp? Service-ID-22). In about 15% of infertility cases, both men and women exhibit some form of abnormality. In about 40% of the cases the problem is only of the man and in the remaining 45% it is only of the woman. The understanding of the causes of infertility and the obtainment of new therapeutic forms is an important filed for new researches. On the other hand, birth control is practiced in the greater part of the reproductive life by most couples throughout the world. The obtainment of new contraceptive methods, with an increase in efficiency and reduction of side effects, has been the objek^ofcteJiαifbiEferte-^BnϊiS€temghEtΘnsin System (RAS) as regulator of homeostase of the bodily liquids and of the blood pressure is quite known. The RAS is responsible for the regulation of arterial pressure, of the cardiovascular homeostase and of the hydroelectrolytic balance, both in physiological and pathological conditions (Santos, RAS; Campagnole-Sanso, MJ; Andrade, SP. Angiotensin^ 1-7): an update. Regulatory Peptides, 91 : 45- 62, 2000). Recently, it was found that, in addition to the system that generates circulating Angiotensin Il (Ang II), different tissues contain local RAS. The components of the RAS tissue are found in various organs and tissues, including the male and female reproductive system. The RAS function in a reproductive system is still not well clarified. (Yoshimura, Y. The ovarian rennin-angiotensin system in reproductive physiology. Frontiers in Neuroendocrinology 18: 247-291 , 1997). The primary components of the classic RAS are: renin, the enzyme that catalyzes the proteolytic conversion of angiotensinogen into Angiotensin I (Ang I); angiotensinogen, the main substrate of rennin and precursor of Angiotensin Il (Ang II); the Angiotensin converting enzyme (ACE) which converts Ang I into Ang II, by cleavage of the two carboxy- terminal amino acids; Angiotensin II, the main biologically active peptide of the system; AT-1 and AT-2 receptors that are responsible for the start of the cellular effects of Ang II. Other peptides have been added to this well known system, such as Angiotensin III (Ang III), Angiotensin IV (Ang IV) and Angiotensin-(1-7) (Ang-(1-7). Ang(1-7) may be generated from Ang I or Ang Il by tissular endopeptidases (Santos et al., 1988).

Ang-(1-7) was identified in the plasma and in various human and animal organs and tissues (Santos et al., 1992), including ovaries of female rats (Costa et al, 1003). Its production independent of ACE was demonstrated by Santos et al. (1088) and its attachment to a specific receptor was described by Santos et al (1994) and Tallant et al (1997). An Ang-(1-7) selective antagonist has been characterized and named A-779 (Asp¹-Arg²-Val³-Tir⁴-Lle⁵-His⁶-D-Ala⁷; Santos et al, 1994).

All the following components of the RAS were described in the ovary: • Pro-renin and rennin: their production was demonstrated in theca cells (Paulson et al, 1989), as well as positive correlation of the rennin activity with the production of androgens in human follicular fluid (Itskovitz θt al, 1991) and with estradiol level (Lightman et al, 1987). An activity similar to that of rennin is present in the human follicular fluid, being 15 times higher than in the plasma (Fernandez et al, 1985). Also, higher levels have been found in the estrus and greater expression regulated by FSH (Ki m et al, 1987).

• ACE: it was identified in the ovary of female rats, located in the germinating epithelium around the corpus luteum and in cells of the granulosa cells of some follicles, vessels and stroma (Speth & Husain, 1988). Higher levels have also been found in atresic and developing follicles and lower levels in preovulatory follicles (Daud et al, 1990).

• Angiotensinogen: messenger RNA identified in the ovary of female rat. It was demonstrated by immunohistochemistry (IHC) that the amount of Angiotensinogen is larger in maturating follicles, smaller in atresic follicles and absent in primordial follicles (Thomas & Sernia,

1990).

• Angiotensin II: the concentrations of Ag Il in homogenate of ovaries of female rats are much higher than the plasmatic levels and a similar result was also found in bilaterally nephrectomized female rats, indicating that ovarian Ang Il does not come from the circulation

(Husain et al, 1987). Immunoreactivity for Ang Il was found in follicular fluid of pre-ovulatory follicles of women with normal cycle or stimulated by gonadotrophins (Lightman et al, 1987). Immunohistochemistry for Ang Il disclosed a dense coloration in the theca layer and in the stroma, as well as in the luteinized granulosa cells of pre-ovulatory follicles (Palumbo et al, 1989).

However, the results of the studies of the Ang Il effects on ovaries are quite discrepant. Pellicer et al (1988) demonstrated the ovulation blocking of female rats by intraperitoneal injection of saralasin, an AT-1 and AT-2 receptors antagonist. Also, Yoshimura et al (1996) demonstrated that the blocking of AT-1 and AT-2 with saralasin inhibited ovulation induced by hCG in in vitro perfused ovaries of female rabbits. On the other hand, the infusion of captopril, an ACE inhibitor, did not affect the ovulation in ovaries of immature female rates stimulated with PMSG/hCC (Daud et al, 1989). Captopril did neither block the ovulation induced by hCG in ovaries of female rabbits perfused in vitro (Yoshimura et al, 1992, 1993, 1996). Angiotensin Il can also act on the production of prostaglandins, primarily stimulating the secretion of PGE2 and PGF_2α- The role of prostaglandins in the ovulatory process is well known (Yoshimura et al, 1996). Angiotensin Il seems to act on the ovulation through AT-2 receptors since it was demonstrated that the blocking thereof with PD 123319 inhibited ovulation in ovaries of female rabbits induced in vitro by hCG, but the blocking of the AT-1 receptors with CV 11974 did not affect it (Kuji et al, 1996). Ang Il effects on the ovarian steroidogenesis was determined in ovaries of female rabbits perfused in vitro: an stimulating effect on the secretion of estradiol was observed, but the progesterone production was not altered. The effects were blocked by the PD123319 antagonist, but not by CV 11974 (Yoshimura et al, 1996). The infusion of captopril in vivo in sexually immature female rats treated with PMSG/Hcg did not affect the production of estradiol and progesterone (Aguillera et al, 1989). The addition of captopril in erfusion medium of ovaries of female rats did neither alter the steroids production (Petterson et al, 1993).

The discrepancy among the Ang Il effects on the ovarian physiology can be explained by the fact that by using captopril, an inhibition of the ACE activity in the pre-ovulatory follicles is effected, which results in an increase of the Bradicinin and Angiotensin-(1-7) levels since both are degraded by the ACE. These contradictory effects can indicate that another component of the RAS, namely Ang-(1-7) may be participating in these regulatory processes in the ovaries since it may be formed by a route independent of the ACE.

Ang Ii receptors: AT-1 receptors are more concentrated in the theca layer and ovarian stroma, whereas AT-2 receptors are predominantly located in the granulosa cells. The expression of Ang Il receptors seems to vary with the development of the follicles. In a female rat ovary an intense coloration for Ang Il receptors was observed in atresic follicles, unlike the discrete coloration seen in follicles in the beginning of atresia (Daud et al, 1988). Most Ang Il effects on the ovaries seem to be mediated via AT-2 receptors, with stimulation of ovulation and of oocyte maturation and apoptotic alterations of the granulosa cells.

Enzymes: several enzymes are involved in the various steps of the RAS cascade, where they are responsible for the degradation of some peptidic fragments as well as for the generation of others. The ACE (Angiotensin converting enzyme) is responsible for the conversion of Ang I into Ang II; the PEP (prolyl-endopeptidase) generates Ang-(1-7) from Ang I and Ang Ii and the NEP (neutral endopeptidase) catalyzes the conversion of Ang I into Ang-(1-7). The ACE also hydrolizes Ang-(1-7), generating Ang-(1- 5) (Chappel et al, 1998). Thus, the actuation of the ACE is important both for the generation and for the degradation of biologically active circulating and tissural peptides of the RAS.

Angiotensin^ 1-7): the present inventors has demonstrated its presence in ovaries of female rats and its distribution according to the phases of the estral cycle. It has been showed higher concentrations in the pro- estrus phase and in the estrus and lower concentrations in the metaestrus and diestrus. In addition, the inventors have demonstrated that Ang-(1-7) increases the estradiol secretion in ovaries of immature female rats treated with PMSG/hCG and perfused in vitro, this effect being blocked by its specific antagonist, namely A-779 (Costa et al, 200).

Angiotensins-(1-7) and Il are the main effectors of the RAS. Two important characteristics separate Ang-(1-7) from Ang II: the first one has highly specific biological actions and its route of formation is independent of the ACE (Santos, RAS; Compagnole-Santos. MJ; Andrade, SP. Angiotensin- (1-7): an update. Regulatory Peptides 91-62, 2000).

Heptapeptid D-[Ala7]-Ang-(1-7) or A-779 has been recently characterized, which is a potent Ang-(1-7) selective angatonist (Santos, RAS, Campagnole-Santos, MJ, Baracho NCV, Fontes MAP, Silva LCS, Neves LAA, Oliveira DR, Galigiorne SM, Rodrigues ARV, Gropen Jr. C, CArvalho WS, Silva ACS, Khosla MC. Characterization of a new angiotensin antagonist selective for angiotensi-(1-7)): Evidence that the actions of angiotensin-(1-7) are mediated by specific angiotensin receptors. Brain Res. Bull 1994; 35:293-299). Moreover, it was recently demonstrated that MAS receptor, initially described as an angiotensin-ll receptor (Jackson, T.R. Blair, A . C, Marshall, J., Goedert, M. & Hanley, M. R. The Mas oncogene encodes an angiotensin receptor. Nature 335: 437-440, 1988), is a receptor for Ang-(1 -7) (Santos RAS, Simδes e Silva AC, Marie C, Silva DM, Machado RP, of Buhr I, Heringer-Walther S. Pinheiro SV,Lopes MT, Bader M. Mendes EP, Lemos VS. Campagnole-Santos MJ. Schluthesiss HP, Speth R; Walther T. Angiotensin-(1-7) is an endogenous ligand for the G progein-coupled receptor MAS. Proc Natl Acad Sci USA, 100, n. 14. p. 8258-2003).

Thus, there is no prior art technology claiming the use of Ang-(1- 7), as well as its pharmaceutical compositions, in the encapsulated or non- encapsulated form, mixtures thereof with pharmaceutically and pharmacologically inactive excipients, as well as mixed with other pharmaceutically or pharmacologically active principles, for controlling diseases associated to the male or female reproductive system. The excipients as well as the pharmaceutically acceptable but not limiting carriers used in the present invention include water, saline solution, buffered solutions, Ringer solution, dextrose solution, Hank 's solution, biocompatible saline solutions, containing or not containing polyethylene glycol, non-aqueous carriers, such as fixed oils, sesame oil, ethyl-oleate, or triglyceride, sodium carboxymethylcellulose, sorbitol, or dextran, timerosal, m- or o-cresol, formalin and benzyl-alcohol, human serum albumin for the study or treatment of the reproductive system disorders, infertility, anovulation and birth control in women and animals.

The present invention is characterized by using a controlled- release system containing Ang-(1-7), Ang-(1-7) analogues and derivatives, which facilitate the access for interaction with the G protein-coupled receptor, MAS. This interaction between the G protein, MAS and Ang-(1-7), itsanalogues or derivatives, allows the control of pathologies associated with the male and female reproductive system.

The satisfactory controlled-release system include, but are not limited to, cyclodextrins, biocompatible polymers, biodegradable polymers, other polymeric matrices, capsules, microcapsules, nanocapsules, microparticles, nanoparticles, bolus preparations, osmotic pumps, diffusion devices, liposomes, lipospheres and transdermal delivery systems. Other controlled release compositions of the present invention include liquids that, after administration to an animal, supplies a solid or a gel in situ. The administration routes of the present invention are preferably but not limited to: oral, intramuscular, intravenous, subcutaneous, topical, inhalation (pulmonary, intranasal, intrabucal) or as devices that can be implanted or injected, for study or treatment of disorders of the reproductive system (anovulation, infertility, etc.), gynecologic diseases and birth control in women and animals.

Ang-(1-7) and its analogues or derivatives has a great potential for the treatment of several diseases, including the control of the reproductive system. Another important aspect related to the RAS refers to the clear need to broaden the knowledge about its physiological properties, which may provide the development of new therapeutic strategies. However, the conventional mode of administering biologically active peptides, like angiotensins and derivatives, has limitations due to its short half-life and the lack of information about its chronic activities. In this regard, the use of more potent Ang-(1-7) analogues or antagonists and its pharmaceutical compositions, as well as the combination thereof with pharmaceutically and pharmacologically acceptable excipients, and the combination or non- combination with other pharmacologically active principles can enhance its effects, whether as therapeutic agents or as an experimental tool.

The present invention can be better understood with the aid of following illustrative examples, which are not limitative thereof. Example 1

This example describes the presence of Ang-(107) and its MAS receptor in ovaries.

Specific antibodies for angiotensin-(1-7) or for its MAS receptor were used for determining the location thereof in ovaries of female rabbits and rats by immunohistochemistry. The ovaries or ovary cut-outs were placed in para-formaldehyde at 4% and kept in a refrigerator for 2 hours. Then, they were fixed in Bouin's solution for 4 hours and transferred to a 70% alcohol solution, which was changed daily until total clearing. The ovaries were then included in paraffin and sectioned into 4-micra thick sliced. The immunohistochemistry technique used was the previously standardized Avidi-Biotina-Peroxidase (Hsu SM, Raine L, Fanger H. A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormone with radioimmunoassay antibodies. Am J. Clin Patho. 75-734-738, 1981 ), using Vectastin Kit (Vector Laboratories, Burlingame CA, EUA). The chromogen used was DAB [3,3 diaminobenidine] (Sigma Chem. Co. St. Louis, MO, USA, and the counter- coloration was made with hematoxylin (Vetec). Anti-MAS and Anti-Ang-(1-7) polyclonal antibodies produced in mice were used. Intense marking for Ang- (1-7) and its receptor was visualized in the interstitial cells of pre-ovulatory ^~ follicles of a female rabbit. Intense coloration for Ang-(1-7) and MAS was also observed in theca cells and interstitial cells, as well as in corpus luteum of ovaries of female rats in various phases of the estrous cycle. Immunoreactiivity for Ang-(1-7) was not observed in cells of the granulosa, except pre-ovulatory Graafs follicles. Treatment with PMSG, which induces the follicular development in impuberal female rats , increased the imunocoloration for Ang-(1-7) and MAS in the theca-intertitial compartment. The immunolocation of Ang-(1-7) and MAS receptors in ovaries of female rats and rabbits provides strong evidence for the participation of those novel RAS components in regulating the follicular development, primarily in the §beaniφl§e2iesis process. This example describes the effect of Ang-(1-7) in ovaries and on the production of estradiol and progesterone in ovaries.

Female rabbits (n=6 per group) were pre-treated with 50 Ul of PMSG 48 hours before, for induction of development of preovulatory follicles. After anesthesia with Ketamin/Xilasin, the female rabbits were subjected to cannulation of the ovarian arteries (Brannstδm M. In vitro perfused rat ovary. In: Heintdel JJ. Female reproductive toxicology, San Diego, Academic Press: 160-169, 1993). After cannulation, the ovaries were placed separately in perfusion systems (Brannstrδm Ml In vitro perfused rat ovary in: In: Heintdel JJ. Female reproductive toxicology, San Diego, Academic Press: 160-169, 1993). The perfusions were made with medium 199 plus Early salt, L-glutamine, 1% BSA, sodium bicarbonate 1mg/mL, heparin sulfate (200 UI/1), insulin (20UI/I) and gentamicin sulfate (60 mg/l). Temperature (37°C, pH (7.4), pressure (80-90 mmHg) and oxygenation (O2 95%/CO2 5%) were kept constant. After coupling the preparation to the system, it was allowed to rest for 1 hour for stabilization and, after collection at the time Oh, the substances under test were added. Two ovaries were perfused per day in individual systems, for 10h after the stabilization period. Samples of the perfusion medium (1.8mL) were collected in the times 0, 1 ,2, 4, 6, 8 and 10 hours. The estradiol (E₂) and Progesterone (P₄) concentrations were determined by radioimmunoassay using MAIA kits (Biochem Immunosystems, Italia). Ang-(1-7) stimulated the release of estradiol and of progesterone. The Ang-(1-7) effect was completely blocked by its specific inhibitor, namely A-779. Example 3:

This example describes the effect of Ang-(1-7) on the ovulation in in vitro perfused rabbit ovaries. In a perfusion system similar to the one described before the effect of Ang-(1-7) and of its specific antagonist, A-779 was tested on the ovulation of female rabbits pre-treated 48 hours before with PMSG. The perfusion with Ang-(1-7) resulted in an increase in the percentage of follicles that ovulated, an effect antagonized by A779. Besides, A-779 reduced the high ovulation rate induced by the hormone responsible for the ovulation process, namely hCG/LH. Thus, ovarian Ang-(1-7) can be an endogenous intermediary of naturally induced ovulation. Exemple 4

This example describes the functional action of the chronic treatment with Ang-(1-7)-cyclodextrin in the ovulation induced by luteinizing hormone (LH) in female rats. Pre-puberal female rats received Cyclodextrin or Ang-(1-

7)/Cyclodextrin (150ug of Ang-(1-7)Kg/day) for 9 days by gavage (n: 4 female rats/group). On the 7^th day they received PMSG to induce development of multiple pre-ovulatory follicles. On the 9^th day they received LH to induce ovulation. In the morning of the 10^th day counted from the beginning of the treatment, the female rats were killed by decapitation and the uterine tube were desiccated, placed between 2 histological slides in an appropriate equipment and observed under the microscope. The ovulatory rate of each ovary was determined by counting the oocytes present in each uterine tube. Ang-(1-7)-cyclodextrin increased the ovulation rate as when compared to the treatment with cyclodextrin (cyclodextrin: 17.30 ± 8.80; Ang-(1-7)- cyclodextrin: 29.8 ± 6.1 oocytes / tube; p < 0.05). Example 5

This example describes the functional consequence of the chronic treatment with Ang-(1-7)-cyclodextrin in steroidogenesis induced by luteinizing hormone (LH).

Mice received cyclodextrin or 100ugKg of Ang-(1-7) with cyclodextrin for 7 days by gavage (n:4 mice/group). On the last day of treatment the animals were sacrificed and their testicles were removed and incubated at 34°C in a medium 199 plus Earle's salt, L-glutamin, 0.1 % BSA, sodium bicarbonate 1 mg/mL, heparin sulfate (200UI/I), insulin (20UI/I and gentamicin sulfate (60mg/l).The oxygenation (02 95%/CO2 5%) was kept constant. After 1 hour of stabilization, the basal sample was collected and LH was added to the incubation medium of one of the testicles; the other continued to be incubated without LH for determining the release of testosterone without stimulation. Samples of the perfusion medium (100 uL) were collected in the times 0, 1 , 2, and 3 hours. The testosterone concentrations were determined by radioimmunoassay by using MAIA kits (Biochem Immunosystems, Italia). The testosterone release induced by the LH was much intensified in the group treated with Ang-(1-7)-cyclodextrin, indicating the participation of this peptide in the gonadal steroidogenesis process. Considering that ovarian steroidogenesis follows routs similar to those of testicular steroidogenesis, differing only in the last step in which androgens are converted into estrogens by the action of the enzyme aromatase, it is possible to appraise the possibility that the hormonal production of ovaries may also be increased by treatment with Ang-(1-7)- cyclodextrin. These non-limitative examples show that Ang-(1-7) may be an important factor in the reproductive functions. Thus, the proposed formulations are important for the treatment of disorders of both human and animal reproductive systems (anovulation, infertility, etc.). On the other hand, its antagonists may be potentially important for birth control.

Claims

1. Pharmaceutical compositions of Angiotensin-(1-7) [Ang~(1-7)] peptide and its analogues, agonists and antagonists, for the control of the functions of the human or animal reproductive system and its pathologies, the compositions comprising cyclodextrins, its derivatives, and biodegradable polymers and/or mixtures of those systems and/or the derived products.

2. Pharmaceutical compositions of Angiotensin^ 1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists, for the study and therapeutics of the reproductive system, the compositions comprising cyclodextrins, its derivatives, and biodegradable polymers and/or mixtures thereof and/or the derived products and wherein the compositions are used in the receptor-ligand interaction between the MAS receptor and Ang-(1-7) and its analogues, its pharmaceutical compositions in the encapsulated or non-encapsulated form.

3. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists, for controlling the functions of the human or animal reproductive system and its pathologies the compositions comprising cyclodextrins, its derivatives, and biodegradable polymers and/or mixtures thereof and/or the derived products, characterized in that the an inclusion compound of Angiotensin^ 1 -7) [Ang-(1 -7) peptide and its analogues, agonists and antagonists in the cyclodextrins is used.

4. Pharmaceutical compositions of Angiotensin^ 1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists, for controlling the functions of the human or animal reproductive system and its pathologies, the compositions comprising cyclodextrins, its derivatives, and biodegradable polymers and/or mixtures thereof and/or the derived products, characterized in that an inclusion compound of Angiotensin-(1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists in cyclodextrins, micro- and nanoencapsulated in biodegradable polymers and liposomes is used

5. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-(1-7) peptide and its analogues, agonists and antagonists, useful in the receptor- ligand interaction between the MAS receptor and Ang-(1-7) and its analogues for controlling the functions of the human or animal reproductive system, the compositions comprising cyclodextrins, its derivatives, and the biodegradable polymers and/or mixtures thereof and/or of the derived products, characterized in that an inclusion compound of the Angiotensin-(1-7) [Ang-1- 7)] peptide and its analogues , agonists and antagonists in cyclodextrins, micro- and nanoencapsulated in biodegradable polymers and liposomes is used.

6. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists for controlling the functions of the human or animal reproductive system and its pathologies, characterized in that the compositions comprise inclusion compounds of the Angiotensin-(1-7) peptide and its analogues, agonists and antagonists in cyclodextrins.

7. Pharmaceutical compositions of Angiotensin-(1 -7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists for controlling the functions of the human or animal reproductive system and its pathologies, characterized in that the compositions comprise inclusion compounds of the Angiotensin-(1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists in cyclodextrins micro- and nanoencapsulated in biodegradable polymers and liposomes.

8. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-1-7) peptide and its analogues, agonists and antagonists for controlling the functions of the human or animal reproductive system and in its pathologies, characterized in that the compositions are used in the receptor-ligand interaction between the MAS receptor and Ang-(1-7) and its analogues, its pharmaceutical compositions in encapsulated or non-encapsulated form, as a target for study and therapeutics of the reproductive system.

9. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-1-7) peptide and its analogues, agonists and antagonists for controlling the functions of the human or animal reproductive system and in its pathologies, characterized in that the compositions comprise the inclusion compounds of Angiotensin-(1-7) [Ang-(1-7)] and its analogues, agonists and antagonists in cyclodextrins, micro- and nanoencapsualted in biodegradable polymers and liposomes, and are used in the receptor-ligand interaction between the MAS receptor and Ang-(1-7) and its analogues, as a target for study and therapeutics of the reproductive system.

10. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-(1-7)] peptide and its analogues , agonists and antagonists according to any one of claims 1 , 2, 3 and 4, characterized in that inclusion compounds of the Angiotensin-(1-7) peptide and/or its analoguesare used with cyclodextrins, in association or without association with a controlled-release system, such as liposomes and biodegradable polymers, for study or treatment of disorders of the reproductive system, infertility, anovulation and birth control in women and animals.

11. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists according to any one of claims 1 , 2, 3, and 4, characterized by further comprising at least one additional pharmacologically active compound and/or pharmaceutically acceptable carriers and/or excipients selected from water, saline solution, buffered solutions, Ringer's solution, dextrose solution, Hank's solution, biocompatible saline solutions, containing or not containing polyethylene glycol, non-aqueous carriers such as fixed oils, sesame oil, ethyl-oleate or triglyceride, sodium carboxymethylcellulose, sorbitol, or dextran, timerosal, m- or o-cresol, formalin and benzyl alcohol, human serum albumin, for the study or treatment of the reproductive system disorders, infertility, anovulation and birth control in women and animals.

12. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-(1-7)] and its analogues, agonists and antagonists, characterized by comprising inclusion compounds of the Angiotensin-(1-7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists in cyclodextrins and in that they are produced for oral, intramuscular, intravenous, subcutaneous or topical administration, inhalation (pulmonary, intranasal, intrabucal) routes, or as devices that may be implanted or injected, for study or treatment of disorders of the reproductive system (anovulation, infertility, etc.), gynecological diseases and birth control in women and animals.

13. Pharmaceutical compositions of Angiotensin-(1-7) [Ang-(1-7) and its analogues, agonists and antagonists, characterized in that they are produced for oral, intramuscular, intravenous, subcutaneous or topical administration, inhalation (pulmonary, intranasal, intrabucal) routes, or as devices that may be implanted or injected, for study or treatment of the reproductive system disorders (anovulation, infertility, etc.), gynecological diseases and birth control in women and animals, wherein the compositions are used in the receptor-ligand interaction between the MAS receptor and Ang-(1-7) and its analogues, its pharmaceutical compositions in encapsulated or non-encapsulated form.

14. Pharmaceutical compositions of Angiotensin^ 1-7) [Ang-(1-7)] and its analogues, agonists and antagonists, characterized by comprising inclusion compounds of the Angiotensin^ 1-7) [Ang-(107)] peptide and its analogues, agonists and antagonists in cyclo dextrins, micro and nanoencapsulated in biodegradable polymers, liposomes, and in that they are produced for oral, intramuscular, intravenous, subcutaneous or topical adminstration, inhalation (pulmonary, intranasal, intrabucal) routes, or as devices that may be implanted or injected, for study or treatment of disorders of the reproductive system (anovulation, infertility, etc.), gynecological diseases and birth control in women and animals, wherein the compositions are used in the receptor-ligand interaction between the MAS receptor and Ang-(1-7) and its analogues.

15. Use of pharmaceutical compositions comprising Angiotensin-^ -7) [Ang-(1-7)] peptide and its analogues, agonists and antagonists, associated with cyclodextrins, its derivatives, and biodegradable polymers and/or mixtures of those systems and/or the derived products characterized in that said use is for the control of the functions of the human or animal reproductive system and its pathologies.

16. Use of pharmaceutical compositions of Angiotensin-(1-7)

[Ang-(1-7)] peptide and its analogues, agonists and antagonists, associated with cyclodextrins, its derivatives, and biodegradable polymers and/or mixtures thereof and/or the derived products, characterized in that said use is in the receptor-ligand interaction between the MAS receptor and Ang-(1-7) and its analogues, its pharmaceutical compositions in the encapsulated or non-encapsulated form for the study and therapeutics of the reproductive system.