HRP20010421A2 - Controlled release formulation comprising gnrh-ii - Google Patents

Description

The field of technology

This invention relates to a pharmaceutical composition that releases a therapeutic agent over a prolonged period.

State of the art

Studies of the physiology of the hypothalamic-pituitary-gonadal axis led to the discovery of gonadotropin-releasing hormone (GnRH, also known as luteinizing hormone-releasing hormone, LHRH) as a key regulatory hormone. GnRH is secreted from the hypothalamus and acts on the pituitary gland to stimulate the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Recently, a peptide homologous to GnRH has been discovered (White et al., Proc. Natl. Acad. Sci. USA 95 305-309, 1998). This peptide was named GnRH-II. A comparison of the sequences of the two peptides is shown below.

GnRH pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (SEQ ID NO: 5)

GnRH-II pyroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (SEQ ID NO: 5)

The name "GnRH-II" is somewhat confusing. The new peptide is the product of a separate gene and clearly differs from GnRH in its tissue distribution. It is unlikely that GnRH-II acts as an endogenous stimulator of LH and FSH release. As clear evidence for the physiological role of GnRH-II has not yet been found, no attention has been paid to the practical aspects of the application of this peptide as a therapeutic agent.

Presentation of the essence of the invention

We discovered that GnRH-II plays an important role in the functioning of numerous organs. For example, it affects osteogenesis and modulates the proliferation of prostate epithelial cells. We have therefore contemplated the circumstances in which this agent and its analogues could be usefully applied in clinical circumstances, and it is therefore the object of the present invention to provide suitable compositions for achieving this purpose. The preparations according to this invention rely on the use of a biodegradable polymer that would hold the peptide in a depot, from which it would be released into the systemic bloodstream at a controlled rate. These preparations contain two key elements, a biologically active peptide and a biodegradable polymer. The biologically active peptide is a decapeptide whose sequence is

pyroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2 (SEQ I.D. No. 7)

wherein Xaa1 is His or Tyr,

Xaa2 is Trp or Leu, a

Xaa3 is Tyr or Arg,

provided that when Xaa1 is Tyr and Xaa2 is Leu, Xaa3 is not Arg. The polymer is any pharmaceutically acceptable biodegradable polymer, preferably a copolymer of glycolic and lactic acid. The invention further encompasses the use of preparations for the treatment of pathological conditions in humans.

Image description

Figure 1 shows the effect of increasing doses of GnRH-II on serum calcium concentrations in ovariectomized rats.

Description of the invention

As used herein, abbreviations referring to amino acids have their usual meanings and represent the natural L-isomer (except for the achiral amino acid glycine).

In a first aspect, the invention comprises a pharmaceutical composition that releases a therapeutic peptide at a controlled rate and over an extended period of time (eg for at least one day, preferably several days, more preferably at least one week), particularly for the treatment of bone and prostate diseases. The therapeutic peptide is a decapeptide whose sequence is

pyroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2 (7)

wherein Xaa1 is His or Tyr, Xaa2 is Trp or Leu, and Xaa3 is Tyr or Arg, provided that when Xaa1 is Tyr and Xaa2 is Leu, Xaa3 is not Arg. Preferably, Xaa1 is His, Xaa2 is Trp, and Xaa3 is Tyr. It should be seen how such a peptide can form salts with acids (for example, acetates, trifluoroacetates, benzoates, chlorides, phosphates and others). To the extent that such salts are formed with pharmaceutically acceptable acids, they are included within the scope of the invention.

The second basic ingredient of the preparation is a biodegradable, pharmaceutically acceptable polymer. Such polymers are known in the art. They can be either homopolymers (ie polymers of one monomer) or copolymers (ie composed of two or more different monomers). Suitable monomers include amino and hydroxy derivatives of carboxylic acids. In a preferred embodiment of the present invention, the polymer is composed of hydroxyacyl monomer units, more preferably of α-hydroxyacyl units. Most preferably, the polymer is poly(glycolic acid), poly(lactic acid) or a copolymer of glycolic and lactic acid. The following is a description of the chemical structure of such a polymer.

[image]

wherein R is hydrogen in poly(glycolic acid), methyl in poly(lactic acid), and optionally hydrogen or methyl in the copolymer.

Two complementary procedures can be distinguished for the preparation of the preparation of this invention. The peptide can either be embedded in a polymer matrix, or, more preferably, it can be coated (encapsulated) with a polymer. Alternatively, the coated peptide may be in solid form or as a solution. It is recommended that the peptide be in solid form.

This preparation is useful in the treatment of disease states in humans, including disorders of bone growth (including involutional osteoporosis, as well as osteoporosis associated with postmenopausal hormone status, primary and secondary hyperparathyroidism, resting osteoporosis, diabetes-related osteoporosis, and glucocorticoid-related osteoporosis) and growth prostate (including benign prostatic hyperplasia and prostate cancer).

In another aspect, the invention comprises a method for treating a subject suffering from, or believed to be at risk of, a bone or prostate growth disorder. This treatment procedure includes the application to the aforementioned person of a therapeutically effective amount of a preparation that contains, as its active part, a peptide whose sequence is

pyroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2 (7)

or a pharmaceutically acceptable salt thereof, wherein Xaa1, Xaa2 and Xaa3 are as previously defined, and, as its second ingredient, a pharmaceutically acceptable biodegradable polymer, wherein said preparation, upon decomposition of the polymer, releases the peptide into the systemic bloodstream. The treatment procedure may comprise a single administration of the composition, but is more likely to comprise a course of repeated administrations. The frequency of applications can be from once a day to once a month. The amount of active peptide in each dose will depend on the dosing schedule and route of administration. Generally, it will range from one milligram (1 mg) to one gram (1 g). The ordinary doctor will determine the exact dose depending on the parameters that are otherwise considered important in the profession. The preparation is administered by intramuscular or subcutaneous injection.

The peptides that are the active agents of the compositions of the present invention can be prepared by methods generally known in the art. For example, peptides can be prepared by solid phase synthesis. This involves the sequential addition of amino acid residues to the resin-bound interface, according to the following strategy.

1. Creation of the first resin bonded interface

PG-Aaa-OH + FG-Res →PG-Aaa-L-Res

Aaa = amino acid

PG = protecting group

FG = functional group

Res = polymer resin

L = linking group (-O- or -NH-)

2. Deprotection

PG-Aaa-L-Res → H-Aaa-L-Res

3. Chain stretching

PG-Bbb-OH + H-Aaa-L-Res → PG-Bbb-Aaa-L-Res

4. Repeat steps 2 and 3 as needed

PG-Bbb-Aaa-L-Res --- PG-Nnn- _ -Bbb-Aaa-L-Res

5. Cleavage/deprotection

PG-Nnn- _ -Bbb-Aaa-L-Res - H-Nnn- _ -Bbb-Aaa-OH (or -NH2)

In the first step, the protected amino acid reacts with the functionalized resin. The protecting group (PG) is usually tert-butyloxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc). The functional group on the resin (FG) is usually a chloroalkyl group, a hydroxyl group, or an amine group. When FG is a chloroalkyl or hydroxyl group, the linking group (L) is an oxygen atom (-O-). When FGg is an amine group, L is -NH-.

In the second step, the protecting group (PG) is removed from the α-amino group. When the PG is Boc, this can be achieved by treating the resin with acids such as trifluoroacetic acid or hydrogen chloride in dichloromethane. When PG is Fmoc, deprotection can be achieved by treating the resin with bases such as piperidine.

In the third step, the peptide chain is extended by one amino acid residue. The protected amino acid binds to the amine group released in the second step. Many reagents are known in the art to achieve this translation. One combination is dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBt). In general, a base is also required. Suitable bases include triethylamine and N,N-diisopropylethylamine. In general, the solvent will be dichloromethane, dimethylformamide or a mixture thereof.

If the amino acid side chains (Aaa-Nnn) contain reactive groups (for example, amino groups, carboxylic acid groups, hydroxyl groups), they will need to be protected. The protecting groups chosen for the side chains are generally those that are stable under the conditions necessary to remove the protecting group (PG) from the α-amino group. If the PG is Fmoc, then it is convenient for the side chain protecting groups to be based on tert-butyl. On the other hand, if PG is Boc, side chain protecting groups can be based on fluorenylmethyl. Other protective groups known in the art may be used.

In the fourth step, the chain deprotection/elongation cycle is repeated until the desired peptide sequence is generated.

In the fifth step, the completed peptide is released from the resin. Protecting groups are removed from side chains before or after cleavage. When L is -NH-, the released peptide is in the form of the C-terminal amide. When L is -O-, the released peptide is often the C-terminal free acid, so a second step is required to form the C-terminal amide.

Peptides can also be prepared by solution-phase synthesis, which can be more convenient when large quantities of substances are required.

The polymers required for the composition are generally well known in the art. As previously stated, the preparation may take the form of a simple dispersion of the peptide in a polymer matrix, or the peptide may be microencapsulated by the polymer. Dispersions can be prepared by mixing peptides (in solid form) and polymers until homogenized, and then pressing the mixture until a solid mass is formed. It may be necessary to add a binding agent to the mixture in order to obtain a composition of suitable cohesiveness. The mass can then be ground to form particles suitable for suspension in a biologically compatible fluid (such as water or saline) and injection.

Microencapsulated preparations can be prepared either from a solid peptide (in powder form) or from a solution, especially an aqueous solution, of the peptide. The polymer is first dissolved in a suitable organic solvent. The peptide is then added to this solution and the mixture is vigorously stirred to disperse the peptide in the organic phase. A second organic solvent is then added. This second solvent is chosen to reduce the solubility of the polymer in the organic phase. The polymer comes out of solution to form a coating around solid peptide particles (or around droplets of a dispersed aqueous solution). The resulting microcapsules are then hardened by washing, in order to remove traces of organic solvents. They are then ready to be suspended in a suitable liquid for use.

The above general description below is supported by numerous examples. Their purpose is to present certain aspects of the invention. They are not intended to limit the invention in any way.

EXAMPLES

Example 1 - Synthesis of GnRH-II

1A. Preparation of the protected peptide bound to the resin

pyroGlu-His(Bom)-Trp(CHO)-Ser(Bzl)-His(Bom)-Gly-Trp(CHO)-Tyr(Bzl)-Pro-Gly-Ores

This peptide was prepared using standard solid phase procedures, starting from Boc-Gly-esterified Merrifield resin (60 g, 1 mmol/g). The synthesis is carried out in a hand-held synthesizer, with a total volume of solvent and reagent of 300 mL for each procedure. The standard deprotection/washing/binding protocol is summarized in Table 1.

Table 1

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Benzotriazolyl esters are used as activated esters during the synthesis. They are prepared from the corresponding protected amino acids by reaction with 1-hydroxybenzotriazole (1 eq.) and dicyclohexylcarbodiimide (1 eq.). The quantities used (in relation to the substitution capacity of the resin) are listed in Table 2.

Table 2

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After the final coupling, the resin is washed with dichloromethane (3 x 3 L) and dried under reduced pressure at +40°C until a constant weight is reached.

Amino acid analysis: Consistent with the assumed sequence

18. Splitting and deprotection

pyroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (6)

The peptidosin prepared in Example 1A is placed in a cloth bag in a pressure vessel. The container is then filled with gaseous ammonia to a final pressure of 4 atm. After 72 h, the excess ammonia was drained and the resin was extracted with acetic acid (3 x 100 mL) and ethanol (3 x 100 mL). The mixed extracts are degassed with nitrogen, 10% palladium on carbon is added and the mixture is stirred in a hydrogen atmosphere. When the reaction is complete (assessed by HPLC), the mixture is filtered and the filtrate is evaporated. The residue was purified by reverse phase HPLC to afford the title compound.

Example 2 - peptide microencapsulation

Copoly (D,L-lactic acid, glycolic acid) is used with a ratio of lactic acid/glycolic acid of 50/50. GnRH-II acetate (0.15 g, prepared by dissolving the peptide from example 1 in acetic acid and lyophilizing the resulting solution) was added to a solution of this polymer (3.7 g) in dichloromethane (100 mL) in a reaction vessel equipped with a stirrer. The mixture is stirred at 500 revolutions per minute, and then silicone oil (Dow Corning 360 Medical Fluid®, 45 g) is added over 10 minutes. The mixture is then introduced in the form of a thin jet into the caprylic-caprylic acid-triglyceride (Miglyol® 812, 3.3 L) with constant stirring at 1000 revolutions per minute. After the addition is complete, stirring is continued for 1 hour, then the microcapsules are collected by filtration, washed twice with isopropanol and finally dried.

Example 3 - Analysis of the effects of GnRH-II and analogues on osteogenic cell populations in vitro

(a) Human osteoblasts are isolated from cancerous bone obtained from orthopedic surgery (Nilsson et al., 1995) using standard procedures known in the art. Bone explants are ground into small pieces of bone and then washed extensively in Dulbecco's modified Eagle's medium (DMEM)/F12 (1:1 Gibco, Paisley, UK). These osteoblast-like cells, murine MC3T3-E1 osteoblasts, and human clonal osteosarcoma cell lines MG-63 (non-mineralizing) and SaOS-2 (mineralizing osteosarcoma) are cultured in DMEM:F12, 1:1, supplemented with 10% fetal calf serum ( FCS, Gibco), fungizone (500 mg/L), gentamicin sulfate (50 mg/L), L-glutamine (2 mM) and L-ascorbic acid (100 mg/L) in a humidified CO2 chamber at 37°C.

(b) Human bone marrow stromal cells are isolated from bone fragments washed in phosphate-buffered saline. Bone marrow cells are harvested and passed through a Ficoll Hypaque column (Kimble et al., J Clin Invest 93 1959-1967, 1994). Cells and interface are pelleted, counted and seeded into 75 cm2 flasks. Cells are incubated in a humidified CO2 chamber at 37°C and the medium is changed weekly. Once confluent, cells are harvested using trypsin EDTA and reseeded in α-minimal essential medium (α-MEM) supplemented with 10% fetal calf serum (FCS, Gibco), penicillin (100 U/mL), streptomycin (100 mg /mL), fungizone and L-glutamine (2 mM).

(c) All cells are left on serum for 48 h before addition of GnRH-I and GnRH-II. Cells are placed in DMEM without phenol red (to avoid the estrogenic effects of phenol red) containing 10% charcoal-stripped serum, for 48 h, in 12-well plates. Dose-dependent effects of GnRH-I and GnRH-II and peptide analogs were observed after addition of peptides in final concentrations ranging from 10-9 to 10-5 M. 1 mM dibutyryl cAMP was used as a control. The cells were incubated for 24, 48 and 96 h, with the peptide being changed every 24 hours.

(d) To assess the effects of peptides on cell proliferation, [3H]thymidine, 1 mCi/mL, was added for an additional 24 hours and [3H]thymidine incorporation was determined. Radioisotope incorporation was determined using a scintillation counter, and results were calculated as cpm/mg of total protein.

(e) Expression of osteoblast differentiation markers was also determined (Tintut Y et al., J Biol Chem 273 7547-53, 1998). Total RNA was isolated at several stages before treatment, 24, 48, 72 and 96 hours after peptide addition. The expression of procollagen type I, osteopontin and 28S RNA (used as an internal control) was determined by Northern blot analysis. Alkaline phosphatase, matrix GLA protein, osteoclastin and GAPDH (as an internal control) were determined by RT-PCR, with specific primers prepared for each gene.

The peptides of the invention showed significant effects at concentrations below 100 μM.

Example 4 - Analysis of the effects of GnRH-II and analogs on osteoclast populations in vitro

(a) Human clonal osteoclast precursor cell lines (FLG 29.1) were used as an in vitro model of osteoclast differentiation (Gattei V et al., Cell Growth Differ 7 753-63, 1996). In addition, the migration, adhesion, cytochemical, morphological and biochemical changes of the co-culture of FLG 29.1 and osteoblastic cells (Saos-2) were investigated. Dose-dependent effects of GnRH-I and GnRH-II and peptide analogs are observed after addition in final concentrations ranging from 10-9 to 10-5 M on FLG 29.1 cultures and on co-cultures. Parathyroid hormone is added as a control. Potentiation (or inhibition) of preosteoclast differentiation (fusion into large multinuclear elements) and numerous other factors were measured (Orlandini et al., Cell Tissue Res 281 33-42, 1995). This includes:

1. Positive staining for tartrate-resistant acid phosphatase in FLG 29.1 cells

2. Reduction of alkaline phosphatase activity expressed by Saos-2 cells

3. Appearance of typical ultrastructural properties of mature osteoclasts in FLG 29.1 cells

4. Release of granulocyte-macrophage colony stimulating factor into the culture medium

5. To assess the effects of peptides on cell proliferation, [3H]thymidine, 1 mCi/mL, was added for an additional 24 hours, and [3H]thymidine incorporation was determined as described above.

(b) Bone marrow cells isolated from human bone fragments were cultured in the presence of 10 nM 1,25-(OH)2 vitamin D3 for seven days to produce multinucleated osteoclasts, using conventional techniques known in the art (Takahashi et al., Endocrinol 122 1473-1482, 1988). Culture medium (α-MEM) was removed and replaced with fresh phenol red-free medium supplemented with antibiotics and 10% charcoal-stripped heat-inactivated FCS containing GnRH-I, GnRH-II, or analogs, and cultures were maintained for a further 24 hours. Floating cells are harvested and osteoclasts are stained for expression of tartrate-resistant acid phosphatase (TRAP), a marker for osteoclast differentiation (Hughes et al., Nat Med 2 1132-1135, 1996).

1. Cells are incubated in 0.2 M acetate buffer, pH 4.7-5.0 containing tartaric acid and 2% naphthol AS-BI phosphate (dissolved, 20 mg/mL in ethylene glycol monomethyl ether) for 15 minutes at 37°C. The cells are then transferred to another solution consisting of the same buffer and concentration of tartaric acid with 0.1% pararosanoyl chloride (hexazotized by mixing an equal volume of 4% sodium nitrite, 5 minutes, at room temperature) for 10 minutes. at 37°C. This treatment causes red staining of the cytoplasm in TRAP-expressing cells. Harris's hematoxylin was used as a counterstain for the nucleus.

2. Apoptotic multinucleated osteoclasts were identified by strong TRAP expression, more extensive than the corresponding live TRAP-positive cells. Confirmation of apoptosis was performed using acridine orange dye. Live osteoclasts were counted after fixation in 95% ethanol and TRAP hematoxylin staining; apoptotic osteoclasts are expressed as a percentage of the total number of multinucleated osteoclasts (viable and apoptotic) in each culture well.

The peptides of the invention achieved significant effects at concentrations below 100 μM.

Example 5 - Expression analysis of GnRH mRNA in osteogenic and osteoclast cell populations

Total RNA was extracted from cells cultured as described above:

1. cells similar to osteoblasts, isolated from cancerous bone

2. mouse osteoblastic MC3T3-E1 cells

3. MG-63 (non-mineralizing)

4. SaOS-2 (mineralizing osteosarcoma)

5. human bone marrow stromal cells

6. human FLG 29.1 osteoclast precursor cells

7. multinuclear osteoclasts obtained from the bone marrow

The expression of GnRH-I and GnRH-II was determined by RT-PCR using the PCR primers listed in SEQ. I.D. no. 1-4. The integrity of the obtained cDNA was determined by evaluating the relative level of actin amplification.

Example 6 - Effect of GnRH-II on bone mineral density in ovariectomized rats

(a) Adult (8 weeks, 200–215 g) Sprague Dawley rats were both ovariectomized (OVX). The animals were kept for 4 weeks after the procedure before starting the treatment. Purina rat food (1.00% calcium, 0.61% phosphorus) and water were provided in the desired amount. Each trial consisted of 6 groups grouped by weight (n=8/group).

(b) Treatment was started 4 weeks after OVX. After 4 weeks, the basal control OVX group was sacrificed (Group A). The remaining groups were injected once a day with the carrier (Group B), 1 μg/kg of body weight (Group C), 10 μg/kg of body weight (Group D), or 100 μg/kg of body weight (Group E) of GnRH-II, and 80 μg/kg body weight (Group F) hPTH (1-34).

(c) All rats were weighed every fourth day and doses were adjusted to a 50 g increase in group average weight. Rats were alternately given subcutaneous injections of calcein (30 mg/kg) or tetracycline (30 mg/kg) in 2% sodium bicarbonate/saline, according to mineralization surface markers on days 10, 19, and 26 after drug administration. Bone mineral density was assessed by dual energy x-ray absorptiometry (DEXA). On day 28, serum calcium levels were determined by a colorimetric assay using a commercial kit.

(d) The success of OVX was confirmed by autopsy, the inability to recognize ovarian tissue and the finding of significant atrophy of the uterine horns. Both legs were amputated at the hip joint. The left tibia and femur were cleaned of excess muscle and soft tissues and placed in 70% ethanol. The anterior eminence of the metaphysis of the right tibia was shaved with a razor, so that the bare bone marrow was shown. The right femur and tibia were then placed in 10% phosphate-buffered formalin for 24 h, and then transferred to 70% ethanol.

Strong hypercalcemia occurred in ovariectomized animals treated daily with 10 and 100 μg/kg GnRH-II and 80 μg/kg PTH for 28 days. The results are shown in Figure 1.

Example 7 - Cellular localization of GnRH-II in paraffin sections of normal rat and human bone

(a) Frozen and/or paraffin-embedded human and rat bone sections were fixed for 3–36 h, depending on size (3–5 h at room temperature, then approximately 24 h at 4°C) and then immersed in 0.1 M Tris + 5% EDTA (12.11 g + 50 g EDTA) pH 7.3 until decalcification.

(b) Sections were then prepared for antibody staining (rabbit polyclonal anti-GnRH-II antibody) by conventional techniques.

GnRH-II staining was observed in platelets, growth plate megakaryocytes (especially proliferating chondrocytes). Some staining was also seen in bone-forming cells, particularly in active osteoblasts, as well as in new osteoid.

Example 1 shows the preparation of the peptides of the invention, which can then be formulated as shown in Example 2. Examples 3 to 7 show the biological activity of the observed peptides. These Examples are not intended to limit the scope of the invention in any form. In particular, it should be seen how different controlled-release preparations of these peptides can be prepared by changing the polymer and/or the physical nature of the peptide-polymer combination. However, these variations provide preparations with equivalent biological properties and are therefore within the scope of the invention as defined by the following Claims.

SEQ I.D. no. 1 to 4 mentioned in Example 5 are as follows:

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Claims (13)

1. Pharmaceutical preparation for the controlled release of a therapeutic peptide or its salt, characterized in that the peptide has the sequence pyroGlu-His-Trp-Ser-Xaa1-Gly-Xaa2-Xaa3-Pro-Gly-NH2 wherein Xaa1 is His or Tyr, Xaa2 is Trp or Leu, a Xaa3 is Tyr or Arg, provided that when Xaa1 is Tyr and Xaa2 is Leu, Xaa3 is not Arg, wherein the composition further comprises a pharmaceutically acceptable biodegradable polymer. 2. Pharmaceutical composition according to Claim 1, characterized in that it is a peptide pyroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2. 3. Preparation according to Claim 1, characterized in that the polymer is a polymer of hydroxyderivatives of carboxylic acid or a copolymer of such derivatives. 4. The preparation according to Claim 3, characterized in that the polymer is a polymer of glycolic acid, a polymer of lactic acid, or a copolymer of lactic and glycolic acid. 5. Preparation according to Claim 1, characterized in that the peptide is microencapsulated with a polymer. 6. A method for treating a medical condition in humans, characterized in that it comprises administering to a person in need of such treatment a therapeutically effective amount of a controlled release peptide composition according to any of the preceding Claims. 7. A preparation according to any one of Claims 1 to 5, characterized in that it is for the treatment or protection against bone growth disorders or prostate growth disorders. 8. The use of peptides or salts defined in Claim 1 or 2, together with a pharmaceutically acceptable biodegradable polymer, for the purpose of preparing a drug with controlled release for the treatment or protection against bone growth disorders or prostate growth disorders. 9. Use according to Claim 8, characterized in that said polymer is [a] polymer of hydroxyderivatives of carboxylic acid or copolymer of such derivatives, or [b] glycolic acid polymer, lactic acid polymer, or lactic and glycolic acid copolymer. 10. Use according to claim 8 or 9, characterized in that said disorder is selected from involutional osteoporosis, osteoporosis associated with postmenopausal hormonal status, primary and secondary hyperparathyroidism, osteoporosis due to rest, osteoporosis associated with diabetes, osteoporosis associated with glucocorticoids, benign prostatic hyperplasia and prostate cancer. 11. Preparation according to claim 7, characterized in that it has the purpose of treatment or protection against a disorder selected from involutional osteoporosis, osteoporosis associated with postmenopausal hormonal status, primary and secondary hyperparathyroidism, osteoporosis due to rest, osteoporosis associated with diabetes, osteoporosis associated with glucocorticoids, benign prostate hyperplasia and prostate cancer. 12. A method for the treatment or protection against bone growth disorders or prostate growth disorders in humans, indicated by the fact that it comprises the application to a person, who needs such treatment or protection, of a therapeutically effective amount of the preparation according to any of Claims 1 to 5. 13. The method according to claim 12, characterized in that said disorder is selected from involutional osteoporosis, osteoporosis associated with postmenopausal hormonal status, primary and secondary hyperparathyroidism, osteoporosis due to rest, osteoporosis associated with diabetes, osteoporosis associated with glucocorticoids, benign prostatic hyperplasia and cancer prostate.