WO2004030687A1 - Long-acting gonadotropin-releasing hormone analogs and methods of use thereof - Google Patents
Long-acting gonadotropin-releasing hormone analogs and methods of use thereof Download PDFInfo
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- WO2004030687A1 WO2004030687A1 PCT/IL2002/000801 IL0200801W WO2004030687A1 WO 2004030687 A1 WO2004030687 A1 WO 2004030687A1 IL 0200801 W IL0200801 W IL 0200801W WO 2004030687 A1 WO2004030687 A1 WO 2004030687A1
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- gnrh
- emo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to the design, synthesis and biological evaluation of potent long-acting gonadotropin-releasing hormone (GnRH) analogs, and to their therapeutic use in fertility regulation or as contraceptives, and in treating and/or preventing sex hormone-related diseases or conditions.
- GnRH gonadotropin-releasing hormone
- Gonadotropin-releasing hormone (GnRH; pGlu-His-Trp-Ser-Tyr-GTy-Leu- Arg-Pro-Gly-NH 2 ) is a key integrator between the neural and the endocrine systems and plays a pivotal role in the regulation of the reproductive system.
- This neurohormone is synthesized in hypothalamic neurosecretory cells and is released in a pulsatile pattern into the hypothalamo-hypophyseal portal circulation.
- GnRH secretion provokes the release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary, which, in turn, stimulate gonadal steroidogenesis and gametogenesis 1 - 2 .
- Chronic administration of GnRH or its super active agonists results in down-regulation of GnRH receptors and desensitization of the pituitary gonadotrophs and thus causes the suppression of gonadotropin secretion 3 ' 4 .
- GnRH analogs agonists as well as antagonists, have attracted remarkable interest because of their potential applications for the treatment of reproductive diseases, such as prostate and breast cancer, and their possible use as contraceptives 5 > 6 .
- the mechanism of action of GnRH analogs in these diseases is believed to be at least partly related to gonadal steroids deprivation, which results from down-regulation and desensitization of the pituitary gonadotrophs.
- GnRH analogs have been demonstrated to exert direct inhibitory effects on the growth of cancer cells through GnRH receptors that are present in prostate, breast and ovarian cancer 5 * 7 .
- GnRH The relatively short half-life time of GnRH in the general circulation (2-4 min) 5 is advantageous for the establishment of a pulsatile secretion pattern.
- potent agonists or antagonists having a prolonged bioactivity are certainly needed in the clinic for the induction of desensitization or contraception. Since the discovery of GnRH, more than 3000 analogs of the peptide have been synthesized and evaluated for their bioactivity. Most of the super agonists usually incorporate a D-amino acid, substituting for Gly in position 6, and an N-ethylamide instead of the terminal Gly-NH 2 in position 10.
- the present invention relates to the design, synthesis and biological evaluation of potent long-acting gonadotropin-releasing hormone (GnRH) agonists or antagonists, comprising GnRH analogs conjugated to emodic acid or an emodic acid derivative.
- GnRH gonadotropin-releasing hormone
- These agonists and antagonists have prolonged duration of action and are thus useful in the control of fertility or as a contraceptive, and in treating and/or preventing sex-hormone related diseases or conditions.
- the present invention relates to the design, synthesis and biological evaluation of the potent long-acting GnRH agonist, [D-Lys 6 (Emo)]GnRH.
- [D-Lys 6 (Emo)]GnRH binds GnRH receptors with high affinity to induce LH release, is devoid of toxicity, and is thus useful in the control of fertility or as a contraceptive, and in treating and/or preventing sex- hormone related diseases or conditions.
- the present invention relates to the design, synthesis and biological evaluation of the potent long-acting GnRH antagonist, [D-Pyr 1 , D-Phe 2 , D-Trp 3 , D-Lys 6 (Emo)]GnRH (denoted herein as [D-Lys 6 (Emo)]GnRH-Antg).
- [D-Lys 6 (Emo)]GnRH-Antg binds GnRH receptors to prevent LH release, is devoid of toxicity, and is thus useful in the control of fertility or as a contraceptive, and in treating and/or preventing sex-hormone related diseases or conditions.
- Additional GnRH agonists according to the invention are represented by [SEQ ID NO:l] peptides of the general formula:
- X is selected from Ser(Emo), D-Ser(Emo), Lys(Emo), D- Lys(Emo), D-Dab(Emo), D-Orn(Emo), D-hSer(Emo); Y is selected from D-
- Lys(Emo), D-Dab(Emo), D-Orn(Emo), D-Ser(Emo), D-hSer(Emo); Z is selected from Gly, Ethylamine, D-Ala; Pyr denotes pyroglutamic acid, Dab denotes diaminobutyric acid; and pharmaceutically acceptable salts, amides, esters and hydrates thereof.
- X is selected from Ser(Emo), hSer(Emo); Y is selected from
- Lys(Emo), Dab(Emo), Z is selected from D-Lys(Emo), D-Dab (Emo), D- Orn(Emo), D-Ser(Emo) D-hSer(Emo); W is selected from Lys(Emo),
- Additional GnRH antagonists according to the invention are represented by [SEQ ID NO:3] peptides of the general formula:
- X is selected from Ser(Emo), hSer(Emo); Y is selected from D-
- D-Nal denotes D-3-(2'-naphtyl)-alanine
- D-Pal denotes 3-(3'- pyridyl)-alanine
- pharmaceutically acceptable salts, amides, esters and hydrates thereof
- the present invention provides a method of controlling fertility in a subject, comprising the step of administering to the subject a gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D-Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to control fertility in the subject.
- GnRH gonadotropin releasing hormone
- peptide having the formula [D-Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof.
- fertility is controlled to prevent conception in a female mammalian subject.
- the present invention provides a method of contraception in a subject, comprising the step of administering to the subject a gonadotropm releasing hormone (GnRH) agonist or antagonist peptide having the formula [D-Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof.
- GnRH gonadotropm releasing hormone
- the present invention provides a method of treating a sex hormone-related disease or condition in a subject, the method comprising the step of administering to the subject a gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D-Lys (Emo)JGnRH, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to treat the disease or condition in said subject.
- GnRH gonadotropin releasing hormone
- the present invention provides a method of preventing a sex hormone-related disease or condition in a subject, the method comprising the step of administering to the subject a gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D-Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to prevent the disease or condition in the subject.
- GnRH gonadotropin releasing hormone
- the present invention provides a method of promoting the release of LH or FSH in a subject, the method comprising the step of administering to the subject a gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D-Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to promote the release of LH or FSH in the subject.
- GnRH gonadotropin releasing hormone
- the present invention provides a method of suppressing or preventing the release of LH or FSH in a subject, the method comprising the step of administering to the subject a long-acting gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D- Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to prevent or suppress the release of LH or FSH in the subject.
- GnRH gonadotropin releasing hormone
- the subject is a mammal.
- the subject is a human.
- the subject is a non-human mammal.
- the subject is a non-mammalian vertebrate.
- the subject is a male subject.
- the subject is a female subject.
- the sex hormone-related disease or condition is a cancer, for example prostate cancer, breast cancer, ovarian cancer, cervical cancer, a tumor of the pituitary, testicular cancer or uterine cancer.
- the sex hormone-related disease or condition is a benign disease or condition, for example benign prostatic hyperplasia, precocious puberty, aberrant sexual behavior, late luteal phase dysphoric disorder (premenstrual syndrome), fibroids, endometriosis, myoma, hirsutism, cyclic auditory dysfunction, porphyria, or polycystic ovarian syndrome.
- the methods of the present invention comprise administering a pharmaceutical preparation comprising the GnRH agonist peptide, and a pharmaceutically acceptable carrier.
- the pharmaceutical preparation is orally administered in solid or liquid dosage form.
- the pharmaceutical preparation is intravenously, intraarterially, subcutaneously, intradermally, intraperitoneally, intramuscularly, intranasally or intralesionally injected in liquid form.
- the pharmaceutical preparation is administered as an intravaginal device or ring.
- the pharmaceutical preparation is formulated as a topical formulation for topical application.
- the pharmaceutical preparation is formulated as a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, a gel, a cream, a suppository, an intra-vaginal ring, or a parenteral formulation.
- the pharmaceutical preparation is formulated as a depot for providing sustained release of the active ingredient.
- Figure 3 Displacement (%) of specific binding of 125 I[D-Lys 6 ]GnRH from pituitary membranes of proestrous rats by increasing concentrations of unlabeled GnRH analogs: [D-Lys 6 (AntrQ)]GnRH (o); [D-Lys 6 (NQ)]GnRH (A); [D- Lys 6 (Emo)]GnRH ( ⁇ ); and [D-Lys 6 ]GnRH (D).
- FIG. 7 Effects of long-term administration of GnRH analogs on the weight of testes and prostate glands.
- Adult male rats were injected daily for 7 days either with [D-Lys 6 (Emo)]GnRH (0.1 or 1 nmol/rat, gray), [D-Lys 6 ]GnRH (1 nmol/rat, white), or PBS (control, black). Rats were sacrificed 24 h after the last injection, and testes (a) and prostate glands (b) were dissected and weighed.
- FIG. 9 Phototoxicity of [D-Lys 6 (Emo)]GnRH and emodic acid to ⁇ T3-l cells.
- Cells were incubated ; with [D-Lys 6 (Emo)]GnRH (black) or emodic acid (white), washed and illuminated.
- Cell survival was determined by the XTT method. Values are expressed as % survival. 100% survival (gray) refers to the survival of cells in the control group that were incubated without any emodic acid derivatives.
- FIG. 10 DNA cleavage in cells treated with [D-Lys 6 (Emo)]GnRH and emodic acid.
- ⁇ T3-l cells were incubated ; in darkness with 10 ⁇ M of the tested compounds, washed and illuminated. After 24 h of incubation DNA was isolated and analyzed by gel electrophoresis.
- Lanes 1, 3 and 5 represent DNA of cells treated with 1% DMSO in PBS, emodic acid or [D-Lys 6 (Emo)]GnRH, respectively, followed by illumination.
- Lane 2, 4 and 6 represent cells treated with 1% DMSO in PBS, emodic acid, or [D-Lys 6 (Emo)]GnRH, respectively, in darkness.
- GnRH GnRH.
- Cells were incubated with GnRH (1 nM) in the absence or presence of increasing concentrations of [D-Lys 6 ]Antg or [D-Lys 6 (Emo)]Antg. Following the incubation period (4 h at 37°C) media were collected and LH concentration was determined by RIA. Results are the mean ⁇ SEM of two independent experiments (4 wells / experimental group, each).
- the present invention relates to the design, synthesis and biological evaluation of potent long-acting gonadotropin-releasing hormone (GnRH) agonists and antagonists, which comprise a GnRH analog conjugated to emodic acid or an emodic acid derivative.
- GnRH gonadotropin-releasing hormone
- GnRH analog is conjugated to a molecule having the general formula:
- n is an integer of 0-5 and R is independently at each occurrence selected from hydrogen, hydroxy, alkoxy, halogen, a straight chain, branched or cyclic alkyl group, lower alkenyl group, lower alkynyl group, carboxyl, carboxyalkyl, amino, aminoalkyl, diaminoalkyl, thio, thioalkyl, amido, alkylamido, dialkylamido or any other suitable substituent that yields a long acting non-toxic derivative of said GnRH analog.
- alkyl group refers to a saturated aliphatic hydrocarbon, including straight- chain, branched-chain and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons.
- the alkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
- a “hydroxy” group refers to an OH group.
- An “alkoxy” group refers to an -O- alkyl group wherein alkyl is as defined above.
- a “thio” group refers to an -SH group.
- a “thioalkyl” group refers to an -SR group wherein R is alkyl as defined above.
- An “amino” group refers to an -NH 2 group.
- An “alkylamino” group refers to an -NHR group wherein R is alkyl is as defined above.
- a “dialkylamino” group refers to an -NRR' group wherem R and R' are alkyl as defined above.
- An “amido” group refers to an -CONH 2 group.
- alkylamido refers to an -CONHR group wherein R is alkyl is as defined above.
- dialkylamido refers to an - CONRR' group wherein R and R' are alkyl as defined above.
- a "nitro” group refers to an N02 group.
- a “carboxyl” group refers to a COOH group.
- a “carboxyalkyl” refers to a COOR group wherein R is an alkyl as defined above.
- the present invention relates to the design, synthesis and biological evaluation of a potent long-acting gonadotropin-releasing hormone (GnRH) agonist, ([D-Lys 6 (Emo)]GnRH), which binds GnRH receptors with high affinity to induce LH release, and which is devoid of any toxicity or antiproliferative effects.
- GnRH gonadotropin-releasing hormone
- the present invention further relates to therapeutic uses of ([D- Lys (Emo)]GnRH) as a contraceptive, and in treating and/or preventing sex-hormone dependent diseases or conditions.
- the present invention further relates to the design, synthesis and biological evaluation of a potent long-acting gonadotropin-releasing hormone (GnRH) antagonist, ([D-Lys 6 (Emo)]GnRH-Antg), which binds GnRH receptors with high affinity to prevent LH release, and which useful as a contraceptive, and in treating and/or preventing sex-hormone dependent diseases or conditions.
- GnRH potent long-acting gonadotropin-releasing hormone
- a receptor agonist is a substance which binds receptors and activates them.
- a receptor antagonist is a substance which binds receptors and inactivates them.
- Assays to determine whether the compounds of the present invention are agonists or antagonists are well known to a person skilled in the art.
- conjugation of bulky moieties to the ⁇ -amino group of [D-Lys 6 ]GnRH do not significantly affect the bioactivity of GnRH analogs.
- incorporation of an anthraquinone moiety such as 2-hydroxymethyl anthraquinone hemiglutarate to [D-Lys 6 ]GnRH generates an agonist ([D- Lys (AntrQ)]GnRH) with superior bioactivity to that of the parent peptide 14 , but which is cytotoxic to cells, and inhibits the growth of human breast and prostate cancer 14 .
- Emodin (Fig 1) is a naturally occurring polyhydroxylated anthraquinone that is widely used for preparation of laxatives. Applicants have previously shown 24 that incorporation of emodic acid to [D-Lys 6 ] GnRH diminished its ability to generate reactive radical species (ROS) 25 .
- ROS reactive radical species
- the present invention provides a potent long-acting GnRH super- active agonist - ([D-Lys 6 (Emo)]GnRH), or a long-acting GnRH antagonist, - [D- Lys6(Emo)]GnRH-Antg which is useful in the prevention and/or treatment of a variety of sex-hormone related conditions (specifically conditions involving cells that carry GnRH receptors), and as a contraceptive.
- [D-Lys (Emo)]GnRH is useful as a contraceptive agent to control fertility in a subject, for example to prevent conception in a female subject.
- chronic administration of GnRH agonists results in down- regulation of GnRH receptors and desensitization of the pituitary gonadotrophs and thus causes the suppression of gonadotropin secretion 3 - 4 .
- [D-Lys6(Emo)]GnRH or [D-Lys6(Emo)]GnRH-Antg may be administered in an amount and dosage effective to suppress the release the gonadotropins LH and FSH, and thus may act as a contraceptive agent and prevent conception.
- [D-Lys6(Emo)]GnRH or [D-Lys6(Emo)]GnRH-Antg is a potent contraceptive in males.
- [D-Lys6(Emo)]GnRH or [D- Lys6(Emo)]GnRH-Antg is a potent contraceptive in females, i.e. is effective in preventing pregnancy in females.
- [D-Lys6(Emo)]GnRH or [D-Lys6(Emo)]GnRH-Antg is a potent contraceptive in humans.
- the present invention provides a method of controlling fertility in a mammalian subject, comprising the step of administering to the subject a gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D-Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]GnRH-Antg , or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to control fertility in the subject.
- GnRH gonadotropin releasing hormone
- peptide having the formula [D-Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]GnRH-Antg , or a pharmaceutically acceptable salt or hydrate thereof.
- fertility is controlled to prevent conception in a female subject.
- the present invention provides a method of contraception in a mammalian subject, comprising the step of administering to the subject a gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D-Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]GnRH-Antg or a pharmaceutically acceptable salt or hydrate thereof.
- GnRH gonadotropin releasing hormone
- analog means any variant and includes both agonists and antagonists
- the term “conception” means the onset of pregnancy, marked by the formation of a viable zygote and subsequent implantation of the blastocyst.
- the term “contraceptive” means an agent that diminishes the likelihood of or that prevents conception.
- administering refers to bringing a subject in contact with a pharmaceutical composition comprising a GnRH peptide of the present invention.
- administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in cells or tissues of living organisms, for example humans.
- the present invention provides a method of treating a sex hormone- dependent disease in a subject, the method comprising the step of administering to the subject [D-Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]GnRH-Antg, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to treat the disease or condition in the subject.
- the present invention provides a method of preventing a sex hormone-dependent disease in a mammalian subject, the method comprising the step of administering to the subject [D-Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to prevent the disease or condition in the subject.
- the term "sex-hormone related disease or condition” encompasses diseases or conditions involving the reproductive system, and/or which are dependent upon a sex hormone, i.e. a male hormone or female hormone. In one embodiment, these include diseases or conditions occurring due to an excess of such hormones in mammals or non-mammalian vertebrates (e.g. human, monkey, bovine, horse, dog, cat, sheep, rabbit, rat, mouse, fish etc.). In another embodiment, the diseases/conditions involve cells that carry GnRH receptors.
- [D-Lys 6 (Emo)]GnRH, or [D-Lys 6 (Emo)]GnRH-Antg is useful for the prevention or treatment of sex hormone-dependent malignant diseases, such as cancer.
- sex hormone-dependent malignant diseases such as cancer.
- Non-limiting examples include prostate cancer, breast cancer, ovarian cancer, cervical cancer, tumor of the pituitary, testicular cancer, and uterine cancer.
- [D-Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]GnRH-Antg is useful for the prevention or treatment of sex hormone-dependent non-malignant (benign) diseases or conditions.
- Non-limiting examples include benign prostatic hyperplasia, precocious puberty, aberrant sexual behavior (treatment by chemical castration), late luteal phase dysphoric disorder (premenstrual syndrome), fibroids, endometriosis, myoma, hirsutism, cyclic auditory dysfunction, porphyria, or polycystic ovarian syndrome.
- treating means remedial treatment, and encompasses the terms “reducing”, “suppressing” “ameliorating” and “inhibiting”, which have their commonly understood meaning of lessening or decreasing.
- preventing means inhibiting the disease or condition, so that the disease or condition does not develop or progress.
- the present invention provides a method of promoting the release of LH and FSH in a subject, the method comprising the step of administering to the subject a gonadotropm releasing hormone (GnRH) agonist peptide having the formula [D-Lys 6 (Emo)]GnRH, or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to promote the release of LH and FSH in the subject.
- GnRH gonadotropm releasing hormone
- the present invention provides a method of preventing suppressing the release of LH and FSH in a subject, the method comprising the step of administering to the subject a long-acting gonadotropin releasing hormone (GnRH) agonist or antagonist peptide having the formula [D- Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]GnRH-Antg. or a pharmaceutically acceptable salt or hydrate thereof, in an amount effective to prevent the release of LH and FSH in the subject.
- GnRH long-acting gonadotropin releasing hormone
- the present invention comprises administering a pharmaceutically acceptable salt of the [D-Lys 6 (Emo)]GnRH or [D- Lys 6 (Emo)]GnRH-Antg peptide.
- pharmaceutically acceptable salt includes acid addition salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
- the term also includes base addition salts which are formed from inorganic bases such as, for example, sodium, potassium, ammonium, and calcium, and from organic bases such as isopropylamine, trimethylamine, histidine, and the like.
- the present invention comprises administering a hydrate of the [D-Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]GnRH-Antg peptide.
- hydrate includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
- the methods of the present invention comprise administering a pharmaceutical preparation comprising the GnRH agonist or antagonist peptide, and a pharmaceutically acceptable carrier.
- pharmaceutical preparation or “pharmaceutical compositions”, used herein interchangeably, means a “therapeutically effective amount” of the [D- Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)]Gr ⁇ RHAntg.
- a "therapeutically effective amount” as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen.
- pharmaceutical preparation is orally administered in solid or liquid dosage form.
- the pharmaceutical preparation is intravenously, intraarterially, subcutaneously, intradermally, intraperitoneally, intramuscularly or intralesionally injected in liquid form.
- the pharmaceutical preparation is administered as an intravaginal ring.
- the pharmaceutical preparation is administered intranasally.
- the pharmaceutical preparation is formulated as a topical formulation for topical application.
- the pharmaceutical preparation is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, a gel, a cream, a suppository, an intra-vaginal ring, or a parenteral formulation.
- the pharmaceutical preparation is formulated as a depot for providing sustained release of the active ingredient.
- the pharmaceutical preparation is formulated for intranasal administration or inhalation.
- the pharmaceutical preparations are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation.
- Suitable solid oral formulations include tablets, capsules, pellets and the like.
- Suitable liquid oral formulations include solutions, suspensions, emulsions, and the like.
- the pharmaceutical preparations are administered by intravenous, intraarterial, intraperitoneal, subcutaneous, intradermal, intramuscular or injection of a liquid preparation.
- suitable liquid formulations include solutions, suspensions, emulsions, and the like.
- Alternative embodiments include depots providing sustained release or prolonged duration of activity of the active ingredient in the subject, as are well known in the art.
- the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, and the like. Further, in another embodiment, the pharmaceutical compositions are administered as a suppository, for example a rectal suppository or a vaginal or urethral suppository. Further, in another embodiment, the pharmaceutical compositions can be applied on conventional intravaginal rings or other intravaginal devices. Further, in another embodiment, the pharmaceutical compositions can be are administered intranasally or by inhalation.
- a "pharmaceutically acceptable carrier” may be a solid carrier for solid formulations, a liquid carrier for liquid formulations, or mixtures thereof.
- Solid carriers include, but are not limited to, a gum, a starch (e.g. corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
- pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, or emulsions.
- non-aqueous solvents examples include propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles for subcutaneous, intravenous, intraarterial, intraperitoneal or intramuscular injection
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
- Examples are sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
- water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
- compositions may further comprise binders (e.g. cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g.
- binders e.g. cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone
- disintegrating agents e.g.
- cornstarch potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and ionic strength, additives such as gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.
- sodium lauryl sulfate sodium lauryl sulfate
- permeation enhancers solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents(e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g.
- stearic acid magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
- plasticizers e.g. diethyl phthalate, triethyl citrate
- emulsifiers e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate
- polymer coatings e.g., poloxamers or poloxamines
- coating and film forming agents e.g. ethyl cellulose
- the pharmaceutical compositions provided herein are controlled release compositions, i.e. compositions in which the [D-Lys 6 (Emo)]GnRH or [D-Lys (Emo)] GnRH- Antg peptide is released over a period of time after administration.
- the composition is an immediate release composition, i.e. a composition in which all of the [D-Lys 6 (Emo)]GnRH or [D- Lys 6 (Emo)] GnRH- Antg. peptide is released immediately after administration.
- compositions which contain an active component are well understood in the art, for example by mixing, granulating, or tablet-forming processes.
- the active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient.
- the [D-Lys 6 (Emo)]GnRH or [D- Lys (Emo)] GnRH- Antg peptide is mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
- the [D-Lys 6 (Emo)]GnRH or [D-Lys 6 (Emo)] GnRH- Antg peptide is converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other.
- the synthesis of [D-Lys 6 ]GnRH conjugates that are modified at the ⁇ -amino group of [D-Lys 6 ] GnRH was carried out by two different routes.
- the first route involved the reaction of the free ⁇ -amino group of solid-phase synthesized [D- Lys 6 ]GnRH, in a homogeneous solution, with the carboxylic functional group of the respective quinone moieties.
- This method employed benzotriazole-1-yl-oxy-tris- pyrrolidino-phosphonium hexafluorophosphate (PyBOP) as a coupling reagent and 4- methylmorpholine (NMM) as a base.
- Such a method is a 'one-pot synthesis', which results in better yield and purity than other methodologies that use active esters, such as N-hydroxysuccinimide, as coupling reagents 19 .
- [D-Lys 6 ] GnRH derivatives were prepared by employing an automatic multiple peptide synthesizer, using Rink amide resin as the polymeric support, and standard Fmoc-protected amino acids and corresponding reagents (Fig. 2).
- the routinely used Fmoc-D-Lys(Boc)-OH was replaced by Fmoc-D-Lys(Mtt)-OH and the protected peptide was not cleaved from the resin.
- the Mtt group was removed selectively from the N ⁇ -amino group of D-Lys 6 by mild acidolysis (2% TFA in CH 2 C1 2 ) without effecting other protecting groups 20 .
- N -amino function of D-Lys 6 occurs by employing the standard coupling reagent and procedure. This reaction leads to the synthesis of [D-Lys (l,3,8-trihydroxy-6- carboxy-anthraquinone)]GnRH ([D-Lys 6 (Emo)]GnRH), [D-Lys 6 (2-hydroxymethyl- anthra-quinone hemiglutarate)] GnRH ([D-Lys 6 (AntrQ)]GnRH) and [D-Lys 6 (N-(2- chloro-1 ,4-naphthoquinonyl)- ⁇ -alanyl)]GnRH ([D-Lys 6 (NQ)]GnRH).
- GnRH analogs molecular mass and relative hydrophobicity and binding affinity (IC 50 ) to rat pituitary receptors.
- GnRH analogs binding affinity (IC 50 ) to rat pituitary receptors.
- [D-Lys 6 (NQ)]GnRH and [D-Lys 6 (AntrQ)]GnRH conjugates [D-Lys 6 (Emo)]GnRH, however, exhibited high LH-releasing potency despite its relatively low binding affinity.
- the gonadotropin-releasing activity of this conjugate could be completely inhibited by the antagonist, [D-Pyr 1 , D-Phe 2 , D-Trp 3 ' 6 ]GnRH, indicating that this activity is receptor mediated.
- Lys 6 ]GnRH although the dose was reduced to 10% of that of the parent peptide (0.04 vs. 0.4 nmol) (Fig. 6). Moreover, the duration of the stimulation was also longer; six h after [D-Lys 6 (Emo)]GnRH administration, LH levels were about 6 folds higher than in the group of rats treated with [D-Lys 6 ] GnRH. Administration of a higher dose of
- HSA human serum albumin
- emodin is known to bind to (HSA).
- HSA HSA
- emodic acid binds to HSA at the range of the concentrations that were examined. Consequently, the conjugation of emodic acid to [D- Lys 6 ]GnRH generates a superagonist, [D-(Emo)]GnRH, which binds significantly to HSA, and thus may explain its prolonged in vivo activity.
- Emodin is known to be a photoactive compound that generates reactive oxygen species upon illumination 21 ' 22 , therefore its cytotoxicity as well as that of [D- (Emo)]GnRH to a mouse gonadotroph cell line ( ⁇ T3-l) that expresses high affinity binding sites for GnRH23, was measured.
- emodic acid and its GnRH analog did not cause any DNA fragmentation in the dark (lanes 4 and 6), while upon illumination, only emodic acid (lane 3) but not [D-Lys 6 (Emo)]GnRH (lane 5) induced DNA fragmentation.
- AntrQ 2-(Hydroxymethyl) anthraquinone
- BSA bovine serum albumin
- DMF N,N'-dimethylformamide
- DMSO dimethylsulfoxide
- ED 50 concentration of the ligand which indicates 50% of maximal effect.
- Emo Emodic acid
- GnRH gonadotropin-releasing hormone
- HPLC high performance liquid chromatography
- IC 50 concentration of ligand which displaces 50% of bound tracer
- LH luteinizing hormone
- MB maximal binding
- NQ 2- ⁇ -alanyl-l,4- naphthoquinone
- PBS phosphate buffered saline
- pGlu or Pyr, pyroglutamic acid
- RIA radioimmunoassay
- SEM standard error of the mean.
- HPLC prepacked columns were: Lichrocart, containing Lichrosorb RP-18 (250 x 10 mm; 7 ⁇ m, Merck, Darmstadt, Germany) for semi-preparative purification and Lichrospher 100 RP-18 (250 x 4 mm; 5 ⁇ m, Merck, Darmstadt, Germany) and wide pore butyl C4 (250 x 4.6 mm; 5 ⁇ m, J. T. Baker Inc., Phillipsburg, NJ) for analytical purposes.
- HPLC purification and analysis were achieved by using a linear gradient established between 0.1% trifluoroacetic acid (TFA) in water as buffer A and 0.1 % TFA in 75% aqueous acetonitrile as buffer B.
- TFA trifluoroacetic acid
- Eluent composition was 10-100% B over 40 min, using RP-18 column, and a gradient of 0-100% B over 40 min employing a wide pore butyl (C4) column.
- N-(2-chloro-l,4-naphtoquinonyl)- ⁇ - alanine (NQ), l,6,8-Trihydroxy-3-carboxylic acid-anthraquinone (Emo) and 2- hydroxymethyl-anthraquinone hemiglutarate (AntrQ) were synthesized as described 14 ' 24 ' 27 (for chemical structure see Fig. 1).
- Wistar-derived rats were obtained from the Weizmann Institute Animal Resource Center. Experiments were carried out in compliance with the regulations of the Weizmann Institute of Science.
- DMEM Dulbecco's modified Eagle's medium
- FCS fetal calf serum
- the completed peptide chain was cleaved from the resin, along with side-chain deprotection, using 3 mL of the mixture TFA:H 2 0:triethylsilane; (95:2.5:2.5, v:v), for 2 h at room temperature.
- the crude products were precipitated with ice-cold tert-butyl methyl ether.
- Precipitated peptides were washed with cold dry tert-butyl methyl ether, dissolved in water or water/acetonitrile solution, and lyophiUzed.
- Peptide purification to homogeneity was achieved with semi-preparative HPLC and tested by analytical HPLC using the above solvent systems.
- [D-Lys 6 ]GnRH was automatically synthesized on a multiple peptide synthesizer and lyophiUzed (purity of crude product was >90%) as described above.
- DMF solution (1 mL) of dry crude peptide (31 mg, 25 ⁇ mol) and corresponding quinone (27.5 ⁇ mol) in the presence of 4-methylmorpholine (NMM) (8.2 ⁇ L, 75 ⁇ mol)
- NMM 4-methylmorpholine
- PyBOP 13 mg, 27.5 ⁇ mol
- Mass spectrometry found m/z [M + H] + 1537.4, calcd for C 72 H 92 ClN 19 O ⁇ 6 [M + H] + 1536.7. Similar to this procedure, [D- Lys 6 (AntrQ)]GnRH and [D-Lys 6 (NQ)]GnRH were synthesized on polymer support to yield 85% and 83%, respectively. Mass spectroscopy and amino acid analysis yielded the expected results, similar to those obtained from the synthesis in solution.
- Displacement binding assays were carried out using rat pituitary membrane preparations and 125 I[D-Lys 6 ]GnRH as radioligand as described 30 . Briefly, membranes were incubated for 90 min at 4°C with 125 I[D-Lys 6 ]GnRH and with the unlabeled peptides. Non-specific binding was defined as the residual binding in the presence of excess [D-Lys 6 ] GnRH (1 ⁇ M). Specific binding was calculated by subtracting the non-specific binding from the maximal binding, determined in the absence of any competing peptide. Results are the mean of two experiments carried out in triplicates. SEM values are omitted for clarity ( Figure 3).
- rat pituitary cells were incubated in M-199 (without serum and antibiotics) containing the desired concentrations of the tested peptides and incubated in the dark at 37°C for 4 h as described 31 .
- the media were then collected and LH concentration were analyzed by double-antibody radioimmunoassay (RIA) 32 using kits kindly supplied by the National Institute of Arthritis, Metabolism and Digestive Diseases (NIMDD).
- Results ( Figure 4) are expressed in terms of LH-RP-3 rat reference preparation, and are the mean ⁇ SEM of LH concentration of two experiments (4 wells / experimental group, each).
- the basal release after 4 h was 9.41+2 ng/mL.
- mice Female rats ( ⁇ 250 gr) were intraperitoneally injected with the desired concentration of [D-Lys 6 (Emo)]GnRH (0.04 nmol/rat) or [D-Lys 6 ]GnRH (0.4 nmol rat) in 0.5 L PBS. Blood samples were withdrawn by cardiac puncture under light ether anesthesia at the indicated time intervals, and serum LH levels were determined by RIA as described above ( Figure 6). Results are the mean ⁇ SEM of LH concentrations in the serum of five animals/experimental group. The LH concentration was determined using three different dilutions of each serum sample. Similar results were obtained in two other experiments. LH concentration in unstimulated rats was 0.53 ng/mL serum. *LH release was significantly higher (p ⁇ 0.01) than in the group treated with [D-Lys 6 ]GnRH.
- the weight of the testes and prostate gland of the control group were 3.367+0.07 and 0.267+0.02 g, respectively. * Weights are significantly different (PO.01) from the control. ** Significantly different (P ⁇ 0.001) from control group or from rats treated with [D- Lys 6 ]GnRH (1 nmol/rat). Binding to HSA
- the binding capacity of [D-Lys 6 (Emo)]GnRH, [D-Lys 6 ]GnRH and emodic acid to HSA was evaluated by incubating various concentrations of the tested compounds with HSA (22.5 nmol, 1.5 mg in 0.5 mL of PBS) at 37 °C for 3 h.
- the concentration of HSA in the solution was determined using a molar extinction coefficient of 39,000 M "1 cm "1 at 277.5 nm 33 .
- the unbound compound was then separated from the HSA solution by applying it on to a Cent ⁇ con concentrator column (Amicon Inc., Beverly, MA) with a band pass membrane of 30,000 kD according to the manufacture's protocol.
- the HSA bound compound ( ⁇ 20 ⁇ L) was then precipitated by adding it to acetonitrile (1 mL). The supernatant was kept and the precipitate was dissolved in PBS (100 ⁇ L) and re-precipitated. The combined supernatants were evaporated, the residue was dissolved in water containing 0.1% TFA (buffer A) and analyzed by HPLC to determine the amount of the tested compounds. Results represent the mean of two experiments ( Figure 8).
- T3-l cells (5xl0 6 /dish) were incubated in phenol red and serum free complete medium (37°C, 5% C0 2 ) with the tested compounds for 5 h in the dark. Cells were then washed with PBS (x3) and illuminated or remained in darkness as described earlier. The media were then replaced by complete medium and cells were incubated for additional 24 h. DNA was then isolated, using Wizard ® genomic DNA purification kit (Promega, Madison, WI) following the company's protocol and analyzed by gel electrophoresis (0.4% cross linked agarose, ethidium bromide staining).
- Emodic acid to the peptides were carried out in a one pot reaction, using benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) as a coupling agent, 4-methylmo ⁇ holine (NMM) as a base and DMF as a solvent for lh.
- PyBOP benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
- NMM 4-methylmo ⁇ holine
- DMF solvent for lh.
- the crude conjugates were then purified to homogeneity by semi- preparative HPLC and characterized by UV, MS and amino acid analysis.
- the antagonist [D-Pyr 1 , D-Phe 2 , D-T ⁇ 3 , D-Lys 6 ]GnRH, has a lower binding affinity to GnRH receptor as compared to [D-Lys 6 ] GnRH and the insertion of emodic acid to either peptides causes a similar loss of binding affinity.
- Figure 11 compares the binding affinities of agonistic and antagonistic derivatives of emodin and Table 3 summarizes the estimated IC 50 (concentration of the competitor which displace 50% of the bound tracer) of different GnRH analogs to the GnRH receptor.
- Figure 12 demonstrates the inhibition of LH secretion from rat pituitary cultures by the two antagonists. Inco ⁇ oration of emodic acid to the antagonist decreases its binding affinity (Figure 11) however its bioactivity is superior as compared to the parent antagonist ( Figure 12).
- This protocol commonly called OVSYNCH, synchronizes follicular development, luteal regression and time of ovulation, thereby allowing for timed insemination 12 to 24 hours after the completion of the GnRH / PGF / GnRH treatment protocol.
- hormone cost per treated cow can be significant. [Frick, P.M., et al., Theriogenology 50:1275-1284 (1998)]. Since retail cost of GnRH constitutes the majority of the cost in using OVSYNCH, availability of a cost effective long acting GnRH that could be used in the OVSYNCH protocol would greatly benefit reproductive management of heifers and cows.
- LRF hypothalamic luteinizing hormone-releasing factor
- GnRH gonadotropm releasing hormone
Abstract
Description
Claims
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CA002500897A CA2500897A1 (en) | 2002-10-02 | 2002-10-02 | Long-acting gonadotropin-releasing hormone analogs and methods of use thereof |
PCT/IL2002/000801 WO2004030687A1 (en) | 2002-10-02 | 2002-10-02 | Long-acting gonadotropin-releasing hormone analogs and methods of use thereof |
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Cited By (6)
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US8580294B2 (en) | 2010-10-19 | 2013-11-12 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
CN105188721A (en) * | 2013-01-22 | 2015-12-23 | 欧梭莱夫公司 | Use of tungsten (VI) salts for the treatment of female infertility in non-diabetic mammals |
CN106715332A (en) * | 2014-07-21 | 2017-05-24 | 欧梭莱夫公司 | Tungsten (vi) salts used to treat infertility, for stimulating fertility and normal reproduction in a non-diabetic female mammal, and for improving the effectiveness of assisted reproduction techniques |
US9956164B2 (en) | 2014-04-16 | 2018-05-01 | Veyx-Pharma Gmbh | Veterinary pharmaceutical composition and use thereof |
US10137031B2 (en) | 2013-11-14 | 2018-11-27 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
RU2785717C2 (en) * | 2019-03-26 | 2022-12-12 | Новел Фарма Инк. | GnRH DERIVATIVES OF PROLONGED ACTION, CONJUGATED WITH FATTY ACID AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CL2016000217A1 (en) * | 2016-01-27 | 2016-07-01 | Farmacologia En Aquacultura Veterinaria Fav S A | New injectable veterinary composition for synchronization of spawning in fish |
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2002
- 2002-10-02 CA CA002500897A patent/CA2500897A1/en not_active Abandoned
- 2002-10-02 WO PCT/IL2002/000801 patent/WO2004030687A1/en not_active Application Discontinuation
- 2002-10-02 AU AU2002368261A patent/AU2002368261A1/en not_active Abandoned
Non-Patent Citations (2)
Title |
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RAHIMIPOUR S. ET AL.: "Design, synthesis and evaluation of a long-acting, potent analogue of gonadotropin-releasing hormone", JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. 22, 25 October 2001 (2001-10-25), pages 3645 - 3652, XP002976151 * |
RAHIMIPOUR S. ET AL.: "Generation of free radicals by emodic acid and its [D-Lys6]GnRH-conjugate", PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 74, no. 2, August 2001 (2001-08-01), pages 226 - 236, XP002976152 * |
Cited By (10)
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US8580294B2 (en) | 2010-10-19 | 2013-11-12 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
US9427400B2 (en) | 2010-10-19 | 2016-08-30 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
CN105188721A (en) * | 2013-01-22 | 2015-12-23 | 欧梭莱夫公司 | Use of tungsten (VI) salts for the treatment of female infertility in non-diabetic mammals |
US10137031B2 (en) | 2013-11-14 | 2018-11-27 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
US11259956B2 (en) | 2013-11-14 | 2022-03-01 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
US11793669B2 (en) | 2013-11-14 | 2023-10-24 | The Population Council, Inc. | Combination therapy intravaginal rings |
US9956164B2 (en) | 2014-04-16 | 2018-05-01 | Veyx-Pharma Gmbh | Veterinary pharmaceutical composition and use thereof |
CN106715332A (en) * | 2014-07-21 | 2017-05-24 | 欧梭莱夫公司 | Tungsten (vi) salts used to treat infertility, for stimulating fertility and normal reproduction in a non-diabetic female mammal, and for improving the effectiveness of assisted reproduction techniques |
CN106715332B (en) * | 2014-07-21 | 2019-01-29 | 欧梭莱夫公司 | For treating infertility, the normal breeding for promoting female mammal and fertility and the tungsten salt for improving assisted reproductive technology effect |
RU2785717C2 (en) * | 2019-03-26 | 2022-12-12 | Новел Фарма Инк. | GnRH DERIVATIVES OF PROLONGED ACTION, CONJUGATED WITH FATTY ACID AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Also Published As
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WO2004030687A8 (en) | 2004-08-26 |
CA2500897A1 (en) | 2004-04-15 |
AU2002368261A1 (en) | 2004-04-23 |
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