US20210030846A1 - LONG-ACTING FATTY ACID-CONJUGATED GnRH DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

LONG-ACTING FATTY ACID-CONJUGATED GnRH DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME Download PDF

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US20210030846A1
US20210030846A1 US17/075,295 US202017075295A US2021030846A1 US 20210030846 A1 US20210030846 A1 US 20210030846A1 US 202017075295 A US202017075295 A US 202017075295A US 2021030846 A1 US2021030846 A1 US 2021030846A1
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gnrh
fatty acid
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Dong Kyu Jin
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NOVEL PHARMA Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • 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
    • A61K47/54—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 an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • 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

Definitions

  • the present disclosure relates to novel long-acting fatty acid-conjugated derivatives of gonadotrophin-releasing hormone (GnRH) and pharmaceutical compositions containing the same.
  • GnRH gonadotrophin-releasing hormone
  • a gonadotrophin-releasing hormone (GnRH) or a luteinizing hormone-releasing hormone is a hypothalamic neurohormone and is a type of neuroendocrine peptide.
  • GnRH is synthesized in the neurovascular terminal cells of the hypothalamus and acts on gonadotropic cells in the anterior pituitary gland to promote the synthesis and release of luteinizing hormone (LH) or follicle stimulating hormone (FSH), which are both gonadotrophins.
  • Luteinizing hormones or follicle stimulating hormones the synthesis and release of which are controlled by GnRH, play a role in controlling male and female sex hormones and maturing reproductive cells.
  • GnRH has the effect of promoting the secretion of gonadotropin or ovulation at normal concentrations, it has an antagonistic inhibitory effect at high concentrations, which is contradictory.
  • a high dose of GnRH may be used to treat prostate cancer or breast cancer, which are hormone-dependent tumors, as well as endometriosis, uterine fibroids, central precocious puberty, and adenomyosis, etc.
  • GnRH or GnRH derivatives can be used in the treatment of various sex hormone-dependent diseases (Kumar P. and Sharma A, J Hum Reprod Sci, 2014; 7(3): pp. 170-174).
  • sustained release products designed to be injected every one or three months, which are in the form of abiodegradable multinuclear storage microcapsules (PLGA or PLA) containing a GnRH agonist.
  • PLGA abiodegradable multinuclear storage microcapsules
  • a sustained-release product comprising a GnRH derivative under the brand name of Lupron® Depot is commercially available.
  • This commercial product contains PLGA [poly(lactic-co-glycolic acid)] microspheres as a sustained release ingredient, with the GnRH derivative of leuprolide acetate as an active ingredient. Due to the use of a biodegradable polymer, Lupron® Depot must be intramuscularly or subcutaneously administered at a large dose.
  • U.S. Pat. No. 9,694,051 discloses that a conjugated adrenomedullin peptide where an alkyl moiety is conjugated to lysine (Lys) at the N-terminals of some adrenomedullin peptides has an increased half-life in blood.
  • lysine Lys
  • the peptide is quite different from GnRH in terms of function and sequence.
  • the peptide differs from GnRH in that the terminal amino residue of the peptide to which the alkyl moiety is conjugated is lysine.
  • a long-acting GnRH formulation in which the GnRH itself has a prolonged in vivo half-life and increased bioavailability, unlike the existing sustained-release formulations which have disadvantages due to the additional ingredients or formulation design for sustained release, etc.
  • a long-acting fatty acid-conjugated GnRH derivative was prepared by conjugating a fatty acid to a GnRH derivative which is designed to have an increased in vivo half-life of GnRH and converting the conjugate to a salt form.
  • the long-acting fatty acid-conjugated GnRH derivative was found to exhibit excellent bioavailability and a prolonged in vivo half-life, maintain a high blood level, and have a therapeutic effect on sex hormone-dependent diseases or deter sexual maturation, which led to the present disclosure.
  • the long-acting fatty acid-conjugated GnRH derivatives according to the present disclosure and a pharmaceutical composition containing the same can be used for the prevention and treatment of various sex hormone-dependent diseases or for the deterrence of sexual maturation.
  • the present disclosure aims to develop a long-acting GnRH formulation having increased bioavailability and in vivo half-life of GnRH itself, which is as short as 2 to 4 min in circulating blood.
  • the purpose of the present disclosure is to provide a long-acting fatty acid-conjugated GnRH derivative with ease of administration and improved efficacy and a pharmaceutical composition containing the same.
  • the term “improved efficacy” of a long-acting fatty acid-conjugated GnRH derivative means that it has a higher therapeutic effect on sex hormone-related diseases at the same concentration with a natural GnRH.
  • the long-acting fatty-conjugated GnRH derivative has higher cytotoxic effects on prostate cancer or breast cancer when administered at the same dose as a natural GnRH or a commercially available GnRH derivative.
  • GnRH has the effect of promoting the release of gonadotropins or ovulation at normal concentrations, while it has antagonistic inhibitory effects at high concentrations which is contradictory. Accordingly, high concentrations of GnRH inhibit the progression of diseases aggravated by sex hormones or are effective for the alleviation and treatment of sex hormone-dependent diseases.
  • the GnRH derivative the long-acting fatty acid-conjugated GnRH derivative, which comprises a GnRH derivative having a fatty acid conjugated thereto, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same according to the present disclosure.
  • An aspect of the present disclosure pertains to a long-acting, fatty acid-conjugated GnRH derivative, which is a gonadotropin-releasing hormone (GnRH) derivative having a fatty acid conjugated thereto, or a pharmaceutically acceptable salt thereof.
  • GnRH gonadotropin-releasing hormone
  • GnRH Gonadotropin-releasing hormone
  • LH luteinizing hormone
  • FSH follicle stimulating hormone
  • GnRH may differ in sequence from one species to another.
  • Mammalian natural GnRH may have the amino acid sequence of SEQ ID NO: 1 as follows.
  • GnRH derivative refers to a substance which is structurally analogous to GnRH, but may act in a different manner in vivo.
  • the GnRH derivative particularly corresponding to a GnRH agonist, binds to a GnRH receptor to promote the in vivo synthesis and secretion of follicle stimulation hormone (FSH) and luteinizing hormone (LH) to a certain level.
  • FSH follicle stimulation hormone
  • LH luteinizing hormone
  • the continuous maintenance of the GnRH derivative concentration in vivo depletes gonadotropins and downregulates the GnRH receptor, resulting in a contradictory effect (i.e., antagonistic effect) in that the synthesis and secretion of FSH and LH are rather suppressed.
  • the GnRH derivatives can thus be used for preventing or treating sex hormone-dependent diseases and for deterring sexual maturation.
  • the GnRH derivative is a GnRH agonist, which may be selected from the group consisting of leuprolide, goserelin, triptorelin, nafarelin, buserelin, histrelin, deslorelin, meterelin, gonadorelin, and modified derivatives thereof.
  • the GnRH derivative has a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% homology to the existing GnRH agonists.
  • the GnRH derivative of the present disclosure may have a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% homology to natural GnRH, leuprolide, goserelin, triptorelin, nafarelin, buserelin, histrelin, deslorelin, meterelin, or gonadorelin and, more particularly, a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% homology to GnRH (SEQ ID NO: 1) or leuprolide (SEQ ID NO: 2).
  • a GnRH derivative is a modified leuprolide where the first amino acid, glutamic acid, on leuprolide is substituted with a different amino acid, more particularly with glutamine.
  • the GnRH derivative may include or consist of an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 11.
  • the long-acting fatty acid-conjugated GnRH derivative may include or consist of an amino acid sequence selected from the group consisting of SEQ ID NOS: 4 to 11.
  • the long-acting fatty acid-conjugated GnRH derivative may include or consists of an amino acid sequence of SEQ ID NO: 5 or 11.
  • the GnRH derivative may mean a derivative having an additional modification of the existing GnRH or GnRH derivative.
  • the GnRH derivative according to an embodiment of the present disclosure may be a long-acting fatty acid-conjugated GnRH derivative, which is a GnRH derivative having a fatty acid conjugated thereto, or a pharmaceutically acceptable salt thereof. More particularly, the fatty acid may be conjugated to the amino terminus of the GnRH derivative.
  • the fatty acid may be a saturated or unsaturated fatty acid of C6 to C30, which may be linear or branched.
  • concrete examples of the fatty acid include, but are not limited to, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, linolenic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid, (EPA), docosahexaenoic acid (DHA), linoleic acid (LA), gamma-linoleic acid (GLA), dihomo gamma-linoleic acid (DGLA), arachidonic acid (AA),
  • any fatty acid may be employed, without limitations.
  • Lauric acid also systemically called dodecanoic acid, is a saturated fatty acid with a normal 12-carbon atom chain and exists as a component of triglycerides. It is structurally stable and is found as one of the main components in human breast milk.
  • the fatty acid has a melting point of 43.8° C. and exists as a white solid at room temperature.
  • the term “palmitic acid” refers to a carboxyl of a hydrocarbon chain which is a hydrophobic normal saturated fatty acid of 16 carbon atoms and has one carboxyl group (—COOH).
  • arachidic acid or “eicosanoic acid” is a saturated fatty acid with a normal 20-carbon chain. It has a melting point of 75.5° C. and exists as a white crystalline solid at room temperature.
  • the long-acting GnRH derivative has the following advantages: i) enhanced renal reabsorption and fat storage efficiency; ii) protection effect resulting from increased binding with serum proteins; iii) delayed renal clearance resulting from increased hydrophobicity of analog series; and iv) increase in release time and pharmaceutical efficacy resulting from attaching to lipid membranes or biological membranes.
  • a “pharmaceutically acceptable salt” is intended to encompass all pharmaceutically acceptable salts that can be used for the purpose of increasing the stability, water solubility, bioavailability, etc., of the fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure, without limitations thereto.
  • the pharmaceutically acceptable salt may be selected from the group consisting of inorganic acids, organic acids, ammonium salts, alkali metal salts, and alkaline earth metal salts.
  • the pharmaceutically acceptable salt may be selected from the group consisting of hydrochloride, hydrobromide, phosphate, metaphosphate, nitrate, sulfate, acetate, sulfonate, benzoate, citrate, ethanesulfonate, furmarate, lactate, maleate, malate, succinate, tartrate, sodium salt, calcium salt, potassium salt, and magnesium salt.
  • the fatty acid-conjugated GnRH derivative of the present disclosure may include or may be composed of an amino acid selected from the group consisting of SEQ ID NOS: 4 to 11, wherein lauric acid, palmitic acid, or arachidic acid may be conjugated to the amino terminus of the GnRH derivative, and the pharmaceutically acceptable salt may be a sodium salt or acetate.
  • the fatty acid-conjugated GnRH derivative may include or may be composed of the amino acid sequence of SEQ ID NO: 3 or 4, wherein lauric acid may be conjugated to the amino terminus of the GnRH derivative, and the pharmaceutically acceptable salt may be an acetate.
  • the palmitic acid-conjugated GnRH derivative may include or may be composed of the amino acid sequence of SEQ ID NO: 9 or 10, wherein arachidic acid may be conjugated to the amino terminus of the GnRH derivative, and the pharmaceutically acceptable salt may be an acetate.
  • compositions Comprising the Fatty Acid-Conjugated GnRH Derivative
  • An aspect of the present disclosure pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising the long-acting, fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure as an active ingredient.
  • the pharmaceutical composition may further comprise a cyclodextrin.
  • the cyclodextrin may be ⁇ -cyclodextrin, ⁇ -cyclodextrin, or ⁇ -cyclodextrin and may be particularly methyl- ⁇ -cyclodextrin.
  • any cyclodextrin may be used.
  • the long-acting fatty acid-conjugated GnRH derivative may exist as being included within a cyclodextrin.
  • the fatty acid-conjugated GnRH derivative and cyclodextrin can form an inclusion complex.
  • a cyclodextrin can form an inclusion complex with an active ingredient that is difficult to dissolve in water, thereby providing the water-insoluble ingredient with stability, improved solubility, and sustainable release in an aqueous solution. Therefore, in an embodiment of the present disclosure, the pharmaceutical composition comprising an inclusion complex of the long-acting fatty acid-conjugated GnRH derivative and a cyclodextrin can exhibit improved sustainability of release of the GnRH derivative.
  • the pharmaceutical composition may contain a cyclodextrin and the active ingredient long-acting fatty acid-conjugated GnRH derivative at a molar ratio of from about 7:1 to 1:1, from 6:1 to 1:1, or from 5:1 to 1:1. At such weight ratios, the pharmaceutical composition according to an embodiment of the present disclosure can exhibit excellent solubility.
  • the pharmaceutical composition comprises a pharmaceutically effective amount of the fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure and may further comprise a pharmaceutically acceptable carrier.
  • pharmaceutically effective amount means a sufficient amount to achieve the efficacy or activity of the fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure.
  • Pharmaceutically acceptable carriers which can be included in the pharmaceutical composition according to an embodiment of the present disclosure are those commonly used for preparing a formulation, and examples of the pharmaceutically acceptable carrier include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.
  • the pharmaceutical composition according to an embodiment of the present disclosure may further comprise a lubricant, a humectant, a sweetener, a flavorant, an emulsifier, a suspending agent, a preservative, and the like.
  • the pharmaceutical composition may be administered orally or parenterally. Particularly, for injection routes, it may be administered in a dosage form of either a subcutaneous injection or an intramuscular injection.
  • a dosage form may be selected in consideration of various factors, such as the effect of controlling in vivo concentrations.
  • the pharmaceutical composition of the present disclosure may be administered in the dosage form of an injection, a paste, a gelling agent, a lotion, a capsule, a tablet, a liquid, a suspension, a sprayer, an inhaler, an eye drop, an adhesive, or a patch and particularly an injection.
  • the suitable dosage of the pharmaceutical composition varies depending on factors including the formulation method, dosing method, patient's age, body weight, gender and morbidity, food, administration time, administration route, excretion rate, and response sensitivity.
  • the pharmaceutical composition of the present disclosure is generally administered at a dose of 0.001 to 100 mg/kg for an adult.
  • the pharmaceutical composition comprises the fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure in an amount of about 0.001 to 30 mg/mL.
  • the term “about” is intended to cover an allowable error for a process or a numerical adjustment falling within the technical spirit of the present disclosure.
  • the term “about” refers to a relative term denoting an approximation of ⁇ 10% of the nominal value to which it refers, in one embodiment, to ⁇ 5%, and in another embodiment, to ⁇ 2%.
  • this level of approximation is appropriate unless the value is specifically stated to require a tighter range.
  • the pharmaceutical composition is formulated using a pharmaceutically acceptable carrier and/or excipient, according to a method that can be easily carried out by a person having ordinary skill in the art.
  • the pharmaceutical composition of the present disclosure may be prepared into a unit dosage form or may be inserted into a multi-dose container.
  • the formulation may be in the form of a solution, a suspension, a syrup, or an emulsion in an oil or aqueous medium or in the form of an extract, powder, granules, a tablet, or a capsule and may further comprise a dispersant or a stabilizer.
  • the pharmaceutical composition may be used for the prevention or treatment of a sex hormone-dependent disease or for deterrence of sexual maturation.
  • the sex hormone-dependent disease may be selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary disease, central precocious puberty, hypertrichosis, gonadotroph pituitary adenoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and contraception, but is not limited thereto.
  • the pharmaceutical composition when used in combination with a conventional biodegradable polymer, may exhibit a remarkably excellent in vivo half-life. Accordingly, the pharmaceutical composition according to an embodiment of the present disclosure may further comprise biodegradable polymers.
  • the biodegradable polymer allows the drug to be delivered to parenteral routes through the body, or allows the polymer comprising the GnRH derivative of the present disclosure or a salt thereof to topically act on a specific site.
  • the biodegradable polymer in the present disclosure reference may be made to Chasin M et al. (“Biodegradable Polymers as Drug Delivery Systems”, New York, Marcel Dekker, 1990) or D. Wescman et al. (“Handbook of Biodegradable Polymers”, Taylor & Francis, 1998), without limitations thereto.
  • the biodegradable polymer according to an embodiment of the present disclosure may be PLA (poly-lactic acid), linear or branched PLGA (poly(lactic-co-glycolic acid)), PGA (poly-glycolic acid), hydrogel, or the like.
  • the present disclosure further provides a method and use for deterring sexual maturation or a method and use for preventing or treating a sex hormone-related symptom or disease by administering the palmitic acid-conjugated GnRH derivative according to an embodiment of the present disclosure, a salt thereof, or a composition containing the same to mammals including humans.
  • An aspect of the present disclosure pertains to a use of the fatty acid-conjugate GnRH derivative or a salt thereof according to an embodiment of the present disclosure in deterring sexual maturation or in preventing or treating a sex hormone-related symptom or disease.
  • An aspect of the present disclosure pertains to a pharmaceutical composition for use in deterring sexual maturation or in preventing or treating a sex hormone-related symptom or disease, the composition comprising the fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure, a salt thereof, or both of them.
  • An aspect of the present disclosure pertains to a use of the fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure or a salt thereof in preparing a pharmaceutical composition (or medicament) for deterring sexual maturation or for preventing or treating a sex hormone-related symptom or disease.
  • the excellent bioavailability and extended in vivo half-life by the novel long-acting fatty acid-conjugated gonadotrophin-releasing hormone (GnRH) derivative according to an embodiment of the present disclosure is expected to make great contributions to the reduction in dosing frequency and dosage.
  • the long-acting fatty acid-conjugated GnRH derivative could overcome the problems with the existing sustained release GnRH formulations, such as the adverse effects of residual feeling and pain at the injection site.
  • the long-acting fatty acid-conjugated GnRH derivative and the pharmaceutical composition comprising the same exhibit remarkably excellent therapeutic effects on sex hormone-dependent diseases and as such, are expected to make great contributions to the reduction in dosing frequency and dosage.
  • FIG. 1 shows images in which the extents of suspensions formed by pharmaceutical compositions (Examples, 9, 10, 15, and 16) comprising fatty acid-conjugated GnRH derivatives (Examples 1, 2, 7, and 8) according to an embodiment of the present disclosure and cyclodextrin are visualized with the naked eye.
  • FIG. 2 shows images in which the extents of suspensions formed by pharmaceutical compositions (Examples 11 to 14) comprising fatty acid-conjugated GnRH derivatives (Examples 3 to 6) according to an embodiment of the present disclosure and cyclodextrin are visualized with the naked eye.
  • FIG. 3 is a graph showing the cell viability (%) of the prostate cancer cell line DU-145 after treatment with compositions of the Examples and the Comparative Examples, compared to the negative control 1% methyl- ⁇ -cyclodextrin.
  • FIG. 4 is a graph showing the cell viability (%) of the prostate cancer cell line PC3 after treatment with compositions of the Examples and the Comparative Examples, compared to the negative control 1% methyl- ⁇ -cyclodextrin.
  • FIG. 5 is a graph showing the cell viability (%) of the prostate cancer cell line LNCaP after treatment with compositions of the Examples and the Comparative Examples, compared to the negative control 1% methyl- ⁇ -cyclodextrin.
  • FIG. 6 shows ovary scan images of non-treated control and ⁇ -cyclodextrin-administered control after staining.
  • FIG. 7 shows ovary scan images of groups which were stained after administration of pharmaceutical compositions (Examples 9 and 10) comprising fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure (Examples 1 and 2) thereto.
  • FIG. 8 shows ovary scan images of groups which were stained after administration of pharmaceutical compositions (Examples 13 and 14) comprising fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure (Examples 5 and 6) thereto.
  • FIG. 9 shows ovary scan images of groups which were stained after administration of pharmaceutical compositions (Examples 15 and 16) comprising fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure (Examples 7 and 8) thereto.
  • FIG. 10 is a graph showing the increased in vivo half-life of fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure, where the blood concentration is plotted over time after the control drugs (Comparative Examples 1 and 4) and the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure are each subcutaneously administered once at a dose of 12.5 mg/kg to animals (rats).
  • FIG. 11 is a graph showing the increased in vivo half-life of fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure, where the blood concentration is plotted over time after the control drug Leuprolide acetate formulation for one-day administration (Comparative Example 1) and the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure (Examples 4 and 6) are each subcutaneously administered once at a dose of 12.5 mg/kg to animals (rats).
  • FIG. 12 is a graph showing the increased in vivo half-life of fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure, where the blood concentration is plotted over time after the control drug Leuprolide Depot formulation for one-day administration (Comparative Example 4) and the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure (Examples 4 and 6) are each subcutaneously administered once at a dose of 12.5 mg/kg to animals (rats).
  • Natural mammalian GnRH has the following sequence.
  • Leuprolide® having the mammalian GnRH sequence with the substituted D-Leu instead of Gly at position 6 and the substituted des-Gly instead of Gly at position 10 was used as a backbone for the derivative and the fatty acid-conjugate derivative according to an embodiment of the present disclosure.
  • triptorelin For reference, the sequence of triptorelin is provided as follows:
  • the derivatives are synthesized using a general Fmoc/tBu solid-phase peptide synthesis (SPPS) method, where the ⁇ -amino groups of amino acid residues are protected by the base-labile group of Fmoc (fluorenylmethyloxycarbonyl chloride) while the side groups are protected by an acid-labile group.
  • SPPS solid-phase peptide synthesis
  • a peptide chain is sequentially extended by repetitive Fmoc cleavage and amino acid coupling.
  • the peptide was purified using a C18 column in the Shimadzu HPLC 10AVP system under HPLC conditions (A buffer 0.05% TFA/H 2 O, B buffer 0.05% TFA/acetonitrile, flow rate 1 mL/min, wavelength 230 nm). Purification results in each Example were entrusted to and obtained from Anygen Co. Ltd. and are shown in Table 1.
  • Example 1 the GnRH derivatives of Example 1 (L1), Example 3 (P1), Example 5 (P3), and Example 7 (A1) have glutamate as the amino acid residue at position 1
  • the GnRH derivatives of Example 2 (L2), Example 4 (P2), Example 6 (P4), and Example 8 (A2) have glutamine as the amino acid residue at position 1 (see Table 2).
  • Lauric acid, palmitic acid, and arachidic acid are sparingly soluble in water and exist as solid phases at room temperature with respective melting points of about 43.8° C., about 60° C., and about 75.5° C.
  • salting was further carried out.
  • the fatty acid-conjugated GnRH derivatives were subjected to salting with sodium salt or acetate to prepare the fatty acid-conjugated GnRH derivative salts of Comparative Examples 1 to 3 and Examples 1 to 8, as shown in Table 2 below. These processes were entrusted to Anygen Co. Ltd.
  • Methyl- ⁇ -cyclodextrin powder (SigmaAldrich; Lot no.: C4555; Mw.: 1303.311 g/mol) was dissolved in the amounts given in Table 3 in 1 mL of sterilized tertiary distilled water.
  • the GnRH derivatives were added in the amounts given in Table 3 to respective 15-mL conical tubes to which 1 mL of the aqueous 3-cyclodextrin solution corresponding to the mole ratios of Table 3 was then added before mixing overnight at room temperature with the aid of a low-speed rotator. Subsequently, the solutions contained in the 15-mL tubes were collected by a brief spin down and then transferred to 1.5 mL tubes, followed by secondary mixing overnight at room temperature by a low-speed rotator. Finally, pharmaceutical compositions containing each the active ingredients at a concentration of about 10 mM were obtained. The compositions were used in the following Experimental Examples optionally after being diluted. For Comparative Examples 1 to 3, the compositions were diluted to 20 mM in tertiary distilled water.
  • a solution of 13 mg of methyl- ⁇ -cyclodextrin powder in 1 mL of sterile, tertiary distilled water was prepared in the same manner as in Preparation Example 2 in a 1.5-mL tube (concentration 10 mM).
  • compositions of Examples 9 and 10 containing the lauric acid-conjugated GnRH derivatives (Examples 1 and 2) and the compositions of Examples 15 and 16 containing the arachidic acid-conjugated GnRH derivatives (Examples 7 and 8) were observed to exist as suspensions in which the active ingredients (inclusion complexes of GnRH derivatives and cyclodextrin) were well dispersed in the solvent sterile distilled water before the spin-down. This phenomenon was also true of the compositions after the spin-down.
  • compositions of Examples 11 to 14 containing the palmitic acid-conjugated GnRH derivatives were also observed to exist as suspensions in which the active ingredients (inclusion complexes of GnRH derivatives and cyclodextrin) were well dispersed in the solvent sterile distilled water before and after the spin-down.
  • compositions containing GnRH derivatives and cyclodextrin according to an embodiment of the present invention exist as suspensions in which the ingredients are well suspended, thus achieving the effects and purposes of long-acting or sustained released agents.
  • GnRH derivatives are clinically applied to the therapy of diseases including breast cancer, prostate cancer, endometriosis, central precocious puberty, and the like.
  • different prostate cancer cell lines (DU-145, PC3, and LNCaP cell lines) were each cultured in an RPMI 1640 medium (containing 10% FBS, penicillin/streptomycin, 1% non-essential amino acids) in a T75 flask and cultured at 37° C. under the atmosphere of 5% CO2/95% air in a sterile incubator.
  • An assay for cell viability was performed using the Cell Counting Kit-8 (CCK-8, manufactured by DOJINDO).
  • Each of the cell lines was separated from the T75 flask by trypsinization and transferred to 96-well plates at a density of 1 ⁇ 104 cells/mL for DU-145 and at a density of 1 ⁇ 105 cells/mL for PC3 and LNCaP, followed by incubation for one hour for attachment.
  • each cell line was treated with 100 ⁇ M and 200 ⁇ M of each of the derivatives of Comparative Examples 1 to 3 and Examples 9 to 16 and the control.
  • 1% methyl ⁇ -cyclodextrin was used as a negative control for cell viability while 0.1% sodium dodecyl sulfate (SDS) served as a positive control.
  • SDS sodium dodecyl sulfate
  • the existing culture medium was removed, and 100 ⁇ L of fresh culture medium and 10 ⁇ L of CCK-8 solution were applied to each cell line.
  • the medium solution was replaced by 100 ⁇ L of fresh culture medium and 104 of CCK-8 solution.
  • the cells were incubated for 4 hours, and then the absorbance was measured at 450 nm to assess cell viability.
  • the measurement results are provided in Tables 4 to 6 and FIGS. 3 to 5 .
  • Example 9 100 50.00 ⁇ 0.63 ⁇ 0.01 200 30.80 ⁇ 0.66 ⁇ 0.01
  • Example 10 100 36.40 ⁇ 6.64 ⁇ 0.01 200 25.40 ⁇ 3.96 ⁇ 0.01
  • Example 11 100 47.25 ⁇ 2.50 ⁇ 0.02 200 35.25 ⁇ 0.25 ⁇ 0.01
  • Example 12 100 36.75 ⁇ 1.11 ⁇ 0.01 200 33.50 ⁇ 0.50 ⁇ 0.01
  • Example 13 100 81.50 ⁇ 1.44 ⁇ 0.01 200 41.75 ⁇ 1.18 ⁇ 0.01
  • Example 14 100 38.50 ⁇ 0.29 ⁇ 0.01 200 32.00 ⁇ 0.71 ⁇ 0.01
  • Example 15 100 68.25 ⁇ 0.95 ⁇ 0.01 200 51.25 ⁇ 2.95 ⁇ 0.01
  • Example 16 100 50.25 ⁇ 3.35 ⁇ 0.01 200 39.00 ⁇ 2.27 ⁇ 0.01 C.
  • Example 1 100 107.50 ⁇ 2.56 not significant (N. S) 200 101.08 ⁇ 3.26 N. S C.
  • Example 2 100 99.42 ⁇ 2.06 N. S 200 100.17 ⁇ 3.07 N. S C.
  • Example 3 100 100.92 ⁇ 2.98 N. S 200 94.27 ⁇ 3.47 N. S Positive Control 18.18 ⁇ 2.32 ⁇ 0.01 (0.1% SDS)
  • Example 9 100 41.00 ⁇ 4.36 ⁇ 0.02 200 39.00 ⁇ 4.73 ⁇ 0.02
  • Example 10 100 41.00 ⁇ 1.53 ⁇ 0.02 200 23.00 ⁇ 5.51 ⁇ 0.02
  • Example 11 100 65.60 ⁇ 1.69 ⁇ 0.01 200 29.80 ⁇ 2.54 ⁇ 0.01
  • Example 12 100 29.20 ⁇ 3.04 ⁇ 0.01 200 19.20 ⁇ 1.93 ⁇ 0.01
  • Example 13 100 99.60 ⁇ 5.84 N.
  • Example 14 100 90.80 ⁇ 4.04 N.
  • Example 15 100 72.50 ⁇ 5.33 ⁇ 0.02 200 63.75 ⁇ 5.56 ⁇ 0.02
  • Example 16 100 45.75 ⁇ 5.41 ⁇ 0.02 200 41.33 ⁇ 3.38 ⁇ 0.02 C.
  • Example 1 100 105.44 ⁇ 1.76 N.
  • S 200 100.11 ⁇ 1.82 N.
  • S C 100 104.22 ⁇ 3.15 N.
  • Example 3 100 99.67 ⁇ 3.17 N. S 200 95.44 ⁇ 4.03 N.
  • Example 9 100 91.33 ⁇ 10.73 N. S 200 45.33 ⁇ 5.61 ⁇ 0.02
  • Example 10 100 28.33 ⁇ 3.18 ⁇ 0.02 200 22.33 ⁇ 2.33 ⁇ 0.02
  • Example 11 100 37.00 ⁇ 0.58 ⁇ 0.02 200 30.67 ⁇ 0.67 ⁇ 0.02
  • Example 12 100 29.67 ⁇ 1.20 ⁇ 0.02 200 30.33 ⁇ 0.88 ⁇ 0.02
  • Example 13 100 72.33 ⁇ 5.84 ⁇ 0.02 200 66.33 ⁇ 5.24 ⁇ 0.02
  • Example 14 100 33.00 ⁇ 1.53 ⁇ 0.02 200 30.33 ⁇ 0.67 ⁇ 0.02
  • Example 15 100 64.25 ⁇ 3.52 ⁇ 0.02 200 36.50 ⁇ 1.94 ⁇ 0.02
  • Example 16 100 18.25 ⁇ 0.63 ⁇ 0.02 200 18.50 ⁇ 0.50 ⁇ 0.02 C.
  • Example 1 100 105.64 ⁇ 4.03 N. S 200 93.64 ⁇ 4.20 N. S C.
  • Example 2 100 99.22 ⁇ 6.11 N. S 200 84.78 ⁇ 6.16 N. S C.
  • Example 3 100 92.89 ⁇ 4.33 N. S 200 90.22 ⁇ 4.03 N.
  • the pharmaceutical compositions comprising the fatty acid-conjugated GnRH derivative according to an embodiment of the present disclosure (Examples 1 to 8) exhibited unpredictably excellent effects, compared to natural GnRH (Comparative Example 1) and the commercially available GnRH derivatives (Comparative Examples 2 and 3).
  • the prostate cell line DU-145 survived the compositions of Comparative Examples 1 to 3 at substantially the same rates as the negative control. Only the composition of Comparative Example 3 allowed a viability of about 94% for the cells. In contrast, the compositions according to an embodiment of the present disclosures reduced the cell viability to at least about 80% and to down to about 25%, compared to the negative control. The remarkably reduced cell viabilities by the compositions according to an embodiment of the present disclosure were statistically significant.
  • the compositions of Comparative Examples 1 to 3 showed slight reducing effects on cell viability. Only the triptorelin of Comparative Example 3 allowed about 95% for the cell viability. In contrast, the compositions according to an embodiment of the present disclosure showed a very significant reduction in the cell viability. Inter alia, the composition of Example 12 exhibited very highly reduced cell viability, compared to those of the Comparative Examples. Particularly, the composition of Example 12 reduced the cell viability to a similar degree to that which the positive control achieved.
  • the compositions of Comparative Examples 1, 2, and 3 allowed cell viabilities of about 93%, about 85%, and about 90%, respectively.
  • the compositions according to an embodiment of the present disclosure showed very high cell death effects, compared to the compositions of the Comparative Examples.
  • the cell death effect was found to be similar between the composition of Example 10 and the positive control and higher in the composition of Example 16 than the positive control.
  • compositions of Examples 10, 12, 14, and 16 comprising the derivatives of Examples 2, 4, 6, and 8 in which the amino acid at position 1 is substituted from glutamic acid to glutamine were superior in cell death effect to those of Examples 9, 11, 13, and 15 comprising the derivatives of Examples 1, 3, 5, and 7 in which the amino acid at position 1 remains intact.
  • GnRH derivatives characterized by amino acid substitution at position 1, fatty acid conjugation, and conversion to salt according to an embodiment of the present disclosure exhibit an unpredictably excellent prostate cancer cell death effect.
  • compositions of Examples 9, 10, 13, 14, 15, and 16 were each subcutaneously injected at a single dose of 12.5 mg/kg once at the back of the neck to female rats 9 weeks old. Rats to which no drugs were administered were used as a non-treated control while an aqueous solution of 3 mg of methyl- ⁇ -cyclodextrin was injected to a negative control. Each group consisted of 3 rats.
  • the rats were subjected to an autopsy to excise the ovaries which were then stained with hematoxylin-eosin (H&E stain). The stained ovaries were observed for histological change and pathogenic aberration.
  • H&E stain hematoxylin-eosin
  • the ovarian tissue was dehydrated with graded alcohols. The dehydration was conducted in a series of gradually graded alcohols beginning from a low concentration to higher concentrations and finally with 100% pure alcohol and benzene.
  • the paraffin-embedded tissue was cut into blocks of suitable sizes and then sectioned at a 4 ⁇ m thickness on a microtome.
  • the sectioned tissue was mounted on a glass slide and deparaffinized with an organic solvent such as xylene.
  • the slide having the tissue attached thereto was hydrated by treatment with a series of alcohols from high to low concentrations.
  • the specimen was dehydrated with graded alcohols and then cover-slipped using an adhesive such as a resin (balsam or a synthetic resin). This process is called mounting.
  • an adhesive such as a resin (balsam or a synthetic resin). This process is called mounting.
  • the specimen slides were scanned using a ScanScope® AT slider scanner (Aperio) and the images thus stored were analyzed using the ImageScope program (Aperio).
  • the scanned images are depicted in FIGS. 6 to 9 .
  • an estrous cycle of diestrus, proestrus, estrus, and metestrus lasts about 4 to 5 days, with the ovary morphologically changing depending on the estrous stages.
  • the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure have an advantageous effect, specifically, an effect of deterring sexual maturation in rats.
  • the observation of a reduction in the number of secondary or Graafian follicles even 28 days after the single dose indicates that the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure or the inclusion complexes of the derivatives and cyclodextrin show sustained release and as such, can be used as long-acting formulations.
  • the present inventor carried out animal experiments (female SD rats, nine weeks old) in order to examine the increased in vivo half-lives of the prepared fatty acid-conjugated GnRH derivatives.
  • DMSO dimethyl sulfoxide
  • Example 4 C Example 1 (Leuprolide acetate Example 4
  • Example 6 (Leuprolide acetate 1-month formulation (P2; (P4; Pa1_[Q1] 1-day formulation) (3.75 mg)) Pa1_[Q1]GnRH) GnRH_AcOH)
  • the measurement results are graphically depicted in FIGS. 10 to 12 .
  • pharmacokinetic analysis was carried out by calculating the half-life (t 1/2 ), clearance rate (CL), volume of distribution (Vd), time to reach the maximum concentration following drug administration (Tmax), maximum concentration following drug administration (Cmax), and systemic exposure to drug (AUCt).
  • t 1/2 half-life
  • CL clearance rate
  • Vd volume of distribution
  • Tmax maximum concentration following drug administration
  • Cmax maximum concentration following drug administration
  • AUCt systemic exposure to drug
  • Example 4 Example 4
  • Example 6 t 1/2 [Day] 0.03 4.17 4.80 4.03 CL [(mg/kg)/ 0.180 0.049 0.051 0.075 (ng/mL)/Day]
  • Vd [(mg/kg)/ 0.007 0.296 0.351 0.436 (ng/mL)]
  • Tmax [Day] 0.02 0.04 0.25 0.25 Cmax [ng/mL] 1020.0 164.0 52.2 45.7
  • the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure are significantly superior to Leuprolide (Comparative Example 1) in terms of the in vivo half-life, clearance rate, volume of distribution, and systemic exposure (AUCt).
  • the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure were found to have similar levels of half-life, clearance rate, and systemic exposure (AUCt) to those of the existing Leuprolide formulation for one-month administration containing a physically mixed biodegradable polymer and particularly to exhibit a superior volume of distribution, a delayed time to reach the maximum concentration following drug administration, and a reduced maximum concentration for a prolonged period of time, compared to the commercially available product.
  • AUCt systemic exposure
  • the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure can be used at a remarkably reduced volume, compared to the existing products in which biodegradable polymers are mixed with GnRH derivatives to achieve a sustained release, and thus can overcome the disadvantage of pain and exclude the side effect that the biodegradable polymer remains in vivo for a long period of time. These properties are advantageous particularly to children.
  • the fatty acid-conjugated GnRH derivatives according to an embodiment of the present disclosure can exhibit excellent effects of killing prostate cancer cells as well as deterring sexual maturation by reducing the numbers of secondary or graafian follicles in the ovary, as identified in Experimental Examples 2 and 3.
  • the half-life is remarkably increased, compared to conventional drugs such as Leuprolide, to become as long as drugs used in invasive methods (surgery), such as for implants (several months to one year).

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