WO2014104791A1 - Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same - Google Patents

Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same Download PDF

Info

Publication number
WO2014104791A1
WO2014104791A1 PCT/KR2013/012269 KR2013012269W WO2014104791A1 WO 2014104791 A1 WO2014104791 A1 WO 2014104791A1 KR 2013012269 W KR2013012269 W KR 2013012269W WO 2014104791 A1 WO2014104791 A1 WO 2014104791A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
sorbitan
weight
group
amount
Prior art date
Application number
PCT/KR2013/012269
Other languages
French (fr)
Inventor
Sang Phil Yoon
Ki Seong KO
Ha Na Yu
Hye Jung Baik
Won Kyu YANG
Jin Young Ko
So Hyun Park
Sung Bum Jung
Sung Won An
Min Hyo Ki
Original Assignee
Chong Kun Dang Pharmaceutical Corp.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL13867921T priority Critical patent/PL2938332T3/en
Priority to BR112015015518-9A priority patent/BR112015015518B1/en
Application filed by Chong Kun Dang Pharmaceutical Corp. filed Critical Chong Kun Dang Pharmaceutical Corp.
Priority to AU2013371101A priority patent/AU2013371101B2/en
Priority to NZ710468A priority patent/NZ710468A/en
Priority to CA2888863A priority patent/CA2888863C/en
Priority to CN201380067822.5A priority patent/CN105188680A/en
Priority to LTEP13867921.2T priority patent/LT2938332T/en
Priority to SI201331022T priority patent/SI2938332T1/en
Priority to RU2015131107A priority patent/RU2646487C2/en
Priority to DK13867921.2T priority patent/DK2938332T3/en
Priority to EP13867921.2A priority patent/EP2938332B1/en
Priority to ES13867921.2T priority patent/ES2664598T3/en
Priority to MX2015008401A priority patent/MX364595B/en
Priority to NO13867921A priority patent/NO2938332T3/no
Priority to US14/440,060 priority patent/US10722585B2/en
Priority to JP2015550323A priority patent/JP6078660B2/en
Publication of WO2014104791A1 publication Critical patent/WO2014104791A1/en
Priority to PH12015500936A priority patent/PH12015500936A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • 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
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • 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
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P5/28—Antiandrogens
    • 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
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates to a sustained-release lipid pre-concentrate comprising a GnRH analogue as a pharmacologically active substance, and a pharmaceutical composition comprising the same.
  • Sustained release formulations are designed to release a single dose of a pharmacologically active substance at a predetermined rate in order to maintain the effective concentration of the substance in the blood stream for a specific period of time, with minimization of the side effects caused by multiple doses.
  • gonadotropin-releasing hormone (GnRH) derivatives are representative of pharmacologically active substance to be designed as sustained-release formulations.
  • Gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a neuroendocrine peptide which is synthesized and released from neurons in the neurovascular terminal of hypothalamus. Once being released from the hypothalamus, GnRH selectively binds to specific receptors on the membrane of anterior pituitary gonadotroph cells to induce the biosynthesis and release of follicle-stimulating hormone (FSH) and leuteinizing hormone (LH). FSH and LH act to regulate the production of sex steroids from sex glands in males and females.
  • FSH follicle-stimulating hormone
  • LH leuteinizing hormone
  • GnRH GnRH-dependent GnRH
  • its analogues may be useful for the treatment of sex hormone-dependent diseases such as prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary syndrome, hypertrichosis, precocious puberty, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility.
  • sex hormone-dependent diseases such as prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary syndrome, hypertrichosis, precocious puberty, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility.
  • Lupron ® Depot is a commercially available, intramuscular or subcutaneous injection for the sustained release of the GnRH analogue leuprolide acetate, with the biodegradable PLGA [poly(lactic-co-glycolic acid)] microparticles delivering as a sustained release matrix.
  • PLGA microparticles degrade into lactic acid and glycolic acid over a specific period of time in vivo, releasing the pharmacologically active substance loaded there within in a sustained manner (U. S. Patent No. 5,480,656).
  • pharmacologically active substance loaded there within in a sustained manner
  • a PLGA microparticles are difficult to filter sterilization, and melt at 40°C or higher, the sterilization thereof cannot be achieved with general processes, but requires highly sterile conditions.
  • An ideal sustained-release profile is obtained using two or more different PLGA microparticles which, however, further complicate the processes of fabrication and mixing (WO 2005/074896), increasing the production cost.
  • acetic acid impurities and acidic degradation products from PLGA microparticles induce inflammation and reduce cell growth rates (K. Athanasiou, G. G. Niederauer, and C. M. Agrawal, Biomaterials, 17, 93 (1996)).
  • a suspension of 10 ⁇ 100 ⁇ m PLGA microparticles in an aqueous solution is injected in a significant amount, but this gives rise to a pain or a tissue damage at the injection site.
  • Eligard ® was introduced as a sustained-release injection formulation for a GnRH analogue (leuprolide acetate) which compensates the problems with PLGA microparticle-based sustained-release formulations.
  • Eligard ® is widely marketed as a subcutaneous injection which is prepared by dissolving PLGA [poly(DL-lactide-co-glycolide)] having a protected carboxyl terminal group and a GnRH analogue (leuprolide acetate) in N-methyl-2-pyrrolidone (NMP).
  • Eligard ® exists as a flowable composition which can be prepared by dissolving a biodegradable polymer in a polar aprotic solvent, and is designed as a subcutaneous injection with an improvement in partially drawbacks with solid PLGA microparticle formulations (U. S. Patent No. 6,773,714).
  • This commercial product is very poor in usability because of no supply of a complete prefilled syringes device, and exhibits low drug stability upon the mixture solution.
  • the device provided in the product comprises two syringes which can be connected to each other, and mixing, preparing and injecting tools. A final mixture solution is not obtained until more than about 10 steps are carried out, and only 30 mins is given to an entire process from preparation to injection.
  • the product must be stored in a refrigerator, and unless stored in a refrigerator, the final mixed solution cannot be used for more than 5 days.
  • no improvements are observed in the product with regard to a high initial burst, which is a drawback typical to PLGA microparticle formulations. Rather, the product exhibits higher initial burst concentration, compared to the PLGA microparticle formulation Lupron ® Depot (U. S. Patent No. 6,773,714).
  • An initial burst concentration greatly exceeding that at which a drug can function is undesirable in both functionally and toxicologically.
  • an excessive initial burst concentration must be avoided.
  • the International Patent Publication No. WO 2005/117830 describes a pre-formulation comprising at least one neutral diacyl lipid and/or at least one tocopherol, at least one phospholipid, and at least one biocompatible, oxygen containing, low viscosity organic solvent.
  • Another alternative is described in the International Patent Publication No. WO 2006/075124 which concerns a pre-formation comprising at least one diacyl glycerol, at least one phosphatidyl choline, at least one oxygen containing organic solution, and at least one GnRH analogue.
  • pre-formulations allow the sustained release of a pharmacologically active substance in vivo for four weeks, and do not form lactic acid or glycolic acid degradation products from their polymer systems, thus not causing pain or inflammation.
  • a diacyl lipid, a component essential for the pre-formulations, as a pharmaceutical excipient is not usable and it has to be proven to be sufficiently safe, and that their obligatory organic solvent incurs a reduction in the activity of some pharmacologically active substances (H. Ljusberg-Wahre, F. S. Nielse, 298, 328-332 (2005); H. Sah, Y. Bahl, Journal of Controlled Release 106, 51-61(2005)).
  • Culminating in the present inventors suggested a sustained-release lipid pre-concentrate comprising a) sorbitan unsaturated fatty acid ester; b) a phospholipid; and c) a liquid crystal hardener, and a pharmaceutical composition comprising the pre-concentrate (Korean Patent Application No. 10-2012-0093677).
  • This sustained-release lipid pre-concentrate exhibits in vivo safety and biodegradability at the same or higher levels, compared to conventional pre-concentrates and the pharmaceutical composition is found to allow for the sustained release of the pharmacologically active substance loaded therein.
  • U. S. Pat. No. 7,731,947 describes a composition comprising: a particle formulation comprising an interferon, sucrose, methionine, and a citrate buffer, and a suspending solution comprising a solvent such as benzyl benzoate, wherein the particle formulation is dispersed in the suspending solution, elucidating the application of GnRH analogues thereto.
  • a suspending solution comprising a solvent such as benzyl benzoate
  • phosphatidylcholine is dissolved together with vitamin E (tocopherol) in an organic solvent and is used to disperse the particle formulation therein.
  • vitamin E tocopherol
  • U. S. Pat. No. 7,871,642 describes a method of preparing a dispersion for delivering a pharmacologically active substance comprising hormone formulation, dispersing a homogeneous mixture of a phospholipid, a polyoxyethylene-containing coemulsifier, triglyceride and ethanol in water, wherein the polyoxyethylene-containing surfactant is selected from among polyoxyethylene sorbitan fatty acid esters (polysorbate) and polyethoxylated vitamin E derivatives.
  • polyoxyethylene sorbitan fatty acid esters and polyethoxylated vitamin E derivatives derived by conjugating the hydrophilic polymer polyoxyethylene to sorbitan fatty acid ester and vitamin E, respectively, are quite different in structure from sorbitan fatty acid ester and vitamin E. They are usually used as hydrophilic surfactants utilizing the property of polyoxyethylene, which is different from the component of the present invention.
  • U. S. Pat. No. 5,888,533 describes a flowable composition for forming a solid biodegradable implant in situ within a body, comprising: a non-polymeric, water-insoluble, biodegradable material; and a biocompatible, organic solvent that at least partially solubilizes the non-polymeric, water-insoluble, biodegradable material and is miscible or dispersible in water or body fluids, and capable of diffusing-out or leaching from the composition into body fluid upon placement within a body, whereupon the non-polymeric material coagulates or precipitates to form the solid implant.
  • this composition sterols, cholesteryl esters, fatty acids, fatty acid glycerides, sucrose fatty acid esters, sorbitan fatty acid esters, fatty alcohols, esters of fatty alcohols with fatty acids, anhydrides of fatty acids, phospholipids, lanolin, lanolin alcohols, and combinations thereof are described as the non-polymeric material, and ethanol is used as the solvent.
  • this composition cannot form liquid crystals and is designed to form solid implants by simple coagulation or precipitation of water-insoluble materials and that a lot of the organic solvent is necessarily used.
  • the present invention provides a pharmaceutical composition, comprising a) at least one sorbitan unsaturated fatty acid ester; b) at least one phospholipid; c) at least one liquid crystal hardener; and d) at least one GnRH analogue, as a pharmacologically active substance, wherein the composition exists as a liquid phase in the absence of aqueous fluid and forms into a liquid crystal in the presence of aqueous fluid.
  • the sorbitan unsaturated fatty acid ester preferably has two or more -OH(hydroxyl) groups in the polar head.
  • This sorbitan unsaturated fatty acid ester is represented by the following Chemical Formula 1.
  • the sorbitan fatty acid ester which accounts for the formation of a liquid crystal in the present invention, is different from conventional counterparts such as oleyl glycerate (OG), phytanyl glycerate (PG), and glycerine monooleate (GMO), glycerine dioleate (GDO) of the following Chemical Formula 2. That is, the conventional molecules responsible for liquid crystalline phases share the common structure consisting of a polar head derived from glycerine or glyceric acid and a non-polar tail derived from a lipid alcohol or fatty acid.
  • OG oleyl glycerate
  • PG phytanyl glycerate
  • GMO glycerine monooleate
  • GDO glycerine dioleate
  • glycerine monooleate (GMO) is useful as a pharmaceutically acceptable excipient, but has weak crystallinity to form liquid crystals necessary for sustained release medications.
  • Glycerol dioleate which is used in International Patent Publication No. WO 2005/117830 as described supra, is a diacyl lipid with glycerin functioning as a polar head. This molecule is not generally used as a pharmaceutical excipient because its safety has not yet been proven.
  • sorbitan unsaturated fatty acid esters have advantages over conventionally used liquid crystalline molecules, glycerine or glyceric acid derivatives in that they form liquid crystals very effectively for the sustained release of pharmacologically active substance, with superiority in safety and biodegradability and are applicable to the development of medical products overcoming the problems encountered in the prior art.
  • materials For use in compositions for medicaments, materials must be guaranteed to be safe and biodegradable. Further, biodegradability is a very important factor for the material which is in charge of sustained release in the body.
  • the sustained release injection using PLGA is designed to release a pharmacologically active substance for one week, it is ideal that the PLGA is degraded in vivo one week after injection. In fact, however, PLGA remains intact for one to several months even after the function of sustained release is finished. Therefore, the sorbitan unsaturated fatty acid ester of the present invention, which has excellent sustained release property, safety and biodegradability, is applicable for a novel liquid crystal-inducing material with great value in pharmaceutical industry.
  • the sorbitan unsaturated fatty acid ester of the present invention may be selected from sorbitan monoester, sorbitan sesquiester, sorbitan diester and a combination thereof, which can be derived from fatty acids obtainable from whale oils and fish oils as well as vegetable oils (e.g., coconut oil, castor oil, olive oil, peanut oil, rapeseed oil, corn oil, sesame oil, cotton seed oil, soybean oil, sunflower seed oil, safflower oil, linseed oil, etc.), and animal fats and oils (e.g., milk fat, lard, and beef tallow).
  • vegetable oils e.g., coconut oil, castor oil, olive oil, peanut oil, rapeseed oil, corn oil, sesame oil, cotton seed oil, soybean oil, sunflower seed oil, safflower oil, linseed oil, etc.
  • animal fats and oils e.g., milk fat, lard, and beef tallow.
  • Sorbitan monoester is a compound in which one fatty acid group is attached to sorbitan via an ester bond, and may be selected from among sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, and a combination thereof.
  • Sorbitan sesquiester is a compound in which 1.5 fatty acid groups, on average, are attached to sorbitan via an ester bond, and may be selected from among sorbitan sesquioleate, sorbitan sesquilinoleate, sorbitan sesquipalmitoleate, sorbitan sesquimyristoleate, and a combination thereof.
  • Sorbitan diester is a compound in which two fatty acid groups are attached to sorbitan via an ester bond, and may be selected from among sorbitan dioleate, sorbitan dilinoleate, sorbitan dipalmitoleate, sorbitan dimyristoleate, and a combiantion thereof.
  • sorbitan unsaturated fatty acid ester is preferably selected from sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, sorbitan sesquioleate, and a combination thereof.
  • Phospholipids are essential for the construction of lamellar structures, such as liposomes, in conventional techniques, but cannot form a non-lamellar phase structure, such as a liquid crystal, by themselves.
  • phospholipids can participate in the liquid crystal former-driven formation of non-lamellar phase structures, serving to stabilize the resulting liquid crystals.
  • the phospholipid useful in the present invention is derived from plants or animals, and contains a saturated or unsaturated alkyl ester group of 4 to 30 carbon atoms with a polar head.
  • the phospholipid may be selected from among phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, phosphatidylinositol, phosphatidic acid, sphingomyelin, and a combination thereof according to the structure of the polar head.
  • Phospholipids are found in plants and animals such as soybeans and eggs.
  • long alkyl ester groups which account for the hydrophobic tails include saturated fatty acid chains such as mono- and dipalmitoyl, mono- and dimyristoyl, mono- and dilauryl, and mono- and distearyl, and unsaturated fatty acid chains such as mono- or dilinoleyl, mono- and dioleyl, mono- and dipalmitoleyl, and mono- and dimyristoleyl.
  • Saturated and unsaturated fatty acid esters may coexist in phospholipids.
  • the liquid crystal hardener of the present invention cannot form a non-lamellar structure, unlike the liquid crystal former, nor a lamellar structure such as liposome) unlike phospholipids, by itself.
  • the liquid crystal hardener contributes to the liquid crystal former-driven formation of non-lamellar phase structures by increasing the curvature of the non-lamellar structures to enhance the ordered co-existence of oil and water.
  • the liquid crystal hardener is advantageously required to have a highly limited polar moiety and a bulky non-polar moiety inside its molecular structure.
  • liquid crystal hardener of the present invention In practice, however, biocompatible molecules which are injectable into the body can be selected as the liquid crystal hardener of the present invention only via direct and repeated experiments.
  • liquid crystal hardeners suitable for the composition of the present invention have molecular structures which are different from one another and thus cannot be elucidated as having only one molecular structure.
  • the common structural feature deduced by observation of all of the liquid crystal hardeners identified is that they are free of ionizable groups, such as carboxyl and amine groups, and have hydrophobic moieties comprising a bulky triacyl group with 15 to 40 carbon atoms or carbon ring structure.
  • liquid crystal hardener of the present invention may be free of ionizable groups, such as carboxyl and amine groups, and have at most one hydroxyl and ester group as a weak polar head, with hydrophobic moieties including a bulky triacyl group with 20 to 40 carbon atoms or carbon ring structure.
  • the liquid crystal hardener of the present invention may include, but are not limited to, triglyceride, retinyl palmitate, tocopherol acetate, cholesterol, benzyl benzoate, ubiquinone, and a combination thereof.
  • the liquid crystal hardener may be selected from among tocopherol acetate, cholesterol, and a combination thereof.
  • GnRH analogues are structurally similar to GnRH, but work in different ways in vivo. On the whole, after pulsatile secretion, GnRH performs a biological function to induce the production of sex steroids whereas GnRH analogues are used to potently inhibit the production of sex steroids for a certain period of time in the body.
  • GnRH analogues may be classified into agonists and antagonists.
  • a GnRH agonist When administered at a therapeutic dose to the body, a GnRH agonist initially binds to a GnRH receptor of the pituitary gland to stimulate the biosynthesis and secretion of follicle stimulating hormone (FSH) and leuteinizing hormone (LH).
  • FSH follicle stimulating hormone
  • LH leuteinizing hormone
  • continuation of the administration with the GnRH agonist results in the depletion of the gonadotropin and inhibition of the biosynthesis and secretion of FSH and LH while down-regulating the GnRH receptor.
  • GnRH analogues may be applied to the treatment of sex hormone-dependent diseases such as prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary syndrome, hypertrichosis, precocious puberty, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility, and may be used as a anticonceptive.
  • sex hormone-dependent diseases such as prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary syndrome, hypertrichosis, precocious puberty, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility, and may be used as a anticonceptive
  • the GnRH agonist as a pharmacologically active substance of the present invention may be selected from among leuprolide, goserelin, triptorelin, nafarelin, buserelin, histrelin, deslorelin, meterelin, gonadrelin, and a pharmaceutically acceptable salt thereof.
  • the pharmacologically active substance may be selected from among leuprolide, goserelin and a pharmaceutically acceptable salt thereof.
  • a GnRH antagonist competes with GnRH for a GnRH receptor of the pituitary gland to block the binding of GnRH to its receptor, thereby suppressing the biosynthesis and secretion of FSH and LH.
  • the GnRH antagonist as a pharmacologically active substance of the present invention include degarelix, abarelix, ganirelix, cetrorelix, and a pharmaceutically acceptable salt thereof.
  • the pharmacologically active substance may be selected from among leuprolide, goserelin and a pharmaceutically acceptable salt thereof.
  • the weight ratio between components of a) and b) suitable for the formation of liquid crystals is in a range of from 10:1 to 1:10, and preferably in a range of 5:1 to 1:5.
  • the weight ratio of a)+b) to c) falls within the range of from 100:1 to 1:1, and preferably within the range of from 50:1 to 2:1. Given these weight ranges, the components efficiently guarantee the sustained release of liquid crystals and the sustained release behaviors can be controlled by regulating the ratio.
  • the suitable weight ratio of a)+b)+c) to d) for providing the sustained release of the GnRH analogue ranges from 10,000:1 to 1:1, and preferably from 1,000:1 to 1:1.
  • the pharmaceutical composition of the present invention comprises a) in an amount of 9 ⁇ 90 weight %; b) in an amount of 9 ⁇ 90 weight %; c) in an amount of 0.1 ⁇ 50 weight %; and d) in an amount of 0.01 ⁇ 50 weight %.
  • the pharmaceutical composition comprises a) in an amount of 9 ⁇ 64 weight %; b) in an amount of 18 ⁇ 76 weight %; c) in an amount of 1 ⁇ 36 weight %; and d) leuprolide, or a pharmaceutically acceptable salt thereof in an amount of 0.1 ⁇ 50 weight % but are not limited thereto.
  • the pharmaceutical composition comprises a) in an amount of 9 ⁇ 64 weight %; b) in an amount of 18 ⁇ 76 weight %; c) in an amount of 1 ⁇ 36 weight %; and d) goserelin or a pharmaceutically acceptable salt thereof in an amount of 0.1 ⁇ 50 weight % but are not limited thereto.
  • the pharmaceutical composition comprises a) in an amount of 9 ⁇ 64 weight %; b) in an amount of 18 ⁇ 76 weight %; c) in an amount of 1 ⁇ 36 weight%; and d) degarelix or a pharmaceutically acceptable salt thereof in an amount of 2 ⁇ 50 weight % but are not limited thereto.
  • compositions of the present invention exhibit excellent sustained release behavior.
  • aqueous fluid is intended to include water and body fluid such as a mucosal solution, a tear, a sweat, a saliva, a gastrointestinal fluid, an extravascular fluid, an extracellular fluid, an interstitial fluid, and a blood plasma.
  • body fluid such as a mucosal solution, a tear, a sweat, a saliva, a gastrointestinal fluid, an extravascular fluid, an extracellular fluid, an interstitial fluid, and a blood plasma.
  • the pharmaceutical composition of the present invention undergoes transition from a liquid phase to a liquid crystalline phase with a semi-solid appearance. That is, the pharmaceutical composition of the present invention exists as a liquid state before application to the human body and shifts into a liquid crystalline phase with sustained release behavior within the body.
  • the liquid crystals formed by the pharmaceutical composition of the present invention have a non-lamellar phase structure in which oil and water are in an ordered mixture and arrangement without distinction between inner and out phases.
  • the ordered arrangement of oil and water renders the non-lamellar phase structure of a mesophase, which is a state of matter intermediate between liquid and solid.
  • the pharmaceutical composition of the present invention is different from conventional compositions that are lamellar structures, such as micelles, emulsions, microemulsions, liposomes, and lipid bilayers, which have been widely used in designing pharmaceutical formulations.
  • lamellar structures are in oil in water (o/w) or water in oil (w/o) type in which there have an arrangement with inner and out phases.
  • liquid crystallization refers to the formation of liquid crystals having a non-lamellar phase structure from the pre-concentrate upon exposure to aqueous fluid.
  • the pharmaceutical composition of the present invention may be prepared at room temperature from a) at least one liquid crystal former, b) at least one phospholipid, c) at least one liquid crystal hardener, and d) at least one GnRH analogue, and if necessary, by heating or using a homogenizer.
  • the homogenizer may be a high-pressure homogenizer, an ultrasonic homogenizer, a bead mill homogenizer, and etc.
  • the sustained-release lipid pre-concentrate of the present invention may be a pharmaceutical composition which exists in a liquid phase in the absence of aqueous fluid and forms into liquid crystals in the presence of aqueous fluid.
  • the pre-concentrate of the present invention may be preferably formulated into various dosage forms including injections, ointments, gels, lotions, capsules, tablets, solutions, suspensions, sprays, inhalants, eye drops, adhesives, plaster and pressure sensitive adhesives.
  • the pharmaceutical composition of the present invention may be administered by subcutaneous or intramuscular injection or other injection routes depending on the properties of the pharmacologically active substance.
  • the pharmaceutical composition of the present invention may be preferably in the formulation form selected from among injections, ointments, gels, lotions, capsules, tablets, solutions, suspensions, sprays, inhalants, eye drops, adhesives, plaster and pressure sensitive adhesives, and more preferably into injections.
  • the pharmaceutical composition of the present invention may be prepared by adding a pharmacologically active substance to the pre-concentrate of the present invention. As needed, heat or a homogenizer may be used in the preparation of the pharmaceutical composition of the present invention, but this is not a limiting factor to the present invention.
  • the dose of the pharmaceutical composition of the present invention adheres to the well-known dose of the pharmacologically active substance employed, and may vary depending on various factors including the patient’s condition, age and sex. It may be administered orally or parenterally depending on the properties of the pharmacologically active substance.
  • the present invention contemplates a method of maintaining pharmaceutical efficacy through the sustained release of a pharmacologically active substance by administering the pharmaceutical composition of the present invention to a mammal including a human, and the use of the pharmaceutical composition for the sustained release of a pharmacologically active substance.
  • the pharmaceutical composition of the present invention based on a sorbitan unsaturated fatty acid ester, is highly safe and exists in a liquid phase in the absence of aqueous fluid but rapidly changes into liquid crystals upon exposure to aqueous fluid within the body. Therefore, the pharmaceutical composition can be easily administered, exhibits excellent sustained release of a GnRH analogue without side effects such as pain and inflammation, compared to conventional sustained release formulations in solid particle phases.
  • FIG. 1 illustrates phase change behaviors of compositions of Examples 2, 6, 9 and 12 upon exposure to aqueous fluid.
  • FIG. 2 shows the liquid crystalline structures of the compositions of Examples 2 and 6, formed in aqueous fluid.
  • FIG. 3 shows the in vivo drug release behaviors of the compositions of Example 2 and Comparative Example 1.
  • FIG. 4 shows the in vivo drug release behaviors of the compositions of Example 6 and Comparative Example 2.
  • the additives and excipients used in the present invention satisfied the requirements of the Pharmacopoeia and were purchased from Aldrich, Lipoid, Croda, and Seppic.
  • Sorbitan unsaturated fatty acid esters, phospholipids, liquid crystal hardeners, and pharmacologically active substances were added, at the weight ratios given in Table 1, below.
  • Example 1 to 12 the substances were homogeneously mixed in a water bath maintained at 20 ⁇ 75°C using a homogenizer (PowerGen model 125. Fisher) for 0.5 ⁇ 3 hrs at 1000 ⁇ 3000 rpm.
  • the resulting lipid solutions were left at room temperature to come to thermal equilibrium at 25°C, followed by adding each of the pharmacologically active substances leuprolide acetate, goserelin acetate, and degarelix acetate thereto. Then, the substances were homogenized using a homogenizer for about 5 ⁇ 30 mins at 1,000 ⁇ 3,000 rpm to prepare pharmaceutical compositions in a liquid phase.
  • compositions prepared in Examples contained pharmacologically active substances at a therapeutically effective concentration
  • contents of leuprolide acetate were quantitated by HPLC, as follows.
  • a standard sample with the same concentration as that of the test samples was prepared from a leuprolide acetate standard.
  • the standard sample and the test samples were loaded in an injection volume of 20 ⁇ L at a flow rate of 1.0 ⁇ 1.5 mL/min to 4.6 ⁇ 100 mm, 3 ⁇ m packing L1 column or like, and quantitatively analyzed at 220 nm using a UV spectrometer. Average contents of leuprolide acetate in the pharmaceutical compositions were obtained from three measurements (see Table 2).
  • the pharmaceutical compositions prepared in Examples 1 to 12 existed in liquid phase in the absence of aqueous fluid.
  • PBS aqueous fluid
  • the pharmaceutical compositions in liquid phase forms into spherical liquid crystals, indicating that the pharmacologically active substance GnRH analogue has no influence on the formation of the pharmaceutical compositions into liquid crystals.
  • liquid crystals of the pharmaceutical compositions of Examples 2 and 6, formed in aqueous fluid, were observed for structure under a polarization microscope (Motic, BA 300 Pol) (FIG. 2).
  • a slide glass was very thinly coated with each of the pharmaceutical compositions of Examples 2 and 6, and left for 4 hrs in deionized water in a schale to form liquid crystals. After being covered with a cover glass to prevent the introduction of air, the test sample on slide glass was observed at 200x magnification using a polarization microscope (Motic, BA 300 Pol). As can be seen in FIG. 2, the pharmaceutical compositions of Examples 2 and 6 are formed into liquid crystals with typical hexagonal crystalline structures for excellent sustained release.
  • the pharmaceutical compositions of the present invention can form physiochemically stable, ideal liquid crystals in the presence of aqueous fluid even if they contain pharmacologically active substances which have large molecular weights and relatively high hydrophobicity.
  • each of the pharmaceutical compositions of Examples 2 and 6 was subcutaneously injected at a leuprolide acetate dose of 12.5 mg/kg (corresponding to a 28-day dose for humans) into the back of 6 SD rats (male), 9 weeks old, with an average body weight of 300 g.
  • the pharmaceutical compositions of Comparative Examples 1 and 2 were subcutaneously injected at a leuprolide acetate dose of 12.5 mg/kg (corresponding to a 28-day dose for humans) into the back of 6 SD rats (male), 9 weeks old, with an average body weight of 300 g.
  • Leuprolide acetate concentrations in plasma samples taken from the SD rats were monitored for 28 days using LC-MS/MS (liquid chromatography-mass spectrometry) to draw PK profiles (pharmacokinetic profiles).
  • the average of leuprolide acetate concentration taken from the 6 SD rats are plotted in graph of each of FIG. 3 and 4, and expressed as calculated logarithm values in the lower graph of each of FIG. 3 and 4 to examine a difference in drug concentration of rat plasma at the late phase.
  • Comparative Example 1 was of 3.75 mg of Leuplin DPS(CJ), which is widely used as a 1-month formulation of leuprolide acetate.
  • the pharmaceutical composition of Example 2 exhibited ideal pK behavior and excellent sustained release.
  • the pharmaceutical composition of Example 2 had an initial burst concentration of 81 ng/mL, which is about half reduced, compared to 155 ng/mL of Comparative Example 1, thus achieving an exceptional improvement in initial burst concentration, a typical problem with PLGA microparticle formulations.
  • the pharmaceutical composition of Example 2 maintained very stable effective plasma concentration of leuprolide acetate.
  • FIG. 4 shows the PK profiles in SD rats of the pharmaceutical compositions of Comparative Example 2 and Example 6.
  • Comparative Example 2 was of 11.25 mg of Leuplin DPS(CJ), which is widely used as a 3-month formulation of leuprolide acetate.
  • the pharmaceutical composition of Example 6 exhibited ideal pK behavior required for sustained release formulations, and particularly excellent sustained release for a long-term.
  • the composition of Comparative Example 2 showed an initial burst concentration about three times as high as that of Comparative Example 1, which was believed to be attributed to the difference of drug content therebetween.
  • Example 6 Although the pharmaceutical composition of Example 6 was 3-fold higher in drug content than that of Example 2, no observations were made of the rapid increase in initial burst concentration, unlike the composition of Comparative Example 2.
  • the initial burst concentration was measured to be 114 ng/ml, which is about 4-fold smaller than 484 ng/ml, which was measured at the initial phase in the composition of Comparative Example 2.
  • the composition of Comparative Example 2 had blood leuprolide acetate levels from 10 days after administration, which was significantly lower level compared to the composition of Comparative Example 1 in the mid- to later phase., drawing an unstable PK profile.
  • Example 6 allowed for a blood leuprolide acetate level curve which was similar to that of Example 2 in the mid- to late phase, demonstrating that the pharmaceutical composition of the present invention, even though 3-fold increasing in drug content, maintained excellent long-term sustained release.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Gynecology & Obstetrics (AREA)
  • Diabetes (AREA)
  • Inorganic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Disclosed is a pharmaceutical composition, comprising: a) at least one sorbitan unsaturated fatty acid ester having a polar head with at least two or more -OH (hydroxyl) groups; b) at least one phospholipid; c) at least one liquid crystal hardener which is free of an ionizable group and has a triacyl group with 15 to 40 carbon atoms or a carbon ring structure in a hydrophobic moiety; and d) at least one GnRH (gonadotropin-releasing hormone) analogue as a pharmacologically active substance, wherein said lipid pre-concentrate exists as a liquid phase in absence of aqueous fluid and forms into a liquid crystal in presence of aqueous fluid. The pharmaceutical composition is configured to enhance the sustained release of the pharmacologically active substance GnRH analogue.

Description

SUSTAINED-RELEASE LIPID PRE-CONCENTRATE OF GNRH ANALOGUES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
The present invention relates to a sustained-release lipid pre-concentrate comprising a GnRH analogue as a pharmacologically active substance, and a pharmaceutical composition comprising the same.
Sustained release formulations are designed to release a single dose of a pharmacologically active substance at a predetermined rate in order to maintain the effective concentration of the substance in the blood stream for a specific period of time, with minimization of the side effects caused by multiple doses.
In consideration of the therapeutic mechanism and physical and chemical properties thereof, gonadotropin-releasing hormone (GnRH) derivatives are representative of pharmacologically active substance to be designed as sustained-release formulations.
Gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a neuroendocrine peptide which is synthesized and released from neurons in the neurovascular terminal of hypothalamus. Once being released from the hypothalamus, GnRH selectively binds to specific receptors on the membrane of anterior pituitary gonadotroph cells to induce the biosynthesis and release of follicle-stimulating hormone (FSH) and leuteinizing hormone (LH). FSH and LH act to regulate the production of sex steroids from sex glands in males and females. Due to the biological functions of GnRH, its analogues may be useful for the treatment of sex hormone-dependent diseases such as prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary syndrome, hypertrichosis, precocious puberty, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility.
Lupron® Depot is a commercially available, intramuscular or subcutaneous injection for the sustained release of the GnRH analogue leuprolide acetate, with the biodegradable PLGA [poly(lactic-co-glycolic acid)] microparticles delivering as a sustained release matrix. Generally, PLGA microparticles degrade into lactic acid and glycolic acid over a specific period of time in vivo, releasing the pharmacologically active substance loaded there within in a sustained manner (U. S. Patent No. 5,480,656). However, not only are the fabrication processes of PLGA microparticles complicated and difficult, but also pharmacologically active substances are loaded thereinto with significantly poor efficiency. In addition, because a PLGA microparticles are difficult to filter sterilization, and melt at 40℃ or higher, the sterilization thereof cannot be achieved with general processes, but requires highly sterile conditions. An ideal sustained-release profile is obtained using two or more different PLGA microparticles which, however, further complicate the processes of fabrication and mixing (WO 2005/074896), increasing the production cost. In addition, acetic acid impurities and acidic degradation products from PLGA microparticles induce inflammation and reduce cell growth rates (K. Athanasiou, G. G. Niederauer, and C. M. Agrawal, Biomaterials, 17, 93 (1996)). For the sustained release, a suspension of 10~100 μm PLGA microparticles in an aqueous solution is injected in a significant amount, but this gives rise to a pain or a tissue damage at the injection site.
Eligard® was introduced as a sustained-release injection formulation for a GnRH analogue (leuprolide acetate) which compensates the problems with PLGA microparticle-based sustained-release formulations. Eligard® is widely marketed as a subcutaneous injection which is prepared by dissolving PLGA [poly(DL-lactide-co-glycolide)] having a protected carboxyl terminal group and a GnRH analogue (leuprolide acetate) in N-methyl-2-pyrrolidone (NMP). Eligard® exists as a flowable composition which can be prepared by dissolving a biodegradable polymer in a polar aprotic solvent, and is designed as a subcutaneous injection with an improvement in partially drawbacks with solid PLGA microparticle formulations (U. S. Patent No. 6,773,714). This commercial product is very poor in usability because of no supply of a complete prefilled syringes device, and exhibits low drug stability upon the mixture solution. The device provided in the product comprises two syringes which can be connected to each other, and mixing, preparing and injecting tools. A final mixture solution is not obtained until more than about 10 steps are carried out, and only 30 mins is given to an entire process from preparation to injection. In addition, the product must be stored in a refrigerator, and unless stored in a refrigerator, the final mixed solution cannot be used for more than 5 days. Moreover, no improvements are observed in the product with regard to a high initial burst, which is a drawback typical to PLGA microparticle formulations. Rather, the product exhibits higher initial burst concentration, compared to the PLGA microparticle formulation Lupron® Depot (U. S. Patent No. 6,773,714). An initial burst concentration greatly exceeding that at which a drug can function is undesirable in both functionally and toxicologically. Particularly in consideration of the mechanism of the GnRH analogue in which the sex hormone release is temporally increased at an initial stage of administration, and then downregulated from a certain time point, an excessive initial burst concentration must be avoided.
As an alternative solution to the problems with PLGA microparticle formulations, the International Patent Publication No. WO 2005/117830 describes a pre-formulation comprising at least one neutral diacyl lipid and/or at least one tocopherol, at least one phospholipid, and at least one biocompatible, oxygen containing, low viscosity organic solvent. Another alternative is described in the International Patent Publication No. WO 2006/075124 which concerns a pre-formation comprising at least one diacyl glycerol, at least one phosphatidyl choline, at least one oxygen containing organic solution, and at least one GnRH analogue. These pre-formulations allow the sustained release of a pharmacologically active substance in vivo for four weeks, and do not form lactic acid or glycolic acid degradation products from their polymer systems, thus not causing pain or inflammation. However, there is a problem with the formulations in that the use of a diacyl lipid, a component essential for the pre-formulations, as a pharmaceutical excipient is not usable and it has to be proven to be sufficiently safe, and that their obligatory organic solvent incurs a reduction in the activity of some pharmacologically active substances (H. Ljusberg-Wahre, F. S. Nielse, 298, 328-332 (2005); H. Sah, Y. Bahl, Journal of Controlled Release 106, 51-61(2005)).
Culminating in the present inventors suggested a sustained-release lipid pre-concentrate comprising a) sorbitan unsaturated fatty acid ester; b) a phospholipid; and c) a liquid crystal hardener, and a pharmaceutical composition comprising the pre-concentrate (Korean Patent Application No. 10-2012-0093677). This sustained-release lipid pre-concentrate exhibits in vivo safety and biodegradability at the same or higher levels, compared to conventional pre-concentrates and the pharmaceutical composition is found to allow for the sustained release of the pharmacologically active substance loaded therein.
Moreover, the further research of the present inventors resulted in the finding that when applied to the sustained-release lipid pre-concentrate, a GnRH analogue can be released in a sustained manner at a concentration sufficient to act as a pharmacological active substance in vivo, leading to the present invention.
A description is given of the prior arts relevant to the present invention, infra.
U. S. Pat. No. 7,731,947 describes a composition comprising: a particle formulation comprising an interferon, sucrose, methionine, and a citrate buffer, and a suspending solution comprising a solvent such as benzyl benzoate, wherein the particle formulation is dispersed in the suspending solution, elucidating the application of GnRH analogues thereto. In one Example, it is described that phosphatidylcholine is dissolved together with vitamin E (tocopherol) in an organic solvent and is used to disperse the particle formulation therein. However, this composition is different from the present invention in that the composition is used to disperse solid particles and does not allow the formation of liquid crystals.
U. S. Pat. No. 7,871,642 describes a method of preparing a dispersion for delivering a pharmacologically active substance comprising hormone formulation, dispersing a homogeneous mixture of a phospholipid, a polyoxyethylene-containing coemulsifier, triglyceride and ethanol in water, wherein the polyoxyethylene-containing surfactant is selected from among polyoxyethylene sorbitan fatty acid esters (polysorbate) and polyethoxylated vitamin E derivatives. polyoxyethylene sorbitan fatty acid esters and polyethoxylated vitamin E derivatives, derived by conjugating the hydrophilic polymer polyoxyethylene to sorbitan fatty acid ester and vitamin E, respectively, are quite different in structure from sorbitan fatty acid ester and vitamin E. They are usually used as hydrophilic surfactants utilizing the property of polyoxyethylene, which is different from the component of the present invention.
U. S. Pat. No. 5,888,533 describes a flowable composition for forming a solid biodegradable implant in situ within a body, comprising: a non-polymeric, water-insoluble, biodegradable material; and a biocompatible, organic solvent that at least partially solubilizes the non-polymeric, water-insoluble, biodegradable material and is miscible or dispersible in water or body fluids, and capable of diffusing-out or leaching from the composition into body fluid upon placement within a body, whereupon the non-polymeric material coagulates or precipitates to form the solid implant. In this composition, sterols, cholesteryl esters, fatty acids, fatty acid glycerides, sucrose fatty acid esters, sorbitan fatty acid esters, fatty alcohols, esters of fatty alcohols with fatty acids, anhydrides of fatty acids, phospholipids, lanolin, lanolin alcohols, and combinations thereof are described as the non-polymeric material, and ethanol is used as the solvent. However, differences from the present invention reside in that this composition cannot form liquid crystals and is designed to form solid implants by simple coagulation or precipitation of water-insoluble materials and that a lot of the organic solvent is necessarily used.
It is therefore an object of the present invention to provide a pharmaceutical composition based on a sorbitan unsaturated ester having a polar head with at least two -OH(hydroxyl) groups that has significantly high safety and biodegradability and exists in a liquid state advantageous for injection applications while forming into a liquid crystal upon exposure to aqueous fluid, thus enhancing the sustained release of a GnRH analogue in vivo.
It is another object of the present invention to provide a pharmaceutical composition which can be injected without producing pain, inflammations and initial burst concentrate, problems which are reported in conventional formulations.
In accordance with an aspect thereof, the present invention provides a pharmaceutical composition, comprising a) at least one sorbitan unsaturated fatty acid ester; b) at least one phospholipid; c) at least one liquid crystal hardener; and d) at least one GnRH analogue, as a pharmacologically active substance, wherein the composition exists as a liquid phase in the absence of aqueous fluid and forms into a liquid crystal in the presence of aqueous fluid.
Below, a detailed description will be given of each component.
a) Sorbitan unsaturated fatty acid ester
For use as a liquid crystal former in the present invention, the sorbitan unsaturated fatty acid ester preferably has two or more -OH(hydroxyl) groups in the polar head. This sorbitan unsaturated fatty acid ester is represented by the following Chemical Formula 1. The compound of Chemical Formula 1 is sorbitan monoester where R1=R2=OH, R3=R, and sorbitan diester where R1=OH, R2=R3=R, R being an alkyl ester of 4 to 30 carbon atoms with at least one unsaturated bond.
[Chemical Formula 1]
Figure PCTKR2013012269-appb-I000001
The sorbitan fatty acid ester, which accounts for the formation of a liquid crystal in the present invention, is different from conventional counterparts such as oleyl glycerate (OG), phytanyl glycerate (PG), and glycerine monooleate (GMO), glycerine dioleate (GDO) of the following Chemical Formula 2. That is, the conventional molecules responsible for liquid crystalline phases share the common structure consisting of a polar head derived from glycerine or glyceric acid and a non-polar tail derived from a lipid alcohol or fatty acid.
[Chemical Formula 2]
Figure PCTKR2013012269-appb-I000002
However, the conventional molecules responsible for liquid crystalline phases are somewhat difficult to apply to the development of medications because of the following disadvantages. Oleyl glycerate (OG) and phytanyl glycerate (PG), although capable of readily forming into liquid crystals, are rarely used as pharmaceutical excipients for human medicine because of their relatively high toxicity. On the other hand, glycerine monooleate (GMO) is useful as a pharmaceutically acceptable excipient, but has weak crystallinity to form liquid crystals necessary for sustained release medications.
Glycerol dioleate (GDO), which is used in International Patent Publication No. WO 2005/117830 as described supra, is a diacyl lipid with glycerin functioning as a polar head. This molecule is not generally used as a pharmaceutical excipient because its safety has not yet been proven.
Following intensive and thorough research, the present inventors found that sorbitan unsaturated fatty acid esters have advantages over conventionally used liquid crystalline molecules, glycerine or glyceric acid derivatives in that they form liquid crystals very effectively for the sustained release of pharmacologically active substance, with superiority in safety and biodegradability and are applicable to the development of medical products overcoming the problems encountered in the prior art. For use in compositions for medicaments, materials must be guaranteed to be safe and biodegradable. Further, biodegradability is a very important factor for the material which is in charge of sustained release in the body. If the sustained release injection using PLGA is designed to release a pharmacologically active substance for one week, it is ideal that the PLGA is degraded in vivo one week after injection. In fact, however, PLGA remains intact for one to several months even after the function of sustained release is finished. Therefore, the sorbitan unsaturated fatty acid ester of the present invention, which has excellent sustained release property, safety and biodegradability, is applicable for a novel liquid crystal-inducing material with great value in pharmaceutical industry.
In detail, the sorbitan unsaturated fatty acid ester of the present invention may be selected from sorbitan monoester, sorbitan sesquiester, sorbitan diester and a combination thereof, which can be derived from fatty acids obtainable from whale oils and fish oils as well as vegetable oils (e.g., coconut oil, castor oil, olive oil, peanut oil, rapeseed oil, corn oil, sesame oil, cotton seed oil, soybean oil, sunflower seed oil, safflower oil, linseed oil, etc.), and animal fats and oils (e.g., milk fat, lard, and beef tallow).
Sorbitan monoester is a compound in which one fatty acid group is attached to sorbitan via an ester bond, and may be selected from among sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, and a combination thereof.
Sorbitan sesquiester is a compound in which 1.5 fatty acid groups, on average, are attached to sorbitan via an ester bond, and may be selected from among sorbitan sesquioleate, sorbitan sesquilinoleate, sorbitan sesquipalmitoleate, sorbitan sesquimyristoleate, and a combination thereof.
Sorbitan diester is a compound in which two fatty acid groups are attached to sorbitan via an ester bond, and may be selected from among sorbitan dioleate, sorbitan dilinoleate, sorbitan dipalmitoleate, sorbitan dimyristoleate, and a combiantion thereof.
For use in the present invention, sorbitan unsaturated fatty acid ester is preferably selected from sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, sorbitan sesquioleate, and a combination thereof.
b) Phospholipid
Phospholipids are essential for the construction of lamellar structures, such as liposomes, in conventional techniques, but cannot form a non-lamellar phase structure, such as a liquid crystal, by themselves. However, phospholipids can participate in the liquid crystal former-driven formation of non-lamellar phase structures, serving to stabilize the resulting liquid crystals.
The phospholipid useful in the present invention is derived from plants or animals, and contains a saturated or unsaturated alkyl ester group of 4 to 30 carbon atoms with a polar head. The phospholipid may be selected from among phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, phosphatidylinositol, phosphatidic acid, sphingomyelin, and a combination thereof according to the structure of the polar head.
Phospholipids are found in plants and animals such as soybeans and eggs. In phospholipids, long alkyl ester groups which account for the hydrophobic tails include saturated fatty acid chains such as mono- and dipalmitoyl, mono- and dimyristoyl, mono- and dilauryl, and mono- and distearyl, and unsaturated fatty acid chains such as mono- or dilinoleyl, mono- and dioleyl, mono- and dipalmitoleyl, and mono- and dimyristoleyl. Saturated and unsaturated fatty acid esters may coexist in phospholipids.
c) Liquid crystal hardener
The liquid crystal hardener of the present invention cannot form a non-lamellar structure, unlike the liquid crystal former, nor a lamellar structure such as liposome) unlike phospholipids, by itself. However, the liquid crystal hardener contributes to the liquid crystal former-driven formation of non-lamellar phase structures by increasing the curvature of the non-lamellar structures to enhance the ordered co-existence of oil and water. In the interests of this function, the liquid crystal hardener is advantageously required to have a highly limited polar moiety and a bulky non-polar moiety inside its molecular structure.
In practice, however, biocompatible molecules which are injectable into the body can be selected as the liquid crystal hardener of the present invention only via direct and repeated experiments. As a result, liquid crystal hardeners suitable for the composition of the present invention have molecular structures which are different from one another and thus cannot be elucidated as having only one molecular structure. The common structural feature deduced by observation of all of the liquid crystal hardeners identified is that they are free of ionizable groups, such as carboxyl and amine groups, and have hydrophobic moieties comprising a bulky triacyl group with 15 to 40 carbon atoms or carbon ring structure. Preferred examples of the liquid crystal hardener of the present invention may be free of ionizable groups, such as carboxyl and amine groups, and have at most one hydroxyl and ester group as a weak polar head, with hydrophobic moieties including a bulky triacyl group with 20 to 40 carbon atoms or carbon ring structure. Examples of the liquid crystal hardener of the present invention may include, but are not limited to, triglyceride, retinyl palmitate, tocopherol acetate, cholesterol, benzyl benzoate, ubiquinone, and a combination thereof. Preferably, the liquid crystal hardener may be selected from among tocopherol acetate, cholesterol, and a combination thereof.
d) GnRH Analogues
GnRH analogues are structurally similar to GnRH, but work in different ways in vivo. On the whole, after pulsatile secretion, GnRH performs a biological function to induce the production of sex steroids whereas GnRH analogues are used to potently inhibit the production of sex steroids for a certain period of time in the body.
According to their acting mechanisms, GnRH analogues may be classified into agonists and antagonists. When administered at a therapeutic dose to the body, a GnRH agonist initially binds to a GnRH receptor of the pituitary gland to stimulate the biosynthesis and secretion of follicle stimulating hormone (FSH) and leuteinizing hormone (LH). However, continuation of the administration with the GnRH agonist results in the depletion of the gonadotropin and inhibition of the biosynthesis and secretion of FSH and LH while down-regulating the GnRH receptor. Based on the biological functions of GnRH, GnRH analogues may be applied to the treatment of sex hormone-dependent diseases such as prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovary syndrome, hypertrichosis, precocious puberty, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility, and may be used as a anticonceptive.
The GnRH agonist as a pharmacologically active substance of the present invention may be selected from among leuprolide, goserelin, triptorelin, nafarelin, buserelin, histrelin, deslorelin, meterelin, gonadrelin, and a pharmaceutically acceptable salt thereof. Preferably, the pharmacologically active substance may be selected from among leuprolide, goserelin and a pharmaceutically acceptable salt thereof.
On the other hand, a GnRH antagonist competes with GnRH for a GnRH receptor of the pituitary gland to block the binding of GnRH to its receptor, thereby suppressing the biosynthesis and secretion of FSH and LH. Examples of the GnRH antagonist as a pharmacologically active substance of the present invention include degarelix, abarelix, ganirelix, cetrorelix, and a pharmaceutically acceptable salt thereof. Preferably, the pharmacologically active substance may be selected from among leuprolide, goserelin and a pharmaceutically acceptable salt thereof.
In the pharmaceutical composition of the present invention, the weight ratio between components of a) and b) suitable for the formation of liquid crystals is in a range of from 10:1 to 1:10, and preferably in a range of 5:1 to 1:5. The weight ratio of a)+b) to c) falls within the range of from 100:1 to 1:1, and preferably within the range of from 50:1 to 2:1. Given these weight ranges, the components efficiently guarantee the sustained release of liquid crystals and the sustained release behaviors can be controlled by regulating the ratio. The suitable weight ratio of a)+b)+c) to d) for providing the sustained release of the GnRH analogue ranges from 10,000:1 to 1:1, and preferably from 1,000:1 to 1:1.
Preferably, the pharmaceutical composition of the present invention comprises a) in an amount of 9~90 weight %; b) in an amount of 9~90 weight %; c) in an amount of 0.1~50 weight %; and d) in an amount of 0.01~50 weight %.
In another embodiment where the pharmacologically active substance is leuprolide, the pharmaceutical composition comprises a) in an amount of 9~64 weight %; b) in an amount of 18~76 weight %; c) in an amount of 1~36 weight %; and d) leuprolide, or a pharmaceutically acceptable salt thereof in an amount of 0.1~50 weight % but are not limited thereto.
In another embodiment where the pharmacologically active substance is goserelin, the pharmaceutical composition comprises a) in an amount of 9~64 weight %; b) in an amount of 18~76 weight %; c) in an amount of 1~36 weight %; and d) goserelin or a pharmaceutically acceptable salt thereof in an amount of 0.1~50 weight % but are not limited thereto.
In a further embodiment where the pharmacologically active substance is degarelix, the pharmaceutical composition comprises a) in an amount of 9~64 weight %; b) in an amount of 18~76 weight %; c) in an amount of 1~36 weight%; and d) degarelix or a pharmaceutically acceptable salt thereof in an amount of 2~50 weight % but are not limited thereto.
Given the content ranges of components a) to d), the pharmaceutical compositions of the present invention exhibit excellent sustained release behavior.
As used herein, the term “aqueous fluid” is intended to include water and body fluid such as a mucosal solution, a tear, a sweat, a saliva, a gastrointestinal fluid, an extravascular fluid, an extracellular fluid, an interstitial fluid, and a blood plasma. When brought into body surfaces, regions or cavities (e.g. inside the body) whose external environments are formed for by aqueous fluids, the pharmaceutical composition of the present invention undergoes transition from a liquid phase to a liquid crystalline phase with a semi-solid appearance. That is, the pharmaceutical composition of the present invention exists as a liquid state before application to the human body and shifts into a liquid crystalline phase with sustained release behavior within the body.
The liquid crystals formed by the pharmaceutical composition of the present invention have a non-lamellar phase structure in which oil and water are in an ordered mixture and arrangement without distinction between inner and out phases. The ordered arrangement of oil and water renders the non-lamellar phase structure of a mesophase, which is a state of matter intermediate between liquid and solid.
The pharmaceutical composition of the present invention is different from conventional compositions that are lamellar structures, such as micelles, emulsions, microemulsions, liposomes, and lipid bilayers, which have been widely used in designing pharmaceutical formulations. Such lamellar structures are in oil in water (o/w) or water in oil (w/o) type in which there have an arrangement with inner and out phases.
The term “liquid crystallization,” as used herein, refers to the formation of liquid crystals having a non-lamellar phase structure from the pre-concentrate upon exposure to aqueous fluid.
The pharmaceutical composition of the present invention may be prepared at room temperature from a) at least one liquid crystal former, b) at least one phospholipid, c) at least one liquid crystal hardener, and d) at least one GnRH analogue, and if necessary, by heating or using a homogenizer. The homogenizer may be a high-pressure homogenizer, an ultrasonic homogenizer, a bead mill homogenizer, and etc.
As described above, the sustained-release lipid pre-concentrate of the present invention may be a pharmaceutical composition which exists in a liquid phase in the absence of aqueous fluid and forms into liquid crystals in the presence of aqueous fluid. As it turns to a pharmaceutical composition which can be applied to the body using a method selected from among injection, coating, dripping, padding, oral administration, and spraying, the pre-concentrate of the present invention may be preferably formulated into various dosage forms including injections, ointments, gels, lotions, capsules, tablets, solutions, suspensions, sprays, inhalants, eye drops, adhesives, plaster and pressure sensitive adhesives.
Particularly, when an injection route is taken, the pharmaceutical composition of the present invention may be administered by subcutaneous or intramuscular injection or other injection routes depending on the properties of the pharmacologically active substance.
The pharmaceutical composition of the present invention may be preferably in the formulation form selected from among injections, ointments, gels, lotions, capsules, tablets, solutions, suspensions, sprays, inhalants, eye drops, adhesives, plaster and pressure sensitive adhesives, and more preferably into injections.
The pharmaceutical composition of the present invention may be prepared by adding a pharmacologically active substance to the pre-concentrate of the present invention. As needed, heat or a homogenizer may be used in the preparation of the pharmaceutical composition of the present invention, but this is not a limiting factor to the present invention.
The dose of the pharmaceutical composition of the present invention adheres to the well-known dose of the pharmacologically active substance employed, and may vary depending on various factors including the patient’s condition, age and sex. It may be administered orally or parenterally depending on the properties of the pharmacologically active substance.
In accordance with a further aspect thereof, the present invention contemplates a method of maintaining pharmaceutical efficacy through the sustained release of a pharmacologically active substance by administering the pharmaceutical composition of the present invention to a mammal including a human, and the use of the pharmaceutical composition for the sustained release of a pharmacologically active substance.
As described hitherto, the pharmaceutical composition of the present invention, based on a sorbitan unsaturated fatty acid ester, is highly safe and exists in a liquid phase in the absence of aqueous fluid but rapidly changes into liquid crystals upon exposure to aqueous fluid within the body. Therefore, the pharmaceutical composition can be easily administered, exhibits excellent sustained release of a GnRH analogue without side effects such as pain and inflammation, compared to conventional sustained release formulations in solid particle phases.
FIG. 1 illustrates phase change behaviors of compositions of Examples 2, 6, 9 and 12 upon exposure to aqueous fluid.
FIG. 2 shows the liquid crystalline structures of the compositions of Examples 2 and 6, formed in aqueous fluid.
FIG. 3 shows the in vivo drug release behaviors of the compositions of Example 2 and Comparative Example 1.
FIG. 4 shows the in vivo drug release behaviors of the compositions of Example 6 and Comparative Example 2.
The following non-limiting Examples serve to illustrate selected embodiments of the invention. It will be appreciated that variations in proportions and alternatives in elements of the components shown will be apparent to those skilled in the art and are within the scope of embodiments of the present invention.
The additives and excipients used in the present invention satisfied the requirements of the Pharmacopoeia and were purchased from Aldrich, Lipoid, Croda, and Seppic.
[EXAMPLES 1 TO 12] Preparation of Pharmacetucial Compositions
Sorbitan unsaturated fatty acid esters, phospholipids, liquid crystal hardeners, and pharmacologically active substances were added, at the weight ratios given in Table 1, below.
In Examples 1 to 12, the substances were homogeneously mixed in a water bath maintained at 20~75℃ using a homogenizer (PowerGen model 125. Fisher) for 0.5~3 hrs at 1000~3000 rpm. The resulting lipid solutions were left at room temperature to come to thermal equilibrium at 25℃, followed by adding each of the pharmacologically active substances leuprolide acetate, goserelin acetate, and degarelix acetate thereto. Then, the substances were homogenized using a homogenizer for about 5~30 mins at 1,000~3,000 rpm to prepare pharmaceutical compositions in a liquid phase.
[TABLE 1]
Figure PCTKR2013012269-appb-I000003
[COMPARATIVE EXAMPLES 1 AND 2]
For the formulation of Comparative Example 1, Leuplin DPS(CJ) containing leuprolide acetate as a pharmacologically active substance was used in an amount of 3.75 mg.
As the formulation of Comparative Example 2, 11.25 mg of Leuplin DPS(CJ) containing the pharmacologically active substance leuprolide acetate was used.
[EXPERIMENTAL EXAMPLE 1] Contents of Pharmacologically Active Substances in Pharmaceutical Compositions
To examine whether the pharmaceutical compositions prepared in Examples contained pharmacologically active substances at a therapeutically effective concentration, the contents of leuprolide acetate were quantitated by HPLC, as follows.
Each of the pharmaceutical compositions was dissolved in an amount corresponding to 2.5 mg of leuprolide acetate in a mobile phase (triethylamine buffer : acetonitrile : n-propyl alcohol = 85 : 9 : 6), and centrifuged for 10 min at 1500 rpm, followed by filtering the supernatants of the test sample through a 0.2 μm filter. For comparison, a standard sample with the same concentration as that of the test samples was prepared from a leuprolide acetate standard. The standard sample and the test samples were loaded in an injection volume of 20 μL at a flow rate of 1.0~1.5 mL/min to 4.6 × 100 mm, 3 μm packing L1 column or like, and quantitatively analyzed at 220 nm using a UV spectrometer. Average contents of leuprolide acetate in the pharmaceutical compositions were obtained from three measurements (see Table 2).
[TABLE 2]
Figure PCTKR2013012269-appb-I000004
As can be seen in Table 2, all of the pharmaceutical compositions prepared in Examples 1 to 8 ideally contained leuprolide acetate in amounts within standard content (100%) ± 3%.
[EXPERIMENTAL EXAMPLE 2] Formation of Liquid Crystals in Aqueous Fluid
An examination was made to comfirm whether the pharmaceutical compositions prepared in Examples form ideal liquid crystals in aqueous fluid. In this regard, the compositions of Examples 2, 6, 9, and 12 which were in liquid phase were loaded into syringes and then injected to 2 g of PBS (pH 7.4). The results are depicted in FIG. 1.
The pharmaceutical compositions prepared in Examples 1 to 12 existed in liquid phase in the absence of aqueous fluid. When injected into an aqueous fluid (PBS), the pharmaceutical compositions in liquid phase forms into spherical liquid crystals, indicating that the pharmacologically active substance GnRH analogue has no influence on the formation of the pharmaceutical compositions into liquid crystals.
[EXPERIMENTAL EXAMPLE 3] Structural Determination of Liquid Crystals in Aqueous Fluid
The liquid crystals of the pharmaceutical compositions of Examples 2 and 6, formed in aqueous fluid, were observed for structure under a polarization microscope (Motic, BA 300 Pol) (FIG. 2).
A slide glass was very thinly coated with each of the pharmaceutical compositions of Examples 2 and 6, and left for 4 hrs in deionized water in a schale to form liquid crystals. After being covered with a cover glass to prevent the introduction of air, the test sample on slide glass was observed at 200x magnification using a polarization microscope (Motic, BA 300 Pol). As can be seen in FIG. 2, the pharmaceutical compositions of Examples 2 and 6 are formed into liquid crystals with typical hexagonal crystalline structures for excellent sustained release.
When an account is taken of results from Experimental Examples 1 to 3, the pharmaceutical compositions of the present invention can form physiochemically stable, ideal liquid crystals in the presence of aqueous fluid even if they contain pharmacologically active substances which have large molecular weights and relatively high hydrophobicity.
[EXPERIMENTAL EXAMPLE 4] In Vivo PK Profile of Pharmaceutical Compositions
Drug release behaviors from the pharmaceutical compositions of the present invention were examined in vivo in the following test.
Using a disposable syringe, each of the pharmaceutical compositions of Examples 2 and 6 was subcutaneously injected at a leuprolide acetate dose of 12.5 mg/kg (corresponding to a 28-day dose for humans) into the back of 6 SD rats (male), 9 weeks old, with an average body weight of 300 g. For comparison with PK profiles of PLGA microparticle formulations, the pharmaceutical compositions of Comparative Examples 1 and 2 were subcutaneously injected at a leuprolide acetate dose of 12.5 mg/kg (corresponding to a 28-day dose for humans) into the back of 6 SD rats (male), 9 weeks old, with an average body weight of 300 g.
Leuprolide acetate concentrations in plasma samples taken from the SD rats were monitored for 28 days using LC-MS/MS (liquid chromatography-mass spectrometry) to draw PK profiles (pharmacokinetic profiles). The average of leuprolide acetate concentration taken from the 6 SD rats are plotted in graph of each of FIG. 3 and 4, and expressed as calculated logarithm values in the lower graph of each of FIG. 3 and 4 to examine a difference in drug concentration of rat plasma at the late phase.
The PK profiles in SD rats of the pharmaceutical compositions of Comparative Example 1 and Example 2 are shown in FIG. 3. As a control (reference drug) for Example 2, Comparative Example 1 was of 3.75 mg of Leuplin DPS(CJ), which is widely used as a 1-month formulation of leuprolide acetate. Compared to the control (reference drug) of Comparative Example 1, the pharmaceutical composition of Example 2 exhibited ideal pK behavior and excellent sustained release. The pharmaceutical composition of Example 2 had an initial burst concentration of 81 ng/mL, which is about half reduced, compared to 155 ng/mL of Comparative Example 1, thus achieving an exceptional improvement in initial burst concentration, a typical problem with PLGA microparticle formulations. In contrast to the composition of Comparative Example 1 which became unstable in PK behavior from 5 days after administration, the pharmaceutical composition of Example 2 maintained very stable effective plasma concentration of leuprolide acetate.
FIG. 4 shows the PK profiles in SD rats of the pharmaceutical compositions of Comparative Example 2 and Example 6. As a control (reference drug) for Example 6, Comparative Example 2 was of 11.25 mg of Leuplin DPS(CJ), which is widely used as a 3-month formulation of leuprolide acetate. Compared to the control (reference drug) of Comparative Example 2, the pharmaceutical composition of Example 6 exhibited ideal pK behavior required for sustained release formulations, and particularly excellent sustained release for a long-term. The composition of Comparative Example 2 showed an initial burst concentration about three times as high as that of Comparative Example 1, which was believed to be attributed to the difference of drug content therebetween. Although the pharmaceutical composition of Example 6 was 3-fold higher in drug content than that of Example 2, no observations were made of the rapid increase in initial burst concentration, unlike the composition of Comparative Example 2. The initial burst concentration was measured to be 114 ng/ml, which is about 4-fold smaller than 484 ng/ml, which was measured at the initial phase in the composition of Comparative Example 2. In addition, the composition of Comparative Example 2 had blood leuprolide acetate levels from 10 days after administration, which was significantly lower level compared to the composition of Comparative Example 1 in the mid- to later phase., drawing an unstable PK profile. On the other hand, the pharmaceutical composition of Example 6 allowed for a blood leuprolide acetate level curve which was similar to that of Example 2 in the mid- to late phase, demonstrating that the pharmaceutical composition of the present invention, even though 3-fold increasing in drug content, maintained excellent long-term sustained release.

Claims (23)

  1. A pharmaceutical composition, comprising:
    a) at least one sorbitan unsaturated fatty acid ester having a polar head with at least two or more -OH(hydroxyl) groups;
    b) at least one phospholipid;
    c) at least one liquid crystal hardener, which is free of an ionizable group, having a hydrophobic moiety of 15 to 40 carbon atoms with a triacyl group or a carbon ring structure; and
    d) at least one GnRH(gonadotropin-releasing hormone) analogue as a pharmacologically active substance, wherein said lipid pre-concentrate exists as a liquid phase in absence of aqueous fluid and forms into a liquid crystal in presence of aqueous fluid.
  2. The pharmaceutical composition of claim 1, wherein the sorbitan unsaturated fatty acid ester is selected from the group consisting of sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, sorbitan sesquioleate, sorbitan sesquilinoleate, sorbitan sesquipalmitoleate, sorbitan sesquimyristoleate, sorbitan dioleate, sorbitan dilinoleate, sorbitan dipalmitoleate, sorbitan dimyristoleate and a combination thereof.
  3. The pharmaceutical composition of claim 1, wherein the sorbitan unsaturated fatty acid ester is selected from the group consisting of sorbitan monooleate, sorbitan monolinoleate, sorbitan monopalmitoleate, sorbitan monomyristoleate, sorbitan sesquioleate and a combination thereof.
  4. The pharmaceutical composition of claim 1, wherein the phospholipid contains a saturated or unsaturated alkyl ester group of 4 to 30 carbon atoms and is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, phosphatidylinositol, phosphatidic acid, sphingomyelin and a combination thereof.
  5. The pharmaceutical composition of claim 4, wherein the phospholipid is phosphatidylcholine.
  6. The pharmaceutical composition of claim 1, wherein the liquid crystal hardener is selected from the group consisting of triglyceride, retinyl palmitate, tocopherol acetate, cholesterol, benzyl benzoate, ubiquinone, and a combination thereof.
  7. The pharmaceutical composition of claim 1, wherein the liquid crystal hardener is tocopherol acetate, cholesterol, and a combination thereof.
  8. The pharmaceutical composition of claim 1, wherein the GnRH analogue is a GnRH agonist or a GnRH antagonist.
  9. The pharmaceutical composition of claim 8, wherein the GnRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, nafarelin, buserelin, histrelin, deslorelin, meterelin, gonadrelin, a pharmaceutically acceptable salt thereof, and a combination thereof.
  10. The pharmaceutical composition of claim 8, wherein the GnRH antagonist is selected from the group consisting of degarelix, abarelix, ganirelix, cetrorelix, a pharmaceutically acceptable salt thereof, and a combination thereof.
  11. The pharmaceutical composition of claim 1, wherein the GnRH analogue is selected from the group consisting of leuprolide, goserelin, triptorelin, degarelix, abarelix, a pharmaceutically acceptable salt thereof, and a combination thereof.
  12. The pharmaceutical composition of claim 1, wherein the GnRH analogue is leuprolide or a pharmaceutically acceptable salt thereof.
  13. The pharmaceutical composition of claim 1, being designed for preventing or treating a sex hormone-dependent disease, or as a contraceptive.
  14. The pharmaceutical composition of claim 13, wherein the sex hormone-dependent disease is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, endometriosis, uterine fibroid, polycystic ovarian disease, precocious puberty, hypertrichosis, gonadotroph pituitary adenomas, sleep apnea syndrome, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and infertility.
  15. The pharmaceutical composition of claim 1, wherein a weight ratio of a) to b) ranges from 10:1 to 1:10.
  16. The pharmaceutical composition of claim 1, wherein a weight ratio of a)+b) to c) ranges from 1,000:1 to 1:1.
  17. The pharmaceutical composition of claim 1, wherein a weight ratio of a)+b)+c) to d) ranges from 10,000:1 to 1:1.
  18. The pharmaceutical composition of claim 1, compring:
    a) at least one sorbitan unsaturated fatty acid ester having a polar head with at least two or more -OH(hydroxyl) groups in an amount of 9~90 weight %;
    b) at least one phospholipid in an amount of 9~90 weight %;
    c) at least one liquid crystal hardener which is free of an ionizable group and has a triacyl group with 15 to 40 carbon atoms or a carbon ring structure in a hydrophobic moiety in an amount of 0.1~50 weight %; and
    d) at least one GnRH (gonadotropin-releasing hormone) analogue in an amount of 0.01~50 weight %.
  19. The pharmaceutical composition of claim 1, comprising:
    a) at least one sorbitan unsaturated fatty acid ester having a polar head with at least two or more -OH (hydroxyl) groups in an amount of 9~64 weight %;
    b) at least one phospholipid in an amount of 18~76 weight %;
    c) at least one liquid crystal hardener which is free of an ionizable group and has a triacyl group with 15 to 40 carbon atoms or a carbon ring structure in a hydrophobic moiety in an amount of 1~36 weight %; and
    d) leuprolide or a pharmaceutically acceptable salt thereof in an amount of 0.1~50 weight %.
  20. The pharmaceutical composition of claim 1, comprising:
    a) at least one sorbitan unsaturated fatty acid ester having a polar head with at least two or more -OH (hydroxyl) groups in an amount of 9~64 weight %;
    b) at least one phospholipid in an amount of 18~76 weight %;
    c) at least one liquid crystal hardener which is free of an ionizable group and has a triacyl group with 15 to 40 carbon atoms or a carbon ring structure in a hydrophobic moiety in an amount of 1~36 weight %; and
    d) goserelin or a pharmaceutically acceptable salt thereof in an amount of 0.1~50 weight %.
  21. The pharmaceutical composition of claim 1, comprising:
    a) at least one sorbitan unsaturated fatty acid ester having a polar head with at least two or more -OH (hydroxyl) groups in an amount of 9~64 weight %;
    b) at least one phospholipid in an amount of 18~76 weight %;
    c) at least one liquid crystal hardener which is free of an ionizable group and has a triacyl group with 15 to 40 carbon atoms or a carbon ring structure in a hydrophobic moiety in an amount of 1~36 weight %; and
    d) degarelix or a pharmaceutically acceptable salt thereof in an amount of 2~50 weight %.
  22. The pharmaceutical composition of claim 1, being in a formulation, said formulation being selected from the group consisting of an injection, a ointment, a gel, a lotion, a capsule, a tablet, a solution, a suspension, a spray, an inhalant, an eye drop, an adhesive, and a plaster and pressure sensitive adhesive.
  23. The pharmaceutical composition of claim 22, wherein the formulation is an injection.
PCT/KR2013/012269 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same WO2014104791A1 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
MX2015008401A MX364595B (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same.
SI201331022T SI2938332T1 (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same
AU2013371101A AU2013371101B2 (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of GnRH analogues and pharmaceutical composition comprising the same
NZ710468A NZ710468A (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same
CA2888863A CA2888863C (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same
CN201380067822.5A CN105188680A (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of GnRH analogues and pharmaceutical composition comprising the same
LTEP13867921.2T LT2938332T (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same
PL13867921T PL2938332T3 (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same
RU2015131107A RU2646487C2 (en) 2012-12-28 2013-12-27 Lipid preconcentrate of gnrh analogues with delayed release, and pharmaceutical composition containing it
EP13867921.2A EP2938332B1 (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same
DK13867921.2T DK2938332T3 (en) 2012-12-28 2013-12-27 DEPOT-LIPID PREPARATION OF GNRH ANALOGS AND PHARMACEUTICAL COMPOSITION
ES13867921.2T ES2664598T3 (en) 2012-12-28 2013-12-27 Lipid preconcentrate of sustained release of GnRH analogs and pharmaceutical composition comprising the same
BR112015015518-9A BR112015015518B1 (en) 2012-12-28 2013-12-27 PHARMACEUTICAL COMPOSITION AND USE THEREOF
NO13867921A NO2938332T3 (en) 2012-12-28 2013-12-27
US14/440,060 US10722585B2 (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of GNRH analogues and pharmaceutical composition comprising the same
JP2015550323A JP6078660B2 (en) 2012-12-28 2013-12-27 Sustained release lipid initial preparation of GnRH derivative and pharmaceutical composition containing the same
PH12015500936A PH12015500936A1 (en) 2012-12-28 2015-04-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020120157583A KR101586791B1 (en) 2012-12-28 2012-12-28 Sustained-release lipid pre-concentrate of GnRH analogues and pharmaceutical composition comprising the same
KR10-2012-0157583 2012-12-28

Publications (1)

Publication Number Publication Date
WO2014104791A1 true WO2014104791A1 (en) 2014-07-03

Family

ID=51021736

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2013/012269 WO2014104791A1 (en) 2012-12-28 2013-12-27 Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same

Country Status (22)

Country Link
US (1) US10722585B2 (en)
EP (1) EP2938332B1 (en)
JP (1) JP6078660B2 (en)
KR (1) KR101586791B1 (en)
CN (2) CN105188680A (en)
AU (1) AU2013371101B2 (en)
BR (1) BR112015015518B1 (en)
CA (1) CA2888863C (en)
DK (1) DK2938332T3 (en)
ES (1) ES2664598T3 (en)
HU (1) HUE036932T2 (en)
LT (1) LT2938332T (en)
MX (1) MX364595B (en)
NO (1) NO2938332T3 (en)
NZ (1) NZ710468A (en)
PH (1) PH12015500936A1 (en)
PL (1) PL2938332T3 (en)
PT (1) PT2938332T (en)
RU (1) RU2646487C2 (en)
SI (1) SI2938332T1 (en)
TR (1) TR201806985T4 (en)
WO (1) WO2014104791A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030334A3 (en) * 2014-08-26 2016-04-21 Betanien Hospital Methods, agents and compositions for treatment of inflammatory conditions
US9618507B2 (en) 2014-02-24 2017-04-11 Betanien Hospital Methods of treating rheumatoid arthritis
JP2018502091A (en) * 2014-12-23 2018-01-25 カムルス エービー Controlled release formulation
US11135264B2 (en) 2016-09-27 2021-10-05 Camurus Ab Formulations containing a somatostatin receptor agonist
EP4173614A4 (en) * 2020-06-30 2024-08-14 Chong Kun Dang Pharmaceutical Corp Injectable composition comprising gnrh derivatives

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101494594B1 (en) 2011-08-30 2015-02-23 주식회사 종근당 Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same
KR101586789B1 (en) * 2012-12-28 2016-01-19 주식회사 종근당 Sustained-release lipid pre-concentrate of cationic pharmacologically active substance and pharmaceutical composition comprising the same
PT2943474T (en) 2013-01-31 2017-08-08 Chong Kun Dang Pharmaceutical Corp Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as cetp inhibitors
KR101601035B1 (en) 2013-02-28 2016-03-08 주식회사 종근당 Composition for gene delivery comprising chitosan and liquid crystal formation material
KR101809908B1 (en) 2014-07-21 2018-01-25 주식회사 종근당 Pharmaceutical composition comprising 5-α reductase inhibitor
US11376220B2 (en) * 2017-06-30 2022-07-05 Therio, LLC Single-injection methods and formulations to induce and control multiple ovarian follicles in bovine, caprine, ovine, camelid and other female animals
US10994018B2 (en) * 2017-09-27 2021-05-04 Novel Pharma Inc. Long-acting palmitic acid-conjugated GnRH derivative, and pharmaceutical composition containing same
WO2020196946A1 (en) * 2019-03-26 2020-10-01 노벨파마 주식회사 Long-acting fatty acid-binding gnrh derivative and pharmaceutical composition comprising same
US20200330547A1 (en) * 2019-04-22 2020-10-22 Tolmar International Limited Method of Treating a Child with Central Precocious Puberty using an Extended Release Composition
CN113368041B (en) * 2020-07-17 2023-01-03 丽珠医药集团股份有限公司 Pharmaceutical composition, sustained-release preparation and preparation method thereof
KR20230124229A (en) * 2022-02-18 2023-08-25 (주)인벤티지랩 Sustained-release injectable compositions comprising deslorelin

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5807573A (en) * 1994-06-15 1998-09-15 Gs Development Ab Lipid based composition containing diacylglycerol, phospholipid, polar liquid and biologically active material
US20070080323A1 (en) * 2003-11-07 2007-04-12 Fedrik Joabsson Compositions of lipids and cationic peptieds
US20080274176A1 (en) * 2005-01-21 2008-11-06 Camurus Ab Pharmaceutical Lipid Compositions
US20110091420A1 (en) * 2008-03-20 2011-04-21 Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, People Liberation Ar Injectable Sustained-Release Pharmaceutical Formulation and the Preparation Method Thereof
US20120269772A1 (en) * 2004-06-04 2012-10-25 Camurus Ab Lipid depot formulations

Family Cites Families (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0224987B1 (en) 1985-11-29 1992-04-15 Biomatrix, Inc. Drug delivery systems based on hyaluronan, derivatives thereof and their salts and method of producing same
DE3706036A1 (en) 1987-02-25 1988-09-08 Basf Ag POLYACETALS, METHOD FOR THE PRODUCTION THEREOF FROM DIALDEHYDES AND POLYOLCARBONIC ACIDS AND USE OF THE POLYACETALS
MY107937A (en) 1990-02-13 1996-06-29 Takeda Chemical Industries Ltd Prolonged release microcapsules.
US5211952A (en) * 1991-04-12 1993-05-18 University Of Southern California Contraceptive methods and formulations for use therein
GB9302492D0 (en) 1993-02-09 1993-03-24 Procter & Gamble Cosmetic compositions
FR2709666B1 (en) 1993-09-07 1995-10-13 Oreal Cosmetic or dermatological composition consisting of an oil-in-water emulsion based on oily globules provided with a lamellar liquid crystal coating.
EP0711557A1 (en) 1994-11-09 1996-05-15 Ciba-Geigy Ag Base for formulating pharmaceutical agents
DE69632859T2 (en) 1995-04-18 2005-07-14 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method for drug treatment of liposomes Composition
EP0760237A1 (en) 1995-08-30 1997-03-05 Cipla Limited Oil-in-water microemulsions
US5736152A (en) 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5968895A (en) * 1996-12-11 1999-10-19 Praecis Pharmaceuticals, Inc. Pharmaceutical formulations for sustained drug delivery
EP0975331A1 (en) 1997-04-17 2000-02-02 Dumex-Alpharma A/S A novel bioadhesive drug delivery system based on liquid crystals
BR9806238A (en) 1997-09-09 2005-07-12 Select Release L C Coated particles: processes for obtaining and using
WO1999033489A1 (en) 1997-12-26 1999-07-08 Yamanouchi Pharmaceutical Co., Ltd. Sustained release medicinal compositions
TWI241915B (en) 1998-05-11 2005-10-21 Ciba Sc Holding Ag A method of preparing a pharmaceutical end formulation using a nanodispersion
US6565874B1 (en) 1998-10-28 2003-05-20 Atrix Laboratories Polymeric delivery formulations of leuprolide with improved efficacy
ATE404172T1 (en) * 1998-12-30 2008-08-15 Dexcel Ltd DISPERSIBLE CONCENTRATE FOR ADMINISTRATION OF CYCLOSPORINE
US7374779B2 (en) 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
IE990935A1 (en) * 1999-11-08 2002-04-03 Procter & Gamble Cosmetic Compositions
AU781682B2 (en) 2000-03-20 2005-06-09 Zoetis Services Llc Sustained-release compositions for parenteral administration
US20030070679A1 (en) 2001-06-01 2003-04-17 Boehringer Ingelheim Pharma Kg Capsules containing inhalable tiotropium
AU2002334358B2 (en) 2001-09-06 2008-02-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem A method for preparing liposome formulations with a predefined release profile
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
US7713440B2 (en) * 2003-10-08 2010-05-11 Lyotropic Therapeutics, Inc. Stabilized uncoated particles of reversed liquid crystalline phase materials
WO2006075124A1 (en) 2005-01-14 2006-07-20 Camurus Ab Somatostatin analogue formulations
US20050118206A1 (en) * 2003-11-14 2005-06-02 Luk Andrew S. Surfactant-based gel as an injectable, sustained drug delivery vehicle
TW200529890A (en) 2004-02-10 2005-09-16 Takeda Pharmaceutical Sustained-release preparations
EP1848403B8 (en) * 2005-01-14 2010-05-19 Camurus Ab Topical bioadhesive formulations
GB0501364D0 (en) * 2005-01-21 2005-03-02 Camurus Ab Compositions
US20060182790A1 (en) 2005-02-17 2006-08-17 Flor Mayoral Dermal medicaments application enhancer
EP1712220A1 (en) 2005-04-15 2006-10-18 PARI GmbH Spezialisten für effektive Inhalation Pharmaceutical aerosol composition
US20080102128A1 (en) 2006-07-28 2008-05-01 Flamel Technologies, Inc. Modified-release microparticles based on amphiphilic copolymer and on active principles(s) and pharmaceutical formulations comprising them
US9918934B2 (en) 2006-12-12 2018-03-20 Edgar Joel Acosta-Zara Linker-based lecithin microemulsion delivery vehicles
GB0711656D0 (en) 2007-06-15 2007-07-25 Camurus Ab Formulations
GB0716385D0 (en) 2007-08-22 2007-10-03 Camurus Ab Formulations
CA2714514C (en) 2008-02-08 2016-08-16 Qps Llc Non-polymeric compositions for controlled drug delivery
BRPI0922041A8 (en) 2008-11-19 2022-08-16 Merial Ltd FORMULATIONS INCLUDING CEFTIOFUR AND KETOPROFENE OR CETIOFUR AND BENZYL ALCOHOL.
EP2544662B1 (en) 2010-03-10 2020-05-20 Nuvo Pharmaceuticals Inc. Foamable formulation
KR20120093677A (en) 2011-02-15 2012-08-23 삼성전자주식회사 X-ray imaging system and position calibration method of the same
KR101319420B1 (en) 2011-03-18 2013-10-17 한남대학교 산학협력단 Water-soluble positive-charged drug delivery system with sustained release behavior
JP6054291B2 (en) * 2011-05-31 2016-12-27 株式会社ナノエッグ Method for producing liquid crystal composition containing lipophilic compound at high concentration and liquid crystal composition produced by the method
KR101494594B1 (en) * 2011-08-30 2015-02-23 주식회사 종근당 Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same
KR101383324B1 (en) 2011-11-10 2014-04-28 주식회사 종근당 Novel composition for gene delivery
KR101586790B1 (en) 2012-12-28 2016-01-19 주식회사 종근당 Sustained-release lipid pre-concentrate of anionic pharmacologically active substances and pharmaceutical composition comprising the same
KR101586789B1 (en) 2012-12-28 2016-01-19 주식회사 종근당 Sustained-release lipid pre-concentrate of cationic pharmacologically active substance and pharmaceutical composition comprising the same
PT2943474T (en) 2013-01-31 2017-08-08 Chong Kun Dang Pharmaceutical Corp Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as cetp inhibitors
KR101601035B1 (en) 2013-02-28 2016-03-08 주식회사 종근당 Composition for gene delivery comprising chitosan and liquid crystal formation material

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5807573A (en) * 1994-06-15 1998-09-15 Gs Development Ab Lipid based composition containing diacylglycerol, phospholipid, polar liquid and biologically active material
US20070080323A1 (en) * 2003-11-07 2007-04-12 Fedrik Joabsson Compositions of lipids and cationic peptieds
US20120269772A1 (en) * 2004-06-04 2012-10-25 Camurus Ab Lipid depot formulations
US20080274176A1 (en) * 2005-01-21 2008-11-06 Camurus Ab Pharmaceutical Lipid Compositions
US20110091420A1 (en) * 2008-03-20 2011-04-21 Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, People Liberation Ar Injectable Sustained-Release Pharmaceutical Formulation and the Preparation Method Thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2938332A4 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9618507B2 (en) 2014-02-24 2017-04-11 Betanien Hospital Methods of treating rheumatoid arthritis
WO2016030334A3 (en) * 2014-08-26 2016-04-21 Betanien Hospital Methods, agents and compositions for treatment of inflammatory conditions
US10821152B2 (en) 2014-08-26 2020-11-03 Betanien Hospital Methods, agents and compositions for treatment of inflammatory conditions
JP2018502091A (en) * 2014-12-23 2018-01-25 カムルス エービー Controlled release formulation
US11135264B2 (en) 2016-09-27 2021-10-05 Camurus Ab Formulations containing a somatostatin receptor agonist
US11241476B2 (en) 2016-09-27 2022-02-08 Camurus Ab Mixtures and formulations comprising an alkyl ammonium EDTA salt
US11564968B2 (en) 2016-09-27 2023-01-31 Camurus Ab Formulations containing a somatostatin receptor agonist
EP4173614A4 (en) * 2020-06-30 2024-08-14 Chong Kun Dang Pharmaceutical Corp Injectable composition comprising gnrh derivatives

Also Published As

Publication number Publication date
AU2013371101B2 (en) 2017-01-05
PL2938332T3 (en) 2018-08-31
PT2938332T (en) 2018-04-06
NZ710468A (en) 2016-04-29
KR101586791B1 (en) 2016-01-19
BR112015015518A2 (en) 2017-07-11
JP2016504353A (en) 2016-02-12
EP2938332A1 (en) 2015-11-04
KR20140086741A (en) 2014-07-08
CA2888863C (en) 2018-04-03
DK2938332T3 (en) 2018-06-06
RU2015131107A (en) 2017-02-01
CA2888863A1 (en) 2014-07-03
PH12015500936B1 (en) 2015-07-06
MX364595B (en) 2019-05-02
CN105188680A (en) 2015-12-23
MX2015008401A (en) 2016-02-16
RU2646487C2 (en) 2018-03-05
ES2664598T3 (en) 2018-04-20
EP2938332B1 (en) 2018-02-21
SI2938332T1 (en) 2018-10-30
EP2938332A4 (en) 2016-08-17
PH12015500936A1 (en) 2015-07-06
TR201806985T4 (en) 2018-06-21
US10722585B2 (en) 2020-07-28
US20150297726A1 (en) 2015-10-22
NO2938332T3 (en) 2018-07-21
AU2013371101A1 (en) 2015-08-13
JP6078660B2 (en) 2017-02-08
HUE036932T2 (en) 2018-08-28
LT2938332T (en) 2018-05-25
CN113350480A (en) 2021-09-07
BR112015015518B1 (en) 2022-08-23

Similar Documents

Publication Publication Date Title
WO2014104791A1 (en) Sustained-release lipid pre-concentrate of gnrh analogues and pharmaceutical composition comprising the same
JP5671451B2 (en) Compositions and preparation processes for GnRH related compounds
WO2013032207A1 (en) Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same
WO2014104784A4 (en) Sustained-release lipid pre-concentrate of cationic pharmacologically active substance and pharmaceutical composition comprising the same
KR100217258B1 (en) Nasal composition
WO2020171491A1 (en) Sustained-release lipid preformulation and pharmaceutical composition for sustained-release injection in form of lipid solution containing same
WO2022005169A1 (en) Injectable composition comprising gnrh derivatives
AU2021299156B2 (en) Injectable composition comprising GnRH analogue
RU2827376C1 (en) INJECTION COMPOSITION CONTAINING GnRH ANALOGUE
WO2010017743A1 (en) The injectable sustained-release formulation of lhrh antagonists and the preparation thereof

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201380067822.5

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13867921

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2888863

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 12015500936

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 14440060

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2015550323

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2015/008401

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015015518

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 2013867921

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2015131107

Country of ref document: RU

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2013371101

Country of ref document: AU

Date of ref document: 20131227

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112015015518

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150626