WO1996022786A1 - Preparation a diffusion prolongee et son emploi - Google Patents

Preparation a diffusion prolongee et son emploi Download PDF

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Publication number
WO1996022786A1
WO1996022786A1 PCT/JP1996/000090 JP9600090W WO9622786A1 WO 1996022786 A1 WO1996022786 A1 WO 1996022786A1 JP 9600090 W JP9600090 W JP 9600090W WO 9622786 A1 WO9622786 A1 WO 9622786A1
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WIPO (PCT)
Prior art keywords
microcapsules
acid
peptide
emulsion
preparation
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PCT/JP1996/000090
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English (en)
Inventor
Yasutaka Igari
Akira Saikawa
Shigeru Kamei
Original Assignee
Takeda Chemical Industries, Ltd.
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Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU44591/96A priority Critical patent/AU4459196A/en
Publication of WO1996022786A1 publication Critical patent/WO1996022786A1/fr

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the present invention relates to a method of producing a sustained-release preparation containing a bioactive peptide possessing LH-RH-antagonizing activity or a salt thereof.
  • EP-A-601,799 describes a method of producing a sustained-release
  • LH-RH lutein-izing hormone-releasing hormone
  • sustained-release preparations such peptides.
  • sustained-release preparations of the long-acting type e.g., 1-3 months
  • more reliable, constant release of bioactive peptide is a key to safe and more reliable effect.
  • a method of producing a sustained-release preparation that constantly releases a bioactive peptide and that possesses excellent storage stability.
  • the present invention relates to:
  • a method of producing a sustained-release preparation which comprises producing a W/O emulsion whose internal aqueous phase is a solution containing a bioactive peptide represented by the formula:
  • X represents a hydrogen atom or a tetrahydrofuryl-carboxamido
  • Q represents a hydrogen atom or methyl
  • A represents nicotinoyl or N,N'-diethylamidino
  • B represents isopropyl or N,N'-diethylamidino, or a salt thereof, and whose oil phase is a solution containing a biodegradable polymer having a free carboxyl group at one end, and adding the W/O emulsion into an external water phase to produce W/O/W emulsion
  • concentration in the internal aqueous phase is about 0.1 to about 150% (w/v)
  • concentration in the oil phase is about 0.01 to about 80% (w/w),
  • preparation is microcapsules
  • microcapsules are for injection.
  • NAcD2Nal N-acetyl-D-3-(2-naphthyl)alanyl
  • Lys(Nisp) (Ipsiron-N-isopropyl)lysyl
  • AbbreviaDions for other amino acids are based on abbreviations specified by the IUPAC-IUB Commission on Biochemical Nomenclature (European Journal of Biochemistry, Vol. 138, pp. 9-37, 1984) or abbreviations in common use in relevant fields.
  • an optical isomer may be present in amino acid, it is of the L-configuration, unless otherwise stated.
  • the bioactive peptide represented by formula [I] (hereinafter also referred to as peptide (I]) or a salt thereof possesses LH-RH-antagonizing activity, and accordingly, is effective in the treatment of hormone-dependent diseases, such as prostatic cancer, prostatic hypertrophy, endometriosis, uterine myoma, uterine fibroma, precocious puberty, breast cancer, bladder cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, gastritis, hodgkin's disease, malignant melanoma, metastasis, multiple myeloma, non-hodgkin's leukemia, non-small-cell lung cancer, ovarian cancer, peptic ulcer, serious fungal infection, small-cell lung cancer, valvular heart disease, mastopathy, polycystic ovary, infertility, controlled induction of ovulation in women with hormone-dependent diseases
  • X is preferably 2-tetrahydrofurylcarboxamido, more preferably (2S)-tetrahydrofurylcarboxamido.
  • A is preferably nicotinoyl; B is preferably isopropyl.
  • peptide [I] has one or more kinds of asymmetric carbon atoms, two or more optical isomers are present.
  • optical isomers and mixtures thereof are also included in the scope of the present invention.
  • Peptide [I] or a salt thereof can be produced by known methods, which include those methods described in Japanese Patent Unexamined Publication No. 101695/1994 and the
  • the salt of peptide [I] is preferably a pharmacologically acceptable salt.
  • Such salts include salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, etc.), organic acids (e.g., carbonic acid, bicar-bonic acid, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.) etc.
  • the salt of peptide [I] is a salt with an organic acid (e.g., carbonic acid, bicarbonic acid, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), with greater preference given to the salt with acetic acid.
  • These salts may be mono- to tri-salts, with preference given to di- or tri-salts.
  • m represents an integer from 1 to 3.
  • n represents an integer from 1 to 3.
  • Peptide [I] or salt thereof is preferably (1) or (2) above.
  • the biodegradable polymer having a free carboxyl group at one end is a biodegradable polymer whose GPC measurement- and terminal group quantitation-based number-average molecular weights almost agree with each other.
  • Number-average molecular weight based on terminal group quantitation is calculated as follows:
  • A is the weight mass (g) of the biodegradable
  • B is the amount (ml) of the 0.05 N alcoholic solution of potassium hydroxide added until the titration end point is reached.
  • molecular weight based on terminal group quantitation is significantly higher than that based on GPC measurement. This difference makes it possible to clearly differentiate a polymer having a free carboxyl group at one end from a polymer having substantially no free carboxyl group at one end.
  • molecular weight based on terminal group quantitation falls within the range from about 0.4 to about 2 times, preferably from about 0.5 to about 2 times, and more preferably from about 0.8 to about 1.5 times, that based on GPC measurement. Also, the fact that the number-average molecular weight based on terminal group quantitation is significantly higher than that based on GPC measurement means that the number-average molecular weight based on terminal group quantitation is about 2 times or more that based on GPC measurement.
  • biodegradable polymers having a free carboxyl group at one end include polymers, copolymers, or mixtures thereof, synthesized by catalyst-free dehydration polymerization condensation from one or more a- hydroxycarboxylic acids (e.g., glycolic acid, lactic acid, hydroxybutyric acid, etc.), hydroxydicarboxylic acids
  • a- hydroxycarboxylic acids e.g., glycolic acid, lactic acid, hydroxybutyric acid, etc.
  • hydroxydicarboxylic acids e.g., glycolic acid, lactic acid, hydroxybutyric acid, etc.
  • hydroxytricarboxylic acids e.g., citric acid, etc.
  • poly-a-cyanoacrylates polyamino acids (e.g., poly-y-benzyl-L-glutamic acid, etc.), maleic anhydride copolymers (e.g., styrene-maleic acid copolymer, etc.) and the like.
  • the biodegradable polymer is preferably an aliphatic polyester such as a homopolymer, copolymer or mixture thereof synthesized from one or more a-hydroxycarboxylic acids (e.g., glycolic acid, lactic acid, hydroxybutyric acid, etc.), hydroxydicarboxylic acids (e.g., malic acid, etc.), hydroxytricarboxylic acids (e.g., citric acid, etc.) and so on.
  • a-hydroxycarboxylic acids e.g., glycolic acid, lactic acid, hydroxybutyric acid, etc.
  • hydroxydicarboxylic acids e.g., malic acid, etc.
  • hydroxytricarboxylic acids e.g., citric acid, etc.
  • the biodegradable polymer having a free carboxyl group at one end is preferably (1) a lactic acid-glycolic acid copolymer or (2) a biodegradable polymer comprising a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid represented by the formula: wherein R represents an alkyl group having 2 to 8 carbon atoms, and (B) polylactic acid. More preferably, the biodegradable polymer having a free carboxyl group at one end is a lactic acid-glycolic acid copolymer.
  • lactic acid/glycolic acid copolymer When a lactic acid/glycolic acid copolymer is used as the biodegradable polymer, its content ratio (lactic acid/glycolic acid) (mol%) is preferably about 100/0 to about 40/60, more preferably about 90/10 to about 50/50.
  • the weight-average molecular weight of the lactic acid/glycolic acid copolymer is preferably about 5,000 to about 25,000, more preferably about 7,000 to about 20,000, still more preferably about 8,000 to about 15,000.
  • the degree of dispersion of the lactic acid/glycolic acid copolymer is preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5.
  • the lactic acid-glycolic acid copolymer can be any suitable lactic acid-glycolic acid copolymer.
  • drug release duration can be extended by lowering the glycolic acid ratio or increasing the molecular weight, since decomposition/elimination is delayed as the glycolic acid ratio decreases. Conversely, drug release duration can be shortened by increasing the glycolic acid ratio or
  • a sustained-release preparation of the long acting type e.g., 1-4 months
  • the linear or branched alkyl group represented by R which has 2 to 8 carbon atoms, is exemplified by ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
  • a linear or branched alkyl group having 2 to 5 carbon atoms is used.
  • alkyl groups include ethyl, propyl, isopropyl, butyl and isobutyl. More preferably, R is ethyl.
  • [II] is exemplified by 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproic acid, 2-hydroxyisocaproic acid and 2- hydroxycapric acid, with preference given to 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methyl butyric acid and 2-hydroxycaproic acid, with greater preference given to 2-hydroxybutyric acid.
  • the hydroxycarboxylic acid may be of the D-, L- or D,L-configuration, it is preferable to use a mixture of the D-and L-configurations wherein the ratio of the D-/L-configuration (mol%) preferably falls within the range from about 75/25 to about 25/75, more preferably from about
  • glycolic acid copolymer (A) polymerization may be of random, block or graft type. A random copolymer is preferred.
  • the hydroxycarboxylic acid represented by the formula [II] may be a mixture of one or more kinds in a given ratio.
  • glycolic acid account for about 10 to 75 mol% and hydroxycarboxylic acid for the remaining portion. More preferably, glycolic acid accounts for about 20 to about 75 mol%, and still more preferably about 40 to about 70 mol%.
  • the weight-average molecular weight of the glycolic acid copolymer is normally about 2,000 to about 50,000,
  • the degree of dispersion of the glycolic acid copolymer is preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5.
  • Glycolic acid copolymer (A) above can be produced by a known processes, such as that described in Japanese Patent Unexamined Publication No. 28521/1986.
  • the polylactic acid may also be of the D- or L-configuration or a mixture thereof, it is preferable that the ratio of the D-/L-configuration (mol%) falls within the range from about 75/25 to about 20/80.
  • the ratio of the D-/L-configuration (mol%) is more preferably about 60/40 to about 25/75, and still more preferably about 55/45 to about 25/75.
  • the weight-average molecular weight of the polylactic acid is preferably about 1,500 to about 30,000, more preferably about 2,000 to about 20,000, and still more preferably about 3,000 to about 15,000.
  • the degree of dispersion of the polylactic acid is preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5.
  • polylactic acid For producing polylactic acid, two methods are known: ring-opening polymerization of lactide, a dimer of lactic acid, and dehydration polymerization condensation of lactic acid.
  • ring-opening polymerization of lactide For obtaining a polylactic acid of relatively low molecular weight for the present invention, direct
  • dehydration polymerization condensation of lactic acid is preferred. This method is, for example, described in
  • Glycolic acid copolymer (A) and polylactic acid (B) are used in a mixture wherein the (A)/(B) ratio (% by weight) falls within the range from about 10/90 to about 90/10.
  • the mixing ratio is preferably about 20/80 to about 80/20, and more preferably about 30/70 to about 70/30. If either component (A) or (B) is in excess, the preparation obtained shows a drug release pattern no more than that obtained with the use of component (A) or (B) alone; no linear release pattern is expected in the last stage of drug release from the mixed base.
  • glycolic acid copolymer (A) and polylactic acid vary widely, depending on molecular weight or composition
  • drug release duration can be extended by increasing the molecular weight of the polylactic acid or lowering the mixing ratio (A)/(B), since the decomposi tion/elimination rate of glycolic acid copolymer (A) is usually higher than that of polylactic acid.
  • drug release duration can be shortened by decreasing the molecular weight of polylactic acid or increasing the mixing ratio (A)/(B).
  • Drug release duration can also be adjusted by altering the kind and content ratio of
  • weight-average molecular weight and degree of dispersion are defined as the molecular weight based on polystyrene obtained by gel permeation chromatography (GPC) with 9 polystyrenes as reference substances with respective weight-average molecular weights of 120,000, 52,000, 22,000, 9,200, 5,050, 2,950, 1,050, 580 and 162, and degree of dispersion calculated. Measurements were taken using a GPC column KF804L ⁇ 2 (produced by Showa Denko, Japan) and an RI monitor L-3300 (produced by
  • peptide [I] or a salt thereof (hereinafter also referred to as a drug) is dissolved or dispersed in water, with a drug support when necessary, such as gelatin, agar, polyvinyl alcohol or a basic amino acid (e.g., arginine, histidine, lysine), dissolved or suspended, to yield an internal aqueous phase.
  • a drug support such as gelatin, agar, polyvinyl alcohol or a basic amino acid (e.g., arginine, histidine, lysine), dissolved or suspended, to yield an internal aqueous phase.
  • the drug concentration in the internal aqueous phase is preferably about 0.1 to about 150% (w/v), more
  • the internal aqueous phase also may be supplemented with a pH regulator for retaining drug stability and solubility, such as carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine or salt thereof.
  • a pH regulator for retaining drug stability and solubility, such as carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine or salt thereof.
  • chlorobutanol, thimerosal etc., as preservatives, may be added.
  • the internal aqueous phase thus obtained is added to a solution containing a biodegradable polymer having a free carboxyl group at one end (hereinafter also referred to as polymer) (oil phase), followed by emulsification, to yield a W/O emulsion.
  • a biodegradable polymer having a free carboxyl group at one end hereinafter also referred to as polymer
  • This emulsification is achieved by a known dispersing method, such as the intermittent shaking method, the method using a mixer, such as a propeller stirrer or a turbine stirrer, the colloidal mill method, the homogenizer method or the ultrasonication method.
  • the above-described polymer-containing solution (oil phase) is prepared by dissolving a polymer in a sub- stantially water-immiscible organic solvent.
  • the water solubility of the organic solvent is preferably not higher than 3% (w/w) at normal temperature (20oC).
  • the boiling point of the organic solvent is preferably not higher than 120oC.
  • Useful organic solvents include
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.
  • alkyl ethers having 3 or more carbon atoms e.g., isopropyl ether, etc.
  • alkyl ester 4 or more carbon atoms
  • aromatic hydrocarbons e.g., benzene, toluene, xylene, etc.
  • the organic solvent is more preferably a halogenated
  • hydrocarbon e.g., dichloromethane, chloroform
  • the polymer concentration in the oil phase varies, depending on the molecular weight of the polymer and the kind of solvent, and is preferably about 0.01 to about 80% (w/w), more preferably about 0.1 to about 70% (w/w), and still more preferably about 1 to about 60% (w/w).
  • the content ratio of drug varies depending on the kind of. drug, desired pharmacologic effect, duration of action and other factors, and is about 0.01 to about 50% (w/w), relative to the base biodegradable polymer.
  • the ratio is preferably about 0.1 to about 40% (w/w), more preferably about 1 to about 30% (w/w).
  • the W/O emulsion thus produced is subjected to in-water drying.
  • the in-water drying method is carried out by adding the W/O emulsion to an aqueous phase (external aqueous phase) to yield a W/O/W emulsion, and removing the solvent from the oil phase.
  • the volume of the external aqueous phase is normally selected within the range from about 1 to about 10,000 times, preferably about 2 to about 5,000 times, and more preferably about 5 to about 2,000 times, that of the oil phase.
  • An emulsifier may be added to the external aqueous phase.
  • the emulsifier may be any one, as long as it is capable of forming a stable W/O/W emulsion.
  • emulsifiers include anionic surfactants (e.g., sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants [e.g., polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60, Atlas Powder Company), polyoxyethylene castor oil derivatives (e.g., HCO-60, HCO-50, Nikko Chemicals), etc.], polyvinylpyrrolidone,
  • polyvinyl alcohol carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid and the like.
  • a preferred emulsifier is polyvinyl alcohol.
  • emulsifiers may be used singly or in combination. Their concentration can be chosen as appropriate over the range from about 0.001 to about 20% (w/w), preferably from about 0.01 to about 10% (w/w), and more preferably from about 0.05 to about 5% (w/w).
  • An osmotic pressure adjustor may also be added to the above external aqueous phase.
  • Any osmotic pressure adjustor can be used in the invention, so long as it produces osmotic pressure in an aqueous solution therof.
  • osmotic pressure adjustor examples include water-soluble polyhydric alcohols; water-soluble monohydric alcohols; water-soluble monosaccharides, disaccharides and oligosaccharides or their derivatives; water-soluble amino acids; water-soluble peptides, proteins or their
  • alcohols include dihydric alcohols (e.g., glycerin, etc.), pentahydric alcohols (e.g., arabitol, xylitol, adonitol, etc.), hexahydric alcohols (e.g., mannitol, sorbitol, dulcitol, etc.) and the like. Among them, hexahydric alcohols, especially, mannitol is preferred.
  • alcohols include methanol, ethanol, isopropyl alcohol and the like. Among them, ethanol is preferred.
  • water-soluble monosaccharides examples include pentoses (e.g., arabinose, xylose, ribose, 2-deoxyri-bose, etc.), hexoses (e.g., glucose, fructose, galactose, mannose, sorbose, rhamnose, fucose, etc) and the like. Among them, hexoses are preferred.
  • water-soluble disaccharides examples include maltose, cellobiose, ⁇ ,or-trehalose, lactose, sucrose and the like. Among them, lactose and sucrose are preferred.
  • water-soluble oligosaccharides examples include trisaccharides (e.g., maltotriose, raffinose. etc.), tetrasaccharides (e.g., stachyose, etc.) and the like. Among them trisaccharides are preferred.
  • monosaccharides, disaccharides and oligosaccharides include glucosamine, galactosamine, glucuronic acid, galacturonic acid and the like.
  • water-soluble amino acids examples include neutral amino acids such as glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, proline, hydroxyproline, cysteine, methionine and the like; acidic amino acids such as aspartic acid, glutamic acid and the like; basic amino acids such as lysine, arginine, histidine and the like.
  • neutral amino acids such as glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, proline, hydroxyproline, cysteine, methionine and the like
  • acidic amino acids such as aspartic acid, glutamic acid and the like
  • basic amino acids such as lysine, arginine, histidine and the like.
  • salts of these water-soluble amino acids with acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or alkalis (e.g., alkaline metals such as sodium, potassium and the like, etc.).
  • acids e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.
  • alkalis e.g., alkaline metals such as sodium, potassium and the like, etc.
  • water-soluble peptides, proteins or their derivatives examples include casein, globulin, prolamine, albumin, gelatin and the like.
  • water-soluble polyhydric alcohols and water-soluble monosaccharides, disaccharides and oligosaccharides or their derivatives are preferred, water-soluble polyhydric alcohols and water-soluble
  • a concentration of the osmotic pressure adjustor is selected so that the tonicity of the external aqueous phase is about 1/50 to about 5 times, preferably about 1/25 to about 3 times, that of
  • physiological saline physiological saline.
  • the osmotic pressure adjustors are non-inonic materials
  • concentration of these osmotic pressure adjustors in the external aqueous phase is about 0.001% to about 60% (w/w), preferably about 0.01 to about 40% (w/w), more preferably about 0.05 to about 30% (w/w), particularly preferably about 1 to about 10% (w/w).
  • concentration of these osmotic pressure adjustors in the external aqueous phase is about 0.001% to about 60% (w/w), preferably about 0.01 to about 40% (w/w), more preferably about 0.05 to about 30% (w/w), particularly preferably about 1 to about 10% (w/w).
  • the viscosity of the W/O emulsion be adjusted to about 150 cp to about 10,000 cp.
  • Viscosity-adjusting methods include (1) adjusting the biodegradable polymer concentration of the oil phase, (2) adjusting the volume ratio of aqueous and oil phases, (3) adjusting the temperature of the W/O emulsion (4) adjusting external aqueous phase temperature, (5) and adjusting the temperature of the W/O emulsion using a line heater, cooler, or the like, during injection of the W/O emulsion to the external aqueous phase. These methods may be used singly or in combination.
  • the temperature of the W/O emulsion falls within the range from about -20oC to the organic solvent's boiling point, preferably about 0 to about 30oC, and more preferably about 10 to about 20°C.
  • the viscosity of the W/O emulsion viscosity can be adjusted during production of the W/O emulsion, in cases (1) and (2) above.
  • the temperature of the external aqueous phase is about 5 to about 30°C, preferably about 10 to about 25°C, and more preferably about 12 to about 20°C.
  • Organic solvent can be removed by known methods, including the method in which the solvent is evaporated under normal or gradually reduced pressure during stirring using a propeller stirrer, magnetic stirrer or the like, and the method in which the solvent is evaporated while the degree of vacuum is adjusted using a rotary evaporator or the like.
  • the thus-obtained sustained-release preparation in the form of e.g., microcapsules ("microcapsules” may be also referred to as "microspheres”), is centrifuged or filtered to separate its particles, which are then washed with distilled water several times to remove the free drug, drug support, emulsifier etc. adhering to the microcapsules surface, and again dispersed in distilled water etc. and lyophilized.
  • An anticoagulant may be added to the above
  • the anticoagulant is exemplified by water-soluble polysaccharides such as mannitol and starches
  • the anticoagulant is preferably mannitol.
  • the mixing ratio (weight ratio) of the microcapsules and anticoagulant is about 50:1 to about 1:1, preferably about 20:1 to about 1:1, still more preferably about 10:1 to about 5:1.
  • an anticoagulant may be added to the distilled water for washing.
  • the anticoagulant is exemplified by water-soluble polysaccharides such as mannitol, lactose, glucose and starches (e.g., corn starch, etc.), proteins such as glycine, fibrin, collagen, etc., and inorganic salts such as sodium chloride, sodium hydrogen phosphate, etc.
  • the preferred anticoagulant is mannitol.
  • the microcapsules may be heated under reduced pressure to further remove the water and organic solvent therefrom, where desired.
  • the heating time cannot be specified in general terms but can be determined in consideration of the physical
  • properties e.g. molecular weight, stability, etc.
  • properties of the component biodegradable polymer e.g. molecular weight, stability, etc.
  • species of bioactive peptide e.g., species of bioactive peptide
  • particle average diameter of microcapsules e.g., particle average diameter of microcapsules
  • heating time e.g., degree of desiccation of microcapsules and heating procedure.
  • the microcapsules are heated at a temperature not below the glass transition temperature of the biodegradable polymer component and not so high as to cause aggregation of the microcapsules.
  • the heating temperature is preferably selected within the range from the glass transition temperature of the biodegradable polymer component to about 30oC higher than the glass transition temperature of the component biodegradable polymer.
  • glass transition temperature is defined as the intermediate glass transition temperature determined using a differential scanning calorimeter during heating at a rate of 10 or 20oC per minute.
  • the heating time is also dependent on the heating temperature and the batch size of microcapsules, among other factors. Generally speaking, however, the heating time is preferably about 24 to about 120 hours, still more preferably about 48 to about 120 hours, after the
  • microcapsules themselves have reached the specified
  • the heating method is not critical but any procedure conducive to a uniform heating of microcapsules can be employed.
  • the organic solvent is efficiently removed from the microcapsules, resulting in a biologically safe microcapsules.
  • the residual organic solvent in the thus-obtained microcapsules is not more than about 100 ppm.
  • microcapsules can be administered, as such or in the form of various dosage forms of non-oral preparations (e.g., intramuscular, subcutaneous or visceral injections or indwellable preparations, nasal, rectal or uterine transmucosal preparations, etc.) or oral
  • non-oral preparations e.g., intramuscular, subcutaneous or visceral injections or indwellable preparations, nasal, rectal or uterine transmucosal preparations, etc.
  • oral preparations e.g., intramuscular, subcutaneous or visceral injections or indwellable preparations, nasal, rectal or uterine transmucosal preparations, etc.
  • preparations e.g., capsules such as hard capsules and soft capsules, etc.
  • solid preparations such as granules and powders
  • liquid preparations such as syrups, emulsions and suspensions.
  • An injectable preparation can be prepared by, for example, suspending microcapsules in water, along with a dispersing agent (e.g., Tween 80, HCO-60, carboxymethyl cellulose (including carboxymethyl cellulose sodium), sodium alginate, etc.), a preservative (e.g., methyl paraben, propyl paraben, etc.), an isotonizing agent (e.g., sodium chloride, mannitol, sorbitol, glucose, etc.) etc., to yield an aqueous suspension, or by dispersing it in a vegetable oil such as sesame oil or corn oil, or the like, to yield an oily suspension, whereby a practically usable sustained-release preparation is obtained.
  • a dispersing agent e.g., Tween 80, HCO-60, carboxymethyl cellulose (including carboxymethyl cellulose sodium), sodium alginate, etc.
  • a preservative e.g., methyl paraben, propyl paraben
  • microcapsules are used as an injectable
  • the average particle size is chosen over the range from about 0.1 to about 500 ⁇ m, as long as the requirements concerning degree of dispersion and needle passage are met.
  • the average particle size is about 1 to about 300 ⁇ m, and more
  • microcapsules by adding the osmotic pressure adjustor as mentioned above, its particle shape become better spheric shape which is better for needle pasage.
  • Methods of preparing microcapsules as a sterile preparation include, but are not limited to, the method in which the entire production process is sterile, the method in which gamma rays are used as sterilant, and the method in which an antiseptic is added.
  • the sustained-release preparation of the present invention is not significantly toxic and can be used safely in mammals (e.g., humans, bovines, swines, dogs, cats, mice, rats, rabbits, etc.).
  • target disease e.g., hormone-dependent diseases such as prostatic cancer, prostatic hypertrophy, endometriosis, uterine myoma, precocious puberty, breast cancer, bladder cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, gastritis,
  • hormone-dependent diseases such as prostatic cancer, prostatic hypertrophy, endometriosis, uterine myoma, precocious puberty, breast cancer, bladder cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal cancer, gastritis
  • the dose of the sustained-release preparation may be any dose of the sustained-release preparation.
  • the dose of the sustained-release preparation may be any dose of the sustained-release preparation.
  • the dose of the drug per administration can be chosen as appropriate over the range from about 0.01 mg to about 100 mg/kg body weight, preferably from about 0.05 mg to about 50 mg/kg body weight, and more preferably from about 0.1 mg to about 10 mg/kg body weight per adult, in the case of a 1-month release preparation.
  • the dose of the sustained-release preparation per administration can be chosen as appropriate within the range from about 0.1 mg to about 500 mg/kg body weight, preferably from about 0.2 mg to about 300 mg/kg body weight per adult.
  • the frequency of administration can be chosen as appropriate, depending on kind, content and dosage form, duration of release of the drug, target disease, subject animal species and other factors, e.g., once every several weeks, once every month or once every several months. Best Mode for Carrying out the Invention
  • peptide A 500 mg of the acetate (produced by TAP Company) of N-(S)-2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-Lys(Nisp)-Pro-DAlaNH 2 (hereinafter referred to as peptide A) was dissolved in 0.6 ml of distilled water. The resulting solution was added to a solution of 4.5 g of a lactic acid-glycolic acid copolymer (hereinafter referred to as PLGA) [produced by Wako Pure Chemical,
  • microcapsules were 5-60 ⁇ m and 9.5% (w/w), respectively.
  • Microcapsules were obtained in the same manner as in Example 1, except that PLGA [produced by Wako Pure
  • Microcapsules were obtained in the same manner as in Example 1, except that PLGA [produced by Wako Pure
  • Microcapsules were obtained in the same manner as in Example 1, except that the amount of peptide A acetate was 794 mg.
  • the particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m. and 14.3% (w/w), respectively.
  • Example 5 15 g of peptide A acetate was dissolved in 18 ml of distilled water. The resulting solution was added to a solution of 135 g of PLGA [produced by Wako Pure Chemical, lot. 940810; lactic acid/glycolic acid (molar ratio), 74/26; weight-average molecular weight based on GPC,
  • Microcapsules were obtained in the same manner as in Example 1, except that the acetate of NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DhArg(Et 2 )-Leu-hArg(Et 2 )-Pro-DAlaNH 2 (produced by Syntex Company) was used in place of peptide A acetate.
  • the particle size distribution and peptide content of the microcapsules were 5-60 ⁇ m and 9.4% (w/w), respectively.
  • Microcapsules were obtained in the same manner as in Example 1, except that 0.5 g of D-mannitol was added to the dispersion, which was lyophilized to yield powdered microcapsules.
  • the particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m and 11.7%
  • Microcapsules were obtained in the same manner as in Example 1, except that the amount of peptide A acetate was 1125 mg, the amount of distilled water was 1.0 ml, the amount of dichloromethane was 6.3 ml.
  • the particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m and 11.7% (w/w), respectively.
  • Microcapsules were obtained in the same manner as in Example 7, except that the amount of peptide A acetate was 1421 mg, the amount of distilled water was 1.2 ml, the amount of dichloromethane was 6.7 ml.
  • the particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m and 17.5% (w/w), respectively.
  • Microcapsules were obtained in the same manner as in Example 8, except that 50 g of D-mannitol was added to 1,000 ml of the 0.1% aqueous solution of polyvinyl alcohol.
  • the particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m and 14.7% (w/w), respectively.
  • Microcapsules were obtained in the same manner as in Example 9, except that 50 g of D-mannitol was added to 1,000 ml of the 0.1% aqueous solution of polyvinyl alcohol.
  • the particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m and 17.0% (w/w), respectively.
  • Microcapsules were obtained in the same manner as in Reference Example 1, except that the amount of peptide A acetate was 1421 mg, the amount of dichloromethane was 6.2 ml.
  • the particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m and 15.9% (w/w),
  • Microcapsules were obtained in the same manner as in Reference Example 2, except that 50 g of D-mannitol was added to 1,000 ml of the 0.1% aqueous solution of polyvinyl alcohol The particle size distribution and peptide A content of the microcapsules were 5-60 ⁇ m and 15.5% (w/w), respectively.
  • Example 4 About 20 mg of the microcapsules obtained in Example 4 was dispersed in 0.5 ml of dispersing solvent (distilled water containing 2.5 mg of carboxymethyl cellulose, 0.5 mg of polysorbate 80 and 25 mg of mannitol dissolved therein) , and injected subcutaneously to the backs of male SD rats at 10 weeks of age, using a 22-G injection needle. After administration, rats were sacrificed at constant intervals; the remaining microcapsules were taken out from the 0.5 ml of dispersing solvent (distilled water containing 2.5 mg of carboxymethyl cellulose, 0.5 mg of polysorbate 80 and 25 mg of mannitol dissolved therein) , and injected subcutaneously to the backs of male SD rats at 10 weeks of age, using a 22-G injection needle. After administration, rats were sacrificed at constant intervals; the remaining microcapsules were taken out from the
  • the microcapsules obtained according to the production method of the present invention release peptide A constantly, with substantially no initial burst.
  • a sustained-release preparation containing peptide [I] or a salt thereof can be obtained easily and at high recover rates.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé de production d'une préparation à diffusion prolongée. Ce procédé inclut la production d'une émission huileuse dont la phase aqueuse interne est une solution contenant un peptide bioactif représenté par la formule (I), dans laquelle X représente un atome d'hydrogène ou tétrahydrofurylcarboxamido; Q représente un atome d'hydrogène ou méthyle; A représente nicotinoyle ou N,N'-diéthylamidino; et B représente isopropyle ou N,N'-diéthylamidino, ou un sel de ce peptide, et dont la phase huileuse est une solution contenant un polymère biodégradable ayant un groupement carboxylique libre à une extrémité. Ce procédé consiste également à ajouter l'émulsion huileuse à une phase aqueuse extérieure pour produire une émulsion eau-huile-eau. Selon le procédé de production de la présente invention, une préparation à diffusion prolongée contenant un peptide (I) ou un sel de celui-ci peut être obtenue facilement et avec des taux de récupération élevés.
PCT/JP1996/000090 1995-01-23 1996-01-19 Preparation a diffusion prolongee et son emploi WO1996022786A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046212A1 (fr) * 1997-04-17 1998-10-22 Amgen Inc. Microparticules biodegradables pour administration soutenue de medicaments therapeutiques
US5853740A (en) * 1996-08-07 1998-12-29 Abbott Laboratories Delivery system for pharmaceutical agents encapsulated with oils
WO2000041678A1 (fr) * 1999-01-11 2000-07-20 Guilford Pharmaceuticals Inc. Procedes de traitement du cancer des ovaires, compositions poly(phosphoester), et articles biodegradables a cet effet
WO2001005380A1 (fr) * 1999-07-15 2001-01-25 Takeda Chemical Industries, Ltd. Compositions a liberation lente, techniques de production et methodes d'utilisation
US6204308B1 (en) 1999-03-01 2001-03-20 Novartis Ag Organic compounds
WO2003011314A2 (fr) * 2001-07-31 2003-02-13 Zentaris Gmbh Utilisation d'antagonistes lhrh dans des doses n'impliquant pas de sterilisation en vue d'ameliorer l'immunite induite par les lymphocytes t
US6740634B1 (en) 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0413209A1 (fr) * 1989-08-07 1991-02-20 TAP Pharmaceuticals Inc. Analogues de LHRH
EP0601799A1 (fr) * 1992-12-07 1994-06-15 Takeda Chemical Industries, Ltd. Préparation du type à libération prolongée

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0413209A1 (fr) * 1989-08-07 1991-02-20 TAP Pharmaceuticals Inc. Analogues de LHRH
EP0601799A1 (fr) * 1992-12-07 1994-06-15 Takeda Chemical Industries, Ltd. Préparation du type à libération prolongée

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5853740A (en) * 1996-08-07 1998-12-29 Abbott Laboratories Delivery system for pharmaceutical agents encapsulated with oils
WO1998046212A1 (fr) * 1997-04-17 1998-10-22 Amgen Inc. Microparticules biodegradables pour administration soutenue de medicaments therapeutiques
US6740634B1 (en) 1998-01-16 2004-05-25 Takeda Chemical Industries, Ltd. Sustained release compositions, process for producing the same and utilization thereof
US7388032B2 (en) 1998-01-16 2008-06-17 Takeda Pharmaceutical Company Limited Sustained release compositions, process for producing the same and utilization thereof
WO2000041678A1 (fr) * 1999-01-11 2000-07-20 Guilford Pharmaceuticals Inc. Procedes de traitement du cancer des ovaires, compositions poly(phosphoester), et articles biodegradables a cet effet
US6350464B1 (en) 1999-01-11 2002-02-26 Guilford Pharmaceuticals, Inc. Methods for treating ovarian cancer, poly (phosphoester) compositions, and biodegradable articles for same
US6204308B1 (en) 1999-03-01 2001-03-20 Novartis Ag Organic compounds
WO2001005380A1 (fr) * 1999-07-15 2001-01-25 Takeda Chemical Industries, Ltd. Compositions a liberation lente, techniques de production et methodes d'utilisation
US7265157B1 (en) 1999-07-15 2007-09-04 Takeda Pharmaceutical Company Limited Sustained release compositions, process for producing the same and use thereof
WO2003011314A2 (fr) * 2001-07-31 2003-02-13 Zentaris Gmbh Utilisation d'antagonistes lhrh dans des doses n'impliquant pas de sterilisation en vue d'ameliorer l'immunite induite par les lymphocytes t
WO2003011314A3 (fr) * 2001-07-31 2003-10-16 Zentaris Gmbh Utilisation d'antagonistes lhrh dans des doses n'impliquant pas de sterilisation en vue d'ameliorer l'immunite induite par les lymphocytes t

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