US20040146561A1 - Compositions for promoting healing of bone fracture - Google Patents

Compositions for promoting healing of bone fracture Download PDF

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Publication number
US20040146561A1
US20040146561A1 US10/478,709 US47870903A US2004146561A1 US 20040146561 A1 US20040146561 A1 US 20040146561A1 US 47870903 A US47870903 A US 47870903A US 2004146561 A1 US2004146561 A1 US 2004146561A1
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Prior art keywords
composition according
fracture
drug
pde4 inhibitor
compound
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US10/478,709
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Naoki Sakurai
Toshiki Takagi
Noriyuki Yanaka
Yuji Horikiri
Takashi Tamura
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Tanabe Seiyaku Co Ltd
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Tanabe Seiyaku Co Ltd
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Assigned to TANABE SEIYAKU CO., LTD. reassignment TANABE SEIYAKU CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YANAKA, NORIYUKI, HORIKIRI, YUJI, TAMURA, TAKASHI, TAKAGI, TOSHIKI, SAKURAI, NAOKI
Publication of US20040146561A1 publication Critical patent/US20040146561A1/en
Priority to US11/826,921 priority Critical patent/US7659273B2/en
Abandoned legal-status Critical Current

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Definitions

  • the present invention relates to a composition for accelerating bone fracture healing, specifically, to a pharmaceutical composition for accelerating bone fracture healing, which comprises as an active ingredient a PDE4 inhibitor, preferably a PDE4 inhibitor together with a biocompatible and biodegradable polymer, which is especially in the form of microsphere preparation, more preferably, microsphere-containing injectable preparation, and which is able to promote bone fracture healing when locally administered.
  • a PDE4 inhibitor preferably a PDE4 inhibitor together with a biocompatible and biodegradable polymer, which is especially in the form of microsphere preparation, more preferably, microsphere-containing injectable preparation, and which is able to promote bone fracture healing when locally administered.
  • Bone fracture is a condition where a physiological continuity of bone tissue is partially or completely broken off and generally classified on the basis of the outbreak mechanism into (a) fracture by external force, (b) pathological fracture, and (c) fatigue fracture.
  • the state of bone fracture is classified on the basis of the fracture line (the line tracing the epiphysis generated by bone transection), into fissure fracture, greenstick fracture, transverse fracture, oblique fracture, spiral fracture, segmental fracture, comminuted fracture, avulsion fracture, compression fracture, depression fracture, and the like (IGAKU-DAIJITEN, 18th ed., pp. 719-720, published by Nanzando).
  • the fracture healing process is mainly classified into the following three stages (“Kossetsu Chiryougaku (Fracture Therapeutics)”, April, 2000, pp. 29-37, 46-51, Nanko-do), and it is considered that, the healing progresses in the reparative phase, an important stage for bone fracture healing, by a mechanism different from that in the bone remodeling phase where osteogenesis and osteolysis (bone resorption) occur repeatedly.
  • a reparative phase two processes progress in parallel; a process in which hematoma in the fracture crevice is removed yielding granulation tissue, soft callus is formed and gradually replaced by hard callus via osteogenic mechanism (endochondral ossification), and a process in which a new bone is formed by osteogenic cells present in periost (fibrous/intramembranous ossification).
  • a re-molding phase the formed new bone extends for a long term by repeating the bone resorption and the bone formation, while the bone deformation is corrected and defect region reinforced.
  • the new bone formed during the re-molding phase has intensity of certain degree, and one's daily life is less hampered; however, the reparative phase takes a long term and restricts patient's daily life greatly. Accordingly, it is clinically important to shorten the term of reparative phase.
  • peptide-type physiologically active substances such as bone morphogenetic protein (BMP) and transforming growth factor (TGF) (Proc. Natl. Acad. Sci., USA, vol. 87, pp. 2220-2224 (1989). Further, it has been disclosed a pharmaceutical preparation for local administration containing a compound of the formula below (JP-04-364179A (1992)) as a bone formation accelerator after microcapsulation with lactic acid-glycolic acid copolymer (PLGA) in JP-09-263545A (1997).
  • BMP bone morphogenetic protein
  • TGF transforming growth factor
  • One of purposes of the present invention is to provide a novel pharmaceutical composition for accelerating bone fracture healing, which accelerates the healing of a fracture in the early stage.
  • Another purpose of the present invention is to provide a novel pharmaceutical composition for local administration which, when applied to a fracture region, exerts efficiently the fracture healing accelerating activity only at an intended site while avoiding the manifestation of systemic action of an active ingredient.
  • Yet another purpose of the present invention is to provide a sustained release depot preparation for accelerating bone fracture healing, which, when applied locally, can release an active ingredient gradually and exert the drug efficacy over a long term by one time dosage.
  • the present inventors have investigated into pharmacological actions of various compounds and noticed that compounds having PDE4 inhibiting activity could affect the fracture healing process. The inventors have then found that the compounds having PDE4 inhibiting activity can accelerate the fracture healing and established the present invention.
  • the present invention provides a composition for accelerating bone fracture healing, which comprises a PDE4 inhibitor as an active ingredient.
  • the present invention provides a pharmaceutical preparation suitable for local administration at the fracture region, specifically, a bone fracture healing accelerating composition in the form of depot preparation.
  • FIG. 1 is a copy of photography showing chondrocyte calcification (calcium deposits) effect of Compound (1) in cultured rabbit costicartilage cells.
  • FIG. 2 is a graph showing the reproduction of a defective radius in a rabbit treated with PDE4 inhibitor (Compound (2)) microsphere.
  • the relation between the total bone area (cross sectional) (mm 2 ) or stress-strain index (SSI: mm 3 ), and the dosage of Compound (2) are shown in the upper and the lower graphs, respectively.
  • FIG. 3 is a graph showing a time-course of cAMP content in rat fibula fracture region that was treated with a PDE4 inhibitor (Compound (2)) microsphere.
  • FIG. 4 is a graph showing a time-course of cAMP content in fibula fracture region of normal and STZ-induced diabetic rats.
  • FIG. 5 is a graph showing the in vitro elution characteristics of microspheres obtained in Example 1-(4), 2-(1) and 3-(1).
  • FIG. 8 is a graph showing the time-course of Compound (1) remaining in the preparation following the subcutaneous injection of microsphere dispersion obtained in Example 2-(2). Data are shown by mean ⁇ standard deviation (n 5).
  • the bone fracture healing accelerating composition of the present invention has a superior effect on the bone fracture healing process especially in the reparative phase.
  • the present composition can accelerate the fracture healing by accelerating the endochondral ossification wherein a soft callus is formed at the fracture region, which in turn is replaced by hard callus.
  • the pharmaceutical composition of the present invention can be prepared by combining a PDE4 inhibitor as an active ingredient and a conventional pharmaceutically acceptable excipient or a diluting agent therefor.
  • Preferred pharmaceutical composition is a sustained release composition for local administration, which contains a PDE4 inhibitor(s) and a biocompatible and biodegradable polymer(s). It is further preferred that said composition for local administration is in the form of microsphere, which microsphere can be formulated as an injectable preparation.
  • Examples of PDE4 inhibitor usable as an active ingredient of pharmaceutical compositions of the present invention include all the compounds having PDE4 inhibitory activity, for example, those described in JP 05-229987A (1993), JP 09-59255A (1997), JP 10-226685A (1998), EP 158380, WO/94/25437, U.S. Pat. No. 5,223,504, WO/95/4045, EP 497564, EP 569414, EP 623607, EP 163965, U.S. Pat. No. 5,605,914, WO/95/35282, WO/96/215, U.S. Pat. No. 5,804,588, U.S. Pat. No.
  • PDE can be classified into PDE1-5 according to the teaching of “Trends in Pharmacological Sciences, vol. 11, pp. 150-155”, and PDE4 inhibitors suitable for the present bone fracture healing accelerating composition are preferably selective to PDE4 with higher inhibitory activity against PDE4 compared to others (PDE1-3, 5), more preferably have 10 times or more inhibitory activity on PDE4 than on the other PDEs.
  • the inhibitory activity of such PDE4 inhibitor on PDE4 is particularly preferably 50 times or more, and yet more preferably 100 times or more of that on the other PDEs.
  • Preferable PDE4 inhibitors are compounds of which IC 50 of PDE4 inhibitory activity is 0.1-1000 nM, preferably 0.1-100 nM, more preferably less than 100 nM, when determined by a method described in “Advances in Cyclic Nucleotide Research”, vol. 10, pp. 69-92, 1979, Raven Press.
  • selective PDE4 inhibitors include Compounds (1) to (57) represented by the following formulas or pharmaceutically acceptable salts thereof.
  • the compounds having PDE4 inhibitory activity can be classified into (A) to (D) below according to the chemical structure, and a PDE4 inhibitor for the present invention can be selected from these compounds appropriately; however, preferred compounds belong to (A) and (B), in particular, (A).
  • (C) Compounds having a xanthine skeleton or a partial structure analogous thereto [e.g., Compounds (5), (7), (28), (29), (30), (31), (32), (36), (37), (41), (43) and (46)]; and
  • (D) Compounds having a different structure from those described in (A) to (C) above [e.g., Compounds (3), (4), (8), (10), (13), (15), (16), (18), (22), (23), (42), (45) and (48)].
  • Examples of compounds of group (A) include those shown by the following formulas (I) to (III) and pharmacologically acceptable salts thereof.
  • R 1 and R 2 are the same or different and each a hydrogen atom, a hydroxyl group, a cyclo-lower alkyloxy group, or an optionally substituted lower alkoxy group, or bind together at the ends to form a lower alkylenedioxy group;
  • R 3 is an optionally substituted 6-membered nitrogen-containing heterocyclic group; and —OR 4 and —OR 5 are the same or different and each an optionally protected hydroxyl group. JP 05-229987A, (1993).
  • R and R 2 are the same or different and each a hydrogen atom or an optionally protected hydroxyl group; either of R 3′ and R 4′ is an optionally protected hydroxy-substituted methyl group and the other is a hydrogen atom, a lower alkyl group or an optionally protected hydroxy-substituted methyl group; and
  • R 5 and R 6 are the same or different and each a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted phenyl group or an optionally protected amino group, or bind together at the ends and form in association with the adjacent nitrogen atom an optionally substituted heterocyclic group. JP-09-59255A, (1993).
  • A is a group selected from those shown by the formulas:
  • R 1′ and R 2′ are the same or different and each a hydrogen atom or an optionally protected hydroxyl group;
  • R 31 is an optionally protected hydroxymethyl group;
  • R 32 is a hydrogen atom, a lower alkyl group or an optionally protected hydroxymethyl group;
  • R 33 is an optionally substituted lower alkyl group;
  • R 41 is an optionally protected hydroxymethyl group;
  • R 42 is an optionally protected hydroxymethyl group; the dotted line represents the presence or absence of a double bond; and
  • R 5′ and R 6′ are the same or different and each a hydrogen atom or an optionally protected amino group, or bind together at the ends and form in association with the adjacent nitrogen atom an optionally substituted heterocyclic group.
  • PDE4 inhibitor which is an active ingredient of the present bone fracture healing accelerating composition
  • group (A) compounds having naphthalene or isoquinoline skeleton and pharmaceutically acceptable salts thereof are more preferred, and Compounds (1) and (2) and their pharmaceutically acceptable salts are still more preferred.
  • the bone fracture healing accelerating composition of the present invention is preferably applied locally to a vicinity of fracture region so that the drug concentration in the systemic blood does not increase but the one at the fracture region is maintained.
  • Examples of preferred embodiments of the present composition include depot preparations which gradually release a drug when administered locally (e.g., pellet preparation, gel preparation, matrix preparation, microsphere preparation, a sustained release preparation obtained by adding a drug into an aqueous solution of a biocompatible and biodegradable polymer, a preparation which is designed to be a liquid at the time of administration and to form a gel in a living body after administration, a preparation embedded in various bases which are reported to be generally used in the field of orthopedics, and the like.)
  • depot preparations which gradually release a drug when administered locally e.g., pellet preparation, gel preparation, matrix preparation, microsphere preparation, a sustained release preparation obtained by adding a drug into an aqueous solution of a biocompatible and biodegradable polymer, a preparation which is designed to be a liquid at the time of administration and to form a gel in a living body after administration, a preparation embedded in various bases which are reported to be generally used in the field of orthopedics, and the like.
  • pellet preparations include a long-term sustained release preparation obtainable by compressing a drug and fine particles of lactic acid-glycolic acid copolymer of which terminal carboxyl group is esterified by an alcohol, and the like. (JP2001-187749A)
  • gel preparations include those obtained by dissolving into a phosphate buffer a drug and hyaluronic acid which is chemically bound to polyethylene glycol (Journal of Controlled Release, 59 (1999) pp. 77-86), and the like.
  • Examples of matrix preparations comprising a drug include those obtained by impregnating a drug into granular material of collagen or fibrous membrane preparation, or by adding a drug to a granular material of collagen or a reaction mixture for preparing a fibrous membrane preparation, and the like (JP10-182499A (1998), JPO6-305983 (1994)).
  • Examples of a sustained release preparation obtained by adding a drug into an aqueous solution of a biocompatible and biodegradable polymer include those obtained by adding a drug into an aqueous sodium hyaluronate solution, and the like.
  • Examples of a preparation designed to be a liquid at the time of administration and to form a gel in a living body after administration include those wherein a drug and a lactic acid-glycolic acid copolymer are dissolved in N-methyl-2-pyrrolidone (Journal of Controlled Release, 33 (1995) pp. 237-243), or a preparation comprising a drug and a polymer that exists as an solution at low temperature but forms a gel at body temperature, such as a block co-polymer of lactic acid-glycolic acid copolymer and polyethylene glycol and the like (ibid., 27(1993), 139-147).
  • Examples of a preparation embedded in various bases which are reported to be generally used in the field of orthopaedics include those prepared by mixing a drug and a base (e.g., water-insoluble biocompatible and biodegradable polymer, polymethyl methacrylate, hydroxyapatite, tricalcium phosphate or the like). Biomaterials, vol. 21, pp. 2405-2412 (2000); and International Journal of Pharmaceutics, vol. 206, pp. 1-12 (2000).
  • a base e.g., water-insoluble biocompatible and biodegradable polymer, polymethyl methacrylate, hydroxyapatite, tricalcium phosphate or the like.
  • Preparations for local administration that release an effective amount of PDE4 inhibitor gradually in affected fracture region are preferred in the respect that the administration frequency during the term required for bone fracture healing can be reduced.
  • the particle size of such microspheres is preferably in the range suitable for passing a needle, more preferably 0.01-150 ⁇ m, particularly preferably 0.1-100 ⁇ m in the respect that the irritation at the affection site can be reduced.
  • the present bone fracture healing accelerating composition containing a PDE4 inhibitor as an active ingredient is administered locally to a vicinity of fracture region, it would be preferable to make the dosage small.
  • the PDE4 inhibitor content in the composition such as microsphere preparation can be preferably 0.0001-80% by weight, more preferably 0.001-50% by weight, and further more preferably 0.01-50% by weight.
  • the dose of a PDE4 inhibitor as an active ingredient may vary depending on the kind of PDE4 inhibitor to be used, the weight, age, conditions of the subject or a site to be applied and is generally determined by a physician; however, for local administration, the dose can usually be in the range of from 1 ng to 1 g per affected site.
  • the bone fracture healing accelerating composition of the present invention can be prepared in a conventional manner using a PDE4 inhibitor and a pharmaceutically acceptable excipient or a carrier therefor.
  • Preferred composition can be prepared by combining a PDE4 inhibitor and a biocompatible and biodegradable polymer.
  • the water-insoluble biocompatible and biodegradable polymer is a water-insoluble biocompatible and biodegradable polymer that requires at least 1000 ml of water to dissolve 1 g of the polymer at 25° C.
  • specific example include hydroxy fatty acid polyesters and derivatives thereof (for example, poly lactic acid, poly glycolic acid, poly citric acid, poly malic acid, poly- ⁇ -hydroxybutyric acid, ring-opening polymerized ⁇ -caprolactones, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, block copolymer of poly lactic acid and polyethylene glycol, block copolymer of poly glycolic acid and polyethylene glycol, and block copolymer of lactic acid-glycolic acid copolymer and polyethylene glycol, etc.), polymers of alkyl ⁇ -cyanoacrylates (e.g., polybutyl-2-cyanoacrylate, etc.), poly
  • hydroxy fatty acid polyesters are particularly preferred. Above all, those of which average molecular weight ranging in between 2000 and about 800000 are more preferred, those ranging in between 2000 and about 200000 are especially preferred and those ranging in between 5000 and 50000 are most preferred.
  • poly lactic acid, lactic acid-glycolic acid copolymer and 2-hydroxybutyric acid-glycolic acid copolymer are more preferred.
  • the molar ratio of lactic acid and glycolic acid in a lactic acid-glycolic acid copolymer is preferably 90:10 to 30:70, more preferably 80:20 to 40:60, and the molar ratio of 2-hydroxybutyric acid and glycolic acid in a 2-hydroxybutyric acid-glycolic acid copolymer is preferably 90:10 to 30:70, more preferably 80:20 to 40:60.
  • Pulverization of PDE4 inhibitor can be carried out using any one of conventional methods for producing fine particles including mechanical pulverization methods such as jet mill, hammer mill, convolution ball mill, jar ball mill, beads mill, shaker mill, rod mill and tube mill pulverizations, or so-called crystallization method wherein a drug is first dissolved in a solvent and then recrystallized by adjusting pH, changing temperature, or altering the constitution of solvent, and recovering the particles by centrifugation, filtration, or the like.
  • mechanical pulverization methods such as jet mill, hammer mill, convolution ball mill, jar ball mill, beads mill, shaker mill, rod mill and tube mill pulverizations, or so-called crystallization method wherein a drug is first dissolved in a solvent and then recrystallized by adjusting pH, changing temperature, or altering the constitution of solvent, and recovering the particles by centrifugation, filtration, or the like.
  • microsphere preparation can be prepared by the following methods.
  • a salt of a PDE4 inhibitor shows low incorporation rate into a microsphere, it may be converted into corresponding free form using an acid or a base prior to the preparation of microspheres.
  • a drug is added to a solution of water-insoluble biocompatible and biodegradable polymer in a water-immiscible organic solvent of which boiling point is lower than water (water-insoluble polymer solution), and the resultant organic phase is dispersed into an aqueous phase to give an O/W emulsion, which is followed by removal of the organic solvent.
  • This method can be conducted in a manner similar to those described in, for example, JP 56-19324B (1981), JP 63-91325A (1988), JP 08-151321A (1996), Kajeev Jain et al., “Controlled Drug Delivery by Biodegradable Poly (Ester) Devices: Different Preparative Approaches”, Drug Development and Industrial Pharmacy, vol. 24(8), pp. 703-727, 1998, JP 60-100516A (1985), JP 62-201816A (1987), JP 09-221417A (1997) and JP 06-211648A (1994).
  • a solution of a drug and a water insoluble biocompatible and biodegradable polymer in a water miscible organic solvent is added to an aqueous solution of protective colloid, followed by emulsification with stirring to yield fine particles.
  • This method can be conducted in a manner similar to those described in, for example, JP 05-58882A (1993), JP 09-110678A (1997) and International Journal of Pharmaceutics, vol. 187, pp. 143-152 (1999).
  • An organic phase which is O/O emulsion which uses two or more water-insoluble, biocompatible and biodegradable polymers, wherein a drug is dissolved or dispersed in a polymer solution that is dispersed in the other(s).
  • O/O emulsion when dispersed in an aqueous phase, gives (0/0)/W emulsion (JP 06-211648A (1994)).
  • the emulsification can be achieved by a conventional method, for example, the intermittent shaking method, the method using a mixer such as a propeller shaker or a turbine shaker, the colloidal mill method, the homogenizer method and the ultrasonication method.
  • a conventional method for example, the intermittent shaking method, the method using a mixer such as a propeller shaker or a turbine shaker, the colloidal mill method, the homogenizer method and the ultrasonication method.
  • organic solvent usable in these methods include halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, chloroethane, dichloroethane, trichloroethane, etc.), aliphatic esters (ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (benzene, etc.), aliphatic hydrocarbons (n-hexane, n-pentane, cyclohexane, etc.), ketones (methylethyl ketone, etc.), ethers (diethyl ether, diisopropyl ether, methyl isobutyl ether, etc.)
  • halogenated hydrocarbons methylene chloride, chloroform, carbon tetrachloride, chloroethane, dichloroethane, trichloroethane, etc.
  • aliphatic esters ethyl acetate, butyl acetate,
  • an emulsifier may be added to an aqueous phase to stabilize emulsion, which emulsifier includes, for example, anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants ⁇ polyoxyethylene sorbitan fatty acid ester [Tween80, Tween 60 (Nikko Chemicals, Co., Ltd.)], polyethylene castor oil derivatives [HCO-60, HCO-50 (Nikko Chemicals, Co., Ltd.)], polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, lecithin, gelatin, etc.
  • anionic surfactants sodium oleate, sodium stearate, sodium lauryl sulfate, etc.
  • nonionic surfactants ⁇ polyoxyethylene sorbitan fatty acid ester
  • the former when one or more other ingredients are incorporated in addition to PDE4 inhibitor, the former can be preferably added to the organic phase at the time of preparation of O/W emulsion.
  • an osmoregulatory agent may be included in an aqueous phase to prevent the outflow of an active ingredient into an aqueous phase (JP 2608245).
  • O/W emulsion obtained in the above-mentioned manner is then subjected to in-water-drying to remove organic solvent present in emulsion to give microspheres.
  • Organic solvent can be removed from emulsion in a conventional manner such as heating, placing under reduced pressure, blowing air, or the like, and for example, a method where a solvent is distilled off in an open system (JP 56-19324B (1981), JP 63-91325A (1988), JP 08-151321A (1996), JP 06-211648A (1994)) or in a closed system (JP 09-221418A (1997)) can be employed. In addition, a method where a solvent is extracted and removed by means of a large quantity of outside water phase (JP-2582186) can also be used.
  • a method wherein a solution containing a drug, a biodegradable polymer and a water-miscible good solvent (Solvent A: acetone, tetrahydrofuran, etc.) for the said polymer is first added to a homogeneous mixed solution comprising a poor solvent (Solvent B: water, ethanol, etc.) for the said polymer, which is miscible with solvent A, and a poor solvent (Solvent C: glycerin, etc.) for the said polymer, which is immiscible with solvent A.
  • the mixture upon emulsification, gives emulsion wherein the polymer solution constitutes the dispersed-phase and the homogeneous mixed solution constitutes the continuous-phase.
  • the solvent A is then removed from the dispersed phase (WO/01/80835).
  • a method for preparing microspheres from emulsion by in-water-drying method in which emulsion an organic phase containing an organic solvent with a boiling point lower than water (methylene chloride, ethyl acetate, etc.) and a water insoluble polymer is emulsified in an aqueous phase, comprising (1) employing a device equipped with a gas separation membrane (permeable evaporation membrane, porous membrane, etc.), (2) providing emulsion to be subjected to the in-water-drying to one side of the gas separating membrane, and (3) distilling off the organic solvent in emulsion to the other side of the gas separating membrane (WO/01/83594).
  • a gas separation membrane permeable evaporation membrane, porous membrane, etc.
  • the organic solvent remaining in microspheres can be removed by heating microspheres in an aqueous phase at temperature higher than the boiling point of the organic solvent (JP 2000-239152A) or heating the microspheres to dry after coating with an additive of high melting point (JP 09-221417A (1997)).
  • the resultant microspheres are recovered by centrifugation, filtration or sieving, washed to remove substances attached on the surface such as additives in the water-phase, and subjected to lyophilization optionally after combining with an aggregation inhibitor to prevent the agglomeration of microspheres, for example, sugar, sugar alcohol or inorganic salt, preferably lactose, mannitol or sorbitol.
  • an aggregation inhibitor to prevent the agglomeration of microspheres
  • sugar, sugar alcohol or inorganic salt preferably lactose, mannitol or sorbitol.
  • a sieve to obtain microspheres of an intended particle size, and it is more preferred to use a sieve allowing particles of, for example, 150 ⁇ m or below to pass so as to improve the syringeability when the microsphere preparation is used as injectable solution.
  • amphiphilic solvents such as acetone, acetonitrile, tetrahydrofuran and dioxane in addition to the organic solvents used in the “In-water Drying Method” above can be used.
  • a PDE4 inhibitor and optionally one or more additional ingredients, or a solution thereof, are dissolved or dispersed in an organic solution of water insoluble polymer in any one of these organic solvents to form an organic phase.
  • the organic phase is added gradually to a solvent (disperse medium) immiscible with the organic solvent above, for example, silicon oil, liquid paraffin, sesame oil, soybean oil, corn oil, cotton seed oil, coconuts oil, linseed oil, with stirring to form O/O emulsion.
  • a surfactant may be added to the disperse medium.
  • the water insoluble polymer can be solidified by cooling the emulsion or evaporating the solvent in the organic phase by heating.
  • a hardening agent such as hexane, cyclohexane, methyl ethyl ketone, octamethyl-cyclotetrasiloxane or the like can be added gently to emulsion with stirring, or versa, to separate out the water insoluble polymer from emulsion thereby forming microspheres.
  • the resultant microspheres are recovered by centrifugation, filtration or sieving, washed with hexane or purified water to remove solvents, additives, etc. attached on its surface, and optionally subjected to air-drying, vacuum-drying, or lyophilization. Alternatively, it can be lyophilized after adding an aggregation inhibitor in a manner similar to that used in the above-mentioned in-water-drying method.
  • Examples of internal organic phase in the phase separation method include the following embodiments.
  • microspheres by “Spray Drying Method” is conducted using the same organic solvent as the above-mentioned phase separation method.
  • a water insoluble biocompatible and biodegradable polymer To an organic solvent is dissolved a water insoluble biocompatible and biodegradable polymer, and a PDE4 inhibitor and optionally one or more additional ingredients, or a solution thereof, are dissolved or dispersed in the solution, and sprayed via a nozzle into a drying chamber of a spray drier to volatilize the organic solvent to form microspheres.
  • any commercially available spray dryers for example, such as Pulvis Mini Spray GS31 (YAMATO Scientific Co., Ltd.), Mini Spray Dryer (Shibata Scientific Technology, Co., Ltd.), can be used.
  • microspheres are then worked-up in a manner similar to that used in the in-water drying method to yield the desired microsphere preparation.
  • Examples of water-miscible organic solvents usable in the “Solvent Diffusion Method include acetone, methanol, ethanol or a mixture thereof, which may further contain a volatile solvent (methylene chloride, chloroform) in which a drug can dissolve, if necessary.
  • Examples of colloid protective agent include polyvinyl alcohol.
  • microsphere preparation of the present composition for accelerating the bone fracture healing comprising a PDE4 inhibitor as an active ingredient
  • a PDE4 inhibitor as an active ingredient
  • An injectable preparation of microspheres can be prepared by dispersing/suspending microspheres obtained by the present invention at a concentration of 0.0001-1000 mg/ml, preferably 0.0005-800 mg/ml, more preferably 0.001-500 mg/ml into an aqueous solution containing a dispersant.
  • dispersant examples include nonionic surfactants such as polyoxyethylene sorbitan fatty acid ester (Tween80, Tween60, Nikko Chemicals Co., Ltd.), polyethylene castor oil (HCO-60, HCO-50, Nikko Chemicals Co., Ltd.), cellulose-derived dispersants such as carboxymethyl cellulose sodium, sodium alginate, dextran, sodium hyaluronate, and the like. These dispersants can serve to improve the dispersibility of microspheres and stabilize the elution of an active ingredient.
  • a dispersant can generally be added to a composition at a concentration of 0.01-2% by weight, preferably 0.05-1% by weight.
  • the injectable preparation above may optionally contain a preservative (methylparaben, propylparaben, benzyl alcohol, chlorobutanol, sorbic acid, boric acid, amino acid, polyethylene glycol, etc.), an isotonizing agent (sodium chloride, glycerin, sorbitol, glucose, mannitol, etc.), a pH modifier (sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, citric acid, oxalic acid, carbonic acid, acetic acid, arginine, lysine, etc.), a buffer (sodium hydrogen phosphate, potassium hydrogen phosphate, etc.) or the like.
  • a preservative methylparaben, propylparaben, benzyl alcohol, chlorobutanol, sorbic acid, boric acid, amino acid, polyethylene glycol, etc.
  • an isotonizing agent sodium chloride, glycerin,
  • a steroid antiinflammatory analgesic or non-steroidal antiinflammatory analgesic may be dissolved or dispersed in the injectable preparation.
  • steroidal antiinflammatory analgesic include dexamethasone, triamcinolone, triamcinolone acetonide, halopredone, paramethasone, hydrocortisone, prednisolone, methylprednisolone, betamethasone, and the like.
  • non-steroidal antiinflammatory analgesic include ibuprofen, ketoprofen, indomethacin, naproxen, piroxicam, and the like.
  • the microsphere injection containing PDE4 inhibitor can be in the form of a kit for preparing an injectable preparation at the time of use, which kit comprises a solid preparation of an aggregation inhibitor and microspheres, a dispersant and injectable distilled water.
  • the solid preparation used in a kit can be prepared by suspending microspheres in an aqueous solution containing an aggregation inhibitor, and subjecting the suspension to lyophilization, vacuum drying, or spray drying, and/or the like.
  • the lyophilization is especially preferred.
  • a dispersant When preparing a solid preparation, a dispersant can be added to an aqueous solution containing aggregation inhibitor (mannitol, sorbitol, lactose, glucose, xylitol, maltose, galactose, sucrose, etc.) in order to improve the re-dispersibility into injectable distilled water, thereby yielding a solid preparation of good dispersibility. If necessary, it can be formulated into a kit for preparing an injectable preparation, in which a steroidal antiinflammatory analgesic and/or a non-steroidal antiinflammatory analgesic as well as a dispersant are combined.
  • aggregation inhibitor mannitol, sorbitol, lactose, glucose, xylitol, maltose, galactose, sucrose, etc.
  • the present bone fracture healing accelerating composition comprising a PDE4 inhibitor as an active ingredient can be used in treatment of various warm blood mammals such as human, a domestic animal (a horse, a bull, a sheep, a pig), a pet (a dog, a cat), and the like.
  • disorders to which the present fracture healing accelerating composition comprising a PDE4 inhibitor as an active ingredient applicable include (a) fracture by external force, (b) pathological fracture (fracture associated with osteoporosis, osteomalacia, malignant tumor, multiple myeloma, osteogenesis imperfecta congenita, cyctic bone, suppurative myelitis, osteopetrosis or nutrition disorders), and (c) fatigue fracture.
  • pathological fracture fracture associated with osteoporosis, osteomalacia, malignant tumor, multiple myeloma, osteogenesis imperfecta congenita, cyctic bone, suppurative myelitis, osteopetrosis or nutrition disorders
  • the present fracture healing accelerating composition comprising a PDE4 inhibitor as an active ingredient can be applied to any of the following fractures, including fissure fracture, greenstick fracture, transverse fracture, oblique fracture, spiral fracture, segmental fracture, comminuted fracture, avulsion fracture, compression fracture, depression fracture, and the like
  • CD (SD) IGS rats (Charles River Japan, Inc.; male; 7-week-old) were housed for seven days at room temperature (23 ⁇ 2° C.) and 40-70% humidity. During the housing period, the rats were free to access commercially available food (from Oriental Bio; CE-2).
  • the fibula excised at 6 weeks after suturing was subjected to a three-point bending test with bone strength tester (from Muromachi Kikai Co., Ltd.; TK-252C) to determine bone strength. Briefly, the fibula was supported by two supports apart from each other by 8 mm and the cut section was positioned at the middle of these supports, i.e., 4 mm apart from the respective two supports. Loading (3 mm/minute) from upper direction was kept on the middle point (fracture section) of fibula until fibula begins to fracture. The maximum pressure necessary to break the bone was defined as the breaking force and the total energy spent to break the bone was defined as the breaking energy.
  • CD CD (SD) IGS rats (Charles River Japan, Inc.; male; 7-week-old) were housed for seven days at room temperature (23+2° C.) and 50 ⁇ 20% humidity. During the housing period, the rats were free to access commercially available food (from Oriental Bio; CE-2).
  • the fibula excised at 4 weeks after suturing was subjected to a three-point bending test with bone strength tester (from Muromachi Kikai Co., Ltd.; TK-252C) to determine bone strength. Briefly, the fibula was supported by two supports apart from each other by 8 mm and the cut section was positioned at the middle of these supports, i.e., 4 mm apart from the respective two supports. Loading (3 mm/minute) from upper direction was kept on the middle point (fracture section) of fibula until fibula begins to fracture. The breaking force and the total energy spent to break the bone was defined as the breaking energy.
  • bone strength tester from Muromachi Kikai Co., Ltd.; TK-252C
  • Costicartilages were isolated from NZ line rabbit (Kitayama Labes., Co Ltd.; male; 4-week-old) and soaked into Hank's balanced salt solution (calcium- and magnesium-free; LifeTech Co., Ltd.; hereinafter, referred to as HBSS”).
  • Hank's balanced salt solution calcium- and magnesium-free; LifeTech Co., Ltd.; hereinafter, referred to as HBSS.
  • One costicartilage and one costa were excised together, the adipose tissue and the muscle tissue were removed and then, the proliferating chondrocyte layer of costicartilage was excised.
  • the collected proliferating chondrocyte layer was cut into sections with a surgical knife (FEATHER Safety Razor Co., Ltd.) and the all proliferating chondrocyte layer sections from 4 rabbits were combined in a centrifuge tube.
  • HBSS HBSS supplied with 0.1% tetrasodium ethylenediamine tetraacetate to obtain suspension of the proliferating chondrocyte layer sections, which was shaken at 37° C. for 20 minutes and centrifuged (1500 rpm, 10 minutes). The supernatant was aspirated off, and 40 ml of HBSS (pH 7.2) supplied with 0.2% trypsin was added to the tube to suspend the precipitates and shaken at 37° C. for 1 hour. The tube was centrifuged (1500 rpm, 10 minutes), and the supernatant was aspirated off.
  • the precipitates were washed twice with HBSS, suspended in 100 ml of HBSS supplied with 0.1% collagenase (Wako Pure Chemical Industries, Ltd., 034-10533) and shaken at 37° C. for 3 hours.
  • the content of the tube was passed through the Cell Strainer (pore size 40 ⁇ m) and the filtrate was divided into four centrifuge tubes.
  • To each of all four tubes was added 40 ml of medium ( ⁇ -MEM, LifeTech Co., Ltd.), and the tubes were centrifuged (1500 rpm, 10 minutes). The supernatant was aspirated off, and the resultant precipitates were collected in one tube with Pipetman.
  • the tube was re-centrifuged (1500 rpm, 10 minutes). Washing procedure comprising addition of medium followed by centrifugation was repeated additional three times. The precipitates were suspended in the same medium to give an about 5 ml suspension, and the cell number was counted.
  • Japanese White rabbits male; 11-week-old; 4 rabbits/group were housed for seven days at room temperature (23+2° C.) and 55 ⁇ 15% humidity. During the housing period, the rabbits were free to access commercially available food (from Oriental Bio Service; LRC4).
  • the shoulder-side on the fracture line was defined as the proximal end and the point 5 mm apart from the proximal end toward wrist defined as the distal end.
  • the total (cross sectional) bone area (mm 2 ) and stress-strain index (SSI: mm 3 ) at the distal end were determined using pQCT (Norland-Stratec; XCT-960A) (Clinical Calcium Vol.10, 35-41, 2000).
  • CD (SD) IGS rats (Charles River Japan, Inc.; male; 7-week-old) were housed for seven days at room temperature (23 ⁇ 2° C.) and 55 ⁇ 15% humidity. During the housing period, the rats were free to access commercially available food (from Oriental Bio Service; CRF-1).
  • Streptozotocin (Sigma), which induce diabetes, was dissolved in citrate-buffered saline (pH 4.5) to obtain 0.05 M streptozocin solution and injected intravenously to each rat at 60 mg/kg.
  • citrate-buffered saline pH 4.5
  • blood-glucose monitor Molecular Devices; M-SPmax250
  • rats were divided into groups so that a significant difference in glucose level may not occur among groups.
  • the average blood-glucose level was from 426.12 to 428.23 mg/dl.
  • PDE4 inhibitor has bone mineral content increasing effects in a dose-dependent manner even in the case of bone fracture of diabetic subjects, of which healing is known to be delayed, as demonstrated in the diabetic model animals
  • the fibula used in the determination of mineral content was subjected to a three-point bending test with bone strength tester (from Muromachi Kikai Co., Ltd.; TK-252C) to determine bone strength. Briefly, the fibula was supported by two supports apart from each other by 8 mm and the cut section was positioned at the middle of these supports, i.e., 4 mm apart from the respective two supports. Loading (3 mm/minute) from upper direction was kept on the middle point (fracture section) of fibula until fibula begins to fracture. The maximum pressure necessary to break the bone was defined as the breaking force. The total energy spent to break the bone was defined as the breaking energy. The results are shown in Table 13.
  • CD (SD) IGS rats (Charles River Japan, Inc.; male; 7-week-old) were housed for seven days at room temperature (23 ⁇ 2° C.) and 55+15% humidity. During the housing period, the rats were free to access commercially available food (from Oriental Bio Service; CRF-1).
  • control group (6 rats/group), the cut sections were re-matched with tweezers and sutured with silk thread without any treatment. Following the suturing, all animals were sterilized with 70% aqueous ethanol. At 0, 3, 7, 14, 28 or 42 days after suturing, each one rat from each group was sacrificed by laparotomy with bleeding under ether anesthesia and the fibula was excised.
  • the fracture segment of the excised fibula was cut into 1 cm sections and frozen with liquid nitrogen.
  • the resultant sections were milled at ⁇ 80° C., suspended in 300 ⁇ l of 6% trichloroacetic acid, and sonicated.
  • the suspension was centrifuged at 12000 rpm for 15 minutes.
  • the supernatant was extracted with ether to remove trichloroacetic acid and incubated at 75° C. for 5 minutes to remove ether from the supernatant.
  • the cAMP in the resultant supernatant was measured using cAMP EIA system (Amersham Pharmacia Biotech).
  • CD (SD) IGS rats (Charles River Japan, Inc.; male; 8-week-old) were housed for seven days at room temperature (23+2° C.) and 55 ⁇ 15% humidity. During the housing period, the rats were free to access commercially available food (from Oriental Bio Service; CRF-1).
  • Streptozotocin (“STZ”, Sigma), which induce diabetes, was dissolved in citrate-buffered saline (pH 4.5) to obtain 0.05 M streptozocin solution and injected intravenously to each rat at 60 mg/kg.
  • PH 4.5 citrate-buffered saline
  • blood-glucose monitor (Molecular Devices; M-SPmax250). Based on the measurements, rats were divided into groups so that a significant difference in glucose level may not occur among groups. The average blood-glucose level was from 404.5 to 410.00 mg/dl.
  • the fracture segment of the excised fibula was cut into 1 cm sections and frozen with liquid nitrogen.
  • the resultant sections were milled at ⁇ 80° C., suspended in 300 ⁇ l of 6% trichloroacetic acid, and sonicated.
  • the suspension was centrifuged at 12000 rpm for 15 minutes.
  • the supernatant was extracted with ether to remove trichloroacetic acid and incubated at 75° C. for 5 minutes to remove ether from the supernatant.
  • the cAMP in the resultant supernatant was measured using cAMP EIA system (Amersham Pharmacia Biotech).
  • microsphere obtained in (4) above was added to physiological saline (dispersion medium) containing 0.5% carboxymethyl cellulose sodium (Nichirin Chemical Industries) and 0.1% polyoxyethylene sorbitan fatty acid ester (Tween 80: Nikko Chemicals Co., Ltd.) at final drug concentration of 2.5 mg/ml, and the mixture was stirred with a mixer (Touch mixer MT-51: YAMATO Scientific Co., Ltd.) thoroughly to yield microsphere dispersion.
  • physiological saline dispersion medium
  • carboxymethyl cellulose sodium Nachirin Chemical Industries
  • polyoxyethylene sorbitan fatty acid ester Teween 80: Nikko Chemicals Co., Ltd.
  • the drug content and the average particle size of microsphere were measured in a manner similar to that described in Example 1-(4) and proved to be 3.70% and 47.7 ⁇ m, respectively.
  • microsphere obtained in (1) above was treated in a manner similar to that described in Example 1-(5) to give microsphere dispersion (drug rate: 2.5 mg/ml).
  • Microsphere (1.5 g) was prepared in a manner similar to that described in Example 1-(1) to (4) except that lactic acid polymer (average molecular weight 20,000; PLA0020: Wako Pure Chemical Industries, Ltd.) was used.
  • microsphere obtained in (1) above was treated in a manner similar to that described in Example 1-(5) to give microsphere dispersion (drug rate: 2.5 mg/ml).
  • microsphere suspension was filtered through 150 ⁇ m filter to remove aggregates and filtered under reduced pressure through 20 ⁇ m filter to remove water phase.
  • the resultant microsphere was combined with a little amount of distilled water and lyophilized to give microsphere.
  • the drug content and the average particle size of microsphere were measured in a manner similar to that described in Example 1-(4) and proved to be 39.6% and 33.4 ⁇ m, respectively.
  • Emulsion was poured into a cylindrical airtight container (inside diameter: 110 mm; volume 1,000 ml) containing 400 ml of purified water, and methylene chloride was removed from the container by stirring at 25° C. and 400 rpm using 4-bladed propeller (diameter: 50 mm, propeller R type: HEIDON) equipped with Three-one motor (BL-600; HEIDON) while supplying nitrogen gas into hollow fibers of cylinder-type hollow fiber membrane module made of silicone rubber (NAGAYANAGI Co., Ltd.) inserted in the container (gas flow rate is 2 L/minute). This procedure was conducted for 1 hour.
  • 4-bladed propeller (diameter: 50 mm, propeller R type: HEIDON) equipped with Three-one motor (BL-600; HEIDON) while supplying nitrogen gas into hollow fibers of cylinder-type hollow fiber membrane module made of silicone rubber (NAGAYANAGI Co., Ltd.) inserted in the container (gas flow rate is 2 L/
  • the cylindrical hollow fiber membrane module made of silicone rubber used in this procedure is cylinder type NAGASEP M60-1800 of the following specification. Cylinder diameter: 100 mm Cylinder length: 120 mm ⁇ 120 mm Membrane thickness of hollow fiber: 60 ⁇ m membrane Inside diameter of hollow fiber: 200 ⁇ m membrane Outside diameter of hollow fiber: 320 ⁇ m membrane Number of hollow fiber: 1800 Effective membrane area of hollow: 0.15 m 2 fiber membrane
  • microsphere suspension was filtered through 150 ⁇ m filter to remove aggregates and filtered under reduced pressure through 20 ⁇ m filter to remove water phase.
  • the resultant microsphere was combined with a little amount of distilled water and lyophilized to give 0.26 g of microsphere.
  • the drug content and the average particle size of microsphere were measured in a manner similar to that described in Example 1-(4) and proved to be 3.07% and 71.7 ⁇ m, respectively.
  • the drug content in microsphere was estimated. Further, the average particle size was measured in a manner similar to that described in Example 1-(4). As a result, the drug content was 9.9% and the average particle size was 26.4 ⁇ m.
  • microsphere dispersion drug rate: 0.1 mg/ml
  • the drug content and the average particle size of microsphere were measured in a manner similar to that described in Example 6-(4) and proved to be 10.1% and 27.0 ⁇ m, respectively.
  • microsphere obtained in (1) above was treated in a manner similar to that described in Example 6-(5) to give microsphere dispersion (drug rate: 0.1 mg/ml).
  • microsphere obtained in (1) above was treated in a manner similar to that described in Example 1-(5) to prepare microsphere dispersion.
  • test tube was centrifuged (2000 rpm, 5 min) and 9 ml of supernatant was sampled and loaded on FL-HPLC (column; Hypersil 5-ODS, diameter: 4 mm, length: 300 mm, GL Sciences, Inc., excitation wavelength: 315 nm, fluorescence wavelength: 465 nm) and the drug content was determined by comparing with a standard curve prepared separately with a drug solution. On the basis of the result and the sampling volume, the elution amount of drug was estimated.
  • FL-HPLC columnumn; Hypersil 5-ODS, diameter: 4 mm, length: 300 mm, GL Sciences, Inc., excitation wavelength: 315 nm, fluorescence wavelength: 465 nm
  • the elution rate was calculated based on the assumption that the sum of drug eluted from and remained in the microsphere being 100%.
  • microspheres were collected from the sites of administration.
  • 5 ml of acetonitrile containing internal control substance was added and dissolved with homogenizer (Polytron: Kinematica A.G.). After centrifugation at 3,000 rpm, 5 minutes, 3 ml of supernatant was collected, combined with 7 ml of 0.5 M aqueous sodium chloride solution, stirred with a mixer (Touch mixer MT-51: YAMATO Scientific Co., Ltd.) and then centrifuged at 2,000 rpm for 5 minutes to separate supernatant.
  • homogenizer Polytron: Kinematica A.G.
  • Microspheres were collected at regular time intervals from the administration site. To the collected microspheres, 10 ml of acetonitrile was added and dissolved with homogenizer (Polytron: Kinematica A.G.). After centrifugation at 3,000 rpm for 5 minutes, 3 ml of supernatant was collected, combined with 6 ml of 0.5 M aqueous sodium chloride, stirred with a mixer (Touch mixer MT-51: YAMATO Scientific Co., Ltd.) and then centrifuged at 2000 rpm for 5 minutes to separate supernatant.
  • homogenizer Polytron: Kinematica A.G.
  • the bone fracture healing accelerating composition of the present invention comprises a PDE4 inhibitor as an active ingredient, which, when administered locally to the fracture region, can promote the fracture healing by accelerating the endochondral ossification in the reparative phase without producing side effects due to systemic action of PDE4 inhibitor, and can accelerate the healing of bone fracture of elderly people, and diabetic or osteoporosis patients in the early stage, which bone fracture is becoming a major social issue of recent years, whereby exerts an effect of preventing the patients from becoming bedridden and ensures their normal daily life.
  • compositions containing a PDE4 inhibitor and a biocompatible and biodegradable polymer into a depot preparation, especially into an injectable microsphere preparation and administering the same locally to a fracture region thereby allowing efficacy to last.
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US20080031958A1 (en) 2008-02-07
MXPA03010679A (es) 2004-03-02
KR20040007596A (ko) 2004-01-24
US7659273B2 (en) 2010-02-09
EP1389468A1 (en) 2004-02-18
JP2010155849A (ja) 2010-07-15
EP1389468A4 (en) 2007-01-10
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AR033918A1 (es) 2004-01-07
CA2447619A1 (en) 2002-11-28

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