WO1988000829A1 - Compositions pharmaceutiques contenant un biphosphonate et leur utilisation pour administration par voie nasale - Google Patents

Compositions pharmaceutiques contenant un biphosphonate et leur utilisation pour administration par voie nasale Download PDF

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Publication number
WO1988000829A1
WO1988000829A1 PCT/DK1987/000084 DK8700084W WO8800829A1 WO 1988000829 A1 WO1988000829 A1 WO 1988000829A1 DK 8700084 W DK8700084 W DK 8700084W WO 8800829 A1 WO8800829 A1 WO 8800829A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
hydroxy
bisphosphonic acid
nasal
bisphosphonate
Prior art date
Application number
PCT/DK1987/000084
Other languages
English (en)
Inventor
Niels Smidt Rastrup Andersen
Ernst Torndal Binderup
Original Assignee
Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis filed Critical Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis
Publication of WO1988000829A1 publication Critical patent/WO1988000829A1/fr
Priority to DK153988A priority Critical patent/DK153988D0/da

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • compositions containing a bisphosphonate and their use for nasal administration are provided.
  • the present invention relates to new pharmaceutical compositions containing a bisphosphonate and their use for the nasal administration to patients suffering from diseases where treatment with a bisphosphonate is indicated.
  • Bisphosphonates are drugs which can be used in certain diseases involving calcium metabolism, such as Paget's disease, hypercalcaemia due to malignancy, osteoporosis and rheumatoid arthritis.
  • Bisphosphonates have hitherto been administered either orally or intravenously to patients.
  • the oral absorption is poor and often accompanied by gastro ⁇ intestinal side effects.
  • the degree of absorption shows substantial individual variations. Consequently, intravenous administration has up till now had to be used whenever a rapid and reliable delivery of bisphosphonates was needed.
  • penetration enhancers can be used to improve the nasal absorption of compounds of higher molecular weight, such as insulin, glucagon and calcitonin, but it was not to be expected that such enhancers would be able to improve the absorption of compounds of relatively low molecular weight like bisphosphonates.
  • Any bisphosphonic acid or salt thereof suitable for treatment of patients can form part of the pharmaceutical compositions according to the present invention.
  • bisphosphonic acids mention may be made of l-hydroxy-alkylidene-l,l-bisphosphonic acids, e.g.
  • the bisphosphonic acids are tetrabasic acids which can form mono-, di-, tri- and tetra-salts with bases.
  • the bisphosphonic acids are preferably being used in the form of neutral salts with pharmaceutically acceptable bases.
  • Suitable enhancers for the nasal absorption of bisphosphonates include, but are not limited to, compounds of the general formula I:
  • X in the o- or ⁇ -position
  • Y in the o- or ⁇ -position
  • Y in the o- or ⁇ -position
  • R stands for -OH or -NHZ, and in which the dotted lines indicate the possibility of double bond(s); when R represents -NHZ, then Z stands for alkyl or aryl, substituted with carboxyl, sulfonic acid groups, and/or quaternary ammonium groups; or compounds of the general formula II:
  • R , R , and R in the o- or ⁇ -position, which can be the same or different, each stands for hydrogen or -OH, and in which R has the same meaning as in formula I, provided that not all R , R , R can be hydrogen at
  • the pharmaceutical composition of the present invention is formed into a nasal preparation.
  • the physiologically active bisphosphonate is contained as the drug, optionally together with an absorption enhancer.
  • the nasal preparation according to the present invention can be produced by conventional processes. For example, small amounts of a pH adjusting agent, preservative, thickening agent (natural gums, cellulose derivatives, acrylic acid polymers, vinyl polymers etc.) and/or excipients are incorporated.
  • the nasal preparation of the present invention may take a solid, liquid or semi-liquid form.
  • a solid form the above components may be simply blended or be freeze-dried to provide a powdery composition, the preferred particle size in either case being about 20 to 250 ⁇ .
  • a liquid preparation it is preferably an aqueous solution, an aqueous suspension or an oil suspension.
  • the semi-solid preparation is preferably an aqueous or oleaginous gel or ointment.
  • the content of bisphosphonate in the final preparation is about 0.005 to 50 w/v% and preferably about 0.01 to 30 w/v% and the optional content of absorption 5 enhancer is from 0 to 5 w/v%, preferably from 0 to 1 w/v%.
  • the amount of bisphosphonate in the preparation is about 0.001 to 50 w/v% and preferably about 0.05 to 40 w/v%, and the optional content of absorption enhancer is from 0 to 5 ° w/v%, preferably from 0 to 1 w/v%.
  • the excipient is exemplified by glucose, mannitol, inositol, sucrose, lactose, fructose, starch, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hydroxy- propylmethyl cellulose, polyvinylpyrrolidone, etc.
  • the liquid preparation can be produced by known procedure.
  • an aqueous preparation for nasal administration can be produced by dissolving, suspending or emulsifying the active components in water, a buffer solution or an aqueous medium.
  • the oil suspension for nasal use can be produced by suspending or emulsifying the active components in an oleaginous base.
  • the above mentioned oleaginous basis is examplified by various oils and fats such as sesame oil, olive oil, corn oil, soybean oil, cotton seed oil, peanut oil, lanoline, vaseline, paraffin, coparaffinate, silicone oil, glycerol fatty acid having 6 to 30 carbon atoms or its glycerol ester or its alcoholic ester, or a mixture thereof.
  • oils and fats such as sesame oil, olive oil, corn oil, soybean oil, cotton seed oil, peanut oil, lanoline, vaseline, paraffin, coparaffinate, silicone oil, glycerol fatty acid having 6 to 30 carbon atoms or its glycerol ester or its alcoholic ester, or a mixture thereof.
  • an aqueous or oleaginous gel or ointment can be produced by the per se conventional procedure.
  • an aqueous gel for nasal administration can be produced in the following manner. First, an aqueous solution or suspension of the active components is prepared and, if required, a pH adjusting agent, a preservative and/or the like are added. The solution is divided into halves and an aqueous gel base is dissolved or dispersed in one of the halves and heated or cooled to give a stable gel. The two halves are combined and evenly mixed to give an aqueous gel preparation.
  • Adjustment of the pH of the preparation can be effected by adding an acid, a base, a buffer solution or the like in the course of the production of the preparation.
  • the acid there may be mentioned inorganic acids (like hydrochloric acid, boric acid, phosphoric acid, carbonic acid, etc), amino acids and organic acids (e.g. monocarboxylic acids, oxycarboxylic acids, polycarboxylic acids).
  • the base is exemplified by sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate etc.
  • aqueous gel basis examples include natural gums (e.g. gum tragacanth, gum acasia, gum karaya, Irish moss, gum guaiac, gum xanthane, locust bean gum etc) , cellulose derivati es (e.g. methylcellulose, carboxymethylcellulose etc), acrylic acid polymers (e.g. polyacrylic acid, polymethacrylic acid etc) , vinyl polymers (e.g. polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, carboxypolymethylene etc) , synthetic polysaccharides (e.g. polysucrose, polyglucose, polylactose etc), starch, dextrin, pectin, sodium alginate etc. These bases may be used in the form of appropriate mixtures of two or more species.
  • natural gums e.g. gum tragacanth, gum acasia, gum karaya, Irish mos
  • the oleaginous ointment for nasal administration can be produced by dispersing the active components evenly in a hot melt of an oleaginous base and cooling the same under stirring.
  • the oleaginous- base may be one of those mentioned hereinbefore.
  • Preservatives may be incorporated in nasal preparations.
  • preservatives include phenolic compounds such as phenol, cresol etc; alcohols such as chlorobutanol, phenylethyl alcohol, propylene glycol etc; invert soaps such as benzalkoniu chloride, benzethonium chloride etc; benzoic acid, sorbic acid, dehydroacetic acid and sulfurous acid and salts thereof; acids and their salts such as sodium hydrogen sulfite.
  • the nasal preparation of the invention is in solid form, it can be administered in the following exemplary way.
  • a capsule containing the powdery preparation is set in an exclusive dust applicator equipped with needles to pierce the capsule at the top and bottom thereof and an air balloon is used to drive the powdery contents into the nasal cavity.
  • a liquid preparation In the case of a liquid preparation, it is put into a nasal douche, an atomizer or a spray-mist applicator suited for nasal application of liquids and dripped or sprayed into the nasal cavity.
  • the semi-solid preparation can be administered, for example by filling a tube with the preparation and sending the preparation directly into the nasal cavity through an applicator attached to the mouth of the tube or by administering the indicated dose of the preparation by means of a nasal insertion device.
  • the proper amount of the solid preparation per dose is about 5 mg to 100 mg, that of the liquid preparation is about 0.05 to 0.5 ml, and that of the semi-solid preparation is about 50 mg to 500 mg.
  • the nasal preparation may be administered from one to about four times per day.
  • the invention also relates to a method for treating patients suffering from a disease where treatment with a bisphosphonate is indicated, such as Paget's disease, hyper- calcaemia due to malignancy, osteoporosis and rheumatoid arthritis, said treatment consisting of administering to the patient in need of treatment an effective amount of the present composition.
  • the final solution was diluted with water to a total volume of 100 ml.
  • Preparation II was sprayed into the nasal cavity of 2 dogs. Preparation I was given either orally, intravenously or nasally (as a spray) to the same two dogs. Urine (0 - 24 hours) was collected in all four experiments and the urinary excretion of EB 899 was determined analytically.
  • Example 2 The following preparation may be used for the nasal administration of the disodium salt of 3-amino-l-hydroxy- propylidene-1,1-bisphosphonic acid (APD) either as drops or as a spray:
  • APD 3-amino-l-hydroxy- propylidene-1,1-bisphosphonic acid
  • Example 3 For the nasal administration of 3-(N,N-dimethylamino)- -l-hydroxy-propylidene-l,l-bisphosphonic acid, the following preparation may be used:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Otolaryngology (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions pharmaceutiques contenant un biphosphonate ou un sel de biphosphonate ainsi qu'éventuellement un agent améliorant l'absorption par voie nasale et leur utilisation pour administration par voie nasale. L'agent améliorant l'absorption par voie nasale est de préférence du tauro-24,25-dihydrofusidate de sodium (STDF).
PCT/DK1987/000084 1986-07-25 1987-07-03 Compositions pharmaceutiques contenant un biphosphonate et leur utilisation pour administration par voie nasale WO1988000829A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK153988A DK153988D0 (da) 1986-07-25 1988-03-22 Farmaceutisk praeparater indeholdende et bisfosfonat og deres anvendelse til nasal indgift

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB868618259A GB8618259D0 (en) 1986-07-25 1986-07-25 Pharmaceutical compositions
GB8618259 1986-07-25

Publications (1)

Publication Number Publication Date
WO1988000829A1 true WO1988000829A1 (fr) 1988-02-11

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ID=10601726

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1987/000084 WO1988000829A1 (fr) 1986-07-25 1987-07-03 Compositions pharmaceutiques contenant un biphosphonate et leur utilisation pour administration par voie nasale

Country Status (5)

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EP (1) EP0276288A1 (fr)
JP (1) JPH01500754A (fr)
DK (1) DK153988D0 (fr)
GB (1) GB8618259D0 (fr)
WO (1) WO1988000829A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0387194A1 (fr) * 1989-03-08 1990-09-12 Ciba-Geigy Ag Acides aminoalcanediphosphoniques N-substitués
EP0407344A2 (fr) * 1989-07-07 1991-01-09 Ciba-Geigy Ag Préparations pharmaceutiques pour application topique
EP0407345A2 (fr) * 1989-07-07 1991-01-09 Ciba-Geigy Ag Formulations topiques
US4994439A (en) * 1989-01-19 1991-02-19 California Biotechnology Inc. Transmembrane formulations for drug administration
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
US5139786A (en) * 1989-07-07 1992-08-18 Ciba-Geigy Corporation Topical formulations
US5283057A (en) * 1992-04-24 1994-02-01 The Procter & Gamble Company Risedronate in oral compositions
WO1995031203A1 (fr) * 1994-05-17 1995-11-23 Merck & Co., Inc. Formulations d'alendronate liquide a absorption orale
WO2000061111A1 (fr) * 1999-04-09 2000-10-19 Astrazeneca Ab Formulation pharmaceutique comprenant un bisphosphonate et un agent d'addition favorisant l'absorption du bisphosphonate
WO2000071104A2 (fr) * 1999-05-21 2000-11-30 Novartis Ag Compositions pharmaceutiques et leurs utilisations
US6160165A (en) * 1998-12-10 2000-12-12 Aesgen, Inc. Method for preparation of disodium pamidronate
US6214812B1 (en) * 1998-04-02 2001-04-10 Mbc Research, Inc. Bisphosphonate conjugates and methods of making and using the same
US6406714B1 (en) 1992-12-02 2002-06-18 Merck & Co., Inc. Dry mix formulation for bisphosphonic acids
EP1310259A2 (fr) * 1997-10-10 2003-05-14 AstraZeneca AB Formulation comprenant un biphosphonate et un agent promoteur d'absorption pour le traitement de l'osteoporose
US6750340B2 (en) 1998-04-02 2004-06-15 Mbc Research, Inc. Bisphosphonate conjugates and methods of making and using the same
US6896871B2 (en) 1998-04-02 2005-05-24 Mbc Research, Inc. Biphosphonate conjugates and methods of making and using the same
US7598246B2 (en) 1998-04-02 2009-10-06 Mbc Pharma, Inc. Bisphosphonate conjugates and methods of making and using the same
US8586781B2 (en) 1998-04-02 2013-11-19 Mbc Pharma, Inc. Bone targeted therapeutics and methods of making and using the same
US9334300B2 (en) 2011-08-01 2016-05-10 Mbc Pharma, Inc. Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4067971A (en) * 1976-05-13 1978-01-10 The Procter & Gamble Company Therapeutic composition
US4234645A (en) * 1977-03-29 1980-11-18 The Procter & Gamble Company Pharmaceutical composition
EP0023359A2 (fr) * 1979-07-31 1981-02-04 Teijin Limited Composition pharmaceutique pulvérulente, préparation pulvérulente pour application aux muqueuses nasales, et procédé pour l'administration de celle-ci
GB2096889A (en) * 1981-02-12 1982-10-27 Gentili Ist Spa Pharmaceutical composition containing 6-amino-1-hydroxyhexane-1,1-diphosphonic acid
EP0128831A2 (fr) * 1983-06-06 1984-12-19 Martin C. Carey Méthode d'administration de médicaments
EP0129285A2 (fr) * 1983-06-21 1984-12-27 The Procter & Gamble Company Compositions pharmaceutiques topiques pénétrantes contenant de la N-(2-hydroxyéthyl)-pyrrolidone
EP0189662A1 (fr) * 1984-12-21 1986-08-06 The Procter & Gamble Company Diphosphonates et leur utilisation dans des compositions pharmaceutiques

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4067971A (en) * 1976-05-13 1978-01-10 The Procter & Gamble Company Therapeutic composition
US4234645A (en) * 1977-03-29 1980-11-18 The Procter & Gamble Company Pharmaceutical composition
EP0023359A2 (fr) * 1979-07-31 1981-02-04 Teijin Limited Composition pharmaceutique pulvérulente, préparation pulvérulente pour application aux muqueuses nasales, et procédé pour l'administration de celle-ci
GB2096889A (en) * 1981-02-12 1982-10-27 Gentili Ist Spa Pharmaceutical composition containing 6-amino-1-hydroxyhexane-1,1-diphosphonic acid
EP0128831A2 (fr) * 1983-06-06 1984-12-19 Martin C. Carey Méthode d'administration de médicaments
EP0129285A2 (fr) * 1983-06-21 1984-12-27 The Procter & Gamble Company Compositions pharmaceutiques topiques pénétrantes contenant de la N-(2-hydroxyéthyl)-pyrrolidone
EP0189662A1 (fr) * 1984-12-21 1986-08-06 The Procter & Gamble Company Diphosphonates et leur utilisation dans des compositions pharmaceutiques

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4994439A (en) * 1989-01-19 1991-02-19 California Biotechnology Inc. Transmembrane formulations for drug administration
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
EP0387194A1 (fr) * 1989-03-08 1990-09-12 Ciba-Geigy Ag Acides aminoalcanediphosphoniques N-substitués
US5036058A (en) * 1989-03-08 1991-07-30 Ciba-Geigy Corporation N-substituted aminoalkanediphosphonic acids
US5133972A (en) * 1989-07-07 1992-07-28 Ciba-Geigy Corporation Topically administrable pharmaceutical preparations
EP0407344A3 (en) * 1989-07-07 1991-06-12 Ciba-Geigy Ag Pharmaceutical preparation for topical application
EP0407345A3 (en) * 1989-07-07 1991-07-24 Ciba-Geigy Ag Topical formulations
EP0407345A2 (fr) * 1989-07-07 1991-01-09 Ciba-Geigy Ag Formulations topiques
US5139786A (en) * 1989-07-07 1992-08-18 Ciba-Geigy Corporation Topical formulations
AU638034B2 (en) * 1989-07-07 1993-06-17 Ciba-Geigy Ag Topical formulations
EP0407344A2 (fr) * 1989-07-07 1991-01-09 Ciba-Geigy Ag Préparations pharmaceutiques pour application topique
US5283057A (en) * 1992-04-24 1994-02-01 The Procter & Gamble Company Risedronate in oral compositions
US6517867B2 (en) 1992-12-02 2003-02-11 Merck & Co., Inc. Dry mix formulation for bisphosphonic acids
US6406714B1 (en) 1992-12-02 2002-06-18 Merck & Co., Inc. Dry mix formulation for bisphosphonic acids
CN1079672C (zh) * 1994-05-17 2002-02-27 麦克公司 口服阿来屈酯液体制剂
WO1995031203A1 (fr) * 1994-05-17 1995-11-23 Merck & Co., Inc. Formulations d'alendronate liquide a absorption orale
EP1310259A3 (fr) * 1997-10-10 2003-05-21 AstraZeneca AB Formulation comprenant un biphosphonate et un agent promoteur d'absorption pour le traitement de l'osteoporose
EP1310259A2 (fr) * 1997-10-10 2003-05-14 AstraZeneca AB Formulation comprenant un biphosphonate et un agent promoteur d'absorption pour le traitement de l'osteoporose
US6896871B2 (en) 1998-04-02 2005-05-24 Mbc Research, Inc. Biphosphonate conjugates and methods of making and using the same
US8586781B2 (en) 1998-04-02 2013-11-19 Mbc Pharma, Inc. Bone targeted therapeutics and methods of making and using the same
US10046055B2 (en) 1998-04-02 2018-08-14 Mbc Pharma, Inc. Bone targeted therapeutics and methods of making and using the same
US9216204B2 (en) 1998-04-02 2015-12-22 Mbc Pharma, Inc. Bone targeted therapeutics and methods of making and using the same
US6214812B1 (en) * 1998-04-02 2001-04-10 Mbc Research, Inc. Bisphosphonate conjugates and methods of making and using the same
US7598246B2 (en) 1998-04-02 2009-10-06 Mbc Pharma, Inc. Bisphosphonate conjugates and methods of making and using the same
US6750340B2 (en) 1998-04-02 2004-06-15 Mbc Research, Inc. Bisphosphonate conjugates and methods of making and using the same
US6268524B1 (en) 1998-12-10 2001-07-31 Aesgen, Inc. Method for preparation of disodium pamidronate
US6160165A (en) * 1998-12-10 2000-12-12 Aesgen, Inc. Method for preparation of disodium pamidronate
WO2000061111A1 (fr) * 1999-04-09 2000-10-19 Astrazeneca Ab Formulation pharmaceutique comprenant un bisphosphonate et un agent d'addition favorisant l'absorption du bisphosphonate
WO2000071104A3 (fr) * 1999-05-21 2001-07-19 Novartis Ag Compositions pharmaceutiques et leurs utilisations
WO2000071104A2 (fr) * 1999-05-21 2000-11-30 Novartis Ag Compositions pharmaceutiques et leurs utilisations
JP2003500352A (ja) * 1999-05-21 2003-01-07 ノバルティス アクチエンゲゼルシャフト 血管形成を処置するためのビスホスホン酸の使用
US9334300B2 (en) 2011-08-01 2016-05-10 Mbc Pharma, Inc. Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates

Also Published As

Publication number Publication date
DK153988A (da) 1988-03-22
GB8618259D0 (en) 1986-09-03
DK153988D0 (da) 1988-03-22
EP0276288A1 (fr) 1988-08-03
JPH01500754A (ja) 1989-03-16

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