WO2001030788A1 - Nouveaux sels d'acide 4- amino-1-hydroxy-butylidene-1,1-bisphosphonique, leur preparation et utilisation - Google Patents

Nouveaux sels d'acide 4- amino-1-hydroxy-butylidene-1,1-bisphosphonique, leur preparation et utilisation Download PDF

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Publication number
WO2001030788A1
WO2001030788A1 PCT/DK2000/000589 DK0000589W WO0130788A1 WO 2001030788 A1 WO2001030788 A1 WO 2001030788A1 DK 0000589 W DK0000589 W DK 0000589W WO 0130788 A1 WO0130788 A1 WO 0130788A1
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WO
WIPO (PCT)
Prior art keywords
amino
hydroxybutylidene
salt
bisphosphonic acid
treatment
Prior art date
Application number
PCT/DK2000/000589
Other languages
English (en)
Inventor
Svend Peter Treppendahl
Hanne Borgelin Petersen
Lotte Basse Jensen
Søren Bols Pedersen
Original Assignee
A/S Gea Farmaceutisk Fabrik
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 A/S Gea Farmaceutisk Fabrik filed Critical A/S Gea Farmaceutisk Fabrik
Priority to AU79028/00A priority Critical patent/AU7902800A/en
Priority to AT0907900U priority patent/AT7407U1/de
Publication of WO2001030788A1 publication Critical patent/WO2001030788A1/fr
Priority to FI20020184U priority patent/FI5558U1/fi
Priority to DK200200115U priority patent/DK200200115U3/da

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease

Definitions

  • the present invention relates to novel salts of the compound, 4-amino-l-hydroxybutylidene-l , 1-bisphos- phonic acid, more particularly the monopotassium salt and hydrates thereof, in particular the monohydrate and the dihydrate, pharmaceutical preparations including such salts as active ingredient, a process for the preparation of the salts and their pharmaceutical use.
  • US 4,621,077 discloses a method of treating urolithiasis and inhibiting bone reabsorption by administration of alendronic acid, in the patent named 4-amino-l-hydroxybutane-l , 1-biphosphonic acid. Salts with alkali metals, organic bases and basic amino acids are mentioned generally and the sodium, aniline and lysine salts specifically.
  • WO 96/39410 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the disodium salt or hydrates thereof, the hemihydrate (CAS NO 185960-02-5), the monohydrate
  • sesquisodium anhydrate and the tetrasodium anhydrate have received CAS numbers (CAS
  • M is NH 4 + , Na + , K + , Ca 2+ or Mg 2+ .
  • the present invention provides novel alendronic acid salts fulfilling the above requirements.
  • the invention provides the monopotassium salt of 4-amino-l-hydroxybutylidene-l , 1- bisphosphonic acid and hydrates thereof.
  • both the anhydrous 4-amino-l-hydroxybutylidene- 1 , 1 -bisphosphonic acid monopotassium salt, the monohydrate and the dihydrate have been isolated in crystalline form. Furthermore, both the monohydrate and the dihydrate have been shown to be stable at 20 °C and relative humidities between 0% and 80%. Accordingly they neither absorb water, nor loose their water of crystallization under normal room conditions. Furthermore, they have melting points well above 100 °C. Thus the monopotassium salt and particularly the monohydrate and the dihydrate thereof show particular advantages from a formulation technical and a stability point of view. In addition there is the possibility that the new salts according to the invention will be capable of reducing the occurrence of oesophagitis .
  • the temperature at which the monohydrate gives up its water of crystallization is 20° - 30°C higher than that of the dihydrate, and from that point of view, the monohydrate is particularly preferred.
  • the invention provides a pharmaceutical preparation comprising the monopotassium salt of 4-amino-l-hydroxybutylidene-l , 1 -bisphosphonic acid or a hydrate thereof as active ingredient.
  • the pharmaceutical preparation can be of any conventional form, such as a tablet, a pellet, a film-, sugar- or entero-coated tablet or pellet, a capsule, a suspension, a solution, an emulsion etc.
  • the active ingredient can be combined with any conventional formulation aids such as one or more formulation aids selected from suitable vehicles, fillers, diluents, disintegrants, binding agents, colorants, surfactants, lubricants, preservatives, etc.
  • suitable vehicles fillers, diluents, disintegrants, binding agents, colorants, surfactants, lubricants, preservatives, etc.
  • the salts and the pharmaceutical preparation according to the invention are useful for treatment or prophylaxis of different diseases relating to the calcium metabolism.
  • they can be used for treatment of urolithiasis or for treatment or prophylaxis of bone resorption related diseases, particularly osteoporosis, hypercalcemia and Paget's disease.
  • salt according to the invention is meant to include both the 4-amino-l-hydroxybutylidene-l , 1 -bisphosphonic acid monopotassium salt and any hydrates thereof .
  • the invention also relates to a process for the preparation of a salt according to the invention, which comprises reacting approximately equimolar amounts of 4-amino-l-hydroxybutylidene-l , 1-bisphosphonic acid and potassium hydroxide in a common solvent and isolating the formed 4-amino-l-hydroxybutylidene-l , 1-bisphos- phonic acid monopotassium salt, optionally as a hydrate thereof.
  • the crystallisation of the salt according to the invention from the solution may be assisted by the addition of another solvent being capable of reducing the solubility of the salt in the combined solvent.
  • solvents which may be of use in the process according to the invention include, but are not limited to water and organic solvents, such as alcohols, ketones and tetrahydrofuran, and mixtures there- of, including mixtures of water and organic solvents.
  • organic solvents such as alcohols, ketones and tetrahydrofuran, and mixtures there- of, including mixtures of water and organic solvents.
  • alcohols are lower aliphatic alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1- butanol , 2-butanol, and 1-pentanol.
  • Acetone and 2- butanone are examples of ketones.
  • the selection of an appropriate solvent or combination of solvents will be within the ordinary skill of the person skilled in the art .
  • the two components will be dissolved in water at 20 - 60 °C, crystallization initiated, the mixture cooled to about 5 °C and the formed crystals collected by filtration.
  • an aqueous solution of alendronic acid may be neutralized with potassium hydroxide to pH 4.3 - 4.5 and crystallization initiated by addition of a lower alkanol such as methanol, and the obtained crystals collected by filtration.
  • a lower alkanol such as methanol
  • the dose regimen will be prescribed by the attending physician, among others depending on the condition, age, weight etc. of the patient.
  • daily dosage rates corresponding to from about 0.001 mg/kg to about 10 mg/kg, preferably from about 0.01 mg/kg to about 1.0 mg/kg body weight of alendronic acid will be prescribed.
  • the preparation may be administered continuously, e.g. on a daily basis, or sequentially.
  • Fig. 1 shows a FT-IR spectrum of monopotassium alendronate monohydrate
  • Fig. 2 shows an X-ray diffractogram of same.
  • Fig. 3 shows a FT-IR spectrum of monopotassium alendronate anhydrate, and
  • Fig. 4 shows an X-ray diffractogram of same.
  • Fig. 5 shows a FT-IR spectrum of monopotassium alendronate dihydrate
  • Fig. 6 shows an X-ray diffractogram of same.
  • Fig. 7 shows a TGA diagram of monopotassium alendronate monohydrate
  • Fig. 8 shows a TGA diagram of monopotassium alendronate dihydrate.
  • a preparation for oral administration containing 4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid potassium salt monohydrate as active ingredient may e.g. be prepared as follows:
  • a tablet comprising the following ingredients is prepared by conventional tabletting techniques such as direct compression of a dry mix formulation. Ingredients mg per tablet
  • thermogravimetric analysis was carried out using a METTLER TOLEDO STAR System whereby the weight loss by heating vs. the heating time and temperature was recorded. The resulting diagram is presented as

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le sel de monopotassium d'acide 4-amino-1-hydroxy-butylidène-1,1-bisphosphonique et ses hydrates, en particulier le monohydrate et le dihydrate et des préparations pharmaceutiques contenant ces sels en tant qu'ingrédient actif. L'invention concerne également un procédé de préparation de ces sels ainsi que leur utilisation dans le traitement ou la prophylaxie de maladies liées au métabolisme calcique.
PCT/DK2000/000589 1999-10-26 2000-10-24 Nouveaux sels d'acide 4- amino-1-hydroxy-butylidene-1,1-bisphosphonique, leur preparation et utilisation WO2001030788A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU79028/00A AU7902800A (en) 1999-10-26 2000-10-24 Novel salts of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, their preparation and use
AT0907900U AT7407U1 (de) 1999-10-26 2000-10-24 Neue salze der 4-amino-1-hydroxibutyliden-1, 1-biphosphonsäure, deren herstellung und verwendung
FI20020184U FI5558U1 (fi) 1999-10-26 2002-04-19 4-amino-1-hydroksibutylideeni-1,1-bisfosfonihapon uudet suolat ja niiden käyttö
DK200200115U DK200200115U3 (da) 1999-10-26 2002-04-23 Hidtil ukendte salte af 4-amino-1-hydroxybutyliden-1, 1-bisphosphonsyre, deres fremstilling og anvendelse

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA199901536 1999-10-26
DKPA199901536 1999-10-26

Publications (1)

Publication Number Publication Date
WO2001030788A1 true WO2001030788A1 (fr) 2001-05-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2000/000589 WO2001030788A1 (fr) 1999-10-26 2000-10-24 Nouveaux sels d'acide 4- amino-1-hydroxy-butylidene-1,1-bisphosphonique, leur preparation et utilisation

Country Status (4)

Country Link
AT (1) AT7407U1 (fr)
AU (1) AU7902800A (fr)
FI (1) FI5558U1 (fr)
WO (1) WO2001030788A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008425A1 (fr) * 2001-07-16 2003-01-30 Universite Paris 13 Nouveaux derives de bisphosphonates, leurs preparations et utilisations
WO2003033508A1 (fr) * 2001-10-18 2003-04-24 Cipla Ltd. Sels d'alendronate pharmaceutiquement acceptables presentes sous une forme amorphe

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4922007A (en) * 1989-06-09 1990-05-01 Merck & Co., Inc. Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
WO1996039410A1 (fr) * 1995-06-06 1996-12-12 Merck & Co., Inc. Preparations d'alendronate disodique
WO1996039149A1 (fr) * 1995-06-06 1996-12-12 Merck & Co., Inc. Formulations de sel de monosodium d'alendronate anhydre
WO1999020635A1 (fr) * 1997-10-21 1999-04-29 Unipharm Ltd. Sel d'un derive de l'acide bisphosphonique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4922007A (en) * 1989-06-09 1990-05-01 Merck & Co., Inc. Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
WO1996039410A1 (fr) * 1995-06-06 1996-12-12 Merck & Co., Inc. Preparations d'alendronate disodique
WO1996039149A1 (fr) * 1995-06-06 1996-12-12 Merck & Co., Inc. Formulations de sel de monosodium d'alendronate anhydre
WO1999020635A1 (fr) * 1997-10-21 1999-04-29 Unipharm Ltd. Sel d'un derive de l'acide bisphosphonique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008425A1 (fr) * 2001-07-16 2003-01-30 Universite Paris 13 Nouveaux derives de bisphosphonates, leurs preparations et utilisations
WO2003033508A1 (fr) * 2001-10-18 2003-04-24 Cipla Ltd. Sels d'alendronate pharmaceutiquement acceptables presentes sous une forme amorphe
US7112577B2 (en) 2001-10-18 2006-09-26 Cipla Limited Pharmaceutically acceptable alendronate salts in amorphous form

Also Published As

Publication number Publication date
FIU20020184U0 (fi) 2002-04-19
AU7902800A (en) 2001-05-08
FI5558U1 (fi) 2002-10-25
AT7407U1 (de) 2005-03-25

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