EP1960412A2 - Sel d'amphotéricine b - Google Patents
Sel d'amphotéricine bInfo
- Publication number
- EP1960412A2 EP1960412A2 EP06820400A EP06820400A EP1960412A2 EP 1960412 A2 EP1960412 A2 EP 1960412A2 EP 06820400 A EP06820400 A EP 06820400A EP 06820400 A EP06820400 A EP 06820400A EP 1960412 A2 EP1960412 A2 EP 1960412A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- amphotericin
- meglumine
- salt
- molar ratio
- solution
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to a salt of amphotericin B and meglumine, pharmaceutical compositions containing said salt and methods of treatment using said salt.
- Amphotericin B also known as fungizone, is a macrolide polyene antibiotic produced by Streptomycetes nodosus M4575 having a formula C 47 H 73 NOi 7 and the molecular weight 924 Da. It is insoluble in water except at strongly acid or base pH values and even then has a solubility of about 0.1 mg/mL.
- Candida Cr ⁇ ptococcus
- Aspergillus Aspergillus
- Ajellomyces Fusarium
- Coccidiodes Fusarium
- Leishmania Schistosomia
- Torulopsis Giardia
- Giardia Trichomonas
- Entamoeba species fungal activity
- amphotericin B is generally administered as a colloidal formulation, e.g. as a complex with cholesteryl sulphate, or in a lipid or liposomal formulation.
- a colloidal formulation e.g. as a complex with cholesteryl sulphate
- injection of the liposomal or lipid formulation is the preferred treatment for the developing world disease leishmaniasis, which affects an estimated 1.5 million new victims per year globally, and is referred to for example by Sundar et al Annals of Internal Medicine 127:133-137(1997).
- Such formulations may however cost 10 to 30 times the simple colloidal formulation and in practice are thus inaccessible to the majority of potential patients.
- Meglumine N-methylglucamine
- Meglumine N-methylglucamine
- MR.imaging e.g. Magnevist® from Schering AG
- the invention provides a salt of amphotericin B and meglumine in which the molar ratio of amphotericin B to meglumine is about 1 : 1 (e.g. 1:1 to 1:1.1).
- Amphotericin B meglumate has a mole ratio of 1 : 1 ; however, it may be presented with a slight excess of meglumine, or less advantageously a slight excess of amphotericin B.
- the salt of the invention has an activity (ED/mg) against Candida albicans of from 500 to 650, especially 550 to 620, as opposed to the value of 750 for amphoglucamine.
- the salt of the invention forms significantly less alkaline aqueous solutions than does amphoglucamine, e.g. at a concentration of 50mg amphotericin B/mL in water at 25 0 C, the pH is below 9.0, typically about 8.6, as opposed to the value of 9.3 for amphoglucamine. This makes the salt more suitable for parenteral injection than amphoglucamine.
- the invention provides a composition of matter consisting essentially of a salt of amphotericin B and meglumine in which the molar ratio of amphotericin B to meglumine is about 1 : 1 (e.g. 1 : 1 to 1 : 1 , 1).
- an injectable pharmaceutical composition comprising an aqueous solution containing dissolved therein amphotericin B and meglumine, or ions thereof, in a molar ratio of about 1 : 1 (e.g. 1:1 to 1:1.1).
- the invention provides the use of a salt of amphotericin B and meglumine in which the molar ratio of amphotericin B to meglumine is about 1:1 (e.g. 1 :1 to 1:1.1) for the manufacture of an injectable medicament for use in the treatment by parenteral injection of systemic fungal infection or other systemic infections responsive to amphotericin B.
- the invention provides a method of treatment of a human or non-human mammalian subject having a systemic infection responsive to amphotericin B (e.g. a fungal or protozoal infection) which method comprises parenterally injecting said subject with an effective amount of an aqueous solution containing dissolved therein amphotericin B and meglumine, or ions thereof, in a molar ratio of about 1 :1 (e.g. 1:1 to 1:1.1).
- amphotericin B e.g. a fungal or protozoal infection
- the injection solution used in the method of the invention should be sterile and preferably pyrogen- free and may be prepared using the salt in sterile form, a form which is preferred.
- the solution may if desired contain further components beyond water and the amphotericin B meglumate complex, e.g. physiologically tolerable osmolality adjusting agents (for example to render the solution isotonic, such as sodium chloride for example), preservatives, buffers, further active agents, etc.
- the solutions may contain up to 0.9% wt. of sodium chloride as an osmolality adjuster.
- the injection solution according to the present invention is preferably isotonic.
- a solution of amphoglucamine is always hypertonic if the concentration of amphotericin is above 60 to 70 mg per ml (calculated as the 1 :1 salt with meglumine) based on the fact that this complex contains 3 moles excess of meglumine.
- the present 1 :1 salt can be formulated as an isotonic solution in concentrations up to 150 mg per ml, and is preferably presented in such a solution at an amphotericin B concentration of 90 to 140 mg/mL.
- amphotericin B: meglumine salt of and used according to the present invention is not identical to amphoglucamine which, as discussed above, contains amphotericin B and meglumine in a mole ratio of less than 1:3.
- the amphoglucamine product is hygroscopic while the amphotericin B meglumate salt of the present invention is not hygroscopic.
- the amphoglucamine is, as it is described in the prior art, a complex with an undefined excess of meglumine.
- a product with an undefined amount of a compontent like in amphoglucamine is not a well-defined product as the 1 :1 salt is , from a regulatory point of view.
- the use of amphoglucamine in aqueous solution for parenteral injection has not been proposed.
- the aqueous solutions of the salt used according to the invention will typically contain the salt at a concentration of 0.5 to 150 mg/mL, preferably 1 to 120 mg/mL, especially 50 to 80 mg/mL. Doses of up to 50 mg amphotericin B for an adult human are preferred. These compositions may be administered at amphotericin B dosages typical for the current lipid or liposomal formulations of amphotericin B, e.g. 0.1 to 8 mg/kg bodyweight/day, preferably 1 to 5 mg/kg/day. The treatment may typically be carried out for up to 80 days.
- the salt according to the invention may if desired be stabilized by autoclaving. It is thought that the salt is more stable to exposure to autoclaving temperatures than the prior art amphoglucamine complex.
- Administration maybe by infusion or routine injection, e.g. bolus injection, for example intravascular, intramuscular, or subcutaneous. Infusion, e.g. over 1 to 2 hours, is preferred.
- the amphotericin B megluminate salt according to the invention may be prepared in solution in solvents such as DMSO, DMF, N-methylpyrrolidone (NMP) and/or alcohols (e.g. Ci -6 alkanols such as methanol) or mixtures thereof.
- solvents such as DMSO, DMF, N-methylpyrrolidone (NMP) and/or alcohols (e.g. Ci -6 alkanols such as methanol) or mixtures thereof.
- NMP and/or alcohols is especially preferred as extensive work-up to remove solvents such as DMSO or DMF is avoided.
- the reaction is effected by using approximately equimolar amounts of amphotericin B and meglumine.
- the salt can be recovered by addition of an ether (e.g. diethyl ether) or a ketone (e.g.
- the invention provides a process for the preparation of a salt of amphotericin B and meglumine which comprises mixing amphotericin B and meglumine in solution in a solvent in approximately equimolar amounts, e.g. a molar ratio of 1 :1 to 1 :1.1, followed by solvent removal or precipitation.
- the resultant salt is substantially non-hygroscopic, unlike amphoglucamine.
- Hygroscopisity of freeze-dried Amphotericin B meglumate Amphotericin B meglumate (16.4 mg) (from Example 1) was kept open in a vial at room temperature (23-24°C) and ambient humidity (34-38%) in the dark for several days. The sample did not gain any appreciable weight. The product was not hygroscopic.
- Aqueous solutions of amphotericin B meglumate (5 mg/mL) were kept at room temperature and at 4O 0 C for 11 days in the dark. No sign of degradation was observed in these samples (visual inspection and HPLC analysis).
- composition 350 mg Amphotericin B meglumate (1:1) (produced according to Example 1) is dissolved in 70 mL water for injections and filled under sterile conditions into a vial which is then sealed.
- MIC values ⁇ Candida albicans) and ⁇ Candida kruse ⁇ ) for amphotericin B meglumate and amphotericin B in water and DMSO was determined in vitro using standard methods.
- Example 8 pH in aqeuous solution of Amphotericin B meglumate (1:1) Amphotericin B meglumate (prepared in Example 7) was dissolved in water ( 50 mg amphotericin per ml). The pH of the solution at 25 0 C was 8.6.
- Amphotericin meglumine complex (1 :3) was prepared according to US 4,002,741. The complex was dissolved in water (50 mg amphotericin B per ml). The pH in the solution was 9.3 at 25°C.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
L'invention concerne un sel d'amphotéricine B et de méglumine dans lequel le rapport molaire entre l'amphotéricine B et la méglumine est d'environ 1:1.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0524685.5A GB0524685D0 (en) | 2005-12-02 | 2005-12-02 | Compound |
PCT/GB2006/004514 WO2007063335A2 (fr) | 2005-12-02 | 2006-12-04 | Sel d'amphotéricine b |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1960412A2 true EP1960412A2 (fr) | 2008-08-27 |
Family
ID=35686013
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06820400A Withdrawn EP1960412A2 (fr) | 2005-12-02 | 2006-12-04 | Sel d'amphotéricine b |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1960412A2 (fr) |
GB (1) | GB0524685D0 (fr) |
WO (1) | WO2007063335A2 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2606781T3 (es) | 2010-07-23 | 2017-03-27 | Acea Biotech, Inc. | Macrólidos polienos antifúngicos y antiparasitarios |
DE102014012022A1 (de) * | 2014-08-13 | 2016-02-18 | Clariant International Ltd. | Organische Ammoniumsalze von anionischen Pestiziden |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4002741A (en) * | 1974-04-24 | 1977-01-11 | Valter Osvaldovich Kulbakh | Meglumine complex fungicidal polyene macrolide antibiotic compositions and treatment method |
GB1430886A (en) * | 1974-05-01 | 1976-04-07 | Le Nii Antibiotikov | Meglumine compolexes of fungicidal polyene antibiotics-macrolides |
US5942495A (en) * | 1996-05-10 | 1999-08-24 | Btg International Limited | Antibiotics |
-
2005
- 2005-12-02 GB GBGB0524685.5A patent/GB0524685D0/en not_active Ceased
-
2006
- 2006-12-04 EP EP06820400A patent/EP1960412A2/fr not_active Withdrawn
- 2006-12-04 WO PCT/GB2006/004514 patent/WO2007063335A2/fr active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2007063335A2 * |
Also Published As
Publication number | Publication date |
---|---|
GB0524685D0 (en) | 2006-01-11 |
WO2007063335A3 (fr) | 2007-09-20 |
WO2007063335A2 (fr) | 2007-06-07 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20080630 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
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17Q | First examination report despatched |
Effective date: 20081107 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 20090519 |