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WO1997036935A1 - Compose a base de primycine et de cyclodextrine - Google Patents

Compose a base de primycine et de cyclodextrine Download PDF

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Publication number
WO1997036935A1
WO1997036935A1 PCT/HU1997/000010 HU9700010W WO9736935A1 WO 1997036935 A1 WO1997036935 A1 WO 1997036935A1 HU 9700010 W HU9700010 W HU 9700010W WO 9736935 A1 WO9736935 A1 WO 9736935A1
Authority
WO
WIPO (PCT)
Prior art keywords
mass
cyclodextπn
pharmaceutical composition
compound
mixtures
Prior art date
Application number
PCT/HU1997/000010
Other languages
English (en)
Inventor
Ágoston DÁVID
Éva SÁTORY
Sándor Szabó
József SZEJTLI
Lajos Szente
Andrásné VIKMON
Original Assignee
Chinoin Gyógyszer És Vegyészeti
Medipharma
Human
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 Chinoin Gyógyszer És Vegyészeti, Medipharma, Human filed Critical Chinoin Gyógyszer És Vegyészeti
Priority to AU21732/97A priority Critical patent/AU2173297A/en
Publication of WO1997036935A1 publication Critical patent/WO1997036935A1/fr

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • This invention relates to non-stoichiometric compounds with a 1:0.3 to 4.0 mole ratio of P ⁇ mycin formed with a cyclodext ⁇ n, or a cyclodextrin-derivative, or mixtures thereof of formula I
  • Szilagyi I.:Nature 174 1 105 (1954)/ and its components are effective agamst Gram-positive micro-organisms, including strains which are resistant and polyresistant to other active mgredients, against pathogenic and apathogenic mycobacterium strains, blastomycetes and hyphomycetes, vib ⁇ os, certain algae, protozoons, macroviruses, and m higher concentrations even against Gram-negative bacte ⁇ a /Uri J.. Actor P.: Antibiotics 32 , 1 1 1207 to 1209 (1979)/. It was reported among the valuable pharmaceutical active mgredients Hansch,C. Editor.
  • the subject of our invention are non-stoichiomet ⁇ c compounds with a 1:0.3 to 4.0 mole ratio of P ⁇ mycin formed with a cyclodext ⁇ n, or a cyclodext ⁇ n-denvative, or mixtures thereof
  • non-stoichiometnc compounds accordmg to the invention can contain as cyclodext ⁇ n ⁇ -, and or ⁇ -, and/or ⁇ -, preferable ⁇ -cyclodext ⁇ n and/or as cyclodext ⁇ n-de ⁇ vative maltosyl- ⁇ -cyclodext ⁇ n, dimethyl- ⁇ -cyclodext ⁇ n or randomly methylated ⁇ -cyclodext ⁇ n.
  • a further subject of the invention is a pharmaceutical composition contammg as active ingredient 0.02 to 99.5 mass % ofthe non-stoichiomet ⁇ c compound with a 1 0 3 to 4 0 mole ratio of P ⁇ mycin formed with a cyclodextrin, or a cyclodext ⁇ n-de ⁇ vative, or with mixtures thereof, if desired 0.5 to 2.5 mass % of other active ingredients as anaesthetics, corticosteroids. antibiotics, chemotherapeutical active ingredients, if desired 1.2 to 1 8 mass % of bone acid, and in the quantity necessary to the 100 mass % other usually applied pharmaceutical auxiliary materials.
  • compositions according to the invention can contain tetracyc nes as OTC, doxycycline, chloromycetin; ammoglycosid antibiotics as neomycm, sisomycm, furthermore sulphonamides, chloramphemcol, etc
  • compositions according to the invention are topic preparations formulated advantageously as aqueous solution, colloidal solution, gel, powder, aerosol, lotion for wound or plaster
  • compositions according to the invention contain, beside the active ⁇ ngred ⁇ ent(s). when formulated as solution, as auxiliary matenals preferably 1.2 to 1 8 mass % of bone acid, 0 1 to 2.0 mass % of a viscosity increasing substance, such as polyvinyl alcohol, bydroxypropyl- methyl cellulose and or 0 01 to 0 03 mass % of chlorophyll and/or carotene, when formulated as gel they preferably contain 0.3 to 1 0 mass % of a gelation agent, preferably polyacrylate such as Carbopol, and related to 1 mass % of the gelation agent they contain as basic component 0 4 to 0.8 mass % of ammonia or ethylendiamine, when formulated as powder they preferably contain as solid carrier lactose and/or dextran and or aerosil, preferably a 99: 1 ratio mixture of lactose and aerosil or a 1 :0.1 to 10 ratio mixture of lactose and urea; when
  • compositions contain the non-stoichiometric compound of Primycin formed with a cyclodextrin, or a cyclodextrin derivative or mixtures thereof preferable in micronised form.
  • the non-stoichiometric compounds with a 1 :0.3 to 4.0 mole ratio of Primycin formed with a cyclodextrin, or a cyclodextrin-derivative, or mixtures thereof can be prepared by reacting Primycin with 0.3 to 4.0 mole cyclodextrin, or cyclodextrin- derivative, or with mixtures thereof a.) in an aqueous and/or alcoholic medium, or b.) in a 1.2 to 1.8 % aqueous boric acid solution, or c.) in solid phase.
  • the eye drops according to our invention can preferably be produced by suspending 1 equivalent mass of finely powdered Primycin-sulphate and 1.5 to 2.5 mole of micronised beta-cyclodextrin in 1.4 to 1.8 % aqueous boric acid solution in such a ratio that the Primycin concentration of the solution should be 0.01 to 0.08 mass %, and reacting the solid components by keeping the suspension at boiling temperature under permanent stirring, and after cooling down the solution completing its volume with distilled water, and packaging it into appropriate containers used for pharmaceutical purposes.
  • the mixture of 1 equivalent mass of Primycin and 0.3 to 4.0 mole ratio of beta-cyclodextrin is reacted with sufficient amount (preferably 7 to 20 fold volume) of 70 v/v % of ethanol calculated to the mass of the mixtv.rc, ".n e- continuous stirring, and boiling under reflux, the hot solution is then filtered, evaporated to dryness. and powdered.
  • the dispersion of the Primycin-beta-cyclodextrin non- stoichiometric compound so obtained is suspended in 0.1 to 0.5 mass % ratio into hydrogel, which was adjusted to a pH value of 5 to 8 starting from a 0.8 to 1.2 mass % aqueous colloidal solution of a polyacrylic acid, preferable Carbopol and adding to it an inorganic or organic base, preferable ammonia, ethylendiamine, or lidocain base, then if desired according to the therapeutic purpose other active ingredient/s/, namely 0.5 to 2.0 mass % of corticosteroid, preferably hydrocortisone, 0.1 to 1.0 mass % antibiotic and/or chemoterapeutic agents, 0.5 to 2.0 mass % local anaesthetis, 0.01 to 0.03 mass % chlorophyll and/or carotene are added and the hydrogel so obtained is used for therapeutic purposes.
  • the beta-cyclodextrm can be characte ⁇ zed with a well defined crystalline, while the P ⁇ mycin with an X-ray-amorphous, non-crystalline solid structure.
  • the peaks characteristic for the powder diagrams of the two components do not appear with an additivity corresponding to their mass ratio
  • the 2 ⁇ ° locations and intensity ratios of the peaks with 100 % intensity and those of the following very characte ⁇ stic high intensity peaks have completely changed.
  • the maximal intensity peaks can be found in the range of 18.6 to 19.6 2 ⁇ ° indicating that the solid-structures of the dispersions are similar, practically they correspond to the isomorphic crystal forms.
  • Inclusion complex-binding ability of the beta-cyclodextrin is known /Szejth J . Cyclodext ⁇ ns and their inclusion complexes (Publishing House of the Hungarian Academy of Sciences Budapest, 1982)/ It was not known however, and we expenenced in surp ⁇ se, that by reacting the beta-cyclodext ⁇ n with P ⁇ mycin in the stoichiometric ratio range of 0.3 to 0 4 it transforms into a dispersion with isomorphic solid state structure, characteristic for the non- stoichiomet ⁇ c compounds / Erdey-Gruz T , Fodorne Csanyi P Rules of the Hungarian Chemical NomenclaUire and Orthography (Publishing House of the Hungarian Academy of Sciences Budapest, 1972.
  • 10.0 ml aqueous solution contains Primycin mg increase of activity %
  • Primycin cyclodextrin boric acid calculated on the basis of mg mg mg microbiological activity
  • Microbiological activity has been determined in the usual way, by the so-called dilution method, applying Streptococcus faecalis ATCC 8043 test organism, and measuring spectro photometric transmission at 570 nm, with a layer thickness of 4 cm.
  • the data if the table indicate that for the solutions containing 4.0, 6 0 and 8 0 mg cyclodextrins, which correspond to the non-stoichiometnc compounds containing beta- cyclodextrin in 2, 3, and 4 mole ratio, the biological activity increased Surprisingly and in a way which could not be calculated from the analogies in the literature /Nuppenau H.
  • a product formulated with alcohol-free hydrogel can be prepared in a way that 0.8 to 1 5 mass % of gelation agent, preferable polyacrylate, more preferable 1 mass % Carbopol 934 are homogenised with water at 20°C temperamre, while stir ⁇ ng.
  • 50 1 volume vessel 950 g bone acid were dissolved in 45 1 water, in a portion of the solution 12.5 g of Primycin and 25.5 g of beta-cyclodextrin were reacted by boiling for 1 hour then it was poured into the 50 1 vessel, completed to 50.00 1 at 20°C, filtered and finally filled into eye drops containers.
  • a solution was prepared by adding 20 1 distilled water, 750 g boric acid, 40.8 g P ⁇ mycin and 92.6 g beta-cyclodext ⁇ n successively into a 50 1 suitable vessel and by heating it. After boiling the solution for 1 hour, it was cooled, diluted with water, then 0.80 kg polyvinyl alcohol were dissolved in it and its volume was completed to 50.00 1. After filte ⁇ ng the ready solution, it was filled into ear drops containers.
  • Hydrogel containing 0.5 mass % of primycin and 1 mass % of lidocain
  • Hydrogel containing 0.5 mass % of primycin and 1.0 mass % of hydrocortisone
  • Example 7 Wound dusting powder containing 1.0 mass % of primycin
  • the very finely powdered dry residue of P ⁇ mycin-beta-cyclodext ⁇ n prepared according to Example 4 was homogenised with 0 5 kg of Aerosil. then this powder mixture was completed with average finely powdered lactose to 50 kg and blended until reaching a uniform particle size. The powder mixture was filled into dusting powder- spreading containers
  • Example 4 It was worked as desc ⁇ bed in Example 4 with the difference that the very finely powdered Primycin-beta-cyclodext ⁇ n was homogenised with 25 kg hydrogel and the suspension gel was completed to 100 kg with distilled water The viscous liquid was filled to containers fitted with atomizers Example 9.
  • Example 2 It was worked as desc ⁇ bed in Example 2 with the difference that following the dissolution of polyvinyl alcohol and cooling of the solution 150 g neomycm sulphate having an activity of at least 650 IU/mg were dissolved in it under steady stirring, then 500 g of very finely powdered hydrocortisone-acetate were suspended in the colloidal solution and afterwards the volume was completed to 50.00 1 with distilled water. Following homogenisation, when necessary with the help of a colloid mill, it was packiged into ear drops containers.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés non stoechiométriques (rapport molaire 1:0,3 à 4,0) à base de primycine ou de ses constituants et d'une cyclodextrine, d'un dérivé de cyclodextrine ou de leurs mélanges.
PCT/HU1997/000010 1996-04-02 1997-03-28 Compose a base de primycine et de cyclodextrine WO1997036935A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU21732/97A AU2173297A (en) 1996-04-02 1997-03-28 Primycin compound with cyclodextrin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU9600847A HUP9600847A3 (en) 1996-04-02 1996-04-02 Nonstochiometric compds. of primycins with ciclodextrin derivatives, pharmaceutical compns. contg. the said compds. and process for preparing them
HUP9600847 1996-04-02

Publications (1)

Publication Number Publication Date
WO1997036935A1 true WO1997036935A1 (fr) 1997-10-09

Family

ID=89993853

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1997/000010 WO1997036935A1 (fr) 1996-04-02 1997-03-28 Compose a base de primycine et de cyclodextrine

Country Status (4)

Country Link
AR (1) AR023625A1 (fr)
AU (1) AU2173297A (fr)
HU (1) HUP9600847A3 (fr)
WO (1) WO1997036935A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000030599A1 (fr) * 1998-11-23 2000-06-02 The Procter & Gamble Company Compositions de desodorisation et d'assainissement de la peau
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
WO2006122183A2 (fr) * 2005-05-10 2006-11-16 Cytophil, Inc. Hydrogels injectables et leurs procedes de fabrication et d'utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0167146A2 (fr) * 1984-07-03 1986-01-08 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Sels de primycine, leur méthode de préparation et compositions pharmaceutiques obtenues

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0167146A2 (fr) * 1984-07-03 1986-01-08 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Sels de primycine, leur méthode de préparation et compositions pharmaceutiques obtenues

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000030599A1 (fr) * 1998-11-23 2000-06-02 The Procter & Gamble Company Compositions de desodorisation et d'assainissement de la peau
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
WO2006122183A2 (fr) * 2005-05-10 2006-11-16 Cytophil, Inc. Hydrogels injectables et leurs procedes de fabrication et d'utilisation
WO2006122183A3 (fr) * 2005-05-10 2007-12-06 Cytophil Inc Hydrogels injectables et leurs procedes de fabrication et d'utilisation

Also Published As

Publication number Publication date
AR023625A1 (es) 2002-09-04
HUP9600847A2 (hu) 1998-01-28
AU2173297A (en) 1997-10-22
HUP9600847A3 (en) 1999-08-30
HU9600847D0 (en) 1996-05-28

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