Antiparasitic and/or antifungal composition comprising hydrophobised chitosan

Patent metadata

Field	Value
Publication number	US-2016243243-A1
Application number	US-201415027147-A
Country	US
Kind code	A1
Filing date	Oct 9, 2014
Priority date	Oct 9, 2013
Publication date	Aug 25, 2016
Grant date	—

Abstract

A composition including hydrophobised chitosan can be used as an antiparasitic and/or antifungal agent or in the treatment of parasitic and/or fungal infections. The composition may include an antifungal agent and hydrophobised chitosan. The antifungal agent can be in association with the hydrophobised chitosan, with the latter being more preferably in the particle form, or the antifungal agent can be encapsulated in particles including the hydrophobised chitosan. The use of the composition as an antifungal agent or in the treatment of fungal infections, and a method for manufacturing the composition are also described.

First claim

1 . Composition comprising:
at least one antifungal agent; hydrophobised chitosan with the general formula (I):

wherein
R 1 , R 2 , R 3 , R 4 and R 5 are identical or different, and represent:
a hydrogen atom;
a hydrophobic group;
a group substituted by a thiol function;

provided that at least one of R 1 , R 2 , R 3 , R 4 and R 5 is a hydrophobic group;
n and m each independently represent an integer between 1 and 3000, preferably between 5 and 1500, more preferably between 25 and 100, provided that the percentage of m with respect to m+n is greater than 50%;
an α-cyclodextrin, said α-cyclodextrin being in the form of a monomer and forming with the hydrophobised chitosan with the general formula (I) a non-covalent inclusion complex.

2 . Composition according to claim 1 , wherein the hydrophobised chitosan with the general formula (I) is such that the hydrophobic group is selected from:
a group with the formula —COR 6 , wherein R 6 represents: a linear or branched alkyl group, comprising from 1 to 1000 carbon atoms, preferably from 1 to 20 carbon atoms, more preferably the groups —(CH 2 ) 14 —CH 3 or —(CH 2 ) 16 —CH 3 ; a linear or branched alkenyl group, comprising from 2 to 1000 carbon atoms, preferably from 2 to 20 carbon atoms, and comprising at least one double bond C═C, preferably from 1 to 4 double bonds, preferably the groups —(CH 2 ) 7 —CH═CH—CH 2 —(CH 2 ) 7 —CH 3 or —(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —CH 3 ; a poly(alkylcyanoacrylate) wherein the alkyl is linear or branched, comprising from 1 to 12 carbon atoms, preferably the alkyl is a methyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, iso-undecyl, dodecyl, isododecyl and derivatives, more preferably the poly(alkylcyanoacrylate) is poly(isobutylcyanoacrylate).

3 . Composition according to claim 1 , wherein the hydrophobised chitosan with the general formula (I) is such that the group substituted by a thiol function is an alkyl substituted by a thiol function, an alkenyl substituted by a thiol function or a group —C(═NH 2 + X − )—(CH 2 ) q —SH wherein X represents a halogen, preferably Cl, and q represents an integer ranging from 1 to 10, preferably 1, 2, 3, 4, or 5.

4 . Composition according to claim 1 , wherein the α-cyclodextrin is with the general formula (II):

wherein
p is equal to 6,
R 7 , R 8 and R 9 are identical or different, preferably identical, and each independently represent a hydrogen atom; an alkyl group comprising 1 to 4 carbon atoms, preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl; —NH 2 , —NH 3 + , or —SO 4 2− ; preferably, R 7 , R 8 and R 9 represent a hydrogen atom or a methyl group.

5 . Composition according to claim 1 , wherein the antifungal agent is selected from the group comprising:
polyenes, such as for example amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidine; imidazole compounds such as for example bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole; triazole compounds, such as for example albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole, voriconazole; thiazole compounds, such as for example abafungine; allylamines, such as for example amorolfine, butenafine, naftifine, terbinafine; echinocandins, such as for example anidulafungine, caspofungine, micafungine; benzoic acid, cerulenin, ciclopirox, olamine, flucytosine, 5-fluorocytosine, griseofulvine, haloprogine, polygodial, tolnaftate, undecylenic acid, crystal violet; or chlorhexidine, polyvinylpyrrolidone (PVP) iodine, benzalkonium chloride, chlorine.

6 . Pharmaceutical, dermatological, dermo-cosmestic or veterinary composition comprising the composition according to claim 1 , in association with a pharmaceutically, dermatologically, dermo-cosmetically or veterinarily acceptable excipient.

7 . Composition according to claim 6 , administrable by parenteral, intramuscular, subcutaneous, intramedullary or intravenous route; by intrathecal injection, intraventricular, intraperitoneal or intraocular route; by oral, sublingual, nasal, aerosol, pulmonary, ear route; by topical, cutaneous, transdermal, ocular, rectal, vaginal route; by application on the nails; by any other route that allows for a localised administration.

8 . Composition according to claim 6 , in the form of a tablet, coated tablet, gastro-resistant tablet, tablet, soft capsule, hard capsule, hard-shelled capsule; powder, pill, granule, solution, emulsion, suspension, syrup, eye drops, subgingival irrigation, mouth bath, chewing gum, toothpaste, patch, implant, suppository, paste, cream, gel, lotion, milk, ointment, spray, shampoo, varnish, plaster, catheter, compress, gauze.

9 . Medicament comprising a composition according to claim 1 .

10 . Composition according to claim 1 for use as an antifungal agent or in the treatment of fungal infections.

11 . Method of association for preparing of a composition according to claim 1 , comprising the following steps:
(a)hydrophobised chitosan with the general formula (I), is placed in a solvent, preferably water, in the presence of an α-cyclodextrin, under stirring, in order to form a suspension of particles; (b) at least one antifungal is added to the suspension.

12 . Method of encapsulation for preparing of a composition according to claim 1 , comprising the following steps:
(a) at least one antifungal agent is dissolved in a solvent, preferably water; (b)hydrophobised chitosan with the general formula (I), and an α-cyclodextrin, are added to the solution; (c) the mixture is stirred in order to form a suspension of particles of chitosan and of cyclodextrin, encapsulating the antifungal agent.

13 . Composition according to claim 2 , wherein the hydrophobised chitosan with the general formula (I) is such that the group substituted by a thiol function is an alkyl substituted by a thiol function, an alkenyl substituted by a thiol function or a group —C(═NH 2 + X − )—(CH 2 ) q —SH wherein X represents a halogen, preferably Cl, and q represents an integer ranging from 1 to 10, preferably 1, 2, 3, 4, or 5.

14 . Composition according to claim 2 , wherein the α-cyclodextrin is with the general formula (II):

wherein
p is equal to 6,
R 7 , R 8 and R 9 are identical or different, preferably identical, and each independently represent a hydrogen atom; an alkyl group comprising 1 to 4 carbon atoms, preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl; —NH 2 , —NH 3 + , or —SO 4 2− ; preferably, R 7 , R 8 and R 9 represent a hydrogen atom or a methyl group.

15 . Composition according to claim 3 , wherein the α-cyclodextrin is with the general formula (II):

wherein
p is equal to 6,
R 7 , R 8 and R 9 are identical or different, preferably identical, and each independently represent a hydrogen atom; an alkyl group comprising 1 to 4 carbon atoms, preferably selected from the group consisting of methyl, ethyl,

Assignees

• Centre Nat De La Rech Scient (Cnrs)
• Université Paris-Sud 11
• Univ Paris-Sud 11

Inventors

• Bouchemal Kawthar
• Bories Christian
• Loiseau Philippe
• Vauthier-Holtzscherer Christine
• Pomel Sebastien
• PRADINES Benedicte

Classifications

• A61K47/6951

  using cyclodextrin (cyclodextrins used as simple excipients A61K47/40) · CPC title

• A61K47/36 Primary

  Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin · CPC title

• A61K31/155 Primary

  Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) · CPC title

• A61P31/10

  Antimycotics · CPC title

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title