Title:  Nanospheres comprising a biocompatible polysaccharide

United States Patent:  6,214,384

Inventors:  Pallado; Paolo (Padova, IT); Benedetti; Luca (Vicenza, IT); Callegaro; Lanfranco (Vicenza, IT)

Appl. No.:  938288

Microspheres, having a size lower than 1.mu. and comprising a biocompatible polysaccharidic polymer, are prepared with a process comprising the precipitation of polymer induced by means of a supercritical antisolvent (SAS). These microspheres are used as vehicling agents or carriers in the preparation of pharmaceutical compositions administrable by oral, nasal, pulmonary, vaginal or rectal route. These microspheres can also be advantageously used as vehicling agent or carriers in the preparation of pharmaceutical compositions for the treatment of human diseases associated with genic defects, for the preparation of diagnostics and in the agro-alimentary industry.

SUMMARY OF THE INVENTION

The Applicant has unexpectedly found that with the discontinuous SAS technique it is possible to obtain in quantitative yields microspheres with a diameter of less than 1 .mu. comprising an ester of a biocompatible acidic polysaccharide polymer, selected from the group consisting of: hyaluronic acid esters, crosslinked esters of hyaluronic acid, esters of chitin, esters of pectin, esters of gellan, esters of alginic acid.

Object of the present invention are therefore microspheres having a mean dimension .gtoreq.0.1 .mu. and <1 .mu. comprising a biocompatible polysaccharide a polymer.

A further object of the present invention are pharmaceutical compositions administrable by oral, nasal, pulmonary, vaginal or rectal route, containing said microspheres as vehicling agents or carriers in combination with at least one active ingredient and optionally with further conventional excipients.

A further object of the present invention relates to said microspheres further comprising at least one of the following active principles: a pharmaceutically active polypeptide, a Granulocyte Macrofage Colony Stimulating Factor (GMCSF), a trophic factor, an immunoglobulin, a natural or a synthetic derivative of a ganglioside, an antiviral, an antiasthmatic an antiinflammatory agent, an antibiotic and an antimycotic agent.

A further object of the present invention relates to pharmaceutical compositions administrable by oral, nasal, pulmonary, vaginal or rectal route containing the microspheres inglobating the above mentioned active principles, optionally in combination with other conventional excipients.

A further object of the present invention relates to the use of said microspheres as carriers in the preparation of diagnostics and in agroalimentary industry. Moreover the microspheres having a diameter ranging from 0.1 to 1 .mu. containing a biocompatible acidic polysaccharide ester selected from the group consisting of:hyaluronic acid esters, esters of chitin, esters of pectin, esters of gellan, esters of alginic acid can be advantageously used as vehicling agent or carriers of a gene, for the preparation of pharmaceutical compositions for the treatment of diseases associated with genic defects.

A further object of the present invention resides in the discontinuous a process for the preparation of microspheres having a dimension comprised between 0.1 and 1 .mu. and comprising the precipitation of said polymer induced by means of a supercritical antisolvent (SAS). The process object of the present invention comprises the following steps:

a) dissolving the polysaccharide biocompatible polymer in an aprotic solvent at concentrations ranging from 0.1 to 5% by weight,

b) charging the solution of step (a) in a pressure proof container having at the top and at the base steel filters with an average cutoff lower than 0.1 .mu.;

c) loading from underneath the antisolvent until reaching the pressure at which said fluid becomes supercritical at a temperature ranging from 25 to 60^oC.,

d) removing the aprotic solvent, by flowing said supercritical fluid,

e) depressurizing the pressure proof container and collecting the precipitated product.

Contrarily to what one could foresee from the above mentioned prior art (teaching that, with the SAS discontinuous technique, process times are longer than with the continuous one, nucleation occurs in the bulk liquid phase where the supercritical antisolvent is dissolved and therefore the formation of large particles with broad granulometric distribution is expected) surprisingly the expanding conditions adopted with the process according to the present invention enable the onset of the nucleation process in a well-expanded media so that the formation of a high number of nucleation centers is achieved. This factor, combined with the amorphous nature of the solid solute, leads to the formation of microspheres whose dimension is comprised in the above mentioned range and moreover with a narrow granulometric distribution curve.

Claim 1 of 14 Claims

What is claimed is:

1. A discontinuous process for the preparation of microspheres having a mean diameter of between 0.1 and 1.mu. and comprising a biocompatible polysaccharide, said process comprising the following steps:

a) dissolving the polysaccharide biocompatible polymer in an aprotic solvent at concentrations ranging from 0.1 to 5% by weight,

b) charging the solution of step (a) in a pressure proof container having at the top and at the base steel filters with an average cut-off lower than 0.1 .mu.;

c) loading the antisolvent from underneath until the pressure at which the fluid becomes supercritical at a temperature ranging from 25^o to 60^oC. is reached,

d) removing the aprotic solvent with a flow of said supercritical fluid,

e) depressurizing the pressure proof container, and collecting the precipitated product.

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