Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-06-01
2003-09-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S425000, C424S484000, C424S486000, C514S002600, C514S012200, C514S014800, C514S015800
Reexamination Certificate
active
06620422
ABSTRACT:
This application is a 371 of PCT/EP 99/09536 P/ED Jun. 12, 1999.
1. Field of the Invention
The present invention refers to compositions comprising a peptide and polylactic-glycolic acid suitable for the preparation of subcutaneous implants.
2. Prior Art
Compositions made up of mixtures of a drug with a polymer of lactic acid or a polymer of glycolic acid or with a copolymer of lactic acid and glycolic acid, as described in the U.S. Pat. No. 3,773,919 (Du Pont) are well known.
These compositions are indicated for parenteral administration and have the characteristics of releasing effective quantities of the drug over a set period of time.
The drug and the polymeric substance can be combined in accordance with any of the known techniques or the particles of the drug can be coated in the polymer operating in accordance with known techniques.
The U.S. Pat. No. 4,767,628 (ICI) describes compositions containing a peptide and a polymer of lactic acid or a copolymer of lactic acid and glycolic acid.
When preparing the compositions, the peptide and the (co)polymer are dissolved in a solvent which can be the same or different for the two substances, for Example dioxane or water, and then the two solutions are mixed.
The subsequent operations consist of removing the solvent at low temperature and in extruding the powder obtained in this way.
In this way a composition in the form of cylinders is obtained in which the peptide is distributed homogeneously throughout the polymer.
It is already known from the U.S. Pat. No. 5,366,734 (Zeneca) that the compositions covered by the U.S. Pat. No. 4,767,628 referred to above can be used in preparing subcutaneous implants.
The polymer of lactic acid and the copolymer of lactic acid and glycolic acid are incompatible with the peptide therefore diffusion of the peptide through the polymer is impossible.
When these implants are introduced into a buffer solution at 37° C., the water penetrates and diffuses in the implant and is distributed between the polymer and the peptide forming regions of hydrated peptides.
The first stage in releasing the peptide described in the U.S. Pat. No. 5,366,734 is a stage of diffusion caused by the polymer swelling.
When the polymer swells this allows channels of hydrated peptide to form where the peptide diffuses to the surface.
If swelling stops, the peptide is no longer released.
The second stage of release is caused by the polymer matrix degrading.
During this stage holes and cracks form in the matrix which allow the release of the hydrated peptides which are still isolated in the matrix.
The total release time is limited to the sum of the release times for each stage. However the maximum release time observed is in the order of three months.
In the application for international patent WO 98/09613 (Deghenghi) a process for preparing subcutaneous implants capable of releasing bioactive peptides is described.
This process consists of the following stages:
milling a copolymer of lactic acid and glycolic acid,
wetting the copolymer with an aqueous slurry of a peptide (in the Examples an aqueous solution of avoreline acetate is used):
mixing this copolymer with the aforementioned slurry so as to obtain a homogeneous mixture;
drying this mixture at a temperature of no higher than 25° C.;
extruding the mixture at 70-110° C. in order to obtain small extruded cylinders suitable for use as subcutaneous implants.
This process cannot be carried out using industrial methods because it is not possible to sufficiently eliminate water from the mixture. The results declared in WO 98/109613 cannot therefore be reproduced.
However the fundamental characteristic of the compositions for subcutaneous implants in the patents referred to above consists of the homogeneous distribution of the peptide in the polymeric substance, resulting from using a solution of at least one of the two components.
The implants currently on the market have the disadvantage of releasing the peptides over a limited period of time, generally of around 3 months.
SUMMARY OF THE INVENTION
The applicant has now found compositions suitable for preparing subcutaneous implants which allow the active substance to be released over a period of time of at least 6 months.
These compositions consist of a polylactic-glycolic acid (PLGA) and a peptide and have the characteristic of distributing peptide particles in the PLGA whose dimensions, under microscopic examination, are extremely heterogeneous, with peptide particles of diameter of between 1 and 60 micrometres dispersed in the polymer matrix.
These and other characteristics of the compositions in accordance with the invention and the process for preparing them will be illustrated in greater depth in the following detailed description.
REFERENCES:
patent: 5134122 (1992-07-01), Orsolini
patent: 5192741 (1993-03-01), Orsolini
patent: 5445832 (1995-08-01), Orsolini
patent: WO 92/11843 (1992-07-01), None
patent: WO9211843 (1992-07-01), None
patent: WO9809613 (1998-03-01), None
patent: WO 98/09613 (1998-03-01), None
Hsu et al., “In Vitro Controlled Release of Isoniazid From Poly(lactide-co-glycolide) Matrices”,Journal of Controlled ReleaseOct. 31 No. 3, (1994).
Maquin Alain
Marion Pierre
Mauriac Patrice
Abelman ,Frayne & Schwab
Bennett Rachel M.
Mediolanum Farmaceutici S.p.A.
Page Thurman K.
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