Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-07-06
2003-10-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S499000, C424S502000, C424S484000, C424S486000, C424S422000, C424S130100, C424S184100, C514S002600, C514S003100, C514S056000, C514S054000
Reexamination Certificate
active
06630171
ABSTRACT:
This application is a 371 of PCT/FR99/02859, filed on Nov. 19, 1999.
The field of the present invention is that of Delivery Particles (DPs) which can be used for the administration of active principles (APs). The latter are preferably medicinal products or nutrients for adminstration to an animal or human organism via the oral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal, intracerebral, parenteral, etc. route. However, they may also be plant-protection products, such as herbicides, pesticides, insecticides, fungicides, etc. In terms of chemical nature, the APs with which the invention is more particularly, but not exclusively, concerned are, for example, proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligonucleotides and polynucleotides.
The present invention relates more specifically to Delivery Particles, advantageously of the submicron type, based on polyamino acids (PAAs). The present invention is directed toward both naked particles per se, and AP vector systems consisting of particles loaded with the AP(s) under consideration. The present invention also relates to aqueous colloidal suspensions comprising these DPs.
The invention also relates to processes for preparing said particles and colloidal suspensions, with and without APs.
The aim of the encapsulation of APs in DPs is in particular to increase the bioavailability of said APs. Many encapsulation techniques have already been proposed. Such techniques are directed, firstly, toward enabling the AP to be transported to its site of therapeutic action, while at the same time protecting it against the body's attacks (hydrolysis, enzymatic digestion, etc.) and, secondly, toward controlling the release of the AP over its site of action, in order to maintain the amount available to the organism at the desired level. The APs with which these misadventures of delivery and residence in the body are concerned are, for example, proteins, but may also be any other products, of synthetic or natural origin. The review by M. J. HUMPHREY (Delivery System for peptide Drugs, edited by S. DAVIS and L. ILLUM, Plenum Press, N.Y., 1986), gives an account of the problem concerning the improvement of the bioavailability of APs and the advantage of systems for delivery and controlled release.
Of all the materials which can be envisaged for making up DPs, polymers are increasingly used on account of their intrinsic properties. As regards the list of specifications which it is desired to obtain for such DPs, this is particularly demanding and comprises, in particular, the following specifications.
1—It should advantageously be possible to obtain a particle size distribution which is controlled and suitable for the mode of administration chosen and/or for the therapeutic site targeted.
2—It is desirable for the DPs to protect the AP until the site of release is reached.
3—The DPs should advantageously control the rate of release of the AP.
4—It is preferable for the polymer which constitutes the DPs to be biocompatible, able to be eliminated (by excretion) and/or biodegradable and, better still, for it to be metabolized into products which are nontoxic to the body.
5—It is also advantageous for the polymer which constitutes the DPs not to induce an immune response.
6—Finally, it is also desirable for it to be possible to obtain the DPs and the DP-AP systems using a process which does not denature the AP.
The prior technical propositions, described above, have attempted to satisfy this set of specifications. By way of illustration, mention will be made of prior propositions (a) to (h): according to a first approach, which comprises propositions (a) to (d), the inclusion of the active principle takes place during the formation of the delivery supports; according to a second approach, mentioned in propositions (e) to (h), DPs are produced which are capable, once manufactured, of associating spontaneously by absorption to the AP.
(a) Patent U.S. Pat. No. 5,286,495 relates to a process of encapsulation by spraying proteins in aqueous phase, using materials having opposite charges, namely: alginate (negatively charged) and polylysine (positively charged). This manufacturing process makes it possible to produce particles greater than 35 &mgr;m in size.
(b) In addition, emulsion techniques are commonly used for preparing microparticles loaded with AP. For example, patent applications WO 91/06286, WO 91/06287 and WO 89/08449 disclose such emulsion techniques in which use is made of organic solvents in order to solubilize polymers, for example of the polylactic type. However, the solvents have proven to be possibly denaturing, in particular for peptide or polypeptide APs.
(c) Biocompatible DPs formed in aqueous solution and called proteinoids, described as early as 1970 by W. FOX and K. DOSE in “Molecular Evolution and the origin of Life”, Ed. Marcel DEKKER Inc. (1977), are also known. Thus, patent application WO 88/01213 provides a system based on a mixture of artificial polypeptides obtained by thermal condensation of amino acids. The microparticles according to that invention are obtained by changing the pH, which causes precipitation of the proteinoid particles.
(d) Mention will also be made, as a matter of interest, of U.S. Pat. Nos. 4,351,337 and 4,450,150. which are the product of a field other than that of the delivery of APs, characteristic of the invention. These patents disclose implants of masses attached and located at quite precise sites in the body. The implants are produced from polymeric materials of the poly-&agr;-amino acid type (Leu/GluOH and GluOEt/GluOH, respectively). According to the teaching of that patent, the preferred polyamino acids are those which are rich in hydrophobic amino acid (eg. more than 50% of Leucine or of Glu OEt) and water-insoluble. The AP can be incorporated into a solution of poly-&agr;-amino acid in an organic solvent. This solution is that used to form the implant by molding/drying (evaporation). According to another variant, the AP can be included in the core of a microcapsule, the case of which is obtained using a copolymer solution, and the diameter of which is greater than or equal to 5000 &mgr;m. The core can consist of pure AP or of a copolymer matrix which includes the AP, and can be obtained from the solution of PAA in an organic solvent.
(e) PCT patent application WO/FR97/02810 discloses a composition for the controlled release of active principles, comprising a plurality of lamellar particles of a biodegradable polymer, at least partly crystalline (lactic acid polymer), and of an active principle absorbed onto said particles. The release of the active principle takes place by desorption.
(f) The publication “
CHEMISTRY LETTERS
1995, 707
, AKIYOSHI et al
” relates to the stabilization of insulin by supramolecular complexation with nanoparticles formed from ten or so polysaccharide chains made hydrophobic by grafting cholesterol.
(g) The article published in “
MACROMOLECULES
1997, 30, 4013-4017” describes copolymers composed of a peptide block based on L-phenylalanine, on &ggr;-benzyl-L-glutamate or on O-(tetra-O-acetyl-&bgr;-D-glucopyranosyl)-L-serine, and a synthetic block, such as poly(2-methyl-2-oxazoline) or poly(2-phenyl-2-oxazoline). Some of these polymers aggregate in aqueous medium to form particles of 400 nm, capable of associating with an enzyme, lipase.
(h) The subject of patent FR 95-03978 is polyamino acid particles which can be used for delivering active principles and which are characterized in that their constituent polyamino acids comprise at least two types of recurrent amino acids, AANs (which are neutral and hydrophobic) and AAIs (which are ionizable and hydrophilic). The particles are obtained spontaneously by dispersion of the polyamino acid powder in an aqueous solution. The particles thus obtained associate spontaneously in aqueous suspension with active principles, which are for example protein in nature.
These prior technical propositions more or less satisfy the specifications of the list
Brison Nathan
Huille Sylvain
Nicolas Florence
Soula Gerard
Di Nola-Baron Liliana
Flamel Technologies
Lydon James C.
Page Thurman K.
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