Composite gel microparticles as active principle carriers

Details Composite gel microparticles as active principle carriers Composite gel microparticles as active principle carriers

1999-01-04

2001-01-30

Page, Thuaman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S499000, C424S493000, C424S491000, C424S479000, C424S497000

Reexamination Certificate

active

06180141

ABSTRACT:

BACKGROUND OF THE INVENTION
The field of the present invention is that of vectors which are useful for the administration of active principles (APs), preferably medicinal or nutritional active principles, in particular via the oral, nasal, vaginal, ocular, subcutaneous, intravenous, intra-muscular, intradermal, intraperitoneal, intracerebral, parenteral, etc. route. These vectors allow the protected delivery of the APs into the body, to their site of action. They are intended to improve the bioavailability of APs. These vectors can be, for example, systems for the sustained release of APs.
The APs with which the invention is more particularly, but not exclusively, concerned are, for example, proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligonucleotides and polynucleotides.
More specifically, the present invention relates to delivery particles (DP)—advantageously of submicron and/or micron type—for delivering APs, in particular medicinal APs.
Besides medicinal and nutritional APs, the invention also relates to plant-protection and cosmetic APs.
The present invention is directed toward both naked particles per se, and AP delivery systems, consisting of particles loaded with the AP(s) considered.
The invention also relates to a process for preparing the said particles.
PRIOR ART
Progress in genetic engineering and biotechnology, as well as the related discoveries of biologically active peptide, proteinic and genetic tools have allowed the development of novel medicinal active principles (APs) offering high intrinsic activity and high selectivity. On the other hand, these APs are easily degraded in the body before reaching their therapeutic site of action, and their bioavailability is consequently very low. In the case of oral administration, the gastrointestinal tract constitutes a formidable chemical and physical barrier for an AP which must, on the one hand, withstand degradation by the digestive system and, on the other hand, pass through the gastrointestinal epithelial membrane. In this respect, reference may be made, for example, to the review by M. J. Humphrey (Delivery System for Peptide Drugs, edited by S. Davis and L. Illum, Plenum Press, N.Y., 1986), which gives an account of the low bioavailability of peptides and of peptides administered orally.
Naturally, these mishaps of delivery and residence in the body are not limited to proteins, but also affect APs formed by genetic tools (oligonucleotides, polynucleotides, plasmids) liable to be used in genetic engineering techniques.
To overcome this, it has been proposed to encapsulate APs in AP delivery particles, also referred to as DPs. The advantage of these encapsulation techniques is that they protect and/or deliver the AP up to its therapeutic site of action, by keeping it safe from attack by the body, in order to increase its bioavailability.
Of all the materials which can be envisaged for encapsulating APs, 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 DPs with an average diameter of between a fraction of a micron and a few microns, with a narrow particle size distribution, so as to be able to adapt the DP particle size to the mode of administration selected and/or the therapeutic site targeted. For example, if a mucosal immunization via the oral route is desired, the DP size should be between 0.5 &mgr;m and 10 &mgr;m in order for the DPs to be able to penetrate the Peyer plates and reach the lymphoid tissues. In the case of subcutaneous administration, it is advantageous to have DPs larger than 10 &mgr;m in size in order for the particles not to enter into the general circulation, in which they are rapidly internalized by the reticuloendothelial system, but for them to diffuse gradually from their site of injection.
This specification implies controlling the size of the DPs, as regards both the DP particle size distribution and their average diameter, which represents a very intricate operation in technological terms.
2—It is desirable for the DPs to protect the AP up to the site of release. For example, in an oral administration of an AP formed of a vaccine, the vaccine would be successfully protected throughout the gastrointestinal tract.
3—It is preferable for the polymer which forms the DPs to be biocompatible and biodegradable and, better still, for it to be metabolized into products that are non-toxic to the body.
4—It is also advantageous for the polymer which forms the DPs not to induce an immune response (immunogenic).
5—The DPs are expected to allow the controlled and sustained release of the AP.
6—Lastly, it is also preferable for the DPs to be obtainable by a process which does not denature the AP. Thus, the use of organic solvents and/or high temperatures should be ruled out.
Many prior technical approaches have attempted, unsuccessfully, to satisfy all of these specifications. The solutions provided hitherto are thus only partial and incomplete.
In all of these unfruitful approaches of the prior art, several constituent base materials have been envisaged for the delivery particles. These materials can be biocompatible polymers, such as proteins and/or polymers of &agr;-hydroxy acids (polylactic and/or glycolic acids) and/or poly(alkyl cyanoacrylates) and/or polyorthoesters and/or fatty substances (oils—fats).
The DPs (microspheres or microcapsules) of protean nature are usually obtained by drastic crosslinking treatments using glutaraldehyde-type chemical agents or by raising the temperature. It goes without saying that such treatments necessarily entail denaturing of a large number of active principles. What is more, the toxicity of glutaraldehyde-type crosslinking agents is particularly unfitting in pharmaceutical applications. As examples of such known microparticles, mention may be made of those disclosed in patent application EP 0,363,921. The particles according to that application are obtained by complex coacervation of a synthetic polyamino acid and an anionic polymer, in aqueous solution, by adjusting the pH. The polyamino acid is an amphiphilic copolymer based on glutamic acid and lysine, whereas the anionic polymer is a water-soluble polysaccharide, such as gum arabic. These particles are given cohesion by crosslinking the coacervate using glutaraldehyde. Besides the toxicity and degradation problems of the APs mentioned above, it should be noted that the polymers in the coacervate according to EP 0,363,921 suffer from an immunogenic nature.
Protean microparticles or microparticles based on biocompatible and biodegradable polymers can also be prepared by standard emulsion techniques.
In this respect, mention may be made, for example, of patent applications WO 91/06 286 and WO 91/06 287 which describe processes for the formation of particles in emulsion, these processes using, as polymer:
either a hydrophobic protein chosen from collagen, casein, keratin and, preferably, prolamines,
or a biocompatible and biodegradable polymer, such as poly(lactics) or poly(orthoesters).
The AP can be hydrophobic or hydrophilic but, in the latter case, the double-emulsion technique is recommended. The size of the microparticles is about 100 &mgr;m and preferably between 50 nm and 100 &mgr;m.
Patent application WO 89/08 449 also makes reference to encapsulation by emulsion, in order to incorporate APs into poly(lactic) microparticles less than 10 &mgr;m in size. Moreover, it is pointed out in that document that this size is a maximum limit for absorption across the lymphoid tissues of mucous membranes (oral, nasal, rectal and ophthalmological administrations).
The emulsion techniques are very appealing in principle, since they allow most of the APs to be used in microparticles whose particle size can be controlled to sizes of about 1 &mgr;m. However, in these techniques, organic solvents are used to dissolve the polymers which make up

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