Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2002-06-24
2004-08-03
Tate, Christopher R. (Department: 1654)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C514S808000, C514S054000, C514S056000, C530S307000, C424S401000
Reexamination Certificate
active
06770292
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel pharmaceutical compositions for oral administration.
Nowadays a large number of drugs need to be administered parenterally, either by intramuscular, subcutaneous or intravenous injection or by incorporation into a perfusion. In general, such a route of administration is necessitated by:
fragility of the active molecule under the physicochemical and biological conditions of the gastrointestinal tract (pH, enzymes, etc.),
non-permeability of the gastrointestinal barrier to the active molecule,
toxicity or excessive irritative capacity of the active molecule towards the gastro-intestinal mucosa.
The following may be mentioned as examples of molecules which fall in the category of those which have to be administered parenterally:
peptides and polypeptides, particularly hormones, which are decomposed by the gastrointestinal media,
heparin, which does not pass through the barrier,
numerous cytostatics, which are known for their toxicity and for the non-permeability of the gastrointestinal barrier thereto.
Furthermore, other mucous tissues which could be preferred drug administration sites are not used as such because of their low permeability to the active molecules in question. This sometimes makes it necessary to use either systemic administration or a strong overdose of the active principle. In both cases, the dose administered is considerably greater than the dose required, which causes numerous disadvantages in terms of cost as well as drug safety.
In addition, the patient's acceptance of the treatment and the patient's comfort are parameters which are increasingly being taken into account in the development of novel drugs. Non-invasive, oral administration therefore represents a distinct advance in this respect.
Several approaches have been developed to facilitate the oral administration of drugs.
The most classical approach, aimed at protecting the active principle from the acidity and enzymatic action encountered in the stomach, consists in coating the active molecule in a tablet whose outer film is resistant to such a medium. In general, said coating dissolves once it is placed under neutral pH conditions such as those encountered in the intestine, thus allowing the release of the active ingredient. This approach is effective for molecules which either act directly in the intestine or have no difficulty in passing into the general circulation through the intestinal mucosa. It is not therefore effective for promoting the transmembrane transport necessary for certain molecules like heparin, nor is it applicable to molecules sensitive to the enzymes present in the intestine (particularly proteases, which destroy proteins).
Derived from this technology, microcapsules coated with polymers make it possible not only to protect the active principle but also to release it in a controlled or delayed manner in the intestine and hence to improve the pharmacokinetics, thereby affording e.g. a reduction in the side effects of the product. Such an invention is described in European patent EP 0 709 087 in the name of Flamel. The particle diameter (in the order of a few hundred to a few thousand micrometers) and the coating thickness can be modified, allowing variations in the kinetic release profiles.
Numerous tests have employed different technologies based on microvesicles or on microspheres or nanospheres of polymers for the purpose of protecting the active principle, but also of facilitating its passage through the gastrointestinal membrane into the bloodstream. There may be mentioned liposomes (cf. M. Ueno et al., Chem. Pharm. Bull., 30 pp. 2245-2247, 1982) used to facilitate the passage of heparin, or polyalkyl cyanoacrylate nanospheres used for the oral administration of insulin (C. Damgé et al., J. Pharma. Sc., 86 pp. 1403-1409, 1997). Based on another technology, adjuvants such as acetylated derivatives of amino acids (A. Leone-Bay et al., J. Controlled Release, 50 pp. 41-49, 1998) or hydrogels (J. M. Dunn & A. S. Hollister, Current Therap. Res., 56 pp. 738-745, 1995) have been used to facilitate the oral administration of heparin.
As regards vesicles, i.e. spherical objects formed of molecular arrangements of amphiphilic molecules, multilamellar vesicles have formed the subject of important researches and have given rise to several applications. Examples which may be mentioned are international patent applications WO 93/19735, WO 95/18601, WO 97/00623, WO 98/02144 and WO 99/16468. Such vesicles, which are referred to in the above-cited documents as multilamellar vesicles with an onion structure, differ from liposomes by:
their method of preparation, which starts from a lamellar liquid-crystal phase, i.e. a phase at thermodynamic equilibrium with a long-range order;
their lamellar liquid-crystal internal structure. This structure is formed of a stack of concentric bilayers of amphiphiles alternating with layers of water, aqueous solution or solution of a polar liquid (e.g. glycerol) from the center to the periphery of these vesicles. Before their dispersion in a use medium, these vesicles are in a state of thermodynamic equilibrium. The specific structure of these vesicles can easily be demonstrated by optical microscopy, particularly polarizing optical microscopy;
the varied nature of the amphiphilic molecules which can be used, by themselves or in a mixture, to form the vesicles;
the media in which the vesicles can be dispersed, which can be hydrophilic or lipophilic depending on the formulation.
The size of these multilamellar vesicles is in the order of a micrometer, the diameter typically being from 0.1 &mgr;m to 20 &mgr;m. Their use for the oral administration of a drug has never been illustrated or demonstrated.
SUMMARY OF THE INVENTION
The inventors of the present invention have now discovered that the oral administration of multilamellar vesicles having the specific structure defined above, incorporating a molecule known for its inability to be administered by this route, either because of its fragility or because of its inability to pass through the gastro-intestinal barrier, is made possible when said molecule is incorporated in these multilamellar vesicles. Incorporating the molecule in this way favors its passage through the gastrointestinal wall and enables it to enter the bloodstream. This discovery was made on the basis of experiments conducted on molecules of very different natures and characteristics, such as heparin on the one hand and calcitonin on the other.
One advantage of the invention is that these multilamellar vesicles are prepared from biocompatible constituents known for their harmlessness.
Another advantage of the invention is that the process for the preparation of vesicles is simple to carry out and only calls for standard chemical apparatus.
Furthermore, the fact that the process involves an initial lamellar phase at thermodynamic equilibrium gives it an excellent reproducibility and gives the resulting vesicles a high stability.
REFERENCES:
patent: 6290987 (2001-09-01), Modi
patent: 93/19737 (1993-10-01), None
Amedee Joëlle
Guinez Charles
Laversanne Rene
Capsules
Chism B. Dell
Dennison Schultz Dougherty & MacDonald
Tate Christopher R.
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