Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2000-02-17
2003-12-02
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S489000, C424S490000, C424S499000, C428S402200, C264S004100, C264S004300, C514S002600, C514S021800, C514S045000, C514S824000
Reexamination Certificate
active
06656497
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to stable liposomal vectors, in pulverulent form, for active principles, and more particularly for active principles which are sensitive to digestive and/or plasmatic degradation, such as proteins, and to their use as medicinal products.
2. Description of the Background
Many vectors have been proposed to protect such fragile active principles; among these, mention should be made of liposomes, which have been considered as a vector of choice.
The first studies on the oral administration of liposomes were not conclusive (Deshmukh D. S. et al., Life Sciences, 1981, 28, 239-242). The results obtained showed that liposomes with the formulation: diether-phosphatidylcholine (indigestible PC analogues)/cholesterol-7:1 allowed gastrointestinal protection of the encapsulated peptide, but did not allow its passage across the intestinal barrier.
Several reasons may be put forward to explain this absence of passage: excessively large and non-calibrated size of the liposomes, low stability of the structure or leakage of the encapsulated compound into the extra-liposomal medium.
Recently, the research team of Robert Greenwood (
Drug Dev. and Ind. Pharm.,
1993, 19, 11, 1303-1315) at the Campbell University, U.S.A., has succeeded in showing that the duodenal intubation of liposomes vectorizing insulin brought about a higher hypoglycaemiant effect than that obtained after a duodenal intubation of a solution of free insulin.
Many tests have been carried out to obtain liposomes with good capacity to transport active principles, in particular as regards the action on the percentage of uptake of the active principle, the stability of the liposomes and the bioavailability of the active principle. Mention may be made, for example, as a guide, of:
S. B. Kulkarni et al. (
J. Microencapsulation,
1995, 12, 3, 229-246) who point out the factors involved in the microencapsulation of medicinal products in liposomes: size of the liposome, type of liposome, surface charge of the liposome, rigidity of the bilayer, addition of encapsulation adjuvants. It emerges from this evaluation that MLVs (multilamellar vesicles) containing several bilayers and with a diameter of between 100 nm and 20 mm are desirable for the encapsulation of hydrophobic medicinal products interacting with the bilayers, whereas LUVs (large unilamellar vesicles) containing a single bilayer and with a size of between 100 and 1000 nm are considered as being the most suitable for the encapsulation of hydrophilic medicinal products.
I. De Miguel et al., (Biochimica et Biophysica Acta, 1995, 1237, 49-48 [sic]), who propose nanoparticles composed of an internal core formed from crosslinked polysaccharides grafted on their exterior with fatty acids and surrounded by a layer of phospholipids;
P. S. Uster et al., (
FEBS Letters,
1996, 386, 243-246) who propose the insertion of phospholipids modified with a poly(ethylene glycol) in preformed liposomes to improve the bioavailability.
Series of experiments relating to the oral administration of peptides have been carried out and use either different liposomal methods of encapsulation, or modification of the lipidic active principle by grafting lipophilic functions. In all cases, the aim is to convert the lipidic active principle into a “prodrug”; this prodrug has the property of withstanding gastrointestinal transit, i.e. resistance to gastric pH, to physiological detergents (bile salts), to proteases (intestinal exopeptidases and endopeptidases) and to metabolization by the intestinal flora. For example, the bridging in position 2 of a 1,3-diglyceride onto a pentapeptide made it possible to impart these qualities to the drug thus modified.
However, these various liposomes of the prior art do not make it possible to obtain both good stability, an acceptable active-principle encapsulation yield and a significantly improved oral bioavailability of the said active principle, without modifying the active principle, which thus conserves all of its functions and properties. The term “bioavailability” means the fraction of the dose which reaches the systemic circulation in pharmacologically active form and the rate at which it does so.
J. C. Hauton has described liposomes with a gelatinized internal core (lipogelosomes®) which are in suspension in aqueous medium containing gelatinizing substances. He has, in particular, developed a process for manufacturing such liposomes (European patent 0 393 049), which differ from conventional liposomes in that the encapsulated aqueous phase is in semi-solid gel form rather than in liquid form, and this prevents the liposomes from fusing during collisions. Such lipogelosomes® are produced entirely from natural substances, thereby minimizing the risk of intolerance. In particular, in European patent 0 393 049, these lipogelosomes® consist of one bilayer interfacial phase, in the case of the unilamellar lipogelosomes, or of a plurality of bilayer interfacial phases, which are superimposed concentrically, in the case of the multilamellar lipogelosomes®, and of a gelatinized encapsulated internal aqueous polar phase in which the gelatinized substance, which may or may not be polymerizable, is selected from polysaccharides, polypeptides or polyacrylamides; for example, the non-polymerizable gelatinizable substance is selected from gelatin, agarose or carrageenans, and the polymerizable gelatinizable substance is selected from polyacrylamide gels. These lipogelosomes® possess a stability which is significantly increased as compared with the liposomes of the prior art, particularly because of the absence of interparticulate fusion during collisions.
However, they suffer from the drawback of being in the form of a dispersion of liposomes in liquid phase, which is not suitable for preparing solid formulations which are easy to store and to administer.
SUMMARY OF THE INVENTION
Consequently, the Applicant set itself the objective of providing a novel vector which effectively makes it possible to obtain both a sufficient encapsulation yield and significantly improved oral bioavailability of the said active principle, compared with the liposomes of the prior art, while at the same time displaying great stability both on storage and in vivo. Said vectors are suited to oral administration; the aqueous solution is also suitable for other routes of administration: transdermal, pulmonary, nasal, genital, intravenous, subcutaneous or ocular, for example, depending on the excipient selected.
The said vectors are characterized in that they consist of:
a pulverulent composition which consists essentially of unilamellar liposomes comprising an external lipid phase which consists of class 4 lipids (phospholipids), optionally combined with class 2 substances (long-chain triglycerides, cholesterol esters), class 3 substances (cholesterol, nonionized long-chain fatty acids) and/or class 5 substances (bile salts, fusidic acid derivatives) and an internal aqueous core forming a temperature-reversible aqueous gel which radiates out up to the external lipid phase, which internal aqueous core essentially consists of a mixture M of at least two different non-polymerizable gelatinizing agents G1 and G2 whose gel-sol phase transition point is higher than or equal to 37° C., with G1 being a gelatinizing agent which is selected from gelatins and carrageenans, such as kappa-carrageenans, and G2 being selected from carrageenans whose properties are different from the carrageenans selected for G1, such as iota-carrageenans, and celluloses, such as hydroxypropylmethylcellulose, which liposomes have a diameter of between 20 nm and 1 mm, preferably of between 20 nm and 500 nm and being in the form of particulate units with an average diameter of between 10 mm and 1000 mm, formed from one or more of the said liposomes, surrounded by a matrix selected from the group consisting of a dehydrated temperature-reversible aqueous gel which is identical to the aqueous gel of the said internal core, dextrins or a mixture thereof,
Kishore Gollamudi S.
Lipogel
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