Powder compositions of unilamellar liposomes

Details Powder compositions of unilamellar liposomes Powder compositions of unilamellar liposomes

2000-02-16

2001-12-18

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C424S489000, C424S490000, C424S499000, C428S402200, C514S824000

Reexamination Certificate

active

06331315

ABSTRACT:

The present invention relates to pulverulent compositions of stabilized unilamellar liposomes, which comprise at least one external lipid phase and an internal aqueous polar nucleus which is gelatinized at ambient temperature, to the process for preparing them and to their applications as nutritional supplements and in pharmaceutical compositions (action on lipaemia).
Liposomes having an internal gelatinized nucleus, which are in suspension in aqueous medium and which contain low concentrations of gelatinizing substances have been described by J. C. Hauton, who has termed them lipogelosomes®. He has, in particular, developed a process for manufacturing such liposomes or lipogelosomes® (European Patent 0 393 049), which differ from conventional liposomes in that the encapsulated aqueous phase is present in semi-solid gel form and not in liquid form, and this prevents the liposomes from fusing when collisions occur. These lipogelosomes® are produced entirely from natural substances, thereby minimizing the risk of intolerance. In particular, in the abovementioned European Patent 0 393 049, these lipogelosomes® consist of one bilayer interfacial phase, in the case of the unilamellar lipogelosomes®, or of a multiplicity 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 disadvantage of being present in a liquid form which is not suitable for preparing solid formulations which are easy to store and administer.
The Applicant has now found, in particular, that, by selecting the lipids of the external lipid phase on the one hand, and the gelatinizing agents, on the other hand, it is possible to prepare stabilized pulverulent lipogelosomes® which exhibit particularly favourable properties, as a nutritional supplement and as a medicament which is intended to be administered by the oral route, in the prevention of hyperlipaemias (hypercholesterolaemias or hypertriglyceridaemias); this is because these stabilized pulverulent lipogelosomes® can either by administered directly by the oral route or be easily dissolved in an aqueous phase at the time of their use.
Cardiovascular diseases are the prime cause of mortality and morbidity in France, as in all the industrialized countries, and represent a real financial burden (30 thousand million francs in 1992). The figures are alarming: 36.4% of all deaths are due to cardiovascular diseases, including 20% due to heart disease and 12% due to strokes. By way of comparison, the next in line are deaths due to the various cancers and violent deaths (accidental or voluntary), in the respective proportions of 24.2% and 9.4%. Such a high incidence of cerebrovascular and cardiac illnesses in western civilisations makes atherosclerosis the prime socioeconomic scourge in the sphere of health.
A long-term prophylaxis is therefore required. It is possible to decrease cholesterolaemia by means of a hypolipidic regime which may or may not be combined with pharmacological products. A method which is widely used in subjects at risk (persons having a cholesterolaemia which is too high) is to sequester the bile salts in the intestine using cholestyramine, and studies have shown that chronic treatment with this synthetic resin decreases the frequency of cardiac illnesses (B M Rifkind,
Atherosclerosis reviews,
1987, 18, 59-70). However, it appears to be difficult to envisage using such a product for a systematic long-term prophylaxis because it is not easy to handle and exhibits side-effects which are poorly accepted by patients.
While a strict hypolipidic regime appears to be the most efficient means for treating a constituted atherosclerosis, experience shows that this is more often than not impossible because sacrificing gastronomic pleasure is an attack on the quality of life and is, furthermore, difficult to apply in the context of the daily activities of modern societies of developed countries.
Use is made of other lipid-lowering agents which act on the internal environment, such as inhibitors of HMG CoA reductase, which decrease the synthesis of endogenous cholesterol and increase the hepatic receptors for atherogenic lipoproteins, thereby reducing their concentration in the plasma (MS Brown et al.,
Atherosclerosis reviews,
1987, 18, 85-93).
However, applying medicinal preventive measures in apparently healthy subjects having a blood lipoproteinogram which is within so-called “normal” limits is questionable because of the side-effects.
A long-term prophylaxis of atherosclerosis which can be applied at population level involves the necessity of having available products which are effective over the long term, which are easy to handle and which exhibit a minimum of unwanted side-effects.
Sensible dietetic measures should therefore be supplemented with actions at intestinal level whose purpose is to decrease the lipolysis of triglycerides into free fatty acids and monoglycerides and to reduce the production of the micellar phase, from which they and cholesterol are absorbed.
The alimentary triglycerides, whose hydrolysis begins in the stomach (sublingual and gastric lipases) and continues in the duodenum (pancreatic lipase) are organized in the proximal intestinal medium in the form of an emulsion whose monolayer interfacial phase, which is in the main formed by the alimentary and biliary phospholipids (G Nalbone et al.,
Lipids,
1974, 9, 765-770), incorporates the products of lipolysis (monoglycerides and free fatty acids) as well as a fraction of the bile salts. The intestinal interfacial phase is unable to dissociate into micelles until the concentration of detergent molecules (bile salts, ionized fatty acids and lysophospholipids) reaches a certain threshold (critical micellar concentration).
In order strongly to inhibit the intestinal lipolysis of triglycerides and to reduce or even suppress the formation of the micellar phase from which the lipolysis products are absorbed, J. C. Hauton has found (Cah. Nutr. Diet., 1990, 25, 2, 87-91) that it is necessary:
to divert a part of the digestive lipases from the interfacial phase of the particles of the lipid emulsion by combining them on a competing interfacial phase; and
to divert a sufficient quantity of bile salts onto the said competing interfacial phase so as to lower their concentration below a given threshold in order to prevent the micellar phase being produced.
The problem to be solved therefore consists in getting an atoxic competing interfacial phase, which exhibits the maximum surface area while having the smallest possible volume, into the proximal intestine during the digestive phase. The present structure which is most suitable is that of small unilamellar liposomes.
From an industrial perspective, and for reasons of handling and storage, such liposomes should be stable. The pulverulent stabilized liposome compositions according to the invention provide an effective solution to this problem, on the one hand because of the presence of the gelatinized internal aqueous nucleus and, on the other hand, due to the fact that they are present in the form of a powder which can either be administered directly by the oral route or easily be dissolved in an aqueous phase at the time of its use.
Consequently, the Applicant has set itself the objective of providing a stable, pulverulent, liposome-based composition which more satisfactorily meets the requirements of practice than do the compositions of the prior art in

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