Liposome formulation of 5 &bgr; steroids

Details Liposome formulation of 5 &bgr; steroids Liposome formulation of 5 &bgr; steroids

1999-04-27

2002-08-20

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C424S423000

Reexamination Certificate

active

06436435

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to liposome preparations capable of enhancing the delivery of DHEA and 5&bgr; steroids to the liver. Additionally the liposomal preparation may also be used to transport an antiobesity peptide or protein in an included aqueous phase.
BACKGROUND OF THE INVENTION
Liposomes are completely closed lipid bilayer membranes containing an entrapped aqueous volume. Liposomes may be unilamellar vesicles (possessing a single bilayer membrane) or multi lamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer). The bilayer is composed of two lipid monolayers having a hydrophobic tail region and a hydrophilic head region. The structure of the membrane bilayer is such that the hydrophobic (nonpolar) tails of the lipid monolayers orient toward the center of the bilayer while the hydrophilic heads orient toward the aqueous phase.
The liposomes originally prepared by Bangham et al.,
J. Mol Biol.,
13,238-252(1965) were produced by suspending phospholipids in an organic solvent and evaporating the mixture to dryness leaving a phospholipid film on the surface of the vessel. An aqueous phase was added, the mixture was allowed to swell and was dispersed by mechanical means. Liposomes resulting from the procedure consisted of multi lamellar vesicles (MLVs). Subsequently, Papahadjopoulos et al.,
Biochim. Biophys. Acta.,
13,624-638(1968) developed small unilamellar vesicles by sonicating the mixture.
LUVETS, unilamellar vesicles extruded under pressure through a membrane filter are disclosed in Cullis et al., PCT Application No. Wo 86/00238, published Jan. 16, 1986, which is herein incorporated by reference. Luvets usually range from about 100 NM to about 500 NM in diameter.
Liposomes having substantially equal lamellar-solute distribution are denominated stable plurilamellar vesicles (SPLV) as defined in U.S. Pat. No. 4,522,803 to Lenk et al., Monophasic vesicles are described by Fountain, et al. in U.S. Pat. No. 4,588,578. Frozen and thawed multi lamellar vesicles (FATML V), which are produced by exposing vesicles to at least one freeze and thaw cycle are described in Bally et al., PCT Publication No. 87/00043 published Jan. 15, 1987. The forgoing references are incorporated herein by reference for the teaching of preparation and various uses of liposomes.
With respect to the lipids used in the formation of liposomes, in general the hydrophobic non-polar regions of lipid monolayers orient toward the center of the bilayer while the hydrophilic regions orient toward the aqueous phase. The aqueous phase including any product dissolved therein may be partially or fully enclosed by the membrane bilayer. Examples of lipids are the phospholipids such as phosphatidylcholine (PG), egg phoshpatidylcholine (EPG), phosphatidylserine, phoshpatidylglycerol, phoshpatidylinositol, phosphatidic acid, sphingomyelin and the like alone or in combination and particularly in hydrogenated or saturated form of the carbon chain. The phospholipids can be synthetic or derived from natural sources. Synthetic phospholipids include dymyristoylphoshpatidylcholine, and dimyristoylphosphatidylglycerol.
Alpha tocopherol-based bilayer vesicles are disclosed in Janoff et al.,, U.S. Pat. No. 5,041,287, Janoff al., U.S. Pat. No. 5,231,112, and Janoff et al., U.S. Pat. No. 5,330,689, which are all herein incorporated by reference. These vesicles are formed from organic acid derivatives of alpha tocopherol which are capable of forming of completely closed bilayers in aqueous solutions.
Liposomes prepared using salt forms of cholesterol hemisuccinate are disclosed in Janoff et al., U.S. Pat. No. 5,231,112, herein incorporated by reference. Peptides and proteins that appear to have an impact upon the tendency of a mammal to become obese and to gain weight in excess of normal are now known. A protein product of the recombinant gene ob in mice as well as its human homologue have been disclosed in Y. Zhang et al,
Nature,
372,425 (1994). In addition, the homologous gene in rats, apparently without mutations, has been cloned as disclosed in T. Murakami and K. Shima,
Biochemical amid Biophysical Research Commiunications,
209 (3), 944 (1995). R. A. Considine et al.,
Journal of Clinical Investigation,
95 (6), 2986 (1995) disclose the isolation of the full coding region of the ob gene from a human adipocyte cDNA library and translation of the cloned sequence resulting in a protein having the predicted amino acid sequence of the normal protein. M. A. Pelleymounter et al.,
Science,
269, 540 (1995), J. L. Halaas et. al.,
Science,
269, 543 (1995), and L. A. Campfield, et al.,
Science,
269, 546 (1995) disclose that this protein has weight reducing effects when administered parenterally to congenitally obese mice carrying the ob ob mutation. In addition serum insulin and glucose levels, usually markedly elevated above normal in ob·ob mice, were significantly reduced in a dose dependent fashion and were normalized to the level typically seen in the non-mutant mice at the highest dose tested (10 mg/kg per day). M. A. Pelleymounter et al., further disclose that the protein may be dissolved in phosphate buffered saline at pH 7.4 and administered intraperitoneal injection.
The steroid dehydroepiandrosterone (3-&bgr;-hydroxy-androst-5-en-17-one, DHEA) and its sulfate derivatives are major steroid adrenal secretory products in humans. DHEA is metabolized to testosterone (17-&bgr;-hydroxy-androst-4-en-3-one) and estradiol (estra-1,3,5 (10)-triene-3,17-diol), two major sex hormones in humans. Other metabolites of DHEA include &agr; ET and &bgr;-ET. They were considered to be inert metabolic end products which were merely conjugated as glucuronides or sulfates and excreted into the urine. &agr; ET is a major metabolite of DHEA, and in normal individuals, is excreted in the urine in amounts of about 3-5 mg per day, whereas &bgr; ET is a minor metabolite in man.
The effect of these compounds upon obesity and diabetes is summarized as follows. Yen et al.,
Lipids.
12, 409 (1977) disclosed that DHEA administered by a variety of routes decreased the rate of weight gain in a strain of genetically obese mice. DHEA treatment markedly reduced the development of diabetes in both genetically obese and diabetic mice and maximal benefit was observed when DHEA was ingested according to Coleman et al.,
Diabetes
31:80 (1982). Coleman et al.,
Endocrinology,
115, 239 (1984) showed that &agr; ET and &bgr; ET reduce blood sugar, increased plasma insulin concentrations and provided a protective effect on the pancreas as demonstrated by increased granulation of islet &bgr; cells. Moreover, &agr; ET and &bgr; ET but not androsterone or epiandrosterone, were four times more effective than DHEA in preventing development of diabetes in C57BL/KsJ-db/db diabetic mice. Coleman et a/., U.S. Pat. No. 4,518,595 showed that oral administration of DHEA restored hyperglycemia to normal levels and improved glucose tolerance even in severely diabetic mammals. In U.S. Pat. No. 4,507,289 Coleman taught the use of &agr; ET and &bgr; ET and an estrogen for the treatment of diabetes, obesity syndromes and associated hypercorticoidism.
Coleman,,
Endocrinology,
117, 2279 (1985) disclosed that &agr; ET and &bgr; ET when supplied in the diet have anti-obesity properties, and can prevent and arrest the development of obesity, ad facilitate weight reduction after obesity in diabetic genetically obese mice. U.S. Pat. No. 4,666,898 to Coleman and Applezweig disclosed the use of Etiocholanolones in the treatment of obesity, diabetes and other symptoms of hypercorticoidism. B. Zumoff et al.,
Obesity Research,
2, 13 (1994) disclosed that ED orally administered at a dose of four grams per day yielded significant fat loss in human obese subjects. In a 20 week randomized double-blind cross over study, 14 subjects lost significantly more weight and body fat during treatment with oral ED than during placebo administration. Mean weight loss during ED administration was 2.8&plusm

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