Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1998-06-10
2001-03-13
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C514S725000
Reexamination Certificate
active
06200597
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to therapeutic compositions of carotenoids encapsulated in liposomes or other lipid carrier particles.
It has been known for more than 50 years that retinoids, the family of molecules comprising both the natural and synthetic analogues of retinol (vitamin A), are potent agents for control of both cellular differentiation and cellular proliferation (Wolbach et al., J. Exp. Med., 42:753-777, 1925). Several studies have shown that retinoids can suppress the process of carcinogenesis in vivo in experimental animals (for reviews, see e.g., Bollag, Cancer Chemother. Pharmacol., 3:207-215, 1979, and Sporn et al., In Zedeck et al. (eds.), Inhibition of Tumor induction and development, pp. 71-100. New York: Plenum Publishing Corp., 1981). These results are now the basis of current attempts to use retinoids for cancer prevention in humans. Furthermore, there is extensive evidence which suggests that retinoids can suppress the development of malignant phenotype in vitro (for review, see e.g., Bertram et al., In: M. S. Arnott et al., (eds.), Molecular interactions of nutrition and cancer, pp 315-335. New York, Raven Press, 1982; Lotan et al., The modulation and mediation of cancer by vitamins, pp 211-223. Basel: S. Karger AG, 1983) thus suggesting a potential use of retinoids in cancer prevention. Also, recently it has been shown that retinoids can exert effects on certain fully transformed, invasive, neoplastic cells leading in certain instances to a suppression of proliferation (Lotan, Biochim. Biophys. Acta, 605:33-91, 1980) and in other instances to terminal differentiation of these cells, resulting in a more benign, non-neoplastic phenotype (see e.g., Brietman et al., Proc. Natl. Acad. Sci. U.S.A., 77:2936-2940, 1980).
Retinoids have also been shown to be effective in the treatment of cystic acne (see e.g., Peck, et al., New Engl. J. Med., 300:329-333, 1979). In addition to cystic acne, retinoid therapy has been shown to be effective in gram-negative folliculitis, acne fulminans, acne conglobata, hidradenitis suppurativa, dissecting cellulitis of the scalp, and acne rosacea (see e.g., Plewig et al., J. Am. Acad. Dermatol., 6:766-785, 1982).
However, due to highly toxic side effects of naturally occurring forms of vitamin A (hypervitaminosis A) at therapeutic dose level, clinical use of retinoids has been limited (Kamm et al., In: The Retinoids. Sporn et al., (eds.), Academic Press, New York, pp 228-326, 1984; Lippman et al., Cancer Treatment Reports, 71:493-515, 1987). In free form, the retinoids may have access to the surrounding normal tissues which might be the basis of their profound toxicity to liver, central nervous system, and skeletal tissue.
Therefore, one potential method to reduce the toxicity associated with retinoid administration would be the use of a drug delivery system. The liposomal format is a useful one for controlling the topography of drug distribution in vivo. This, in essence, involves attaining a high concentration and/or long duration of drug action at a target (e.g. a tumor) site where beneficial effects may occur, while maintaining a low concentration and/or reduced duration at other sites where adverse side effects may occur (Juliano, et al., In: Drug Delivery Systems, Juliano ed., Oxford Press, New York, pp 189-230, 1980). Liposome-encapsulation of drug may be expected to impact upon all the problems of controlled drug delivery since encapsulation radically alters the pharmacokinetics, distribution and metabolism of drugs.
There are additional difficulties in using a liposomal formulation of a retinoid for therapeutic purposes. For example, it is often desirable to store the composition in the form of a preliposomal powder, but many prior formulations are not satisfactory for such use, because they either contain an inadequate amount of retinoid, or they generate undesirable liposomes when they are reconstituted in aqueous solution.
For compositions that are to be administered intravenously, typically the composition must provide at least about 100 mg of the active ingredient in a single container; if it contains a lesser amount of the active ingredient, an impractically large number of vials will be needed for dosing a single patient.
Typically a vial having a volume of 120 cc is the largest that can be accommodated in a commercial freeze drier, and 50 cc is the maximum volume of liquid that can be filled in such a vial. If more than 1 g of lipids are included in 50 cc of liquid volume, the resulting liposomes after reconstitution have a size distribution which is not acceptable for parenteral administration. This is because the packing of the lipids during lyophilization is affected by the concentration of the lipids in the solution. Thus, the concentration of lipids in the solution must be limited. However, when this is done in previously-known liposomal retinoid formulations, the retinoid tends to crystallize, and separate from the liposomes shortly after reconstitution.
In order to both limit the concentration of lipids and supply a sufficient amount of retinoid, it is necessary to provide a molar ratio of retinoid to lipid greater than about 1 to 10. Previously known formulations have not had, and are believed not to be capable of having such a high packing of retinoid in the liposomes. Therefore, a need exists for improved compositions and methods which will minimize or eliminate the problems of the prior art.
SUMMARY OF THE INVENTION
The present invention relates to therapeutically useful, reduced toxicity compositions of carotenoids. The compositions comprise a carotenoid, lipid carrier particles, and an intercalation promoter agent. “Carotenoid” is used here to include retinoids, pro-retinoids, carotenes, xanthophylls, and analogs thereof. A preferred example is all-trans retinoic acid. The carotenoid is substantially uniformly distributed with the lipid in the lipid carrier particles. More particularly, the carotenoid is substantially uniformly distributed in an intercalated position throughout a hydrophobic portion of the lipid carrier particles, as opposed to the aqueous phase. “Substantially uniformly distributed” means that at least 50% of the lipid carrier particles will contain carotenoid in a molar ratio between about 5:85 carotenoid:lipid and about 15:70. Preferably at least 75% of all lipid carrier particles will contain such a ratio of the active ingredient.
The composition is stable in an aqueous environment. In this context, “stable in an aqueous environment” means that the composition (1) will not exhibit any therapeutically significant degradation over a period of at least 24 hours, (2) will not exhibit a substantial degree of fusions of liposomes over that same period, and (3) will not exhibit substantial redistribution of the carotenoid over that same period, including no substantial movement of the drug into the aqueous phase of a liposome, and no substantial state change into a crystalline form.
The molar ratio of carotenoid to lipid in the lipid carrier particles is greater than about 1:10, and is most preferably at least about 15:85. The intercalation promoter agent preferably comprises at least about 15% by weight of the composition, and can suitably be, for example, a triglyceride.
“Lipid carrier particles” is used here to include liposomes, having a bilayer structure formed of one or more lipids having polar heads and nonpolar tails, as well as micelles, amorphous particulates of lipid, and other lipid emulsion state entities. When the particles are liposomes, suitable forms include multilamellar liposomes.
The present invention also relates to a pharmaceutical unit dosage formulation of a carotenoid, which comprises a carotenoid, lipid carrier particles, an intercalation promoter agent, and a pharmaceutically acceptable carrier. As stated above, the carotenoid is substantially uniformly distributed with the lipid in the lipid carrier particles, and the composition is stable in an aqueous environment.
In another aspect, the invention relates to a method of inhibi
Hayman Alan C.
Hayman Katherine J.
Lenk Robert
Lopez-Berestein Gabriel
Mehta Kapil
Board of Regents , The University of Texas System
Fulbright & Jaworski L.L.P.
Hayman Katherine J.
Kishore Gollamudi S.
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