Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-18
2001-02-27
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S078000, C514S825000, C514S863000, C514S895000
Reexamination Certificate
active
06194401
ABSTRACT:
FIELD OF THE INVENTION
The following description sets forth new pharmaceutical compositions containing cyclosporine as active ingredient, combined with a carrier comprising an ester of &agr;-glycerophosphoric acid, esterified on the phosphoric group with a choline, serine, ethanolamine or inositol hydroxyl group, which allow cyclosporine bioavailability to be significantly increased.
The claimed compositions are useful for the curative and symptomatic treatment of human and animal diseases wherefor cyclosporine is efficacious, e.g. inflammatory—especially chronic—states, rejection of transplanted organs or bone marrow, autoimmune diseases, tumours immunotherapy, parasitosis.
Cyclosporines are compounds having a peptide-cyclic chemical structure. Among cyclosporines, cyclosporin A is not only therapeutically important, but also commercially significant due to its high cost.
From a therapeutic point of view, cyclosporin A has decisively contributed to the success of organs and bone marrow transplantations, by effectively fighting the so-called “rejection phase”, and proved to be particularly useful also for the treatment of autoimmune diseases, of some types of tumours and, in general, whenever a modulation of the immune system is required.
Lipid derivatives of glycerophosphorylcholine, glycerophosphoryl-ethanolamine, glycerophosphorylserine and glycerophosphoryl-inositol are widely distributed in nature combined in lecithins, cephalins, plasmalogens and phosphatidylserine (Remington's Sciences, Mack Publishing Ed., 18th Ed., 1990, p. 390).
L-&agr;-glycerophosphorylcholine, herein referred to as GPC and commonly known as choline “alfoscerate” is produced on a commercial scale by biochemical processes, generally starting from lecithin and especially from soybean lecithin, and is absolutely biocompatible and non-toxic. GPC is highly soluble in water, has a sweet and agreeable taste, and is commercially available in the anhydrous form as a highly hygroscopic powder, although it is preferably marketed in the monohydrate form as a stable syrupy liquid.
TECHNICAL PROBLEM
Treatment with cyclosporine is seriously limited by the markedly low bioavailability of the drug, especially when orally administered. For example, cyclosporine administered within a soft gelatin capsule is slowly and not completely absorbed, showing bioavailability ranges from 20% to 50% of the dose administered (Goodman & Gilman's, “The Pharmacological Basis of Therapeutics”, 9th Ed., p. 1299).
STATE OF THE ART
Several formulations have been investigated with a view to solving the problem of cyclosporine low availability. To this end, several compounds, either alone or as a mixture thereof, were used as carriers of the drug to improve its absorbability and bioavailability. For example, U.S. Pat. No. 5,342,625 describes compositions in the form of preconcentrated water-dispersible microemulsions, including cyclosporine, a lipophilic phase consisting of triglycerides of fatty acids, a hydrophilic phase consisting of polethylene glycol ethers, and surfactants, e.g. phospholipids (lecithins). However, the problem of cyclosporine bioavailability has never been satisfactorily solved, and also the treatment cost-benefits ratio is not satisfactory.
Furthermore, the various carriers cause several problems connected with their therapeutic use. For example, most compounds obtained by chemical synthesis are absolutely non-physiological or are not entirely physiological; others, exhibiting a non-negligible toxicity, may also increase the toxicity index of cyclosporine; some may contain even highly toxic impurities derived from the process of synthesis, or originate negative secondary reactions when metabolized (e.g. glycerides with fatty acids, transesterified oils, vegetable oils may undergo lipoperoxidation with consequent formation of “free radicals”, which are extremely noxious to cellular structures); some may easily cause gastric and intestinal intolerance and seriously irritate the mucous membranes and/or vascular walls (as is the case, e.g., of some carriers having surface-active, emulsifying surface-active, dispersing, solubilizing properties, etc.).
SUMMARY
The Applicant has now surprisingly found that by combining cyclosporine with a carrier including &agr;-glycerophosphorylcholine or other esters of &agr;-glycerophosphoric acid, e.g. &agr;-glycerophosphorylethanolamine, &agr;-glycerophosphorylserine, or &agr;-glycerophosphorylinositol, cyclosporine bioavailability is considerably improved.
It is, therefore, an object of the present invention to provide pharmaceutical compositions containing cyclosporine as active ingredient in a therapeutically effective dose, characterized in that they comprise a cyclosporine and at least an ester of &agr;-glycerophosphoric acid selected from the group consisting of &agr;-glycerophosphorylcholine, &agr;-glycerophosphorylethanolamine, &agr;-glycerophosphorylserine, &agr;-glycerophosphorylinositol, and salts or pharmaceutically acceptable complexes thereof.
In addition to the aforesaid carriers, the compositions of the present invention may optionally contain additional components, such as pharmaceutically acceptable excipients and/or diluents other than the aforesaid esters of &agr;-glycerophosphoric acid with choline, ethanolamine, serine or inositol.
It is a further object of the present invention to use the claimed formulations to treat the diseases for which cyclosporines are used.
REFERENCES:
patent: 4576930 (1986-03-01), Sugiyama et al.
patent: 4761407 (1988-08-01), Campan et al.
patent: 5342625 (1994-08-01), Hauer et al.
patent: 5547946 (1996-08-01), Molinari
patent: 0697214 (1996-02-01), None
Flarer S.A.
Weddington Kevin E.
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