Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1998-12-10
2001-09-04
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S423000, C424S443000, C424S451000, C424S452000, C424S456000, C514S784000, C514S785000, C514S786000, C514S937000, C514S974000
Reexamination Certificate
active
06284268
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions containing an omega-3 fatty acid oil and a therapeutic agent. In particular, the present invention relates to the administration, particularly oral, of self-emulsifying microemulsion and emulsion preconcentrate formulations or microemulsions and emulsions which contain omega-3 fatty acid oil and a poorly water soluble therapeutic agent, for example, cyclosporin. Preferably, the omega-3 fatty acid oil and therapeutic agent exert an additive or synergistic therapeutic effect or the omega-3 fatty acid oil mediates the negative side effects of the therapeutic agent.
BACKGROUND OF THE INVENTION
Omega-3 fatty acid oils possess properties that can be used for numerous therapeutic advantages, including treatment of autoimmune and inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; immunosuppressive treatment; hypertension prophylaxis in normal humans and in heart transplant patients; coronary heart disease; hyperlipidemia; hypertriglyceridemia; improvement of renal function and nephrotoxicity reduction. U.S. Pat. No. 4,678,808 describes the use of these oils to treat disorders associated with arachidonic acid metabolites, including autoimmune syndromes, acute and chronic inflammatory diseases, atherosclerosis, stroke, myocardial infarction, deep vein thrombosis, surgery, hyperlipidaemic states, hypertension, enhanced platelet responsiveness, vascular lesions and occlusions, vascular spasm and diabetes. According to U.S. Pat. No. 5,225,441, which describes compositions for treating gingivitis and periodontitis, omega-3 polyunsaturated fatty acids compete with omega-6 polyunsaturated fatty acids as a substrate in the arachidonic acid cascade and can therefore alter the synthesis of prostaglandin and leukotrienes, both of which are powerful mediators of inflammation and immune response. Other uses of omega-3 fatty acid oils are described in U.S. Pat. No. 5,034,415 (diabetes mellitus), U.S. Pat. No. 4,843,095 (rheumatoid, arthritis), JP 2253629 (anticancer), U.S. Pat. No. 4,879,312 (enhancing angiogenesis), JP 1290625 (improvement of cerebral function), EP 378,824 (anti-cachexia, cholesterol and triglyceride levels reduction, platelet aggregation inhibition, colon adenocarcinomas growth inhibition), U.S. Pat. No. 5,457,130 (cancer cachexia, malignant tumors, abnormal cAMP levels in adipose tissue, lipolytic activity inhibition) and U.S. Pat. No. 5,436,269 (hepatitis).
Cyclosporins are an example of a class of drugs that is soluble in omega-3 fatty acid oil and capable of exerting an additive or synergistic therapeutic effect with the omega-3 fatty acid oil. Alternatively, the omega-3 fatty acid oil mediates the negative side effects, such as nephrotoxicity, of a cyclosporin such as cyclosporin A.
Cyclosporin A (CyA) is a lipophilic cyclic undecapeptide that can be isolated from the fungus
Tolypoclodium inflatum
Gams and which produces calcium dependent, specific and reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. Because of its immunosuppressive properties, it is widely used as first line therapy in the prophylaxis and treatment of transplant rejection (e.g., allo- or xeno-transplant rejection such as in patients receiving heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants) and various autoimmune and inflammatory diseases. CyA is used in the treatment of multi-drug resistance syndrome, for example in patients undergoing chemotherapy or following organ transplantations. In patients with severe disease refractory to standard treatment; CyA is an effective therapy in acute ocular Behcet's syndrome; endogenous uveitis; psoriasis; atopic dermatitis; arthritis, particularly rheumatoid arthritis; active Crohn's disease and nephrotic syndrome. Other conditions include arthritis chronica progrediente and arthritis deformans, autoimmune hematological disorders including hemolytic anemia, aplastic anemia, pure red-cell anemia and idiopathic thrombocytopenia, systemic lupus erythematosus, polychondroitis, scleroderma, Wegener granulamtosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-John syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, e.g., ulcerative colitis, endocrine ophthalmology, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, juvenile dermatitis, asthma, tumors, hyperproliferative skin disorders and fungal infections. This drug has also been used to treat patients with moderate or severe aplastic anemia who are ineligible for bone marrow transplantation and those with primary biliary cirrhosis. CyA may be effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. CyA is known to have a very specific effect on T-cell proliferation although the precise mechanism remains unclear. A number of non-immunosuppressive analogues of cyclosporin A have been shown to have resistance modifier activity and some are more potent than the parent compound. Nephrotoxicity, hepatotoxicity, hypertension, headache, hypertrichosis, gingival hyperplasia, neurological and gastrointestinal effects, thrombocytopenia and microangiopathic hemolytic anemia, hyperkalemia and hyperuricemia and development of skin and lymphoproliferative malignancies are the most common adverse events in cyclosporin recipients.
CyA and fish oils have been administered concurrently to organ transplant patients in various clinical trials. For instance, Andreassen et al. (JAAC, 29(6): 1324-31 (1997) reported effective hypertention prophylaxis in heart transplant patients who were given cyclosporin A and 4 g of fish oil. Cyclosporin A-treated and fish oil fed renal transplant recipients had improved renal function following a rejection episode (
Transplantation,
54:257 (1992)). U.S. Pat. No. 5,118,493 describes the administration of CyA together with an omega-3 fatty acid oil to mediate the nephrotoxic effects of the cyclosporin.
Certain oil mixtures of lipophilic drugs such as a cyclosporin with vegetable oils or other lipidic substances, surface active agents, solvents and other excipients are known to spontaneously produce dispersions of very low mean particle size (such as<200 nm) when mixed with an aqueous medium. These dispersions are known as microemulsions and the oily mixtures that produce the microemulsions are popularly referred to as microemulsion preconcentrates. Upon oral delivery, the microemulsion preconcentrates are thought to produce similar dispersions of very low particle size with gastric and other physiological fluids.
Cyclosporins are highly lipophilic, poorly water soluble and, therefore, have been supplied as an olive oil or peanut oil solution for clinical use. However, the bioavailability of cyclosporin from such oily solutions is very low and gives rise to great intersubject variation with reported systemic availability ranging from 4 to 25% (Takada, K. et al,
J. Pharmacobio-Dyn.,
11:80-7 (1988)). The bioavailability of cyclosporin has been reported to be dependent on food, bile and other interacting factors (
Clin. Pharmacokinetics,
24:472-95 (1993)). A widely used commercial formulation of CyA, SANDIMMUNE® for oral administration, is a solution of cyclosporin A in vegetable oil derivatives containing some other inactive excipients. Very high inter- and intra-patient and food dependent variability in the bioavailability of CyA has been observed from this formulation. The commercial microemulsion preconcentrate formulation, NEORAL®, has been claimed to provide high bioavailability for CyA with low inter-and intra-patient variability. However, risks of adverse drug reactions have been indicated on switching to Neoral® (see, e.g
Clarke Nuala
Mishra Awadhesh
Moussa Iskander
Ramtoola Zeibunissa
Cyclosporine Therapeutics Limited
Dann Dorfman Herrell and Skillman
Eland Stephen H.
Spear James M.
LandOfFree
Pharmaceutical compositions containing an omega-3 fatty acid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical compositions containing an omega-3 fatty acid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical compositions containing an omega-3 fatty acid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2547767