| Pharmaceutical compositions of pyrimidine-2,4,6-triones -> Monitor Keywords |
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Pharmaceutical compositions of pyrimidine-2,4,6-trionesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos, Pyrimidines With Chalcogen Bonded Directly To A Ring Carbon Of Said Pyrimidine Moiety, Barbituric Acid Or Derivative (including Thioanalogs)Pharmaceutical compositions of pyrimidine-2,4,6-triones description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070191404, Pharmaceutical compositions of pyrimidine-2,4,6-triones. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The invention comprises a pharmaceutical composition of pyrimidine-2,4,6-triones (trioxopyrimidines), methods for the manufacture and uses thereof. [0002] Matrix metalloproteases (MMPs) are a family of zinc- and calcium-dependent proteases that are capable of degrading the extracellular matrix (ECM) and basement membrane (Egeblad, M., and Werb, Z., Nat. Rev. Cancer 2 (2002) 161-174; Overall, C. M., and Lopez-Otin, C., Nat. Rev. Cancer 2 (2002) 657-672). They are believed to have pivotal roles in embryonic development and growth (Holmbeck, K., et al., Cell 99 (1999) 81-92; Vu, T. H., et al., Cell 93 (1998) 411-422) as well as in tissue remodeling and repair (Shapiro, S. D., Curr. Opin. Cell Biol. 10 (1998) 602-608; Lund, L. R., et al., EMBO J. 18 (1999) 4645-4656). Excessive or inappropriate expression of MMPs may therefore contribute to the pathogenesis of many tissue-remodelling processes, including tumor progression (Egeblad, M., and Werb, Z., Nat. Rev. Cancer 2 (2002) 161-174; Overall, C. M., and Lopez-Otin, C., Nat. Rev. Cancer 2 (2002) 657-672) and aneurysm formation (Carmeliet, P., et al., Nat. Genet. 17 (1997) 439-444). MMP effects are far from being restricted to ECM degradation (Chang, C., and Werb, D., Trends Cell Biol. 11 (2001) S37-43). Peptide growth factors that are sequestered by ECM proteins become available once degraded by MMP-9 (Manes, S., et al., J. Biol. Chem. 274 (1999) 6935-6945). MMPs can increase the bioavailability of VEGF (Bergers, G., et al., Nat. Cell Biol. 2 (2000) 737-744) but also generate angiogenesis inhibitors such as angiostatin by cleavage of plasminogen (Dong, Z., et al., Cell 88 (1997) 801-810). MMPs are thought to be involved in the mobilization of bone marrow stem cells (Janowska-Wieczorek, A., et al., Blood 93 (1999) 3379-3390). High concentration of MMP9 was observed during the G-CSF induced HPC mobilization (Carstanjen, D., et al., Transfusion 42 (2002) 588-596). [0003] Trioxopyrimidines are compounds from a well-known structural class. Such compounds are described in, for example, U.S. Pat. Nos. 6,242,455 and 6,110,924; WO 97/23465; WO 98/58915; WO 01/25217, which are incorporated herein by reference, and Grams, F., et al., Biol. Chem. 382 (2001) 1277-1285, and are effective and highly selective for MMP-2, MMP-9 and MMP-14. [0004] Cyclodextrins are cyclic carbohydrates derived from starch. They differ from one another by the number of glucopyranose units in their structure. The parent cyclodextrins contain six, seven and eight glucopyranose units, and are referred to as alpha, beta and gamma cyclodextrins respectively. The .alpha.-, .beta.- or .gamma.-cyclodextrins prepared by enzymatic starch conversion differ in the diameter of their hydrophobic cavity and are generally suitable for the inclusion of numerous lipophilic substances. [0005] Trioxopyrimidines which are highly potent MMP inhibitors are only poorly soluble in water and water-based solvents. The object of the invention is therefore to provide an aqueous composition in which such a trioxopyrimidine is soluble and whereas such an aqueous composition of such a trioxopyrimidine can be used as a pharmaceutical composition. SUMMARY OF THE INVENTION [0006] It was surprisingly found that a trioxopyrimidine-cyclodextrin complex formed of a trioxopyrimidine derivative represented by the below-described formula (I) and a water-soluble cyclodextrin (further abbreviated as CD) exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent. [0007] It was furthermore found that such a trioxopyrimidine complex with cyclodextrin and an adjuvant such as L-lysine or L-arginine show improved water solubility and bioavailability, excellent stability, and low topical stimulation and is useful as a therapeutic agent. Accordingly, the present invention provides a trioxopyrimidine-cyclodextrin complex formed of a trioxopyrimidine derivative or a salt thereof and a cyclodextrin, preferably .alpha.-, .beta.- or .gamma.-cyclodextrin or a water-soluble cyclodextrin derivative (water-soluble being defined as a solubility of at least 0.5 gr/100 ml water at 25.degree. C.), wherein the trioxopyrimidine derivative is represented by formula (I). [0008] Furthermore the present invention provides a trioxopyrimidine-cyclodextrin complex formed of a trioxopyrimidine derivative represented by formula (I) or a salt thereof and a cyclodextrin, preferably .alpha., .beta.- or .gamma.-cyclodextrin or a water-soluble cyclodextrin derivative (water-soluble being defined as a solubility of at least 0.5 gr/100 ml water at 25.degree. C.), in the presence of an adjuvant such as L-lysine or L-arginine, preferably L-lysine. [0009] Such a complex according to the invention is an inclusion complex of trioxopyrimidine-cyclodextrin and is provided in a liquid or solid form. [0010] In the complex according to the present invention, preferably 1 mol of trioxopyrimidine is complexed and enclosed by about 1 mol to 2 mol of cyclodextrin, preferably of .beta.- or .gamma.-cyclodextrin or a derivative thereof. [0011] The present invention also provides a pharmaceutical agent for the treatment of a patient in the need thereof, referrably for the treatment of bronchial inflammatory diseases, containing a trioxopyrimidine-cyclodextrin complex according to the invention as an active component in a pharmaceutical effective amount. [0012] The pharmaceutical agent according to the invention is applicable therapeutically, prophylactically or preventively, to pathologies resulting from a very important or unsuitable MMP expression. Preferably such treatment is a therapeutic, prophylactic or preventive treatment of rheumatoid arthritis, tumors, metastatic invasion, osteoporosis, macular degeneration, diabetic retinopathies, ulcerations of the cornea, atherosclerosis, bronchial inflammatory diseases, bronchial inflammatory diseases such as asthma, chronic obstructive pulmonary disease or emphysema. [0013] The present invention also provides an injection formulation containing a trioxopyrimidine-cyclodextrin complex according to the invention in a pharmaceutically effective amount. [0014] A further object of this invention is a liquid aqueous formulation of a complex according to the invention, the pharmaceutically acceptable carrier is water, the composition to administrate being an aqueous solution. The active substance according to the invention is then in the complex state by inclusion in a cyclodextrin in solution in water. [0015] A further object of this invention is a liquid aqueous formulation of a complex according to the invention in the presence of L-Lysine (L-Lysine concentration between 10 mM and 1000 mM, preferably between 10 mM and 500 mM and more preferred between 10 mM and 100 mM) the pharmaceutically acceptable carrier is water, the composition to administrate being an aqueous solution. The active substance according to the invention is then in the complex state by inclusion in a cyclodextrin in solution in water in the presence of L-lysine. [0016] A further object of this invention is a complex according to the invention in a solid state, the complex is in the form of a powder dissolvable in water and to dissolve before administration or to administrate on its own. [0017] A further object of this invention is a complex included in different galenical forms according to the desired form of administration which can be tablets, capsules, multiparticulate systems, oral solutions, oral suspensions, solutions, suspensions, and implants for parenteral administration, solutions or powders for inhaling, hydrophilic or lipophilic type creams and ointments, aqueous or hydro-alcoholic gels, lotions, for topical, transcutaneous or vaginal use, intra-uterine devices, solutions, suspensions, implants, for ophthalmic use, suppositories, suspensions, sprays, solutions, and foams for rectal use. [0018] The present invention further provides use of such a pharmaceutical agent in a pharmaceutically effective amount for the treatment of such diseases in a patient suffering from such a disease, preferably bronchial inflammatory diseases. The complex according to the invention is preferably administrated at a topical, percutaneous, transdermal, oral or parenteral level. [0019] The present invention further provides a method for the manufacture of a pharmaceutical agent, preferably for the treatment of such diseases, preferably bronchial inflammatory diseases, characterized by complexing a trioxopyrimidine with cyclodextrin in a pharmaceutically effective amount in water or buffered aqueous solution preferably containing, in addition, an auxiliary substance, buffer, preservative, solvent and/or viscosity modulating agent. [0020] The preferred cyclodextrins are [0021] alpha-cyclodextrin and its synthetic derivatives such as HP.alpha.CD, methylated .alpha.CD, hydroxybutyl .alpha.CD, maltosyl .alpha.CD, glucosyl .alpha.CD. [0022] beta-cyclodextrin and its synthetic derivatives such as HP.beta.CD, SBE.beta.CD, RM.beta.CD, DIME.beta.CD, TRIME.beta.CD, hydroxybutyl .beta.CD, glucosyl .beta.CD, maltosyl .beta.CD. [0023] gamma-cyclodextrin and its synthetic derivatives such as HP.gamma.CD, RM.gamma.CD and DIME.gamma.CD, hydroxybutyl .gamma.CD, glucosyl .gamma.CD, maltosyl .gamma.CD. [0024] This invention also concerns use of a pharmaceutical composition including, in a therapeutically effective quantity, a pyrimidine-2,4,6-trione and at least one cyclodextrin, as well as possibly a pharmaceutically acceptable carrier, for the manufacture of a medicine for a therapeutic, prophylactic or preventive treatment of the above-mentioned illnesses. [0025] This invention also concerns use of a pharrmaceutical composition including, in a therapeutically effective quantity, a) a pyrimidine-2,4,6-trione, b) at least one cyclodextrin c) L-lysine or L-arginine, preferably L-lysine, as well as d) possibly a pharmaceutically acceptable carrier, for the manufacture of a medicine for a therapeutic, prophylactic or preventive treatment of the above-mentioned illnesses. DETAILED DESCRIPTION OF THE INVENTION Continue reading about Pharmaceutical compositions of pyrimidine-2,4,6-triones... Full patent description for Pharmaceutical compositions of pyrimidine-2,4,6-triones Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Pharmaceutical compositions of pyrimidine-2,4,6-triones patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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