Patent EA-004700-B1 (EA)
Title: Pharmaceutical compositions containing plasma protein
Inventor: HEGEDUS LAJOS
IPC: A61K47/42
Filed: 1998-09-17
Abstract: 1. A water-soluble pharmaceutical product in a solid state and true aqueous solutions of said product comprising a) a therapeutically active substance having a low aqueous solubility of less than 1x10<-4> moles/litre and having a high binding affinity to a plasma protein - wherein the term "high binding affinity" means that more than 90% of the active substance is bound to the applied plasma protein in an aqueous medium in spontaneous equilibrium and room temperature; b) a plasma protein fraction in controlled aggregation state excluding undesirable protein aggregation, c) wherein said solid product comprises the therapeutically active substance and the plasma protein fraction bound to each other by way of noncovalent bonds, and d) wherein said true aqueous solution does not comprise any organic solvent and e) wherein molar ratio of active substance and plasma protein fraction ranges from 1:0.05 to 1:100 and a concentration of said active substance in the true aqueous solution corresponds to a therapeutically effective dose. 2. A solid state product and its aqueous solution according to claim 1, wherein the plasma protein fraction is human serum albumin, animal serum albumin, recombinant human serum albumin, recombinant animal serum albumin, gamma-globulin, and recombinant gamma-globulin. 3. A solid state product and its aqueous solution according to claims 1 or 2, wherein the active substance is cytostatic, antibiotic, a vitamin, an antiinflammatory, an analgesic, an antiviral, an anticonvulsant, an immunosuppressant, an antiepileptic, an anxiolytic, a hypnotic, an antifungal agent, an anticoagulant, a lipid peroxidase inhibitor, a coronary vasodilator, an anti-arrythmic agent, a cardio tonic, an uricosuric, an anti-thrombotic, a steroid hormone (progesterone, androgen, testogen) and a photosensitizer, and where a concentration of said in the aqueous solution corresponds to a therapeutically effective dose. 4. A solid state product and its aqueous solution according to any of claims 1-3, wherein at least one or more active substance is selected from the group consisting of amphotericin B, an adriamicine analogue, apazone, azathioprine, bromazepam, camptothecin, carbamazepine, clonazepam, cyclosporine A, diazepam, dicumarol, digitoxine, dipyridamole, disopyramide, flunitrazepam, gemfibrozil, ketochlorin, ketoconazole, miconazole, niflumic acid, oxazepam, phenobarbital, phenytoin, progesterol, propofol, ritonavir, sulfinpyrazone, suprofene, tacrolimus, tamoxifen, taxonoid, testosteron, tirilazad, trioxsalen, valproic acid, warfarin, or a combination thereof, and wherein the protein fraction is selected from the group consisting of human serum albumin, animal serum albumin, recombinant human serum albumin, recombinant animal serum albumin, gamma-globulin, and recombinant gamma-globulin and wherein a molar ratio of the active substance and protein fraction is within a range of 1 : 0.05 to 1 : 100 and a concentration of said active substance in the aqueous solution corresponds to a therapeutically effective dose. 5. A product according to any of claims 1-4 containing as a therapeutically active compound a taxonoid of the general formula wherein R<1> represents tertiary butyl-oxy-carboxylic acid amide or benzoyl amide, and R<2> represents hydrogen, and acyl or an acetyl group, preferably paclitaxel and wherein the protein fraction is selected from the group consisting of human serum albumin, animal serum albumin, recombinant human serum albumin, recombinant animal serum albumin, gamma-globulin, and recombinant gamma-globulin and wherein a molar ratio of the active substance and protein fraction is within a range of 1 : 0.05 to 1 : 100 and a concentration of said active substance in the aqueous solution corresponds to a therapeutically effective dose. 6. A homogeneous solid product comprising at least one of therapeutically active substance having low water solubility, of less than 1x10<-4> moles/litre, selected from the group comprising amphotericin B, an adriamicine analogue, apazone, azathioprine, bromazepam, camptothecin, carbamazepine, clonazepam, cyclosporine A, diazepam, dicumarol, digitoxine, dipyridamole, disopyramide, flunitrazepam, gemfibrozil, ketochlorin, ketoconazole, miconazole, niflumic acid, oxazepam, phenobarbital, phenytoin, progesteron, propofol, ritonavir, sulfinpyrazone, suprofene, tacrolimus, tamoxifen, taxonoid, testosteron, tirilazad, trioxsalen, valproic acid, warfarin, and at least one protein fraction selected from the group consisting of human serum albumin, animal serum albumin, recombinant human serum albumin, recombinant animal serum albumin, gamma-globulin, and recombinant gamma-globulin and wherein said solid product comprises the therapeutically active substance and the plasma protein fraction bound to each other by way of noncovalent bonds, and wherein molar ratio of active substance and plasma protein fraction ranges from 1:0.05 to 1:100 and a solubility in an aqueous solution is sufficient for a concentration corresponding to a therapeutically effective dose of the active substance. 7. A homogeneous solid product comprising at least one of therapeutically active substance having low water solubility, of less than 1x10<-4> moles/litre, selected from the group comprising amphotericin B, an adriamicine analogue, apazone, azathioprine, bromazepam, camptothecin, carbamazepine, clonazepam, cyclosporine A, diazepam, dicumarol, digitoxine, dipyridamole, disopyramide, flunitrazepam, gemfibrozil, ketochlorin, ketoconazole, miconazole, niflumic acid, oxazepam, phenobarbital, phenytoin, progesteron, propofol, ritonavir, sulfinpyrazone, suprofene, tacrolimus, tamoxifen, taxonoid, testosteron, tirilazad, trioxsalen, valproic acid, warfarin, and one protein fraction selected from the group consisting of glycoprotein, interferon, interleikin and said therapeutically active substance and the plasma protein fraction bound to each other by way of noncovalent bonds, and wherein molar ratio of active substance and plasma protein fraction ranges from 1:0.05 to 1:100 and a solubility in an aqueous solution is sufficient for a concentration corresponding to a therapeutically effective dose of the active substance. 8. A homogeneous solid water-soluble product according to claims 6 or 7, wherein molar ratio of therapeutically active substance and plasma protein fraction ranges from 1.0:0.1 to 1:50. 9. A homogeneous solid water-soluble product according to any of claims 6-8, wherein said therapeutically active substance represents a taxonoid of the general formula: wherein R<1> represents tertiary butyl-oxy-carboxylic acid amide or benzoyl amide, and R<2> represents hydrogen, and acyl or an acetyl group, preferably paclitaxel and wherein the protein fraction is selected from the group consisting of human serum albumin, animal serum albumin, recombinant human serum albumin, recombinant animal serum albumin, gamma-globulin, and recombinant gamma-globulin and wherein a molar ratio of the active substance and protein fraction is within a range of 1 : 0.05 to 1 : 100 and a concentration of said active substance in the aqueous solution corresponds to a therapeutically effective dose. 10. A product according to any of claims 1-9, wherein molar ratio of therapeutically active substance and plasma protein fraction ranges from 1.0:0.1 to 1:50. 11. A process for the preparation of a water-soluble product in solid state as defined in any of claims 1-10, the product having a water-solubility sufficient to ensure the concentration corresponding to the therapeutically effective dose of the active substance which comprises a) completely dissolving the therapeutically active substance in a water-miscible, pharmaceutically acceptable organic solvent to form an organic solvent solution, b) combining said organic solvent solution with an aqueous solution of a plasma protein fraction in controlled aggregation state, whereby a true aqueous solution is obtained containing the said active substance and the said protein fraction bound together by way of noncovalent bonds, c) removing the organic solvent and optionally lyophilising the true aqueous solution. 12. A process for the preparation of true, organic solvent-free aqueous solutions as defined in any of claims 1-10 substance, which comprises a) completely dissolving the therapeutically active substance in a water-miscible, pharmaceutically acceptable organic solvent to form an organic solvent solution, b) combining said organic solvent solution with an aqueous solution of a plasma protein fraction in controlled aggregation state, whereby a true aqueous solution is obtained containing the said active substance and the said protein fraction bound together by way of noncovalent bonds; c) removing the organic solvent and optionally lyophilising the solution, d) dissolving the obtained solid state product in organic solvent-free water whereby a clear, true aqueous solution, free of organic solvents is obtained where the concentration of said active substance corresponds to the therapeutically effective dose and which is suitable for therapeutical administration. 13. A process as defined in claim 12, which further comprises finishing the solution obtained into a parenteral dosage form. 14. A process as defined in any one of claims 11-13, wherein step a) is carried out with an organic solvent having the following properties: a) it is capable to completely dissolve the active substance in its mixture with water and b) its mixture with at least 50% of water does not denaturalize the protein. 15. A process according to claim 14, wherein the organic solvent is selected from any of the group consisting of an aliphatic C(2-4) monoalcohol or polyalcohol, 70-100% ethanol, dimethyl formamide, methyl formamide. 16. A process according to any of claims 11-15, wherein step a) is carried out with using as plasma protein a protein selected from the group consisting of serum albumin, immunoglobu