Liquid Compositions of Insoluble Drugs and Preparation Methods Thereof

• US 20130156853A1
• Filed: 08/31/2011
• Published: 06/20/2013
• Est. Priority Date: 09/01/2010
• Status: Active Grant

• Current Assignee: Peking University
• Original Assignee: Peking University
• Inventors: Zhang, Qiang, Wang, Jiancheng, Zhang, Xuan, Dai, Wenbing
• Granted Patent: US 9,339,553 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

A liquid composition of an insoluble medicament and a preparation method thereof are disclosed. The composition includes insoluble medicament, oil for injection, phospholipid, and solvent; the percentage by weight of each component is as follows: insoluble medicament 0.01-10%, oil for injection 0%-20%, phospholipid 10-80%, solvent 20-89%. The preparation method for the composition includes the following steps: dissolving an insoluble medicament into solvent or oil for injection or a mixture thereof firstly, and then adding other components, and mixing uniformly; or dissolving an insoluble medicament into a mixture of other components, and mixing uniformly; or dissolving an insoluble medicament into part of solvent firstly, and then adding into a mixed solvent of other components and the remaining solvent, and mixing uniformly.

Claims

1. A liquid composition of an insoluble medicament, said liquid composition containing insoluble medicament, oil for injection, phospholipid, solvent, with the following percentage by weight for each component:

insoluble medicament 0.01-10%,

oil for injection 0%-20%,

phospholipid 10-80%,

solvent 20-89%.

2. The liquid composition of claim 1, wherein the percentage by weight for each component is as follows:

insoluble medicament 0.1-2.5%,

oil for injection 0.5%-10%,

phospholipid 20-45%,

solvent 42.5-79%.

3. The liquid composition of claim 1, wherein the insoluble medicament is selected from:

docetaxel, paclitaxel, capecitabine, oxaliplatin, gefitinib, doxorubicin, irinotecan, gemcitabine, pemetrexed, temozolomide, imatinib, vinorelbine, letrozole, teniposide, etoposide, podophyllotoxin, camptothecin, 10-hydroxycamptothecin, 9-hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin SN-38, topotecan, irinotecan, vinblastine, vincristine, vindesine, vinflunine, vinpocetine, norcantharidin, silibinin, propofol, florfenicol, mitiglinide, artemisinin, dihydroartemisinin, sirolimus, ibuprofen, nitrendipine, nicardipine, nimodipine, gliclazide, cisapride, nifedipine, felodipine, glibenclamide, acyclovir, oleanolic acid, breviscapine, ferulic acid, acetaminophen, clindamycin palmitate, penclomedine, Vitamin A, tamoxifen, navelbine, valproic acid, tacrolimus, ciclosporin A, amphotericin B, ketoconazole, domperidone, sulpiride, fenofibrate, bezafibrate, azithromycin, itraconazole, miconazole, brimoxidine, latanoprost, silibinin, erythromycin, roxithromycin, rifaximin, cisapride, cyclosporin, diclofenac, felodipine, ibuprofen, indomethacin, nicardipine, nifedipine, teldane, theophylline, ketoprofen, furosemide, spironolactone, dipyridamole, piroxicam, mefenamic acid, trichloromethiazide, indolol or a mixture thereof, preferably paclitaxel, docetaxel, capecitabine, vinorelbine, temozolomide, doxorubicin, gefitinib, tenipo side, etopo side, podophyllotoxin, artemisinin, camptothecin, vinblastine or a mixture thereof, more preferably paclitaxel, docetaxel, capecitabine, vinorelbine, temozolomide, doxorubicin, gefitinib, teniposide, etopo side, artemisinin, camptothecin or the mixture of paclitaxel and tenipo side.

4. The liquid composition of claim 1, wherein the phospholipid is selected from natural phospholipids, semisynthetic phospholipids, synthetic phospholipids or a mixture thereof.

5. The liquid composition of claim 4, wherein said natural phospholipids are lecithin, and said lecithin is preferably selected from egg yolk lecithin, soybean lecithin or a mixture thereof in any proportion.

6. The liquid composition of claim 4, wherein said semisynthetic phospholipids and synthetic phospholipids are selected form hydrogenated soybean phosphatidylcholine (HSPC), dioleoyl phosphatidylcholine (DOPC), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl phosphatidylserine (DMPS), distearyl pho sphatidylethanolamine (DSPE), dilauroyl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearyl phosphatidylcholine (DPPC), distearyl phosphatidylcholine (DSPC), 1-myristoyl-2-palmitoyl phosphatidylcholine (MPPC), the PEGylated derivates of the above phospholipids or a mixture of them, preferably hydrogenated soybean phosphatidylcholine and PEG-distearyl pho sphatidylethanolamine.

7. The liquid composition of claim 1, wherein said oil for injection is selected from one of or a mixture of some of soybean oil, corn oil, median chain triglyceride (MCT), castor oil, olive oil, peanut oil, cottonseed oil, sesame oil, safflower oil, glyceryl monostearate or glyceryl monooleate, preferably soybean oil, corn oil, median chain triglyceride or a mixture thereof.

8. The liquid composition of claim 1, wherein said solvent is selected from one of or a mixture of some of absolute ethanol, glycerol, propylene glycol, PEG, N,N-dimethyl acetamide, benzyl benzoate, ethyl oleate, benzyl alcohol.

9. The liquid composition of claim 8, wherein said solvent is absolute ethanol or a mixture of absolute ethanol and N,N-dimethyl acetamide, or a mixture of absolute ethanol and PEG, or a mixture of glycerol and N,N-dimethyl acetamide.

11. The liquid composition of claim 1, further containing pharmaceutically acceptable pharmaceutical additive(s).

12. The liquid composition of claim 11, wherein said pharmaceutical additive(s) include coemulsifier, stabilizing agent, pH regulator and antioxidant.

13. The liquid composition of claim 1, wherein said liquid composition is in an injectable concentrated solution form, which is formulated with an injectable solution before use, for injection;

or in a capsule, soft capsule or oral liquid formulation form.

14. The liquid composition of claim 13, wherein said injectable concentrated solution is dispersed with 5% dextrose solution or normal saline or water for injection or a mixture thereof during clinical use, to form a uniform hydration emulsion for intravenous injection.

16. A preparation method for the liquid composition of claim 1, characterized in that the insoluble medicament is dissolved into a solvent or an oil for injection or a mixture thereof, and then the phospholipid and other components in the liquid composition are added, and mixed uniformly to form the liquid composition;

or the insoluble medicament is dissolved into a mixture of solvent, oil for injection, phospholipid and other components in the liquid composition, and mixed uniformly to form the liquid composition;

or the insoluble medicament is dissolved into part of solvent firstly, and then added into a mixture of phospholipid, oil for injection, the remaining solvent and other components, and mixed uniformly to form the liquid composition.

17. The liquid composition of claim 2, wherein the insoluble medicament is selected from:

docetaxel, paclitaxel, capecitabine, oxaliplatin, gefitinib, doxorubicin, irinotecan, gemcitabine, pemetrexed, temozolomide, imatinib, vinorelbine, letrozole, teniposide, etoposide, podophyllotoxin, camptothecin, 10-hydroxycamptothecin, 9-hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin SN-38, topotecan, irinotecan, vinblastine, vincristine, vindesine, vinflunine, vinpocetine, norcantharidin, silibinin, propofol, florfenicol, mitiglinide, artemisinin, dihydroartemisinin, sirolimus, ibuprofen, nitrendipine, nicardipine, nimodipine, gliclazide, cisapride, nifedipine, felodipine, glibenclamide, acyclovir, oleanolic acid, breviscapine, ferulic acid, acetaminophen, clindamycin palmitate, penclomedine, Vitamin A, tamoxifen, navelbine, valproic acid, tacrolimus, ciclosporin A, amphotericin B, ketoconazole, domperidone, sulpiride, fenofibrate, bezafibrate, azithromycin, itraconazole, miconazole, brimoxidine, latanoprost, silibinin, erythromycin, roxithromycin, rifaximin, cisapride, cyclosporin, diclofenac, felodipine, ibuprofen, indomethacin, nicardipine, nifedipine, teldane, theophylline, ketoprofen, furosemide, spironolactone, dipyridamole, piroxicam, mefenamic acid, trichloromethiazide, indolol or a mixture thereof, preferably paclitaxel, docetaxel, capecitabine, vinorelbine, temozolomide, doxorubicin, gefitinib, teniposide, etoposide, podophyllotoxin, artemisinin, camptothecin, vinblastine or a mixture thereof, more preferably paclitaxel, docetaxel, capecitabine, vinorelbine, temozolomide, doxorubicin, gefitinib, teniposide, etoposide, artemisinin, camptothecin or the mixture of paclitaxel and teniposide.

18. The liquid composition of claim 2, wherein the phospholipid is selected from natural phospholipids, semisynthetic phospholipids, synthetic phospholipids or a mixture thereof.

19. The liquid composition of claim 2, wherein said oil for injection is selected from one of or a mixture of some of soybean oil, corn oil, median chain triglyceride (MCT), castor oil, olive oil, peanut oil, cottonseed oil, sesame oil, safflower oil, glyceryl monostearate or glyceryl monooleate, preferably soybean oil, corn oil, median chain triglyceride or a mixture thereof.

20. The liquid composition of claim 2, wherein said solvent is selected from one of or a mixture of some of absolute ethanol, glycerol, propylene glycol, PEG, N,N-dimethyl acetamide, benzyl benzoate, ethyl oleate, benzyl alcohol.

21. The liquid composition of claim 2, further containing pharmaceutically acceptable pharmaceutical additive(s).

22. The liquid composition of claim 2, wherein said liquid composition is in an injectable concentrated solution form, which is formulated with an injectable solution before use, for injection;

or in a capsule, soft capsule or oral liquid formulation form.

23. The liquid composition of claim 11, wherein said liquid composition is in an injectable concentrated solution form, which is formulated with an injectable solution before use, for injection;

or in a capsule, soft capsule or oral liquid formulation form.

24. The liquid composition of claim 21, wherein said liquid composition is in an injectable concentrated solution form, which is formulated with an injectable solution before use, for injection;

or in a capsule, soft capsule or oral liquid formulation form.

10. (canceled)

15. (canceled)