CN1925874A

CN1925874A - Compositions and methods of delivery of pharmacological agents

Info

Publication number: CN1925874A
Application number: CNA2003801096069A
Authority: CN
Inventors: N·P·德赛; A·杨; S·X·司; T·德; V·德留; P·宋祥; B·比尔斯·格里姆; 姚强
Original assignee: American Bioscience Inc
Current assignee: ABRAXIS BIOSCIENCE Inc; Abraxis Bioscience LLC
Priority date: 2002-12-09
Filing date: 2003-12-09
Publication date: 2007-03-07
Anticipated expiration: 2023-12-09
Also published as: CN1925874B; ZA200505380B

Abstract

The present invention relates to a pharmaceutical composition comprising a pharmaceutical agent and a pharmaceutically acceptable carrier, which carrier comprises a protein, for example, human serum albumin and/or deferoxamine. The human serum albumin is present in an amount effective to reduce one or more side effects associated with administration of the pharmaceutical composition. The invention also provides methods for reducing one or more side effects of administration of the pharmaceutical composition, methods for inhibiting microbial growth and oxidation in the pharmaceutical composition, and methods for enhancing transport and binding of a pharmaceutical agent to a cell.

Description

The method of compositions and transmission medicament

To CROSS-REFERENCE TO RELATED PATENT

The interests of the U.S. Provisional Patent Application 60/432,317 that present patent application requires to propose in 9th at December in 2002, the U.S. Provisional Patent Application (lawyer's number of putting on record 225519) that proposed in 3rd at December in 2003, the U.S. Provisional Patent Application (lawyer's number of putting on record 225549) that proposed in 4th at December in 2003 and the U.S. Provisional Patent Application (lawyer's number of putting on record 225585) that proposed in 5th at December in 2003.

Invention field

The present invention relates to be used for parenteral or other inner pharmaceutical compositions that uses, comprises pharmaceutically active agents, it has the effect of some undesirable side effects when being reduced in administration during with the similar pharmaceutical preparation comparison that can obtain.

Background of invention

Generally acknowledge many medicines, particularly those of intravenous administration that parenteral uses that are used for, cause undesirable side effects such as venous stimulation, phlebitis, burn feeling during injection and pain, venous thrombosis blends the relevant side effect of other administration outward.Many water insoluble in these medicines, therefore with solubilizing agent, surfactant, solvent and/or emulsifying agent preparation, these solubilizing agents, surfactant, solvent and/or emulsifying agent are irritating, allergic or deleterious (referring to for example when delivering medicine to the patient, Briggs etc., Anesthesis 37,1099 (1982), with Waugh etc., Am.J.Hosp.Pharmacists, 48,1520 (1991)).Often, be present in free drug induction pain or stimulation after administration in the preparation.For example, as late period nonsmall-cell lung cancer a linearize therapy accept among the patient of peripheral vein administration ifosfamide and vinorelbine, 50% among the patient observed phlebitis.(referring to for example Vallejo etc., Am.J.Clin.Oncol., 19 (6), 584-8 (1996)).In addition, shown that vancomycin induces side effect such as phlebitis (referring to for example, Lopes Rocha etc., Braz.J.Infect.Dis., 6 (4), 196-200 (2002)).In patients with solid tumor, use cisplatin, gemcitabine and SU5416 to cause adverse events such as degree of depth venous thrombosis and phlebitis (referring to for example, Kuenen etc., J.Clin.Oncol., 20 (6), 1657-67 (2002)).In addition, propofol (a kind of anesthetis) can induction pain in when injection, burn feeling and venous stimulation, particularly when as the stable lipomul administration of lecithin (referring to for example, Tan etc., Anathesia, 53,468-76, (1998)).Other shows that the medicine of administration related side effects for example comprises that taxol (paclitaxel) is (referring to for example, the package insert I.V. of taxol), codarone (Amiodarone Hydrochloride) is (referring to for example, the package insert of Codarone), thyroxin T3 or liothyronine (can be used as Triostat is purchased), plug is for group, bleomycin and diagnostic radiation contrast agent.

With relevant another problem of preparation injectable drug, particularly water-insoluble drug be guarantee aseptic.By before preparation, all components definitely being sterilized, then can finish the sterile preparation of pharmaceutical emulsion/dispersion by the absolutesterility technology in all preparatory phases.Yet these methods are consuming time and expensive.In addition, oxidation pharmaceutical preparation can cause the pH that for example reduces by being exposed to air at preparation or lay up period, and drug degradation, and variable color make pharmaceutical preparation unstable and/or reduced shelf-life thus.

For fear of the pharmaceutical preparation side effect relevant problem relevant, attempted displaced preparation with administration.For example about propofol, the method that reduces the inductive pain of propofol comprises the fat content (for example long chain triglycerides (LCT)) that increases solvent, and premedication is with the pretreatment of on-steroidal medicine, local anesthesia, opioid adds lignocaine, adds cyclodextrin, and microfiltration (referring to for example, Mayer etc., Anaesthesist, 45 (11), 1082-4 (1996), Davies, Deng Anaesthesia, 57,557-61 (2002), Doenicke, etc., Anaesth.Analg., 82,472-4 (1996), Larsen etc., Anaesthesitis, 50,842-5 (2001), Lilley etc., Anaesthesia, 51,815-8 (1996), Bielen etc., Anaesth.Analg., 80 (5), 920-4 (1996) and Knibbe etc., Br.J.Clin.Pharmacol., 47 (6), 653-60 (1999)).Yet these preparations are induced other side effect (for example cardiovascular complication) or are caused the instability of propofol formulations.

In order to overcome the problem of germ contamination, used antibacterial such as EDTA equivalent (as edetate), pentetate or contained the reagent exploitation propofol formulations of sulphite, perhaps with they with low pH preparation (referring to for example, United States Patent (USP) 5,714,520,5,731,355,5,731,356,6,028,108,6,100,302,6,147,122,6,177,477,6,399,087,6,469,069 and international patent application no WO 99/39696).Yet because edetate and pentetate are metal ion chelation agents, they have removes the ionic dangerous potentiality of essential metal from soma.In addition, sulphite is added pharmaceutical preparation and brought potential detrimental effect to pediatric population with among the general population of sulfur sensitive those.

Therefore, still need to reduce or the compositions and the method for the side effect that elimination is relevant with parenteral or vivo medicine-feeding medicine.Also need aseptic pharmaceutical composition and this method for compositions of preparation.In addition, need reduction or elimination pharmaceutical preparation oxidation to prevent unsettled pharmaceutical composition of medicine and method.

The invention provides these compositionss and method.These and other advantage of the present invention and other inventive features will become obvious here from the description of the invention that provides.

Summary of the invention

The invention provides the various embodiments of pharmaceutical composition.In the various embodiments one, some or all of performances can be found in the different embodiment of the present invention and still belong in the scope of appended claim.

The invention provides a kind of pharmaceutical composition that comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises protein such as albumin, more preferably human serum albumin, its amount effectively reduces one or more and pharmaceutical composition is delivered medicine to people's side effect, and wherein said pharmaceutical carrier comprises deferoxamine, and it measures the growth of microorganism in effective depressant compositions.The present invention also provides the pharmaceutical composition that comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises protein such as albumin, its amount effectively reduces one or more and pharmaceutical composition is delivered medicine to people's side effect, and wherein said pharmaceutical carrier comprises deferoxamine, and it measures the oxidation in effective depressant compositions.

The invention provides and reduce one or more and the method that pharmaceutical composition is delivered medicine to the relevant side effect of people, this method comprises (a) and comprises the pharmaceutical composition of medicament and pharmaceutical carrier to people's administration, and wherein said pharmaceutical carrier comprises albumin and deferoxamine.The present invention also is provided for suppressing growth of microorganism in pharmaceutical composition, or inhibited oxidation, or suppresses the method for growth of microorganism and oxidation.These methods comprise preparation and comprise the pharmaceutical composition of medicament and pharmaceutical carrier, and wherein said pharmaceutical carrier comprises deferoxamine with the amount of growth of microorganism in effective depressant compositions or with the amount of effective depressant compositions oxidation.

The present invention also is provided for strengthening the method for medicament to the transhipment of weak position, this method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to people's administration, wherein said pharmaceutical carrier comprises albumin, and wherein the ratio of the medicament in albumin and the pharmaceutical composition is about 18: 1 or littler.The present invention further provides and be used to strengthen medicament and the external or bonded method of cells in vivo, this method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to described external or cells in vivo administration, wherein said pharmaceutical carrier comprises albumin, and wherein the ratio of the medicament in albumin and the pharmaceutical composition is about 18: 1 or littler.

The present invention also provides the pharmaceutical composition that comprises medicament and pharmaceutical carrier, and wherein said pharmaceutical carrier comprises albumin with effective increase medicine to the amount of people's weak position transhipment, and wherein the ratio of albumin and medicament is about 18: 1 or littler.

The present invention further provides by with described medicament and the incompatible increase medicament of protein group to method external or the cells in vivo transhipment, specific cell surface receptor on the described cell of wherein said protein bound, the combination of wherein said protein-medicament causes the transhipment generation with combining of described receptor, and wherein the ratio of albumin and medicament is about 18: 1 or littler.

Detailed Description Of The Invention

The invention provides a kind of pharmaceutical composition that comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises protein such as albumin, preferred human serum albumin, its amount effectively reduces one or more and pharmaceutical composition is delivered medicine to people's side effect, and wherein said pharmaceutical carrier comprises deferoxamine, and it measures the growth of microorganism in effective depressant compositions.The present invention also provides the pharmaceutical composition that comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises protein such as albumin, its amount effectively reduces one or more and pharmaceutical composition is delivered medicine to people's side effect, and wherein said pharmaceutical carrier comprises deferoxamine, and it measures the oxidation in effective depressant compositions.

Any suitable medicament can be used for pharmaceutical composition of the present invention.Suitable medicament includes but not limited to anticarcinogen or antineoplastic agent, anti-microtubule agent, immunosuppressant, anesthetis, hormone, the medicament that is used for cardiovascular disorder, antiarrhythmics, antibiotic, antifungal, antihypertensive, antiasthmatic drug, analgesic, anti-inflammatory agent, arthritis agent, and vasoactive agent.The present invention is also effective with many other medicines classifications.More specifically, suitable medicament includes but not limited to taxanes, (for example taxol  (paclitaxel), and taxotere ^TM(docetaxel)), Epothilones (epothilones), camptothecine, colchicine, amiodarone, thyroid hormones, vasoactive peptide (for example vasoactive intestinal peptide), amphotericin, corticosteroid, propofol, melatonin, cyclosporin, rapamycin (sirolimus), tacrolimus, Mycophenolic Acid, ifosfamide, vinorelbine, vancomycin, gemcitabine, SU5416, plug is for sending bleomycin, diagnostic radiation contrast agent, and their derivant.The other medicines that can be used for the present composition are described in the United States Patent (USP) first of for example United States Patent (USP) 5,916,596 and common pending trial please number 09/446,783, and preferably, medicament is a propofol, paclitaxel, or docetaxel.More preferably, medicament is propofol or paclitaxel.Most preferably, medicament is a propofol.

Taxol ^(paclitaxel) (Bristol-Myers Squibb) has activity to ovarian cancer, breast carcinoma, pulmonary carcinoma, the esophageal carcinoma and head and neck cancer.Yet taxol has shown induces the toxicity relevant with administration, and significant acute and cumulative toxicity, and as bone marrow depression, neutrophilic granulocyte reduces heat pyrexia, anaphylaxis, and peripheral neuropathy.Because paclitaxel is insoluble in water, typically polyoxyethylene castor oil (cremophor) is used as solvent, need big volume infused and special conduit and filter.Polyoxyethylene castor oil is relevant with side effect, these side effect can be serious, comprise anaphylaxis and other anaphylactic reaction, this may require with corticosteroid, antihistamine and the pretreatment of H2 blocker (referring to for example, Gelderblom etc., Eur.J of Cancer, 37,1590-1598, (2001)).Taxotere ^TM(docetaxel) is used for the treatment of the breast carcinoma of anti-anthracycline, but also shown the side effect of induced hypersensitivity and fluid retention, and this may be serious.Also typically administration in polyoxyethylene castor oil of Epothilones (and derivant), and shown and induce serious neutrophilic granulocyte to reduce allergy and neuropathy.

Propofol (2, the 6-diisopropyl phenol) is hydrophobic, water-insoluble oil, is widely used as humans and animals was induced and kept to intravenous anesthetic general anesthesia and calmness.Propofol typically directly delivers medicine in the blood flow and passes through blood brain barrier.The pharmaceutical composition that comprises propofol must have enough fat-soluble with by this barrier with suppress the related mechanism of brain.Propofol is 1.0+/-0.02 μ M (referring to for example, Tonner etc., Anesthesiology, 77,926-931 (1992)) at 22.5 ℃ of maxima solubilities that have in water.Therefore, propofol is usually as the Emulsion preparation that contains solubilizing agent, surfactant, solvent, or as oil-in-water emulsion preparation (referring to for example, U.S. patent 6,150,423,6,326,406 and 6,362,234).Except active agents, compositions of the present invention also comprises pharmaceutical carrier or excipient.The selection of carrier is not necessarily crucial, and any carrier known in the art can be used for compositions.The selection of carrier is preferred partly to be determined with the concrete grammar that is used for the administration medicine compositions by the concrete position of pharmaceutical composition administration.Preferably, pharmaceutical carrier comprises protein.Can use any suitable protein.Suitable proteinic example includes but not limited to albumin, comprises the immunoglobulin of IgA, lipoprotein, apolipoprotein B, β-2-macroglobulin, Elityran etc.Most preferably, pharmaceutical carrier comprises albumin, most preferably the human serum albumin.Be suitable for of the present inventionly comprising that albuminised protein can be preparation natural origin or synthetic.

Human serum albumin (HSA) is the soluble globulin of height of Mr65K, is made up of 585 aminoacid.HSA is rich in protein and account for the 70-80% of human plasma colloid osmotic pressure in the blood plasma.The aminoacid sequence of HSA comprises 17 disulphide bridgeses altogether, free mercaptan (Cys 34) and single tryptophan (Trp 214).Vein use HSA solution to show to be used for prevention and treatment hypovolemic shock (referring to for example, Tullis, JAMA, 237,355-360,460-463, (1977)) and Houser etc., Surgery, Gynecology and Obstetrics, 150,811-816 (1980)) and exchange transfusion be used for the treatment of together the neonate hyperbilirubinemia (referring to for example, Finlayson, Seminars in Thrombosisand Hemostasis, 6,85-120, (1980)).

Human serum albumin (HSA) has a plurality of hydrophobic binding sites, and (8 at fatty acid altogether, the endogenic ligand of HSA) with in conjunction with various medicine, particularly neutral or electronegative hydrophobic compound (Goodman etc., The Pharmacological Basis of Therapeutics, the 9th edition, McGraw-Hill New York (1996)).Subdomain IIA and IIIA at HSA have proposed two high affinity combined sites, and they are the hydrophobic capsules that highly extend, and have charged lysine and arginine residues near surface, as the junction point of polar ligand feature (referring to for example, Fehske etc., Biochem.Pharmcol., 30,687-92 (1981), Vorum, Dan.Med.Bull., 46,379-99 (1999), Kragh-Hansen, Dan.Med.Bull., 1441,131-40 (1990), Curry etc., Nat.Struct.Biol., 5,827-35 (1998), Sugio etc., Protein.Eng., 12,439-46 (1999), He etc., Nature, 358,209-15 (1992), with Carter etc., Adv.Protein.Chem., 45,153-203 (1994)).Paclitaxel and propofol shown in conjunction with HSA (referring to for example, Paal etc., Eur.J.Biochem., 268 (7), 2187-91 (2001), Purcell etc., Biochim.Biophys.Acta, 1478 (1), 61-8 (2000), Altmayer etc., Arzneimittelforschung, 45,1053-6 (1995) and Garrido etc., Rev.Esp.Anestestiol.Reanim., 41,308-12 (1994)).In addition, docetaxel has shown in conjunction with human plasma protein fraction (referring to for example, Urien etc., Invest.NewDrugs, 14 (2), 147-51 (1996)).Therefore, although do not wish to be bound by any concrete theory, but think protein such as albumin are included in the reduction that causes the side effect relevant with the administration medicine compositions in the pharmaceutical composition of the present invention, this to small part be since the human serum albumin be present in compositions in the combining of any free drug.

The albuminised amount that is included in the pharmaceutical composition of the present invention will change according to the approach and the site of pharmaceutically active agents, other excipient and expection administration.Ideally, the albuminised amount that is included in the compositions is owing to effectively reduce the amount of the side effect of one or more active agents to people's administration pharmaceutical composition of the present invention.Typically, preparation of pharmaceutical compositions is become liquid form, then albumin is added in the solution.Preferably, the pharmaceutical composition of liquid form comprises the albumin of about 0.1 weight % to about 25 weight % (for example about 0.5 weight %, about 5 weight %, about 10 weight %, about 15 weight %, or about 20 weight %).Most preferably, the pharmaceutical composition of liquid form comprises the albumin of about 0.5 weight % to about 5 weight %.Pharmaceutical composition can be for example by lyophilizing, spray drying, fluid bed drying, wet granulation method and other proper method dehydration known in the art.When with solid form, when preparing compositions, preferably albumin is coated on active agents and other excipient (if existence) as solution by wet granulation method, fluid bed drying and other method well known by persons skilled in the art.HSA solution is preferably had an appointment 0.1 weight % to the albumin of about 25 weight % (about 0.5 weight %, about 5 weight %, about 10 weight %, about 15 weight %, or about 20 weight %).

Except albumin, compositions of the present invention preferably also comprises deferoxamine.Deferoxamine is the natural product that separates from Streptomyces pilous, can form iron complex.The deferoxamine mesylate that for example is used to inject USP by Food and Drug Administration's approval for iron chelating agent and be available for intramuscular, subcutaneous and intravenous administration.Deferoxamine mesylate USP is that white is to linen powder.Its soluble in water and its molecular weight is 656.79.The chemical name of deferoxamine mesylate is the amino amyl group of N-[5-[3-[(5-)-the hydroxyl amino formoxyl]-third-acylamino-] amyl group]-3[[5-((N-glycoloyl amino) amyl group]-carbamoyl] propionyl hydroxamic acid one mesylate (salt), its structural formula is C ₂₅H ₄₈N ₆O ₈CH ₃SO ₃H.As described in embodiment, free drug in its binding compositions is thought in growth of microorganism and oxidation in deferoxamine or its analog, derivant or salt (for example mesylate) the depressant compositions.Deferoxamine also shows in conjunction with phenolic compound (referring to for example, Juven etc., J.Appl.Bacteriol., 76 (6), 626-31 (1994)).Paclitaxel, docetaxel, propofol etc. or similar phenol or have phenol or phenyl substituent.Therefore, think that deferoxamine can be in conjunction with the amount of the free drug in free drug in the pharmaceutical composition of the present invention or the minimizing pharmaceutical composition of the present invention, stimulation or pain when also having reduced or having alleviated injection thus.

The amount that is included in deferoxamine in the compositions or its preferred salt (being the mesylate of deferoxamine) will depend on active agents and other excipient.Ideally, the amount of deferoxamine, its salt and analog thereof is effectively to suppress the amount of growth of microorganism and/or inhibited oxidation in compositions.As mentioned above, typically pharmaceutical composition prepares with liquid form, then deferoxamine and analog thereof is added with the solution form.Preferably, the pharmaceutical composition of liquid form comprises deferoxamine, its salt or its analog of about 0.0001 weight % to about 0.5 weight % (for example, about 0.005 weight %, about 0.1 weight %, or about 0.25 weight %).More preferably, the compositions of liquid form comprises the preferred de-iron amine salt of similar quantity, deferoxamine mesylate.More preferably, the pharmaceutical composition of liquid form comprises the deferoxamine mesylate of about 0.1 weight %.When with solid form, as mentioned above, when preparing compositions, preferably deferoxamine mesylate is added active agents and other excipient (if existence) as solution by wet granulation method, fluid bed drying and other method well known by persons skilled in the art.Deferoxamine mesylate solution is preferably had an appointment 0.0001 weight % to the deferoxamine of about 0.5 weight % (for example, about 0.005 weight %, about 0.1 weight %, or about 0.25 weight %).

Consistent with the present invention, pharmaceutical composition can comprise other medicament, and excipient or stabilizing agent are to improve the performance of compositions.For example, for the negative zeta potential that drips by increase nanoparticle or nanometer increases stability, can add some electronegative component.These electronegative components include but not limited to the bile salts of bile acid, described bile acid is made up of following: glycocholic acid, cholic acid, chenodeoxy cholic acid, taurocholic acid, sweet chenodeoxy cholic acid (glycochenodeoxycholic acid), cattle sulphur chenodeoxy cholic acid (taurochenodeoxycholic acid), lithocholic acid, ursodesoxycholic acid (ursodeoxycholic acid), dehydrocholic acid and other; Phospholipid; comprise the basic phospholipid of lecithin (egg yolk); the basic phospholipid of this lecithin (egg yolk) comprises following phosphatidylcholine: palmityl oleoyl phosphatidylcholine; the inferior oleoyl phosphatidylcholine of palmityl; the inferior oleoyl phosphatidylcholine of stearoyl; stearoyl oleoyl phosphatidylcholine, stearoyl arachidonic phosphatidyl choline, and dipalmitoyl phosphatidyl choline.Other phospholipid comprises L-α-dimyristoyl phosphatidyl choline (DMPC); dioleoyl phospholipid phatidylcholine (DOPC); distearoyl phosphatidylcholine (DSPC); hydrogenated soya phosphatide phatidylcholine (HSPC); D-α-phosphatidylcholine; β-acetyl group-γ-O-cetyl; L-α-phosphatidylcholine, β-acetyl group-γ-O-cetyl, DL-α-phosphatidylcholine; β-acetyl group-γ-O-cetyl; L-α-phosphatidylcholine, β-acetyl group-γ-O-octadecyl, L-α-phosphatidylcholine; β-arachidonic acyl-γ-O-cetyl; L-α-phosphatidylcholine, β-acetyl group-γ-O-(Linolenic Acid-suitable-thiazolinyl), D-α-phosphatidylcholine; β-arachidonic acyl-γ-O-palmityl; the 3-sn-phosphatidylcholine, 2-arachidonic acyl-1-stearoyl, L-α-phosphatidylcholine; β-arachidonic acyl-γ-stearoyl; L-α-phosphatidylcholine, two Semen arachidis hypogaeae tetraene acyls, L-α-phosphatidylcholine; two (behenolyls); L-α-phosphatidylcholine, β-(suitable-8,11; 14-20 carbon triolefin acyls)-γ-O-cetyl; L-α-phosphatidylcholine, beta-oil acyl-γ-myristoyl, L-α-phosphatidylcholine; β-(pyrene-1-yl) capryl-γ-palmityl; 3-sn-phosphatidyl-N, N-dimethylethanolamine, 1; 2-two palmityls; L-α-PHOSPHATIDYL ETHANOLAMINE, two (heptadecanoyls), 3-sn-PHOSPHATIDYL ETHANOLAMINE; 1; 2-two lauroyl, 3-sn-PHOSPHATIDYL ETHANOLAMINE, 1; 2-two myristoyls; the 3-sn-PHOSPHATIDYL ETHANOLAMINE, 1,2-two oleoyls; the 3-sn-PHOSPHATIDYL ETHANOLAMINE; 1,2-two palmityls, L-α-PHOSPHATIDYL ETHANOLAMINE; two palmityls; L-α-PHOSPHATIDYL ETHANOLAMINE, two palmityls, N-dansyl; L-α-PHOSPHATIDYL ETHANOLAMINE; two palmityls, N, N-dimethyl; L-α-GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (sodium salt) (DMPG); two palmityl phosphatidyl glycerols (sodium salt) (DPPG), distearyl phosphatidyl glycerol (sodium salt) (DSPG), N-(carbonyl-methoxy poly (ethylene glycol) 2000)-1; 2-distearyl-sn-glycerol-3-phosphate ethanolamine sodium (MPEG-DSPE); L-α-phosphatidic acid, two capryl sodium salts, L-α-phosphatidic acid; two (17 phosphinylidyne) sodium salt; the 3-sn-phosphatidic acid, 1,2-two myristoyl sodium salts; L-α-phosphatidic acid; two caprylyl sodium salts, L-α-phosphatidic acid, two oleoyl sodium salts; L-α-phosphatidic acid; two palmityl sodium salts, L-α-phosphatidyl-DL-glycerol, two myristoyl sodium salts; L-α-phosphatidyl-DL-glycerol; two oleoyl sodium salts, L-α-phosphatidyl-DL-glycerol, two palmityl ammonium salts; L-α-phosphatidyl-DL-glycerol; the distearyl ammonium salt, L-α-phosphatidyl-DL-glycerol, beta-oil acyl-γ-palmityl ammonium salt; L-α-phosphatidylinositols ammonium salt; L-α-phosphatidyl-4 sodium alkoxide, L-α-phosphatidyl-L-serine, two oleoyl sodium salts; L-α-phosphatidyl-L-serine and two palmityl sodium salts.The surfactant of electronegative emulsifying agent also is suitable as additive, for example cholesteryl sodium sulfate etc.

Medicament (for example propofol) can use separately or be dissolved in the immiscible solvent of water.Can use immiscible solvent of various water such as soybean oil, safflower oil, Oleum Gossypii semen, Semen Maydis oil, Oleum helianthi, Oleum Arachidis hypogaeae semen, Oleum Ricini, olive oil.Preferred oil is vegetable oil, wherein soybean oil most preferably.Soybean oil can use in the 1%-10% of composition weight scope.Preferred soybean oil is present in the compositions with the amount of about 3 weight %.

Pharmaceutical composition of the present invention can be stable with medicinal surfactant.Term used herein " surfactant " is meant amphiphilic surface active groups.Surfactant can be anionic, and is cationic, nonionic and amphoteric ion type.Any suitable surfactant can be included in the pharmaceutical composition of the present invention.Suitable surfactant comprises nonionic surfactant such as phospholipid, polyoxyethylene sorbitan ester and tocopherol polyoxyethylene succinate.Preferred surfactants is a lecithin, Tween 80 and vitamin E-t d-alpha-tocopherol polyoxyethylene-1000 succinate (TPGS).For the preparation that contains soybean oil, preferably lecithin and be no more than 1.2 weight % of compositions, preferred 1.1 weight % for the preparation that contains 3% soybean oil.For the preparation that does not contain soybean oil, Tween 80 or vitamin E-TPGS are preferred surfactants.The typical case, vitamin E-TPGS of the Tween 80 of 0.1-1.5 weight % or 0.5-4 weight % is suitable.Preferably, use the Tween 80 of 1.5 weight % or vitamin E-TPGS of 1 weight %.The case description of other suitable surfactant is in for example Becher, Emulsions:Theory and Practice, and Robert E.KriegerPublishing, Malabar is among the Fla. (1965).

The suitable preparation (referring to for example, U.S. patent 5,916,596) that has various pharmaceutical compositions of the present invention.Following series preparation and method only are exemplary and restrictive absolutely not.The preparation that is suitable for oral administration can be made up of the following: (a) liquid solution, the chemical compound in the diluent of being dissolved in as effective dose, described diluent such as water, saline or orange juice, (b) capsule, sachet or tablet, contain separately scheduled volume as solid or particulate active component, (c) suspensoid in suitable liquid and (d) suitable Emulsion.Tablet form can comprise one or more lactose, mannitol, corn starch, potato starch, microcrystalline Cellulose, arabic gum, gelatin, silica sol, cross-linking sodium carboxymethyl cellulose, Talcum, magnesium stearate, stearic acid and other excipient, coloring agent, diluent, buffer agent, wetting agent, antiseptic, flavoring agent and pharmaceutically-compatible excipient.Lozenge form can comprise active component in flavoring agent, described flavoring agent is generally sucrose and arabic gum or Tragacanth, and the lozenge that in inert base, comprises active component, described inert base such as gelatin and glycerol, or sucrose and arabic gum, except active component, also contain Emulsion such as excipient known in the art, gel etc.

The preparation that is suitable for parenteral comprises aqueous and nonaqueous isotonic sterile injection liquid, it can contain antioxidant, buffer agent, antibacterial, with make preparation and expectation receiver the isoosmotic solute of blood and can comprise the aqueous and the nonaqueous aseptic suspensoid of suspending agent, solubilizing agent, thickening agent, stabilizing agent and antiseptic.Preparation can provide with the container of unit dose or multiple dose sealing, cuts open and bottle as peace, and can be stored under lyophilization (lyophilizing) condition, and this only requires before using at once and add the sterile liquid excipient that for example water is so that injection.Interim injection and suspensoid can be from sterilized powder, granule and the preparation tablets of aforesaid kind.Preferred ejection preparation.

The preparation that is suitable for the aerosol administration comprises pharmaceutical composition of the present invention, it comprises the aqueous that can contain antioxidant, buffer agent, antibacterial and solute and the sterile solution that oozes such as nonaqueous, and the aqueous and the non-aqueous aseptic suspensoid that can comprise suspending agent, solubilizing agent, thickening agent, stabilizing agent and antiseptic, these components separately or with other suitable combination of components, can be prepared into aerosol preparations to pass through inhalation.These aerosol preparations can be put into the acceptable propellant of pressurization, described propellant such as dichlorodifluoromethane, propane, nitrogen etc.They can also be mixed with the medicine that is used for non-pressurised preparation, as in aerosol apparatus or nebulizer.

Other appropriate formulations is possible, for example can prepare suppository as emulsifying base or water-insoluble substrate by using various substrate (base).The preparation that is suitable for vagina administration can be provided as vaginal suppository, tampon, and ointment, gel, paste, foam, or spray preparation, it also contains except active component such as suitable carrier known in the art.

In a preferred embodiment of the invention, pharmaceutical composition is mixed with the pH with 4.5-9.0, more preferably the pH of 5.0-8.0.Can also make pharmaceutical composition and blood etc. ooze by adding suitable Osmolyte regulator such as glycerol.In addition, pharmaceutical carrier preferably also contains water or the water for injection that does not contain pyrogen, USP.Preferably, pharmaceutical composition of the present invention is prepared to the sterile aqueous preparation, nanoparticle, oil-in-water emulsion, or water-in-oil emulsion.Most preferably, pharmaceutical composition is an oil-in-water emulsion.

According to the present invention, for the pharmaceutical composition that comprises propofol, can be by propofol being dissolved in the immiscible solvent of water separately and preparing the water that contains albumin, deferoxamine, surfactant and other water soluble ingredient, with the oil oil-in-water emulsion for preparing mixed with water.Rough Emulsion is 10,000 to 25, and a high pressure homogenize and a recirculation 5-20 cycle are to form ideal Emulsion under the pressure of 000psi.Preferred pressure is 15,000 to 20,000psi, more preferably 10,000psi.Rough Emulsion can a recirculation 7-15 cycle and preferred 15 cycles of recirculation.Alternatively, can use branch open walk by homogenizer.

Preferably, pharmaceutical composition of the present invention can contain granule or the drop of size less than about 200 nanometers (nm).For example, at paclitaxel, docetaxel, rapamycin, cyclosporin, in propofol and other the situation, the average-size of these dispersions is less than 200nm.

The present invention provides in addition and reduces one or more and method to the relevant side effect of people's administration medicine compositions.This method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to people's administration, and wherein said pharmaceutical carrier comprises albumin and deferoxamine.Above pharmaceutical composition, medicament and pharmaceutical carrier and the description of composition those identical aspects of also being applicable to the inventive method thereof in conjunction with pharmaceutical composition of the present invention statement.

In the context of the invention, the dosage that pharmaceutical composition of the present invention delivers medicine to the people will change along with concrete pharmaceutical composition, medication and the concrete position of being treated.This dosage should be enough to realize expected response that in the expected time scope as treatment or the prophylactic response to specified disease, perhaps anesthesia is reacted when medicament is anesthetis such as propofol.

Although any suitable mode to people's administration medicine compositions can be used for the context of the invention, preferably pharmaceutical composition of the present invention is delivered medicine to the people by administration in intravenous administration, intra-arterial administration, feeding drug into pulmones, oral administration, suction, intravesical administration, intramuscular administration, the trachea, subcutaneous administration, eye drops, intrathecal drug delivery or transdermal administration.For example, pharmaceutical composition of the present invention can be by inhalation with the treatment respiratory passage diseases.With the relevant side effect minimum of suction pharmaceutical composition of the present invention, because albumin is the natural component of respiratory tract internal layer and secretions.The present composition can be used for the treatment of respiratory passage diseases such as pulmonary fibrosis, bronchiolitis obliterans, pulmonary carcinoma, bronchovesicular cancer etc.

Method of the present invention causes and reducing to one or more relevant side effect of people's administration medicine compositions.These side effect for example comprise, bone marrow depression, neurotoxicity, allergy, inflammation, venous stimulation, phlebitis, pain, skin irritation, and combination.Yet these side effect only are exemplary, and the new compositions of the application of the invention can reduce or avoid other side effect or the side effect combination relevant with various medicaments with method.

The present invention provides the method for growth of microorganism in the depressant compositions in addition." inhibition growth of microorganism " is meant and eliminates microorganism fully from pharmaceutical composition, or reduce the amount or the speed of growth of microorganism in the pharmaceutical composition.This method comprises the pharmaceutical composition that preparation comprises medicament and pharmaceutical carrier, and wherein said pharmaceutical carrier comprises deferoxamine, its salt, its analog, and combination, the growth of microorganism in the effective depressant compositions of their amount.In addition, the invention provides the method for depressant compositions oxidation.This method comprises the pharmaceutical composition that preparation comprises medicament and pharmaceutical carrier, and wherein said pharmaceutical carrier comprises deferoxamine, its salt, its analog, and combination, the oxidation of the effective depressant compositions of their amount.The description of above pharmaceutical composition, medicament and pharmaceutical carrier of illustrating in conjunction with pharmaceutical composition of the present invention and component thereof also is applicable to those identical aspects of the inventive method.

Be included in the deferoxamine in the compositions, or the amount of its preferred salt (mesylate of deferoxamine) will depend on active agents and other excipient.Ideally, deferoxamine in the compositions, its salt, the amount of its analog is effectively to suppress the amount of growth of microorganism and/or inhibited oxidation.As mentioned above, typically, pharmaceutical composition prepares with liquid form, and then with deferoxamine, its salt and its analog are added in the solution.Preferably, the pharmaceutical composition of liquid form comprises the deferoxamine of about 0.0001 weight % to about 0.5 weight % (for example about 0.005 weight %, about 0.1 weight % or about 0.25 weight %), its salt, or its analog.More preferably, the compositions of liquid form comprises the preferred de-iron amine salt of similar quantity, deferoxamine mesylate.Most preferably, the pharmaceutical composition of liquid form comprises the deferoxamine mesylate of about 0.5 weight %.When compositions prepares with solid form, as mentioned above, when preparing compositions, preferably deferoxamine mesylate is coated to active agents and other excipient (if existence) as solution by wet granulation method, fluid bed drying and other method well known by persons skilled in the art.Deferoxamine mesylate solution preferably has the deferoxamine of about 0.0001 weight % to about 0.5 weight % (for example about 0.005 weight %, about 0.1 weight % or about 0.25 weight %).

The present invention also is provided for strengthening the method for medicament to the transhipment of weak position, this method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to people's administration, wherein said pharmaceutical carrier comprises albumin, and wherein in the pharmaceutical composition ratio of albumin and medicament be about 18: 1 or littler.The present invention further provides and be used to strengthen medicament and the external or bonded method of cells in vivo, this method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to described external or cells in vivo administration, wherein said pharmaceutical carrier comprises albumin, and wherein in the pharmaceutical composition ratio of albumin and medicament be about 18: 1 or littler.The description of above pharmaceutical composition, medicament, pharmaceutical carrier, route of administration and the component of illustrating in conjunction with pharmaceutical composition of the present invention and the inventive method thereof also is applicable to those identical aspects of transhipment and associated methods.

Medicament is transitted to weak position or is used to strengthen medicament and the bonded method of cell being used for, pharmaceutical carrier preferably comprises albumin, most preferably human serum albumin.Be not bound by any concrete theory, think protein for example the ratio of the medicament in human serum albumin and the pharmaceutical composition influence medicament and bonded ability of cell and the cytotropic transhipment of medicament.In this, the higher rate of protein and medicament combines with the cell of the medicament of difference usually and transports relevantly, and this may be the result that receptor is competed on cell surface.Protein for example albumin must be to make capacity medicament medicament combine or be transported to cell with cell with the ratio of active agents.The exemplary scope of protein-pharmaceutical preparation is that protein and medicine ratio (w/w) are 0.01: 1 to about 100: 1.More preferably, ratio is 0.02: 1 to about 40: 1.Although the ratio of protein and medicament must be to different protein and medicament Combinatorial Optimization, usually protein for example the ratio of albumin and medicament be about 18: 1 or littler (for example about 15: 1, about 10: 1, about 5: 1, or about 3: 1).More preferably, ratio is about 0.2: 1 to about 12: 1.Most preferably, ratio is about 1: 1 to about 9: 1.Preferably, preparation is substantially free of polyoxyethylene castor oil, does not more preferably contain polyoxyethylene castor oil EL ^(BASF).Polyoxyethylene castor oil EL ^Being nonionic emulsifier, is as Oleum Ricini and polyoxyethylated polyethers.As mentioned above, polyoxyethylene castor oil by typically as the solvent of paclitaxel, and with may be serious adverse relevant (referring to for example, Gelderblom etc., above).

Medicament can be any suitable medicament described herein (for example, propofol, a paclitaxel, or docetaxel).In addition, medicament can be nucleotide sequence, most preferably DNA sequence.This respect, pharmaceutical composition of the present invention can be transported gene delivery to cell by receptor-mediated/cave, chamber (caveolar)/capsule.For with DNA sequence such as gene or other hereditary material, include but not limited to plasmid or c-DNA, in the transporte to cells (for example endotheliocyte or tumor cell), can prepare and comprise the pharmaceutical composition of albumin in conjunction with hereditary material.Because have proteinic high picked-up, preferably hereditary material is sucked in these cell types and can be incorporated in the hereditary material of cell to reach effective therapeutic effect at the tumor cell of inflammation part and other cell.Protein such as human serum please proteic use work to do the non-virus carrier of transmission hereditary material and the disease relevant with virus or the risk of side effect.For example, can prepare the pharmaceutical composition that comprises coding beta-galactosidase or green fluorescent protein (GFP) and albuminised nucleotide sequence, and with derive from human umbilical vein or the microvascular endotheliocyte of people's lung contacts, to promote that nucleotide sequence is incorporated in the endotheliocyte.The integration of nucleotide sequence can use methods known in the art to detect, as for example fluorescence or dyeing.

Be used for strengthening the method for medicament to the transhipment of weak position in the present invention, weakness can be any suitable disease or disease.Preferably, weakness is a cancer, cardiovascular disease, or arthritis.

Be used for strengthening medicament and the external or bonded method of cells in vivo in the present invention, deliver medicine to external pharmaceutical composition or cells in vivo.Ideally, cell is a zooblast.More preferably, cell is a mammalian cell, and most preferably, cell is people's cell.Preferably pharmaceutical composition is delivered medicine to cells in vivo.Cell can be as any suitable cell of the desired target target of administration medicine compositions.For example, cell can be positioned at or derive from the digestive system tissue, comprises for example esophagus, stomach, small intestinal, colon, rectum, anus, liver, gallbladder, and pancreas.Cell can also be positioned at or derive from the respiratory system tissue, comprises for example larynx, lung, and bronchus.Cell can be positioned at or derive from the cervix uteri of for example forming the sex reproductive system, body of uterus, ovary hole, vagina, prostate, testis, and the bladder of penis and composition urinary system, kidney, renal pelvis, and ureter.Cell can be positioned at or derive from the tissue of cardiovascular system, comprises for example endotheliocyte and myocardial cell.Cell can also be positioned at or derive from lymphoid tissue (for example lymphocyte), nervous system (for example neuron or neurogliocyte), and hormonal system (for example thyroid cell).Preferably, cell is positioned at or derives from the tissue of cardiovascular system.Most preferably, cell is an endotheliocyte.Be used for strengthening the content of transhipment and medicament and the bonded method of cell in the present invention, pharmaceutical composition contacts ideally more than a kind of cell.

In another aspect of this invention, the present invention is used for strengthening transhipment and enhancing medicament and the bonded method of cell and can be used for the treatment of tumor cell.Compare with normal cell, tumor cell shows enhanced protein uptake, and this protein comprises albumin and transferrins.Because tumor cell divides fast, so compare with normal cell, they require more source of nutrition.The tumor research that the present invention contains paclitaxel and human serum albumin's pharmaceutical composition shows the height picked-up of tumor to albumin-paclitaxel.Have been found that this is that these glycoprotein 60 receptors are specific for albumin owing to the phenomenon of albumin-transport of drug of passing through glycoprotein 60 (" gp60 ") receptor of not recognizing in the past.

Therefore, according to another aspect of the present invention, other protein transport receptor that exists on specific gp60 receptor of albumin and the tumor cell can be as the target that suppresses tumor growth.Antibody by using anti-gp60 receptor or in conjunction with other big or micromolecular compound blocking-up gp60 receptor of, blocking-up or inactivation gp60, with blocking-up other protein transport receptor on tumor cell or tumor endothelial cell, can blocking protein to the transhipment of these cells, reduce their growth rate thus and cause cell death.Therefore, the blocking-up of this mechanism causes suffering from the patient's (for example people) of cancer or other disease treatment.Blocking-up/combination of identifying the differential protein receptor is any amount of at the chemical compound of isolating gp60 or other receptor such as gp16 or gp30 or by using full cell preparation to finish by screening.In addition, appropriate animal model also can be used for this purpose, as for example containing coding gp60 or caveolin-1 or " knocking out " mice that suddenlys change for other special proteic gene of transhipment.Therefore, identify blocking-up or in conjunction with gp60, gp16, the method for the chemical compound of gp30 or other protein receptor belongs in the scope of the present invention.

In addition, blocking-up or can be used for the treatment of the several conditions that comprises cancer in conjunction with the chemical compound of gp60 receptor or other protein receptor.About treatment for cancer, blocking-up or binding compounds can combine as single medicament or with other standard chemotherapy or multiple chemotherapy.For example, it and conventional chemotherapy or with albumin of the present invention-medication medication compositions (it shows high accumulation in tumor), then be used for the treatment of cancer to the chemical compound of tumor cell transhipment with blocking protein.Blocking compound can be before other chemotherapy or anticarcinogen or in conjunction with administration.Therefore, anyly can block or belong in the scope of the present invention in conjunction with the chemical compound of gp60 receptor or other protein receptor.

Albumin-pharmaceutical composition of the present invention, as for example albumin-paclitaxel, albumin-docetaxel, albumin-Epothilones, albumin-camptothecine, or albumin-rapamycin and other can be used for the treatment of disease.Think that these pharmaceutical compositions effectively are because of the receptor-mediated transhipment of the protein-pharmaceutical composition that increases to desired area (for example tumor).Do not wish to be bound by any concrete theory, the transhipment of the protein-pharmaceutical composition of the receptor-mediated transhipment by causing therapeutic effect for example is considered to albumin-paclitaxel compositions and sees through the transporting mechanism of lung to tumor and albumin-paclitaxel and albumin-rapamycin transhipment.Transhipment is subjected to gp60 in these tissues, the influence of the existence of gp16 or gp30.Therefore, to the disease for example transhipment and the gp60 of inflammation (for example arthritis) or tumor sites, gp16 or gp30 receptor are relevant and cause the medicine of therapeutic effect and protein-pharmaceutical composition to be considered as compositions of the present invention.

According to another aspect of the present invention, endotheliocyte can with the co-culture of cells with specific function.The incubation of endotheliocyte and other cell type such as islet cells, hepatocyte, neuroendocrine cell and other cell allows the transfer to these cells of required component such as protein and other useful component.Endotheliocyte provides the transfer of these components to the cultured cells type so that condition in the analogue body, promptly wherein these cell types usually with endotheliocyte closely near and will depend on endotheliocyte and transport nutrition, somatomedin, hormone signal etc., and these normal functions for them need.When endotheliocyte does not exist, before can not cultivate these different cell types fully and obtain physiological property.The existence of endotheliocyte allows the differentiation and the suitable function of islets of langerhans, hepatocyte or the neuroendocrine tissue of external or ex vivo in the culture with expectation cell type.Therefore find and compare lacking those that cultivate under the endotheliocyte, the common cultivation of endotheliocyte and islets of langerhans causes having the islets of langerhans of the physiological property (for example ability of excreting insulin) of improvement.This tissue can or be transplanted in the body with treatment owing to lacking the disease that suitable cell function causes (diabetes in the situation at islet cells for example in external use then, hepatic dysfunction in the hepatocyte situation and neuroendocrine disturbance in the situation of neuroendocrine cell or pain relief).The cell (as mentioned above) that derives from other tissue and organ also can be cultivated so that identical benefit to be provided altogether with endotheliocyte.In addition, cultivation can be used for hereditary material is incorporated into target cell type altogether.Discovery albuminised existence in these cultures is highly profitable.

The following example further illustrates the present invention, but should not be considered to limit by any way its scope certainly.

Embodiment 1

For example clear paclitaxel and the albuminised preparation of drug combination of containing of present embodiment.Paclitaxel-albumin preparation of compositions is described in United States Patent (USP) 5,439, and in 686 and 5,916,596, they intactly are incorporated into this by reference.Particularly, the 30mg paclitaxel is dissolved in the 3.0ml dichloromethane.This solution is added in the 27.0ml human serum albumin solution (2%w/v).Add deferoxamine as required.This mixture homogenize 5 minutes (Vitris homogenizer, model TempestI.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to rotary evaporator, removed dichloromethane 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of the paclitaxel of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.

Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When be dissolved in the polyoxyethylene castor oil preparation in the toxicity of paclitaxel when comparing, the present invention contains albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 2

For example clear amiodarone and the albuminised preparation of drug combination of containing of present embodiment.The 30mg amiodarone is dissolved in the 3.0ml dichloromethane.Solution is added in the 27.0ml human serum albumin solution (1%w/v).Add deferoxamine as required.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to rotary evaporator, removed dichloromethane 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of the amiodarone of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.

Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When be dissolved in the tween preparation in the toxicity of amiodarone when comparing, the present invention contains albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 3

Present embodiment is for example understood the preparation of drug combination that contains liothyronine and albumin compositions.The concentration of liothyronine (or suitable salt) with 0.5-50mg/ml is dissolved in water-alcoholic solutions or the alkaline solution.Be added in the albumin soln (0.1-25%w/v) alcohol (or alkalescence) solution and stirring.Stirring is to use the low shearing of agitator or uses the high shear of ultrasonoscope or homogenizer.Under the liothyronine of low concentration, obtain (5-1000 μ g/ml) settled solution.When concentration increases, obtain stable emulsus suspensoid.These solution or suspensoid filter by sterile filters.Remove organic solvent by evaporation or other proper method.

Embodiment 4

For example clear rapamycin and the albuminised preparation of drug combination of containing of present embodiment.The 30mg rapamycin is dissolved in the 2ml chloroform/ethanol.Solution is added in the 27.0ml human serum albumin solution (3%w/v).Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.

Embodiment 5

For example clear epothilone B and the albuminised preparation of drug combination of containing of present embodiment.The 30mg epothilone B is dissolved in the 2ml chloroform/ethanol.Solution is added in the 27.0ml human serum albumin solution (3%w/v).Add deferoxamine as required.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When be dissolved in the polyoxyethylene castor oil preparation in the toxicity of epothilone B when comparing, the present invention contains albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 6

For example clear colchicine dimer and the albuminised preparation of drug combination of containing of present embodiment.30mg colchicine-dimer is dissolved in the 2ml chloroform/ethanol.Solution is added in the 27.0ml human serum albumin solution (3%w/v).Add deferoxamine as required.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When be dissolved in tween in the dimeric toxicity of colchicine when comparing, the present invention contains albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 7

For example clear docetaxel and the albuminised preparation of drug combination of containing of present embodiment.The 30mg docetaxel is dissolved in the 2ml chloroform/ethanol.Solution is added in the 27.0ml human serum albumin solution (3%w/v).Add deferoxamine as required.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When with the standard solvent that is dissolved in this medicine--when the toxicity of the docetaxel in tween/ethanol was compared, the present invention contained albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 8

For example clear docetaxel and the albuminised preparation of drug combination of containing of present embodiment.The 150mg docetaxel is dissolved in 1ml ethyl acetate and butyl acetate and 0.5ml oil for example in soybean oil or the vitamin E oil.Use the solvent and the oil of other ratio, these compositionss also are considered a part of the present invention.Also randomly add a small amount of electronegative component, for example benzoic acid (0.001%-0.5%).Solution is added in the 27.0ml human serum albumin solution (5%w/v) then.Add deferoxamine as required.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, the particulate typical mean diameter of acquisition be 50-220nm (the Z-meansigma methods, MalvernZetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When with the standard solvent that is dissolved in this medicine--when the toxicity of the docetaxel in tween/ethanol was compared, the present invention contained albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 9

For example clear taxane IDN5390 and the albuminised preparation of drug combination of containing of present embodiment.150mg IDN5390 is dissolved in 1ml ethyl acetate and butyl acetate and 0.5ml oil for example in soybean oil or the vitamin E oil.Use the solvent and the oil of other ratio, these compositionss also are considered a part of the present invention.Also randomly add a small amount of electronegative component, for example benzoic acid (0.001%-0.5%).Solution is added in the 27.0ml human serum albumin solution (5%w/v) then.Add deferoxamine as required.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When be dissolved in tween in the toxicity of IDN5390 when comparing, the present invention contains albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 10

For example clear taxane IDN5109 and the albuminised preparation of drug combination of containing of present embodiment.150mg IDN5109 is dissolved in the 2ml chloroform/ethanol.Use the solvent and the oil of other ratio, these compositionss also are considered a part of the present invention.Also randomly add a small amount of electronegative component, for example benzoic acid (0.001%-0.5%).Solution is added in the 27.0ml human serum albumin solution (5%w/v) then.Add deferoxamine as required.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.When be dissolved in tween in the toxicity of IDN5109 when comparing, the present invention contains albuminised pharmaceutical composition and shows significantly lower toxicity.

Embodiment 11

For example clear 10-hydroxycamptothecine (10HC) and the albuminised preparation of drug combination of containing of present embodiment.30mg 10HC is dissolved in 2.0ml DMF/ dichloromethane/soybean oil.Solution is added in the 27.0ml human serum albumin solution (3%w/v) then.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest L.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.

Embodiment 12

For example clear cyclosporin and the albuminised preparation of drug combination of containing of present embodiment.The 30mg cyclosporin is dissolved in the 3.0ml dichloromethane.Solution is added in the 27.0ml human serum albumin solution (1%w/v) then.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to Rotavap, removed solvent 20-30 minute fast down in decompression (30mm Hg) at 40 ℃.The dispersion that obtains is translucent, and the particulate typical mean diameter of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.

Embodiment 13

Present embodiment is for example clear to be contained oil and comprises cyclosporin and albuminised preparation of drug combination.The 30mg cyclosporin is dissolved among the 3.0ml suitably oily (Oleum sesami that contains 10% orange oil).Solution is added in the 27.0ml human serum albumin solution (1%w/v) then.Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The particulate typical mean diameter that obtains is 50-220nm (Z-meansigma methods, Malvern Zetasizer).Directly use dispersion or by randomly adding suitable antifreezing agent lyophilizing 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.

Embodiment 14

For example clear amphotericin and the albuminised preparation of drug combination of containing of present embodiment.The 30mg amphotericin is dissolved in 3.0ml methyl pyrrolidone/dichloromethane.Solution is incorporated in the 27.0ml human serum albumin solution (1%w/v).Mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to rotary evaporator, removed solvent 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of the amphotericin of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.Will be appreciated that the medicine, solvent, proteinic amount, type and the ratio that are used for present embodiment are not subjected to the restriction of any way.Add other component such as lipid, cholate etc. and also produce appropriate formulations.

Embodiment 15

Present embodiment illustrates the preclinical pharmacokinetics and the pharmacodynamics of the pharmaceutical composition that contains albumin and paclitaxel.

Carry out several Preclinical metabolism and pharmacokinetics study in mice and the rat with assessment albumin-taxol drug compositions with respect to the possible advantage of polyoxyethylene castor oil-paclitaxel (taxol) pharmaceutical composition.These studies have shown that: (1) pharmacokinetics of albumin-paclitaxel in rat is linear, and the pharmacokinetics of taxol is non-linear with respect to dosage, and the pharmaceutical composition that (2) comprise albumin and paclitaxel shows lower plasma A UC and C _Max, the faster distribution (drainage be similar) of albumin-paclitaxel compositions to tissue compared in prompting with taxol, and the pharmaceutical composition that (3) comprise albumin and paclitaxel shows lower C _MaxThis possible explanation compare the toxicity of the reduction relevant with the blood peak level with taxol, (4) compare with taxol, the metabolism that comprises paclitaxel in the pharmaceutical composition that half-life that the pharmaceutical composition of albumin and paclitaxel shows high about 2-high 4-times and (5) doubly and in carrying the mice of tumor in rat comprise albumin and paclitaxel is lower than the metabolism of the paclitaxel in the taxol pharmaceutical composition.Injection is back 24 hours in rat, and for the pharmaceutical composition that comprises albumin and paclitaxel, 44% gross activity is still relevant with paclitaxel, compares down for taxol only 22%.The final effect of the above-mentioned pharmacokinetics that shows for the pharmaceutical composition that contains albumin and paclitaxel, it is picked-up in the enhanced cell, it is high 1.7 times that the half-life that prolongs and lower metabolism cause comparing with taxol in carrying the mice of tumor tumor AUC, tumor C _Max1.7 times of high 1.2 times and tumor long half times.

Embodiment 16

Present embodiment is for example understood the side effect of the reduction relevant with albuminised pharmaceutical composition with comprising paclitaxel and the toxicity of reduction.

Because at the peculiar property that does not have to comprise under the polyoxyethylene castor oil paclitaxel and albuminised pharmaceutical composition, the toxicity that comprises paclitaxel and albuminised pharmaceutical composition significantly is lower than taxol.In the preclinical study in mice and rat, the single dose studies on acute toxicity in mice shows for containing paclitaxel and albuminised pharmaceutical composition, its LD ₅₀About 59 times of dosage than taxol.In the multiple dose toxicity research in mice, for containing paclitaxel and albuminised pharmaceutical composition, its LD ₅₀About 10 times of dosage than taxol.Further research is evaluated at myelosuppressive degree in the rat that contains the processing of paclitaxel and albuminised pharmaceutical composition and taxol.The result is presented at etc. under the dosage, comprises paclitaxel and albuminised pharmaceutical composition and produce significantly littler bone marrow depression than taxol in rat.In the studies on acute toxicity in rat, in the animal of accepting the 9mg/kg taxol, observe the downright bad or serious neurotoxicity of cortex, but in the animal of accepting up to 120mg/kg dosage that comprises paclitaxel and albuminised pharmaceutical composition, do not observe.Therefore, compare, comprise in the pharmaceutical composition of paclitaxel albuminised existence and cause side effect and toxicly significantly reduce with the conventional medicine compositions that comprises paclitaxel.

Embodiment 17

For example clear paclitaxel and the clinical effectiveness of albuminised pharmaceutical composition in the people of comprising of present embodiment.

Clinical research in surpassing 500 people patients so far provides support to compare the toxicity of reduction and the evidence of side effect with polyoxyethylene castor oil-paclitaxel compositions (taxol) for the pharmaceutical composition that contains paclitaxel and albumin (" albumin-paclitaxel ").In studying in 19 patients' the I phase, it is 300mg/m that the maximum tolerated dose of albumin-paclitaxel is provided in per 3 weeks ²This is significantly higher than the dosage of the polyoxyethylene castor oil-paclitaxel of common administration, and promptly per 3 weeks provide 175mg/m one time ²Hematotoxicity is gentle in these patients, does not have allergy, slight neuropathy, side effect relevant with there not being administration such as venous stimulation etc.

In studying in another I phase to 27 patients, the maximum tolerated dose of the albumin-paclitaxel that provides according to weekly program is 125-150mg/m ²This is significantly higher than the dosage of the polyoxyethylene castor oil-paclitaxel of common administration, i.e. the 80mg/m that provides according to weekly program ²Hematotoxicity is gentle in these patients, does not have allergy, slight neuropathy, side effect relevant with there not being administration such as venous stimulation etc.

In 43 and 63 patients, provide 175 or 300mg/m per 3 weeks respectively ²Two II phases of albumin-paclitaxel study, hematotoxicity is low, at 175mg/m ²And 300mg/m ²7% and 24% patient ANC＜500/mm is only arranged respectively down ³At 175mg/m ²And 300mg/m ²There is 0% and 14% patient that serious neuropathy takes place respectively down.Serious allergy does not take place, administration relevant side effect such as venous stimulation do not take place, injection pain etc., these side effect significantly are lower than uses that taxol experienced.

In the III phase of albumin-paclitaxel compositions ABI-007 and taxol (containing polyoxyethylene castor oil-paclitaxel) comparison is tested, the significantly higher (260mg/m of the dosage of ABI-007 ², the 175mg/m of comparison taxol ²), show that it is tolerated better.When comparing with polyoxyethylene castor oil-paclitaxel, albumin-paclitaxel compositions also shows the neutrophilic granulocytopenia of remarkable minimizing.

Embodiment 18

Present embodiment is for example understood the enhanced clinical preceding effect of using the pharmaceutical composition that contains albumin and paclitaxel.

Relatively albumin-paclitaxel and taxol studies show that the vitro cytotoxicity of the effect of cervix uteri squamous cell carcinoma A431: albumin-paclitaxel cytotoxic activity increases about 4 times, the IC of albumin-paclitaxel and taxol ₅₀Be respectively 0.0038 and 0.012 μ g/ml.

Five different people xenotransplantation tumor model (MX-1 breast in athymic mouse, the NCI-H522 lung, the SK-OV-3 ovary, the PC-3 prostate, with the HT-29 colon) in, the MTD of ABI-007 or etc. the toxic agent amount than the high 1.5-3.4 of taxol doubly, cause in all tumors except lung tumor (p=0.15) that statistics improves (p＜0.05) significantly aspect the tumor growth delay.

In the MX1 breast model, absolutely the animals survived of the albumin-paclitaxel treatment of (100%) is 103 days, the 20-40% survival in the group for the treatment of with the taxol of DE of comparing down.

Embodiment 19

Present embodiment is for example understood the enhanced clinical efficacy of the pharmaceutical composition that comprises albumin and paclitaxel of using the intra-arterial administration.

In studying in the I/II phase that the intra-arterial administration comprises the pharmaceutical composition of albumin and paclitaxel, as described herein, recruit head and neck cancer patient (N=31) and cancer of anal canal patient (N=12).By percutaneous super-selective endoarterial infusion, the dosage of dosage administration in 30 minutes is from 120mg/m ²Progressively be increased to 300mg/m ², q3-4 week.Head and neck cancer patient shows the response rate of 76% (N=29), and the cancer of anal canal patient shows the response rate of 64% (N=11).

Embodiment 20

Present embodiment is for example clear to be contained 3% oil and comprises propofol and albuminised preparation of drug combination.

Be prepared as follows the oil-in-water emulsion of the propofol that contains 1 weight %.Prepare water by glycerol (2.25 weight %) and human serum albumin (0.5 weight %) being added in the water for injection and stirring until dissolving.Water is passed through filter (0.2um filter).By under about 50 ℃-60 ℃, lecithin (0.4 weight %) and propofol (1 weight %) be dissolved in the soybean oil (3 weight %) and stir until dissolving prepare oil phase.Oil phase is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and in 15 cycles of 5 ℃ of recirculatioies under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.The pharmaceutical composition that obtains comprises the component (% meter by weight) of following common scope: propofol 0.5-5%; Human serum albumin 0.5-3%; Soybean oil 0.5-3.0%; Lecithin 0.12-1.2%; Glycerol 2.25%; Water for injection is in right amount to 100; PH5-8.Randomly add suitable chelating agen, for example deferoxamine (0.001-0.1%).

Embodiment 21

Present embodiment is for example clear to be contained 5% oil and comprises propofol and albuminised preparation of drug combination.

Be prepared as follows the oil-in-water emulsion of the propofol that contains 1 weight %.Prepare water by glycerol (2.25 weight %) and human serum albumin (0.5 weight %) being added in the water for injection and stirring until dissolving.Water is passed through filter (0.2um filter).By under about 50 ℃-60 ℃, lecithin (0.8 weight %) and propofol (1 weight %) be dissolved in the soybean oil (5 weight %) and stir until dissolving prepare oil phase.Oil phase is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and in 15 cycles of 5 ℃ of recirculatioies under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.The pharmaceutical composition that obtains comprises the component (% meter by weight) of following common scope: propofol 0.5-5%; Human serum albumin 0.5-3%; Soybean oil 0.5-10.0%; Lecithin 0.12-1.2%; Glycerol 2.25%; Water for injection is in right amount to 100; PH5-8.Randomly add suitable chelating agen, for example deferoxamine (0.001-0.1%).

Embodiment 22

Present embodiment is for example understood and is contained propofol and albumin, not butyraceous preparation of drug combination.

Use is similar to embodiment 18 described methods, and preparation contains the propofol composition of albumin and Tween 80.By with glycerol (2.25 weight %), human serum albumin (0.5 weight %), Tween 80 (1.5 weight %) and deferoxamine mesylate (0.1 weight %) are added in the water for injection and stir until dissolving and prepare water.Water is passed through filter (0.2 μ m filter).Propofol (1 weight %) is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and in 15 cycles of 5 ℃ of recirculatioies under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.The pharmaceutical composition that obtains comprises the component (% meter by weight) of following common scope: propofol 0.5-5; Human serum albumin 0.5-3%; Tween 80 0.1-1.5%; Deferoxamine mesylate 0.0001-0.1%; Glycerol 2.25%; Water for injection is in right amount to 100; PH5-8.

Embodiment 23

For example clear propofol, albumin and vitamin E-TPGS, the not butyraceous preparation of drug combination of containing of present embodiment.

Use is similar to embodiment 19 described methods, and preparation contains the propofol composition of albumin and vitamin E-TPGS.By with glycerol (2.25 weight %), human serum albumin (0.5 weight %), vitamin E-TPGS (1 weight %) and deferoxamine mesylate (0.1 weight %) are added in the water for injection and stir until dissolving and prepare water.Water is passed through filter (0.2 μ m filter).Propofol (1 weight %) is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and in 15 cycles of 5 ℃ of recirculatioies under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.The pharmaceutical composition that obtains comprises the component (% meter by weight) of following common scope: propofol 0.5-5; Human serum albumin 0.5-3%; Vitamin E-TPGS 0.5-4.0%; Deferoxamine mesylate 0.0001-0.1% randomly; Glycerol 2.25%; Water for injection is in right amount to 100; PH5-8.

Embodiment 24

Present embodiment is for example understood the preparation of drug combination that contains propofol, albumin, vitamin E-TPGS and 1% oil.

The Emulsion that contains the propofol of 1 weight % by following method preparation.Prepare water by glycerol (2.25 weight %) and human serum albumin (0.5 weight %) being added in the water for injection and stirring until dissolving.Water is passed through filter (0.2 μ m filter).With surfactant for example vitamin E-TPGS (0.5%) be added to aqueous phase.Oil phase is made up of propofol (1 weight %) and 1% soybean oil.Oil phase is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and 5 ℃ of maximum 15 cycles of recirculation under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.

The pharmaceutical composition that obtains comprises the component (% meter by weight) of following common scope: propofol 0.5-5%; Human serum albumin 0.01-3%; Vitamin E-TPGS 0.1-2%; Soybean oil or other oil (0.1%-5%); Glycerol 2.25%; Water for injection is in right amount to 100; PH5-8.Randomly add deferoxamine (0.001 weight %-0.1 weight %).

Embodiment 25

Present embodiment is for example understood the preparation of drug combination that contains propofol, albumin, vitamin E-TPGS, 1% oil and electronegative component.

The Emulsion that contains the propofol of 1 weight % by following method preparation.Prepare water by glycerol (2.25 weight %) and human serum albumin (0.5 weight %) being added in the water for injection and stirring until dissolving.Water is passed through filter (0.2 μ m filter).With surfactant for example vitamin E-TPGS (0.5%) be added to aqueous phase.Oil phase is made up of propofol (1 weight %) and 1% soybean oil.Add a small amount of electronegative component (0.001%-1%), for example phospholipid or cholate.Oil phase is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and 5 ℃ of maximum 15 cycles of recirculation under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.

Embodiment 26

Present embodiment is for example understood the preparation of drug combination that contains propofol, albumin, vitamin E-TPGS, 1% oil and electronegative component (NaTDC).

The Emulsion that contains the propofol of 1 weight % by following method preparation.Prepare water by glycerol (2.25 weight %) and human serum albumin (0.5 weight %) being added in the water for injection and stirring until dissolving.Water is passed through filter (0.2 μ m filter).With surfactant for example vitamin E-TPGS (0.5%) be added to aqueous phase.Oil phase is made up of propofol (1 weight %) and 1% soybean oil.Add a small amount of electronegative component (0.001%-1%), for example NaTDC.Oil phase is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and 5 ℃ of maximum 15 cycles of recirculation under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.

Embodiment 27

Present embodiment is for example understood the preparation of drug combination that contains propofol, albumin, vitamin E-TPGS, 1% oil and electronegative component (phospholipid, cholate, polyamino acid etc.).

The Emulsion that contains the propofol of 1 weight % by following method preparation.Prepare water by glycerol (2.25 weight %) and human serum albumin (0.5 weight %) being added in the water for injection and stirring until dissolving.Water is passed through filter (0.2 μ m filter).With surfactant for example vitamin E-TPGS (0.5%) be added to aqueous phase.Oil phase is made up of propofol (1 weight %) and 1% soybean oil.Add a small amount of electronegative component (0.001%-1%), for example phosphatidylcholine.Oil phase is added to aqueous phase and 10,000RPM homogenize 5 minutes.With thick Emulsion 20, high pressure homogenize and 5 ℃ of maximum 15 cycles of recirculation under the 000psi.Alternatively, use is by the split tunnel of homogenizer.Final Emulsion is filtered (0.2 μ m filter) and under nitrogen, store.

Embodiment 28

Present embodiment understands that for example propofol combines with albuminised.

Following mensuration propofol combines with albuminised.The dissolubility of test propofol in water and in containing albuminised solution.Be added to 250 μ L propofol in 10mL water or the albumin soln and in scintillation vial, stirred 2 hours.Then solution is transferred in the 15mL polyethylene centrifuge tube and remain on 40 ℃ about 16 hours.Measure the propofol in water and the albumin soln sample.The dissolubility of propofol in water is measured as 0.12mg/ml.The dissolubility of propofol in albumin soln depends on albuminised concentration, increases to 0.44mg/ml when albuminised concentration is 2% (20mg/ml).With the solution ultrafiltration by 30kD MWCO filter and measure propofol in the filtrate.Discovery is for propofol/aqueous solution, and 61% propofol can reclaim in filtrate, and for propofol/albumin soln, only 14% is recovered in the filtrate, shows propofol and albuminised sizable the combination.Based on these results,, albumin is added the minimizing that the pharmaceutical composition that comprises propofol causes the amount of free propofol because albumin combines with propofol.

Embodiment 29

Present embodiment is for example understood the minimizing by filtration/film contact free propofol in pharmaceutical composition.

As observed in experiment described in the embodiment 28, comprise the filtration of pharmaceutical composition of propofol or the minimizing that ultrafiltration causes the amount of free propofol.Disoprivan and according to the albuminised pharmaceutical composition that contains of the present invention preparation contains 1% propofol (10mg/ml) separately, uses the 30kD membrane ultrafiltration.Use HPLC to measure the amount of free propofol in filtrate.Concentration for Disoprivan free propofol in filtrate is about 17 μ g/ml, and is about 7 μ g/ml for the concentration of the free propofol of pharmaceutical composition of the present invention in filtrate.The result corresponding to for effective minimizing of the free propofol that comprises propofol and albuminised pharmaceutical composition greater than 2 times.

Embodiment 30

Present embodiment is for example clear to comprise propofol and albuminised pharmaceutical composition to people's administration.

Carry out double blinding clinical trial at random, relatively to comprise propofol and albuminised pharmaceutical composition and propofol formulations--the disadvantageous dermal sensation of Disoprivan that is purchased.Test and obtain Informed Consent Form according to good clinical practice (Good Clinical Practices) from the experimenter.The adult experimenter of any sex can participate in, and prerequisite is that they have unbroken, the normal the back of the hand surface skin in surface.

Originally the preparation that was stored in the refrigerator is brought in the room temperature environment, then 10 μ L preparations slowly is placed on the back of the hand of two handss of experimenter simultaneously.Write down general reaction and the sensation of their hands for preparation.The result of this research lists in table 1.

Table 1

Test sequence to the experimenter	Use the experimenter % sensation of ABI-propofol		Use the experimenter % sensation of Disoprivan
	Use the experimenter % sensation of ABI-propofol		Use the experimenter % sensation of Disoprivan		Warm or thorn sense or twinge	Numbness	Warm or thorn sense or twinge	Numbness
	The 1st incidence rate	0.0	100.0	75	Warm or thorn sense or twinge	Numbness	Warm or thorn sense or twinge	Numbness	25

Embodiment 31

Present embodiment is for example understood in comprising the pharmaceutical composition of propofol the application as the deferoxamine of antioxidant.

Comprise propofol and deferoxamine mesylate and contain tween or the pharmaceutical composition of TPGS is stored in 4 ℃, 25 ℃ or 40 ℃, to detect the effect of deferoxamine mesylate in preventing the propofol oxidation.The concentration of measuring propofol for these preparations in time with, measure the antioxidant activity of deferoxamine.These data are reported as the effectiveness % with respect to time zero in following table 2 and 3.

Table 2. albumin/tween preparation

	Stored in 1 month
	Stored in 1 month			Temperature	4℃	25℃	40℃
Contrast	100％	88％	48％	Temperature	4℃	25℃	40℃
Contrast	100％	88％	48％	0.01% deferoxamine mesylate	101％	89％	61％
0.1% deferoxamine mesylate	103％	89％	64％	0.01% deferoxamine mesylate	101％	89％	61％

Table 3. albumin/TPGS preparation

	Stored in 1 month
	Stored in 1 month			Temperature	4℃	25℃	40℃
Contrast	99％	73％	42％	Temperature	4℃	25℃	40℃
Contrast	99％	73％	42％	0.01% deferoxamine mesylate	99％	87％	55％
0.1% deferoxamine mesylate	99％	85％	58％	0.01% deferoxamine mesylate	99％	87％	55％

Under these conditions, deferoxamine is enough to reduce the oxidation level of propofol.This effect is remarkable more at high more relaxing the bowels with purgatives of warm nature.Remarkable oxidation does not take place at 4 ℃.Use and do not carried out this research by inert material or teflon-coating stopper.

Embodiment 32

Present embodiment is for example understood transmission in the lung that contains paclitaxel and albuminised pharmaceutical composition (ABI-007).

The purpose of this research be measure [ ³H] ABI-007 in blood time-histories and behind SpragueDawley rat intratracheal instillation, selecting tissue.

Based on the dose volume of every kg body weight 1.5mL, calculate the target volume of dosage particles in the trachea of animals administer.The dosed administration device is by Penn-Century micro-sprayer (the model 1A-1B that is connected with the gastight luer-lock of 1-mL syringe; Penn-Century, Inc., Philadelphia, PA; Available from DeLong Distributors, Long Branch, NJ).With the dosage particles inhalation dose doser of proper volume, device that weighing is filled and record weight.Conduit is put into the trachea of dopey animal, the micro-sprayer of dosed administration device part is placed in the trachea dosage by conduit.Behind dosed administration, the dosed administration device of weighing sky again calculates the dosage of administration as the weight difference of dosed administration device before and after the dosed administration.For all animal mean doses is 4.7738 ± 0.0060 (CV 1.5059) mg paclitaxel/kg body weight.

The moment after following predetermined close administration is collected the blood sample of about 250 μ L from the jugular vein sleeve pipe of the indwelling of JVC rat: 1,5,10,15,30 and 45 minutes (min) and 1,4,8 and 24 hours (h).24 hours blood samples, and the blood sample of collecting from the animal of putting to death 10 minutes, 45 minutes and 2 hours is to collect from the rat of anesthesia by heart puncture when putting to death.All blood samples that will be used for the gross activity analysis are distributed to preweighted sample cell, sample cell are weighed again, by the weight of each sample of subtraction.Total tritium level of the blood aliquot of blood sample that mensuration is collected from jugular vein and the 250-μ L that when putting to death, collects from each animal.

For all rats, in the Cmax of tritium 5 minutes (0.0833 hour) times behind dosed administration, observed in the blood.In the elimination half-life of the tritium of measuring in the interval of 4h to 24h is 19.73h to 43.02h.It should be noted that this interval only comprises three data points, it can explain the variability of this parameter.The apparent clearance rate of tritium from blood is about 0.04L/h.These result of experiment are listed in following table 4.

Table 4. intratracheal instillation [ ³H] behind the ABI-007 in rat blood tritium concentration (mg-eq/L) for the non-compartment analysis of time graph

Parameter mean+/-SD

C _max(mg-eq/L) 1.615+/-0.279

T _max(hr) 0.0833+/-0.0

t _1/2β(hr) 33.02+/-1.99

AUC is (mg-eq x hr/L) 7.051+/-1.535 eventually

Cl/F(L/hr) 0.0442+/-0.0070

Fa (bioavailability) 1.229+/-0.268

Functional Analysis as the time after administration in rat vein, derive from [ ³H] the radioactive average blood concentration of ABI-007 so that assessment derive from administration in the trachea [ ³H] bioavailability of tritium of ABI-007.This analysis causes the 24-hour AUC (AUC eventually) of 6.1354mg-eq hr/L.Based on these data, derive from administration in the trachea [ ³H] radioactivity of ABI-007 is high bioavailability.These analyses are based on gross activity.

Derive from [ ³H] tritium of ABI-007 after the intratracheal instillation by fast Absorption.Administration in trachea [ ³H] behind the ABI-007 in blood the average absorption of tritium and eliminate the half-life (being respectively k01 half-life and k10 half-life) and be respectively 0.0155+/-0.0058 hour and 4.738+/-0.366 hour.The average apparent clearance rate of tritium from blood be 0.1235+/-0.0180L/ hour (referring to above table 4).

Derive from [ ³H] tritium of ABI-007 is absorbed after the administration in trachea and distributes.The time-histories of tritium in blood is well by two compartment model descriptions, and average absorption and elimination half-life were respectively 0.0155 and 4.738 hour.The dosage of recovery about 28% in lung in 10 minutes after the administration in trachea.Except gastrointestinal tract,, in other tissue, be recovered to maximum less than 1% dosage in the moment of all inspections.

Based on from previous use [ ³H] Capxol ^TMThe intravenous dosages administration result of study of carrying out, for three animals of this dosage group, (meansigma methods ± SD) that the bioavailability that derives from the tritium of administration in the trachea is 1.229 ± 0.268.Yet, should be noted that this estimation for bioavailability is based on gross activity.Surprisingly, but the application of the invention contains paclitaxel that the lung approach of albuminised compositions transmits biological utilisation fast, shows the fabulous transhipment that strides across the lung endothelium.Toxicity not to be noted in animal, this is wonderful, because known lung transfer sell endotoxin causes lung toxicity.

Back 24 hours of dosed administration (administration in 27% the trachea), the radioactivity of a great deal of was present in the gastrointestinal tract (comprising inclusions).In gastrointestinal tract the existence of tritium may be since bile excretion or tritium from respiratory tract by the mucociliary clearance and the removing of swallowing subsequently.

Embodiment 33

Present embodiment understands that for example being used for pulmonary transmits Aerotech II and the Pari aerosol apparatus that comprises paclitaxel and albuminised pharmaceutical composition.

This research is to use paclitaxel-albumin pharmaceutical composition A BI-007 to carry out under following condition: room temperature (20-23 ℃), and relative humidity (48-54%), ambient pressure (629mmHg), (for Aerotech II is 10L/min to the aerosol apparatus flow rate; For Pari is 7L/min), total flow rate (28.3L/min), aerosol apparatus pressure descend, and (for Aerotech II is 23lb/in ²For Pari is 32lb/in ²), running time (15-60 second), sample volume (1.5mL), ABI-007 paclitaxel concentration (5,10,15 and 20mg/mL).

When with ABI-007 during with the concentration reconstruct of 5-15mg/mL, Aerotech II and Pari aerosol apparatus all provide acceptable aggregate efficiency (30%-60%).Pari aerosol apparatus efficient has than the higher efficient of Aerotech II aerosol apparatus.Pari aerosol apparatus efficient has decline a little along with the increase of ABI-007 concentration.Observe fabulous fine fraction (74%-96%).Aerotech II aerosol apparatus has the fine fraction higher than Pari aerosol apparatus.Fine fraction and concentration are irrelevant.

Use the ABI-007 solution of 15mg/mL, the Pari aerosol apparatus transmits the 100mg paclitaxel in less than 30 minutes.Use the ABI-007 solution of 10mg/mL or 15mg/mL, Aerotech II aerosol apparatus transmits the 100mg paclitaxel in about 65 minutes.Detect stability for Aerotech II and Pari aerosol apparatus.Drain until medicine, the aerosol concentration of two kinds of aerosol apparatus and efficient are stable.At 15mg/mL, the speed that the Pari aerosol apparatus consumes medicine is the twice of Aerotech II aerosol apparatus, produces than the higher aerosol concentration of Aerotech II aerosol apparatus.

In a word, when by the lung administration, the nanoparticle of paclitaxel/albumin preparation (ABI-007) shows fabulous bioavailability in rat.Under dosage, there is not early stage toxic visible marking.The lung transmission of nanoparticle paclitaxel (ABI-007) can use conventional aerosol apparatus to realize.

Embodiment 34

Present embodiment has been described interior transmission of lung of the pharmaceutical composition that comprises albumin and rapamycin.The purpose of this research is to be determined at the lung of rapamycin absorption in blood after Sprague Dawley rat intratracheal instillation, and compares with intravenous drip.

Calculate the target volume of dosage particles in the trachea of animals administer based on the dose volume of every kg body weight 1mL.The dosed administration device is by Penn-Century micro-sprayer (the model 1A-1B that is connected with the gastight luer-lock of 1-mL syringe; Penn-Century, Inc., Philadelphia, PA; Available from DeLong Distributors, Long Branch, NJ).With the dosage particles inhalation dose doser of proper volume, device that weighing is filled and record weight.Conduit is put into the trachea of dopey animal, the micro-sprayer of dosed administration device part is placed in the trachea dosage by conduit.Behind dosed administration, the dosed administration device of weighing sky again calculates the dosage of administration as the weight difference of dosed administration device before and after the dosed administration.

Blood sample at about 250 μ L of collection from the jugular vein sleeve pipe of the indwelling of rat of the following predetermined close administration moment: 1,5,10,15,30 and 45 minutes (min) and 1,4,8 and 24 hours (h).The blood sample of all analyses is assigned in the sample cell of weighing in advance, sample cell is weighed again, by the weight of each sample of subtraction.Use LC/MS/MS to measure total rapamycin concentrations of the blood sample of collecting.

Surprisingly, the result is presented between the blood concentration by lung approach and the rapamycin by the intravenous transmission does not have significant difference.Use comprises albuminised pharmaceutical composition, and the bioavailability of the rapamycin by the transmission of lung approach is calculated as 109%, shows the fabulous transhipment that strides across the lung endothelium.

Embodiment 35

Present embodiment illustrate feeding drug into pulmones according to system of the present invention each comprise rapamycin and albuminised pharmaceutical composition after, the tissue distribution of albumin-rapamycin.The purpose of this research is to be determined at the lung absorption of rapamycin in tissue after Sprague Dawley rat intratracheal instillation, and compares with intravenous drip.

Constantly from the brain of every group of 3 rats, collect sample in the lung regulating liver-QI in each of 10 minutes, 45 minutes, 2 hours and 24 hours.Collect sample and use LC/MS/MS analyzing total rapamycin concentrations.The result shows that when transmitting by lung to compare rapamycin concentrations bigger in lung tissue with the intravenous transmission.Yet, compare with intravenous (IV) transmission, the total concentration of rapamycin in brain is lower when transmitting by (IT) in the trachea.As if in liver, no matter IT or IV transmit, and the concentration of rapamycin does not have difference.Based on these results, transmit rapamycin in the lung and go for treating disease (being lung transplantation), wherein the rapamycin of high local concentrations will be useful.

Embodiment 36

Present embodiment understands that for example oral delivery contains paclitaxel and albuminised pharmaceutical composition (ABI-007).

The ABI-007 of tritiate is used for measuring oral bioavailability of taxol rat after oral gavage.After overnight fast, give 5.5mg/kg paclitaxel (group A) and other 5 rats (group B) in ABI-007 with 5 rats and use cyclosporin (5.0mg/kg) pretreatment, then with the taxol treatment of 5.6mg/kg in ABI-007.After the radioactivity of measuring by burning in the blood sample, carry out 0.5,1 the pharmacokinetic analysis of the blood sample that extracted in 2,3,4,5,6,8,12 and 24 hours.Measure oral administration biaavailability by comparing with the intravenous data of previous acquisition.The result lists in following table 5.

Table 5. is behind oral administration ³Radioactive average A UC 0-24 in H-paclitaxel source, C _Max, T _MaxAbsorb with %

Group	Handle	Dosage/approach mg/kg	AUC0-24 (μg eq x hr/mL)	Absorb (%)	Cmax(mg/kg) (μg x eq/mL)	Tmax (hr)
Group	Handle	Dosage/approach mg/kg	AUC0-24 (μg eq x hr/mL)	Absorb (%)	Cmax(mg/kg) (μg x eq/mL)	Tmax (hr)	A B	The ABI-007 of ABI-007 in normal saline in containing the normal saline of CsA	5.5/PO(P) 5/PO(C)， 5.6/PO(P)	2.92 8.02	44.3 121.1	0.245 0.565	1 0.5

AUC 0-24IV (6.06 μ g x hr./mL) and IV dosage (5.1mg/kg) are used to calculate PA (based on the data of the IV dosage of ABI-007).

Observe 44% oral administration biaavailability for independent ABI-007.This is significantly higher than for other formulation for paclitaxel viewed.When handling animal with cyclosporin (CsA), bioavailability is increased to 121%.This reckons with, because CsA is the known inhibitor of p-glycoprotein pump, it will suppress chemical compound such as paclitaxel usually and absorb from the GI road.Bioavailability greater than 100% can by with the paclitaxel bile excretion to the GI road later absorption again explain.Other known absorption inhibitor or reinforcing agent also can be used for this purpose.

Embodiment 37

Present embodiment is for example understood in administration and is comprised paclitaxel the penetrating to erythrocyte and tumor cell of improving behind paclitaxel and the albuminised pharmaceutical composition.

With people MX-1 mastadenoma fragment subcutaneous transplantation in athymic mouse.With ³H paclitaxel paclitaxel prepares aforesaid paclitaxel and albuminised pharmaceutical composition (" paclitaxel-albumin ") and the taxol of comprising, and specific activity is 25 μ Ci/mg paclitaxels.When gross tumor volume reaches about 500mm ³The time, the administration in the saline medium-sized vein with radiolabeled paclitaxel-albumin of 20mg/kg or taxol.With blood plasma, blood and tumor tissues sampling and after administration 5,15 and 30 minutes and 1,3,8 and 24 hours display analysis radioactivity.Use WinNonlin, Pharsight, USA analyzes tumor pharmacokinetics (AUC and absorption constant).

Paclitaxel-albumin shows the quick distribution to erythrocyte (RBC), and blood plasma after at the intravenous administration medicine/blood activity ratio is reduced to shown in the unanimity fast.Distribution fully in RBC just took place behind administration paclitaxel-albumin in 1 hour.By contrast, the paclitaxel that is formulated as taxol is many lentamente to the distribution of RBC, and does not also finish until surpassing 8 hours.

Paclitaxel-albumin shows the quick distribution to tumor tissues, absorption constant (K _a) than the big 3.3X of taxol.K _aBe respectively 0.43hr for paclitaxel-albumin and taxol ^-1And 0.13hr ^-1The quick picked-up of paclitaxel causes paclitaxel-albuminised tumor AUC higher by 33% than taxol.AUC is respectively 3632nCi*hr/g and 2739nCi*hr/g for paclitaxel-albumin and taxol.

Embodiment 38

Present embodiment is for example understood the safety that contains paclitaxel and albuminised pharmaceutical composition to the mice administration.

Handle athymic mouse, continuous 5 day with paclitaxel-albumin that increases dosage gradually or taxol every day.Survival rate is mapped to measure LD to dosage ₅₀Compare with taxol, paclitaxel-albumin greatly increased survival rate (p=0.017, ANOVA).For qld x 5 programs, the LD of paclitaxel-albumin and taxol ₅₀Be calculated as 47mg/kg/ days respectively and 30mg/kg/ days.Under 13.4mg/kg/ days dosage level, paclitaxel-albumin and taxol are all tolerated well, and mortality rate is respectively 1% (1 death in 72 mices) and 4% (2 death in 47 mices).Under 20mg/kg/ days dosage level, paclitaxel-albuminised mortality rate is 1% (1 death in 72 mices), the taxol mortality rate be 17% (8 death in 47 mices) (p=0.0025).Under 30mg/kg/ days dosage level, paclitaxel-albuminised mortality rate is 4% (3 death in 72 mices), and the taxol mortality rate is 49% (23 death in 47 mices) (p＜0.0001).

Embodiment 39

Present embodiment is for example understood for paclitaxel-albumin compositions, is striden across the IDN5111 IDN 5111 transporting mechanism of microvascular endotheliocyte (EC).

Because the EPR effect that " seepage " vascular causes in the tumor, nanoparticle and albumin-paclitaxel compositions can be accumulated in tumor tissues.The special gp60 receptor (albondin) of albumin is by the dysuria with lower abdominal colic of the receptor in the caveolae at cell surface place, with albumin transhipment passing through EC.This dysuria with lower abdominal colic mechanism allows albumin-paclitaxel to be transported in the intercellular space of bottom.On the contrary, the polyoxyethylene castor oil in the taxol suppresses paclitaxel and combines with albuminised, has greatly reduced the transhipment of paclitaxel to tumor.In addition, gp16 and gp30 receptor also relate to the albuminised intracellular transport of the modification that contains bonded paclitaxel, cause combining of the paclitaxel that increases and endotheliocyte, and to compare blood vessel formation against function bigger with taxol.

Embodiment 40

Present embodiment is for example clear to be compared with taxol, contains the increase of the endothelium dysuria with lower abdominal colic of paclitaxel and albuminised pharmaceutical composition.

People's lung microvascular endotheliocyte (HLMVEC) is cultured on transwell converges.With concentration is that 20 μ g/mL the present invention contain paclitaxel and albuminised pharmaceutical composition or taxol and are added in the transwell chamber.

Use exometer continuous monitoring paclitaxel to be transported to down transhipment the chamber from last chamber by dysuria with lower abdominal colic.Also use only contains Flutax and does not have albuminised contrast.The contrast that contains Flutax does not show transhipment, proves the integrity that converges the HLMVEC monolayer.In the presence of 5% HSA (physiological concentration), recently faster from the paclitaxel of taxol from the transhipment of the paclitaxel of albumin-paclitaxel compositions.Transport velocity constant (K _t) be respectively 1.396hr for albumin-paclitaxel compositions and taxol ^-1And 0.03hr ^-1The total amount that the transhipment of albumin-paclitaxel compositions strides across the paclitaxel of monolayer strides across monolayer than the transhipment of taxol the total amount of paclitaxel is high 3 times.

Embodiment 41

Present embodiment is for example clear to be compared with taxol, contains endotheliocyte (EC) combination that paclitaxel and albuminised pharmaceutical composition improve.

Human umbilical vein endothelial cells (HUVEC) is cultivated on the microtitration plate of 96-hole.In an experiment, in the presence of the polyoxyethylene castor oil EL/EtOH (carrier of taxol) that increases concentration, with HUVEC and paclitaxel (paclitaxel of Flutax-Oregon Green labelling) reaction.In another experiment, the pharmaceutical composition and the taxol-Flutax compositions that contain albumin and Flutax are reacted with HUVEC under various final concentrations.Paclitaxel and combining of cell are subjected to the inhibition of polyoxyethylene castor oil.0.02% IC by polyoxyethylene castor oil EL/EtOH ₅₀Show and suppress.The polyoxyethylene castor oil of this concentration has been presented at the taxol chemotherapeutic period and has continued at least 24 hours.Therefore, it is a correlated process in the body.Under all detectable concentrations, the paclitaxel from albumin-paclitaxel compositions of significant quantity combines with cell.By contrast, observe seldom or do not observe combination for taxol.

Embodiment 42

Present embodiment is for example clear to be compared with taxol, contains the albumin combination of the improvement of paclitaxel and albuminised pharmaceutical composition.

Human serum albumin (HSA) is fixed on the plastics elisa plate.Paclitaxel (paclitaxel of Flutax-Oregon Green labelling) is reacted in the presence of the polyoxyethylene castor oil EL/EtOH that increases concentration with fixed HSA.In another experiment, albumin-paclitaxel-Flutax compositions and taxol-Flutax compositions and fixed HSA react under the final concentration of 20 μ g paclitaxel/mL.Paclitaxel combines the inhibition that is subjected to polyoxyethylene castor oil with albuminised.0.003% IC by polyoxyethylene castor oil EL/EtOH ₅₀Show and suppress.The polyoxyethylene castor oil of this concentration has been presented at the taxol chemotherapeutic period and has continued at least 24 hours.Therefore, it is a correlated process in the body.Under related drugs paclitaxel concentration (20 μ g/mL), the paclitaxel from albumin-paclitaxel compositions of significant quantity combines with fixed HSA.By contrast, do not observe combination for taxol.

Embodiment 43

Present embodiment for example understands and compares with taxol, for containing paclitaxel that paclitaxel and albuminised pharmaceutical composition increase to albuminised transhipment.

With 20 μ g/mL, 40 μ g/ml and 80 μ g/ml mix with 5% HSA in the Hanks buffer or with serum with taxol-Flutax and albumin-paclitaxel-Flutax compositions.Separating mixture on natural 3-14% polyacrylamide gel is immediately measured amount with the bonded paclitaxel of albumin by scanning fluorimeter.Compare with taxol, for albumin-paclitaxel compositions, paclitaxel is faster to the transhipment of HSA.When with serum or 5% HSA and albumin-paclitaxel-Flutax compositions or taxol-Flutax compositions incubation, more paclitaxel is swum with the HSA common-battery.Compare with taxol-Flutax compositions, 20 μ g/ml, 40 μ g/ml, with albumin-paclitaxel-Flutax compositions of 80 μ g/ml after contacting 5% HSA, have 45%, 60% and 33% more paclitaxel to be transported to HSA respectively.For 260mg/m ²ABI-007, C _MaxBe about 20 μ g/mL, so this is important physiological disposition.

Embodiment 44

Present embodiment understands that for example glycoprotein receptor gp60 is responsible for the combination and the dysuria with lower abdominal colic of albumin-paclitaxel.

Fluorescently-labeled paclitaxel (Flutax) albumin compositions contacts with microvascular endotheliocyte in the culture.Examine under a microscope fluorescence staining, evidence is a speckle regions, and this supposition is and the bonded gp60 receptor of albumin-paclitaxel.This confirms that by the albumin that uses the rhodamine labelling albumin of rhodamine labelling is identical with the speckle fluorescence position of paclitaxel.

Embodiment 45

Present embodiment for example understand recruitment albumin can with the competition that combines of paclitaxel.

Albumin is fixed on the microtitration plate.The fluorescence paclitaxel is added in the hand-hole, use scanning fluorimeter to measure the combination of paclitaxel.Add in the hand-hole albumin of recruitment and the inhibition level of measurement and the bonded paclitaxel of fixed albumin.Data show is observed bonded corresponding reduction along with the albuminised amount that adds increases.For observing similar effect with combining of endotheliocyte.This shows that higher albumin concentration suppresses the combination of paclitaxel.Preferred the present invention has the albuminised compositions of low amount.

Embodiment 46

Present embodiment understands that for example the albumin of low amount in pharmaceutical composition of the present invention causes stable compositions.

For whether low albumin of measuring in seminar's compound influences the stability of pharmaceutical composition of the present invention, preparation contains low amount albuminised albumin-paclitaxel compositions.When checking down paclitaxel effect, impurity formation, particle diameter, pH and other stable canonical parameter in different temperatures (2-8 ℃, 25 ℃ and 40 ℃), find that these compositionss are the same stable with the albuminised compositions with a large amount more.Therefore the albuminised compositions that preferably has low amount is because this combination and cytotropic transhipment that can greatly reduce cost and allow to increase.

Embodiment 47

Present embodiment is for example understood the pharmaceutical composition that contains albumin and paclitaxel, and it has high albumin and paclitaxel ratio.

The 30mg paclitaxel is dissolved in the 3.0ml dichloromethane.Solution is added to (ratio that is equivalent to albumin and paclitaxel is 27) in the 27.0ml human serum albumin solution (3%w/v).Add deferoxamine as required.This mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to rotary evaporator, removed dichloromethane 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of the paclitaxel of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.

Embodiment 48

Present embodiment is for example understood the pharmaceutical composition that contains albumin and paclitaxel, and it has low albumin and paclitaxel ratio.

Particularly, the 300mg paclitaxel is dissolved in the 3.0ml dichloromethane.Solution is added to (ratio that is equivalent to albumin and paclitaxel is 4.5) in the 27ml human serum albumin solution (5%w/v).Add deferoxamine as required.This mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to rotary evaporator, removed dichloromethane 20-30 minute fast down at 40 ℃, decompression (30mm Hg).The dispersion that obtains is translucent, and the particulate typical mean diameter of the paclitaxel of acquisition is 50-220nm (Z-meansigma methods, Malvern Zetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.

Embodiment 49

Present embodiment is for example understood the pharmaceutical composition that contains albumin and paclitaxel, and it has medium albumin and paclitaxel ratio.

Particularly, the 135mg paclitaxel is dissolved in the 3.0ml dichloromethane.Solution is added in the 27ml human serum albumin solution (5%w/v).Add deferoxamine as required.This mixture homogenize 5 minutes (Vitris homogenizer, model Tempest I.Q.) under low RPM is transferred in the high-pressure homogenizer (Avestin) then so that form thick Emulsion.At 9000-40, carry out emulsifying under the 000psi, simultaneously with at least 5 cycles of Emulsion recirculation.The system that obtains is transferred to rotary evaporator, removed dichloromethane 20-30 minute fast down in decompression (30mm Hg) at 40 ℃.The dispersion that obtains is translucent, the particulate typical mean diameter of the paclitaxel of acquisition be 50-220nm (the Z-meansigma methods, MalvernZetasizer).With the further lyophilizing of this dispersion 48 hours.By adding sterilized water or saline, the cake piece of acquisition can easily be reconstructed into original dispersion.Identical before particle diameter after reconstruct and the lyophilizing.In the present composition, the calculating ratio of albumin and paclitaxel (w/w) is about 10.

Embodiment 50

Present embodiment is for example understood with the rheumatoid arthritis in albumin-paclitaxel combination treatment animal model.

To in the Louvain rat, be used to detect albumin-paclitaxel compositions to arthritic therapeutic effect by the inductive arthritis model of collagen protein.The pawl size that monitors laboratory animal is to assess arthritic seriousness.

After arthritis develops fully (usually after collagen injections about 9-10 days), laboratory animal is not divided into accepts albumin-paclitaxel 1mg/kg q.o.d with intraperitoneal on the same group, or albumin-paclitaxel 0.5mg/kg+ prednisone 0.2mg/kg q.o.d. (therapeutic alliance) reaches 6 dosage, and a dosage reached for three weeks on every Mondays then.Measuring claw size when treatment beginning (the 0th day) and per injection medicine.Only accept one group of normal saline in contrast.When experiment finished, the group pawl size of accepting albumin-paclitaxel realized 42% reduce, and the therapeutic alliance group shows that the pawl size reduces 33%, and matched group pawl size is compared during with the treatment beginning and increased about 20%.

In a word, albumin-paclitaxel compositions shows therapeutic effect to arthritis.The combination of albumin-paclitaxel may be positioned the position of arthritis damage by the transhipment of receptor-mediated mechanism such as gp60.

Embodiment 51

Present embodiment is for example understood the application of albumin-paclitaxel compositions in the treatment cardiovascular restenosis.

Paclitaxel outflow support (Paclitaxel eluting stents) causes incomplete healing in the animal, in some situation, causes lacking the lasting inhibition to the neointima growth in tremulous pulse.This research has checked new systems communicate albumin-paclitaxel present composition for the effect that reduces in-stent restenosis.

In accepting 38 New Zealand white rabbit of bilateral iliac artery support, detect the albumin-paclitaxel of saline reconstruct.With the endoarterial infusion administration of the dosage (1.0-5.0mg/kg dose of paclitaxel) of albumin-paclitaxel as 10-minute; Control animals received carrier (0.9% normal saline).

In ensuing chronic experiment, 5.0mg/kg albumin-paclitaxel is offered support, at the 28th day intravenous repeated doses administration 3.5-mg/kg albumin-paclitaxel; These researchs stopped at 3 months.At the 28th day, reduced average neointima thickness (p＜=0.02) by dosed administration albumin-paclitaxel＞=2.5mg/kg, the healing of evidence for prolonging.Yet the effect of the 5.0mg/kg albumin-paclitaxel of single dose was lost before 90 days.On the contrary, 28 days second time, repeat administration 3.5mg/kg albumin-paclitaxel caused the lasting inhibition at 90 days stylish inner film thickness (to be compared with contrast with single dose 5.0mg/kg albumin-paclitaxel behind upper bracket, p＜=0.009), neointima almost completely heals.

Although the albumin-paclitaxel of system has reduced the neointima growth at 28 days, suppress to require the single repeated doses for lasting neointima.Therefore, the present composition is applicable to treatment cardiovascular disease such as restenosis.The present invention comprises medicament except paclitaxel (rapamycin for example, other taxanes, Epothilones etc.) compositions is applicable to that all treatment blood vessel or artificial blood vessel graft are as being used for those restenosis of artery-vein inlet in needing the patient of hemodialysis.

Claims

1. pharmaceutical composition that comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises with effective reduction the albumin of the amount of one or more side effect that described pharmaceutical composition delivered medicine to the people, and wherein said pharmaceutical carrier comprises deferoxamine with the amount of the growth of microorganism in effective depressant compositions.

2. the pharmaceutical composition of claim 1, wherein said medicament is selected from the group of being made up of following: anticarcinogen, anesthetis, anti-microtubule agent is used for the treatment of the medicament of cardiovascular disorder, antihypertensive, anti-inflammatory agent, arthritis agent, antiasthmatic drug, analgesic, vasoactive agent, immunosuppressant, antifungal, antiarrhythmics, antibiotic, and hormone.

3. the pharmaceutical composition of claim 2, wherein said medicament is selected from the group of being made up of following: paclitaxel, docetaxel, taxanes, camptothecine, propofol, amiodarone, cyclosporin, rapamycin, amphotericin, liothyronine, Epothilones, colchicine, thyroid hormones, vasoactive intestinal peptide, corticosteroid, melatonin, tacrolimus, Mycophenolic Acid and their derivant.

4. the pharmaceutical composition of claim 3, wherein said medicament is a propofol.

5. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.1 weight % to about 25 weight %.

6. the pharmaceutical composition of claim 5, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.5 weight % to about 5 weight %.

7. the pharmaceutical composition of claim 5, wherein said pharmaceutical composition is dehydrated.

8. the pharmaceutical composition of claim 6, wherein said pharmaceutical composition is by lyophilizing.

9. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises the mesylate of deferoxamine.

10. the pharmaceutical composition of claim 9, wherein said pharmaceutical composition are liquid and comprise the deferoxamine mesylate of about 0.0001 weight % to about 0.5 weight %.

11. the pharmaceutical composition of claim 10, wherein said pharmaceutical composition comprises the deferoxamine mesylate of about 0.1 weight %.

12. the pharmaceutical composition of claim 10, wherein said pharmaceutical composition is dehydrated.

13. the pharmaceutical composition of claim 12, wherein said pharmaceutical composition is by lyophilizing.

14. the pharmaceutical composition of claim 1, wherein said pharmaceutical composition is an oil-in-water emulsion.

15. the pharmaceutical composition of claim 5, wherein said medicament is a propofol.

16. the pharmaceutical composition of claim 10, wherein said medicament is a propofol.

17. the pharmaceutical composition of claim 9, wherein said medicament is a propofol, propofol exists to the amount of about 5 weight % with about 0.1 weight %, and albumin exists and deferoxamine mesylate exists to the amount of about 0.5 weight % with about 0.0001 weight % to the amount of about 25 weight % with about 0.1 weight %.

18. pharmaceutical composition that comprises medicament and pharmaceutical carrier, one or more comprise albumin with the amount that described pharmaceutical composition delivers medicine to people's side effect to wherein said pharmaceutical carrier with effective reduction, and wherein said pharmaceutical carrier comprises deferoxamine with the amount of the oxidation in effective depressant compositions.

19. one kind is reduced one or more and the method that pharmaceutical composition is delivered medicine to the relevant side effect of people, this method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to people's administration, and wherein said pharmaceutical carrier comprises albumin and deferoxamine.

20. the method for claim 19, wherein said medicament is selected from the group of being made up of following: anticarcinogen, anesthetis, anti-microtubule agent is used for the treatment of the medicament of cardiovascular disorder, antihypertensive, anti-inflammatory agent, arthritis agent, antiasthmatic drug, analgesic, vasoactive agent, immunosuppressant, antifungal, antiarrhythmics, antibiotic, and hormone.

21. the method for claim 20, wherein said medicament is selected from the group of being made up of following: paclitaxel, docetaxel, taxanes, camptothecine, propofol, amiodarone, cyclosporin, rapamycin, amphotericin, liothyronine, Epothilones, colchicine, thyroid hormones, vasoactive intestinal peptide, corticosteroid, melatonin, tacrolimus, Mycophenolic Acid and their derivant.

22. the method for claim 21, wherein said medicament is a propofol.

23. the method for claim 19, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.1 weight % to about 25 weight %.

24. the method for claim 23, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.5 weight % to about 5 weight %.

25. the method for claim 23, wherein said pharmaceutical composition is dehydrated.

26. the method for claim 25, wherein said pharmaceutical composition is by lyophilizing.

27. the method for claim 23, wherein said medicament is a propofol.

28. the method for claim 19, wherein said pharmaceutical composition comprises the mesylate of deferoxamine.

29. the method for claim 28, wherein said pharmaceutical composition are liquid and comprise the deferoxamine mesylate of about 0.0001 weight % to about 0.5 weight %.

30. the method for claim 29, wherein said pharmaceutical composition comprises the deferoxamine mesylate of about 0.1 weight %.

31. the method for claim 29, wherein said pharmaceutical composition is dehydrated.

32. the method for claim 31, wherein said pharmaceutical composition is by lyophilizing.

33. the method for claim 29, wherein said medicament is a propofol.

34. the method for claim 28, wherein said medicament is a propofol, propofol exists to the amount of about 5 weight % with about 0.1 weight %, and albumin exists and deferoxamine mesylate exists to the amount of about 0.5 weight % with about 0.0001 weight % to the amount of about 25 weight % with about 0.1 weight %.

35. the method for claim 19 wherein delivers medicine to the people with described pharmaceutical composition by administration in intravenous administration, intra-arterial administration, feeding drug into pulmones, oral administration, suction, the trachea, intravesical administration, intramuscular administration, subcutaneous administration, eye drops, intrathecal drug delivery or transdermal administration.

36. the method for claim 19, wherein said one or more side effect are selected from the group of being made up of following: bone marrow depression, neurotoxicity, allergy, venous stimulation, inflammation, phlebitis, pain, skin irritation, and combination.

37. a method that is used for depressant compositions growth of microorganism, this method comprise the pharmaceutical composition that preparation comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises the deferoxamine with the amount of the growth of microorganism in effective depressant compositions.

38. the method for claim 37, wherein said pharmaceutical composition comprises the mesylate of deferoxamine.

39. the method for claim 38, wherein said pharmaceutical composition are liquid and comprise the deferoxamine mesylate of about 0.0001 weight % to about 0.5 weight %.

40. the method for claim 39, wherein said pharmaceutical composition comprises the deferoxamine mesylate of about 0.1 weight %.

41. the method for claim 39, wherein said pharmaceutical composition is dehydrated.

42. the method for claim 41, wherein said pharmaceutical composition is by lyophilizing.

43. the method for claim 37, wherein said pharmaceutical composition comprises albumin in addition.

44. the method for depressant compositions oxidation, this method comprise the pharmaceutical composition that preparation comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises deferoxamine with the amount of the oxidation of the described pharmaceutical composition of effective inhibition.

45. the method for claim 44, wherein said pharmaceutical composition comprises the mesylate of deferoxamine.

46. the method for claim 45, wherein said pharmaceutical composition are liquid and comprise the deferoxamine mesylate of about 0.0001 weight % to about 0.5 weight %.

47. the method for claim 46, wherein said pharmaceutical composition comprises the deferoxamine mesylate of about 0.1 weight %.

48. the method for claim 46, wherein said pharmaceutical composition is dehydrated.

49. the method for claim 48, wherein said pharmaceutical composition is by lyophilizing.

50. the method for claim 44, wherein said pharmaceutical composition comprises albumin in addition.

51. one kind is used to strengthen the method for medicament to the transhipment of weak position, this method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to people's administration, wherein said pharmaceutical carrier comprises albumin, and wherein in albumin and the pharmaceutical composition ratio of medicament be about 18: 1 or littler.

52. the method for claim 51, wherein said medicament is selected from the group of being made up of following: anticarcinogen, anesthetis, anti-microtubule agent is used for the treatment of the medicament of cardiovascular disorder, antihypertensive, anti-inflammatory agent, arthritis agent, antiasthmatic drug, analgesic, vasoactive agent, immunosuppressant, antifungal, antiarrhythmics, antibiotic, and hormone.

53. the method for claim 52, wherein said medicament is selected from the group of being made up of following: paclitaxel, docetaxel, taxanes, camptothecine, propofol, amiodarone, cyclosporin, rapamycin, amphotericin, liothyronine, Epothilones, colchicine, thyroid hormones, vasoactive intestinal peptide, corticosteroid, melatonin, tacrolimus, Mycophenolic Acid and their derivant.

54. the method for claim 51, wherein said medicament is a nucleotide sequence.

55. the method for claim 54, wherein said nucleotide sequence is a DNA sequence.

56. the method for claim 51, wherein said weakness is selected from cancer, arthritis or cardiovascular disease.

57. the method for claim 51, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.1 weight % to about 25 weight %.

58. the method for claim 57, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.5 weight % to about 5 weight %.

59. the method for claim 57, wherein said pharmaceutical composition is dehydrated.

60. the method for claim 59, wherein said pharmaceutical composition is by lyophilizing.

61. the method for claim 51, wherein the ratio of medicament is about 12: 1 or littler in albumin and the pharmaceutical composition.

62. the method for claim 51, wherein the ratio of medicament is about 9: 1 or littler in albumin and the pharmaceutical composition.

63. the method for claim 51 wherein delivers medicine to the people with described pharmaceutical composition by administration in intravenous administration, intra-arterial administration, feeding drug into pulmones, oral administration, suction, the trachea, intravesical administration, intramuscular administration, subcutaneous administration, eye drops, intrathecal drug delivery or transdermal administration.

64. one kind strengthens medicament and the external or bonded method of cells in vivo, this method comprises the pharmaceutical composition that comprises medicament and pharmaceutical carrier to described external or cells in vivo administration, wherein said pharmaceutical carrier comprises albumin, and wherein in albumin and the pharmaceutical composition ratio of medicament be about 18: 1 or littler.

65. the method for claim 64, wherein said medicament is selected from the group of being made up of following: anticarcinogen, anesthetis, anti-microtubule agent is used for the treatment of the medicament of cardiovascular disorder, antihypertensive, anti-inflammatory agent, arthritis agent, antiasthmatic drug, analgesic, vasoactive agent, immunosuppressant, antifungal, antiarrhythmics, antibiotic, and hormone.

66. the method for claim 65, wherein said medicament is selected from the group of being made up of following: paclitaxel, docetaxel, taxanes, camptothecine, propofol, amiodarone, cyclosporin, rapamycin, amphotericin, liothyronine, Epothilones, colchicine, thyroid hormones, vasoactive intestinal peptide, corticosteroid, melatonin, tacrolimus, Mycophenolic Acid and their derivant.

67. the method for claim 64, wherein said medicament is a nucleotide sequence.

68. the method for claim 67, wherein said nucleotide sequence is a DNA sequence.

69. the method for claim 64, wherein said cell is an endotheliocyte.

70. the method for claim 64, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.1 weight % to about 25 weight %.

71. the method for claim 70, wherein said pharmaceutical composition are liquid and comprise the albumin of about 0.5 weight % to about 5 weight %.

72. the method for claim 70, wherein said pharmaceutical composition is dehydrated.

73. the method for claim 72, wherein said pharmaceutical composition is by lyophilizing.

74. the method for claim 64, wherein the ratio of medicament is about 12: 1 or littler in albumin and the pharmaceutical composition.

75. the method for claim 64, wherein the ratio of medicament is about 9: 1 or littler in albumin and the pharmaceutical composition.

76. the method for claim 64 wherein delivers medicine to the people with described pharmaceutical composition by administration in intravenous administration, intra-arterial administration, feeding drug into pulmones, oral administration, suction, the trachea, intravesical administration, intramuscular administration, subcutaneous administration, eye drops, intrathecal drug delivery or transdermal administration.

77. a pharmaceutical composition that comprises medicament and pharmaceutical carrier, one or more comprise albumin with amount to the side effect of people's administration medicine compositions to wherein said pharmaceutical carrier with effective reduction, and wherein the ratio of albumin and medicament is about 18: 1 or littler.

78. the pharmaceutical composition of claim 77, the ratio of the medicament in wherein said albumin and the pharmaceutical composition are about 12: 1 or littler.

79. the pharmaceutical composition of claim 77, the ratio of the medicament in wherein said albumin and the pharmaceutical composition are about 9: 1 or littler.

80. a pharmaceutical composition that comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises albumin with effective increase medicine to the amount of people's weak position transhipment, and wherein the ratio of albumin and medicament is about 18: 1 or littler.

81. the pharmaceutical composition of claim 80, the ratio of the medicament in wherein said albumin and the pharmaceutical composition are about 12: 1 or littler.

82. the pharmaceutical composition of claim 80, the ratio of the medicament in wherein said albumin and the pharmaceutical composition are about 9: 1 or littler.

83. the pharmaceutical composition of claim 80, wherein said weakness is selected from cancer, arthritis or cardiovascular disease.

84. the pharmaceutical composition of claim 1, the ratio of wherein said albumin and medicament are about 18: 1 or littler.

85. one kind by increasing described medicament to method external or the cells in vivo transhipment with medicament and protein bound, specific cell surface receptor on the described cell of wherein said protein bound, the combination of wherein said protein-medicament causes the transhipment generation with combining of described receptor, and wherein the ratio of protein and medicament is about 18: 1 or littler.

86. the method for claim 85, wherein said protein is albumin.

87. the method for claim 85, wherein said medicament is selected from the group of being made up of following: anticarcinogen, anesthetis, anti-microtubule agent is used for the treatment of the medicament of cardiovascular disorder, antihypertensive, anti-inflammatory agent, arthritis agent, antiasthmatic drug, analgesic, vasoactive agent, immunosuppressant, antifungal, antiarrhythmics, antibiotic, and hormone.

88. the method for claim 87, wherein said medicament is selected from the group of being made up of following: paclitaxel, docetaxel, taxanes, camptothecine, propofol, amiodarone, cyclosporin, rapamycin, amphotericin, liothyronine, Epothilones, colchicine, thyroid hormones, vasoactive intestinal peptide, corticosteroid, melatonin, tacrolimus, Mycophenolic Acid and their derivant.

89. the method for claim 85, wherein the ratio of the medicament in albumin and the pharmaceutical composition is about 12: 1 or littler.

90. the method for claim 85, wherein the ratio of the medicament in albumin and the pharmaceutical composition is about 9: 1 or littler.

91. a pharmaceutical composition that comprises medicament and pharmaceutical carrier, one or more comprise protein with amount to the side effect of people's administration medicine compositions to wherein said pharmaceutical carrier with effective reduction, and wherein the ratio of protein and medicament is about 18: 1 or littler.

92. the pharmaceutical composition of claim 91, wherein the ratio of the medicament in protein and the described pharmaceutical composition is about 12: 1 or littler.

93. the pharmaceutical composition of claim 91, wherein the ratio of the medicament in protein and the described pharmaceutical composition is about 9: 1 or littler.