CN101357939A - Protein conjugate and pharmaceutical compositions thereof - Google Patents
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- CN101357939A CN101357939A CNA2008102120159A CN200810212015A CN101357939A CN 101357939 A CN101357939 A CN 101357939A CN A2008102120159 A CNA2008102120159 A CN A2008102120159A CN 200810212015 A CN200810212015 A CN 200810212015A CN 101357939 A CN101357939 A CN 101357939A
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Abstract
The invention discloses a novel protein conjugate which is the conjugate of proteins and endogenous substances modified by cystine or cysteine. Besides, the invention also discloses a drug combination comprising the protein conjugate and the preparation method of the protein conjugate and the drug combination comprising the protein conjugate. The invention does not relate to toxic organic solvents and catalysts, reactions are simple and easy, and products are easy for separation, refinement and quality control, and moreover, the active targeting property of the obtained drug combination is improved.
Description
Technical field
The present invention relates to drug preparation technique, more particularly, relate to novel protein conjugate and preparation method thereof and the pharmaceutical composition that contains this protein conjugate.
Background technology
Find that in drug research it is slightly water-soluble that nearly 40% medicine is arranged, some medicines even be insoluble in organic solvent cause its bioavailability low.In the preparation process, adopt cyclodextrin inclusion technique, surface active agent solubilization, emulsion, micro emulsion and solid dispersion technology etc. can solve the low bioavailability problem of some insoluble drugs, but still have a large amount of medicines to be abandoned using owing to the bioavailability problem.And the nanometer suspension technology provides the chance of reappearing self-value for these medicines.Nano suspension system adopts low quantity of surfactant or other carrier to stablize the formed a kind of submicron colloidal dispersion system of pure drug particle.Discovering in recent years, nano suspension can increase drug dissolution, improves bioavailability of medicament, increases medicine stability and improve drug effect, and this makes those poorly soluble antibiotics, antitumor drug and the narrow medicine of some treatment windows can bring into play better effect.And some water soluble drugs also can be made nano suspension increase target or can slowly-releasing (Zhu Jianfen, Wu Xianggen, the preparation method of nano suspension and the progress of using [J] in pharmaceutics; Chinese Journal of Pharmaceuticals; 2006 03 phases: 196-200).
2005, what FDA had ratified the exploitation of American Pharmaceutical Partners company was the paclitaxel prodrugs Abraxane of carrier with human serum albumin (HSA), and Abranane has the remarkable advantage better than paclitaxel injection (Taxol).This product is with taxol and a kind of nanometer suspension preparation of human serum albumin bonded.Because the solubleness of Abraxane improves greatly than taxol, needn't use toxic solvents, need not the reaction of premedication Ammonium Glycyrrhizate, can adopt standard venoclysis conduit, with than the dosage of Taxol high 50%, in internal jugular vein administration in 30 minutes.Clinical trial shows, Abraxane is used for the treatment of through the auxiliary combined chemotherapy failure of anthracene nucleus medicament or in 6 months again behind the metastatic breast cancer patient of recurrence, and its curative effect reactivity and patient's survival rate all significantly are better than Taxol.Studies show that Abraxane can passively put aside in the growing tumors fast.Taxol is received and brilliant is kept long-time causes for stable to be among the Abraxane: be on the one hand human serum albumin intermolecular under high pressure and high shear disulfide bond crosslinking receive at taxol and form one deck shell around brilliant; Be the charged formed space static electricity repulsive force of human serum albumin molecule on the other hand.International patent application ((publication No. WO/1998/014174) denomination of invention: PROTEINSTABILIZED PHARMACOLOGICALLY ACTIVE AGENTS, METHODS FORTHE PREPARATION THEREOF AND METHODS FOR THE USE THEREOF) has been introduced the preparation method of Abraxane.
Human serum albumin has been obtained very big success as the carrier of injection taxol nanosuspension, but also exist not enough: Abraxane is a passive targeted preparation on the one hand, still can further study and make active target preparation, improve target in the ability of tumor tissues; In our research, find on the other hand to the brilliant stability of receiving of the other drug outside taxol, the ciclosporin A a little less than.
Summary of the invention
The purpose of this invention is to provide a kind of novel protein conjugate.
Another object of the present invention provides the pharmaceutical composition that comprises above-mentioned protein conjugate.
Another object of the present invention provides above-mentioned protein conjugate and comprises above-mentioned protein conjugate preparation of drug combination method.
Specifically, the invention discloses a kind of novel protein conjugate, this conjugate is the conjugate of the endogenous material of protein and Gelucystine or cysteine modified, wherein, described protein is serum albumin, be selected from human serum albumin, recombination human serum albumin or bovine serum albumin, be preferably human serum albumin; Described endogenous material is selected from the one or more kinds of combinations in cholic acid or derivatives thereof, oligomerization hyaluronic acid, phosphatidylserine, the folic acid.
Described cholic acid and derivative thereof, wherein the chemical formula of cholic acid is 3a, 7a, 12a-trihydroxy-cholestane-24-acid is also referred to as ursodeoxycholic acid, colalin, cholalic acid etc.; Chlolic acid derivatives is selected from Deoxycholic Acid, dehydrocholic acid, Chenodiol, ursodesoxycholic acid, Hyodeoxycholic Acid, lithocholic acid, glycocholic acid, taurocholate, glycochenodeoxycholate, ox sulphur gallodesoxycholic acid, sweet ammonia Deoxycholic Acid, taurodeoxycholic acid, sweet ammonia Hyodeoxycholic Acid, ox sulphur Hyodeoxycholic Acid, sweet ammonia ursodesoxycholic acid, ursodeoxycholic acid, sweet ammonia lithocholic acid, taurolithocholic acid etc.
Described oligomerization hyaluronic acid is meant that in the present invention molecular weight is 1000～10000 daltonian hyaluronic acids.
Human serum albumin, recombination human serum albumin, bovine serum albumin, folic acid, phosphatidylserine do not have particular restriction in the present invention.
The carboxyl of endogenous material of the present invention randomly carries out the acid amides reaction with the amino of Gelucystine or halfcystine, generates the derivative that contains disulfide linkage or sulfydryl accordingly.Contain more cysteine residues in the albumin, under the situation of being heated, can carry out crosslinkedly, obtain the novel protein conjugate with the above-mentioned derivative that contains disulfide linkage or sulfydryl.The constitutional features of this conjugate is that the carboxyl of endogenous material and the primary amino of halfcystine or Gelucystine structure pass through to pass through halfcystine structure and serum albumin again with the disulfide linkage coupling after the amido linkage coupling, passes through the further coupling of disulfide linkage between the protein.
In the structure of novel protein conjugate of the present invention, each serum albumin and 1-35 endogenous material of the present invention coupling by the way basically; And each endogenous material of the present invention has the primary amino of 1-25 carboxyl and 1-25 halfcystine structure to pass through the amido linkage coupling basically, passes through halfcystine structure and single or multiple serum albumin again with 1-25 disulfide linkage coupling; The novel protein conjugate can have halfcystine to pass through disulfide linkage coupling with it simultaneously; In the endogenous material of the present invention one or more can mix by the way with serum albumin with the disulfide linkage coupling; Said structure is all in protection scope of the present invention.
In addition, the present invention also provides the pharmaceutical composition that contains medicament and pharmaceutical carrier, and pharmaceutical carrier wherein contains above-mentioned novel protein conjugate.
Any suitable medicament can be used in the pharmaceutical composition of the present invention, and suitable medicament includes but are not limited to the antipyretic-antalgic agent, anti-asthmatic, microbiotic, thymoleptic, antidiabetic drug, antiphlogiston, antitumour drug, anxiolytic, immunological reagent, sedative hypnotics, anti-anginal drug, antipsychotic drug, antimanic drug, anti-arthritic, anti-arrhythmic, antigout drug, antithrombotics, thrombolytic agent, antifibrinolytic agent, hemorheologic agent, antiplatelet drug, anticonvulsive drug, anti-Ba Jinsen medicine, antihistaminic, be used for the medicine that calcium is regulated, antiviral, bronchodilator, hormone, lipid lowerers, protein, polypeptide, nucleic acid, antiulcer agent or anti-reflux medicine, antiemetic, diagnostic medicament, with the trophicity medicine.Wherein preferably, medicament is an antitumour drug, concrete taxol and derivative, docetaxel, camptothecine and derivative thereof, Etoposide, teniposide, doxorubicin hydrochloride, endoxan, actinomycin, bleomycin, zhengdingmeisu, Zorubicin, pidorubicin, mitomycin, Rheumatrex, 5 FU 5 fluorouracil, carboplatin, carmustine, lomustine, cis-platinum, vinealeucoblastine(VLB), vincristine(VCR), tamoxifen, A-20968, the phenesterin of including but are not limited to.More preferably, medicament is a taxol or derivatives thereof [concrete D51-7059, referring to " Li Yan; Wang Yonghua; room China; etc. the D-M (Determiner-Measure) construction-antitumour activity of taxoid derivatives concerns progress; " Chinese Pharmacological Bulletin; 2008,24 (3): 288～93) ", the content of the document and reference thereof are introduced here as a reference fully], docetaxel, camptothecine or derivatives thereof [concrete camptothecin derivative, referring to " swim bright; Zhang Wannian, Zhang Lijun, Miu Zhenyuan. camptothecine and derivative latest Progress thereof; " Chinese pharmaceutical chemistry magazine "; 2007,17 (5): 327-332 ", the content of the document and reference thereof are introduced here as a reference fully].Most preferably, medicament is a taxol.
The present invention also provides above-mentioned novel protein conjugate and preparation of drug combination method thereof.
The invention provides the method for preparation protein conjugate of the present invention, it comprises the steps:
1) endogenous material of described protein and more than one Gelucystine or cysteine modified is dissolved in the appropriate solvent;
2) the resulting mixture of step 1) is heated, and temperature is the 20-80 degree, preferred 25-70 degree, most preferably 30-60 degree;
3) separate the uncrosslinked Gelucystine of removal or the endogenous material of cysteine modified;
4) drying;
Here, described protein, the definition of endogenous material is the same, described appropriate solvent can be selected from water, methyl alcohol, dehydrated alcohol, the ethanol that contains certain water gaging, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, dimethyl sulfoxide (DMSO), N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, methyl acetate, ethyl acetate, Iso Butyl Acetate, acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), toluene, tetrahydrofuran (THF), 1,4 one dioxane, glycol dimethyl ether, methylene dichloride, ethylene dichloride, trichloromethane, a kind of in tetrachloromethane or the ether, perhaps two or more combinations, preferably, solvent is a water, ethyl acetate, methylene dichloride, trichloromethane, or a kind of, the perhaps two or more combination in the tetrachloromethane;
The Gelucystine that described separation is uncrosslinked or the endogenous material of cysteine modified can adopt methods such as ultrafiltration, high speed centrifugation, dialysis, preferred ultrafiltration, supercentrifugal process;
The drying means of described solution comprises lyophilize, spraying drying, drying under reduced pressure, constant pressure and dry etc., preferably freeze drying, spraying drying and drying under reduced pressure;
More particularly, above-mentioned preparation method comprises:
The endogenous material of serum albumin and Gelucystine or cysteine modified is soluble in water, and solution is heated, and separates the uncrosslinked Gelucystine or the endogenous material of cysteine modified, and drying promptly obtains protein conjugate of the present invention.
Perhaps the endogenous material of Gelucystine or cysteine modified is dissolved in other suitable non-aqueous solvent the back and mixes the formation emulsion with the serum albumin aqueous solution, through again being heated, separating, drying, obtain protein conjugate of the present invention.
Wherein, the mol ratio of the endogenous material of serum albumin and Gelucystine or cysteine modified is 0.001: 1-1000: 1, be preferably 0.01: 1-100, more preferably 35: 1-1: 35;
Sero-abluminous concentration of aqueous solution is 0.001%-50% (w/v), is preferably 0.01%-10% (w/v);
The concentration of aqueous solution of the endogenous material of Gelucystine or cysteine modified is 0.00001%-50% (w/v), is preferably 0.0001%-10% (w/v).
Perhaps the non-aqueous solvent concentration of the endogenous material of Gelucystine or cysteine modified is 0.001%～50% (w/v), is preferably 0.01%～30% (w/v);
Carboxyl coupling degree is 2%～99% in the endogenous material of Gelucystine or cysteine modified, is preferably 2%～50%.
The invention provides the method for pharmaceutical composition that preparation contains protein conjugate of the present invention, can select a kind of in following two kinds of methods for use:
A. prepare described protein conjugate; Conjugate is mixed with medicament;
1) described protein conjugate and medicine are dissolved in the appropriate solvent;
2) the resulting mixture of step 1) is heated, and temperature is the 20-80 degree, preferred 25-70 degree, most preferably 30-60 degree;
3) drying;
Here, described protein, endogenous material, appropriate solvent, drying means are the same.
More particularly, this preparation method is:
Protein conjugate is soluble in water, and medicine is dissolved in the appropriate solvent, mixes two kinds of solution and forms emulsion, is heated, and drying promptly obtains the medicament nano suspensoid that protein conjugate of the present invention wraps up;
Wherein,
The concentration of aqueous solution of protein conjugate is 0.001%-50% (w/v), is preferably 0.01%-10% (w/v);
The concentration of drug solution is 0.001%～50% (w/v), is preferably 0.01%～30% (w/v);
The aqueous solution of protein conjugate and the volume ratio of drug solution are 0.0001: 1～10000: 1, are preferably 5: 1～100: 1;
B.
1) described protein, more than one Gelucystine or the endogenous material and the medicine of cysteine modified are dissolved in the appropriate solvent;
2) the resulting mixture of step 1) is heated, and temperature is the 20-80 degree, preferred 25-70 degree, most preferably 30-60 degree;
Here, described protein, endogenous material, appropriate solvent, drying means are the same.
More particularly, this preparation method is:
The endogenous material of serum albumin and Gelucystine or cysteine modified is soluble in water, medicine is dissolved in the appropriate solvent, mix two kinds of solution and form emulsion, be heated, the oligomerization hyaluronic acid that randomly separates uncrosslinked Gelucystine or cysteine modified, drying promptly obtains the medicament nano suspensoid that protein conjugate of the present invention wraps up;
Perhaps endogenous material and the medicine with Gelucystine or cysteine modified is dissolved in the appropriate solvent, mixes with the serum albumin aqueous solution to form emulsion, is heated, and drying promptly obtains the medicament nano suspensoid that protein conjugate of the present invention wraps up.Protein conjugate and medicament nano suspensoid prepare simultaneously in the method.
Wherein,
The mol ratio of the endogenous material of serum albumin and Gelucystine or cysteine modified is 0.001: 1-1000: 1, be preferably 0.01: 1-100: 1, more preferably 35: 1-1: 35.；
Sero-abluminous concentration of aqueous solution is 0.001%-50% (w/v), is preferably 0.01%-10% (w/v);
The concentration of aqueous solution of the endogenous material of Gelucystine or cysteine modified is 0.00001%-50% (w/v), is preferably 0.0001%-10% (w/v);
The non-aqueous solvent concentration of the endogenous material of Gelucystine or cysteine modified is 0.001%～50% (w/v), is preferably 0.01%～30% (w/v);
The concentration of drug solution is 0.001%～50% (w/v), is preferably 0.01%～30% (w/v);
The aqueous solution of the endogenous material of serum albumin and Gelucystine or cysteine modified and the volume ratio of drug solution are 0.0001: 1～10000: 1, are preferably 5: 1～100: 1;
The volume ratio of the endogenous material of the serum albumin aqueous solution and Gelucystine or cysteine modified and the solution of medicine is 0.0001: 1～10000: 1, is preferably 5: 1～100: 1.
In protein conjugate of the present invention and preparation of drug combination method thereof,
The compound that contains disulfide linkage or sulfydryl can carry out crosslinked under the situation of being heated; therefore the every equipment or method that can produce heat all may make the endogenous material of serum albumin and Gelucystine or cysteine modified carry out coupling; so these equipment or method are for example ultrasonic; microwave; infrared; spraying drying etc.; high-pressure homogeneous; high speed shear; high-speed stirring; vacuum-drying etc. are all in protection scope of the present invention; preferred high pressure homogenizer carries out homogeneous to the aqueous solution or the emulsion of the endogenous material of serum albumin and Gelucystine or cysteine modified; because the heat that high pressure and shearing force produce, the endogenous material of serum albumin and Gelucystine or cysteine modified can coupling.
Useful technique effect of the present invention is: general modified albumin method needs toxic organic solvent and catalyzer, and product is difficult to separation and purification, generally can not be used for intravenous injection.The present invention serves as the reaction basis with the crosslinked of disulfide linkage in the amino-acid residue, adopt preparation equipment and method that human serum albumin is carried out chemically modified, the mentality of designing uniqueness does not need toxic organic solvent and catalyzer, easy reaction, product are easy to separation and purification and carry out quality control.
In addition, the present invention can prepare the novel nano suspensoid carrier with active target tumor characteristics by human body endogenous material oligomerization hyaluronic acid and modified with folic acid serum albumin, improves the target of antitumor drug.Serum albumin is as the carrier of nano suspension, to other outer antitumor drugs of taxol receive brilliant stability a little less than, can not add other tensio-active agent in the system, otherwise stability is poorer.The present invention modifies serum albumin by human body endogenous material phosphatidylserine and Deoxycholic Acid, has increased the suitable antitumor drug scope of serum albumin as injection nanometer suspension agent carrier, for example docetaxel.Adopt described nanometer suspension agent carrier, can make the relative uptake ratio (r of tumor bearing nude mice knurl body
e) raising 25-60%, target efficient (t
e) improving 20-80%, peak concentration is than (C
e) raising 15-80%.
Embodiment
Embodiment 1
Ultrasonication prepares folic acid-bovine serum albumin conjugate
With the 30.0ml bovine serum albumin (1%, w/v) and the folic acid modified of Gelucystine (0.1%, w/v) solution was handled 2 minutes in the ultrasonic processor of 60kHz, thin up, molecular weight is 10,000 ultra-filtration membrane ultrafiltration, and the concentrated solution lyophilize promptly obtains folacin coupled bovine serum albumin.
Embodiment 2
Be equipped with the oligomerization LMW-HA/HAS with the high pressure homogenization legal system
With 200.0ml human serum albumin (1%, w/v) and the oligomerization hyaluronic acid (0.1% modified of Gelucystine, w/v, oligomerization hyaluronan molecule amount is 3500, and Gelucystine coupling degree is 10%) solution transfers in the high pressure homogenization device, high pressure homogenization circulation 5 times, even matter liquid thin up, molecular weight is 30,000 ultra-filtration membrane ultrafiltration, and the concentrated solution lyophilize promptly obtains oligomerization hyaluronic acid link coupled human serum albumin.
Embodiment 3
The taxol nanosuspension that contains folic acid-human serum albumin conjugate with the preparation of high pressure homogenization method
200mg taxol (Paclitaxel) is dissolved in the dehydrated alcohol of the chloroform of 2.7ml and 0.3ml, add 97.0ml human serum albumin (3%, w/v) and the folic acid (0.3% modified of Gelucystine, w/v) aqueous solution, mixture homogenate 5 minutes under the slow speed of revolution, to form rough emulsion, then it is transferred in the high pressure homogenization device, high pressure homogenization circulation 8 times, even matter liquid evaporates under 40 ℃ of decompressions removed methylene dichloride in 20 minutes rapidly, the dispersion liquid that obtains is translucent, taxol particulate diameter is generally 130～160nm, and thin up, molecular weight are 10,000 ultra-filtration membrane ultrafiltration, with concentrated solution lyophilize 48 hours, do not add any freeze-drying propping agent.Gained cake piece adds and very easily behind sterilized water or the physiological saline to reconstruct original dispersion liquid, and it is preceding identical with lyophilize to reconstruct the back granular size.
The folate conjugate of human serum albumin and taxol nanosuspension prepare simultaneously in the present embodiment, and it is outer as stablizer that the folate conjugate of human serum albumin is enclosed in the pure medicament nano particle of taxol.
Embodiment 4
The docetaxel nanometer suspensoid that contains phosphatidylserine-human serum albumin conjugate with the preparation of high pressure homogenization method
The phosphatidylserine that 30mg docetaxel, 30mg Gelucystine are modified is dissolved in the 3.0ml methylene dichloride, add 30.0ml human serum albumin (1%, w/v), mixture homogenate 5 minutes under the slow speed of revolution, to form rough emulsion, it is transferred in the high pressure homogenization device then, high pressure homogenization circulation 8 times, even matter liquid evaporates under 40 ℃ of decompressions removed methylene dichloride in 30 minutes, the dispersion liquid that obtains is translucent, docetaxel particulate diameter is generally 180～230nm, and lyophilize 48 hours does not add any freeze-drying propping agent.Gained cake piece adds and very easily behind sterilized water or the physiological saline to reconstruct original dispersion liquid, and it is preceding identical with lyophilize to reconstruct the back granular size.
The phosphatidylserine conjugate of human serum albumin and docetaxel nanometer suspensoid prepare simultaneously in the present embodiment, and it is outer as stablizer that the phosphatidylserine conjugate of human serum albumin is enclosed in the pure medicament nano particle of docetaxel.
Embodiment 5
The taxol nanosuspension of folic acid-human serum albumin conjugate contains the Nimodipime nanometer suspension of cholic acid-bovine serum albumin conjugate with the preparation of high pressure homogenization method
The cholic acid that 30mg nimodipine, 30mg Gelucystine are modified is dissolved in the 3.0ml ethanol, add in the 30.0ml human serum albumin (2%), transfer in the high pressure homogenization device then rapidly, high pressure homogenization circulation 6 times, even matter liquid evaporates under 40 ℃ of decompressions removes most of ethanol, the dispersion liquid that obtains is translucent, nimodipine particulate diameter is generally 320～460nm, vacuum-drying 8 hours, add and very easily behind the physiological saline reconstruct original dispersion liquid, it is preceding identical with vacuum-drying to reconstruct the back granular size.
The cholic acid conjugate nano suspension of the cholic acid conjugate of bovine serum albumin and nimodipine prepares simultaneously in the present embodiment, and it is outer as stablizer that the cholic acid conjugate of bovine serum albumin is enclosed in the pure medicament nano particle of nimodipine.
Embodiment 6
Personnel selection breast cancer cell line mcf-7 inoculation nude mice right fore is subcutaneous, treat that knurl body diameter begins experiment when growing to about 10mm, random packet, the Abraxane of difference tail vein injection same dose, the taxol nanosuspension of folic acid-human serum albumin conjugate (pressing embodiment 3 preparations), measure blood concentration and the interior drug distribution of different tissues in the different time body, carry out data processing with 3P97 software, the result compares with Abraxane, the relative uptake ratio (r of human breast carcinoma nude mice knurl body
e) improve 55%, target efficient (t
e) improving 48%, peak concentration is than (C
e) improve 42%.
Claims (16)
1. a protein conjugate is characterized in that this conjugate is the endogenous material coupling of albumin and Gelucystine or cysteine modified.
2. protein conjugate according to claim 1, wherein said albumin is selected from human serum albumin, recombination human serum albumin or bovine serum albumin.
3. protein conjugate according to claim 1, wherein said endogenous material are selected from the one or more kinds of combinations in cholic acid or derivatives thereof, phosphatidylserine, oligomerization hyaluronic acid or the folic acid.
4. protein conjugate according to claim 1, wherein the mol ratio of the endogenous material of albumin and Gelucystine or cysteine modified is 0.01: 1-100: 1.
5. protein conjugate according to claim 1, wherein the mol ratio of the endogenous material of albumin and Gelucystine or cysteine modified is 35: 1-1: 35.
6. pharmaceutical composition that comprises medicament and pharmaceutical carrier, wherein said pharmaceutical carrier comprises the described protein conjugate of arbitrary claim in the claim 1 to 5.
7. pharmaceutical composition according to claim 6, wherein said medicament is selected from: the antipyretic-antalgic agent, anti-asthmatic, microbiotic, thymoleptic, antidiabetic drug, antiphlogiston, antitumour drug, anxiolytic, immunological reagent, sedative hypnotics, anti-anginal drug, antipsychotic drug, antimanic drug, anti-arthritic, anti-arrhythmic, antigout drug, antithrombotics, thrombolytic agent, antifibrinolytic agent, hemorheologic agent, antiplatelet drug, anticonvulsive drug, anti-Ba Jinsen medicine, antihistaminic, be used for the medicine that calcium is regulated, antiviral, bronchodilator, hormone, lipid lowerers, protein, polypeptide, nucleic acid, antiulcer agent or anti-reflux medicine, antiemetic, diagnostic medicament, with the trophicity medicine.
8. pharmaceutical composition according to claim 7, wherein said medicament are antitumour drug
9. pharmaceutical composition according to claim 8, wherein said medicament are selected from taxol or derivatives thereof, docetaxel or camptothecine or derivatives thereof.
10. pharmaceutical composition according to claim 9, wherein said medicament are taxol.
11. pharmaceutical composition according to claim 6, wherein the mol ratio of the endogenous material of albumin and Gelucystine or cysteine modified is 0.01: 1-100: 1, and the volume ratio of protein conjugate and medicament is 0.0001: 1-10000: 1.
12. pharmaceutical composition according to claim 11, wherein the mol ratio of the endogenous material of albumin and Gelucystine or cysteine modified is 35: 1-1: 35, and the volume ratio of protein conjugate and medicament is 5: 1-100: 1.
13. pharmaceutical composition according to claim 11, medicament wherein are taxol.
14. pharmaceutical composition according to claim 12, medicament wherein are taxol.
15. the preparation method of the described protein conjugate of arbitrary claim comprises the steps: in the claim 1 to 5
1) endogenous material of described protein and more than one Gelucystine or cysteine modified is dissolved in the appropriate solvent;
2) the resulting mixture of step 1) is heated, temperature is the 20-80 degree, preferred 25-70 degree, most preferably 30-60 degree;
3) drying.
16. the described preparation of drug combination method of arbitrary claim in the claim 6 to 14 comprises a kind of in two kinds of methods of following A, B:
A. prepare described protein conjugate; Conjugate is mixed with medicament;
B. described protein, more than one Gelucystine or the endogenous material and the medicine of cysteine modified are dissolved in the appropriate solvent.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102078306A (en) * | 2011-01-11 | 2011-06-01 | 无锡圆容生物医药股份有限公司 | Taxol nanoparticle freeze-drying preparation containing recombinant human serum albumin |
| CN107362352A (en) * | 2016-05-12 | 2017-11-21 | 上海昊海生物科技股份有限公司 | A kind of albumen or peptide composition and its production and use |
| EP3372226A4 (en) * | 2015-12-14 | 2018-09-12 | AC Pharmaceuticals Co., Ltd. | Targeted hydrophobic anti-tumour drug nanoformulation and preparation method thereof |
| CN111529716A (en) * | 2020-06-02 | 2020-08-14 | 南方医科大学 | Polypeptide-paclitaxel conjugate and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4336185A (en) * | 1976-03-02 | 1982-06-22 | Rohm And Haas Company | Folic acid derivatives |
| CN101220093A (en) * | 2008-01-22 | 2008-07-16 | 中国药科大学 | Biological degradable albumin derivant, pharmacy composition, preparation and application of the same |
-
2008
- 2008-09-11 CN CN2008102120159A patent/CN101357939B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102078306A (en) * | 2011-01-11 | 2011-06-01 | 无锡圆容生物医药股份有限公司 | Taxol nanoparticle freeze-drying preparation containing recombinant human serum albumin |
| EP3372226A4 (en) * | 2015-12-14 | 2018-09-12 | AC Pharmaceuticals Co., Ltd. | Targeted hydrophobic anti-tumour drug nanoformulation and preparation method thereof |
| CN107362352A (en) * | 2016-05-12 | 2017-11-21 | 上海昊海生物科技股份有限公司 | A kind of albumen or peptide composition and its production and use |
| CN107362352B (en) * | 2016-05-12 | 2021-04-02 | 上海昊海生物科技股份有限公司 | Protein or polypeptide composition and preparation method and application thereof |
| CN111529716A (en) * | 2020-06-02 | 2020-08-14 | 南方医科大学 | Polypeptide-paclitaxel conjugate and application thereof |
| CN111529716B (en) * | 2020-06-02 | 2021-05-28 | 南方医科大学 | Polypeptide-paclitaxel conjugate and application thereof |
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| CN101357939B (en) | 2012-07-04 |
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