CN105267158A - Docetaxel pharmaceutical composition - Google Patents
Docetaxel pharmaceutical composition Download PDFInfo
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- CN105267158A CN105267158A CN201410336638.2A CN201410336638A CN105267158A CN 105267158 A CN105267158 A CN 105267158A CN 201410336638 A CN201410336638 A CN 201410336638A CN 105267158 A CN105267158 A CN 105267158A
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- docetaxel
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- polylactide
- aspartic acid
- methoxypolyethylene glycol
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Abstract
The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a docetaxel pharmaceutical composition. The docetaxel pharmaceutical composition comprises the following components in parts by weight: 3.21-26.48 parts of docetaxel, and 100 parts of polyethylene glycol methyl ether-polylactide-aspartic acid; the beneficial effects of the docetaxel pharmaceutical composition are that: by the use of lower-toxicity polyethylene glycol methyl ether-polylactide-aspartic acid as a carrier, the docetaxel pharmaceutical composition only contains pharmaceutical active ingredients and the carrier, and does not contain other additives, and is simpler in components and more secure. The docetaxel pharmaceutical composition has the docetaxel content of up to 20% or more, and is simple in process, and easy in industrial applications.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of docetaxel medicament composition.
Background technology
Docetaxel (Docetaxel, Docetaxel, C
43h
53nO
14), on the architecture basics of natural antitumor drug taxol, a kind of new antitumor drug obtained after structural modification, its anti-spectrum and taxanes are seemingly, mechanism of action promotes tubulin polymerization and stops microtubule depolymerization, thus the mitosis of anticancer and propagation, drug effect is stronger than paclitaxel.
External research shows, at people's mammary gland, colon, bladder and epithelioid cell strain, its IC50 is lower than paclitaxel 9 times.In vivo study shows, docetaxel has high resistance tumor promotion, and after medication, Mus tumor and mouse transplanting tumor can disappear completely.The more important thing is, docetaxel spontaneously can not produce the cross resistance to docetaxel to the cell strain of taxol resistance.
Docetaxel is white or the powder of off-white color, is highly fat-soluble and is insoluble in the medicine of water, and its dissolubility in water is 6-7 μ g/ml.In order to increase its dissolubility, all need in the equal formula of docetaxel injecta commercially available at present to add Tween 80 as surfactant.And adopt Tween 80 to have two large shortcomings.
First shortcoming brings stronger untoward reaction to patient.Tween 80 may cause the untoward reaction comprising anaphylaxis, haemolysis, cardiovascular adverse effects and fluid retention etc.(" tween 80 causes the reason desk study of animal anaphylactoid reaction ", " toxicology magazine " 04 phase in 2007; " pharmacology of pharmaceutic adjuvant Tween 80, pharmacokinetics and analytical method progress ", " Chinese Pharmaceutical Affairs " the 22nd volume the 8th phase in 2008).Therefore need to desensitize to patient's oral glucocorticoid class medicine in advance, to there is anaphylactoid client need Injection of Adrenaline, this has increased the weight of the burden of patient undoubtedly.
Second shortcoming is medication more complicated, adds the difficulty of use.For taxotere: need first to mix concentrated medicine and dilute solution to prepare aqueous premix, then with the normal saline of 0.9%, aqueous premix is diluted, in 4 hours after obtained premixing diluent, the premixing diluent obtained is carried out to the instillation of about 1 hour.Need in this process carefully the concentrated medicine being mixed with dilute solution to be put upside down 45 seconds, and do not stir, bubble may be formed in the solution obtained like this, therefore need this solution left standstill to discharge to make bubble for 5 minutes.Following comment is had: " every bottle of labelled amount is the Docetaxel of 1ml:20mg; the actual 1.2ml of being equipped with concentration is the docetaxel solution of 20mg/ml, is equivalent to the docetaxel of 24mg in the product description of the docetaxel injection " Docetaxel " of Shandong pharmaceutical manufacturing.This volume supplements the loss of liquid that the reason such as the medicinal liquid adhesion bottle wall caused due to medicinal liquid thickness in set-up procedure and " dead volume " that can not extract out causes.During use, with syringe, every bottle of solution extraction is clean and be diluted in 5% glucose injection or 0.9% sodium chloride injection.Toxicity is caused for avoiding overdose.Be sure not to do the wash cillin bottle and syringe with solvent! ".
Polymer micelle is by the spontaneous a kind of nucleocapsid structure formed of amphipathic nature block polymer, has Nano Particle.Polymer micelle was proposed in 1984 by Bader etc. first as a kind of drug administration carrier.Drug encapsulation in the hydrophobic inner core of micelle, is reached the effect that solubilising insoluble drug improves bioavailability further by use amphipathic nature block polymer.In addition, good polymer micelle energy prolong drug circulation time in vivo, reduces drug toxicity, and reaches passive target effect by EPR effect.
Polymer is adopted to make the shortcoming that docetaxel micellar preparation can overcome commercially available docetaxel medicament, but the micelle achievement in research at present for docetaxel generally lacks practical value, main shortcoming comprises particle diameter cannot play EPR effect too greatly, and drug loading is too low, preparation stability is poor.The Yu Kewei of such as Shandong University adopts Pluronic F68 as micellar carrier, VE TPGS does solubilizing agent, docetaxel is wrapped up, the docetaxel micelle drug loading that result obtains only has 0.923%, and mean diameter is up to 135.1 ± 3.42nm (Yu Kewei, " research of docetaxel polymer micelle ").The people such as Shandong University Zhai Guang happiness adopt TPGS, MPEG-PLA, CSO-SA to be that micellar carrier material obtains docetaxel micelle, drug loading is no more than 5.2% " a kind of carrying docetaxel mixed micelle preparation and preparation method thereof ", number of patent application: 201210372072.X).
Lyophilized powder is a kind of effective ways of preservation medicine.To dry goods be needed to make the moisture contained by it freeze at low temperatures, dry under being then placed on the environment of vacuum, allow moisture directly be distilled by solid state and be steam and get rid of from goods to make goods active dry.The method effectively prevent the change of goods physics and chemistry and biological nature, the stability of available protecting thermal sensitivity medicament effective component; Freeze-dried products after the drying loose, the color of form does not change substantially, adds water or can rapid solution recover physicochemical property and the biological activity of original aqueous solution after hydrophilic organic solvent; Because drying is carried out under vacuum, for some oxidizable materials, there is good protective effect; Goods water content after lyophilizing is very low, and the stability of goods is improved, and contaminated chance reduces, and this not only facilitates transport and also extends the goods pot-life.
Achievement in research at present for docetaxel lyophilization dry powder does not make a breakthrough, in the particle diameter especially after component, redissolution and drug loading etc.Hao Shouzhu discloses preparation method (" a kind of Pharmaceutical composition of docetaxel, Preparation method and use " number of patent application: 200780000695.1), but still containing Tween 80 in lyophilized powder of a kind of docetaxel lyophilization dry powder.Shandong University Zhang Na etc. utilizes PLA-PEG copolymer to obtain docetaxel micelle freeze-drying powder; but the particle diameter after redissolving is at more than 200nm (" preparation method of polyene-containing taxol nanoparticle mixed micelle preparation and lyophilized preparation ", number of patent application: 201010151501.1).
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of pharmaceutical composition of docetaxel is provided.It adopts methoxypolyethylene glycol-polylactide-aspartic acid to make as carrier material and docetaxel, and prescription is reliably simple and safe, and in lyophilized powder, docetaxel drug loading is the highest more than 25%, and the particle diameter after lyophilized powder redissolves is less, stability is higher.
Technical solution of the present invention is as follows.
A pharmaceutical composition for docetaxel, it is made up of the component containing following weight portion:
Docetaxel 3.21 ~ 26.48 parts,
Methoxypolyethylene glycol-polylactide-aspartic acid 100 parts;
Wherein: the molecular formula of methoxypolyethylene glycol-polylactide-aspartic acid is as follows:
Wherein a=10-200, b=3-30.
The polyethylene glycol stabilized property of block is very high, is more difficultly degraded; Block polylactide only has just easily degrades under strongly acidic conditions; Grafted amino group acid is reacted in neutral conditions.Therefore methoxypolyethylene glycol-the stability of polylactide-aspartic acid in normal body fluid environment is higher.Preferably, in methoxypolyethylene glycol-polylactide-aspartic acid of the present invention, the mean molecule quantity of polylactide block is 495 ~ 4996, and the mean molecule quantity of methoxypolyethylene glycol block is 987 ~ 3020.The numerical value of different block mean molecule quantity in methoxypolyethylene glycol-polylactide-aspartic acid can be obtained by means such as mass spectral analyses.
Above-mentioned pharmaceutical composition of stating can adopt lyophilization to be prepared as freeze-dried powder preparation.
In above-mentioned lyophilized powder redissolution solution, the mass ratio of contained docetaxel and methoxypolyethylene glycol-polylactide-aspartic acid is (3.21 ~ 26.48): 100.
After above-mentioned redissolution, in solution, the mean diameter of micelle is 20.6 ~ 28.1nm.
In the present invention, described docetaxel refers to anhydrous docetaxel crude drug, according to C
43h
53nO
14meter, purity is more than 98.0%.
In the present invention, research shows, methoxypolyethylene glycol-polylactide-aspartic acid is without obvious carcinogenecity, and without genotoxicity, without teratogenesis, mutagenicity, degradable is lactic acid, aminoacid PEG in vivo, all can directly excrete.Acute toxicity test is carried out to mice, the LD50>2.00g/kg of mice; In long term toxication, 1.00g/kg dosage, 1 times/day, successive administration 2 days weekly, drug withdrawal 5 days, successive administration, after 13 weeks, recovers to observe after 4 weeks, has no obvious toxic-side effects.
Cytotoxicity test shows, the cytotoxicity of methoxypolyethylene glycol-polylactide-aspartic acid is lower than the block copolymer mPEG-PLA of current generally recognized as safe (seeing the following form 1).
Table 1MTT method hepatotoxicity test result
Compared with prior art, the present invention has following beneficial effect:
1. methoxypolyethylene glycol-polylactide-the aspartic acid adopting toxicity lower is carrier, and except effective ingredient and carrier, not containing other additives, prescription is simpler, safety is higher.
2. compositions makes the form of solid-state lyophilized powder by the common freeze-dry process of pharmacy industry, uses Normal Saline, water for injection or glucose for injection to redissolve rapidly, and the preparation of medicine, transport, storage, use are easier.
3. in the pharmaceutical composition of docetaxel, docetaxel content can reach more than 20%, and preparation technology is simple, is easy to commercial Application.
Detailed description of the invention
Be described in detail the present invention below in conjunction with embodiment, the present embodiment is implemented under premised on technical solution of the present invention, give detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
Embodiment (1-7)
Docetaxel is anhydrous docetaxel crude drug (CAS:114977-28-5), is produced by Tian Feng bio tech ltd, Xi'an;
Methoxypolyethylene glycol-polylactide-aspartic acid, is prepared according to the technique described in patent No. PCT-CN-2013000453 voluntarily by inventor.Mass spectral analysis the molecular weight of association reaction raw material is adopted to determine the mean molecule quantity of different block.
The freeze-dried powder preparation of the pharmaceutical composition of the docetaxel in embodiment, its preparation technology comprises the following steps.
1. docetaxel and methoxypolyethylene glycol-polylactide-aspartic acid (see table 2) is weighed according to different rate of charges;
2. drop in container by above-mentioned raw materials, add organic solvent to dissolving completely, the kind of organic solvent comprises ethanol, acetonitrile etc.30-50 DEG C of rotary evaporation 2h is to organic solvent distilled-to-dryness, and at 10-60 DEG C, vacuum drying > 12h removes residual organic solvent, obtains the polymer mixed film containing docetaxel.
3. hybrid films is in 40-60 DEG C of water-bath to transparence, and add ultra-pure water or normal saline, the phosphate buffer of identical preheating temperature, shake well aquation, obtains transparent polypeptide drug-loaded micelle solution.
4. by described polypeptide drug-loaded micelle solution 0.45 μm of filtering with microporous membrane.
5. above-mentioned polypeptide drug-loaded micelle solution adopted conventional, the freeze-dry process not adding any excipient obtains solid-state dry powder.
Embodiment 1-7 selects different rate of charges respectively, and selects the methoxypolyethylene glycol-polylactide-aspartic acid of different block molecule amount respectively, obtains docetaxel lyophilization dry powder according to above-mentioned steps.Adopt its drug loading of high-performance liquid chromatogram determination, the mean diameter of solution after redissolving with Dynamic Light Scattering Determination, (see table 2).
The different embodiment actual measurement drug loading of table 2 and particle diameter
Carrier=methoxypolyethylene glycol-polylactide-aspartic acid
Experimental example 8
Normal saline, commercially available docetaxel injection (taxotere) and docetaxel micellar solution (being obtained by the embodiment of the present invention) is utilized to carry out tumor suppression test respectively respectively.The Balb/c mice transplanting the strain of L7912 tumor is adopted to be subjects.Route of administration is intravenously administrable, within every 3 days, is administered once, successive administration 30 days.Taxotere and docetaxel drug level of the present invention are similarly 10mg/kg.Measure weekly the gross tumor volume 2 times of mice, its result is as shown in table 3.Result shows: the mouse tumor volume of instillation normal saline increases rapidly; The mouse tumor volume growth rate of instillation taxotere is necessarily controlled, but gross tumor volume still increases; The mouse tumor volume of the present invention that instils obtains controlling and reduces (see table 3) rapidly.Prove that the inhibition of the present invention to mouse T cell leukemia transplanted tumor is remarkable.
Table 3 mouse tumor volume measurements
Claims (6)
1. a pharmaceutical composition for docetaxel, is characterized in that, it is made up of the component containing following weight portion:
Docetaxel 3.21 ~ 26.48 parts,
Methoxypolyethylene glycol-polylactide-aspartic acid 100 parts;
Wherein: the molecular formula of methoxypolyethylene glycol-polylactide-aspartic acid is as follows:
Wherein a=10-200, b=3-30.
2. the pharmaceutical composition of docetaxel according to claim 1, is characterized in that: in described methoxypolyethylene glycol-polylactide-aspartic acid, and the mean molecule quantity of polylactide block is 495 ~ 4996.
3. the pharmaceutical composition of docetaxel according to claim 1 and 2, is characterized in that: in described methoxypolyethylene glycol-polylactide-aspartic acid, and the mean molecule quantity of methoxypolyethylene glycol block is 987 ~ 3020.
4. the pharmaceutical composition of docetaxel according to claim 1, is characterized in that: described compositions is freeze-dried powder preparation, adopts lyophilization preparation.
5. the pharmaceutical composition of docetaxel according to claim 4, is characterized in that: after described lyophilized powder redissolves, in solution, the mass ratio of contained docetaxel and methoxypolyethylene glycol-polylactide-aspartic acid is (3.21 ~ 26.48): 100.
6. the pharmaceutical composition of docetaxel according to claim 5, is characterized in that: after described redissolution, in solution, the mean diameter of micelle is 20.6 ~ 28.1nm.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410336638.2A CN105267158A (en) | 2014-07-15 | 2014-07-15 | Docetaxel pharmaceutical composition |
| PCT/CN2015/083928 WO2016008401A1 (en) | 2014-07-15 | 2015-07-14 | Pharmaceutical composition comprising docetaxel |
| US15/325,939 US10080720B2 (en) | 2014-07-15 | 2015-07-14 | Pharmaceutical composition containing docetaxel |
| GB1700560.4A GB2542092B (en) | 2014-07-15 | 2015-07-14 | Polyethylene glycol methyl ether-polylactide-lysine micellar compositions comprising docetaxel |
| ZA2017/00278A ZA201700278B (en) | 2014-07-15 | 2017-01-12 | Pharmaceutical composition containing docetaxel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410336638.2A CN105267158A (en) | 2014-07-15 | 2014-07-15 | Docetaxel pharmaceutical composition |
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|---|---|
| CN105267158A true CN105267158A (en) | 2016-01-27 |
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| CN201410336638.2A Pending CN105267158A (en) | 2014-07-15 | 2014-07-15 | Docetaxel pharmaceutical composition |
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|---|---|
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011011978A1 (en) * | 2009-07-31 | 2011-02-03 | 西安力邦医药科技有限责任公司 | Nanosphere or microsphere drug carrier, preparation method, composition and use thereof |
| CN102617843A (en) * | 2012-04-09 | 2012-08-01 | 福州市台江区泽越医药技术有限公司 | Preparation of biomedical amino acid-polyether-polyester triblock copolymer |
| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
-
2014
- 2014-07-15 CN CN201410336638.2A patent/CN105267158A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011011978A1 (en) * | 2009-07-31 | 2011-02-03 | 西安力邦医药科技有限责任公司 | Nanosphere or microsphere drug carrier, preparation method, composition and use thereof |
| CN102617843A (en) * | 2012-04-09 | 2012-08-01 | 福州市台江区泽越医药技术有限公司 | Preparation of biomedical amino acid-polyether-polyester triblock copolymer |
| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
Non-Patent Citations (1)
| Title |
|---|
| YAMAMOTO ET AL.: "Surface charge modulation of poly(ethylene glycol)-poly(D, L-lactide) block copolymer micelles: conjugation of charged peptides", 《COLLOIDS AND SURFACES B-BIOINTERFACES》 * |
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Application publication date: 20160127 |