CN108066335B - A pharmaceutical composition containing paclitaxel or its analogues and its preparation method - Google Patents
A pharmaceutical composition containing paclitaxel or its analogues and its preparation method Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a pharmaceutical composition taking paclitaxel or analogues thereof as active ingredients, which also comprises polyethylene glycol pentadecyl hydroxystearate (Solutol HS15) as a solubilizer. The invention adopts pentadecanoyl stearic acid polyethylene glycol ester (Solutol HS15) as an optimized solubilizer, and solves the problem of adverse reaction caused by the adoption of polyoxyethylene hydrogenated castor oil and polysorbate 80 as auxiliary materials in the existing paclitaxel and taxol preparations. In addition, the medicinal composition optimizes the selection of a solvent, and removes the solvent after preparation, thereby solving the problem that the existing paclitaxel and taxol preparations adopt ethanol as a redissolving solvent and have strong irritation. The invention obtains a high-quality pharmaceutical composition which has ideal stability and therapeutic activity and extremely high popularization value.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing paclitaxel or analogues thereof and a preparation method thereof.
Background
Paclitaxel or its analogues can promote microtubule formation from tubulin dimer, and simultaneously has uniform microtubule depolymerization effect, so as to stabilize microtubule, and block cell and G2 and M phase, thereby inhibiting mitosis and proliferation of cell, further causing cell apoptosis, and having anticancer effect. However, based on the problems of very low solubility in water and physical instability, at present, a large amount of polysorbate 80 or polyoxyethylene hydrogenated castor oil and the like are added into paclitaxel or paclitaxel analogue preparations on the market, and the large amount of polysorbate 80 and polyoxyethylene hydrogenated castor oil can cause severe acute allergic reaction in vivo, so that antihistamine and glucocorticoid need to be taken clinically, and the polysorbate 80 may interfere the combination of the drug and serum protein in a concentration-dependent manner, so that the in vivo behavior of the drug is changed to be in a nonlinear pharmacokinetics manner, and inconvenience and pain are brought to medical staff and patients. No ideal pharmaceutical composition can be popularized, so that the clinical application of the pharmaceutical composition is limited. Therefore, many of these problems with paclitaxel or its analogs are being studied in large quantities. In particular, it is difficult to prepare an injection due to its poor solubility.
Therefore, the invention is proposed to solve the problems of poor stability, high toxicity and strong hemolysis of the solubilizer.
Disclosure of Invention
The first object of the present invention is to provide a pharmaceutical composition comprising paclitaxel or an analog thereof as an active ingredient.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pharmaceutical composition comprising: one or more of paclitaxel or its analogues (as active ingredient, preferably only one of them) with the following structural formula:
and polyethylene glycol pentadecyl hydroxystearate (Solutol HS15) as a solubilizer.
Wherein when
Wherein said paclitaxel or analog thereof is substantially docetaxel;
when in use
When the paclitaxel or the analog thereof is actually the compound A (the primary drug)Preferred for the active ingredient);
when in use
When the paclitaxel or the analog thereof is paclitaxel, the paclitaxel or the analog thereof is paclitaxel.
The pharmaceutical composition provided by the invention takes paclitaxel or paclitaxel analogues as active ingredients, and the solubility of the pharmaceutical composition can be improved and the toxicity of the pharmaceutical composition is low by adding the Solutol HS15 solubilizer, so that the pharmaceutical composition has certain compatibility stability in 5% glucose injection or 0.9% sodium chloride injection.
Preferably, the mass dosage of the solubilizer is 10-150 times, preferably 40-120 times of that of the paclitaxel or the analogues thereof.
Further, the pharmaceutical composition also comprises a first solvent, wherein the first solvent is one or a mixture of any two of propylene glycol, PEG-400 or glycerol, and is preferably propylene glycol.
The first solvent can ensure that a sample of the drug is colorless and clear viscous liquid at room temperature (20-30 ℃), and is convenient for clinical use.
Further, the mass dosage of the first solvent is 0-100 times, preferably 5-75 times of that of the paclitaxel or the analogues thereof.
The pharmaceutical composition of the present invention further comprises a second solvent which is sufficiently removed in the preparation process in the raw materials for preparing the pharmaceutical composition, wherein the second solvent is selected from one or a mixture of any more of ethanol, propanol, isopropanol, tert-butanol or water, preferably ethanol.
The second solvent is preferably contained in the raw materials for preparing the pharmaceutical composition in a mass percentage of 40-85%, and preferably 55-80%.
Preferably, in the raw materials for preparing the pharmaceutical composition, the volume dosage ratio of the first solvent to the solubilizer is 10: 1-1: 15, preferably 5: 1-1: 12;
more preferably, the first solvent is propylene glycol and the second solvent is ethanol.
The raw materials for preparing the pharmaceutical composition also comprise a pH regulator, the pH regulator is one or more of sodium hydroxide, hydrochloric acid, phosphoric acid, citric acid, lactic acid, acetic acid, boric acid and salts thereof, and the pH regulator is preferably citric acid and/or lactic acid. By adopting the pH regulator, on the basis of controlling the pH value of the pharmaceutical composition (the pH value of the pharmaceutical composition is properly controlled within the range of 3-4), the stability of the drug is ensured, and the drug effect reduction caused by the degradation of the drug is prevented.
More specifically, the pharmaceutical composition is prepared from the following raw materials in parts by mass: 1 part of paclitaxel or analogues thereof, 10-150 parts of solubilizer and 0-100 parts of first solvent; 150 portions and 350 portions of second solvent. More preferably, the composition is prepared from raw materials comprising at least the following components in parts by mass: preferably 1 part of paclitaxel or analogues thereof, 40-120 parts of Solutol HS15 solubilizer, 5-75 parts of propylene glycol as a first solvent and 300 parts of ethanol as a second solvent.
In the above embodiment, the paclitaxel or analog thereof is preferably compound a (i.e. in the paclitaxel or analog thereof,
)。
under the prescription, the pharmaceutical composition can be diluted in 5% glucose injection or 0.9% sodium chloride injection, and is stable within 7 hours without precipitation. Is very effective for clinical administration. When the taxol or the analogues thereof are used as the active ingredient, the use of HS15 can avoid toxic and side effects and obtain more ideal anticancer effect.
The pharmaceutical composition of the invention is preferably an injection, and more specifically, is a colorless clear injection with certain viscosity.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
(a) melting the solubilizer at 30-70 deg.C;
(b) adding paclitaxel or its analogue and pH regulator into the second solvent and regulating pH to obtain mixture;
(c) adding the melted solubilizer or the melted solubilizer and the first solvent into the mixture in the step (b), and uniformly stirring;
(d) and (c) volatilizing, rotary evaporating, drying under reduced pressure or freeze-drying the mixture uniformly stirred in the step (c) to remove the second solvent.
Preferably, the process of volatilizing, rotary evaporating, drying under reduced pressure or freeze drying is carried out under the following conditions:
(1) the vacuum degree of the sample is lower than 3000 Pa;
(2) at a temperature and pressure sufficient to remove the second solvent.
By adopting the preparation method, the colorless and clear viscous liquid injection medicine composition with certain fluidity can be prepared, and the medicine composition is solid at the temperature of 20 ℃ and liquid at the temperature of 20 ℃.
When in use, the medicine composition prepared by the method is placed at the room temperature higher than 20 ℃ to be colorless, clear and viscous liquid, then 3-5ml of 5% glucose injection is taken to completely dissolve the medicine composition, and then the medicine composition is injected into the remaining 5% glucose injection and is shaken up for injection.
The invention obtains an ideal pharmaceutical composition (injection) taking the paclitaxel or the analogues thereof as active ingredients for the first time, has the advantages of avoiding serious acute anaphylactic reaction caused by using a large amount of polysorbate 80 and polyoxyethylene hydrogenated castor oil, avoiding injecting a large amount of ethanol into the body, being applicable to the treatment of various cancers, such as ovarian cancer, breast cancer, head and neck cancer, non-small cell lung cancer and the like, and having extremely high popularization value.
Detailed Description
The invention is further illustrated by the following examples, which should not be construed as limiting the invention thereto. All the starting materials referred to in the following examples are known substances and are commercially available.
EXAMPLE 1 preparation of paclitaxel or analog thereof (e.g., Compound A)
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) melting Solutol HS15 at 30 deg.C;
(b) adding the compound A and lactic acid into absolute ethyl alcohol, and adjusting the acidity to pH3.2 to obtain a mixture;
(c) adding propylene glycol and melted Solutol HS15 into the mixture in the step (b), and uniformly stirring;
(d) and (c) volatilizing the mixture uniformly stirred in the step (c), and removing the absolute ethyl alcohol to obtain the catalyst.
EXAMPLE 2 preparation of paclitaxel or analog thereof (e.g., Compound A)
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) melting Solutol HS15 at 40 deg.C;
(b) adding the compound A and phosphoric acid into 95% ethanol, and adjusting the acidity to pH3.6 to obtain a mixture;
(c) adding PEG-400 and the melted Solutol HS15 into the mixture in the step (b), and stirring uniformly;
(d) and (c) carrying out rotary evaporation on the mixture uniformly stirred in the step (c) to remove 95% ethanol, thus obtaining the product.
EXAMPLE 3 preparation of paclitaxel or analog thereof (e.g., Compound A)
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) melting Solutol HS15 at 50 deg.C;
(b) adding the compound A and boric acid into 75% ethanol, and adjusting the acidity to pH3.3 to obtain a mixture;
(c) adding glycerol and the melted Solutol HS15 into the mixture in the step (b), and uniformly stirring;
(d) and (c) drying the mixture uniformly stirred in the step (c) under reduced pressure to remove 75% ethanol, thus obtaining the compound.
EXAMPLE 4 preparation of paclitaxel or analog thereof (e.g., Compound A)
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) melting Solutol HS15 at 60 deg.C;
(b) adding the compound A, acetic acid and sodium acetate into tert-butyl alcohol, and adjusting the acidity to pH3.3 to obtain a mixture;
(c) adding propylene glycol and melted Solutol HS15 into the mixture in the step (b), and uniformly stirring;
(d) and (c) freeze-drying the mixture uniformly stirred in the step (c) to remove the tert-butyl alcohol, thus obtaining the compound.
EXAMPLE 5 preparation of paclitaxel or analog thereof (e.g., docetaxel) formulations
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) melting Solutol HS15 at 70 deg.C;
(b) adding docetaxel and hydrochloric acid (1mol/L) into propanol, and adjusting the acidity to pH3.5 to obtain a mixture;
(c) adding PEG-400 and the melted Solutol HS15 into the mixture in the step (b), and stirring uniformly;
(d) and (c) freeze-drying the mixture uniformly stirred in the step (c) to remove the propanol.
EXAMPLE 6 preparation of paclitaxel and paclitaxel analog (e.g., paclitaxel) formulations
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) melting Solutol HS15 at 60 deg.C;
(b) adding paclitaxel and citric acid into isopropanol, and adjusting acidity to pH3.2 to obtain mixture;
(c) adding the melted Solutol HS15 into the mixture in the step (b), and uniformly stirring;
(d) and (c) drying the mixture uniformly stirred in the step (c) under reduced pressure to remove the isopropanol to obtain the product.
Comparative example 1 preparation of paclitaxel formulation
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) adding paclitaxel into anhydrous ethanol, and stirring to dissolve completely;
(b) and (b) adding polyoxyethylene hydrogenated castor oil into the mixture obtained in the step (a), and uniformly stirring to obtain the polyoxyethylene hydrogenated castor oil.
Comparative example 2 preparation of docetaxel formulation
The formula is as follows:
the embodiment also provides a preparation method of the preparation, which specifically comprises the following steps:
(a) adding docetaxel into ethanol, and stirring until the solubilizer is completely dissolved;
(b) adding polysorbate 80 into the mixture in the step (a), and uniformly stirring to obtain the compound.
(c) And (c) drying the mixture uniformly stirred in the step (b) under reduced pressure to remove ethanol, thus obtaining the bottle A.
(d) Preparing 13% ethanol solution to obtain bottle B.
And preparing the docetaxel preparation in two bottles by using the bottle A and the bottle B.
Quality evaluation of pharmaceutical preparations of Experimental examples
Subject:
the pharmaceutical composition prepared in the embodiments 1-6 and the pharmaceutical composition prepared in the comparative examples 1-2 are provided, and the formulas of the comparative examples 1-2 are derived from the specifications of paclitaxel and docetaxel;
the experimental method comprises the following steps: in order to investigate the reasonability of the prescription of the preparation, the preparation investigation conditions are designed according to the guiding principle of the raw material drug and preparation stability test of 9001 in 2015 edition of Chinese pharmacopoeia:
a. placing the test sample in a clean container at 60 deg.C for 10 days, sampling on 5 th and 10 th days, and testing according to stability focus examination item.
b. The room temperature test sample is placed in a proper clean container, placed at the temperature of 25 ℃ for 10 days, sampled on the 5 th day and the 10 th day, and detected according to the stability focus examination item.
c. The test sample is placed in a lighting box or other suitable lighting device with fluorescent lamps, placed for 10 days under the condition of the illumination of 4500lx and 500lx, sampled on the 5 th and 10 th days, and detected according to the key stability inspection items, and the change of the appearance of the test sample is particularly noticed.
d. The test sample is placed at the temperature of minus 20 to minus 10 ℃ for 2 days in a freeze-thaw cycle test, then placed at the temperature of 40 ℃ for 2 days for three cycles, and sampled at the end of each cycle to be detected according to a stability key examination project.
e. And (3) placing the test sample at 2-8 ℃ for 2 days, then placing the test sample at 40 ℃ for 2 days for three times of circulation, sampling at the end of each circulation, and detecting according to the stability key investigation project.
The experimental results are as follows: see tables 1-13.
Table 1: time quality investigation results for each experimental formulation 0:
table 2: the quality investigation result of each experimental preparation in 5 days under the illumination condition is as follows:
table 3: the quality inspection result of each experimental preparation in 10 days under the illumination condition is as follows:
table 4: the quality investigation result of each experimental preparation at the high temperature of 60 ℃ for 5 days is as follows:
table 5: the quality inspection result of each experimental preparation at the high temperature of 60 ℃ for 10 days is as follows:
table 6: the quality investigation result of each experimental preparation at room temperature for 5 days is as follows:
table 7: the quality inspection result of each experimental preparation at room temperature for 10 days is as follows:
table 8: the low-temperature one-time circulation quality investigation result of each experimental preparation is as follows:
table 9: the low-temperature secondary cycle quality investigation result of each experimental preparation is as follows:
table 10: the low-temperature three-cycle quality investigation result of each experimental preparation is as follows:
table 11: the freeze-thaw one-cycle quality investigation result of each experimental preparation is as follows:
table 12: the freeze-thaw secondary cycle quality investigation result of each experimental preparation is as follows:
table 13: the freeze-thaw three-cycle quality investigation result of each experimental preparation is as follows:
in addition, the pharmaceutical compositions obtained in examples 1 to 6 were taken as samples, 3 to 5ml of 5% glucose injection was injected into the samples, the samples were shaken until the samples were completely dissolved, the completely dissolved samples were injected into the remaining 5% glucose hot injection, the samples were shaken and kept still to observe the compatibility stability of the samples, and the test results are shown in table 14:
table 14: results of the compatibility stability test of each sample
The above experiment results show that the pharmaceutical composition prepared in the embodiments 1 to 6 of the present application is subjected to influence factor investigation under the conditions of illumination (4500lx 500lx), high temperature (60 ℃), room temperature, low temperature three cycles and freeze thawing three cycles, except that the related substances are slightly increased under the high temperature condition, all indexes meet the requirements of the national pharmacopoeia 2015 edition, and all quality indexes of the preparation are within the qualified range. The pharmaceutical composition prepared in the comparative examples 1-2 is subjected to influence factor investigation under the conditions of illumination (4500lx 500lx), high temperature (60 ℃), room temperature, low temperature three cycles and freeze thawing three cycles, except that related substances are slightly increased under the high temperature condition, all indexes meet the requirements of 'Chinese pharmacopoeia' 2015 edition, and all quality indexes of the preparation are in a qualified range.
The appearance of the sample can be improved after the propylene glycol is added into the sample, so that the sample can be quickly dissolved, the clinical use is convenient, and the compatibility stability of the sample in 5% glucose injection can be enhanced.
The composition uses Solutol HS15 as a solubilizer, and avoids the use of polyoxyethylene hydrogenated castor oil and polysorbate 80 which are used in the existing marketed preparations of paclitaxel and docetaxel. In addition, multiple studies show that polysorbate 80 has direct or indirect toxic effects during the use of injections, and generally agree that the polysorbate has a problem of hemolysis and should be regarded as important. The formula provided by the invention is equivalent to the existing commercial preparations of paclitaxel and docetaxel in the aspect of drug stability, but the solubilizer SolutolHS15 can avoid the occurrence of anaphylactic reaction, and the comparison effect (under the same experimental conditions) of the paclitaxel and the docetaxel is detailed in tables 15-16.
Table 15: haemolysis of human erythrocytes and serum histamine levels in dogs after intravenous injection
Table 16: histamine levels (injection dose 100mg/kg dog)
In summary, the invention has the following advantages: 1. the Solutol HS15 is used as a solubilizer, so that the problem of adverse reaction caused by the fact that the prior paclitaxel and taxol preparations adopt polyoxyethylene hydrogenated castor oil and polysorbate 80 as auxiliary materials is solved; 2. ethanol is preferably used as a second solvent, and the second solvent is removed after preparation, so that the problem of strong irritation of the existing paclitaxel and taxol preparations which adopt ethanol as a redissolving solvent is solved; 3. the propylene glycol is preferably used as the first solvent, so that the appearance of the preparation is improved, and the clinical use is convenient. 4, the residual quantity of the ethanol is effectively controlled by adopting a new process; 5. solving the problem of clinical medication of taxol analogs such as compound A and the like; 6. the influence factor test shows that the preparation has stable chemical stability.
The embodiments in the above embodiments can be further combined or replaced, and the embodiments are only used for describing the preferred embodiments of the present invention, and do not limit the concept and scope of the present invention, and various changes and modifications made to the technical solution of the present invention by those skilled in the art without departing from the design idea of the present invention belong to the protection scope of the present invention.
Claims (6)
1. The pharmaceutical composition is prepared from the following raw materials in parts by mass: 1 part of taxol analogue, 40-120 parts of solubilizer Solutol HS15, 5-75 parts of first solvent propylene glycol, 200-300 parts of second solvent ethanol which can be fully removed in the preparation process and a pH regulator; wherein the paclitaxel analog has the following structural formula:
X＝-Ac,
the pharmaceutical composition is an injection.
2. The composition of claim 1, wherein: in the raw materials for preparing the pharmaceutical composition, the volume usage ratio of the first solvent to the solubilizer is 10: 1-1: 15.
3. The composition of claim 2, wherein: in the raw materials for preparing the pharmaceutical composition, the volume usage ratio of the first solvent to the solubilizer is 5: 1-1: 12.
4. The composition according to any one of claims 1 to 3, characterized in that: the pH regulator is one or more of sodium hydroxide, hydrochloric acid, phosphoric acid, citric acid, lactic acid, acetic acid, boric acid, and their salts.
5. The composition of claim 4, wherein: the pH regulator is citric acid and/or lactic acid.
6. A process for preparing a pharmaceutical composition according to any one of claims 1 to 5, characterized in that: the method comprises the following steps:
(a) melting the solubilizer at the temperature of 30-70 ℃;
(b) adding paclitaxel analogue and pH regulator into the second solvent and regulating pH value to obtain mixture;
(c) adding the melted solubilizer and the first solvent into the mixture obtained in the step (b), and uniformly stirring;
(d) and (c) volatilizing, rotary evaporating, drying under reduced pressure or freeze-drying the mixture uniformly stirred in the step (c) to remove the second solvent.
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| CN1660071A (en) * | 2004-12-09 | 2005-08-31 | 天津大学 | Application of injection of quick dissolving solid in yew alkyl class in preparing medicine for anti transfer of tumor |
| CN101366696A (en) * | 2008-10-16 | 2009-02-18 | 姚定全 | Medicament composition for water-soluble injection of paclitaxel, preparation method and uses thereof |
| CN102988285A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Docetaxel injection composition and preparation method thereof |
| CN103800909A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating HS15 clouding formation phenomenon and application of composition in medicinal preparation |
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| BR0215184A (en) * | 2001-12-20 | 2006-06-06 | Bristol Myers Squibb Co | orally active taxane derivative pharmaceutical compositions having increased bioavailability |
| CN103980232A (en) * | 2014-06-05 | 2014-08-13 | 北京诺普德医药科技有限公司 | 10-acetyldocetaxel and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660071A (en) * | 2004-12-09 | 2005-08-31 | 天津大学 | Application of injection of quick dissolving solid in yew alkyl class in preparing medicine for anti transfer of tumor |
| CN101366696A (en) * | 2008-10-16 | 2009-02-18 | 姚定全 | Medicament composition for water-soluble injection of paclitaxel, preparation method and uses thereof |
| CN103800909A (en) * | 2012-11-14 | 2014-05-21 | 沈阳药科大学 | Composition capable of eliminating HS15 clouding formation phenomenon and application of composition in medicinal preparation |
| CN102988285A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Docetaxel injection composition and preparation method thereof |
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