An oral taxane drug composition

Abstract

The present invention provides an oral taxane pharmaceutical composition, which comprises a taxane drug and an excipient, wherein the excipient comprises a surfactant mixture, and the surfactant mixture is composed of Tween 80 and 15-hydroxystearate polyethylene glycol. The present invention significantly improves the solubility of taxane drugs (such as paclitaxel) through the synergistic solubilization effect of Tween 80 and 15-hydroxystearate polyethylene glycol, and the obtained preparation forms small particles after dilution, and can maintain the solution clear and transparent for more than 2 hours, solving the problem of rapid crystal precipitation and unfavorable absorption of the prior art preparation after dilution. The oral paclitaxel pharmaceutical composition of the present invention is combined with a P-glycoprotein inhibitor, and the oral bioavailability is significantly improved.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to an oral taxane drug composition. Background Art

[0002] Taxanes are a typical cytotoxic drug with high efficiency and broad-spectrum anti-tumor activity. They can bind to the subunits of tubulin to inhibit microtubule dynamics, induce G2 / M cycle arrest in tumor cells, and induce apoptosis of tumor cells by activating multiple signal transduction pathways. Taxanes mainly include paclitaxel, docetaxel, cabazitaxel, and derivatives with a taxane skeleton structure. In the early 1960s, the National Cancer Institute (NCI) of the United States first extracted and isolated a diterpenoid compound paclitaxel (PTX) with a unique taxane skeleton structure from Taxus chinensis, and found that it had a broad-spectrum anti-tumor activity. It was approved for marketing by the US FDA in 1992. Docetaxel (DTX) is a second-generation taxane derivative and was approved for marketing by the US FDA in 1998. Cabazitaxel was developed by Sanofi-Aventis and was approved for marketing in the United States in June 2010. It is suitable for patients with metastatic hormone-refractory prostate cancer whose disease has worsened during or after docetaxel treatment.

[0003] Although paclitaxel and docetaxel have achieved great clinical success, there are still some problems in their clinical use. Taxane drugs have low water solubility and need to be solubilized by adding a large amount of surfactant. Because polyoxyethylene castor oil is used in the solvent, the histamine induction of polyoxyethylene castor oil and the diethylhexyl phthalate (DEHP) leached from polyoxyethylene (PVC) infusion sets can cause severe allergic reactions, which makes injection Before treatment, corticosteroids and antihistamines must be used. (Paclitaxel liposome), Products such as paclitaxel (albumin-bound paclitaxel nanoparticles), Cynviloq (paclitaxel micelles, without polyoxyethylene castor oil), PICN (paclitaxel nanoparticles, without polyoxyethylene castor oil), and Apealea (paclitaxel micelles with the new excipient XR-17) have been launched one after another. With the improvement and optimization of paclitaxel injection preparations, adverse reactions have been significantly reduced, and compliance and adaptability have been significantly increased. However, the injection still has serious adverse reactions such as neurotoxicity and hair loss. The development of paclitaxel oral preparations shows great prospects.

[0004] In 2017, paclitaxel oral solution Listed in South Korea, this is a paclitaxel oral solution preparation developed using lipid self-emulsifying drug delivery technology. CN106999440B protects a paclitaxel oral solution, characterized in that it contains (a) 0.8-1.2% by weight of paclitaxel or docetaxel, (b) 25-30% by weight of medium-chain triglycerides; (c) 50-55% by weight of an oleoylglycerol complex having a monoglycerol content of 30%-65%, a diglycerol content of 15-50% by weight, and a triglycerol content of 2%-20% by weight, and (d) 15-20% by weight of a surfactant, the surfactant being selected from polyoxyethylene-polypropylene copolymers, dehydrated sorbitan esters, polyoxyethylene sorbitan anhydride, and polyoxyethylene ethers, wherein the pharmaceutical composition is a clear solution at room temperature, and wherein when the pharmaceutical composition is stored at 4°C and then left to stand at room temperature, the pharmaceutical composition becomes a clear solution. The preparation composition develops self-microemulsification technology for solubilization to address the problem of low solubility of paclitaxel. However, paclitaxel is also a substrate of gastrointestinal P-gp protein. When taken orally, the drugs are transported back to the gastrointestinal tract by P-gp, limiting their absorption. Although the problem of low solubility of paclitaxel has been solved, the problem of P-gp efflux during oral administration has not been solved.

[0005] Oraxol is a combination of paclitaxel capsules and Encequidar tablets. In 2020, Athenex announced that the FDA accepted its NDA application. The preparation composition is developed and studied for the low solubility of paclitaxel and the characteristics of P-gp efflux. By combining the P-gp inhibitor Encequidar (also known as HM30181A), the gastrointestinal P-gp efflux effect of paclitaxel is reduced. CN108697683B protects an oral taxane composition, which comprises: a taxane and a surfactant mixture, wherein the surfactant mixture is composed of polysorbate 80 and The composition is composed of a weight ratio of 80:20 to 65:35, or a ratio of polysorbate 80 to the polysorbate 20 of 80:20 by weight. The surfactants are mixed in a specific ratio to increase the solubility of docetaxel in a synergistic manner, and form micelles when diluted in gastric / intestinal fluid, which is beneficial to the absorption of docetaxel. When Encequidar (HM30181A) is taken in advance, the bioavailability of oral docetaxel can be greatly improved. However, the preparation composition system is unstable, and the drug precipitates rapidly after dilution. The in vitro dissolution data show that the oral capsule preparation has a fast release rate at the beginning, reaches the maximum concentration within 30 minutes, and then the release percentage decreases, and can only maintain 60%-80% in vitro release. It shows that docetaxel produces precipitation in the dissolution medium, the solubilization effect is not ideal, and it is not conducive to the absorption of the drug in the body. In addition, the patent only uses docetaxel as an example to study the effect of the surfactant mixture on the solubility of the active ingredient and the oral preparation, and there is no evidence that its preferred mixed surfactant system is also applicable to paclitaxel.

[0006] Compared with paclitaxel injection, oral paclitaxel increases patient compliance and significantly reduces neurotoxicity. It is also beneficial to reduce hospital bed pressure and optimize medical resources. In addition, there are literature reports that paclitaxel exposure is related to effectiveness. max Related to toxicity. Oral preparations are more likely to obtain a stable blood drug concentration curve than injectable preparations, indicating lower side effects at the same effectiveness. Therefore, the development of oral paclitaxel preparations has huge market prospects and clinical needs. Summary of the invention

[0007] The invention provides an oral taxane drug composition, which can significantly improve the solubility of taxane drugs (especially paclitaxel), can still maintain the stability of the system after dilution, and the drug is not easy to precipitate, which is conducive to the absorption of the drug in the body.

[0008] Specifically,

[0009] The present invention provides an oral taxane drug composition, which comprises an active ingredient taxane drug and an excipient, wherein the excipient comprises a surfactant mixture, wherein the surfactant mixture is composed of Tween 80 and 15-hydroxystearate polyethylene glycol in a weight ratio of 80:20 to 60:40, wherein the surfactant mixture accounts for at least 90% by weight of the excipient.

[0010] Preferably, the auxiliary material does not contain oil.

[0011] In some embodiments, the taxane is selected from paclitaxel, docetaxel, cabazitaxel, larotaxel (XRP9881), ortataxel, tesetaxel, milataxel and other derivatives with a taxane skeleton structure (such as BMS-184476, BMS-188797, BMS-275183, etc.), preferably paclitaxel and docetaxel. The taxane is dissolved in the excipient, and the taxane is present in the pharmaceutical composition at a concentration of at least 30 mg / g to 70 mg / g, preferably at a concentration of at least 30 mg / g to 60 mg / g, and more preferably at a concentration of at least 40 mg / g to 50 mg / g.

[0012] In some embodiments, the weight ratio of Tween 80 and 15-hydroxystearate in the surfactant mixture is preferably 75:25-60:40, further preferably 70:30-60:40, or 68:32-60:40, or 68:32-62:38, or 66:34-64:36, or 65:35, or 64.5:34.5.

[0013] In some embodiments, the surfactant mixture accounts for at least 93%, or at least 95%, or at least 96%, or at least 97% of the weight of the excipient.

[0014] Optionally, the excipient contains a stabilizer. The stabilizer can prevent the degradation of taxane drugs. In some embodiments, the stabilizer is an organic acid, such as one or more of citric acid, ascorbic acid, malic acid, tartaric acid, lactic acid, p-toluenesulfonate, succinic acid, glutamic acid, alginic acid, maleic acid and adipic acid, preferably citric acid and / or ascorbic acid, more preferably citric acid. The organic acid described in the present invention includes its hydrate, such as citric acid monohydrate. The weight percentage of the stabilizer in the excipient is 0.1% to 5%, preferably 0.1% to 3%, or 0.2% to 3%, or 0.2% to 2%, or 0.3% to 1.5%, or 0.4% to 1.2%, more preferably 0.5% to 1.0% or 0.8%-1.2% or 1.0%.

[0015] Optionally, the adjuvant further comprises excipients, such as water, ethanol, low molecular weight polyethylene glycol (e.g., PEG200 and PEG 400), starch / sugar, fat and / or talc. Excipients may also comprise any water-soluble organic solvent, nonionic surfactant, water-insoluble lipid, organic liquid / semisolid, cyclodextrin and phospholipid described by Strickley in "Solubilizing Excipients in Oral and Injectable Formulations", Pharm. Res., vol. 21, no. 2, 201-229 (February 2004).

[0016] In some embodiments, the excipient comprises:

[0017]

[0018]

[0019] Alternatively, the auxiliary material comprises:

[0020] Element Weight Percent Twain 80 80％～60％ 15-Hydroxystearate Polyethylene glycol 20％～40％ Citric acid monohydrate 0.1％～3％

[0021] Alternatively, the auxiliary material comprises:

[0022] Element Weight Percent Twain 80 75％～60％ 15-Hydroxystearate Polyethylene glycol 25％～40％ Citric acid monohydrate 0.2％～3％

[0023] Alternatively, the auxiliary material comprises:

[0024] Element Weight Percent Twain 80 70％～60％ 15-Hydroxystearate Polyethylene glycol 30％～40％ Citric acid monohydrate 0.2％～2％

[0025] Alternatively, the auxiliary material comprises:

[0026] Element Weight Percent Twain 80 70％～60％ 15-Hydroxystearate Polyethylene glycol 30％～40％ Citric acid monohydrate 0.3％～1.5％

[0027] Alternatively, the auxiliary material comprises:

[0028] Element Weight Percent Twain 80 68％～60％ 15-Hydroxystearate Polyethylene glycol 32％～40％ Citric acid monohydrate 0.4％～1.2％

[0029] Alternatively, the auxiliary material comprises:

[0030] Element Weight Percent Twain 80 68％～60％ 15-Hydroxystearate Polyethylene glycol 32％～40％ Citric acid monohydrate 0.8％～1.2％

[0031] Alternatively, the auxiliary material comprises:

[0032] Element Weight Percent Twain 80 68％～62％ 15-Hydroxystearate Polyethylene glycol 32％～38％ Citric acid monohydrate 0.4％～1.2％

[0033] Alternatively, the auxiliary material comprises:

[0034] Element Weight Percent Twain 80 68％～62％ 15-Hydroxystearate Polyethylene glycol 32％～38％ Citric acid monohydrate 0.8％～1.2％

[0035] Alternatively, the auxiliary material comprises:

[0036] Element Weight Percent Twain 80 66％～64％ 15-Hydroxystearate Polyethylene glycol 34％～36％ Citric acid monohydrate 0.5％～1％

[0037] Alternatively, the auxiliary material comprises:

[0038] Element Weight Percent Twain 80 66％～64％ 15-Hydroxystearate Polyethylene glycol 34％～36％ Citric acid monohydrate 0.8％～1.2％

[0039] Alternatively, the auxiliary material comprises:

[0040] Element Weight Percent Twain 80 64.5％ 15-Hydroxystearate Polyethylene glycol 34.5％ Citric acid monohydrate 1％

[0041] Optionally, the pharmaceutical composition of the present invention can be filled into a hard gelatin capsule or a soft gelatin capsule for administration or can be administered as a liquid preparation. Preferably, the pharmaceutical composition is filled into a hard gelatin capsule or a soft gelatin capsule for administration.

[0042] The present invention also provides a method for preparing the above-mentioned oral taxane pharmaceutical composition, comprising:

[0043] a. Weigh the prescribed amount of Tween 80 and 15-hydroxystearate polyethylene glycol, stir and mix to obtain a surfactant mixture.

[0044] b. Weigh the prescribed amount of stabilizer, add it to the surfactant mixture obtained in step (a), and continue stirring until it is completely dissolved to obtain a mixture.

[0045] c. Weigh the prescribed amount of taxane drugs, add them to the mixture obtained in step (b), and continue stirring until dissolved.

[0046] Preferably, the method for preparing the above-mentioned oral taxane pharmaceutical composition comprises stirring under heating conditions, and the heating temperature is preferably 30-50°C, preferably 35-45°C, and preferably 40°C.

[0047] Preferably, in the method for preparing the above oral taxane drug composition, in step c, the prescribed amount of the taxane drug is divided into several small portions, and the small portions are added to the mixture obtained in step (b) in batches.

[0048] Optionally, the preparation method further comprises a step of capsule filling after step (c).

[0049] The present invention also provides use of the above-mentioned oral taxane pharmaceutical composition in the preparation of anti-tumor drugs.

[0050] In order to further enhance the bioavailability of oral taxanes, the present invention also provides a combination product comprising a P-gp inhibitor and the above-mentioned oral taxane pharmaceutical composition. The P-gp inhibitor is selected from one or more of verapamil, trifluoperazine, cyclosporine, other antihypertensive agents (such as quinidine and reserpine), yohimbine, antiestrogens, tamoxifen, toremifene, antitumor vincristine and its derivatives, HM30181A (ie, Encequidar), XR9576 and GF120981; preferably HM30181A (ie, Encequidar).

[0051] The present invention also provides the use of the above combination product in preparing anti-tumor drugs.

[0052] In order to provide a more concise description, the quantitative data herein do not use the term "about". It should be understood that, whether the term "about" is used explicitly or not, each numerical value given here includes not only the actual given value (given value), but also means to include an approximate value to such given value reasonably inferred by a person of ordinary skill in the art, including equivalent values ​​and approximate values ​​of such given value due to experimental and / or measurement conditions. The approximate value is preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, ±1% based on the given value.

[0053] In some embodiments, the numerical ranges and numerical parameters describing the broad scope of some embodiments of the present invention are approximate and should be interpreted in light of the number of reported significant digits and by applying ordinary rounding techniques. Although the numerical values ​​set forth in the specific examples are reported as accurately as possible, the numerical values ​​presented in some embodiments of the present invention may contain certain errors, which are errors necessarily caused by the standard deviation in the testing measurements.

[0054] The present invention achieves the following beneficial technical effects:

[0055] 1. A paclitaxel solution was prepared using the preferred Tween 80 / polyoxyethylene (35) hydrogenated castor oil (65:35) of CN108697683B as a surfactant mixture. The resulting preparation was diluted with water to obtain a micelle solution that could only maintain a clear and transparent state for 10 minutes, and a precipitate was quickly precipitated, resulting in poor stability and affecting absorption and utilization. The present invention screened the types and ratios of surfactants, and significantly improved the solubility of taxane drugs (such as paclitaxel) through the synergistic solubilization effect of Tween 80 and 15-hydroxystearic acid polyethylene glycol. The micelles formed by the resulting preparation after dilution had a small particle size, and the optimal formulation could maintain the clarity and transparency of the solution for more than 2 hours. Pharmacokinetic studies have shown that the oral bioavailability of the preferred formulation of the present invention in rats is significantly higher than that of the preparation using Tween 80 / polyoxyethylene (35) hydrogenated castor oil (65:35) as a surfactant mixture. It can be seen that the present invention solves the problem of rapid precipitation of crystals and adverse absorption of the prior art preparations after dilution.

[0056] 2. The oral bioavailability of the paclitaxel pharmaceutical composition of the present invention in combination with a P-glycoprotein inhibitor can reach 75.3% in rats and 23.3% in beagle dogs, which is significantly higher than that of taking the paclitaxel pharmaceutical composition alone. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 The concentration-time curve of the pharmacokinetic study in rats.

[0058] Figure 2 Drug-time curves of canine pharmacokinetic studies. DETAILED DESCRIPTION

[0059] In order to more clearly illustrate the present invention, the specific embodiments of the present invention are described in more detail below through specific implementation examples. However, it should be understood that the specific implementation examples described below are only used to illustrate the present invention, rather than to limit the present invention in any nature, wherein the materials, reagents, instruments, and operating conditions used are only representative, and are not limited to the listed situations. Those skilled in the art can make changes and improvements to the present invention without departing from the scope of protection defined by the claims of the present invention by reading the following description, and these changes and improvements are also within the scope of protection claimed in the present invention.

[0060] 1. Dissolution curve determination method

[0061] Referring to the dissolution and release determination method (Method 1, Part IV, 0931, 2020 edition of the Pharmacopoeia of the People's Republic of China), 900 ml of 0.1% Tween-0.1 mol / L hydrochloric acid solution was used as the dissolution medium, the rotation speed was 100 rpm, and 10 ml of samples were taken at 5, 10, 15, 30, and 45 min. Filter, and add the same volume of dissolution medium at the same time, and the filtrate was used as the test solution.

[0062] Take an appropriate amount of paclitaxel reference substance, weigh it accurately, dissolve it in acetonitrile and quantitatively dilute it to make a solution containing about 0.15 mg per 1 ml as the reference substance solution.

[0063] Determine the content of paclitaxel in the test solution and the reference solution, and calculate the dissolution amount of the test sample at each sampling point.

[0064] 2. Paclitaxel content determination method

[0065] The content of paclitaxel in the sample was detected by high performance liquid chromatography (Pharmacopoeia of the People's Republic of China 2020 Edition Part IV 0521). The specific method is as follows:

[0066] Chromatographic column: octadecylsilane bonded silica gel as filler (Tnature C18, 4.6mm×250mm, 5μm); methanol-water-acetonitrile (23:41:36) as mobile phase; detection wavelength at 227nm; injection volume at 10μl; flow rate at 1.0ml / min; column temperature at 30℃.

[0067] Unless otherwise specified, the solubility and dissolution curve tests herein use the above-mentioned paclitaxel content determination method.

[0068] 3. Determination of Paclitaxel-related Substances

[0069] Refer to the high performance liquid chromatography method (Part IV 0521 of the 2020 edition of the Pharmacopoeia of the People's Republic of China) to detect the related substances of paclitaxel in the sample. The specific method is as follows:

[0070] Chromatographic column: octadecylsilane bonded silica gel as filler (YMC-PaK ODS-A C18, 4.6mm×150mm, 3μm); acetonitrile-water (40:60) as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the table below; detection wavelength at 227nm; injection volume at 15μl; flow rate at 1.2ml / min; column temperature at 35℃.

[0071]

[0072] Example 1 Effect of Solvent pH on Paclitaxel Solubility

[0073] An excess of paclitaxel API was added into conical flasks containing 40 ml of pH 1.0 hydrochloric acid solution, pH 3.0 acetate buffer solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution, pH 8.0 phosphate buffer solution and purified water, respectively. The mixture was shaken in a 37°C water bath for 48 h, filtered, and the filtrate was sampled to measure the saturated solubility of paclitaxel.

[0074] The results showed that the solubility of paclitaxel raw material in different pH media was low.

[0075] Table 1 Effect of solvent pH on the solubility of paclitaxel

[0076]

[0077] Note: The maximum dose is 30 mg.

[0078] Example 2 Effect of a single surfactant on the solubility of paclitaxel

[0079] An excess of paclitaxel API was added to stoppered glass test tubes containing various surfactants to prepare a saturated paclitaxel solution, which was ultrasonically dispersed for 5 to 15 minutes and placed in a 37°C water bath constant temperature incubator for oscillation equilibrium for 24 hours. The solution was centrifuged (10,000 rpm, 2 minutes), 100 μl was transferred to a 50 ml volumetric flask, diluted to the mark with acetonitrile, and shaken to detect the effects of different surfactants on the saturated solubility of paclitaxel.

[0080] Table 2 Effect of single surfactant on the solubility of paclitaxel

[0081]

[0082] Note: Polyoxyethylene (35) hydrogenated castor oil is Cremophor EL, the same below.

[0083] The results in Table 2 show that different surfactants have different abilities to promote the dissolution of paclitaxel. Tween 80 and caprylic acid capric acid macrogol glyceride alone have better solubilization effects, while oleic acid macrogol glyceride alone has the worst solubilization effect.

[0084] Example 3 Preparation of Oral Paclitaxel Preparation

[0085] 1. Preparation prescription

[0086] (1) The preparation comprises the active ingredient paclitaxel and excipients, wherein the concentration of paclitaxel in the preparation composition is 45 mg / g.

[0087] (2) The composition of the auxiliary materials is as follows:

[0088] Table 3 Excipient composition of oral paclitaxel preparation of Example 3

[0089]

[0090] 2. Preparation process

[0091] a. Weigh the prescribed amount of Tween 80 and 15-hydroxystearate polyethylene glycol, stir and mix to obtain a surfactant mixture.

[0092] b. Weigh the prescribed amount of citric acid monohydrate and add it to the surfactant mixture obtained in step (a), and continue stirring until all the citric acid monohydrate is dissolved.

[0093] c. Weigh the prescribed amount of paclitaxel, divide it into several small portions, and add them to the mixture obtained in step (b) in batches, and continue stirring until all the paclitaxel is dissolved to obtain a paclitaxel solution.

[0094] d. The paclitaxel solution obtained in step (c) was filled into No. 0 gelatin capsules (containing 30 mg of paclitaxel).

[0095] Example 4 Effect of a single surfactant on drug stability after dilution

[0096] Paclitaxel preparations containing different surfactants were prepared by referring to the method described in Example 3, and the proportion of the surfactant in the total amount of the preparation remained unchanged. The paclitaxel solution obtained in step c was taken and diluted with water to a concentration of 1.25 mg / ml, the phenomenon after dilution was observed, and the particle size (nm) was measured using a Malvern nanometer particle size and potential analyzer (ZETASIZER NANO ZS).

[0097] Table 4 Effect of single surfactant on drug stability after dilution

[0098]

[0099]

[0100] The results in Table 4 show that under the experimental conditions, except for oleic acid polyethylene glycol glyceride, the use of a single surfactant for solubilization can form micelles after dilution with water, but the time for which the clear and transparent liquid state can be maintained stably is short. Only 15-hydroxystearate polyethylene glycol ester can remain stable within 30 minutes, and the other four surfactants can only remain stable within 10 minutes.

[0101] In order to further improve the stability of the micelle state after dilution with water, the solubilization effect of the composite surfactant was investigated.

[0102] Example 5 Effect of composite surfactant on the solubility of paclitaxel

[0103] Referring to the method described in Example 2, the effect of the composite surfactant on the solubility of paclitaxel was determined.

[0104] Table 5 Effect of composite surfactant on the solubility of paclitaxel

[0105]

[0106] Note: Theoretical solubility = solubility in surfactant A × percentage of surfactant A + solubility in surfactant B × percentage of surfactant B

[0107] The above results show that the combination of different surfactants can further improve the solubility of paclitaxel and has a synergistic solubilization effect. Among them, the combination of 65% Tween 80 / 35% 15-hydroxystearate polyethylene glycol ester and 80% Tween 80 / 20% 15-hydroxystearate polyethylene glycol ester has a better solubilization effect.

[0108] Example 6 Effect of complex surfactant on drug stability after dilution

[0109] 1. Dilute with water

[0110] Paclitaxel preparations containing different surfactants were prepared by referring to the method described in Example 3, and the proportion of the surfactant in the total amount of the preparation remained unchanged. The paclitaxel solution obtained in step c was taken and diluted with water to a concentration of 1.25 mg / ml, the phenomenon after dilution was observed, and the particle size (nm) was measured using a Malvern nanometer particle size and potential analyzer (ZETASIZER NANO ZS).

[0111] The results showed that although the use of different surfactants in combination can increase the solubility of paclitaxel, the stability of the micelle liquid obtained by dilution with water is significantly different. Among them, the combination of Tween-80 / 15-hydroxystearate polyethylene glycol ester is more conducive to maintaining the stability of the micelle system than other surfactant combinations, and can maintain stability for at least 30 minutes. The combination of 65% Tween 80 / 35% 15-hydroxystearate polyethylene glycol ester has the best effect and can maintain the liquid state of a clear and transparent liquid for more than 2 hours.

[0112] Table 6-1 Effect of complex surfactants on the stability of drugs after dilution with water

[0113]

[0114]

[0115] 2. Dilute with 0.1mol / L hydrochloric acid solution

[0116] Paclitaxel preparations containing different surfactants were prepared by referring to the method described in Example 3, and the proportion of the surfactant in the total amount of the preparation remained unchanged. The paclitaxel solution obtained in step c was diluted to a concentration of 1.25 mg / ml with 0.1 mol / L hydrochloric acid solution, the phenomenon after dilution was observed, and the particle size (nm) was measured using a Malvern nanometer particle size and potential analyzer (ZETASIZER NANO ZS).

[0117] Table 6-2 Effect of complex surfactants on the stability of drugs after dilution with 0.1 mol / L hydrochloric acid solution

[0118]

[0119]

[0120] After oral administration of paclitaxel capsules, the contents of the capsules are released in the stomach. In order to investigate the effect of the acidic environment of the stomach on the stability of the liquid after dilution, the contents of the capsules were diluted with a 0.1 mol / L hydrochloric acid solution. The results in Table 6-2 show that the micelles formed by dilution of the mixture of paclitaxel and surfactants are more difficult to maintain a stable state in a 0.1 mol / L hydrochloric acid solution. When the weight ratio of Tween 80 / 15-hydroxystearate polyethylene glycol ester is greater than 70:30, the stability time of the obtained preparation diluted with a 0.1 mol / L hydrochloric acid solution is significantly shortened relative to the stability time diluted with water. The paclitaxel solution obtained with 80% Tween 80 / 20% 15-hydroxystearate polyethylene glycol ester and 20% Tween 80 / 80% 15-hydroxystearate polyethylene glycol ester as surfactants cannot even form a stable micelle system in a 0.1 mol / L hydrochloric acid solution. Once diluted, it immediately becomes a milky white suspension. Surprisingly, when 65% Tween 80 / 35% 15-hydroxystearate polyethylene glycol ester and 60% Tween 80 / 40% 15-hydroxystearate polyethylene glycol ester are used as surfactant mixtures, the stability time of the obtained paclitaxel solution after dilution with 0.1 mol / L hydrochloric acid solution has no significant change compared with the stability time after dilution with water, and the stability of the system is better.

[0121] Example 7 Effects of different types of stabilizers on drug stability after dilution

[0122] Referring to the method described in Example 3, paclitaxel preparations containing different types of stabilizers were prepared, the proportion of the stabilizer to the total amount of the preparation remained unchanged, and the types of stabilizers were citric acid monohydrate, ascorbic acid, maleic acid and tartaric acid. The paclitaxel solution obtained in step c was taken and diluted with water to a concentration of 1.25 mg / ml, the phenomenon after dilution was observed, and related substances were detected.

[0123] Table 7-1 Effects of different types of stabilizers on drug stability after dilution

[0124]

[0125]

[0126] Table 7-2 Effects of different types of stabilizers on drug-related substances

[0127]

[0128] The above results show that the type of stabilizer will affect the stability of the drug after dilution. When 1% of maleic acid and tartaric acid are added, the stability of the drug after dilution is poor and can only remain stable within 20 minutes. When ascorbic acid is selected as a stabilizer, the drug can remain clear and transparent for 1 hour after dilution. When citric acid monohydrate is selected as a stabilizer, the drug remains stable for more than 2 hours after dilution with water without precipitation. Further testing of related substances in more stable preparations showed that compared with ascorbic acid, citric acid monohydrate as a stabilizer can better inhibit the increase of related substances and the chemical stability of the preparation is better.

[0129] Example 8 Effect of the amount of stabilizer on the stability of the drug after dilution

[0130] Paclitaxel preparations containing different amounts of stabilizers were prepared by referring to the method described in Example 3. The paclitaxel solution obtained in step c was diluted with water to a concentration of 1.25 mg / ml, the phenomenon after dilution was observed, and related substances were detected.

[0131]

[0132] Table 8-1 Effects of different dosages of stabilizers on drug stability after dilution

[0133]

[0134]

[0135] Table 8-2 Effects of different dosages of stabilizers on drug-related substances

[0136]

[0137] The above results show that the dosage of the stabilizer citric acid monohydrate will affect the dilution stability of the preparation. When the dosage of citric acid monohydrate is selected in the range of 0.3%-1.5%, the stability of the preparation after dilution is better than other tested dosages, and the content of other single impurities and total impurities does not change significantly, and the chemical stability also meets the requirements. In particular, when the dosage of citric acid monohydrate is 1%, the effect of maintaining the stability of the preparation after dilution is the best, and the diluted micelle liquid can maintain a clear and transparent stable state for more than 2 hours.

[0138] Example 9 Dissolution curve of paclitaxel capsules

[0139] 1. Dissolution curve of paclitaxel capsules described in Example 3

[0140] The paclitaxel capsules prepared in Example 3 were taken for dissolution curve measurement.

[0141] Table 9-1 Dissolution curve test results of paclitaxel capsules in Example 3

[0142]

[0143]

[0144] The results showed that paclitaxel capsules were rapidly released in 0.1% Tween-0.1 mol / L hydrochloric acid solution, which was beneficial for the absorption of the preparation in the gastrointestinal tract.

[0145] 2. Effects of different surfactants on the dissolution of paclitaxel capsules

[0146] Referring to the method described in Example 3, paclitaxel preparations containing different surfactants (each capsule contains 30 mg of paclitaxel) were prepared. Three paclitaxel capsules with different prescriptions were taken for dissolution curve determination. The composition of the excipients is as follows:

[0147]

[0148] Table 9-2 Effects of different surfactants on the dissolution curve of paclitaxel capsules

[0149]

[0150] The results showed that the paclitaxel capsule was rapidly released in 0.1% Tween-0.1 mol / L hydrochloric acid solution, dissolving more than 90% in 15 minutes and maintaining a stable state. No drug precipitation was precipitated during the test (45 minutes), which was beneficial to the absorption of the preparation in the gastrointestinal tract.

[0151] Example 10 Accelerated stability test of paclitaxel capsules

[0152] Paclitaxel capsules were prepared according to the method described in Example 3, and stability tests were performed under accelerated conditions (40°C / RH75%) for 1 month, 2 months, and 3 months and under long-term conditions (25°C / RH60%) for 3 months.

[0153] Table 10 Results of accelerated and long-term stability tests of paclitaxel capsules

[0154]

[0155]

[0156] Note: * Refer to the method of Example 4 and dilute the capsule contents with water before testing.

[0157] The stability test results are shown in Table 10. The above results show that the paclitaxel capsules are stored under accelerated and long-term conditions for 3 months, and the appearance of the capsule contents, the particle size of the micelles obtained by diluting the contents, the content of impurities and active ingredients, and the water content do not change significantly, and the preparation has good stability.

[0158] Example 11 Pharmacokinetic Experiment in Rats

[0159] The paclitaxel solution obtained in step c of Example 3 was used to conduct a single oral PK test in rats. The specific method is as follows:

[0160] SD rats, weighing about 200 g, were randomly divided into groups according to their body weight, with 6 rats in each group (each group contained 5 males and 1 female): (1) paclitaxel solution (20 mg / kg) of Example 3 alone, administered orally by gavage; (2) paclitaxel solution (20 mg / kg) of Example 3 combined with HM30181A (10 mg / kg, administered 30 min before paclitaxel), administered orally by gavage; (3) control paclitaxel solution (20 mg / kg) combined with HM30181A (10 mg / kg, administered 30 min before paclitaxel), administered orally by gavage. Using paclitaxel injection, another 6 rats were given intravenous administration of paclitaxel (5 mg / kg) for calculation of relative bioavailability of paclitaxel. Blood samples were collected through the orbital vein before administration and 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration to determine plasma paclitaxel concentrations, and calculate T 1 / 2 , T max , C max , AUC last , AUC Inf And other pharmacokinetic parameters and the relative bioavailability of the paclitaxel solution.

[0161] The test results are shown in Table 11. The results show that when the paclitaxel solution of Example 3 is co-administered with HM30181A (ie, paclitaxel is administered half an hour after HM30181A), the pharmacokinetic data is improved, which can significantly increase the maximum blood drug concentration (C max ), area under the concentration-time curve (AUC), and oral bioavailability of paclitaxel.

[0162] Compared with the control paclitaxel solution, the Cmax and AUC of the paclitaxel solution in Example 3 were significantly increased, and the bioavailability was significantly improved.

[0163] Table 11 Pharmacokinetic test results in rats

[0164]

[0165] Note: * The auxiliary material of the control paclitaxel solution contains 64.5% by weight of Tween 80 and 34.5% by weight of polyoxyethylene (35) hydrogenated castor oil as a surfactant mixture, and the remaining components, dosage ratios and preparation methods are the same as those in Example 3.

[0166] Example 12 Pharmacokinetic Experiment in Dogs

[0167] The paclitaxel capsule prepared in step d of Example 3 was used for a single oral PK test in dogs. The specific method is as follows:

[0168] Beagle dogs, weighing 6-11 kg, were randomly divided into groups of 4 (each group contained 3 males and 1 female): (1) paclitaxel capsules (6 mg / kg) alone, administered orally; (2) paclitaxel capsules (6 mg / kg) combined with HM30181A (1.5 mg / kg, 30 min before paclitaxel), administered orally. Another 6 beagles (each group contained 4 males and 2 females, weighing 6-11 kg) were given paclitaxel (1 mg / kg) intravenously using paclitaxel injection to calculate the relative bioavailability of paclitaxel. Blood samples were collected through the upper limb vein before administration and 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Plasma paclitaxel concentrations were measured and T was calculated. 1 / 2 , T max , C max , AUC last , AUC Inf And other pharmacokinetic parameters and relative bioavailability of paclitaxel capsules.

[0169] The test results are shown in Table 12. The results showed that when paclitaxel capsules were co-administered with HM30181A (ie, paclitaxel was administered half an hour after HM30181A), the maximum blood concentration of paclitaxel (C max ), area under the concentration-time curve (AUC) and oral bioavailability were significantly increased.

[0170] Table 12 Results of dog pharmacokinetic tests

[0171]

Claims

1. An oral taxane drug composition, which is composed of an active ingredient taxane drug and an excipient, wherein the excipient is a surfactant mixture and a stabilizer, and the taxane drug is paclitaxel. (1) The surfactant mixture is composed of Tween 80 and 15-hydroxystearate polyethylene glycol in a weight ratio of 68:32 to 62:38, (2) the surfactant mixture accounts for at least 97% by weight of the excipient, (3) the stabilizer is selected from citric acid and / or ascorbic acid, (4) the stabilizer accounts for 0.8% to 1.2% by weight of the auxiliary material; The taxane drug is dissolved in the excipient, and the taxane drug is present in the pharmaceutical composition at a concentration of 30 mg / g to 70 mg / g.

2. The pharmaceutical composition according to claim 1, characterized in that: The surfactant mixture consists of Tween 80 and 15-hydroxystearate polyethylene glycol in a weight ratio of 66:34 to 64:

36.

3. The pharmaceutical composition according to claim 1, characterized in that: The surfactant mixture consists of Tween 80 and 15-hydroxystearate polyethylene glycol in a weight ratio of 65:35 or 64.5:34.

5.

4. The pharmaceutical composition according to claim 1, characterized in that: The stabilizer accounts for 1.0% by weight of the auxiliary material.

5. The pharmaceutical composition according to claim 1, characterized in that: The taxane drug is present in the pharmaceutical composition at a concentration of 30 mg / g to 60 mg / g.

6. The pharmaceutical composition according to claim 5, characterized in that: The taxane drug is present in the pharmaceutical composition at a concentration of 40 mg / g to 50 mg / g.

7. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition is filled into a hard gelatin capsule or a soft gelatin capsule for administration or administered as a liquid preparation.

8. The pharmaceutical composition according to claim 1, characterized in that: The auxiliary materials are: 。 9. The pharmaceutical composition according to claim 1, characterized in that: The auxiliary materials are:

10. The pharmaceutical composition according to claim 1, characterized in that: The auxiliary materials are: 。 11. A method for preparing the oral taxane pharmaceutical composition according to any one of claims 1 to 10, comprising: a. Weigh the prescribed amount of Tween 80 and 15-hydroxystearate polyethylene glycol, stir and mix to obtain a surfactant mixture; b. Weigh the prescribed amount of stabilizer and add it to the surfactant mixture obtained in step (a), stirring continuously until completely dissolved; c. Weigh the prescribed amount of taxane drugs, add them to the mixture obtained in step (b), and continue stirring until dissolved.

12. The preparation method according to claim 11, characterized in that: Stir under heating conditions, the heating temperature is 30-50℃.

13. The preparation method according to claim 12, characterized in that: The heating temperature is 35-45℃.

14. The preparation method according to claim 13, characterized in that: The heating temperature is 40°C.

15. The preparation method according to claim 11, characterized in that: Step (c) dividing the prescribed amount of the taxane drug into several small portions and adding the portions to the mixture obtained in step (b) in batches.

16. The preparation method according to claim 11, characterized in that: The preparation method further comprises a step of capsule filling after step (c).

17. Use of the oral taxane pharmaceutical composition according to any one of claims 1 to 10 or the oral taxane pharmaceutical composition prepared by the method according to any one of claims 11 to 16 in the preparation of anti-tumor drugs.

18. A combination product comprising (1) an oral taxane pharmaceutical composition according to any one of claims 1 to 10 or an oral taxane pharmaceutical composition prepared by the method according to any one of claims 11 to 16, (2) P-gp inhibitors; the P-gp inhibitors are selected from one or more of verapamil, trifluoperazine, cyclosporine, quinidine, reserpine, yohimbine, antiestrogens, tamoxifen, toremifene, antitumor vincristine and its derivatives, HM30181A (ie, Encequidar), XR9576 and GF120981.

19. The combination product according to claim 18, characterized in that: The P-gp inhibitor is HM30181A (ie, Encequidar).

20. Use of the combination product according to claim 18 in the preparation of anti-tumor drugs.

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