CN116350619A

CN116350619A - Oral taxane pharmaceutical composition

Info

Publication number: CN116350619A
Application number: CN202211681176.9A
Authority: CN
Inventors: 玄京姬; 王娜娜; 孔飞飞; 吴利霞; 束云; 王江宁; 刘爱丽; 刘玉锋; 邢希旺; 姚俊娜
Original assignee: Beijing Kangchuanglian Biopharmaceutical Technology Research Co ltd
Current assignee: Beijing Kangchuanglian Biopharmaceutical Technology Research Co ltd
Priority date: 2021-12-28
Filing date: 2022-12-27
Publication date: 2023-06-30

Abstract

The invention provides an oral taxane pharmaceutical composition, which comprises taxane medicines and auxiliary materials, wherein the auxiliary materials comprise a surfactant mixture, and the surfactant mixture consists of tween 80 and 15-hydroxystearic acid polyethylene glycol ester. According to the invention, through the synergistic solubilization of Tween 80 and 15-hydroxystearic acid polyethylene glycol, the solubility of taxane medicines (such as paclitaxel) is obviously improved, the particle size of the obtained preparation after dilution is small, the clear and transparent solution can be maintained for more than 2 hours, and the problems of rapid crystal precipitation and adverse absorption after dilution of the preparation in the prior art are solved. The oral paclitaxel pharmaceutical composition of the invention combines the P-glycoprotein inhibitor, and the oral bioavailability is obviously improved.

Description

Oral taxane pharmaceutical composition

Technical Field

The invention belongs to the field of medicines, and in particular relates to an oral taxane pharmaceutical composition.

Background

The taxane is a typical cytotoxic drug, has high-efficiency broad-spectrum anti-tumor activity, can be combined with subunits of tubulin to inhibit microtubule dynamics, and induce tumor cells to generate G ₂ Cycle arrest in the M phase, tumor cells can also be induced to undergo apoptosis by activating multiple signal transduction pathways. The taxane medicine mainly comprises paclitaxel, docetaxel, cabazitaxel and derivatives with taxane skeleton structure. At the beginning of the 60 s of the 20 th century, the national cancer institute (National Cancer Institute, NCI) first extracted and separated a diterpenoid taxol (PTX) with a unique taxane skeleton structure from taxus chinensis, and found that it had a broad spectrum of antitumor activity, and was approved by the us FDA in 1992. Docetaxel (DTX) is a 2 nd generation taxane derivative and was approved by the FDA in 1998 for sale in the united states. Cabazitaxel is prepared from cinrofilThe development of Anvant, approved for use in patients with metastatic, hormone refractory prostate cancer who have had their condition worsened during or after docetaxel treatment, in the United states at month 6 of 2010.

Despite the great clinical success of paclitaxel and docetaxel, there are still problems during clinical use. The taxane has low water solubility and needs to be solubilized by adding a large amount of surfactant. The first global paclitaxel formulation on the market

Because of the use of polyoxyethylated castor oil in the vehicle, the histamine induction of such polyoxyethylated castor oil and the leaching of diisooctyl phthalate (DEHP) from Polyoxyethylene (PVC) infusion sets can cause severe allergic reactions, which can lead to injections

The pretreatment such as corticoids, antihistamines and the like is needed before. To solve this problem, lipoxin +.>

(paclitaxel liposome), ++>

Products such as (albumin-bound paclitaxel nanoparticles), cynviloq (paclitaxel micelles, without polyoxyethylated castor oil), PICN (paclitaxel nanoparticles, without polyoxyethylated castor oil), apealea (paclitaxel micelles with novel excipients XR-17) and the like are marketed sequentially. Along with the improvement and optimization of the taxol injection preparation, adverse reactions are obviously reduced, compliance and adaptability are obviously improved, but the injection always has serious adverse reactions such as nervous system toxicity, alopecia and the like. The development of taxol oral preparation shows great prospect.

In 2017, paclitaxel oral solution

In korea, this is a drug delivery technology using lipid self-emulsificationThe taxol oral solution preparation is developed by the operation. CN106999440B protects an oral paclitaxel solution comprising (a) 0.8-1.2 wt.% paclitaxel or docetaxel, (B) 25-30 wt.% medium chain triglycerides; (c) 50 to 55% by weight of an oleoyl glycerol complex having a monoacylglycerol content of 30 to 65%, a diacylglycerol content of 15 to 50% and a triacylglycerol content of 2 to 20% by weight, and (d) 15 to 20% by weight of a surfactant selected from the group consisting of polyoxyethylene-polypropylene copolymer, sorbitan ester, polyoxyethylene sorbitan and polyoxyethylene ether, wherein the pharmaceutical composition is in a clear solution state at room temperature, and wherein the pharmaceutical composition becomes in a clear solution state when left standing at room temperature after storage at 4 ℃. The formulation composition developed self-microemulsion technology for solubilization against the problem of low paclitaxel solubility. However, paclitaxel is also a substrate for the gastrointestinal P-gp protein, and drugs are transported back to the gastrointestinal tract by P-gp when taken orally, limiting their absorption. />

Although solving the problem of low solubility of paclitaxel, the problem of P-gp efflux existing orally is not solved.

Oraxol is a combination of paclitaxel capsule and Encequidar tablet formulation, athenex announced by the FDA that received its NDA declaration in 2020. The preparation composition is developed and researched aiming at the characteristics of low solubility and P-gp efflux of paclitaxel, and the P-gp of the gastrointestinal tract is reduced to be in efflux of the paclitaxel by combining a P-gp inhibitor Encequidar (also called HM 30181A). CN108697683B protects an oral taxane composition comprising: taxane and surfactant mixture composed of polysorbate 80 and

in a weight ratio of 80:20 to 65:35, or from 80:20 by weight of polysorbate 80 to said polysorbate 20. The surfactant is mixed in a specific ratio defined by the surfactant to synergistically increase the solubility of docetaxel when in the stomach/intestineThe liquid forms micelle when diluted, is favorable for docetaxel absorption, and can greatly improve the bioavailability of the oral docetaxel under the condition of taking Encequidar (HM 30181A) in advance. However, the preparation composition system is unstable, the medicine is quickly precipitated after dilution, and in-vitro dissolution data show that the oral capsule preparation is fast in release speed at the beginning, reaches the maximum concentration within 30min, and then the release percentage is reduced, so that only 60-80% of in-vitro release can be maintained. The docetaxel is shown to precipitate in a dissolution medium, the solubilization effect is not ideal, and the absorption of the medicine in vivo is not facilitated. Furthermore, the patent only takes docetaxel as an example to study the effect of surfactant mixtures on the solubility of active ingredients and oral formulations, and there is no evidence that the preferred mixed surfactant system is also suitable for paclitaxel.

Compared with taxol injection, the taxol has the advantages of increased patient compliance and obviously reduced nervous system toxicity, and is beneficial to reducing the pressure of the hospital bed and optimizing medical resources. In addition, there are literature reports that paclitaxel exposure is related to effectiveness, C _max Is related to toxicity. The oral formulation is easier to obtain a smooth blood concentration profile than the injectable formulation, suggesting lower side effects with the same effectiveness. Therefore, the development of oral paclitaxel formulations has great market prospect and clinical demand.

Disclosure of Invention

The invention provides an oral taxane pharmaceutical composition, which can obviously improve the solubility of taxane medicines (especially paclitaxel), can keep a stable system after dilution, is not easy to separate out and precipitate, and is beneficial to the absorption of medicines in vivo.

In particular, the method comprises the steps of,

the invention provides an oral taxane pharmaceutical composition, which comprises an active ingredient taxane medicine and auxiliary materials, wherein the auxiliary materials comprise a surfactant mixture, and the surfactant mixture is prepared from tween 80 and 15-hydroxystearic acid polyethylene glycol ester with a weight ratio of 80: 20-60: 40, wherein the surfactant mixture comprises at least 90% by weight of the adjuvant.

Preferably, the adjuvant does not comprise oil.

In some embodiments, the taxane is selected from paclitaxel, docetaxel, cabazitaxel, raloxixel (Larotaxel, XRP 9881), octataxel (Ortataxel), tesetaxel (Tesetaxel), milataxel, and other derivatives having a taxane skeleton (e.g., BMS-184536, BMS-188797, BMS-275183, etc.), preferably paclitaxel, docetaxel. The taxane is dissolved in the adjuvant and is present in the pharmaceutical composition at a concentration of at least 30mg/g to 70mg/g, preferably at a concentration of at least 30mg/g to 60mg/g, more preferably at a concentration of at least 40mg/g to 50 mg/g.

In some embodiments, the weight ratio composition of tween 80 and 15-hydroxystearic acid polyethylene glycol ester in the surfactant mixture is preferably 75:25 to 60:40, further preferably 70:30 to 60:40, or 68:32 to 62:38, or 66:34 to 64:36, or 65:35, or 64.5:34.5.

In some embodiments, the surfactant mixture comprises at least 93%, or at least 95%, or at least 96%, or at least 97% by weight of the adjunct.

Optionally, the auxiliary material contains a stabilizer. The stabilizer can prevent taxane degradation. 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-toluenesulfonic acid salt, succinic acid, glutamic acid, alginic acid, maleic acid, adipic acid, and the like, preferably citric acid and/or ascorbic acid, more preferably citric acid. The organic acid of the present invention includes a hydrate thereof, such as citric acid monohydrate. The stabilizer accounts for 0.1 to 5 percent, preferably 0.1 to 3 percent, or 0.2 to 2 percent, or 0.3 to 1.5 percent, or 0.4 to 1.2 percent, more preferably 0.5 to 1.0 percent, or 0.8 to 1.2 percent, or 1.0 percent of the weight of the auxiliary materials.

Optionally, the excipients further comprise excipients such as water, ethanol, low molecular weight polyethylene glycols (e.g., PEG200 and PEG 400), starches/sugars, fats and/or talc. Excipients may also include any of the water-soluble organic solvents, nonionic surfactants, water-insoluble lipids, organic liquids/semisolids, cyclodextrins, phospholipids, and the like described by Strickley in "Solubilizing Excipients in Oral and Injectable Formulations", pharm.res., vol.21, no.2, 201-229 (month 2 2004).

In some embodiments, the adjuvant comprises:

alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	80％～60％
15-hydroxy-stearic acid polyethylene glycol ester	20％～40％
		Citric acid hydrate	0.1％～3％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	75％～60％
15-hydroxy-stearic acid polyethylene glycol ester	25％～40％
		Citric acid hydrate	0.2％～3％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	70％～60％
15-hydroxy-stearic acid polyethylene glycol ester	30％～40％
		Citric acid hydrate	0.2％～2％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	70％～60％
15-hydroxy-stearic acid polyethylene glycol ester	30％～40％
		Citric acid hydrate	0.3％～1.5％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	68％～60％
15-hydroxy-stearic acid polyethylene glycol ester	32％～40％
		Citric acid hydrate	0.4％～1.2％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	68％～60％
15-hydroxy-stearic acid polyethylene glycol ester	32％～40％
		Citric acid hydrate	0.8％～1.2％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	68％～62％
15-hydroxy-stearic acid polyethylene glycol ester	32％～38％
		Citric acid hydrate	0.4％～1.2％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	68％～62％
15-hydroxy-stearic acid polyethylene glycol ester	32％～38％
		Citric acid hydrate	0.8％～1.2％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	66％～64％
15-hydroxy-stearic acid polyethylene glycol ester	34％～36％
		Citric acid hydrate	0.5％～1％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	66％～64％
15-hydroxy-stearic acid polyethylene glycol ester	34％～36％
		Citric acid hydrate	0.8％～1.2％

Alternatively, the auxiliary materials comprise:

composition of the components	Weight percent
		Tween 80	64.5％
15-hydroxy-stearic acid polyethylene glycol ester	34.5％
		Citric acid hydrate	1％

Optionally, the pharmaceutical composition of the present invention may be filled into hard gelatin capsules or soft gelatin capsules for administration or as a liquid preparation for administration. Preferably, the pharmaceutical composition is filled into hard gelatin capsules or soft gelatin capsules for administration.

The invention also provides a preparation method of the oral taxane pharmaceutical composition, which comprises the following steps:

a. weighing Tween 80 and 15-hydroxy stearic acid polyethylene glycol ester with the prescribed amount, and stirring and mixing to obtain surfactant mixture.

b. Weighing a prescribed amount of stabilizer, adding the stabilizer into the surfactant mixture obtained in the step (a), and continuously stirring until the stabilizer is completely dissolved to obtain a mixture.

c. Weighing the prescription amount of taxane medicine, adding the taxane medicine into the mixture obtained in the step (b), and continuously stirring until the taxane medicine is dissolved.

Preferably, the preparation method of the oral taxane medicinal composition is carried out under heating condition by stirring, preferably at 30-50deg.C, preferably 35-45deg.C, preferably 40deg.C.

Preferably, in the above preparation method of oral taxane composition, step c is to divide the prescription amount of taxane into several small parts, and add the small parts into the mixture obtained in step (b) in a divided manner.

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

The invention also provides application of the oral taxane pharmaceutical composition in preparing antitumor drugs.

In order to further enhance the bioavailability of the oral taxane, the invention also provides a combination product comprising a P-gp inhibitor and the 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, antiestrogen, tamoxifen, toremifene, antitumor vincristine and derivatives thereof, HM30181A (namely Encequidar), XR9576 and GF 120981; preferably HM30181A (i.e., encequidar).

The invention also provides the application of the combination product in preparing anti-tumor drugs.

In order to provide a more concise description, the term "about" is not used herein for quantitative data. It is to be understood that each numerical value given herein, whether explicitly or implicitly using the term "about," is intended to include not only the actual given value (the given value), but also to include approximations to such given value based on reasonable inferences of one of ordinary skill in the art, including equivalents and approximations that result from experimental and/or measurement conditions. The approximation is preferably + -20%, + -15%, + -10%, + -8%, + -6%, + -5%, + -4%, + -3%, 2%, + -1% on the basis of the given values.

In some embodiments, the numerical ranges and numerical parameters setting forth the broad scope of some embodiments of the present invention are approximations that should be construed according to the numerical values reported as significant digits and by applying ordinary rounding techniques. Although the numerical values set forth in the specific examples are reported as precisely as possible, the numerical values set forth in some embodiments of the invention may contain certain errors due to the standard deviation in the test measurements.

The invention has the following beneficial technical effects:

1. the taxol solution is prepared by taking Tween 80/polyoxyethylene (35) hydrogenated castor oil (65:35) which is preferable in CN108697683B as a surfactant mixture, and the micelle solution obtained by diluting the obtained preparation with water can only maintain a clear and transparent state for 10min, and precipitates are quickly separated out, so that the stability is poor, and the absorption and utilization are influenced. The invention screens the kind and proportion relation of the surfactant, through the synergistic solubilization of Tween 80 and 15-hydroxystearic acid polyethylene glycol, the solubility of taxane medicines (such as paclitaxel) is obviously improved, the particle size of the micelle formed by the diluted preparation is small, and the optimal place can maintain the clear and transparent solution for more than 2 hours. Pharmacokinetic studies indicate that the oral bioavailability in rats preferably prescribed in the present invention is significantly higher than formulations with tween 80/polyoxyethylene (35) hydrogenated castor oil (65:35) as surfactant blend. The invention solves the problems of rapid crystal precipitation and adverse absorption after the preparation in the prior art is diluted

2. The oral paclitaxel pharmaceutical composition is combined with the P-glycoprotein inhibitor, the oral bioavailability in rats can reach 75.3 percent, the oral bioavailability in beagle dogs can reach 23.3 percent, and the oral bioavailability is obviously improved compared with the single administration of the paclitaxel pharmaceutical composition.

Drawings

FIG. 1 is a graph of the pharmacokinetic profile of rats.

Figure 2 time-of-flight profile of canine pharmacokinetic experiments.

Detailed Description

In order to more clearly illustrate the present invention, specific embodiments of the present invention will be described in more detail below by way of specific examples. It should be understood, however, that the following examples are illustrative of the present invention and are not intended to limit the present invention in any way, and the materials, reagents, instruments, and operating conditions used are representative only and are not intended to limit the scope of the present invention. Modifications and improvements of the invention may occur to those skilled in the art upon reading the following description without departing from the scope of the invention as defined by the claims.

1. Dissolution curve determination method

With reference to the dissolution and release rate measurement method (first method of four parts 0931 in the pharmacopoeia of the people's republic of China, 2020 edition), 900ml of 0.1% Tween-0.1 mol/L hydrochloric acid solution is taken as a dissolution medium, the rotating speed is 100rpm, 10ml is sampled at 5, 10, 15, 30 and 45min, filtration is carried out, the dissolution medium with the same volume is supplemented, and the subsequent filtrate is taken as a sample solution.

And (3) taking a proper amount of taxol reference substance, precisely weighing, adding acetonitrile for dissolving and quantitatively diluting to prepare a solution containing about 0.15mg of taxol reference substance per 1ml, and taking the solution as a reference substance solution.

And measuring the content of paclitaxel in the test solution and the reference solution, and calculating the leaching amount of the test at each sampling point.

2. Method for measuring content of taxol

The content of paclitaxel in the sample was measured by referring to high performance liquid chromatography (four parts 0521 in 2020 pharmacopoeia of the people's republic of China). The specific method comprises the following steps:

chromatographic column: octadecylsilane chemically bonded silica as filler (Tnate C18,4.6 mm. Times.250 mm,5 μm); methanol-water-acetonitrile (23:41:36) is used as a mobile phase; the detection wavelength is 227nm; sample volume 10. Mu.l; the flow rate is 1.0ml/min; the column temperature was 30 ℃.

The above-mentioned paclitaxel content measurement method is used for the solubility, dissolution profile test, etc. herein unless otherwise specified.

3. Method for measuring paclitaxel related substance

The sample was examined for paclitaxel related substances by high performance liquid chromatography (four parts 0521 in 2020 pharmacopoeia of the people's republic of China). The specific method comprises the following steps:

chromatographic column: octadecylsilane chemically bonded silica as filler (YMC-PaK ODS-A C18, 4.6mm.times.150mm, 3 μm); acetonitrile-water (40:60) is used as a mobile phase A, acetonitrile is used as a mobile phase B, and gradient elution is carried out according to the following table; the detection wavelength is 227nm; sample volume 15. Mu.l; the flow rate is 1.2ml/min; the column temperature was 35 ℃.

EXAMPLE 1 Effect of solvent pH on paclitaxel solubility

And (3) adding the excessive taxol raw material into 40ml of conical flasks containing the pH1.0 hydrochloric acid solution, the pH3.0 acetate buffer solution, the pH4.5 acetate buffer solution, the pH6.8 phosphate buffer solution, the pH8.0 phosphate buffer solution and purified water respectively, shaking for 48 hours in a water bath at 37 ℃, filtering, taking the subsequent filtrate, and sampling to obtain the saturation solubility of taxol.

The result shows that the solubility of the taxol raw material medicine in different pH mediums is small.

TABLE 1 Effect of solvent pH on paclitaxel solubility

Note that: the highest dose was 30mg.

EXAMPLE 2 Effect of Single surfactant on paclitaxel solubility

Adding excessive taxol raw material into glass test tubes with plugs containing various surfactants respectively to prepare taxol saturated solution, performing ultrasonic dispersion for 5-15 min, placing into a water bath constant temperature culture shaking table at 37 ℃ for shaking balance for 24h, centrifuging (10000 rpm,2 min), transferring 100 μl, placing into a 50ml measuring flask, adding acetonitrile for dilution to scale, shaking uniformly, and detecting the influence of different surfactants on taxol saturated solubility.

TABLE 2 Effect of Single surfactants on paclitaxel solubility

Note that: the polyoxyethylene (35) hydrogenated castor oil is Cremophor EL, as follows.

The results in Table 2 show that the different surfactants have different capacities for promoting the dissolution of paclitaxel, wherein the solubilization effect of the polyethylene glycol glyceride of tween 80 and caprylic/capric acid is better, and the solubilization effect of the polyethylene glycol glyceride of oleic acid is the worst.

EXAMPLE 3 preparation of oral paclitaxel formulation

1. Formulation prescription

(1) The preparation comprises paclitaxel as an active ingredient and auxiliary materials, wherein the concentration of paclitaxel in the preparation composition is 45mg/g.

(2) The auxiliary materials comprise the following components:

TABLE 3 example 3 adjuvant composition of oral paclitaxel formulation

2. Preparation process

b. Weighing a prescribed amount of citric acid monohydrate, adding the citric acid monohydrate to the surfactant mixture obtained in the step (a), and continuously stirring until all citric acid monohydrate is dissolved.

c. Weighing the prescribed amount of paclitaxel, dividing into a plurality of small parts, adding into the mixture obtained in the step (b) in a plurality of times, and continuously stirring until all the paclitaxel is dissolved, thereby obtaining the paclitaxel solution.

d. The paclitaxel solution obtained in step (c) was filled into size 0 gelatin capsules (containing 30mg of paclitaxel).

EXAMPLE 4 Effect of Single surfactant on stability after drug dilution

With reference to the method described in example 3, paclitaxel formulations containing different surfactants were prepared with the surfactant in a constant ratio to the total formulation. Taking the taxol solution obtained in the step c, diluting the taxol solution to the concentration of 1.25mg/ml by using water, observing the phenomenon after dilution, and measuring the particle size (nm) by using a Markov nanometer particle size and potential analyzer (ZETASIZER NANO ZS).

TABLE 4 Effect of Single surfactants on stability after drug dilution

The results in Table 4 show that, under the test conditions, the micelles can be formed by water dilution with a single surfactant in addition to the polyethylene glycol glyceride, but the time to stabilize the clear transparent liquid state is short, only 15-hydroxystearate polyethylene glycol ester can remain stable within 30min, and the remaining 4 surfactants can remain stable within 10 min.

To further improve the stability of the micelle state after dilution with water, the solubilization effect of the complex surfactant was examined.

EXAMPLE 5 Effect of Complex surfactants on paclitaxel solubility

The effect of the complex surfactant on paclitaxel solubility was determined as described in example 2.

TABLE 5 Effect of Complex surfactants on paclitaxel solubility

Note that: theoretical solubility = solubility in surfactant a%o of surfactant a + solubility in surfactant B%o of surfactant B

The results show that the combination of different surfactants can further improve the solubility of paclitaxel and have synergistic solubilization effect. Wherein, the combination of 65 percent of Tween 80/35 percent of 15-hydroxystearic acid polyethylene glycol ester and 80 percent of Tween 80/20 percent of 15-hydroxystearic acid polyethylene glycol ester has better solubilization effect.

Example 6 Effect of Complex surfactants on stability after drug dilution

1. Diluting with water

The results show that although the combination of different surfactants increases the solubility of paclitaxel. However, the stability of the resulting micelle liquids diluted with water is significantly different, wherein the combination of tween-80/15-hydroxystearic acid polyethylene glycol ester is more favorable to maintaining the steady state of the micelle system, at least for 30min, relative to other surfactant combinations. The combination effect of 65% Tween 80/35% 15-hydroxystearic acid polyethylene glycol ester is best, and the liquid state of clear transparent liquid can be maintained for more than 2 hours.

TABLE 6-1 Effect of Complex surfactants on stability of drugs after dilution with Water

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2. Dilution with 0.1mol/L hydrochloric acid solution

With reference to the method described in example 3, paclitaxel formulations containing different surfactants were prepared with the surfactant in a constant ratio to the total formulation. Taking the taxol solution obtained in the step c, diluting the taxol solution to the concentration of 1.25mg/ml by using 0.1mol/L hydrochloric acid solution, observing the phenomenon after dilution, and measuring the particle size (nm) by using a Markov nanometer particle size and potential analyzer (ZETASIZER NANO ZS).

TABLE 6-2 Effect of Compound surfactants on stability of drugs after dilution with 0.1mol/L hydrochloric acid solution

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After oral administration of the paclitaxel capsule, the capsule contents are released in the stomach. To examine the effect of gastric acid environment on stability of the diluted liquid, the capsule contents were diluted with 0.1mol/L hydrochloric acid solution. Table 6-2 shows that micelles formed by dilution of paclitaxel and surfactant mixture are more difficult to maintain in a stable state in 0.1mol/L hydrochloric acid solution. The weight ratio of tween 80/15-hydroxystearic acid polyethylene glycol ester is more than 70: at 30, the stability time of the obtained preparation diluted by 0.1mol/L hydrochloric acid solution is obviously shortened compared with that diluted by water. The paclitaxel solution obtained by using 80% tween 80/20% 15-hydroxystearic acid polyethylene glycol ester and 20% tween 80/80% 15-hydroxystearic acid polyethylene glycol ester as surfactants could not even form a stable micelle system in 0.1mol/L hydrochloric acid solution, and became a milky suspension immediately upon dilution. Surprisingly, the stability of the resulting paclitaxel solution was not significantly altered from the stability of the solution diluted with 0.1mol/L hydrochloric acid solution, with respect to the stability of the solution diluted with water, by 65% tween 80/35% 15-hydroxystearic acid polyethylene glycol ester, 60% tween 80/40% 15-hydroxystearic acid polyethylene glycol ester as surfactant mixture.

EXAMPLE 7 Effect of different kinds of stabilizers on stability after drug dilution

With reference to the method described in example 3, paclitaxel formulations containing different types of stabilizers were prepared, the proportions of stabilizers in the total formulation being unchanged, the stabilizer types being citric acid monohydrate, ascorbic acid, maleic acid and tartaric acid, respectively. Taking the taxol solution obtained in the step c, diluting the taxol solution to the concentration of 1.25mg/ml by using water, observing the phenomenon after dilution, and detecting related substances.

TABLE 7-1 Effect of different kinds of stabilizers on stability after drug dilution

TABLE 7-2 Effect of different kinds of stabilizers on drug-related substances

The results show that the type of the stabilizer can influence the stability of the diluted medicine, and 1% of maleic acid and tartaric acid are added, so that the stability of the diluted medicine is poor and the medicine can be kept stable within 20 minutes; ascorbic acid is selected as a stabilizer, and the medicine can be maintained to be clear and transparent for 1h after being diluted; the stabilizer is citric acid monohydrate, and the medicine is diluted with water and then kept stable for more than 2 hours without precipitation. Further examination of the related substances of the more stable formulation revealed that the use of citric acid monohydrate as a stabilizer better inhibited the increase of the related substances and the chemical stability of the formulation was better than that of ascorbic acid.

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

Paclitaxel formulations containing varying amounts of stabilizer were prepared as described in example 3. Taking the taxol solution obtained in the step c, diluting the taxol solution to the concentration of 1.25mg/ml by using water, observing the phenomenon after dilution, and detecting related substances.

TABLE 8-1 Effect of different amounts of stabilizers on stability after drug dilution

TABLE 8-2 Effect of different amounts of stabilizers on drug related substances

The above results indicate that the amount of stabilizer citric acid monohydrate can have an effect on the dilution stability of the formulation. The dosage range of 0.3% -1.5% of citric acid monohydrate is selected, the stability of the preparation after dilution is superior to other tested amounts, the contents of other single impurities and total impurities are not obviously changed, and the chemical stability also meets the requirements. Especially, when the citric acid monohydrate is used in an amount of 1%, the stability of the preparation after dilution is best maintained, and the diluted micelle liquid can maintain a clear and transparent stable state for more than 2 hours.

EXAMPLE 9 dissolution profile of paclitaxel capsules

1. Paclitaxel capsule dissolution profile described in example 3

The paclitaxel capsules prepared in example 3 were taken for dissolution profile determination.

TABLE 9-1 results of dissolution profile detection of paclitaxel capsules example 3

The result shows that the taxol capsule is quickly released in 0.1 percent Tween-0.1 mol/L hydrochloric acid solution, which is beneficial to the absorption of the preparation in the gastrointestinal tract.

2. Effect of different surfactants on paclitaxel capsule dissolution

With reference to the procedure described in example 3, paclitaxel formulations (30 mg paclitaxel per capsule) containing different surfactants were prepared. The dissolution profile was determined using 3 different prescription paclitaxel capsules. The auxiliary materials comprise the following components:

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TABLE 9-2 Effect of different surfactants on the dissolution profile of paclitaxel capsules

The result shows that the taxol capsule can be rapidly released in 0.1% Tween-0.1 mol/L hydrochloric acid solution, can be dissolved out for more than 90% in 15min, and maintains a stable state, and no drug precipitate is separated out in the test process (45 min), thereby being beneficial to the absorption of the preparation in the gastrointestinal tract.

EXAMPLE 10 accelerated stability test of paclitaxel capsules

Paclitaxel capsules were prepared as described in example 3 and subjected to stability experiments for 1 month, 2 months, 3 months under accelerated conditions (40 ℃/RH 75%) and 3 months under prolonged conditions (25 ℃/RH 60%).

TABLE 10 results of accelerated and long-term stability test of paclitaxel capsules

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Note that: * Referring to the method of example 4, the capsule contents were diluted with water and then tested.

The stability test results are shown in Table 10. The results show that the taxol capsule is stored for 3 months under the accelerated and long-term conditions, the particle size of micelles obtained by diluting the content of the capsule, impurities, the content of active ingredients and moisture are not obviously changed, and the stability of the preparation is good.

EXAMPLE 11 rat pharmacokinetic experiments

The paclitaxel solution obtained in step c of example 3 was used for single oral PK test in rats. The specific method comprises the following steps:

SD rats weighing about 200g, randomly grouped by body weight, 6 per group (each group contains 5 males, 1 female): (1) Paclitaxel solution of example 3 alone (20 mg/kg), administered orally by intragastric administration; (2) Example 3 paclitaxel solution (20 mg/kg) in combination with HM30181A (10 mg/kg, administered 30min before paclitaxel), was administered orally by gavage; (3) Control paclitaxel solution (20 mg/kg) was administered orally by gavage in combination with HM30181A (10 mg/kg, 30min before paclitaxel administration). Using paclitaxel injection, another 6 rats received intravenous administration of paclitaxel (5 mg/kg) for calculation of the relative bioavailability of paclitaxel. Blood samples were collected through orbital veins before and 0.25, 0.5, 1, 2, 4, 8, 24 hours after dosing, plasma paclitaxel concentrations were determined, and T was calculated _1/2 、T _max 、C _max 、AUC _last 、AUC _Inf And pharmacokinetic parameters and the relative bioavailability of the paclitaxel solution.

The test results are shown in Table 11. The results show that the paclitaxel solution of example 3 when co-administered with HM30181A (i.e., half an hour after administration of HM 30181A) improved the pharmacokinetic data, which significantly increased the maximum blood concentration (C) _max ) Area under the curve (AUC) and the oral bioavailability of paclitaxel.

The Cmax and AUC of the paclitaxel solution of example 3 were significantly increased and the bioavailability was significantly improved compared to the control paclitaxel solution.

TABLE 11 results of rat pharmacokinetic experiments

Note that: * The auxiliary materials of the control taxol solution comprise 64.5% of Tween 80 and 34.5% of polyoxyethylene (35) hydrogenated castor oil by weight percentage as a surfactant mixture, and the rest components, the dosage proportion and the preparation method are the same as those of the prescription of the example 3.

EXAMPLE 12 dog pharmacokinetic experiments

The paclitaxel capsules prepared in step d of example 3 were taken for the canine single oral PK test. The specific method comprises the following steps:

beagle dogs weighing 6-11 kg, randomly grouped according to body weight, 4 animals per group (each group3 males, 1 female): (1) paclitaxel alone capsules (6 mg/kg), administered orally; (2) Paclitaxel capsules (6 mg/kg) were administered orally in combination with HM30181A (1.5 mg/kg, 30min before paclitaxel). An additional 6 beagle dogs (4 males, 2 females each, weighing 6-11 kg) were given intravenous paclitaxel (1 mg/kg) using paclitaxel injections, for calculation of the relative bioavailability of paclitaxel. Blood samples were collected through the upper limb veins before and 0.25, 0.5, 1, 2, 4, 8, 24 hours after dosing. Plasma paclitaxel concentration was determined and T was calculated _1/2 、T _max 、C _max 、AUC _last 、AUC _Inf And pharmacokinetic parameters and the relative bioavailability of paclitaxel capsules.

The test results are shown in Table 12. The results show that: when the paclitaxel capsule is co-administered with HM30181A (i.e., paclitaxel is administered half an hour after administration of HM 30181A), the maximum blood concentration of paclitaxel (C _max ) The area under the curve (AUC) and the oral bioavailability are obviously increased.

TABLE 12 results of canine pharmacokinetic experiments

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Claims

1. An oral taxane pharmaceutical composition comprises an active ingredient taxane drug and an auxiliary material, wherein the auxiliary material comprises a surfactant mixture,

(1) The surfactant mixture is prepared from tween 80 and 15-hydroxystearic acid polyethylene glycol ester with a weight ratio of 80:

20-60: 40, preferably 75:25 to 60:40, further preferably 70:30 to 60:40, or 68:32 to 62:38, or 66:34 to 64:36, further preferably 65:35 or 64.5:34.5;

(2) The surfactant mixture comprises at least 90%, preferably at least 93%, or at least 95%, or at least 96%, or at least 97% by weight of the adjuvant;

preferably, the adjuvant does not comprise oil.

2. The pharmaceutical composition of claim 1, wherein: the taxane is selected from paclitaxel, docetaxel, cabazitaxel, ralostaxel (XRP 9881), ortataxel, tesetaxel, milataxxel, and other derivatives having taxane skeleton structure (such as BMS-184740, BMS-188797, BMS-275183, etc.), preferably paclitaxel, docetaxel.

3. The pharmaceutical composition according to any one of claims 1-2, wherein: the taxane is dissolved in the adjuvant and is present in the pharmaceutical composition at a concentration of at least 30mg/g to 70mg/g, preferably at a concentration of at least 30mg/g to 60mg/g, more preferably at a concentration of at least 40mg/g to 50 mg/g.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein: the auxiliary materials further comprise a stabilizer and/or an excipient.

5. The pharmaceutical composition of any one of claims 1-4, wherein: the pharmaceutical composition may be filled into hard or soft gelatin capsules for administration or may be administered as a liquid preparation.

6. The pharmaceutical composition of any one of claims 1-5, wherein: the auxiliary materials comprise:

composition of the components Weight percent Tween 80 80％～60％ 15-hydroxy-stearic acid polyethylene glycol ester 20％～40％ Stabilizing agent 0.1％～5％

Alternatively, the auxiliary materials comprise:

alternatively, the auxiliary materials comprise:

Alternatively, the auxiliary materials comprise:

composition of the components Weight percent Tween 80 70％～60％ 15-hydroxystearic acid polyethylene glycolEsters of 30％～40％ Citric acid hydrate 0.3％～1.5％

Alternatively, the auxiliary materials comprise:

alternatively, the auxiliary materials comprise:

Alternatively, the auxiliary materials comprise:

。

7. A method of preparing an oral taxane pharmaceutical composition according to any one of claims 1-6 comprising:

a. weighing Tween 80 and 15-hydroxystearic acid polyethylene glycol ester with the prescribed amount, and stirring and mixing uniformly to obtain a surfactant mixture;

b. weighing a prescribed amount of stabilizer, adding the stabilizer into the surfactant mixture obtained in the step (a), and continuously stirring until the stabilizer is completely dissolved;

c. weighing the taxane medicine with the prescription amount, adding the taxane medicine into the mixture obtained in the step (b), and continuously stirring until the taxane medicine is dissolved;

preferably, the preparation method of the oral taxane pharmaceutical composition comprises stirring under heating condition, preferably at 30-50deg.C, preferably 35-45deg.C, preferably 40deg.C;

preferably, in the preparation method of the oral taxane pharmaceutical composition, step c is to divide the prescription amount of taxane into a plurality of small parts, and add the small parts into the mixture obtained in step b in a divided manner;

8. Use of an oral taxane composition according to any one of claims 1 to 6 or an oral taxane composition prepared by the method of claim 7 in the preparation of an antitumor agent.

9. A combination comprising (1) the oral taxane composition of any one of claims 1-6 or the oral taxane composition prepared by the method of claim 7, (2) a P-gp inhibitor; the P-gp inhibitor is selected from one or more of verapamil, trifluoperazine, cyclosporine, other antihypertensive agents (such as quinidine and reserpine), yohimbine, antiestrogen, tamoxifen, toremifene, antitumor vincristine and derivatives thereof, HM30181A (namely Encequidar), XR9576 and GF 120981; preferably HM30181A (i.e., encequidar).

10. Use of a combination product according to claim 9 for the preparation of an antitumor drug.