CN101854919B

CN101854919B - Compositions for the treatment of neoplastic diseases

Info

Publication number: CN101854919B
Application number: CN2008801042752A
Authority: CN
Inventors: J·H·贝内恩; J·H·M·舍伦斯; J·默斯; B·努伊耶恩
Original assignee: Stichting Het Nederlands Kanker Instituut; SLOTERVAART PARTICIPATIES BV
Current assignee: Stichting Het Nederlands Kanker Instituut; SLOTERVAART PARTICIPATIES BV
Priority date: 2007-08-24
Filing date: 2008-08-22
Publication date: 2012-02-15
Anticipated expiration: 2028-08-22
Also published as: RU2488384C2; BRPI0816144A2; GB0716591D0; JP5404625B2; JP2010536837A; RU2010110658A; ES2535401T3; CN101854919A

Abstract

Pharmaceutical compositions and methods for the treatment of neoplastic disease and comprising the combination of a taxane, such as docetaxel, with a CYP3A4 inhibitor, such as ritonavir. Methods of treatment of neoplastic disease incorporating the administration of a taxane and the administration of a CYP3A4 inhibitor, either simultaneously or separately, are also included. Further, kits for carrying out the methods are included. Solid pharmaceutical taxane compositions for oral administration comprising a substantially amorphous taxane, a carrier and a surfactant are also included.

Description

Be used to treat the compositions of tumor disease

Technical field

The present invention relates to pharmaceutical composition.More specifically, but non exhaustive ground, the present invention relates to be used to treat the compositions and the method for tumor disease.

Background technology

Medicine with the oral forms administration provides multiple advantage.In the time of when essential long-term treatment and the most effectively, the availability of oral cancer therapy drug is important, for example, and the transduce medicine [I] of path or angiogenesis of 5-fluorouracil (5-FU) prodrug (for example capecitabine (capecitabine)) and interfering signal.In addition, oral drugs can improve convenience and patient's quality of life to outpatient's administration or home clothes usefulness, and owing to the number of times that reduces entering hospital possibly reduce cost [2].Therefore, advantageously attempt the oral administration cancer therapy drug.

Generally speaking, the oral administration medicine is convenient and practical.But regrettably, the oral administration biaavailability of most of cancer therapy drugs is low and be variable [I].Typical instance is widely used taxane, and docetaxel (docetaxel) and paclitaxel, its oral administration biaavailability are lower than 10% [3,4].Have several kinds of other cancer therapy drugs of higher bioavailability, demonstrate higher transmutability.The example comprises: topoisomerase I inhibitor, catharanthus alkaloid and mitoxantrone [1,5,6].Consider the treatment window narrows, when the blood plasma level that can not reach in the treatment, variable bioavailability can cause the effect of unexpected toxicity or reduction.People such as Hellriegel prove under study for action, behind intravenous administration, and blood plasma level more variable usually [7] behind oral administration.When the time of drug exposure was the main determining factor of anticancer therapy, enough oral administration biaavailabilities were important [8].For preventing local drug concentration high (that kind possibly produce local toxicity) in stomach-intestinal canal, enough oral administration biaavailabilities also are important.

People such as Chen [95] experimentize to attempt to improve the dissolubility of cancer therapy drug docetaxel, so that improve its bioavailability.People such as Chen attempt to use the solid dispersion of docetaxel and various carrier (that is, glyceryl monostearate, PVP-K30 or poloxamer 188).People such as Chen find; When the ratio of docetaxel and poloxamer (poloxamer) was 5: 95, after 20 minutes, poloxamer 188 was increased to about 3.3 μ g/ml (in the standard solubility test) with the dissolubility of docetaxel; After about 120 minutes, dissolubility is maximum to about 5.5 μ g/ml.After 20 minutes, PVP-K30 only is increased to about 0.8 μ g/ml with the dissolubility of docetaxel, and after about 300 minutes, dissolubility is maximum to about 4.2 μ g/ml.Glyceryl monostearate almost can not improve the dissolubility of docetaxel at all.Therefore, can not the dissolubility and the rate of dissolution of docetaxel be increased to extra high level.

Variable and/or the low oral administration biaavailability that has many important soluble cancer therapy drugs of mechanism, for example the affinity to the transport of drug body is high in gastrointestinal tract, has limited absorption like this; And the high extraction (first pass effect) (first pass effect) [1,4,9] of the medicine that causes of the strong metabolism in intestinal and/or liver (extensive metabolism).Other important factors comprise: structural instability and medicine limited dissolubility, drug-drug interactions and medicine-food interaction, mobility's disease, obstructive disease, the nausea and vomiting that in gastrointestinal tract, exists or the local toxicity in gastrointestinal fluid.

About the transport of drug body and the metabolic enzyme of the bioavailability that influences oral drugs, supposition can cause that the main transport of drug body and the metabolic enzyme of the low/variable oral administration biaavailability of cancer therapy drug are P-glycoprotein (P-gp) and Cytochrome P450 (CYP) isozyme.

P-glycoprotein (P-gp) is film-bonded multiple medicines transporter, and it is assembled through heterobiotin is exported in the cell that reduces medicine from cell as energy-dependency transhipment or efflux pump.P-gp identified in having the normal structure that decorporation lets out function, the teleblem of the syntrophoblast of the said chamber film of organizing the little periosteum of for example hepatocellular bile, the endotheliocyte in blood-brain barrier and blood-testis barrier, Placenta Hominis, the epithelium teleblem and the kidney proximal tubule of intestinal.P-gp can have important barrier function [9-12] in the mechanism of the anti-external source toxin of protective tissue (xenotoxins).

We think that P-gp can prevent the mucomembranous cell of some drugs chemical compound crosscut small intestinal, therefore, can prevent that said medical compounds is absorbed in systemic circulation.Having the physicochemical characteristics of variation and the multiple medicine of pharmacological activity (for example verapamil, quinidine and ciclosporin A (CsA)) and novel active blocker GF120918 (Iraq reaches (elacridar)), LY335979 (zosuquidar) and R101933 has shown in clinical research and can regulate [13-18] to P-gp.Behind intravenous administration; The P-gp regulator can influence the mechanism of the pharmacodynamics of cancer therapy drug can compete [19,20] mutually with the inhibition that bile secretion, intestinal transhipment and the kidney of the intestinal of Cytochrome P450 (CYP)-mediation or hepatic metabolism, inhibition P-gp-mediation are removed (renalelimination).Only carried out several kinds with cancer therapy drug and regulator coupling or not with the random research of the expection of regulator coupling.These study announcement, when with the regulator coupling, need to reduce the cancer therapy drug of dosage, to prevent the serious toxicity relevant with medicine.In addition, these study undeclared cancer therapy drug and the regulator coupling can produce any benefit [21-23] to survival rate.

For many cancer therapy drugs, Cytochrome P450 (CYP) is main oxidisability drug metabolism enzyme system.The CYP isozyme is expressed liver and intestinal camber, but every kind of isozyme definite contribution in drug metabolism is unknown.We recognize that the intestinal of this enzyme system extracts (intestinal extraction) and in the oral administration biaavailability of limit drug, plays important effect [31].The people has four kinds of fixed functional CYP3A enzymes, and they are main drug metabolism enzyme, can cause about 30% liver CYP and greater than the expression [24,30,32,33] of 70% intestinal CYP.

Some P-gp regulators also can be used as the substrate of CYP3A, and CYP3A is the isozyme of CYP system.The stack of the selective substrate of localized P-gp of conjunctive tissue and CYP3A shows that these two kinds of protein can cooperate and form the absorption barrier [24-26] to the mithridatism heterobiotin.People such as Cummins have confirmed this point, and show that P-gp can influence intestinal drug metabolism (particularly isozyme C YP3A4) [27] through the entering of control medicine in the endocellular metabolism enzyme system.Therefore can find out, can play effect in the limited and/or variable oral administration biaavailability of CYP3A and the P-gp medicine of shared substrate in intestinal.

Proved taxane, paclitaxel and the docetaxel active anticancer in several kinds of tumor types (for example, breast carcinoma, ovarian cancer, head and neck cancer and nonsmall-cell lung cancer [NSCLC]).At present, various medicines pass through intravenous administration [34] with different dosages and scheme.But in oral formulations, taxane has low-down bioavailability.Infer that this is because the effect of P-gp and CYP3A.In the mice and the mankind, attempted to improve the research of the bioavailability of medicament of oral administration with several kinds of cancer therapy drugs (for example, taxane).

When the paclitaxel oral administration, bioavailability very low (＜10%).This causes [4,10,35,36] by paclitaxel to the high-affinity that is present in the P-gp in the gastrointestinal tract.In addition, through CYP isozyme 3A4 and 2C8, remove (presystemic elimination) also can work [37-39] before the system in the intestinal wall regulating liver-QI to the low oral administration biaavailability of paclitaxel.Recently the research to wild mouse and mdr1aP-gp knock out mice shows that clearly P-gp has limited the absorption of paclitaxel.Compare with wild mouse, in viewpoint evidence (proof-of-concept) research in knock out mice, researcher proves that behind oral and intravenous administration, the area of the PC-time graph of paclitaxel (AUC) increases by six times and twice [4] respectively.Behind oral administration, the mark of the unchanged paclitaxel that from the feces of wild mouse, reclaims is 87% dosage, and by comparison, in mdr1a P-gp knock out mice, this mark is 3%.Although absorbed fully by gastrointestinal tract, bioavailability is not increased to 100% yet, and this possibly be because the head of intestinal/liver crosses extraction [4,40].

Based on this discovery,, begin to carry out the research of several Xiang Xin of relevant paclitaxel and the coupling of P-gp inhibitor in order to improve oral administration biaavailability.Research to mice discloses, and with paclitaxel co-administered SDZPSC833, ciclosporin D analog and effective P-gp inhibitor, causes systemic exposure to increase by 10 times [41].Use CsA and paclitaxel similarly to study [42] with suitable effect.When co-administered CsA, the oral administration biaavailability of wild mouse is increased to 67% from 9%.Be also noted that with the wild mouse of CsA co-therapy in the paclitaxel that obtains blood plasma level in addition be higher than the blood plasma level that in the knock out mice without the CsA treatment, obtains with oral paclitaxel treatment.This point may be interpreted as through in gastrointestinal tract, suppressing P-gp and improves absorption, and reduces by suppressing the removing [42-45] that CYP3A causes.But, can not get rid of the retardance that other the transport of drug bodies confirmed not yet or medicine are removed the path.

The use of CsA in long-term oral taking medicine is relevant with immunosuppressive effect, and immunosuppressive effect is deleterious to the health of object.Therefore, as a kind of selection, study non--immunosuppressant P-gp blocker (GF120918) and improve oral bioavailability of taxol.Exploitation GF120918 is mainly used in the multi-drug resistant [16] of reverse P-gp-mediation in tumor.In the research of announcing recently, people such as Bardelmeijer prove that GF 120918 has significantly improved oral bioavailability of taxol [46].Oral bioavailability of taxol is increased to 40% from 8.5% in wild mouse, and the pharmacodynamics of paclitaxel is similar with result in mdr1a/b P-gp knock out mice in the wild mouse of accepting GF 120918.Therefore, GF 120918 blocks the P-gp in the intestinal effectively, and does not disturb other paths that relate to the paclitaxel picked-up or remove probably.Notice, prove that recently GF 120918 also is effective inhibitor [28,29] of abc drug transporter BCRP (ABCG2).

Docetaxel still is the substrate of P-gp, and this point is shown in people's such as WiIs in 1994 article [47,48] for the first time.Because the promotion result of paclitaxel and the coupling of P-gp inhibitor uses docetaxel also mice to be studied.These study confirmation, and P-gp also plays important effect in the low bioavailability of docetaxel.Through with the CsA co-administered, the AUC of oral docetaxel improves 9 times [49].In addition, in mice, tested the co-administered with ritonavir, ritonavir is the inhibitor with CYP3A4 of a small amount of P-gp rejection.CYP3A4 is a main enzyme [50] of in the mankind, being responsible for the metabolism decomposition of docetaxel.The inventor has carried out preclinical study in mice, wherein with ritonavir and docetaxel co-administered, show that apparent bioavailability (apparent bioavailability) is increased to 183% from 4%.Stronger first pass metabolism (first-pass metabolism) also possibly cause the low bioavailability [49] of oral docetaxel in mice to a great extent.Cytochrome P 450 enzymes in the mice intestinal (being called Cyp) is different to be found in the mankind, and has different substrate specificities.In addition, the rule that CYP expresses between the mice and the mankind is obviously different, and this is because the difference [88-92] of activity, expression and the adjusting of transcription factor (for example, the transcription factor of people CYP3A is PXR).Because the physiology of mice, enzyme etc. are different fully with the mankind, therefore, must not be according to these of mice are studied the result who explains in the mankind.Therefore, the mice data can not be extrapolated to the mankind simply.In addition, in this research, use the docetaxel (10-30mg/kg) (, being fatal) of high dosage and the ritonavir (12.5mg/kg) of high dose for people's object as far as mice.For the individuality of 72kg, mean and use the 720-2160mg docetaxel.But nowadays patient's clinical treatment is with the dosage of docetaxel (intravenous) between 100-200mg.Significantly, because the high dose of the medicine of administration, this method can not be used for the mankind.In addition, the mice data do not provide any evidence about the safety of the oral route of this coupling in the mankind.

Be based on the extensive clinical preceding result in the mice, begin several kinds of clinical point evidences (proof-of-concept) research.The patient who suffers from solid tumor accepts the 60mg/m of a course of treatment ²Oral paclitaxel is as single medicine, perhaps 60mg/m ²Oral paclitaxel and 15mg/kg CsA coupling.Oral paclitaxel of co-administered and CsA cause the systemic exposure of oral paclitaxel is improved 8 times, and the apparent bioavailability of oral paclitaxel never uses 4% of CsA to be increased to 47% [3] of use CsA in this research.The raising of systemic exposure is likely by the inhibition of P-gp in gastrointestinal tract and causes, but infers that from preclinical study the metabolic inhibition of paclitaxel also can have contribution [41,42] to this effect.In order further to improve the systemic exposure of paclitaxel, the dosage of oral paclitaxel and CsA coupling progressively increases research and discloses, and maximum tolerated dose is 300mg/m ², and under higher dosage, raising and the dosage of AUC disproportionate [52].Under this maximum dose level level, carry out mass balance research and measure feces secretions.At 300mg/m ²The maximum dose level level under, total feces secretions is 76%, wherein 61% is parent drug (parentdrug), the paclitaxel that this point may be interpreted as oral administration is not absorbed [53] fully by gastrointestinal tract.Infer thus, be used for the high-load cosolvent polyoxyethylene castor oil of paclitaxel iv formulation of oral administration, hinder the paclitaxel of oral administration to be absorbed fully.In addition, owing to do not detect the blood plasma level of polyoxyethylene castor oil, polyoxyethylene castor oil is not absorbed behind the oral administration paclitaxel, and polyoxyethylene castor oil causes the non-linear pharmacodynamics and the severe anaphylactic reaction [54-56] of intravenous paclitaxel.The additional advantage [51,52] that this point possibly be the oral administration paclitaxel.Subsequently, surpass the threshold level of 0.1 μ M, the dosage of oral paclitaxel of research and CsA coupling every day twice (b.i.d.) in the patient for persistent period of the systemic exposure that improves oral paclitaxel.At 2 * 90mg/m ²Dosage level under, reach the systemic exposure [57] of the sufficiently long paclitaxel that surpasses 0.1 μ M level with good safety characteristic.In these researchs, the oral absorption intravenous of patient formulation for paclitaxel (also containing polyoxyethylene castor oil and ethanol) [57].In addition, dosage-outcome research of oral paclitaxel and CsA shows that under the 10mg/kg single dose, CsA is to the inhibition effect maximum [58] of P-gp.

In studying in the another kind of I phase, before oral paclitaxel 1 hour, the patient accepted 1, the GF 120918 [59] of 000mg.The raising of paclitaxel systemic exposure magnitude with the CsA coupling time is identical.The result who studies based on these I phases, the beginning II phase study repetition oral administration paclitaxel whether feasible with have activity.Weekly, several kinds of tumors continuously in every day twice (b.i.d.) drug administration oral administration paclitaxel: in NSCLC, be used as a line and second line treatment [60], be used as first-line treatment [99] late in the gastric cancer, be used as second line treatment [100] late in the breast carcinoma.Weekly, all patients are with 90mg/m ²Dosage twice (b.i.d.) oral paclitaxel treatment every day.Each paclitaxel administration 30 minutes before, with the dosed administration CsA of 10mg/kg.In suffering from the patient of advanced NSCLC, in the patient of 23 evaluations, always replying speed (ORR) is 26% [60].This point is suitable with early stage research, and the middle bit time of progress (median time toprogression) is 3.5 months, and median survival interval is 6 months.Wherein use these researchs of several kinds of single medicines (for example vinorelbine, gemcitabine and taxane) to show that replying speed is 8%-40%, median survival interval (median overall survival time) is in 6-11 month scope [61-66].

In the gastric cancer, (palliative intent) carries out chemotherapy with alleviating medicine late.Use various drug combination chemotherapy to be common scheme, and show that replying speed is 20%-50%, for example 5-FU/ doxorubicin and mitomycin or methotrexate coupling, or epirubicin/cisplatin/5-FU scheme [67-70].In a line and second line treatment, in suffering from the patient of late gastric cancer (ORR:5%-23%), paclitaxel also shows anti-tumor activity [71-73].In 24 evaluate patient, the ORR in this research is 32%.This b.i.d. toxicity characteristic of scheme weekly can control [99] well.The most general toxicity is 3/4 neutrophilic granulocyte minimizing in suffering from the patient of NSCLC, and this all observes in 54% patient.This point and standard per 3 all intravenous paclitaxel schemes suitable [65,66].

Neurovirulent prevalence rate is lower than per 3 all schemes, and the peak plasma concentrations that this point may be interpreted as paclitaxel in this research is lower.The patient who accepts to inject in 24 hours and the patient who accepts to inject in 3 hours paclitaxel compare and also observe this point [74]; But query (therefore at intravenous administration; In the presence of polyoxyethylene castor oil) whether back paclitaxel blood plasma level can compare with the paclitaxel blood plasma level behind the oral paclitaxel (therefore, not containing polyoxyethylene castor oil).

For docetaxel, in suffering from the patient of solid tumor, carry out similar clinical point evidence (proof-of-concept) research.Contain or do not contain the CsA of the single oral dose of 15mg/kg, the patient accepts the 75mg/m of a course of treatment ²The oral docetaxel of dosage.Pharmacodynamic result shows that oral docetaxel and CsA co-administered cause the systemic exposure of docetaxel to improve 7.3 times.The apparent bioavailability of oral docetaxel is never used 8% of CsA to be increased to and is used 90% [75] of CsA.The raising of systemic exposure may be interpreted as the inhibition of CYP3A4, and the P-gp through CsA suppresses in gastrointestinal tract, but the magnitude of two kinds of mechanism can not accurately be confirmed.Compare with the mankind [75], CsA is to the influence of the bioavailability of docetaxel in mice not too obviously [49], but the reason of this appropriateness influence of mice it be unclear that.Also carry out weekly oral docetaxel late in the breast carcinoma and add that the II phase of CsA studies.This scheme administration was weekly carried out for 6 weeks altogether, then 2 not administrations of week.The oral dose weekly of administration 100mg docetaxel causes AUC and 40mg/m ²Intravenous dosages weekly identical, this dosage is suitable well tolerable [76].30 minutes administration CsA before the oral docetaxel of picked-up 15mg/kg dosage.The iv formulation of docetaxel is as drinkable solutions.In 25 patients that evaluation is replied, notice that ORR is 52%.The toxicity that the most often records is neutrophilic granulocyte minimizing, diarrhoea, fingernail toxicity and fatigue.But behind intravenous administration, haematics toxicity seems not too serious [77].The speed of replying in this research is the upper range [76-79] in the result described in the document.

In the AUC of docetaxel behind the oral administration and transmutability [80,81] in identical scope between the observed patient in intravenous administration docetaxel (29%-53%) back and in the patient.

Weekly or the CsA of b.i.d. drug administration oral administration dosage, with oral docetaxel or paclitaxel coupling, because immunosuppressant can produce nephrotoxicity or infection [82].Therefore, from the inventor's angle, preferably improve a kind of optional medicine of the clinical bioavailability of oral docetaxel or paclitaxel.

It is feasible using the oral weekly scheme of reinforcement of taxane, and shows significant clinically activity among breast carcinoma, gastric cancer and the NSCLC late.Oral scheme is convenient and have favourable haematics toxicity characteristic, and non--haematics toxicity is acceptable.

Prior art seems mainly to be devoted to suppress the effect of P-gp, with bioavailability and the pharmacodynamics performance of improving cancer therapy drug.Use various medicines (for example, CsA and GF 120918) to carry out this research.In order to improve the bioavailability of oral drugs, P-gp looks like the most important protein that is used to block.

Summary of the invention

Therefore, in first aspect, the invention provides a kind of pharmaceutical composition for oral administration that is used for, wherein, said composition contains taxane and CYP3A4 inhibitor (for example ritonavir) and one or more pharmaceutically acceptable excipient.

Use the advantage of ritonavir to be to improve the oral administration biaavailability of taxane with the taxane coupling, make more medicine from intestinal, be absorbed in the blood flow.This is because medicine is stopped by the inhibition of metabolic CYP3A4 and a small amount of P-gp rejection.Through suppressing CYP3A4 metabolism in liver, ritonavir also reduces the removing of taxane from health.This means the higher blood plasma level that keeps taxane in the long period.For example, the docetaxel metabolite is poorer than the pharmacological activity of docetaxel itself.Therefore, through suppressing the metabolism of docetaxel, tool pharmacological activity form was present in the blood flow with higher level and long period.Better therapeutic effect is provided like this.The result is to reduce the amount of the taxane of each dosage.In addition, the inhibition of CYP3A4 reduced bioavailability that the difference owing to CYP activity level in the different patients causes with remove patient's differences property.

Use the ritonavir targeting and suppress CYP3A4 rather than targeting P-gp, through stopping the bioavailability that its metabolism improves oral taxane.On the whole, this point is the approach different with prior art.

Pharmaceutical composition of the present invention contains any taxane or its pharmaceutically acceptable salt and ester and ritonavir (or its pharmaceutically acceptable salt and ester) and any pharmaceutically acceptable carrier, adjuvant or excipient.The pharmaceutically acceptable carrier, adjuvant and the excipient that can be used for pharmaceutical composition of the present invention include, but are not limited to: ion-exchanger; Aluminium oxide; Aluminium stearate; Lecithin; Serum proteins (for example human serum albumin); Buffer substance (for example phosphate); Glycerol; Sorbic acid; Potassium sorbate; The mixture of the partial glyceride of saturated vegetable fatty acid; Water; Salt or electrolyte (for example protamine sulfate); Sodium hydrogen phosphate; Potassium hydrogen phosphate; Sodium chloride; Zinc salt; Colloidal silica; Magnesium trisilicate; Polyvinyl pyrrolidone; Based on cellulosic material; Polyethylene Glycol; Sodium carboxymethyl cellulose; Polyacrylate; Wax; Polyethylene-polyoxypropylene-block polymer; Polyethylene Glycol and lanoline.Pharmaceutical composition of the present invention can contain the pharmaceutically acceptable carrier of non-toxicity, adjuvant or the excipient of any routine.

Pharmaceutical composition of the present invention can include but not limited to: capsule, tablet, powder or coated granules agent with any oral acceptable forms oral administration.Also can use suspension, solution and emulsion agent, preferably in the aqueous excipient.Can tablet formulation be become to discharge immediately, postpone to discharge, repeat to discharge or sustained release formulation.Perhaps, said tablet also can be tablet foaming, double-deck and/or coating.Delay discharges, repeats to discharge and sustained release formulation can contain one or both active component.Said tablet can be formed by the solid dispersion or the solid solution agent of taxane and/or ritonavir.Can capsule be mixed with immediately and discharge, postpone to discharge, repeat to discharge or sustained release formulation.Capsule can be capsule solid-filling or liquid-filling.Delay discharges, repeats to discharge and sustained release formulation can contain one or both active component.Capsule can be formed by the solid dispersion or the solid solution agent of taxane and/or ritonavir, perhaps can or be dispersed in the liquid taxane and/or ritonavir dissolving.For example, the possible solvent that is used for the capsule of liquid filling is a triacetin.This is the good especially solvent of paclitaxel.The aqueous solution agent can " at once use ", by one or more powder preparations, by one or more solid dispersion preparations, or prepares through the solution mixing with taxane and ritonavir.The aqueous solution agent also can comprise the other drug excipient, for example, and polysorbate 80 and ethanol.Under the situation of tablet that is used to orally use and capsule, carrier commonly used comprises: sucrose, cyclodextrin, Polyethylene Glycol, polymethacrylates, polyoxyethylene sorbitan fatty acid esters, Myrj 45, mannitol, dahlin (inulin), sugar (glucose, galactose, sucrose, fructose or lactose), HPMC (hydroxypropyl emthylcellulose), PVP (polyvinyl pyrrolidone) and corn starch.Usually also can add lubricant, for example magnesium stearate.For the oral administration of Capsule form, available diluent comprises lactose and exsiccant corn starch.For tablet and capsule, the other drug excipient that can add is binding agent, filler, filler/binding agent, adsorbent, wetting agent, disintegrating agent, lubricant, slippage agent, surfactant etc.Can tablet and capsule be carried out coating,, for example, change the tablet of coating or the taste or the color of capsule to change the outward appearance or the performance of tablet and capsule.When the aqueous suspension oral administration, active component is mixed with emulsifying agent and suspending agent.If desired, can add some sweeting agent and/or correctives and/or coloring agent.

The solid dispersion of taxane and ritonavir or solid solution agent can use any suitable method to form, and can comprise carrier, for example, and polymer.These methods are those skilled in the art well-known [93,94].That taxane in the solid dispersion and ritonavir can be is amorphous, crystal or part are amorphous/the crystalline state of part.Usually, organic solvent is used to prepare solid dispersion.These organic solvents can be any appropriate organic solvent, for example, and TBA (tert-butyl alcohol), ethanol, methanol, DMSO (dimethyl sulfoxide) and IPA (isopropyl alcohol).Can use any method of from the solid dispersion liquid solution, removing organic and/or aqueous solvent, for example, lyophilization, spray drying, spraying-lyophilization and vacuum drying.

Be used for liquid preparations for oral administration (particularly solid composite), taxane and ritonavir can be present in the same dosage form, perhaps can be present in the independent dosage form.If be present in the same dosage form, can taxane and ritonavir is formulated together, perhaps can be present in the independent chamber of multicell dosage form (the for example capsule of multilayer tablet or compartmentalization).

For the compositions that contains the modification delivery formulations, for example, postpone to discharge, repeat to discharge and extended release preparation, target is that the blood level of one or both active component of maintenance is enough high in long-time after administration.

Repeat delivery formulations; For example tablet or capsule; For the taxane (for example docetaxel) that can discharge sufficient dosage immediately and ritonavir (for example time t=0 hour time) and discharged the preparation of the ritonavir (for example when reaching the Cmax of ritonavir usually, in the time of time t=4 hour) of other enhancing dosage afterwards.This point can realize as follows, for example, through casing or have and coating is destroyed and the polymer coating of dissolved enzymatic cleavable key in intestinal, with the docetaxel of predose and ritonavir from the ritonavir that strengthens dosage separately.Perhaps, this point can realize as follows, and with coating and coated granules agent filling capsule not, wherein, the coated granules agent only contains ritonavir, and the coated granules agent does not contain docetaxel and ritonavir.Certainly, this point also can be realized as follows, with docetaxel tablets/capsules agent that discharges immediately and the ritonavir tablets/capsules agent coupling that repeats to discharge.Can use any suitable casing, for example, acetic acid-phthalic acid-cellulose, acetic acid-phthalic acid-polyvinyl ester (polyvinyl acetatephthalate) and suitable acrylic acid derivative, for example polymethacrylates.

In one embodiment, strengthened dosage (for example) several hours afterwards when reaching first when strengthening the Cmax of ritonavir of dosage first, can adopt identical principle (that is, repeating to discharge) send second strengthen dosage (therefore, totally three dosage) ritonavir.

Extended release preparation is for for example having the preparation of following characteristic: can discharge the taxane of sufficient dosage and the ritonavir of initial start/load doses, then slowly discharge the ritonavir of maintenance dose.For example, this point can be realized as follows, the docetaxel of single peroral dosage form and ritonavir, the tablets/capsules agent coupling of docetaxel tablets/capsules agent that perhaps will discharge immediately and the lasting ritonavir that discharges.

The modification delivery formulations can for example utilize inertia insoluble matrix, hydrophilic matrix, ion exchange resin, the controlled preparation of infiltration and reservoir system.For example, typical modification delivery systme can be made up of following material: active medicine, release control agent (for example substrate forms agent, film former), substrate or film modifier, solubilizing agent, pH regulator agent, lubricant and flow promortor, augment coating and density modifier [84].Suitable inert excipient comprises: calcium hydrogen phosphate, ethyl cellulose, methacrylate-polyamide copolymer (methacrylate copolymer polyamide), polyethylene, polyvinyl acetate.Suitable lipid excipient comprises: Brazil wax, acetyl group alcohol, hydrogenated vegetable oil, microwax, monoglyceride and triglyceride, PEG monostearate and PEG.Suitable hydrophilic excipient comprises: alginate, carbopol (carbopol), gelatin, hydroxypropyl cellulose, hydroxypropyl emthylcellulose and methylcellulose [84].

In one embodiment of the present invention, can prepare the compositions that comprises taxane and ritonavir, make ritonavir discharge a little earlier or allegretto than taxane.Before a large amount of taxanes discharges, has the effect that suppresses the CYP3A4 enzyme in the intestinal like this from compositions.Therefore, before taxane arrives blood flow, reduce, and,, also have the metabolism of the taxane that reduces the arrival blood flow and the effect of removing at the commitment of its absorption according to the influence of ritonavir to the CYP3A4 in the liver by the amount of the destructive taxane of CYP3A4 enzyme.This effect can prove through Fig. 1, and Fig. 1 is illustrated in before the docetaxel trend that 60 minutes administration ritonavirs improve oral administration biaavailability and AUC.But this result is not obvious on statistics in embodiment 2, but can see this trend.

Taxane is for being derived from the diterpene compound of Cercocarpus (Taxus (yews)) plant.But some taxanes are produced through synthetic method at present.Taxane is cell growth inhibiting through stopping cell division, and is used to treat cancer.Through destroying microtubule formation stopping cell division.Also can be used as angiogenesis inhibitor.The term that this paper uses " taxane " comprises and combines with tubulin and/or no matter be all diterpene taxane, functional deriv and pharmaceutically acceptable salt or the ester of natural or artificial generation as the CYP3A4 substrate.Preferred taxane is docetaxel, paclitaxel, BMS-275183, their functional deriv and their pharmaceutically acceptable salt or ester.BMS-275183 be paclitaxel C-3 '-tert-butyl group-3 '-N-tert-butoxycarbonyl analog [83].Most preferred taxane is docetaxel, its functional deriv or its pharmaceutically acceptable salt or ester, particularly, is those derivants of CYP3A4 substrate.

Containing various groups is also included within the present invention with the derivant of the taxane of modification physical and chemical performance.Therefore, the present invention includes the PAG (for example Polyethylene Glycol) or the saccharide conjugate of taxane with dissolubility property improvement or modification.

Pharmaceutical composition of the present invention can comprise the taxane of any appropriate amount and each in the ritonavir.Preferably, said compositions contains the taxane of 0.1mg to about 1000mg of having an appointment.Preferably, said compositions also contains the ritonavir of 0.1mg to about 1200mg of having an appointment.The amount of each in taxane and the ritonavir depends on the expection administration frequency of compositions.For example, said compositions can be according to like the lower frequency administration: every day three times, twice of every day or once a day, per two days, weekly, per two weeks, per three weeks or any other suitable taking medicine at interval.Also can use the combination of these dosages, for example, said compositions can be weekly in twice administration every day, or twice administration every day or twice administration every day in three weeks in per two weeks.For example, paclitaxel or docetaxel can interior weekly twice administrations every day.Will be normally weekly dosage separately for example make that object is taken a half-value dose in the morning, takes second half dosage at night, weekly.Have the effect that reduces the peak level of medicine in blood plasma like this, can help to reduce side effect like this.Also can improve the total time of medicine systemic exposure.

If administration every day of said compositions, preferred said compositions contain the extremely taxane of about 100mg of 0.1mg of having an appointment, more preferably, about 5mg is to the taxane of about 40mg; More preferably, about 5mg is to the taxane of about 30mg, more preferably; About 10mg is the taxane of about 20mg extremely, most preferably, and the taxane of about 15mg.Preferably, said compositions also contains the extremely ritonavir of about 1200mg of 50mg of having an appointment, and more preferably, about 50mg is to the ritonavir of about 500mg, and more preferably, about 50mg is the ritonavir of about 200mg extremely, most preferably, and the ritonavir of about 100mg.

If the administration weekly of said compositions, preferred said compositions contain the extremely taxane of about 500mg of 30mg of having an appointment, more preferably, about 50mg is the taxane of about 200mg extremely, most preferably, and the taxane of about 100mg.Preferably, said compositions also contains the extremely ritonavir of about 1200mg of 50mg of having an appointment, and more preferably, about 50mg is to the ritonavir of about 500mg, and more preferably, about 50mg is the ritonavir of about 200mg extremely, most preferably, and the ritonavir of about 100mg.

Be surprised to find that, at low dosage (for example, 100mg) the following required performance of using ritonavir still to have the bioavailability that improves taxane, the therapeutic effect that is improved.This means and to use low dose of ritonavir, make the risk of side effect minimum simultaneously to have required effect.

The present invention also provides the purposes of compositions in treatment that comprises taxane and CYP3A4 inhibitor (for example ritonavir).

In addition, the present invention also provides the purposes of the compositions that comprises taxane and CYP3A4 inhibitor (for example ritonavir) in the treatment tumor disease.

The tumor disease of the present invention's treatment is preferably solid tumor.Said solid tumor is preferably selected from breast carcinoma, pulmonary carcinoma, gastric cancer, colorectal carcinoma, head and neck cancer, the esophageal carcinoma, hepatocarcinoma, renal carcinoma, cancer of pancreas, bladder cancer, carcinoma of prostate, carcinoma of testis, cervical cancer, carcinoma of endometrium, ovarian cancer and non--Hodgkin lymphoma (NHL).Said solid tumor more preferably is selected from breast carcinoma, gastric cancer, ovarian cancer, carcinoma of prostate, head and neck cancer and nonsmall-cell lung cancer.

In one embodiment, the treatment of tumor disease comprises the said compositions of administration, subsequently, after the preset time section, the ritonavir of administration enhancer amount.Strengthen preferably administration in about 0 hour to about 12 hours after the said compositions of administration of dosage, more preferably, administration in about 1 hour to about 10 hours after the said compositions of administration; More preferably; Administration in about 2 hours to about 8 hours after the said compositions of administration, more preferably, administration in about 3 hours to about 5 hours after the said compositions of administration; Most preferably, administration in about 4 hours after the said compositions of administration.Strengthen dosage and be preferably the ritonavir to about 1200mg at about 50mg, more preferably, at the ritonavir of about 50mg to about 500mg, more preferably, at the ritonavir of about 50mg to about 200mg, most preferably, the ritonavir of about 100mg.

Be surprised to find that the ritonavir of administration enhancer amount provides the taxane of treatment level for a long time in blood flow, thereby have bigger therapeutic effect.

At related aspect, the present invention also provides the method for treatment tumor disease, and said method comprises taxane and the CYP3A4 inhibitor (for example ritonavir) to the object effective dosage that these treatment needs are arranged.

About above-mentioned composition, taxane can be any suitable taxane.Preferably, taxane is selected from docetaxel, paclitaxel, BMS-275183, their functional deriv and their pharmaceutically acceptable salt or ester, and more preferably, taxane is docetaxel, its functional deriv or its pharmaceutically acceptable salt or ester.

When with taxane and ritonavir during to the object administration, administration simultaneously basically each other.Perhaps, administration separately from each other.When administration respectively, preferred administration ritonavir before taxane, more preferably, about 60 minutes administration ritonavirs before taxane.

" basically simultaneously " that this paper uses be meant in about 20 minutes, more preferably in 15 minutes, and more preferably in 10 minutes, also more preferably administration taxane or ritonavir in 5 minutes, most preferably administration ritonavir or taxane in 2 minutes.Usually, ritonavir should be with taxane administration simultaneously or in taxane administration before.In some embodiments, the administration simultaneously of ritonavir and taxane, i.e. administration or administration simultaneously in two kinds of independent preparations together in a kind of preparation.

Can be according to the taxane or the ritonavir of any appropriate amount of said method administration.The dosage of taxane and/or ritonavir can the absolute dosages administration (promptly all identical for all patients, and no matter its weight or body surface area) or be based on the dosage of weight or based on the dosage of body surface area.Preferably, taxane and/or ritonavir are with the absolute dosages administration.Preferably, the about 0.1mg of administration is to the taxane of about 1000mg.Preferably, the about 0.1mg of administration is to the ritonavir of about 1200mg.The amount of the taxane of administration and each in the ritonavir depends on the expection administration frequency of taxane and ritonavir.For example, but every day three times, twice of every day or once a day, per two days, weekly, per two weeks, per three weeks or any other suitable administration at interval of taking medicine.Also can use the combination of these dosages, for example, can be weekly in twice administration every day, or twice administration every day or twice administration every day in three weeks in per two weeks.

If said method relates to administration every day taxane and ritonavir, the preferred about 0.1mg of administration is to the taxane of about 100mg, more preferably; The about 5mg of administration is to the taxane of about 40mg, and more preferably, the about 5mg of administration is to the taxane of about 30mg; More preferably; The about 10mg of administration is the taxane of about 20mg extremely, most preferably, and the taxane of the about 15mg of administration.Preferably, also the about 50mg of administration is to the ritonavir of about 1200mg, and more preferably, the about 50mg of administration is to the ritonavir of about 500mg, and more preferably, the about 50mg of administration is the ritonavir of about 200mg extremely, most preferably, and the ritonavir of the about 100mg of administration.

If said method relates to administration taxane and ritonavir weekly, the preferred about 30mg of administration is to the taxane of about 500mg, and more preferably, the about 50mg of administration is the taxane of about 200mg extremely, most preferably, and the taxane of the about 100mg of administration.Preferably, also the about 50mg of administration is to the ritonavir of about 1200mg, and more preferably, the about 50mg of administration is to the ritonavir of about 500mg, and more preferably, the about 50mg of administration is the ritonavir of about 200mg extremely, most preferably, and the ritonavir of the about 100mg of administration.

Said method can be used for treating any tumor disease.Preferably, said tumor disease is a solid tumor.Preferably, said solid tumor is selected from breast carcinoma, pulmonary carcinoma, gastric cancer, colorectal carcinoma, head and neck cancer, the esophageal carcinoma, hepatocarcinoma, renal carcinoma, cancer of pancreas, bladder cancer, carcinoma of prostate, carcinoma of testis, cervical cancer, carcinoma of endometrium, ovarian cancer and NHL.More preferably, said solid tumor is selected from breast carcinoma, ovarian cancer, carcinoma of prostate, gastric cancer, head and neck cancer and nonsmall-cell lung cancer.

Preferably, said method be used to treat to as if the people.

In one embodiment, said method also is included in preset time after the ritonavir of administration first dosage, the CYP3A4 inhibitor of administration enhancer amount (for example ritonavir) (being the coupling of taxane of ritonavir and the doses of doses).Strengthen preferably administration in about 0 hour to about 12 hours after the said compositions of administration of dosage, more preferably, administration in about 1 hour to about 10 hours after the said compositions of administration; More preferably; Administration in about 2 hours to about 8 hours after the said compositions of administration, more preferably, administration in about 3 hours to about 5 hours after the said compositions of administration; Most preferably, administration in about 4 hours after the said compositions of administration.Strengthen dosage and be preferably the ritonavir to about 1200mg at about 50mg, more preferably, at the ritonavir of about 50mg to about 500mg, more preferably, at the ritonavir of about 50mg to about 200mg, most preferably, the ritonavir of about 100mg.

The present invention also provides the method for treatment tumor disease; Wherein, This method comprises: use the compositions that contains taxane and one or more pharmaceutically acceptable excipient that the object of accepting CYP3A4 inhibitor (for example ritonavir) is carried out administration, said object is accepted said simultaneously, respectively or successively.Taxane and CYP3A4 inhibitor.

The present invention also provides the method for treatment tumor disease; Wherein, This method comprises: use the compositions that contains CYP3A4 inhibitor (for example ritonavir) and one or more pharmaceutically acceptable excipient and the object of accepting taxane is carried out administration, said object is accepted said CYP3A4 inhibitor and taxane simultaneously, respectively or successively.

In addition; The invention provides a kind of test kit that is used to treat tumor disease; Wherein, This test kit comprises first pharmaceutical composition that contains taxane and second pharmaceutical composition that contains CYP3A4 inhibitor (for example ritonavir), and said first pharmaceutical composition and second pharmaceutical composition are applicable to while, difference or administration successively.

In one embodiment; Said test kit also can comprise the 3rd pharmaceutical composition that contains CYP3A4 inhibitor (for example ritonavir), and the 3rd pharmaceutical composition is applicable to administration after second pharmaceutical composition that contains CYP3A4 inhibitor (for example ritonavir).It should be understood that the substantially the same compositions that second pharmaceutical composition that contains CYP3A4 inhibitor (for example ritonavir) in the said test kit separately and the 3rd pharmaceutical composition can be unit dosage forms.

Perhaps, the said test kit that is used to treat tumor disease can comprise first pharmaceutical composition that contains taxane and CYP3A4 inhibitor (for example ritonavir).In this case, said test kit also can comprise second pharmaceutical composition that contains CYP3A4 inhibitor (for example ritonavir), and this second pharmaceutical composition is applicable to administration after first pharmaceutical composition.

In addition; The invention provides a kind of compositions; Wherein, Said composition contains taxane and one or more pharmaceutically acceptable excipient, and said composition is used for the object of accepting CYP3A4 inhibitor (for example ritonavir) is carried out administration with the treatment tumor disease, and said CYP3A4 inhibitor and said taxane are simultaneously, accepted by said object respectively or successively.

Also have; The invention provides a kind of compositions; Wherein, Said composition contains CYP3A4 inhibitor (for example ritonavir) and one or more pharmaceutically acceptable excipient, and said composition is used for the object of accepting taxane is carried out administration with the treatment tumor disease, and said taxane and said CYP3A4 inhibitor are simultaneously, accepted by said object respectively or successively.

What it will be understood by those skilled in the art that is; Above-mentioned any or all preferred characteristic about the compositions, method or the test kit that use ritonavir is equally applicable to use those of other CYP3A4 inhibitor, and said other CYP3A4 inhibitor are grapefruit fruit juice or St.John beerwort (or any component), Lopinavir or imidazolium compounds (for example ketoconazole) for example.

Another problem relevant with prior art is to develop has the low variable Orally administered composition that comprises taxane, and makes wherein that taxane has high bioavailability.Oral paclitaxel [for example 3] and oral docetaxel [for example 75] clinical research, wherein oral absorption intravenous taxane formulations (also containing excipient, for example polyoxyethylene castor oil and ethanol, or polysorbate 80 and ethanol) have been carried out.Patient often report feels sick, vomits and makes the unjoyful taste of people.

As described in early days, people such as Chen [95] attempt to use solid dispersion and the poloxamer 188 or the PVP-K30 coupling of docetaxel, with dissolubility and the rate of dissolution that improves docetaxel.When the ratio of docetaxel and poloxamer was 5: 95, after 20 minutes, poloxamer was increased to about 3.3 μ g/ml with the dissolubility of docetaxel, and after about 120 minutes, the maxima solubility of docetaxel reaches about 5.5 μ g/ml (referring to Fig. 7 of Chen paper).After 20 minutes, PVP-K30 is increased to about 0.8 μ g/ml with the dissolubility of docetaxel, and after about 300 minutes, the maxima solubility of docetaxel reaches about 4.2 μ g/ml (referring to Fig. 2).In order to obtain good oral bioavailability, medicine must have higher dissolubility and rate of dissolution, makes in first about 0.-1.5 hour, in solution, has the medicine of enough a large amounts.

On the other hand, the invention provides the solid composite medicament that is used for oral administration, said compositions contains unbodied basically taxane, hydrophilic carrier (preferred polymers carrier) and surfactant.

The advantage of the compositions of this aspect is to improve with surprising degree the dissolubility of taxane.In addition, the taxane rate of dissolution also is increased to surprising degree.These two kinds of factors cause the bioavailability of taxane to significantly improve.We think that this at least partly is because taxane is an amorphous state.The crystal taxane has low-down dissolubility.In addition, find in clinical trial that the AUC of Orally administered composition of the present invention is high, and the transmutability between individuality reduces significantly than the transmutability between the individuality of liquid preparation demonstration.Provide a kind of more foreseeable taxane to expose like this, this sees very from safety perspective in oral chemotherapy regimen and expects.Intraindividual transmutability seems also significantly to reduce.Other advantages are that the tolerance (that is, aspect side effect) of Orally administered composition of the present invention seems identical at least or better with liquid oral taxane solution.

The advantage that carrier provides is that when taxane is placed aqueous medium, helping to keep taxane is amorphous state.Help to make taxane to stop crystallization like this or prolong taxane and in solution, begin crystallization time span before.The high-dissolvability and the rate of dissolution that therefore, can keep taxane.In addition, carrier is that compositions provides good physics and chemical stability.Help to prevent the taxane degraded like this, and help also to prevent that unbodied basically taxane from becoming the crystalline structure of having more of solid-state form after long-time.Good physical stability guarantees to keep the high-dissolvability of taxane.

When taxane was placed aqueous medium, it was amorphous state that surfactant also helps to keep taxane, all of a sudden, compared with the compositions that contains amorphous taxane and carrier, had significantly improved the dissolubility of taxane.

Term " has basically no setting " and is meant that the positional alignment order of taxane molecule is very little or not long.Most of molecules are answered random orientation.Impalpable structure has not long putting in order fully, and does not contain crystal structure in any case, and crystalline solids antithesis.But,, be difficult to obtain complete impalpable structure for some solids.Therefore, many " amorphous " structure is not amorphous fully, but still contains a certain amount of long array order or degree of crystallinity.For example, solid can be mainly crystal structure amorphous but that have a zonule maybe can contain very little crystal, therefore at real unbodied edge.Therefore, term " has basically no setting " and comprises the solid that has some impalpable structures but also have some crystal structures simultaneously.The degree of crystallinity that has basically no the setting taxane should be lower than 50%.Preferably, the degree of crystallinity that has basically no the setting taxane is lower than 40%, also more preferably, is lower than 30%, still more preferably; Be lower than 25%, also more preferably, be lower than 20%, still more preferably, be lower than 15%; Also more preferably, be lower than 12.5%, still more preferably, be lower than 10%, also more preferably; Be lower than 7.5%, still more preferably, be lower than 5%, most preferably, be lower than 2.5%.Because the dissolubility of crystal taxane is low, therefore the degree of crystallinity of unbodied taxane is low more basically, and then the dissolubility of unbodied taxane is good more basically.

Basically unbodied taxane can adopt any suitable manner and the technology that it will be apparent to those skilled in the art that to prepare.For example, can use solvent evaporated method or lyophilizing to prepare.Preferably, amorphous taxane prepares through lyophilizing.Be surprised to find that, compare, use lyophilizing to prepare unbodied taxane, can produce compositions with better dissolubility and rate of dissolution with evaporation.Think that this is that lyophilization produces more unbodied taxane owing to compare with solvent evaporated method.

Being used for liquid preparations for oral administration is solid form.Said solid composite can be any suitable form, as long as taxane is unbodied state basically.For example, said compositions can contain the physical mixture of unbodied taxane, carrier and surfactant.Preferably, taxane and carrier are the solid dispersion form.Term " solid dispersion " is that those skilled in the art are well-known, is meant that taxane part molecular dispersion is in carrier.More preferably, taxane and carrier are the solid solution form.Term " solid solution " is that those skilled in the art are well-known, is meant that the complete basically molecular dispersion of taxane is in carrier.Think that the solid solution agent is more amorphous than solid dispersion in nature.The method for preparing solid dispersion and solid solution agent is those skilled in the art well-known [93,94].Use these methods, taxane and carrier are unbodied state.When taxane and carrier were solid dispersion or solution form, the dissolubility of taxane and rate of dissolution were bigger than the dissolubility and the rate of dissolution of the physical mixture of amorphous taxane and carrier.We think, when taxane is solid dispersion or solution form, self compare with unbodied taxane, and taxane is amorphous state more.We think, cause the dissolubility and the dissolving that improve like this.The degree of crystallinity of solid dispersion or solution should be lower than 50%.Preferably, the degree of crystallinity of solid dispersion or solution is lower than 40%, also more preferably, is lower than 30%, still more preferably; Be lower than 25%, also more preferably, be lower than 20%, still more preferably, be lower than 15%; Also more preferably, be lower than 12.5%, still more preferably, be lower than 10%, also more preferably; Be lower than 7.5%, still more preferably, be lower than 5%, most preferably, be lower than 2.5%.

When taxane and carrier were the solid dispersion form, surfactant can be the physical mixture form with solid dispersion or solution.But preferred, said compositions contains taxane, carrier and the surfactant of solid dispersion form (or more preferably, solid solution agent form).Advantage with all three kinds of components of solid dispersion or solution form is to use the surfactant of low amount to reach the identical improvement of dissolubility and rate of dissolution.

In one embodiment, said compositions can contain and be used for the capsule of oral administration.Capsule can adopt many different modes to fill.For example, unbodied taxane can be prepared as follows: lyophilizing, powdered is mixed with carrier and surfactant, is assigned in the capsule subsequently.A kind of optional preferred embodiment in, unbodied taxane prepares through the taxane solution of lyophilizing at the capsule that is used for oral administration.The taxane solution that will contain the taxane of aequum is distributed in the capsule, and lyophilizing subsequently is contained in the capsule simultaneously.Because the flowing fluid ratio powder more is prone to distribute, the taxane with aequum is distributed in the capsule so more easily.Also omitted the capsule filling step, made that this method is more effective.Can add pulverous carrier and surfactant subsequently.Preferably, said capsule is the HPMC capsule.

If taxane and carrier are solid dispersion or solution form, the solution that preferably will contain taxane and carrier is distributed in the capsule, and lyophilizing subsequently is contained in the capsule simultaneously.Adopt this mode, prepare solid dispersion or solution at the taxane and the carrier solution of the capsule that is used for oral administration through lyophilizing.Omitted the capsule filling step so once more.Can add pulverous surfactant subsequently.

If taxane, carrier and surfactant are solid dispersion or solution form, the solution that preferably will contain taxane, carrier and surfactant is distributed in the capsule, and lyophilizing subsequently is contained in the capsule simultaneously.Adopt this mode, prepare solid dispersion or solution at taxane, carrier and the surfactant solution of the capsule that is used for oral administration through lyophilizing.Omitted the capsule filling step so once more, and the needs of non-processor powder, handle powder and then possibly have problems.

The taxane of said compositions can be the as above any suitable taxane of definition.Preferably, taxane is selected from docetaxel, paclitaxel, BMS-275183, their functional deriv and their pharmaceutically acceptable salt or ester.More preferably, taxane is selected from docetaxel, paclitaxel, their functional deriv and their pharmaceutically acceptable salt or ester.

The hydrophilic carrier of said compositions (preferred polymers carrier) is for being can be partially dissolved in the aqueous medium at least 7.4 times and/or can swelling in this aqueous medium or the organic compound (preferred polymeric compounds) of gelation at pH.Carrier can be guarantees that taxane remains amorphous state and improves the dissolubility of taxane and any suitable hydrophilic carrier (preferred polymers carrier) of rate of dissolution in compositions.Preferably, said carrier is selected from: polyvinyl pyrrolidone (PVP); Polyethylene Glycol (PEG); Polyvinyl alcohol (PVA); Crospovidone (PVP-CL); Polyvinyl pyrrolidone-polyvinyl acetate ester copolymer (PVP-PVA); Cellulose derivative, for example methylcellulose, hydroxypropyl cellulose, carboxymethylethylcellulose, hydroxypropyl emthylcellulose (HPMC), acetic acid-phthalic acid-cellulose and Hydroxypropyl Methylcellulose Phathalate; Polyacrylate; Polymethacrylates; Sugar, polyhydric alcohol and polymer, for example mannitol, sucrose, Sorbitol, glucose and chitosan; And cyclodextrin.More preferably, said carrier is selected from PVP, PEG and HPMC, and most preferably, said carrier is PVP.

If carrier is PVP, it can be any suitable PVP [98], is amorphous state to be used as carrier with helping to keep taxane.For example, PVP can be selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP-K90 and PVP-K120.Preferably, PVP is selected from PVP-K30, PVP-K60 and PVP-K90.

With respect to unbodied taxane, said compositions can contain the carrier of any appropriate amount, and making carrier can keep unbodied taxane is amorphous state.Preferably, the weight ratio of taxane and carrier is about 0.01: 99.99 to about 75: 25.More preferably, the weight ratio of taxane and carrier is about 0.01: 99.99 to about 50: 50, also more preferably, and about 0.01: 99.99 to about 40: 60, still more preferably; About 0.01: 99.99 to about 30: 70, also more preferably, about 0.1: 99.9 to about 20: 80, still more preferably, about 1: 99 to about 20: 80; Also more preferably, about 2.5: 97.5 to about 20: 80, still more preferably, about 2.5: 97.5 to about 15: 85; Also more preferably, about 5: 95 to about 15: 85, most preferably, be about 10: 90.

Said surfactant can be any suitable pharmaceutically acceptable surfactant, and this surfactant is that those skilled in the art are well-known.Preferably, said surfactant is selected from: triethanolamine, sunflower oil, stearic acid, dibastic sodium phosphate, two hydration sodium citrates, alginate propylene glycol, oleic acid, ethanolamine, mineral oil and lanolin alcohol, methylcellulose, MCT (medium chaintriglyceride), lecithin, agnolin, lanoline, hydroxypropyl cellulose, glyceryl monostearate, ethylene glycol Palmic acid/stearate (ethylene glycol pamitostearate), diethanolamine, lanolin alcohol, cholesterol, hexadecanol, hexadecanol/octadecanol (cetostearyl alcohol), Oleum Ricini, sodium lauryl sulphate (SDS), sorbitan ester (sorbitan fatty acid esters), Myrj 45, polyoxyethylene sorbitan fatty acid esters, castor oil derivatives, polyoxyethylene alkyl ether, poloxamer, glyceryl monooleate, docusate sodium, cetab, benzoic acid benzyl ester, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifing wax, anion emulsifing wax and triethyl citrate.More preferably, said surfactant is selected from sodium lauryl sulphate (SDS), sorbitan ester (sorbitan fatty acid esters), Myrj 45, polyoxyethylene sorbitan fatty acid esters, castor oil derivatives, polyoxyethylene alkyl ether, poloxamer, glyceryl monooleate, docusate sodium, cetab, benzoic acid benzyl ester, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifing wax, anion emulsifing wax and triethyl citrate.Most preferably, said surfactant is SDS.

The surfactant of any appropriate amount can be used in the said compositions, with dissolubility and the rate of dissolution that improves taxane.Preferably, the weight ratio of surfactant and taxane and the two gross weight of carrier is about 1: 99 to about 50: 50, more preferably, and about 1: 99 to about 44: 56; Also more preferably, about 1: 99 to about 33: 67, still more preferably, about 2: 98 to about 33: 67; Also more preferably, about 2: 98 to about 17: 83, still more preferably; About 5: 95 to about 17: 83, most preferably, be about 9: 91.

Perhaps, the weight ratio of surfactant and taxane is preferably about 1: 100 to about 60: 1, more preferably, and about 1: 50 to about 40: 1; Also more preferably, about 1: 20 to about 20: 1, still more preferably, about 1: 10 to about 10: 1; Also more preferably, about 1: 5 to about 5: 1, still more preferably, about 1: 3 to about 3: 1; Also more preferably, about 1: 2 to about 2: 1, most preferably, be about 1: 1.

The UD of the taxane that contains in the said compositions depends on the expection administration frequency of compositions.Suitable dosage and frequency were discussed in above compositions about taxane and ritonavir.

In one embodiment, said compositions comprises casing.Suitable casing as stated.Casing can prevent that taxane from discharging under one's belt, thereby prevents the degraded of the acid-mediation of taxane.In addition, casing can be with the absorbed intestinal of taxane targeted delivery to taxane, and only be used in can absorbent position the taxane limited time of (before crystallization takes place) of existing in solution during therefore guaranteeing.

In one embodiment, said compositions also can contain one or more other active component pharmaceutically.Preferably, one or more other pharmaceutically active component are the CYP3A4 inhibitor.Appropriate C YP3A4 inhibitor is as discussed above.Preferably, said CYP3A4 inhibitor is a ritonavir.

Said pharmaceutical composition can be included as those skilled in the art well-known other pharmaceutically acceptable adjuvant and excipient.The pharmaceutically acceptable adjuvant and the excipient that can be used for pharmaceutical composition of the present invention include, but are not limited to: ion-exchanger; Aluminium oxide; Aluminium stearate; Serum proteins (for example human serum albumin); Buffer substance (for example phosphate); Glycerol; Sorbic acid; Potassium sorbate; The mixture of the partial glyceride of saturated vegetable fatty acid; Water; Salt or electrolyte (for example protamine sulfate); The sodium hydrogen phosphate potassium hydrogen phosphate; Sodium chloride; Zinc salt; Colloidal silica; Magnesium trisilicate and lanoline.

Said pharmaceutical composition can be with any oral acceptable forms oral administration, and said dosage form includes, but are not limited to: capsule, tablet, powder or coated granules agent.Can tablet formulation be become to discharge immediately, postpone to discharge, repeat to discharge or sustained release formulation.Perhaps, tablet also can be tablet foaming, double-deck and/or coating.Can capsule be mixed with immediately and discharge, postpone to discharge, repeat to discharge or sustained release formulation.Usually also add lubricant, for example magnesium stearate.For the oral administration of Capsule form, available diluent comprises lactose and exsiccant corn starch.For tablet and capsule, the other drug excipient that can add is binding agent, filler, filler/binding agent, adsorbent, wetting agent, disintegrating agent, lubricant, slippage agent etc.Can tablet and capsule coating to change the outward appearance or the performance of tablet and capsule, for example, be used to change the taste or the color of coated tablet or capsule.

Other pharmaceutically acceptable additives that can join in the said compositions are well-known for those skilled in the art, and wherein some are as above discussed about the compositions of first aspect of the present invention.

The present invention also provides the purposes of above-mentioned composition in treatment.

In addition, the invention provides the purposes of above-mentioned composition in the treatment tumor disease.Suitable tumor disease is as discussed above.

The present invention also provides the method for treatment tumor disease, and wherein, this method comprises the above-mentioned composition to the object effective dosage that these treatment needs are arranged.

Preferably, said method be used to treat to as if the people.

It will be understood by those skilled in the art that under the suitable situation that the present composition that comprises unbodied basically taxane and carrier can be used in the method for above-mentioned purposes about taxane and CYP3A4 inhibitor or ritonavir.

On the other hand, the invention provides a kind of pharmaceutical composition for oral administration that is used for that comprises unbodied basically taxane and carrier, wherein, unbodied basically taxane prepares through lyophilizing.

The advantage that said composition provides is to improve the dissolubility of taxane and also improves rate of dissolution.We think, this be because with the data by MoM and MEI that produces amorphous taxane, lyophilization produces more unbodied taxane.We think that the more unbodied characteristic of taxane has improved dissolubility and rate of dissolution.

The other optional characteristic of said compositions is identical with the compositions that contains unbodied taxane, carrier and surfactant.For example, the compositions that preferably contains unbodied basically taxane and carrier also contains surfactant, and wherein, unbodied basically taxane prepares through lyophilizing.Preferred embodiment as above defining of the state of the ratio of the degree of crystallinity of taxane, carrier, taxane, taxane and carrier, taxane and carrier etc.

Description of drawings

Only illustrate the present invention now with reference to accompanying drawing, wherein:

Fig. 1 illustrates docetaxel PC and time relation, relatively uses the oral administration (administration simultaneously, and before docetaxel 60 minutes administration ritonavirs) and intravenous administration (not containing ritonavir) of ritonavir (RTV); The dosage of oral docetaxel: 100mg.With the commercially available intravenous docetaxel injecta that gets (

2ml=80mg docetaxel; The excipient polysorbate 80) use alcohol 95 %: water (13: 87) dilution, 10mg/ml docetaxel solution is provided, let patients (the 10mg/ml solution of 10ml) with the 100ml tap water.The dosage of ritonavir: 1 capsule contains 100mg ritonavir

Fig. 2 illustrates ritonavir PC and time relation, relatively with the administration simultaneously of oral docetaxel or before oral docetaxel 60 minutes oral administration ritonavir (dosage 100mg;

capsule).When the administration docetaxel, T=0.Therefore, the first corresponding to the curve of administration ritonavir before docetaxel can't see.The dosage of oral docetaxel: 100mg.With the commercially available intravenous docetaxel injecta that gets (

Fig. 3 is the pharmacodynamics pattern with the oral docetaxel of ritonavir (RTV) coupling.Chambers (compartments) different in this pharmacodynamics pattern is as follows:

C1-gastrointestinal tract (the input chamber of oral docetaxel)

C2-centre chamber (docetaxel)

C3-first peripheral compartment (docetaxel)

C4-second peripheral compartment (docetaxel)

C5-gastrointestinal tract (the input chamber of ritonavir)

C6-centre chamber (ritonavir)

The active CYP3A4 enzyme of C7-;

The nonactive CYP3A4 enzyme of C8-;

Fig. 4 illustrate active CYP3A4 enzyme relative quantity and with the oral administration time relation of the docetaxel of ritonavir coupling, a plurality of objects, every line is represented an object;

Fig. 5 explain the solubility test result of paclitaxel solid dispersion and paclitaxel physical mixture comparison (condition: 900mL WfI, 37 ℃, 75rpm);

Fig. 6 explanation contains when not containing sodium lauryl sulphate, and the solubility test result of paclitaxel (PCT) solid dispersion capsule (condition: 900mL WfI, 37 ℃, 75rpm);

Fig. 7 explains to use and mixes in the solid dispersion or join the sodium lauryl sulphate in the capsule, the solubility test result of paclitaxel solid dispersion (condition: 500mL WfI, 37 ℃, 75rpm (condition with 100rpm joins SDS in the capsule));

Fig. 8 explain the solubility test result that uses various carriers, paclitaxel solid dispersion (condition: 500mL WfI, 37 ℃, 100rpm);

Fig. 9 explains use various medicines-carrier ratio, and the result of the dissolubility test of paclitaxel/PVP-K17 solid dispersion (condition: 25mL WfI, 37 ℃, 7200rpm)

Solubility test result (the condition: 500mL FaSSIF (light gray), 37 ℃, 75rpm of Figure 10 explanation paclitaxel solid dispersion in various media; Or 500mL SGF _SpWith 629mL SIF _Sp, 37 ℃, 75rpm (Dark grey));

Figure 11 explains the docetaxel dissolubility (referring to table 15) of 5 kinds of different preparations.A: anhydrous docetaxel; B: unbodied docetaxel; C: the physical mixture of anhydrous docetaxel, PVP-K30 and SDS; D: the physical mixture of unbodied docetaxel, PVP-K30 and SDS; E: the solid dispersion of unbodied docetaxel, PVP-K30 and SDS (dissolution conditions: ± 6mg docetaxel, 25mL WfI, 37 ℃, 720rpm);

Figure 12 explains and uses different carriers, the docetaxel dissolubility (referring to table 15) of solid dispersion.E: the solid dispersion of unbodied docetaxel, PVP-K30 and SDS; F: the solid dispersion of unbodied docetaxel, HP β-CD and SDS.(dissolution conditions: ± 6mg docetaxel, 25mLWfI, 37 ℃, 720rpm);

Figure 13 explains the PVP that uses various chain lengths, the docetaxel dissolubility (referring to table 15) of solid dispersion.E: the solid dispersion of unbodied docetaxel, PVP-K30 and SDS; G: the solid dispersion of unbodied docetaxel, PVP-K12 and SDS; H: the solid dispersion of unbodied docetaxel, PVP-K17 and SDS; I: the solid dispersion of unbodied docetaxel, PVP-K25 and SDS; J: the solid dispersion of unbodied docetaxel, PVP-K90 and SDS.(dissolution conditions: ± 6mg docetaxel, 25mL WfI, 37 ℃, 720rpm);

Figure 14 explains the docetaxel dissolubility (referring to table 15) that uses various drug loadings, solid dispersion.The E:1/11 docetaxel; The K:5/7 docetaxel; The L:1/3 docetaxel; The M:1/6 docetaxel; The N:1/21 docetaxel.(dissolution conditions: ± 6mg docetaxel, 25mL WfI, 37 ℃, 720rpm);

The data in literature of the solid dispersion of Figure 15 explanation and docetaxel and PVP-K30 [people such as Chen, 95] is compared, about the dissolving result of the relative quantity of the dissolved docetaxel of the solid dispersion of docetaxel, PVP-K30 and SDS;

The data in literature of the solid dispersion of Figure 16 explanation and docetaxel and PVP-K30 [people such as Chen, 95] is compared, about the dissolving result of the absolute magnitude of the dissolved docetaxel of the solid dispersion of docetaxel, PVP-K30 and SDS;

Figure 17 explanation and data in literature people such as [, 95] Chen are compared the solubility test result of docetaxel capsule (each contains the capsule of PVP-K30+SDS, 15mg docetaxel (DXT)).

Figure 18 explanation is about the dissolving result of the absolute magnitude of the dissolved docetaxel of the solid dispersion of docetaxel, PVP-K30 and SDS.Solubility test is at apancrea enzyme simulation intestinal fluid (SIF _Sp) in carry out;

Figure 19 explanation is about the dissolving result of the relative quantity of the dissolved docetaxel of the solid dispersion of docetaxel, PVP-K30 and SDS.Solubility test is at apancrea enzyme simulation intestinal fluid (SIF _Sp) in carry out;

The patient's of docetaxel and ritonavir pharmacodynamics curve is accepted in Figure 20 explanation simultaneously in the period 1.In second round, when t=0, the patient accepts docetaxel and ritonavir simultaneously, subsequently, in the time of t=4 hour, accepts the ritonavir of other enhancing dosage;

Figure 21 explanation is accepted the liquid preparation of docetaxel and/or is comprised 4 patients' the pharmacodynamics curve of the solid dispersion (being called MODRA) of docetaxel;

Figure 22 explanation is compared with the patient of the solid orally ingestible of accepting docetaxel (MODRA), accepts patient's the pharmacodynamics curve of the liquid oral medicine of docetaxel; With

The pharmacodynamics curve of Figure 23 explanation behind intravenous and oral administration docetaxel.Intravenous and oral docetaxel administration all with the coupling of administration ritonavir.N.B. for dosage, the bioavailability of corrected Calculation.

The specific embodiment

Embodiment 1

With 100mg ritonavir dosage and the coupling of 100mg docetaxel dosage, and 22 patients of while oral administration.

compared with intravenous administration docetaxel (100mg), with intravenous perfusion administration (standard method) (not containing ritonavir) in 1 hour.

Oral ritonavir: 1 capsule contains 100mg ritonavir

.Oral docetaxel dosage: 100mg.With the commercially available intravenous docetaxel injecta that gets ( 2ml=80mg docetaxel; The excipient polysorbate 80) use alcohol 95 %: water (13: 87) dilution, 10mg/ml docetaxel solution is provided, let patients (the 10mg/ml solution of 10ml) with the 100ml tap water.

The pharmacodynamics data that obtain are as follows:

Do not contain ritonavir, the AUC 0.29 ± 0.26 (mg.h/L) of oral administration docetaxel

Use ritonavir, the AUC 2.4 ± 1.5 (mg.h/L) of oral administration docetaxel

Do not contain ritonavir, the AUC 1.9 ± 0.4 (mg.h/L) of intravenous administration docetaxel

The result shows that ritonavir is to the absorption of docetaxel with remove the two double effect.When with ritonavir coupling oral administration, the AUC of docetaxel improves 8.2 times.All of a sudden, expose more tallerly, reflected that ritonavir removes the other influence that suppresses to docetaxel than what behind intravenous administration, reach.

Conclusion

In several patients, clearly confirmed following viewpoint: ritonavir can the systemic exposure of oral docetaxel be increased to being on close level or even higher level behind the intravenous administration docetaxel under the identical dosage level.Coupling seems safety, has very favorable pharmacodynamic profiles.

Embodiment 2

Solid malignant is treated in the oral coupling of docetaxel and ritonavir.

The patient is divided into two treatment groups, X and Y at random.The X group in first week, is accepted the 100mg ritonavir, after 60 minutes, accepts the oral docetaxel of 100mg, and in second week, these patients accept 100mg ritonavir and the oral docetaxel of 100mg simultaneously.Patient in the Y group in first week, accepts the oral docetaxel of 100mg ritonavir and 100mg simultaneously, in second week, accepts the 100mg ritonavir, after 60 minutes, accepts the oral docetaxel of 100mg.After 15 days, X and Y group are all accepted intravenous docetaxel (

standard method that 100mg does not contain ritonavir at the beginning oral administration; Perfusion in 1 hour).

Oral docetaxel dosage: 100mg.With the commercially available intravenous docetaxel injecta that gets (

2ml=80mg docetaxel; The excipient polysorbate 80) use alcohol 95 %: water (13: 87) dilution, 10mg/ml docetaxel solution is provided, let patients (the 10mg/ml solution of 10ml) with the 100ml tap water.Ritonavir dosage: 1 capsule contains 100mg ritonavir

Pharmacodynamic result is as follows:

Table 1A docetaxel

¹F (obviously) is confirmed by (oral AUC/ intravenous AUC) * (intravenous dosages/oral dose) * 100%

Table 1B docetaxel

Conclusion

Simultaneously administration docetaxel and ritonavir with do not have significant difference between the administration ritonavir in 60 minutes before at docetaxel.The AUC of oral administration is greater than the AUC (referring to Fig. 1) of intravenous administration.This point may be interpreted as ritonavir and docetaxel is removed the influence that suppresses.

Remarks

Use is carried out this clinical research than the docetaxel of low dosage, but obtains high AUC value (2.4 ± 1.5mg.h/L; The 100mg docetaxel), and behind the intravenous administration same dose, than this AUC value even higher.Immediately; Must recognize; Volume of distribution behind the oral route (just administration after soon) is bigger than the volume of distribution behind the intravenous route, and this is the tissue distribution that (behind intravenous administration, exist, but behind oral administration no show systemic circulation) limited docetaxel because drug excipient.The inventor has set up a kind of pharmacodynamics pattern and has understood these effects (vide infra).This pattern explains that also when ritonavir no longer was present in the blood flow, the influence that ritonavir is removed docetaxel had not existed.Do not exist under the ritonavir, 35% level is reduced in the removing of ritonavir inhibition docetaxel.

Compare with the dosage of the prior art of the preclinical study that is used for mice, 100mg ritonavir and 100mg docetaxel are used in this clinical research, and the preclinical study of mice use 12.5mg/kg ritonavir and 10-30mg/kg docetaxel.The docetaxel dosage of 10-30mg/kg is extremely deleterious (being in peril of one's life) to the mankind.12.5mg/kg ritonavir dosage be significantly higher than and just be usually used in the dosage that the mankind suppress CYP3A4.

In the prior art preclinical study, 30 minutes administration ritonavirs before docetaxel.In clinical research, various medicines are administration simultaneously also, and administration and before 60 minutes between the administration ritonavir does not at the same time have significant difference aspect the docetaxel pharmacodynamics improving.This explanation, two kinds of medicines can administration in single medicine form (for example contain docetaxel and ritonavir the two tablet, capsule or drinkable solutions agent).

When with 100mg ritonavir co-administered, the docetaxel AUC value of using 100mg docetaxel dosage to obtain is 2.4 ± 1.5mg.h/L, for example, in metastatic breast cancer, can think that this AUC value has therapeutic activity in the scheme weekly.It tests very suitable with the early stage II phase; In testing in the II phase, with scheme weekly, with the dosage of 15mg/kg with CsA oral administration 100mg docetaxel; The speed of always replying that causes suffering from the patient of metastatic breast cancer is 50%, and docetaxel AUC is about 2.3mg.h/L.

Below provide whole ritonavir pharmacodynamics data (referring to Fig. 2):

Table 2 ritonavir

Pharmacodynamic profiles

Use NONMEM (non--linear hybrid effect pattern) program (GloboMax LLC, Hanover, MD, the pharmacodynamics (PK) of the data of USA) carrying out being produced by above-mentioned test is analyzed, to produce pharmacodynamic profiles.Use absorption, removing and the distribution of different chamber imitation medicines.Below provide the pharmacology's difference between oral and the intravenous administration.

Test is only taken the docetaxel of single dose and is exposed with the oral docetaxel of ritonavir coupling.Administration simultaneously or before oral docetaxel 1 hour administration ritonavir.

Behind the administration medicine, collect blood sample and be used for pharmacodynamic analysis.Before taking medicine, get blank sample.With the blood sample centrifugalize, with separating plasma, and be stored in-20 ℃ immediately, until analysis.In the laboratory of GLP (Good Laboratory Practice) permission, use the HPLC method of approval to analyze.This is related to all pharmacodynamic studies that the inventor appears here.

The PK pattern

The PK pattern is based on the PK pattern of intravenous docetaxel.This pattern is used three chambers, and fully is described in people [85] such as Bruno.In this pattern, carry out the data by the docetaxel generation of oral administration, increase is used for the other apotheca pattern of gastrointestinal.Use 2 Room patterns to come the best pharmacodynamics pattern of describing ritonavir, be described in people such as Kappelhoff [87].The pharmacodynamics pattern that Fig. 3 schematic illustration is final.Imitate the influence of ritonavir through two kinds of mechanism of different: a) in the presence of ritonavir, improve the absorption (line that ritonavir (RTV) chamber is connected with absorption from the docetaxel of C1-C2) of docetaxel to the pharmacodynamics of docetaxel; B) ritonavir suppresses active CYP3A4 (line that C6 is connected with C7), and active CYP3A4 causes the removing (line that C7 is connected with the removing route of docetaxel) of docetaxel.

Absorb

When with the ritonavir co-administered, the absorption of docetaxel significantly improves.Only the bioavailability of the calculating of oral docetaxel is 14% (based on 3 patient's data accepting the oral docetaxel of 100mg).With the bioavailability of the oral docetaxel of ritonavir coupling be 4 times high, be 56%.This effect can give the credit to ritonavir to being present in the inhibition of the CYP3A4 enzyme in the gastrointestinal tract.

Remove

Docetaxel is mainly through the CYP3A4 metabolism.Ritonavir suppresses CYP3A4.When ritonavir and docetaxel co-administered, cause removing and reduce like this.The removing of docetaxel is relevant with the amount of CYP3A4, therefore becomes in time.The relative enzyme concentration that Fig. 4 explains estimation over time.The removing of docetaxel and enzyme concentration are 1: 1 relations.Therefore, the removing of docetaxel and time relation figure and Fig. 4 are similar.

Volume of distribution

The volume of centre chamber (C2 among Fig. 3) intravenous (+/-6L) and oral (+/-60L) significant difference between the administration.This maybe be because polysorbate 80 causes that polysorbate 80 is a kind of main excipient of docetaxel injecta.Polysorbate 80 forms the micelle [86] that can catch docetaxel.Under the situation of intravenous administration, polysorbate 80 gets into circulation, but under case of oral administration, is not absorbed.Therefore, behind oral administration,, therefore do not influence the pharmacodynamic properties of docetaxel because polysorbate is not absorbed.

Conclusion

When with the ritonavir co-administered, the bioavailability of oral docetaxel improves about 4 times.Because ritonavir is to the combined effect (that is, being respectively absorption and removing) of the CYP3A4 in the gastrointestinal tract regulating liver-QI, systemic exposure (with regard to AUC) improves 8.2 times.

When with the ritonavir coupling, the removing of docetaxel reduces.

In the presence of polysorbate 80, volume of distribution (volume of centre chamber) is little, and when not containing polysorbate 80, volume of distribution (volume of centre chamber) is big.

In above-mentioned oral docetaxel research, with the commercially available intravenous docetaxel injecta that gets (

2ml=80mg docetaxel; The excipient polysorbate 80) use alcohol 95 %: water (13: 87) dilution provides 10mg/ml docetaxel solution.Will by this solution of pharmacists preparation with the 100ml tap water as drinkable solutions by the oral absorption of patient (the 10mg/ml solution of 10ml, corresponding 100mg dosage).For the purpose of studying, be feasible like this, still, can not be used for convention and use and use at home.It is very consuming time to prepare this drinkable solutions by the pharmacists.This solution has limited stability.The patient complains taste difference and unjoyful (possibly be because polysorbate and ethanol excipient) of drinkable solutions usually.Significantly, preferred oral solid dosage forms (for example taking) with capsule or tablet form, and the patient more benefits from.

Generally speaking, the present invention has improved the bioavailability and the systemic exposure of taxane, has improved the clinical efficacy of taxane, particularly oral taxane, and possibly also reduce the possible side effect relevant with treatment.This point is economical, and clinical useful.

The oral formulations of embodiment 3-paclitaxel

3.1: solid dispersion is compared with physical mixture

In this experiment, will comprise with the compositions of the solid dispersion of blended paclitaxel of SDS and PVP-K17 and comparing with the dissolubility and the rate of dissolution of the physical mixture of anhydrous paclitaxel, PVP-K17 and SDS.

The 5mg capsule of paclitaxel solid dispersion in PVP-K 17

Through the 100mg paclitaxel is dissolved in the 10mL tert-butyl alcohol, 400mg PVP-K17 is dissolved in the 6.67mL water, prepare the solid dispersion of 20% paclitaxel in PVP-K17.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K17/ aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to the condition of table 3) through lyophilizing subsequently.25mg paclitaxel 20%/PVP-K17 solid dispersion (=5mg paclitaxel) is mixed with 125mg lactose, 30mg sodium lauryl sulphate and 30mg cross-linking sodium carboxymethyl cellulose.Resulting powder mixture is sealed (referring to table 4).

Table 3: lyophilisation condition: Lyovac GT4 (AMSCO/Finn-Aqua)

Step	Time (hh:mm)	Shelve temperature (℃)	Room pressure (%)	Maximum pressure (%)
					1	00:00	Ambient temperature	100	100
2	01:00	-35	100	100
					3	03:00	-35	100	100
4	03:01	-35	40	50
					5	48:00	-35	40	50
6	63:00	25	40	50
					7	66:00	25	40	50

The capsule formulation of table 4:5mg paclitaxel/PVP-K17 solid dispersion

Composition	Amount (mg)
		Paclitaxel (in solid dispersion)	5mg
PVP-K17 (in solid dispersion)	20mg
		One Lactose hydrate	125mg
Sodium lauryl sulphate	30mg
		Cross-linking sodium carboxymethyl cellulose	30mg

Paclitaxel with the physical mixture of PVP-K17 in the 5mg capsule

Through being mixed with 20mg PVP, 125mg lactose, 30mg sodium lauryl sulphate and 30mg cross-linking sodium carboxymethyl cellulose, the anhydrous paclitaxel of 5mg prepares physical mixture.Resulting powder mixture is sealed.

Table 5:5mg paclitaxel/PVP-K17 physical mixture capsule formulation

Composition	Amount (mg)
		Paclitaxel	5mg
PVP-K17	20mg
		One Lactose hydrate	125mg
Sodium lauryl sulphate	30mg
		Cross-linking sodium carboxymethyl cellulose	30mg

Solubility test

Under the 75rpm rotary speed, in USP 2 (slurry formula) dissolver, in remaining on 37 ℃ 900mL injection water, test two kinds of capsule preparations.In first experiment, use a capsule of every kind of preparation.In second experiment, use two capsules of every kind of preparation.Collect sample at each time point, and analyze (referring to table 4) through HPLC-UV.

Table 6: chromatography condition

Post	Apex?octyl?150×4.6mm?5μm
		Eluent	Methanol/acetonitrile/0.02M ammonium acetate 1/4/5 volume/volume
Flow velocity	1.0mL/min
		Volume injected	50μL
Flowing time	15 minutes
		Detect wavelength	227nm

Result and conclusion

The result is shown in Fig. 5.The amount (5 and 10mg) of representing dissolved taxane with respect to labeling requirement.Can be clear that, improve the dissolving of paclitaxel greatly through in solid dispersion, mixing PVP.When using physical mixture, with respect to labeling requirement, the maximum of dissolved taxane keeps below 20%.When using solid dispersion, dissolubility is about 65% (5mg paclitaxel) or surpasses 70% (10mg paclitaxel).For the experiment of 10mg paclitaxel, be about 8 μ g/ml corresponding to absolute dissolubility, reach this dissolubility after about 15 minutes.Therefore, solid dispersion significantly improves dissolubility, and quick rate of dissolution also is provided, and these two characteristics are important for bioavailability.

In solid solution or solid dispersion, the amorphous state of carrier can make carrier fully mix with taxane.In the dissolved process, carrier prevents crystallization in storage process and in aqueous medium.

3.2: in capsule formulation, add sodium lauryl sulphate

In this experiment, confirm in capsule, to exist or do not exist the influence of surfactant SDS to dissolubility.

20% paclitaxel solid dispersion is in PVP-K17

Through the 100mg paclitaxel is dissolved in the 10mL tert-butyl alcohol, 400mg PVP-K17 is dissolved in the 6.67mL water prepares solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in PVP-K 17/ aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

The 5mg paclitaxel capsule that does not contain sodium lauryl sulphate

25mg paclitaxel 20%/PVP-K17 solid dispersion (=5mg paclitaxel) is mixed with the 125mg lactose, and seal.(referring to table 7).

Table 7: the preparation that does not contain the 5mg paclitaxel/PVP-K17 solid dispersion of sodium lauryl sulphate

Composition	Amount (mg)
		Paclitaxel (in solid dispersion)	5mg
PVP-K17 (in solid dispersion)	20mg
		One Lactose hydrate	125mg

The 5mg paclitaxel capsule that contains sodium lauryl sulphate

25mg paclitaxel 20%/PVP-K17 solid dispersion (=5mg paclitaxel) is mixed with 125mg lactose, 30mg sodium lauryl sulphate and 30mg cross-linking sodium carboxymethyl cellulose.Resulting powder mixture is sealed.(referring to table 8).

Table 8: the 5mg paclitaxel/PVP-K17 solid dispersion capsule formulation that contains sodium lauryl sulphate

Become component (mg)

Paclitaxel (in solid dispersion) 5mg

PVP-K17 (in solid dispersion) 20mg

One Lactose hydrate 125mg

Sodium lauryl sulphate 30mg

Cross-linking sodium carboxymethyl cellulose 30mg

Solubility test

Under the 75rpm rotary speed, in USP 2 (slurry formula) dissolver, two kinds of capsule preparations of test in remaining on 37 ℃ 900mL injection water.Collect sample at each time point, and analyze (referring to table 6) through HPLC-UV.

Result and conclusion

The result is shown in Fig. 6.The amount of representing dissolved taxane with respect to labeling requirement (in this case, 5mg).The porosity of freeze dried taxane and carrier solid dispersion is enough high, when being powder type, dissolves fast (result does not show) guaranteeing.But when with powders compression in capsule the time, wettability significantly reduces.Therefore, when boil down to capsule or tablet, need surfactant to come the moistening solid dispersion.

Be clear that by Fig. 6, improve the dissolving of paclitaxel through adding surfactant sodium lauryl sulphate greatly.Previous experiment shows, adds cross-linking sodium carboxymethyl cellulose, more lactose or uses the rate of dissolution raising that does not cause capsule formulation than the large capsule agent.Surfactant (like SDS) is used in explanation again, in about 10-15 minute, reaches maximum dissolving.

3.3: in solid dispersion preparation, add sodium lauryl sulphate

In this experiment, confirm in solid dispersion, to add the influence of SDS to dissolubility.

Paclitaxel 40% solid dispersion is in PVP-K 17

Through the 600mg paclitaxel is dissolved in the 60mL tert-butyl alcohol, 900mg PVP-K17 is dissolved in the 40mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K17/ aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 40% solid dispersion is in PVP-K17 and sodium lauryl sulphate 10%

Through the 250mg paclitaxel is dissolved in the 25mL tert-butyl alcohol, 375mg PVP-K17 and 62.5mg sodium lauryl sulphate (SDS) are dissolved in the 16.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in PVP-K 17/ sodium lauryl sulphate/aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

The 25mg paclitaxel capsule of paclitaxel/PVP-K17 solid dispersion

62.5mg paclitaxel 40%/PVP-K17 solid dispersion (=25mg paclitaxel) is mixed with 160mg lactose, 30mg sodium lauryl sulphate and 10mg cross-linking sodium carboxymethyl cellulose.Resulting powder mixture is sealed (referring to table 9).

Table 9:25mg paclitaxel/PVP-K17 solid dispersion capsule formulation

Composition	Amount (mg)
		Paclitaxel (in solid dispersion)	25mg
PVP-K17 (in solid dispersion)	37.5mg
		One Lactose hydrate	125mg
Sodium lauryl sulphate	30mg
		Cross-linking sodium carboxymethyl cellulose	10mg

The 25mg paclitaxel capsule of paclitaxel/PVP-K17/ sodium lauryl sulphate solid dispersion

68.75mg paclitaxel 40%/PVP-K17/ sodium lauryl sulphate 10% solid dispersion (=25mg paclitaxel) is mixed with 160mg lactose and 10mg cross-linking sodium carboxymethyl cellulose.Resulting powder mixture is sealed (referring to table 10).

The capsule formulation of table 10:25mg paclitaxel/PVP-K17 solid dispersion

Composition	Amount (mg)
		Paclitaxel (in solid dispersion)	25mg
PVP-K17 (in solid dispersion)	37.5mg
		Sodium lauryl sulphate (in solid dispersion)	6.25mg
One Lactose hydrate	125mg
		Cross-linking sodium carboxymethyl cellulose	10mg

Solubility test

In USP 2 (slurry formula) dissolver, in remaining on 37 ℃ 500mL injection water, test two kinds of capsule preparations.For the capsule that contains paclitaxel/PVP-K17/ sodium lauryl sulphate solid dispersion, rotary speed is set at 75rpm, and for the capsule that contains paclitaxel/PVP-K17 solid dispersion, rotary speed is set at 100rpm.Collect sample at each time point, and analyze (referring to table 6) through HPLC-UV.

Result and conclusion

The result is shown in Fig. 7.The amount (in this case, being 25mg) of representing dissolved taxane with respect to labeling requirement.Can be clear that the dissolving of paclitaxel that contains the capsule that mixes the sodium lauryl sulphate in the solid dispersion is suitable with the dissolving of paclitaxel that contains the capsule that joins the sodium lauryl sulphate in the capsule.In addition, only the 6.25mg sodium lauryl sulphate is used for incorporation in the solid dispersion, and uses the 30mg sodium lauryl sulphate to join in the capsule formulation.This explanation in being incorporated into solid dispersion rather than when joining in the capsule, needs less surfactant, can reach similar result.The unexpected result of another of this experiment is that it is about 26 μ g/ml that two kinds of compositionss make the absolute dissolubility of paclitaxel, and in 20-30 minute, reaches this level.Compared with the result who had before reached, this result provides higher dissolubility and rate of dissolution faster.

3.4: the influence of carrier

After initial experiment does not show the notable difference between the drug loading, produce the solid dispersion of the experiment that is used for embodiment 3.4.Because these preparations are identical with the performance of 20% drug loading preparation in previous experiments, and in a tablet or capsule, can send more taxane, so select 40% drug loading.

Paclitaxel 40% solid dispersion is in PVP-K12

Through the 250mg paclitaxel is dissolved in the 25mL tert-butyl alcohol, 375mg PVP-K12 is dissolved in the 16.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K12 aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 40% solid dispersion is in PVP-K17

Through the 600mg paclitaxel is dissolved in the 60mL tert-butyl alcohol, 900mg PVP-K17 is dissolved in the 40mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K17 aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 40% solid dispersion is in PVP-K30

Through the 250mg paclitaxel is dissolved in the 25mL tert-butyl alcohol, 375mg PVP-K30 is dissolved in the 16.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K30 aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 40% solid dispersion is in the HP-cyclodextrin

Through the 250mg paclitaxel is dissolved in the 25mL tert-butyl alcohol, the 375mgHP-cyclodextrin is dissolved in the 16.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the HP-cyclodextrin aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

25mg paclitaxel solid dispersion capsule

62.5mg paclitaxel/carrier solid dispersion (=25mg paclitaxel) is mixed with 160mg lactose, 30mg sodium lauryl sulphate and 10mg cross-linking sodium carboxymethyl cellulose.Resulting powder mixture is sealed (referring to table 11).

Table 11:25mg paclitaxel/carrier solid dispersion capsule formulation

Composition	Amount (mg)
		Paclitaxel (in solid dispersion)	25mg
Carrier (in solid dispersion)	37.5mg
		One Lactose hydrate	125mg
Sodium lauryl sulphate	30mg
		Cross-linking sodium carboxymethyl cellulose	10mg

Solubility test

In rotary speed is under the 100rpm, in USP 2 (slurry formula) dissolver, in remaining on 37 ℃ 500mL injection water, tests all capsule formulation.Collect sample at each time point, and analyze (referring to table 6) through HPLC-UV.

Result and conclusion

The average result of 2-3 experiment is shown in Fig. 8.The amount (in this case, being 25mg) of representing dissolved taxane with respect to labeling requirement.Can be clear that the dissolving of the paclitaxel of PVP-K30 solid dispersion is the same with the dissolving of the paclitaxel of PVP-K17 solid dispersion fast.But under the situation of PVP-K30 solid dispersion, in experiment in whole 4 hours, it is higher that the amount of dissolved taxane keeps.

Chain length decision crystalline time in aqueous environments of polymer support.

3.5: the influence of drug/vehicle ratio

After not showing notable difference between the carrier, produce the solid dispersion of the experiment that is used for embodiment 3.5 in initial experiment.Before the more detailed experiment of embodiment 3.4, carry out these initial experiment.The result is to select the carrier of PVP-K17 as further experiment at random.

Paclitaxel 10% solid dispersion is in PVP-K17

Through the 100mg paclitaxel is dissolved in the 10mL tert-butyl alcohol, 900mg PVP-K17 is dissolved in the 40mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K17 aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 25% solid dispersion is in PVP-K17

Through the 250mg paclitaxel is dissolved in the 25mL tert-butyl alcohol, 750mg PVP-K17 is dissolved in the 16.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K17 aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 40% solid dispersion is in PVP-K17

Through the 600mg paclitaxel is dissolved in the 60mL tert-butyl alcohol, 900mg PVP-K17 is dissolved in the 6.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K17 aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 75% solid dispersion is in PVP-K17

Through the 250mg paclitaxel is dissolved in the 25mL tert-butyl alcohol, 83mg PVP-K17 is dissolved in the 16.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the PVP-K17 aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Paclitaxel 100% solid dispersion

Through being dissolved in the 25mL tert-butyl alcohol, the 250mg paclitaxel prepares solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in the 16.67mL water.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

Solubility test

A certain amount of solid dispersion powder (being equivalent to about 4mg paclitaxel) is placed in the 50mL beaker.Magnetic stirring bar and 25mL water are joined in the beaker.Agitating solution under 7200rpm.Collect sample at each time point, and analyze (referring to table 6) through HPLC-UV.

Result and conclusion

The average result of 2-3 experiment is shown in Fig. 9.The amount (in this case, being about 4mg) of representing dissolved paclitaxel (PCT) with respect to labeling requirement.Influence by the obviously visible drug/vehicle ratio of Fig. 9.The peak concentration value and the drug/vehicle ratio of paclitaxel are inversely proportional to.Use minimum drug/vehicle ratio (10%) to reach peak-peak concentration, and use the highest drug/vehicle ratio (100%) to reach minimum peak concentration.In addition, the AUC-value of 10% drug/vehicle ratio solid dispersion is the highest, then is the AUC-value of 25%, 40%, 75% and 100% drug/vehicle ratio solid dispersion.

The amount of carrier has determined the crystalline time in aqueous environments with respect to the amount of medicine.

3.6: the influence of casing

Paclitaxel 40% solid dispersion is in PVP-K17 and sodium lauryl sulphate 10%

Through the 250mg paclitaxel is dissolved in the 25mL tert-butyl alcohol, 375mg PVP-K17 and 62.5mg sodium lauryl sulphate (SDS) are dissolved in the 16.67mL water, prepare solid dispersion.Under continuous stirring, paclitaxel/t-butanol solution is joined in PVP-K17/ sodium lauryl sulphate/aqueous solution.Final mixture is transferred in the 8mL bottle that maximum fill level is 2mL.Remove the tert-butyl alcohol and water (referring to table 3) through lyophilizing subsequently.

68.75mg paclitaxel 20%/PVP-K17/ sodium lauryl sulphate 10% solid dispersion (=25mg paclitaxel) is mixed with 160mg lactose and 10mg cross-linking sodium carboxymethyl cellulose.Resulting powder mixture is sealed (referring to table 12).

Table 12:25mg paclitaxel/PVP-K17/SDS solid dispersion capsule formulation

Solubility test

Capsule is carried out two kinds of different solubility tests in duplicate.First test is included in not contain in the pepsic 500mL simulated gastric fluid and carries out 2 hours solubility test (SGF for two-layer solubility test _SpReferring to table 13), then in not containing pepsic 629mL simulation intestinal fluid, carry out 2 hours solubility test (SIF _SpReferring to table 13).Second test is at 500mL fasting state simulation intestinal fluid (FaSSIF; Referring to table 14) carried out 4 hours in the medium.

Two kinds of solubility tests carry out in USP 2 (slurry formula) dissolver, use the 500mL medium that remains on 37 ℃, and the lodicule rotary speed are 75rpm.Through adding the 129mL transfer medium, with SGF _SpMedium becomes SIF _SpMedium.Collect sample at each time point, and analyze (referring to table 6) through HPLC-UV.

Table 13:SGF _Sp, SIF _SpAnd transfer medium [96]

Medium	Volume	Composition
			?SGF _sp(USP?26)	500mL	1.0g NaCl, 3.5mL HCl is to the 500mL injection water
Transfer medium	129mL	4.08g?KH ₂PO ₄, 30mL NaOH solution 80g/L (2.0 M) is to the 129mL injection water
			?SIF _sp+NaCl?(USP?24)	629mL	500mL?SGF _spWith the 129mL transfer medium

Table 14: fasting state simulation intestinal fluid (FaSSIF) medium [97]

Composition	Amount
		KH ₂PO ₄	3.9g
NaOH	To pH 6.5
		Sodium taurocholate	3mM
Lecithin	0.75mM
		KCl	7.7g
Distilled water	To 1L

Result and conclusion

The result is shown in Figure 10.The amount (in this case, being 25mg) of representing dissolved taxane with respect to labeling requirement.The dissolving ratio of taxane is at simulated gastric fluid (SGF in fasting state simulation intestinal fluid _Sp) middle high about 20%.At SGF _SpIn after 2 hours, when medium being become simulation intestinal fluid (SIF _Sp) time, the amount of the paclitaxel in the solution only improves slightly.

Casing can prevent that taxane from discharging under one's belt, thereby prevents the active component degraded.In addition, can targeted delivery to taxane absorbed intestinal, only be used in can absorbent position the taxane limited time of (before crystallization takes place) of existing in solution during therefore guaranteeing.

The oral formulations of embodiment 4-docetaxel

Material and method

The preparation that is used for following experiment according to following method with in the preparation of the composition described in the table 15.

Pure anhydrous docetaxel

Use derives from the anhydrous docetaxel of Taiwan ScinoPharm.

Pure amorphous docetaxel

Through the anhydrous docetaxel of 300mg is dissolved in the 30mL tert-butyl alcohol, with the docetaxel amorphization.Under continuous stirring, docetaxel/t-butanol solution is joined in the 20mL injection water (WfI).Final mixture is transferred to rustless steel freeze drying box (Gastronorm size 1/9), removes the tert-butyl alcohol and water (referring to table 16) through lyophilizing subsequently.

Physical mixture

Use mortar and pestle,, prepare physical mixture through the 150mg docetaxel is mixed with the carrier and the surfactant (referring to table 15) of respective amount.

Solid dispersion

Through the anhydrous docetaxel of 300mg is dissolved in the 30mL tert-butyl alcohol, the carrier and the surfactant (referring to table 15) of respective amount is dissolved in the 20mL injection water, make solid dispersion.Under continuous stirring, docetaxel/t-butanol solution is joined in carrier/surfactant/WfI solution.Final mixture is transferred to rustless steel freeze drying box (Gastronorm size 1/9), removes the tert-butyl alcohol and water (referring to table 16) through lyophilizing subsequently.

Table 16: lyophilisation condition

Step	Time (hh:mm)	Shelve temperature (℃)	Room pressure (mbar)	Maximum pressure (mbar))
					1	00:00	Ambient temperature	1000	?1000
2	01:00	-35	1000	?1000
					3	03:00	-35	1000	?1000
4	03:01	-35	0.2	?0.6
					5	48:00	-35	0.2	?0.6
6	63:00	25	0.2	?0.6
					7	66:00	25	0.2	?0.6

Solubility test

A certain amount of powder (being equivalent to about 6mg docetaxel) is placed in the 50mL beaker.Magnetic stirring bar and 25mL water are joined in the beaker.Agitating solution under 720rpm, and be maintained at about 37 ℃.Collect sample at each time point, use 0.45 μ m filter to filter, use 1 of methanol and acetonitrile subsequently: the 4v/v mixture diluted.Filter, the sample after will diluting is subsequently analyzed (referring to table 17) through HPLC-UV.

Table 17: chromatography condition

Post	Apex?octyl?150×4.6mm?5μm
		Eluent	Methanol/acetonitrile/0.02M ammonium acetate 1/4/5 volume/volume
Flow velocity	1.0mL/min
		Volume injected	10μL
Flowing time	20 minutes
		Detect wavelength	227nm

4.1: preparation type

In first experiment, the test preparation type is to the influence of docetaxel dissolubility.The data of the solubility test that will carry out preparation A-E are compared.The result is shown in Figure 11.Preparation E tests in quadruplicate, and preparation A-D tests in duplicate.

The result

Preparation A (pure anhydrous docetaxel), after stirring 5 minutes, Cmax reaches about 12 μ g/mL (having total docetaxel of 4.7%), and after stirring 15 minutes, equilibrium concentration reaches about 6 μ g/mL (2%).

Preparation B (pure amorphous docetaxel), after 0.5 minute, Cmax reaches 32 μ g/mL (13%), and from 10 minutes to 60 minutes, dissolubility was suitable with preparation A.

Formulation C (physical mixture of anhydrous docetaxel, PVP-K30 and SDS), after 5 minutes, concentration reaches about 85 μ g/mL (37%).Between 15-25 minute, docetaxel concentration sharply drops to 30 μ g/mL (12%) from 85 μ g/mL (37%), in the time of 60 minutes, further drops to 20 μ g/mL (9%) subsequently.

Preparation D (physical mixture of amorphous docetaxel, PVP-K30 and SDS), after 7.5 minutes, maximum docetaxel concentration reaches 172 μ g/mL (70%).Between 7.5-20 minute, the amount of the docetaxel in the solution is reduced to 24 μ g/mL (10%).In the time of 60 minutes, equilibrium concentration reaches 19 μ g/mL (7%).

Preparation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS), after 5 minutes, the highest Cmax reaches 213 μ g/mL (90%).Between 10-25 minute, the amount of the docetaxel in the solution descends fast, and after 45 minutes, equilibrium concentration reaches 20 μ g/mL (8%).

Conclusion

Show higher dissolubility when all preparations begin, after stirring 45-60 minute, reduce to equilbrium solubility.The reduction of dissolubility is the docetaxel crystallization that is caused by supersaturated solution and causing.Degree of super saturation depends on the physical state of medicine, and promptly medicine is amorphous or crystal state.When PVP-K30 was carrier, hypersaturated state kept the long period, so the unhappy prompt drop of the dissolubility of docetaxel is low.In addition, the result shows, compares with anhydrous docetaxel, uses amorphous docetaxel to significantly improve the dissolubility of docetaxel.In addition, amorphous docetaxel showed higher rate of dissolution, reached peak value at about 5-7.5 minute.

This description of test, the amount of the docetaxel in the solution significantly improves through the physical mixed with anhydrous docetaxel and PVP-K30 and SDS, and through improving amorphous docetaxel and PVP-K30 and SDS physical mixed more.But,, realize that the maximum of dissolubility improves through docetaxel being mixed in the solid dispersion of PVP-K30 and SDS.

4.2: bearer type

In second experiment, the test bearer type is to the influence of docetaxel dissolubility.The data of the solubility test that will carry out preparation E and F are compared.The result is shown in Figure 12.Preparation E tests in quadruplicate, and preparation F tests in duplicate.

The result

Preparation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS), after 5 minutes, the highest Cmax reaches 213 μ g/mL (having total docetaxel of 90%).Between 10-25 minute, the amount of the docetaxel in the solution descends fast, and after 45 minutes, equilibrium concentration reaches 20 μ g/mL (8%).

Preparation F (solid dispersion of amorphous docetaxel, HP β-CD and SDS), after about 2 minutes, maximum docetaxel concentration reaches about 200 μ g/mL (81%).Between 5-10 minute, the amount of the docetaxel in the solution is reduced to 16 μ g/mL (6%), and after 45 minutes, equilibrium concentration reaches 11 μ g/mL (4%).

Conclusion

This description of test, PVP-K30 and HP β-CD all can improve the dissolubility of docetaxel.Compare with HP β-CD, when using PVP-K30 as carrier, his Cmax of many west is high slightly, and the hypersaturated state maintenance long period, and therefore, the dissolubility of docetaxel does not reduce in time fast.In addition, compare with HP β-CD, higher with the equilibrium concentration that reaches behind the PVP-K30 deposition docetaxel.

4.3: chain length

In the 3rd experiment, test PVP chain length is to the influence of docetaxel dissolubility.The data of the solubility test that will carry out preparation E and G-J are compared.The result is shown in Figure 13.Preparation E tests in quadruplicate, and preparation G-J tests in duplicate.

The result

Preparation G (PVP-K12), after 5 minutes, the Cmax of docetaxel reaches 206 μ g/mL (having total docetaxel of 77%).Between 5-30 minute, the amount of the docetaxel in the solution is reduced to 20 μ g/mL (7%), and in the time of 45 minutes, docetaxel concentration is 17 μ g/mL (6%).

Preparation H (PVP-K17), after 5 minutes, the Cmax of docetaxel reaches 200 μ g/mL (83%); And stirring in 10 minutes more than under this this concentration, being retained to; The amount of the docetaxel in the solution descends fast subsequently, and in the time of 15 minutes, the amount of docetaxel is 44 μ g/mL (18%); In the time of 30 minutes, the amount of docetaxel is 22 μ g/mL (9%).Equilibrium concentration between 45-60 minute is about 21 μ g/mL (8%).

Preparation I (PVP-K25), after stirring 5 minutes, maximum docetaxel concentration reaches 214 μ g/mL (88%).Between 10-30 minute, the amount of the docetaxel in the solution is reduced to 22 μ g/mL (9%), and in the time of 60 minutes, the concentration of docetaxel is 19 μ g/mL (8%).

Preparation E (PVP-K30), after 5 minutes, the Cmax of docetaxel reaches 213 μ g/mL (90%).Between 10-25 minute, the amount of the docetaxel in the solution descends fast, and after 45 minutes, equilibrium concentration reaches 20 μ g/mL (8%).

Preparation J (PVP-K90), after stirring 10 minutes, the Cmax of docetaxel reaches 214 μ g/mL (88%).In the time of 15 minutes, the amount of the docetaxel in the solution still is 151 μ g/mL (61%).After 60 minutes, docetaxel concentration is reduced to 19 μ g/mL (7%).

Conclusion

This description of test, the chain length of PVP influence time that degree of super saturation and supersaturation keep the two.Use higher PVP chain length to cause the Cmax of higher docetaxel and the supersaturation of long period, therefore, keep higher dissolubility in the long period.

4.4: drug loading

In the 4th experiment, the test drug loading is to the influence of docetaxel dissolubility.The data of the solubility test that will carry out preparation E and K-N are compared.The result is shown in Figure 14.Preparation E tests in quadruplicate, and Formulation K-N tests in duplicate.

Preparation N (1/21 docetaxel of composition total weight; The weight ratio of docetaxel: PVP is 5: 95), after 10 minutes, maximum docetaxel concentration reaches 197 μ g/mL (having total docetaxel of 79%).After 15 minutes, the amount of the docetaxel in the solution still is 120 μ g/mL (48%), and between 15-30 minute, docetaxel concentration is reduced to 24 μ g/mL (12%).In the time of 60 minutes, docetaxel concentration is 20 μ g/mL (8%).

Preparation E (1/11 docetaxel of composition total weight; The weight ratio of docetaxel: PVP is 10: 90), after 5 minutes, Cmax reaches 213 μ g/mL (90%).Between 10-30 minute, the amount of the docetaxel in the solution descends fast, and after 45 minutes, equilibrium concentration reaches 20 μ g/mL (8%).

Preparation M (1/6 docetaxel of composition total weight; The weight ratio of docetaxel: PVP is 20: 80), after stirring 10 minutes, docetaxel concentration is 196 μ g/mL (80%).Between 10-30 minute, the amount of the docetaxel in the solution is reduced to 25 μ g/mL (10%), and in the time of 60 minutes, the concentration of docetaxel is 18 μ g/mL (7%).

Preparation L (1/3 docetaxel of composition total weight; The weight ratio of docetaxel: PVP is 40: 60), docetaxel concentration reaches 176 μ g/mL (71%).Between 10-15 minute, the amount of the docetaxel in the solution is reduced to 46 μ g/mL (18%) fast, and after 60 minutes, the amount of the docetaxel in the solution is 18 μ g/mL (7%).

Formulation K (5/7 docetaxel of composition total weight; The weight ratio of docetaxel: PVP is 75: 25), after stirring 5 minutes, maximum docetaxel value reaches 172 μ g/mL (71%).Between 5-10 minute, docetaxel concentration sharply drops to 42 μ g/mL (17%), and after 60 minutes, docetaxel concentration reaches 18 μ g/mL (7%).

Conclusion

This description of test, the amount of PVP-K30 with respect to the amount of the docetaxel that is used for solid dispersion influence time that degree of super saturation and supersaturation keep the two.Use the higher drug load to cause the Cmax of docetaxel low shorter with the supersaturation time, therefore, dissolubility reduces over time.

4.5: compare with the dissolubility of prior art compositions

In this experiment, the data in literature of compositions of solid dispersion of the disclosed 5mg of the comprising docetaxel of people [95] such as compositions and Chen and PVP-K30 that will contain the solid dispersion of 15mg docetaxel, 135mg PVP-K30 and 15mg SDS is compared.The described solubility tests of people [95] such as use Chen obtain solubility results, and are shown in Figure 15 and 16.Also in simulation intestinal fluid, carry out solubility test, and compare with the data in literature of Chen.The result is shown in Figure 17.

The result

Visible by Figure 15, the 5mg docetaxel of people's such as Chen compositions the most about 80% in solubilized compositions in 900ml water.Surpass 5 hours and reach this maximum.Docetaxel, PVP-K30 and SDS compositions were dissolved 100% 15mg docetaxel in about 60 minutes.

In Figure 16, provide the absolute concentration of docetaxel.The compositions of Chen maximum docetaxel concentration after about 5 hours is about 4.2 μ g/ml.Docetaxel, PVP-K30 and SDS compositions maximum docetaxel concentration after about 60 minutes is about 16.7 μ g/ml.

In Figure 17, the dissolubility of docetaxel capsule reaches 28 μ g/ml (＞90% dissolubility).The dissolubility that is described in people's such as Chen solid dispersion (docetaxel+PVP K30) reaches 4.2 μ g/ml (in the dissolving test, in 900ml water, dissolving is lower than 80% 5mg docetaxel solid dispersion).Therefore, the dissolubility of capsule formulation is high 6.6 times, has higher rate of dissolution (after 30 minutes, reach maxima solubility, and people's such as Chen solid dispersion reaching maxima solubility after 90-120 minute).

Conclusion

Visible by these results, to compare with the compositions of Chen, the rate of dissolution of docetaxel, PVP-K30 and SDS compositions is faster and dissolubility is higher.For bioavailability, see importantly what kind of dissolubility how medicine to dissolve and in 0.5-1.5 hour, to reach fast.

By the result of Chen, the technical staff can not think that the amount that improves docetaxel in the compositions can improve the absolute dissolubility of docetaxel.Because the compositions of Chen is only dissolved 80% 5mg docetaxel (being 4mg) in 900ml water, people's amount with docetaxel of can not expecting is increased to 15mg and can causes that any docetaxel greater than 4mg dissolves.Therefore, people expect maximum about 27% the docetaxel of 15mg docetaxel composition dissolves of Chen, by comparison, and the docetaxel of docetaxel, PVP-K30 and SDS composition dissolves maximum 100%.Therefore, compare with Chen, docetaxel, PVP-K30 and SDS compositions provide unexpected good result.

4.6: at apancrea enzyme simulation intestinal fluid (SIF _Sp) in solubility test

In this experiment, at apancrea enzyme simulation intestinal fluid (SIF _Sp) the middle dissolving of testing the capsule of the solid dispersion that contains docetaxel, PVP-K30 and SDS.Capsule contains the 15mg docetaxel (referring to table 15) of preparation E.According to USP 28 preparation SIF _SpUnder 37 ℃, under 75rpm stirred, the capsule that will contain the 15mg docetaxel was dissolved in 500mL USP SIF _SpIn.The result is shown in Figure 18 and 19.

Figure 18 and 19 shows, almost 100% docetaxel dissolving.This equates the docetaxel absolute concentration is about 29 μ g/ml, and in about 30 minutes, reaches this concentration.Therefore, said composition provides higher dissolubility in the short period of time.

4.7: stability

Also find; According to preparation E (referring to table 15) and be used for clinical trial with the solid dispersion of docetaxel, PVP-K30 and the SDS of capsule (referring to following examples) when between 4-8 ℃, storing; Chemically (do not have degraded) and physically (dissolubility property no change) stable, last at least 80 days.

Embodiment 5: the clinical testing data of various preparations

Material and method

The clinical I phase that 10 patients participate in carrying out tests.

Give following numbering with these patients:

301,302,303,304,305,306,307,308,309 and 310.

With these patient's administrations, comprise the liquid preparation of docetaxel or comprise the solid composite (hereinafter being called MODRA) of the solid dispersion of docetaxel, PVP-K30 and SDS.

Liquid preparation

Docetaxel dosage: for all patient's administration 30mg (No. 306 patient's exceptions, it accepts the 20mg docetaxel).30mg dosage is prepared as follows: (every ml contains the 10mg docetaxel to pre-composition will to be used for the 3.0mL of intravenous administration; In polysorbate 80 (25% volume), ethanol (10% w/w; In water) mix with water, to final volume be 25mL.This solution with the 100mL tap water by the oral absorption of patient.

MODRA

Docetaxel dosage: 30mg; Take in 2 capsules that each capsule contains the 15mg docetaxel.Selection is used for the further test in clinical trial from the preparation E (1/11 docetaxel, 9/11PVP-K30 and 1/11SDS) of previous embodiment.Through the anhydrous docetaxel of 1200mg is dissolved in the 120mL tert-butyl alcohol, 10800mg PVP-K30 and 1200mg SDS (referring to table 15) are dissolved in the 80mL injection water, produce new one batch of preparation E.Under continuous stirring, docetaxel/t-butanol solution is joined in the PVP-K30/SDS/WfI solution.Final mixture is transferred to rustless steel freeze drying box (Gastronorm size 1/3), removes the tert-butyl alcohol and water (referring to table 16) through lyophilizing subsequently.

With totally 60 gelatine capsule agent of No. 0 size of a certain amount of solid dispersion filling that is equivalent to the 15mg docetaxel, HPLC measures the accurate amount that is used for confirming every mg solid dispersion docetaxel.This measures confirmation, and capsule contains the 15mg docetaxel.

The patient is in the morning with oral the taking medicine of 100mL tap water empty stomach.

Patient treatment

301,302,303,304 and No. 305 patients acceptable solution body preparation only.

No. 306 patients in the period 1, accept the docetaxel+ritonavir of 20mg liquid preparation form, in second round, carry out identical taking medicine, and just after taking in docetaxel, take extra ritonavir in 4 hours.

307,308,309 and No. 310 patient's acceptable solution body preparations and/or MODRA.With cycle administration every other week.

Instruct according to mechanism, for oral and intravenous docetaxel the two, all patients treat with oral dexamethasone.1 hour administration 4mg doses of dexamethasone before the research medicine is followed per 12 hours administration 4mg dexamethasone (2 times).Treating with docetaxel 1 hour before, the patient also accepts 1mg granisetron

to prevent nausea and vomiting.

Behind the administration medicine, collect blood sample and be used for pharmacodynamic analysis.Before taking medicine, get blank sample.With the blood sample centrifugalize, with separating plasma, and be stored in-20 ℃ immediately, until analysis.In the laboratory of GLP (Good Laboratory Practice) permission, use the HPLC method of approval to analyze [101].

The result

Table 18 provides the general introduction of individual pharmacodynamic result.

DocLF: docetaxel liquid preparation

MODRA: docetaxel capsule formulation

Tlast: take time in the last sample of measuring docetaxel concentration (unit: hour)

Conc last: the docetaxel concentration (unit: ng/mL) when Tlast

AUC last: the AUC (ng.h/mL) that when Conc last, calculates

AUC inf:AUC last+ is extrapolated to infinity (ng.h/mL)

In all cases; Ritonavir dosage is 100mg (capsule,

301,302,303,304,305,307,309 and No. 310 patient's acceptable solution body preparations.95% confidence interval (being extrapolated to infinity) of meansigma methods and AUC meansigma methods is: 1156 (± 348) ng*h/mL.Transmutability is 85% between individuality.

No. 306 patients in the period 1, accept 20mg docetaxel (liquid preparation form); Concomitant dosing 100mg ritonavir is after one week, in second round; Identical coupling, but after taking in docetaxel, took the extra ritonavir of 100mg in 4 hours, promptly take the ritonavir of 2 dosage; Once when t=0, for the second time in the time of t=4 hour.The pharmacodynamics curve description is in Figure 20.

307,308,309 and No. 310 patient's acceptable solution body preparations and/or MODRA.The pharmacodynamics curve description is in Figure 21.

Figure 22 describes patient's (307,309 and No. 310) of acceptable solution body preparation and accepts 4 patients' (307,308,309 and No. 310) of MODRA the pharmacodynamics curve of all processes (n=6).

Below the pharmacodynamic result of general introduction liquid preparation and MODRA (all with the coupling of 100mg ritonavir) is relatively:

Liquid preparation (30mg docetaxel)

AUC _Inf(95% confidence interval of meansigma methods): 1156 (808-1504) ng*h/ml

Transmutability between individuality: 85% (n=8)

MODRA (30mg docetaxel)

AUC _Inf(95% confidence interval of meansigma methods): 768 (568-968) ng*h/ml

Transmutability between individuality: 29% (n=4)

Transmutability: 33% (n=2) in individual

Use is from the average A UC of 6 curve calculation MODRA of 4 patients.The MODRA of every patient's of administration first dosage is used to calculate transmutability between individuality.Transmutability is based on 307 and No. 308 patient's data from the MODRA that accepts 2 dosage in individual.

Conclusion

The AUC value that the docetaxel liquid preparation of test produces is than high about 1.5 times of administration same dose (30mg) in novel capsule formulation (MODRA).

Transmutability high (85%) between the individuality of liquid preparation, and transmutability obviously lower (29%) between the individuality of capsule formulation.This point is the important characteristic of novel capsule formulation, and provides much better foreseeable docetaxel to expose.From the angle of safety, in oral chemotherapy regimen, need very much transmutability lower between individuality equally.

In individual between transmutability (limited data) and individuality the variable order of magnitude identical.

After the administration docetaxel 4 hours, take in second strengthen dosage the 100mg ritonavir, docetaxel AUC is improved 1.5 times.

The comparison of oral capsule agent formulation and intravenous administration

Figure 23 explains intravenous (20mg intravenous docetaxel; Perfusion in 1 hour,

(n=5 name patient) and oral administration docetaxel (30mg docetaxel; The MODRA capsule is seen above-mentioned) (n=4 name patient; 6 processes) the pharmacodynamics curve after.Intravenous and oral docetaxel administration all with administration 100mg ritonavir (capsule,

) coupling.Instruct according to mechanism, for oral and intravenous docetaxel the two, all patients treat with oral dexamethasone.1 hour administration 4mg doses of dexamethasone before the research medicine is followed per 12 hours administration 4mg dexamethasone (2 times).Treating with docetaxel 1 hour before, the patient also accepts 1mg granisetron

to prevent nausea and vomiting.

The following bioavailability of calculating the MODRA capsule:

(AUC 30mg oral/AUC 20mg intravenous) * (20/30) * 100%=73% (SD 18%).

This explanation, the bioavailability of capsule is higher, and transmutability is low between individuality.

Previous embodiment is intended to explain the specific embodiment of the present invention, rather than will limit scope of the present invention, and scope of the present invention is defined by the following claims.All documents that this paper quotes are incorporated into as a reference through quoting in full.

List of references

1.Demario?MD，Ratain?MJ.Oral?chemotherapy：rationale?and?future?directions.J?Clin?Oncol1998；16：2557-2567.

2.Liu?G，Franssen?E，Fitch?MI?et?al.Patient?preferences?for?oral?versus?intravenous?palliativetherapy.J?Clin?Oncol?1997；15：110-115.

3.Meerum?Terwogt?JM，Beijnen?JH，ten?Bokkel?Huinink?WW?et?al.Co-administration?ofcyclosporin?A?enables?oral?therapy?with?paclitaxel.Lancet?1998；352：285.

4.Sparreboom，A，van?Asperen?J.Mayer?U?et?al.Limited?oral?bioavailability?and?active?epithelialexcretion?of?paclitaxel?caused?by?P-glycoprotein?in?the?intestine.Proc?Natl?Acad?Sci?USA1997；94：2031-2035.

5.Kuhn?J，Rizzo?J.Eckhardt?J?et?al.Phase?I?bioavailability?study?of?oral?topotecan.Proc?Am?SocClin?Oncol?1995；14：474.

6.Schellcns?JHM，Creemcrs?GJ，Beijnen?JH?et?al.Bioavailability?and?pharmacokonetcs?of?oraltopotecan：a?new?topoisomerase?inhibitor?Br?J?Cancer?1996；73：1268-1271.

7.Hellriegel?ET，Bjomnson?TD，Hauck?WW.Interpatient?variability?in?bioavailability?is?relatedto?the?ecxtent?of?absorption：implications?for?bioavailability?and?bioequivalence?studies.Clin?PharmacolTher?1996；60：601-607.

8.Huiizng?MT，Giaccone?G，van?Warmerdam?LJC?et?al.Pharmaokinetics?of?paclitaxel?andcarboplatin?in?a?dose-escalating?and?sequencing?study?in?patients?with?non-small?cell?lung?cancer.J?ClinOncol?1997；15：317-329.

9.Van?Asperen?J，van?Tellingen?O，Beljnen?JH?et?al.The?pharmacological?role?of?P-glycoproteinin?the?intestinal?epithelium.Pharmacol?Res?1998；37：429-435.

10.Thiebaut?F，Tsuruo?T，Hamada?H?et?al.Celluler?localization?of?the?multidrug-resistance?geneproduct?P-glycoprotein?in?normal?human?tissues.Proc?Natl?Acad?Sci?USA?1987；84：7735-7738.

11.Fojo?AT，Ueda?K，Slamon?DJ?et?al.Exprssion?of?a?multidrug?resistance?gene?in?humantumours?and?tissucs.Proc?Natl?Acad?Sci?USA?1987；84：265-269.

12.Van?Asperen?J，Mayer?U，van?Tellingen?O?et?al.The?pharmacological?role?of?P-glycoprote?in?inthe?blood-brain?barrier，J?Pharm?Sci?1997；86：881-884.

13.Tsuruo?T，lida?H，Tsukcagoshi?S?et?al，Overcoming?of?vincristine?resistance?in?P388?leukemiain?vivo?and?in?vitro?through?enhanoed?cytotoxicity?of?vincristi?and?vinblastine?by?verapamil.CancerRes?1981；41：1967-1972.

14.Ford?JM，Hait?WN.Pharmacology?of?drugs?that?alter?multidrug?resistaance?in?cancer.Pharmacol?Rev?1990；42：155-199.

15.Slater?LM，Sweet?P，Stupecky?M?et?al.Cyclosporin?A?reverses?vincristine?and?daunorubicinresistance?in?acute?lymphatic?lculcemia?in?vitro.J?Clin?Invest?1986；77：1405-1408.

16.Hyafil?F，Vergely?C，Du?Vignaud?P?et?al.In?vltro?and?in?vivo?reversal?of?multidrug?resistanceby?GF?120918，an?acridonccarboxamide?derivative.Cancer?Res?1993；53：4595-4602.

17.Van?Zuylen?L，Sparreboom?A，Van?der?Gaast?A?et?al.The?orally?administered?P-glycoproteininhibitor?R101933?does?not?alter?the?plasma?pharmacokinetics?of?docetaxel.Clin?Cancer?Res2000；6：1365-1371.

18.Dantzig?AH，Shepard?RL，Cao?J?et?al.Reversal?of?P-glycoprotein-mediated?multidrugresistatance?by?a?potent?cyclopropyldibenzosuberane?modulator，LY335979.Cancer?Res?1996；56：4171-4179.

19.Relling?MV.Are?the?major?effects?of?P-glycoprotein?modulators?due?to?alteredpharmacokinetics?of?anticancer?drugs?Ther?Drug?Monit?1996；18：350-356.

20.Lum?BL，Fisher?GA，Brophy?NA?et?al.Clinical?trials?of?modulation?of?multidrug?resistance：pharmacokinetic?and?pharmacodynamic?considerations.Cancer?1993；72(suppl?11)：3502-3514.

21.Dalton?WS，Crowley?JJ，Salmon?SS?et?al.A?phase?III?randomized?sudy?of?oral?verapamil?as?achemosensitizer?to?reverse?drug?resistance?in?patients?with?refractory?myeloma：a?Southwest?OncologyGroup?Study.Cancer?1995；75：815-820.

22.Milroy?R.A?randomiscd?clinical?study?of?verapamil?in?addition?to?combination?chemotherapyin?small?cell?lung?cancer.West?of?Scotland?Lung?Cancer?research?Group?and?the?Aberdeen?OncologyGroup.Br?J?Canoer?1993；68；813-818.

23.Wishart?GC，Bissett?D，Paul?J?et?al.Quinidine?as?a?resistance?modulator?of?epirubicin?inadvanced?breast?cancer：mature?results?of?a?placebo?controlled?randomized?trial.J?Clin?Oncol1994；12：1771-1777.

24.Wacher?VJ，Wu?CY，Benet?LZ.Overlapping?substrate?specificities?and?tissue?distribution?ofcytochrome?P450?3A?and?P-glycoprotein：implications?for?drug?delivery?and?activity?in?cancerchemotherapy.Mol?Carcinog?1995；13：129-134.

25.Watkins?PB.The?barrier?function?of?CYP3A4?and?P-glycoprotein?in?the?small?bowel.AdvDrug?Deliv?Rev?1997；27：161-170.

26.Wacher?VJ，Silverman?JA，Zhang?Y?et?al.Role?of?P-glycoprotein?and?cytochrome?P450?3A?inlimiting?oral?absorption?of?peptides?and?peptidomimetics.J?Pharm?Sci?1998；87：1322-1330.

27.Cummins?CL，Jacobsen?W，Benet?LZ.?Unmasking?the?dynamic?interplay?between?intestinal?P-glycoprotein?and?CYP3?A4.J?Pharmacol?Exp?Ther?2002；300：1036-1045.

28.De?Bruin?M，Miyake?K，Litman?K?et?al.Reversal?of?resistance?by?GF120918?in?cell?linesexpressing?the?half?transporter，MXR.Cancer?Lett?1999；46：117-126.

29.Maliepaard?M，van?Gastelen?MA，Tohgo?A?et?al.Circumvention?of?BCRP-mediated?resistanceto?camptothecins?in?vitro?using?non-substrate?drugs?or?the?BCRP?inhibitor?GF120918.Clin?Cancer?Res2001；7：935-941.

30.Guengerich?FP.In?vitro?techniques?for?studying?drug?metabolism.J?Phatmacokinet?Biopharm1998；24：521-533.

31.Lin?JH，Lu?AY.Inhibition?and?induction?of?cytochrome?P450?and?the?clinieal?implications.Clin?Pharmacokinet?1998；35：361-390.

32.Watkins?PB，Wrighton?SA，Schuetz?EG?et?al.Identification?of?glucocorticoid-induciblecytochromes?P450?in?the?intestinal?mucosa?of?rats?and?man.J?Clin?Invest?1987；80：1029-1036.

33.Lown?KS，Kolars?JC，Thummel?KE.Interpatient?heterogeneity?in?expression?of?CYP3A4?andCYP3A5?in?small?bowel.Lack?of?prediction?by?the?erythromycin?breath?test.Drug?Metab?Dispos1994；22：947-955.

34.Huizing?MT，Misser?VH，Pieters?RC?et?al.Taxanes；a?new?class?of?antitumor?agents.CancerInvest?1995；13：381-404.

35.Fujita?H，Okamoto?M，Takao?A?et?al.Pharmacokinetics?of?paclitaxel?in?experimental?animals.Part?1.Blood?levels.Gan?To?Kagaku?Ryoho?1994；21：653-658.

36.Eiseman?JL，Eddington?ND，Leslie?J?et?al.Plasma?pharmacokinetics?and?tissue?distribution?ofpaclitaxel?in?CD2F1?mice.Cancer?Chemother?Phamacol?1994；34：465-471.

37.Rowinsky?EK，Wright?M，Monsarrat?B?et?al.Clinical?pharmacokogy?and?metabolism?of?taxol(paclitaxel)：update?1993.Ann?Oncol?1994；5(suppl?6)：S7-S16.

38.Sonnichsen?DS，Liu?Q，Schuetz?EG?et?al.Variability?in?human?cytochrome?P450?paclitaxelmetabolism.J?Pharmacol?Exp?Ther?1995；275：566-575.

39.Walle?T，Walle?K，Kumar?GN?et?al.Taxol?metabolism?and?disposition?in?cancer?patients.DrugMetabol?Dispos?1995；23：506-512.

40.Sparreboom?A，van?Tellingen?O，Nooijen?WJ?et?al.Preclinical?pharmacokinetics?of?paclitaxeland?docetaxel.Anticancer?Drugs?1998；1：1-17.

41.Van?Asperen?J，van?Tellingen?O，Sparreboom?A?et?al.Enhanced?oral?bioavailability?ofpaclitaxel?in?mice?treted?with?the?P-gylycoprotein?blocker?SDZ?PSC?833.Br?J?Cancer?1997；76：1181-1183.

42.Van?Asperen?J，van?Tellingen?O，van?der?Valk?MA?et?al.Enhanced?oral?absorption?anddecreased?elimination?of?paclitaxel?in?mice?with?cyclosporin?A.Clin?Cancer?Res?1998；4：2293-2297.

43.Harris?JW，Rahman?A，Kim?BR?et?al.Metabolism?of?taxol?by?human?hepatioc?microsomes?andliver?slices：partcipation?of?cytochrome?P450?3A4?and?an?unknown?P450?enxyme.Cancer?Res1994；54：4026-4035.

44.Cresteil?T，Monsarrat?B，Alvinerie?P?et?al.Taxol?metabolism?by?human?liver?microsomes：identification?of?cytochrome?P450?isozymes?involved?in?its?biotransformation.Cancer?Res1994；54：386-392.

45.Webber?IR，Peters?WH，Back?DJ.Cyclosporin?metabolism?by?human?gastrointestinal?mucosalmicrosomes.Br?J?Clin?Pharmacol?1992；33：661-664.

46.Bardelmeijer?HA，Beijnen?JH，Brouwer?KR?et?al.Increased?oral?bioavailability?of?paelitaxelby?GF120918?in?mice?through?selecctive?modulation?of?P-glycoprotein.Clin?Cancer?Res?2000；6：4416-4421.

47.Wils?P，Phung-Ba?V，Wamery?A?et?al.Polarized?transport?of?docetaxel?and?vinblastinemediated?by?P-glycoprotein?in?human?intestinal?epithelial?cell?monolayers.Biochem?Parmacol1994；48：1528-1530.

48.Shirakawa?K，Takar?K，Tanigawara?Y?et?al.Interaction?of?docetaxel(Taxotera)with?human?P.glycoprotein.Jpn?J?Cancer?Res?1999；90：1380-1386.

49.Bardelmeijer?HA，Ouwehand?M，Buckle?T?et?al.Low?aystemic?exposure?of?oral?docetaxel?inmice?resulting?from?extensive?first-pass?metabolism?is?boosted?by?ritonavir.Proc?Am?Assoc?Cancer?Res2002；43：262?and?Cancer?Ressarch?2002；62：6158-6164.

50.Marre?F，Sanderink?GJ，Desousa?G?et?al.Hepatic?biotransformation?of?docetaxel(taxotere)invitro：involvement?of?the?CYP3A?subfamily?in?humans.Cancer?Res?1996；56：1296-1302.

51.Meerum?Terwogt?JM，Malingré?MM，Beijnen?JH?et?al.Coadministration?of?cyclosporinenables?oral?therapy?with?paclitaxel.Clin?Cancer?Res?1999；5：3379-3384.

52.Malingré?MM，Terwogt?JM，Beijnen?JH?et?al.Apase?I?and?pharmacokinetic?study?of?oralpaclitaxel.J?Clin?Oncol?2000；18：2468-2475.

53.Malingré?MM，Schellens?JHM，van?Tellingen?O?et?al.Metabolism?and?exeretion?of?paclitaxelafter?oral?administration?in?combination?with?cyclosporin?A?and?after?intravenous?adminisration.Anticancer?Drugs?2000；11：813-820.

54.Gianni?L，Kearns?CM，Giani?A?et?al.Nonlinear?pharmacokinetics?and?metabolism?of?paclitaxeland?its?phamacokinetic/pharmacodynamic?relationship?in?humans.J?Clin?Oncol?1995；13：180-190.

55.Sparreboom?A，van?Tellingen?O，Nooijen?WJ?et?al.Tissue?distribution，metabolism?andexcretion?of?paclitaxel?in?mice.Anticancer?Drugs?1996；7：78-86.

56.van?Tellingen?O，Huizing?MT，Panday?VR?et?al.Cremophor?EL?causes(pseudo)nonlinearpharmacokinetics?of?paclitaxel?in?patients.Br?J?Cancer?1999；81：330-335.

57.MalingréMM，Beijnen?JH，Rosing?H?et?al.A?phase?I?and?pharmacokinetic?study?of?bidailydosing?of?oral?paclitaxel?in?combination?with?cyclosporin?A.Cancer?Chemother?Pharmacol2001；47：347-354.

58.Malingré?MM，Beijnen?JH，Rosing?H?et?al.The?effect?of?different?doses?of?cycksporin?A?onthe?systemic?exposure?of?orally?administered?paclltaxel.Anticancer?Drugs?2001；12：351-358.

59.MalingréMM，Beijnen?JH，Rosing?H?et?al.Co-administration?of?GF120918?significantlyinereases?the?systemic?exposure?to?oral?paclitaxel?in?cancer?patients.Br?J?Cancer?2001；84：42-47.

60.Kruijtzer?CMF，Schellens?JHM，Mezger?J?et?al.Aphae?II?and?pharmacological?study?ofweekly?oral?paclitaxel(

)plus?cyclosporin?A(CsA)in?patients?with?advanced?non-small?celllung?cancer(NSCLC).J?Clin?Oncol?2002；20：4508-4516.

61.Wozniak?AJ.Single?agent?vinorelbine?in?the?treatment?of?non-small?cell?lung?cancer.SeminOncol?1999；26(suppl?16)：62-66.

62.Ten?Bokkel?Huinink?WW，Bergman?B，Chemaissaini?A?et?al.Single-agent?gemcitabine：anactive?and?better?tolerated?altemative?to?standard?cisplatin-based?therapy?in?locally?advanced?ormetastatic?non-small?cell?ling?cancer.Lung?Cancer?1999；26：85-94.

63.Socinski?MA.Single-agent?paclitaxel?in?the?treatment?of?advanced?non-small?cell?lung?cancer.The?Oncologist?1999；4：408-416.

64.Miller?V，Kris?M，Docetaxel(Taxotere)as?a?single?agent?and?in?combination?chemotherapy?forthe?treatment?of?patients?with?advanced?non-small?cell?lung?cancer.Semin?Oncol?2000；27(suppl?3)：3-10.

65.Ranson?M，Davidson?N，Nicolson?M?et?al.Randomized?trial?of?paclitaxel?plus?supportive?careversus?supportive?care?for?patients?with?advanced?non-small?cell?lung?cancer.J?Natl?Cancer?Inst2000；92：1074-1080.

66.Gatzemeier?U，Heckmayr?M，Neuhauss?R?et?al.Phase?II?study?with?paclitaxol?for?the?treatmentof?advanced?inoperable?non-small?cell?lung?cancer.Lung?Cancer?1995；12(suppl?2)：S101-S106.

67.Cullinan?SA，Moertel?CG，Wicand?HS?et?al.Controlled?evaluation?of?three?drug?combinationregimens?versus?fluorouracil?alone?for?the?therapy?of?advanced?gastric?cancer.J?Clin?Oncol1994；12：412-416.

68.Wils?JA，Klein?HO，Wagener?DJ?et?al.Sequantial?high-dose?methotrexate?and?fluorouracilcombined?with?doxorubicin.A?step?ahead?in?the?treatment?of?advanced?gastric?cancer；a?trial?of?theEuropean?Organization?for?Rescarch?and?Treatment?of?Cancer?Gastrointestinal?Tract?CooperativeGroup.J?Clin?Oncol?1991；9：827-831.

69.Webb?A，Cunningham?D，Scarffe?H?et?al.Randomized?trial?comparing?epirubicin，cisolatin，and?fluorouracil?versus?fluorourcall，doxorubicin?and?methotrexate?in?advanced?esophagogastric?cancer.J?Clin?Oncol?1997；15：261-267.

70.Boot?H，Cats?A，Tonino?S?et?al.Epirubicin，cisplatin?and?continuoes?5-FU?chernotherapy(ECF-regimen)in?patients?with?cancer?of?the?gastroesophageal?junction?and?stomach.Gastroenterology2002；122(suppl)：A601.

71.Ohtsu?A，Boku?N，Tamura?F?et?al.An?early?phase?II?study?of?a?3-hour?infusion?of?paclitaxel?foradvanced?gastric?cancer.Am?J?Clin?Oncol?1998；21：416-419.

72.Cascinu?S，Graziano?F，Cardarclli?N?et?al.Phase?II?study?of?paclitaxel?in?pretreated?advancedgastric?cancer.Anticancer?Drugs?1998；9：307-310.

73.Einzig?AL，Lipsitz?S，Wiernik?PH?et?al.Phase?II?trial?of?Taxol?in?patients?with?adenocarcinomaof?upper?gastrointestinal?tract(UGIT)，The?Eastern?Cooperative?Oncology?Group(ECOG)results.Invest?New?Drugs?1995；3：223-227.

74.Huizing?MT，Keung?AC，Rosing?H?et?al.Pharmacokinetics?of?paclitaxel?and?metabolites?in?arandomized?comparative?study?in?platinum?pretreated?ovarian?cancer?patients.J?Clin?Oncol1993；11：2127-2135.

75.MalingréMM，Richel?DJ，Beijnen?JH?et?al.Coadministration?of?cyclosporin?A?stronglyenhances?the?oral?bioavailability?of?docetaxel.J?Clin?Oncol?2001；19：1160-1166.

76.Burstein?HJ，Manola?J，Younger?J?et?al.Docetaxel?adminlstered?on?a?weekly?basis?formetastatic?breast?cabcer.J?Clin?Oncol?2000；18：1212-1219.

77.Kruijtzer?CMF，MalingréMM，Schomagel?JH?et?al.A?phase?II?study?with?weekly?oraldocetaxel?and?cyclosporin?A?in?patients?with?metastatic?breast?cancer.Proc?Am?Soc?Clin?Oncol2001；20：1941.

78.Lück?HJ，DonnèS，Glaubitz?M?et?al.Phase?I?study?of?weekly?docetaxel(

)in?heavilypretrcated?breast?cancer?patients.Eur?J?Cancer?1997；33(suppl)：158.

79.Hainsworth?JD，Burris?3rd?HA，Yardley?DA?et?al.Weekly?docetaxel?in?the?treatment?of?elderlypatients?with?advanced?breast?cancer：a?Minnie?Pearl?Cancer?Research?Network?Phase?II?trial.J?ClinOncol?2001；19：3500-3505.

80.Bruno?R，Hille?D，Riva?A?et?al.Population?pharmacokinetics/pharmacodynamics?of?docetaxelin?phase?II?studies?in?patients?with?cancer.J?Clin?Oncol?1998；16：187-196.

81.Rosing?H，Lustig?V，van?Warmerdam?LJ?et?al.Pharmacokinetics?and?metabolism?of?docetaxeladministered?as?a?l-h?intravenous?infusion.Cancer?Chemother?Pharmacol?2000；45：213-218.

82.Myers?BD，Ross?J，Newton?L?et?al.Cyclosporine-associated?chronic?nephropathy.N?Engl?JMed?1984；311：699-705.

83.Mastaler?H，Cook?D，Fairchild?CR，Hansel?S，Johnson?W，Kadow?JF，Long?BH，Rose?WC，Tarrant?J，Wu?MJ，Xue?MQ，Zhang?G，Zoeckler?M，Vyas?DM.The?discovery?of?BMS-275183：anorally?efficacious?novel?taxane.Bioorg?Med?Chem.2003；11：4315-23.

84.J.Collett，C.Moreton.Modified-release?peroral?dosage?forms.In：M.E.Aulton，editor.Pharmaceutics：the?science?of?dosage?form?deslgn，2nd?edition.London：Churchill?Livingstone，2002：289-305.

85.R.Bruno?and?G.J.Sanderink，Pharmacokinetics?and?metabollsm?of?Taxotere(docetaxel).Cancer?Surv?17，305-313(1993).

86.W.J.Loos，S.D.Baker，J.Verweij，J.G.Boonstra?and?A.Sparreboom，Clinicalpharmacokinetics?of?unbomd?docetaxel：role?of?polysor?bate?80?and?serum?proteins.Clin?PharmacolTher?74，364-371(2003).

87.B.S.Kappelhoff，A.D.R.Huitema，K.M.L.Crommentuyn，J.W.Mulder，P.L.Meenhorst，E.C.van?Gorp，A.T.Mairuhu?and?J.H.Beijnen，Development?and?validation?of?a?populationpharmacokinetic?model?for?ritonavir?used?as?a?booster?or?as?an?antiviral?agent?in?HIV-I-infectedpatients.Br?J?Clin?Pharmacol?59，174-182(2005).

88.Martignonl?M，Groothuis?GM，de?Kanter?R.Species?differences?between?mouse，rat，dog.monkey?and?human?CYP-mediated?drug?metabolism.inhibition?and?induction.Expert?Opin?DrugMetab?Toxicol.2006?Dec；2(6)：875-94

89.Xie?W，Evans?RM.Pharmaceutical?use?of?mouse?models?humanized?for?the?xenobioticreceptor.Drug?Discov?Today.2002?May?1；7(9)：509-15.

90.lyer?M，Reschly?EJ，Krasowski?MD.Functional?evolution?of?the?pregnane?X?receptor.ExpertOpin?Drug?Metab?Toxicol.2006?Jun；2(3)：381-97.

91.Wang?H，LeCluyse?EL.Role?of?orphan?nuclear?receptors?in?the?regulation?of?drug-metabolising?enzymnes.Clin?Pharmacokinet.2003；42(15)：1331-57.

92.Nelson?DR，Zeldin?DC，Hoffman?SM，Maltals?LJ，Wain?HM，Nebert?DW.Comparison?ofcytochrome?P450(CYP)genes?from?the?mouse?and?human?genomes，including?nomenclaturerecommendations?for?genes，pseudogenes?and?altemative-splice?varints.Pharmacogenetics.2004Jan；14(1)：1-18.

93.Serajuddin?AT，Solid?dispersion?of?poorly?water-soluble?drugs：early?promises，subsequentproblems，and?recent?breakthroughs.J?Pharm?Sci?1999；88(10)：1058?1066.

94.Karanth?H，Shenoy?VS，Murthy?RR.Industrially?feasible?alternaive?approaches?in?themanufacture?of?solid?dispersions：a?technical?report.AAPS?PharmSciTech?2006；7(4)：87.

95.Chen?J，Qiu?L，Hu?M，Jin?Y，Han?J，Preparation，characterization?and?in?vitro?evaluation?ofsolid?dispersions?containing?docetaxel.Drug?Development?and?Industrial?Pharmacy?2008；34：588-594.

96.Schellekens?RC，Stuurman?FE，van?der?Weert?FH，Kosterink?JG，Frijlink?HW.A?noveldissolution?method?relevant?to?intestinal?release?behaviour?and?its?application?in?the?evaluation?ofmodified?relesse?mesalazine?products.Eur.J.Pharm.Sci.2007?Jan；30(1)：15-20.

97.Dressman?JB，Reppas?C.In?vitro-in?vivo?correlations?for?lipophilic，poorly?water-solubledrugs.Eur.J.Pharn.Sci.2000?Oct；11：S73-S80.

98.The?Handbook?of?Pharmaceutical?Excipients.Fifth?Edition.Edited?by?Raymond?Rowe，PaulSheskey?and?Sian?Owen.See?section?on?Povidone.

99.Kruijtzer?CM，Boot?H，Beijnen?JH?et?al.Weekly?oral?paclitaxel?as?first?line?treatment?inpatients?with?advanced?gastric?cancer.Ann?Oncol?2003；14：197-204.

100.Helgason?H，Kruijtzer?CM，Huitema?ADR?et?al.Phse?II?and?pharmacological?study?of?oralpaclitaxel(Paxoral)plus?ciclosporin?inanthracycline-pretreated?metastatic?breast?cances.Brit?J?Cancer2006；95：794-800.

101.Kuppens?IE，Van?Maanen?MJ，Rosing?H，Schellens?JHM，Beijnen?JH.Quantitative?analysis?ofdocetaxel?in?human?plasma?using?liquid?chromatography?coupled?with?tandem?mass?spectrometry.Biomed?Chromatogr?2005；19：355-361.

Claims

1. solid composite medicament that is used for oral administration; Wherein, Said composition contains unbodied taxane, hydrophilic carrier and surfactant; Wherein said taxane, said carrier and said surfactant are the solid dispersion form, and the weight ratio of said taxane and carrier is 2.5: 97.5 to 15: 85.

2. compositions according to claim 1, wherein, said unbodied taxane uses solvent evaporated method or lyophilizing to prepare.

3. according to any described compositions in the aforementioned claim, wherein, said carrier is selected from: polyvinyl pyrrolidone; Polyethylene Glycol; Polyvinyl alcohol; Crospovidone; Polyvinyl pyrrolidone-polyvinyl acetate ester copolymer; Methylcellulose; Hydroxypropyl cellulose; Carboxymethylethylcellulose; Acetic acid-phthalic acid-cellulose; Hydroxypropyl Methylcellulose Phathalate; Polyacrylate; Polymethacrylates; Mannitol, sucrose, Sorbitol, glucose and chitosan; And cyclodextrin.

4. compositions according to claim 1 and 2, wherein, said carrier is selected from: PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP-K90 and PVP-K120.

5. compositions according to claim 1 and 2, wherein, the weight ratio of said taxane and carrier is 2.5: 97.5 to 10: 90.

6. compositions according to claim 1 and 2, wherein, the weight ratio of said taxane and carrier is 5: 95 to 10: 90.

7. compositions according to claim 1 and 2, wherein, said unbodied taxane prepares through lyophilizing.

8. compositions according to claim 7, wherein, said unbodied taxane is that the taxane solution lyophilizing through the capsule that will be used for oral administration prepares.

9. according to claim 1,2 or 8 described compositionss, wherein, said composition also contains one or more other active component pharmaceutically.

10. compositions according to claim 9, wherein, said one or more other active component pharmaceutically are the CYP3A4 inhibitor.

11. compositions according to claim 10, wherein, said CYP3A4 inhibitor is a ritonavir.

12. according to claim 1,2,8,10 or 11 described compositionss, wherein, said taxane is a docetaxel.

13. according to claim 1,2,8,10 or 11 described compositionss, wherein, the purposes that said composition is used to treat.

14. according to claim 1,2,8,10 or 11 described compositionss, wherein, said composition is used to treat the purposes of tumor disease.

15. according to any described compositions in the claim 1,2,8,10 or 11, wherein, the weight ratio of said taxane and carrier is 1: 9; And the weight ratio of surfactant and taxane is 1: 1.

16. any described method for compositions for preparing among the claim 1-12, wherein, this method may further comprise the steps:

In solvent, wherein, the weight ratio of said taxane and carrier is 2.5: 97.5 to 15: 85 with taxane, hydrophilic carrier and surfactant dissolves; With

With solution lyophilizing that obtains or use solvent evaporated method, to form said compositions.

17. any described compositions among the claim 1-12 is used for treating the purposes of the medicine of tumor disease in preparation.