CN1615130A - Taxane based compositions and methods of use - Google Patents

Abstract

Disclosed are taxane-based compostions and methods of using the same to achieve target blood levels of a taxane in a mammal, e.g., to treat taxane-responsive malignant and non-malignant diseases. Compositions of the invention exhibit long-term stability and overall palatability. Also disclosed are methods for using the compositions as analytical tools for pharmacokinetic studies.

Description

Compositions and using method based on taxane

Invention field

The present invention relates to a kind of novel composition that is used for the water-insoluble drug administration, the difficult medicine that absorbs when these medicines comprise known oral administration.The invention further relates to compositions and use the method for these compositionss with the target blood drug level that in mammalian body, reaches taxane.In addition, the invention still further relates to the method for utilizing this compositions to treat.

Background of invention

Lacking the effective way of handling the indissoluble characteristics of useful chemical compound (for example, lipotropy, hydrophobicity and amphiphilic compound) on a lot of pharmacology is to hinder the major defect of drug development.Kagkadis etc. in PDA J.Pharm.Sci.50 (5): 317-323 (1996) and Sweetana etc. in PDA Pharm.Sci.50 (5): 330-342 (1996), all instructed and comprised for example insoluble chemical compound of cortisone, etoposide, ciclosporin and A Desi leukin.In the usual course, because the very poor or inconsistent whole body absorption in gastrointestinal tract of insoluble drug, they come administration (cause health and the psychological discomfort and the potential local damage of certain degree, also cause extra economic loss simultaneously) by vein always.

When being comprised taxane by oral administration, for example when such slightly solubility chemotherapy of paclitaxel and/or cancer therapy drug, they generally do not have biological utilisation.Wani etc. are at J.Am Chem.Soc., and 93:2325 has instructed paclitaxel in (1971), and a kind of in the terpenic taxane family is isolated natural diterpene product from Pacific yew Codium fragile (Sur.) Har. tree (the short leaf plant of Cercocarpus).Do not cause paclitaxel chemotherapy character cutter reason really although instruct, some researchs, the Proc.Natl.Acad.Sci.USA of Schiff etc. for example, 77:1561-1565 (1980); The Nature of Schiff etc., 277:665-667 (1979); And the J.Biol.Chem. of Kumar, 256:10435-10441 (1981), supposed that all paclitaxel suppresses to come from it in conjunction with the terminal 31 amino acid whose abilities of the N-of beta tubulin subunit in the microtubule (referring to Rao etc., J Biol Chem 269:3132-3134 (1994)) to the ability of cancer development.Wood etc. cause cell death owing to it by destroying required normal power in cell division and the crucial interval progress with the antitumor character of paclitaxel in New Eng.J.M.332 (15): 1004-1014 (1995), to the inhibitory action that causes the especially stable and handicapped microtubule of microtubule to decompose.

Be full of report in the scientific and technical literature to the different uncorrelated diseases of paclitaxel treatment aspect effect.For example referring to report in Proc.Am.Soc.Clin.Oncol.20:46 (1996) such as Einzig to pulmonary carcinoma and head and neck cancer; Forastire etc. are at Sem.Oncol., excrescent report in the relevant skin among the 20:56 (1990); Chang etc. in Cancer77 (1): 14-18 (1996) to the report of gastric cancer; Woo etc. are at Nature, among the 368:750 (1994) to the report of polycystic kidney disease; And Pouvelle etc. in J.Clin.Invest.44:413-417 (1994) to the report of malaria.

Some incoherent diseases are treated in the clinical use that gone through of paclitaxel and Ramulus et folium taxi cuspidatae terpene (docetaxel).Markman etc. are at Bio.﹠amp; Med. Yale J.64:583 (1991) and McGuire etc. discloses in Ann.Intern.Med.111:273 (1989) in the purposes of pacific yew alcohol in the intractable ovarian cancer; Mavrodius etc. have put down in writing the purposes of Ramulus et folium taxi cuspidatae terpene in gastric cancer in ASCO 18:254a (1999); Holmes etc. disclose paclitaxel and have comprised purposes (also can join Taxol (paclitaxel) Mead Johnson OncologyProducts package insert) in the breast carcinoma in the vegetation of chemotherapy several types in J.Nat.Cancer Inst.83:1797 (1991); Fencel etc. have instructed paclitaxel and the purposes of Ramulus et folium taxi cuspidatae terpene in esophageal carcinoma in ASCO 18:283a (1999); Vanhoefer etc. have put down in writing in ASCO 18:303a (1999) and have used the II phase of Ramulus et folium taxi cuspidatae terpene treatment metastatic gastric carcinoma to study; The Ramulus et folium taxi cuspidatae terpene that Kourossis etc. instruct in ASCO 17:266 (a) (1998) rescues the purposes of chemotherapy as late gastric cancer; Xiao etc. have estimated paclitaxel treatment scheme new among the esophageal carcinoma patient who formerly accepted paclitaxel treatment in ASCO 17:306 (a) (1998); Schultz etc. have reported that the II phase of Ramulus et folium taxi cuspidatae terpene in hormone intractable patients with prostate cancer test; Ajani etc. are in J.Nat.Cancer Inst.86:1086-1091 (1994), and Kelsen etc. has put down in writing the paclitaxel treatment scheme of squamous cell carcinoma and adenocarcinoma and esophagus epidermal carcinoma in Seminarsin Oncology 21:44-48 (1994).

Up to now, be intended to the injection of the suitable taxane of development (i) and inculcate preparation and (ii) more water-soluble taxane analog, derivant and prodrug aspect made effort.Therefore, utilization can CREMOPHOR EL ^TMThe GREMAPHOR GS32 of buying has been developed most formulation for paclitaxel that IV inculcates that are used for as pharmaceutical carrier.Yet GREMAPHOR GS32 itself is virose, and causes vasodilation in the Canis familiaris L. body, dyspnea, drowsiness, hypotension and death, its anaphylactic type reaction that causes also under a cloud when intravenously administrable.

The replacement approach has pointed to more taxane water-soluble analogues, derivant and prodrug.Therefore, " modified taxol IV for example; Synthetic and biological activity (the Modified Taxols IV of the taxol that side chain is modified; Synthesis and biological activity oftaxols Modified in the side chain) ", Magri, N.F.; Kingston, DGI; J.Nat.Prod 1988,51,298, instructed deutero-paclitaxel analogs, wherein 2 ' and/or the 7-position be enhanced water miscible group derivatization.By these effort obtained than parent compound more water-soluble and on activation, have a Cytotoxic prodrug compound.An important class of this class prodrug comprise 2 of paclitaxel and Ramulus et folium taxi cuspidatae terpene '-salt (referring to the Angew.Chin.Int.Engl.33:1583-1587 (1994) of for example Nicolaou etc.), especially PCT announce 2 of record among the No.WO 98/58927 '-the picoline mesylate (2 '-MPM) salt.Suffness (ed.) is at Taxol ^Science and Applications has stated among the CRC Press (1995) that improvement and low regeneration rate are feasible also not to make progress up to now owing to seldom obtaining aspect clinical evaluation on dissolubility, stability problem.

Preclinical study proves that only paclitaxel originally is not absorbed behind oral medication.Walle etc. have reported that taxol is not absorbed behind oral administration in Drug Metabo.Disp.26 (4): 343-346 (1998), and will hang down the effect of oral administration biaavailability owing to the directed outwards efflux pump.Similarly, Eiseman etc. are at Second NCI Workshop on Taxol and Taxus (1992.9), and Suffness (ed.) is at Taxol ^Instructed among the Science and ApplicationslCRC Press (1995) that paclitaxel is difficult to be absorbed (being lower than 1%) when oral using.Say that more specifically Eiseman etc. point out that when oral administration, paclitaxel has 0% bioavailability, and Suffness etc. has reported that also the oral administration paclitaxel is seemingly impossible.Owing to these reasons, paclitaxel is not also by by oral administration to human patients.Equally, in order to treat breast carcinoma, with TAXOTERE ^(Rhone-Poulenc-Rorer S.A.) sells Ramulus et folium taxi cuspidatae terpene (N-takes off benzoyl-N-uncle-butoxy carbonyl-10-and takes off the acetyl paclitaxel) for trade mark and uses in the parenteral mode.

The low bioavailability of paclitaxel behind oral administration is attributable to a kind of membrane-bound P-glycoprotein, and it can reduce intracellular drug accumulation (referring to for example Taxol by xenobiotics being evicted from cell as transhipment of energy dependent form or efflux pump ^Science andApplications, the same).According to hypothesis, by the motion of prevention small intestinal cell, the P-glycoprotein can prevent that whole body from absorbing.A large amount of known factors demonstrate and can suppress P-glycoprotein (for example Ciclosporin A, verapamil, tamoxifen, quinidine and phenothiazines).From logically, the directed research ciclosporin of effort that comprises clinical trial is to the known effect that is easy to produce the cancer therapy drug of multidrug resistance (MDR), for example paclitaxel (Fisher etc., Proc.Am.Soc.Clin.Oncol 13:143 1994); Amycin (Bartlett etc., J.Clin.Onc.12:835-842 (1994); And etoposide (Lum etc., J.Clin.Onc.10:1635-1642 (1992)).The intravenously administrable of ciclosporin and cancer therapy drug associating has demonstrated result's (may be to remove by reducing body) of higher blood drug level and has quite shown expection toxicity on the low dosage level.As for can be referring to the Drug Resist.Clin.Onc.Hemat.9:319-336 (1995) of Lum etc. to the generality discussion of the pharmacology of P-glycoprotein inhibitors clinical practice hint; The Eur.J.Cancer 31A:1295-1298 (1995) of Schinkel etc.

PCT announces that WO 95/20980 (1995.8.10 announcement) (after this being " Benet ") means the method that increases oral administration hydrophobic pharmaceutical compounds bioavailability of having instructed.This method comprises the concurrent oral administration of the bio-enhancer of the film transport inhibitors that comprises Cytochrome P450 3A enzyme inhibitor or the mediation of P-glycoprotein.But Benet does not identify bioavailability strengthens the availability that reagent can improve specific target's medical compounds, does not also instruct clear and definite dose value, scheme or the drug regimen of this enhancing or targeting agent administration.Disclosed unique drug combination is as the ketoconazole of reinforcing agent with as the Ciclosporin A of targeted drug.

Benet only provide bio-enhancer-this class for the hydrophobic compound of nitrogen groups that comprises two coplanar aromatic rings, positively charged usually or carbonyl comprise can not quantification chemical compound, comprise the embodiment that some can not be implemented.And, active agent by disclosed these kinds of Benet has comprised the most medicinal reagents that are listed in " internist's desk reference book Physicians ' Desk Reference ", therefore, for the medicine practice person who seeks method safe, practical and effective oral administration specific medicament, this is nugatory.At last, Benet does not provide and can be adopted to distinguish suitable bio-enhancer/active medicine associating or to design the instruction that effective oral medication formula is gone up in treatment by the technical staff.

PCT publication No. WO 98/30205 (being published in 1998.7.16) (after this being " Quay ") allegedly discloses the method that increases the insoluble drug bioavailability.This application discloses the Emulsion of the alpha-tocopherol that comprises a kind of surfactant.The vitamin E that Pegylation is arranged that is also comprised.The alpha-tocopherol of Pegylation comprises by succinic diester and is attached at Polyethylene Glycol subunit on the vitamin E ring hydroxyl.Alpha-tocopherol it is said as a kind of surfactant in the alpha-tocopherol Emulsion, stabilizing agent and secondary solvent.It should be noted that this list of references is confined to (a) Emulsion and (b) essentially no alcoholic acid preparation especially.

The PCT publication number WO 97/15269 that owns together discloses the method and composition that novel preparation comprises the biological available targeting agent of taxane, by oral administering drug combinations bioavailability reinforcing agent ciclosporin for example, these reagent can demonstrate very poor oral administration biaavailability else if.

There are the interpolation compositions of the suitable taxane oral administration of exploitation and the needs of effective ways always.These compositionss can reach the goal treatment blood drug level of taxane.Because some significantly put into practice reason, these compositionss will be biological available for (i), (ii) be suitable for taxane is remained in the solution, and will be chemically stable in (iii) long-term, (iv) also have whole palatability when showing long-time stability.

Summary of the invention

The inventor has invented based on the compositions of taxane and has used the method for these compositionss with the target blood level that reaches taxane in mammalian body.Said composition shows long-time stability and whole palatability.As the illustration at this, for example, this approach provides and has reached and existing inconvenient method, for example effectively inculcates the means of the suitable taxane blood drug level of modality in the treatment.Therefore enter blood from gastrointestinal absorption target blood drug level is provided thereby the invention provides compositions and be used to improve taxane, comprise this taxane effective method of blood drug level in the intravital treatment of mammal.In some embodiments, the taxane blood drug level that reaches has surpassed those by disclosed compositions reached in WO 97/15269 concentration.In addition, the method according to this invention and compositions can be used as the analytical tool and the treatment tool of biochemical research.

In first aspect, the invention provides the pharmaceutical composition that demonstrates long-time stability and whole palatability.This compositions comprises insoluble medicine, carrier, secondary solubilizer and stabilizing agent.In a more preferred of the present invention, this medicine is a taxane.The preferred embodiments of the invention can provide more than one type taxane, carrier, secondary solubilizer or stabilizing agent.Some compositions of the present invention has further comprised supplementary element, such as specific descriptions at this, and for example surfactant, pharmaceutical excipient, diluent, sweeting agent, flavoring agent or coloring agent.In the concrete preferred embodiment of the present invention, taxane is paclitaxel or Ramulus et folium taxi cuspidatae terpene.As for the oral administration of oral administration biaavailability reinforcing agent associating, preferred compositions more of the present invention provide and the suitable taxane blood drug level of blood drug level by intravenous injection reached.

In second aspect, the invention provides by the described pharmaceutical composition of oral administration, suit in mammalian body, to reach the method for effective taxane blood drug level in the treatment.In an especially preferred embodiment, method of the present invention comprises administration bioavailability reinforcing agent, caused and for example be shown as treatment and go up and (for example to inculcate the taxane blood drug level of being on close level that reached in effective 96 hours by inculcating for a long time, be used for the treatment of the breast carcinoma that shifts late period at Wilson etc. what J.Clin.Oncol.12:1621-1629 (1994) and Seidman etc. described in J.Clin.Oncol.16:3353-3361 (1998)).According to this on the one hand, useful pharmaceutical composition and bioavailability reinforcing agent are those that put down in writing in first aspect present invention.

In aspect the 3rd, the invention provides the method for research diterpene-kind compound character.More particularly, the invention provides the instrument that research can mediate the biochemical property of the taxane part in the novel formulation that dissolubility increases considerably.These researchs will cause for distinguishing novel application and can further optimizing existing vital more fully taxane pharmacokinetics and the pharmacy explanation of therapeutic outcome.

Another aspect of the present invention relates to treating by the oral administration aforementioned pharmaceutical compositions suffers from the mammiferous method that taxane is replied disease.In some embodiments, thus pharmaceutical composition of the present invention can provide the suitable taxane blood drug level that is reached with the taxane intravenous injection with the administration of oral administration biaavailability reinforcing agent Combined with Oral.According to this on the one hand, useful pharmaceutical composition and biological utilisation reinforcing agent are that those are put down in writing in according to a first aspect of the invention.

Brief Description Of Drawings

Caption (PG/TPGS/ETOH and the ascorbyl palmitate (40: 40: 20) and (●) 12mg/ml of Fig. 1 for showing present composition ability, () 15mg/ml, (■) 20mg/ml, (zero) 25mg/ml, () paclitaxel of 50mg/ml), in solution, in the double vibrations water-bath, keep a period of time in 〉=2 hours.

Fig. 2 for show a kind of preparation based on polyoxyethylene castor oil of (●) 9 oral administrations the patient's and (zero) 2 the oral administration present composition (caption of the patient's of PG/TPGS/ETOH and ascorbyl palmitate (40: 40: 20) paclitaxel mean plasma concentration.

DESCRIPTION OF THE PREFERRED

The inventor has invented novel compositions and has used these composition orals to give the insoluble medicine of liquid medicine, comprises the known method that is difficult to absorbed medicine when oral administration.The invention further relates to compositions and use these compositionss, comprise the method for therapeutic blood level in mammalian body, to reach taxane target blood drug level.In addition, the present invention relates to utilize the therapeutic scheme of these compositionss.Technical staff through being accredited as this field is familiar with United States Patent (USP) in the scope and other and is published in this and is all quoted with for referencial use.

Unless otherwise specified, otherwise have technical staff's art-recognized meanings in field related to the present invention in this used technology scientific and technical terminology.In order to ensure to description and claims, comprise these terms the clear complete understanding of appointed scope, provided following definition.Be understandable that defined term can occur with noun, verb, odd number and corresponding plural form.

The whole bag of tricks known to those skilled in the art is learned herein and material as a reference.The canonical reference school bag that provides the materia medica principle of generality is drawn together Goodman and Gilman ' s ThePharmacological Basis of Therapeutics, the 9th edition, McGraw HillCompanies Inc., New York (1996).Provide the canonical reference book (Remington ' s Pharmaceutical Sciences of modern medicinal agents principle of generality, the 18 edition, Gennaro, Mack Publishing Co., Easton, PA (1990) and Remington:The Scienceand Practice of Pharmacy, Lippincott, Williams ﹠amp; Wilkins (1995)).

Suitable material and/or method known to any technical staff can be used among the present invention.Yet, will describe to some extent preferred substance and method.Unless note separately, otherwise the reference material in following explanation and embodiment, reagent etc. are that commerce is buied.

The present invention is intended to use for any mammal that may experience the benefit of the inventive method.At first refer to the mankind in these mammals, although the present invention does not think limitation like this, it also can be suitable for the veterinary and use.

In aspect first, the invention provides the pharmaceutical composition that shows long-time stability and whole palatability.This based composition comprises taxane, carrier, secondary solubilizer and stabilizing agent.In order to reach purpose of the present invention, the water miscible part of (improving to some extent in preferred embodiments) taxane in pharmaceutical composition of the present invention kept in the normal expression of term " carrier ".Support according to the present invention unrestriction ground comprises the part that also can be used as secondary solubilizer.Carrier of the present invention with the paired core texture that can be the polyethers of straight chain or the glycol of side chain (for example ethylene glycol) of at least a fatty acid ester be feature.The preferred vector that uses for the present invention is as nonionic surfactant or have emulsifying agent at least about 10 HLB value.Found this nonionic surfactant or emulsifying agent be not only lipotropy taxane (it is indissoluble in water) but the compatibility carrier, it also promotes active component to absorb from gastrointestinal tract to enter in the blood flow.Have only in this class surfactant those have about 10 or the carrier that just can be used as of higher HLB value be used in this theme composition.

The non-limiting representative embodiment of support according to the present invention comprises the Co.Kingsport available from EastmanChemical, the vitamin E TPGS of TN (d-alpha-tocopherol) cetomacrogol 1000 succinate; Saturated poly-dihydric alcohol is separated glyceride and is for example comprised C ₈-C ₁₈The GELUCIRE of the glyceride of fatty acid ^TMAnd LABRASOL ^TMProduct (Gattefoss é Corp., Westwood, NJ); CREMOPHOR ^TMEL or other modified castor oils, comprise the ethylating or castor oil hydrogenated of polyoxy for example EL-P or RH40 improvement Oleum Ricini (available from BASF, Mt.Olive, NJ); MYRJ ^TMPolyoxy ethylization stearate (by ICI Americas, Charlotte, NC sells); TWEEN ^TM(ICI Americas) and CRILLE ^TM(available from Croda Inc., Parsippany, NJ) polyoxy ethylization sorbitol ester; BRIJ ^TMPolyoxy ethylization aliphatic ether (ICI Americas); CROVOL ^TMModification (Polyethylene Glycol) Semen Armeniacae Amarum and Semen Maydis oil glyceride, comprise Polyethylene Glycol Semen Armeniacae Amarum or Semen Maydis oil glyceride (Croda Inc., Edison, NJ); EMSORB ^TMTwo isostearic acid sorbitol esters (Henkel Corp., Ambler, PA); SOLUTOL ^TMPolyoxy ethylization hydroxy stearic acid ester (BASF); And cyclodextrin.

Preferred pharmaceutical compositions of the present invention comprises the carrier of at least 30 weight %.In an especially preferred embodiment, this vector contg is the composition weight of about 30-about 90%.In an especially preferred embodiment, pharmaceutical composition of the present invention comprises the vitamin E TPGS of about 40 weight %.

Term " secondary solubilizer " is used in reference to generation viscosity drop lower part, and desired usually as oral administration biaavailability, it can increase the flowability of the present composition under body temperature, and/or reduces the fusing point of said composition when being lower than body temperature.Preferred secondary solubilizer according to the present invention reduces its viscosity and increases the flowability of carrier under body temperature, and with only use carrier to compare also can to increase the active component dissolving or be dispersed in quantity in the carrier.Secondary solubilizer according to the present invention comprises can also be as the part of carrier.Comprise according to secondary solubilizer unrestriction of the present invention ground the deliquescent part of taxane through improving also can be provided.

The non-limiting representative embodiment that viscosity reduces secondary solubilizer comprises PHARMASOLVE ^TM(the N-N-methyl-2-2-pyrrolidone N-, International Specialty Products, Wayne, NJ); MIGLYOL ^TMThe glycerol of sad and capric acid or propylene glycol ester (H ü ls AG, Marl, Germany); Polyoxy ethylization hydroxy stearic acid ester comprises stearoyl or oleyl ether (SOLUTOL for example ^TMHS 15) (BASF, Mt.Olive, NJ); TWEEN ^TMPolyoxy ethylization sorbitol ester (ICIWilmington, DE); SOFTIGEN ^TMThe macrogol ester (H ü ls AG) of sad and capric acid; Modified castor oil comprises that polyoxy ethylizes or castor oil hydrogenated (CREMOPHOR for example ^TMEL, EP-P or RH 40) (BASF, Mt.Olive, NJ); Vegetable oil is olive oil for example, polyoxy ethylization aliphatic ether or modified castor oil; Some saturated GELUCIRE50/13 GELUCIRE 50/13 comprises C ₈-C ₁₈The glyceride of fatty acid (LABRASOL for example ^TM); Citrate is tributyl citrate for example, triethyl citrate and acetyl triethyl citrate, propylene glycol, independent or and PHARMASOLVE ^TMAssociating, ethanol (preferred dewatered ethanol), water and low-molecular-weight propylene glycol be PEG 200,300 and 400 for example.In an especially preferred embodiment, this secondary solubilizer is an ethanol.In a preferred embodiment, this secondary solubilizer comprises propylene glycol and ethanol.Composition weight up to 90% is a secondary solubilizer.In some embodiments of the present invention, the weight of about 10-about 70% is secondary solubilizer.In a preferred embodiment of the invention, the content of this secondary solubilizer is about 60% weight of about 20%-.Correspondingly, preferred pharmaceutical compositions can comprise the propylene glycol of about 70% weight of about 10%-, the propylene glycol of about 60% weight of more preferably about 20-.Pharmaceutical composition of the present invention comprises the propylene glycol of about 40% weight in an especially preferred embodiment.

In an especially preferred embodiment, pharmaceutical composition of the present invention comprises the ethanol of about 50% weight of about 5-, the ethanol of more preferably about 10-30% weight.In the most preferred embodiment, pharmaceutical composition of the present invention comprises the ethanol of about 20% weight.

Several materials of confirming as carrier also are found to be effective secondary solubilizer, separately or with viscosity reduce the reagent associating all can, or contain other carriers.On the whole, any paclitaxel or other taxanes under body temperature or during slight fever appropriate at least therein dissolved solvent can be used as secondary solubilizer in this novel composition carrier.Preferred secondary solubilizer under about 20-25 ℃ wherein at least the paclitaxel of 25mg/ml or other taxanes soluble those.Comprise more than a kind of secondary solubilizer in embodiments more of the present invention.In some preferred embodiments, the present composition comprises at least two kinds of solubilizing agents.

Increase the part of taxane stability in this used term " stabilizing agent " expression.According to stabilizing agent of the present invention can be by reducing solvolysis speed (for example; at side chain that loses ester on the C-13 or the deacetylation on C-10) and/or with respect to taxane; make the surface isomerization of taxane molecule (for example, on C-7) turn into and make taxane stable.Can be (for example to the Stabilization of taxane according to the present invention by the one or more known degradation productses of minimizing by stabilizing agent; 7-table-paclitaxel (taxol) C; 10-deacetylation paclitaxel (taxol); 7-table-paclitaxel (taxol); 7-shows-10 deacetylations-paclitaxel (taxol); Baccatine III; 10-deacetylation baccatin III; cephalomannine; nitine; 7-table-cephalomannine) and determined (referring to; for example, J.Chromatography B 696:99-115 (1997) such as J.Org.Chem.46:1469-1474 (1981) such as Miller and Volk).In an especially preferred embodiment of the present invention, this stabilizing agent is ascorbic acid 6-palmitate (that is an ascorbyl palmitate).The slaine that other useful in the present invention stabilizing agents comprise acid is Alpha-hydroxy or beta-hydroxy acid, metal sulfate class (for example, FeSO4), metal alpha-hydroxymethyl sulfinate and metal sulfonate for example.These slaines are themes of by name " slaine stable based on the purposes in the compositions of taxane (Uses of Metal Salts to Stabilize Taxane-basedCompositions) " U.S. Patent application PCT/US01/09416 number of the usual application meanwhile of holding of applicant, are referred to herein as a reference.

Do not want to be fettered by any restriction special theory of the present invention, the applicant believes that some stabilizing agents can reduce the degraded of taxane by the formation that suppresses former subbase and/or by be formed on the synthetic that contains substituent on the taxane-skeleton between the oxygen of two neighboring pole.This new structure produces one " lock ", and it can be kept at original position with these chemical groups.The interaction of these substituent groups and surrounding medium is minimized, reduce the speed of solvolysis and/or deprotonation and so and degradation rate of reduction parent compound in those sites thus.Therefore, in some embodiments of the present invention, preferred stabilizer is former subbase inhibitor.Former subbase inhibitor is (referring to for example, Remington ' s Pharmaceutical Sciences, the same) well known in the art.The former subbase inhibitor packages of non-limiting representativeness according to the present invention is drawn together gluconic acid Fe, gluconic acid Cu ²⁺, gluconic acid Zn ²⁺, vitamin C a ²⁺, HOCH ₂SO ₂Na, ascorbyl palmitate, beta-carotene, methionine zinc and Chinese holly edge acid zinc.

Yet advised other preferred stabilizers of the applicant can additionally help to keep the color of this pharmaceutical composition.The example of such stabilizing agent has the d1-alpha-tocopherol, available from BASF (Mt.Olive, NJ).

The content range of the stabilizing agent in the present composition is preferably the 0.2%-about 1.0% of about composition total weight.Generally speaking, this scope is about 2.0% weight of about 0.05%-.Need to measure whether given material can be used as stabilizing agent is used for the object of the invention, if can, the amount that adds compositions the best determines by routine test.For example, make and contain the different taxane formulations that quantize compounds and suffer stress condition (for example, 80 ℃ 24 hours) and then analyze with HPLC.Said preparation and tester (not containing this chemical compound) are compared, and from the HPLC scattergram, calculate the percentage ratio of unaltered taxane.The chemical compound that reaches 97% taxane ratio is generally considered to be acceptable; Preferably reach the chemical compound of 98.5% ratio.Also can announce referring to above Miller and Volk.

Can comprise more than one type carrier, secondary solubilizer or stabilizing agent according to pharmaceutical composition of the present invention.In some embodiments, compositions of the present invention can be randomly and the supplementary element prescription, such as the description of doing at this more specifically for example surfactant, pharmaceutical excipient, diluent, sweeting agent, flavoring agent or coloring agent.Common pharmaceutical excipient, diluent, sweeting agent, flavoring agent, coloring agent and any other inert filler generally comprise and are being used for the dosage form of oral administration, this be known in the field (, the same) referring to Remington ' s PharmaceuticalSciences.

" surfactant " according to the present invention is the dispersion that can safeguard and/or promote hydrophobic compound in aqueous medium, has surface-active amphipathic part.Those skilled in the art it will be appreciated that the surfactant that suits in the present composition is well known in the art.Nonrestrictive representative surfactant comprises vitamin E (for example alpha-tocopherol) and bata-carotene.

Be used for distinguishing that the term " taxane " of diterpene part is sl. sol. at water.Comprise the part of separating from Pacific yew Codium fragile (Sur.) Har. tree (mountain mahogany genus) without limitation according to taxane of the present invention, its derivant, analog, metabolite and prodrug and other taxanes also are like this.This taxane is preferably selected from derivant, analog, metabolite and the prodrug by paclitaxel, Ramulus et folium taxi cuspidatae terpene, paclitaxel and Ramulus et folium taxi cuspidatae terpene, and the group of salt, polymorph and hydrate composition.This taxane more preferably comprises paclitaxel.In some embodiments of the present invention, comprised more than a kind of taxane as active component.

Taxane concentration in the present composition can determine according to selected carrier, secondary solubilizer and/or stabilizing agent and the mammiferous taxane accumulated dose of required oral administration.Can be the about 100mg/ml of about 2-according to the taxane concentration range in the pharmaceutical composition of the present invention, the about 60mg/ml of preferably about 6-, the more preferably from about about 50mg/ml of 10-.

The applicant finds that effectively the bioavailability reinforcing agent of oral dose is united the suitable taxane blood level of blood level that use can promote to reach and be reached by the intravenous injection taxane with compositions according to the present invention.As described below, the bioavailability reinforcing agent can be before present composition administration, simultaneously or be right after thereafter and use.Correspondingly, in certain preferred embodiments of the present invention, this pharmaceutical composition comprises the bioavailability reinforcing agent.

Term " bioavailability reinforcing agent " also can refer to " reinforcing agent " or " facilitating agent ", and it also is used to refer to and a kind ofly can promotes the absorption of other reagent or the reagent of bioavailability.Preferred bioavailability reinforcing agent comprises ciclosporin and the relevant oligopeptide that is produced by the Topycladium species, ketoconazole, dexverapamil, amiodarone, nifedipine, reserpine, quinidine, nicardipine, Ethacrynic, Propafenone, reserpine, amiloride, peptide, cefoperazone, tetracycline, chloroquine, fosfomycin, her Vitamycin, tamoxifen VX-710, VX-853, dye section's genitein and relevant osajin, calphotin, ceramide, morphine, the morphine congener, other opioids and opium sample antagonist.Ciclosporin is one group of nonpolarity cyclic oligopeptides (some of them have immunosuppressive activity), belong to generation by Topycladium, comprise, for example, Topycladium inflatum gams (being designated as trichoderma polysporum in the past), Topycladium terricola and other fungi impertectis.Main component, Ciclosporin A (Ciclosporin A or CsA) is identified with other several analog, for example, and ciclosporin B to Z, wherein some show the immunosuppressive activity more much lower than Ciclosporin A.Many synthetic and semisynthetic analog have been prepared.Usually can be referring to Jegorov etc., phytochemistry (Phytochemistry), 38:403-407 (1995).Present invention includes analog natural, semi-synthetic, synthetic ciclosporin, and derivant.Ciclosporin, especially Ciclosporin A, the inhibitor that is known P-glycoprotein efflux pump also is other carrier pumps, or the inhibitor of some P450 digestive enzyme, but at clinical and commercial viability or regulation and control permission, also do not develop this character is applied to clinical effective drug regimen up to now.

The ciclosporin that can be used in the preferred embodiment of the invention comprises; but be not limited to: Ciclosporin A is to Z; but especially be Ciclosporin A (ciclosporin); ciclosporin F, ciclosporin D, dihydro Ciclosporin A, dihydro ciclosporin C, acetyl Ciclosporin A, PSC-833, SDZ-NIM 811; it is (Me-Ile-4)-ciclosporin, is antiviral, non-inhibitive ability of immunity ciclosporin.Preferred ciclosporin compositions is to put down in writing in WO 98/10747 and WO 01/12229.Describe to some extent in the special amino acid variant table 1 below of definition Ciclosporin A-Z.

Table 1: the mould A-Z element of ring spore

?Cy	Aminoacid
												?CyA	?Mebmt	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
?CyB	?Mebmt	?Ala	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyC	?Mebmt	?Thr	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
?CyD	?Mebmt	?Val	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyE	?Mebmt	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Val
?CyF	?Desoxy-M ?ebmt	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyG	?Mebmt	?Nva	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
?CyH	?Mebmt	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?D-Mev
												?CyI	?Mebmt	?Val	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?Leu	?Meval
?CyK	?Desoxy-M ?ebmt	?Val	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyL	?Bmt	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
?CyM	?Mebmt	?Nva	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyN	?Mebmt	?Nva	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?Leu	?Meval
?CyO	?MeLeu	?Nva	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyP	?Bmt	?Thr	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
?CyQ	?Mebmt	?Abu	?Sar	?Val	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyR	?Mebmt	?Abu	?Sar	?MeLeu	?Val	?Leu	?Ala	?D-Ala	?MeLeu	?Leu	?Meval
?CyS	?Mebmt	?Thr	?Sar	?Val	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyT	?Mebmt	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?Leu	?Meval
?CyU	?Mebmt	?Abu	?Sar	?MeLeu	?Val	?Leu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyV	?Mebmt	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
?CyW	?Mebmt	?Thr	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Val
												?CyX	?Mebmt	?Nva	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?Leu	?MeLeu	?Meval
?CyY	?Mebmt	?Nva	?Sar	?MeLeu	?Val	?Leu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval
												?CyZ	?MeAmino ?octyl ?Acid	?Abu	?Sar	?MeLeu	?Val	?MeLeu	?Ala	?D-Ala	?MeLeu	?MeLeu	?Meval

The Cy=ciclosporin

In a preferred embodiment, the invention provides a kind of pharmaceutical composition of long-term stability, be used for comprising taxane, vitamin E TPGS, Polyethylene Glycol, ethanol and ascorbyl palmitate to oral the using of mammal.

A particularly preferred embodiment of the present invention comprises following composition:

Composition %w/v U/mL

Paclitaxel 1.20 12.0mg

Vitamin E TPGS (*) 40.00 400.00mg

Propylene glycol USP 40.00 400.00mg

Ascorbyl palmitate NF 0.50 5.0mg

D1-alpha-tocopherol USP 0.50 5.0mg

Dehydrated alcohol in right amount to 100mL in right amount to 1.0mL

(*) d-alpha-tocopherol cetomacrogol 1000 succinate

Another especially preferred embodiment of the present invention comprises following composition:

Composition weight (gram)

Paclitaxel 1.2

Vitamin E TPGS (*) 40.0

Propylene glycol 35.0

Ascorbyl palmitate 0.50

Vitamin E 0.50

Dehydrated alcohol ≈ 22.3 (28.1mL)

(*) d-alpha-tocopherol cetomacrogol 1000 succinate

In these embodiments, the content of propylene glycol is about 35-about 40% of composition total weight.

Compositions of the present invention can be comprised the liquid or the used conventional method preparation of other fluid flow port formulation of supporting surfactant and lipotropy active component by any preparation known to the technical staff in this pharmaceutical field.The suitable non-limiting representative method that is used to prepare the present composition for example comprises the experimental design of record in these embodiments.Because the great majority in the preferred vector at room temperature are heavy-gravity, and in some cases, even add a spot of secondary solubilizer, they also keep high relatively viscosity, so usually preparation during these compositionss preferred mixed carrier and secondary solubilizer with to be used, add the taxane active component, and stir with the mixture intensification of advancing to make gained, for example to 40 ℃.This method can make settled solution.Yet, some secondary solubilizer, especially PHARMASOLVE ^TMTo such an extent as to the dissolubility that but can reduce the viscosity of carrier to a certain extent and increase taxane can be under the situation that need not to heat at room temperature stirs the preparation said composition.The viscosity that it is desirable to this final compositions (is about 37 ℃) and is not higher than 40,000cps under body temperature.

Orally administered composition of the present invention can be the form of true solution, Emulsion or suspension, but the solution form of the active taxane composition in carrier or carrier/secondary solubilizer system is preferred.

The invention allows for the method that said composition is used for various purposes, these purposes include, but are not limited to treatment and use.Therefore, aspect second in, the invention provides the method that in mammalian body, reaches taxane target blood drug level by the aforementioned pharmaceutical compositions of Orally administered effective dose.These methods are suitable for providing and the suitable taxane target blood drug level of concentration that reaches by the intravenous administration taxane.Although some combination of oral medication among the present invention can provide target blood drug level when using separately, the treatment blood drug level that comprises paclitaxel, but the preferred method of the present invention is to use this combination of oral medication altogether with the oral administration biaavailability reinforcing agent of at least one dosage, because the taxane concentration that is reached subsequently is actually and is associated with the pharmacological activity of taxane.

According to this on the one hand useful pharmaceutical composition and the bioavailability reinforcing agent be in the first aspect present invention to be put down in writing those.

" target blood drug level " according to the present invention is to observe active especially necessary threshold concentration that the taxane sought with quilt is associated or the taxane haemoconcentration on it.Non-limiting representative instance comprises that tubulin decomposes inhibitory action, and it occurs under the blood drug level of about 0.1 μ M or about 85ng/ml, and albumen isoprenylation inhibitory action (it occurs under the blood drug level of about 0.03 μ M or about 25ng/ml).In addition, shown the phosphorlation that suppresses the blood vessel generation and suppress Bcl-2 in the cell such as the such taxane of paclitaxel.In these activity some (for example direct inhibition of oncogene function or the inhibitory action of transducing element) are directly related with the antitumorigenic character of taxane.Therefore, in especially preferred embodiments more of the present invention, target blood drug level is treatment blood drug level, can be observed special pharmacological activity under this concentration.Target blood drug level can change according to many variablees, for example, and uses medicine, the variation between the quilt intravital hepatitis state of mammal, albumin level and the different pharmaceutical preparation for the treatment of together.Target blood drug level can be determined by the conventional method opinion at an easy rate, for example progressively increases in the mammal bulk concentration at the monitoring paclitaxel and uses the present composition.

In certain preferred embodiments of the present invention, mammal wherein is to need a kind of drug regimen to suppress the people that tubulin decomposes, and target blood drug level (for example several hrs) in one period is at least about 0.1 μ M or about 85ng/ml.In certain preferred embodiments of the present invention, the people of mammal wherein for needing a kind of drug regimen to come the Profilin isoprenylation, target blood drug level is at least about 0.03 μ M or about 25ng/ml.Such target blood drug level comprises the blood drug level of the about 85ng/ml of about 25ng/ml-without limitation.

Aspect the 3rd, the invention provides a kind of method of studying the diterpene-kind compound physical property.More particularly, the invention provides the instrument that is used to study taxane biochemical property partly, this taxane partly is in vivo to mediate under not increasing toxic situation in the novel formulation that increases substantially of tissue distribution.This instrument that can expand the taxane volume of distribution, to make researcher can illustrate intravital various biochemical property, for example paclitaxel on the tubulin level and/or to microtubule-associated protein (MAPs) cross to express, the influence of the nucleation of microtubule assembling in cell division cycle progress and the various tissue.These researchs will cause one for the pharmacokinetics of differentiating the novel vital more fully paclitaxel of application and pharmacology's explanation and make the existing therapeutic outcome of further optimization become possibility.

At last, method and composition of the present invention can be used for taxane and replys in the treatment of diseases approach." taxane is replied disease " is to be used to refer to any state that comprises morbid state, and it can be improved by the pharmaceutical composition in this record of Orally administered effective dose.Generally speaking, it is to be characteristics with not controlled hyperplasia that taxane is replied disease, and it includes, but are not limited to xenogenesis disease, tumor, blood vessel generation, psoriasis and the POLYCYSTIC KIDNEY DISEASE of cancer.Same as above, the non-limiting representative example that taxane is replied disease comprises supervention sexual cell hypertrophy after cancer, tumor, Kaposi, malignant tumor, non-controlled tissue and the tissue damaged.The method according to this invention can be hepatocarcinoma and hepatic metastases, gastrointestinal tract, pancreas, prostate and pulmonary carcinoma and Kaposi by what partly effectively treat in the carcinoma of these types.According to the present invention, the non-cancer disease that can effectively be treated is that not controlled tissue or hyperplasia of supervention, POLYCYSTIC KIDNEY DISEASE, inflammatory diseases be (for example after the tissue damaged, arthritis) and malaria, comprise anti-chloroquine and the plasmodium of anti-pyrimethamine the (Pouvelle etc., the same).

Used herein reply the term " treatment " of disease and " processing " about taxane and be meant by changing taxane blood drug level and prevent and improve the symptom that on individuality, occurs.Can be understood that a kind of treatment not necessarily in full force and effect aspect the ward off disease generation or the related symptoms that eliminates a disease, also not necessarily requires a kind of treatment to cure a kind of disease for onset by the technical staff.Any reduction to symptom seriousness, delay paresthesia epilepsy or delay serious symptoms tempo all are considered.Being in the development taxane, to reply the factor that people in the danger of disease can any various proof disease possibility occurrences be that prophylactic treatment is accepted on the basis, this probability for example, family history, environment contact, genetic marker, early symptom etc.

Identical with discussion at other fermentation, although combination of oral medication more of the present invention can provide target blood drug level when using separately, the treatment blood drug level that comprises taxane is to use altogether with a kind of oral administration biaavailability reinforcing agent to contain for example Orally administered composition of paclitaxel of taxane but the present invention is used for the treatment of the mammiferous method for optimizing that suffers taxane to reply disease.Therefore, when a preferred embodiment of the inventive method is included in this oral administration or before or simultaneously and Orally administered before a kind of reinforcing agent, absorb quantity in the blood to increase taxane.This useful pharmaceutical composition and bioavailability reinforcing agent on the one hand of the present invention is those that put down in writing in the first aspect present invention.

In general, according to the present invention, the dosage range of the bioavailability reinforcing agent of using altogether with taxane is the about 20mg/kg of about 0.1-of weight in patients, is preferably the about 15mg/kg of about 3-of weight in patients, more preferably 5-10mg/kg." using altogether " of reinforcing agent comprised basically with taxane uses (before being less than 0.5 hour, be less than 0.5 hour after or) simultaneously, about 0.5-used taxane before about 72 hours, or two all, gave the different reinforcing agents of one or more dosage before promptly at least 0.5 hour, and give a dosage (or before or after being right after) basically simultaneously with target reagent.In addition, " use " taxane of using in 72 hours behind the reinforcing agent that is included in a dosage more than a dosage altogether, in other words, these one or more reinforcing agents before using taxane at every turn or not necessarily be applied once more simultaneously, but can use in the therapeutic process discontinuous.

" effective dose " is used for indicating pharmaceutical composition of the present invention to be enough to reach the known taxane amount of special taxane blood drug level.The dosage range of the Orally administered taxane in the present composition will change according to many factors, and they comprise concrete taxane, based on stage of therapeutic index, the needs of being treated disease, mammiferous age and state, the character of being treated disease, disease, and the other drug that uses of mammal etc.The pharmacology and the pharmacokinetics of taxane, especially paclitaxel and Ramulus et folium taxi cuspidatae terpene are known.Thereby can being used with the mammiferous urgent need of receiving treatment, its pharmacology's information optimizes dosage and administration time arrangement scheme.Thereby those skilled in the art it will be appreciated that is can (referring to Rowinsky, Oncology 11 (3): 7-19 (1997) for dosing and schedulingconsiderations) by constantly groping specifically to formulate the concrete dosage of said composition and demand that each patient is satisfied in the administration time arrangement and the reaction of monitored patient simultaneously.

Each exact amount that is included in taxane in the oral dosage form will change according to patient's age, body weight, disease and state.For example, thus paclitaxel or other taxane dosage forms can contain the target medicament of sufficient amount provides about 20-200mg/m as every day list or divided dose ²Dosage every day (based on this mammal/patient's body surface area) or about 0.5-30mg/kg (based on mammal/patient's body weight).Preferred dose quantity is about 50-200mg/m ²Thereby or behind the each oral dose of about 2-6mg/kg in the interval that prolongs (for example 8-12 hour) blood drug level of taxane is remained in the scope of 50-500ng/ml.(this is different from extreme inconvenience, discomfort, disappearance quality time, potential infectiousness of the patient that oral administration causes etc.) (Wilson etc., the J.Clin.Oncol.12:1621-1629 (1994)) that these concentration are equivalent at least that those 96 hours IV inculcate that the paclitaxel treatment method reaches.In addition, these paclitaxel blood drug level are higher than the amount that target medicine expection pharmacologically active enough is provided, these are active in for example, suppress tubulin and decompose and Profilin matter isoprenylation, they are regarded as rising the signal transducer of central action by known oncogene and inhibition and directly relevant with its antitumaous effect in cell cycle regulation.

Preferred oral paclitaxel dosage scheme provides about 20-1000mg/m for using 1-3 for (a) every day the patient that this needs are arranged ²(based on body surface area), preferably about 50-200mg/m ²Five equilibrium dosage, every 2-3 week administration every day sustained continuous 1-4 days, (b) about one day of administration week about, and (c) continue 2 or 3 week administrations every day was the time of having a rest in a week subsequently.Previous administration time arrangement is suitable with the usage of inculcating every 2-3 96-hour week paclitaxel, and this is thought preferred IV therapeutic scheme by some.

In an especially preferred embodiment of the present invention, the pharmaceutical composition of being used comprises about 60mg/m ²The paclitaxel of weight ratio.In another especially preferred embodiment, this pharmaceutical composition comprises about 180mg/m ²Weight ratio.

In the various aspects of the inventive method two or more different reinforcing agents and/or two or more different taxane target reagent can be simultaneously, replace or use off and on.

As discussed below, independent Orally administered paclitaxel (for example, with the solid preparation form or even not contain the liquid-carrier that oral absorption promotes carrier) shows and is close to zero bioavailability.The Orally administered present composition after effective oral dose of oral administration biaavailability reinforcing agent is used 1 hour, when the amount that absorbs the taxane in the blood is at least with the paclitaxel of the vein carrier intravenously administrable same dose of standard absorbed amount about 15%, this vein carrier for example has CREMOPHOR ^TMEL/ ethanol carrier.Can measure the relative percentage value of absorption by the standard method opinion in this area, for example by contrast AUC (be exactly the area plasma concentration-time graph under, be generally used for the absorption and the removing percentage value of the medicine measured behind/intravenously administrable oral in the pharmacokinetics) separately to quantize.High AUC just hinting the medicine of surveying can obtain probably to arrive target tissue or organ.This novel pharmaceutical combination thing can be used by any known drug dosage form.For example, said composition can be loaded in the hard gelatin capsule or form that can liquid preparation is used.

According to the present invention, the oral administration of taxane is compared with used IV therapy, can reduce toxic and side effects in fact as a rule.The absorption (by reinforcing agent promoted) of this active agent by intestinal do not produce as inculcates high rapidly suddenly blood drug level in the situation at IV usually, but a cumulative performance is provided in blood drug level.With oral administration comparable in immunocompromised host with inconvenient and have that the easier realization of method of risk of infection is long-time in an ideal range or near it to remain on these concentration stable, a lasting state at interval.

In a further embodiment of the present invention, can two parts system use Orally administered composition of the present invention (for example, regulate with the auxiliary composition of expection for example flavoring agent or coloring agent chemically or the use of inconsistent carrier physically).In this case, this taxane can be used as the medicine first in the solubilization carrier and is applied, it can as desired for sweeten, through seasoning or painted.Can use the liquid of more volumes after the using of taxane, for example 1-8 ounce fluid ounce (30-240ml) comprises at least a carrier or a kind of carrier/secondary solubilizer system according to the present invention.Have now found that, second " tracking " prescription of using after the taxane administration short time can delay the precipitation of taxane, and this precipitation may take place when entering gastric juice in other cases, also can promote oral absorption dramatically simultaneously, make it be equivalent to taxane is mixed with carrier and viewed absorption when using simultaneously.

The exemplary embodiment of " tracking " prescription can be used in the oral taxane medicine of two parts, and this comprises:

A) the vitamin E TPGS+ water of 2-20% (weight) is an amount of;

B) PHARMASOLVE of the vitamin E TPGS+2-25% of 2-25% ^TM+ water is an amount of; And

C) propylene glycol+water of the vitamin E TPGS+2-25% of 2-20% is an amount of.

According to another aspect of the present invention, Orally administered composition of the present invention not only comprises one or more taxanes in a combination dosage form, but also comprises one or more bioavailability reinforcing agents.For example, this combination dosage form can comprise one or more Ciclosporin As, D, C, F and the G of the about 20mg/kg of about 0.1-(based on patient's average weight), dihydro CsA, dihydro CsC and acetyl CsA, and the about 1000mg/m of about 20- ²(based on patient's average body surface area), preferably about 50-200mg/m ²Paclitaxel, Ramulus et folium taxi cuspidatae terpene, other taxanes or paclitaxel or Ramulus et folium taxi cuspidatae triterpene derivative.

Compare with the intravenous administration scheme with prior art, the compositions and methods of the invention provide lot of advantages (for example, better stability, whole palatability, the toxicity that is reduced owing to lower peak concentration, patient's facility and comfortableness, the convenience of administration and lower cost).In addition, the compositions and methods of the invention have also reduced the probability of the anaphylactic hypersensitivity that the IV administration sends out often dramatically, therefore, reduce or overcome the necessity (for example H-1 and H-2 blocker add steroidal) of premedication.Because well-known is that steroidal can cause diabetes, so the latter is especially relevant with diabetes cancer patient's treatment.

The invention provides with more frequent daily dose (for example, about twice/day) and/or according to administration time arrangement use for example paclitaxel of taxane, these arrangements of time in other cases by intravenous route may be impossible or unpractiaca.Even use the taxane more than a dosage in one day, it is also enough to use a kind of bioavailability reinforcing agent (for example, Ciclosporin A) once a day.Therefore, in order to keep this concentration in safely and effectively " window ", for example, paclitaxel can be as the single dose mixing administration in the fixedly administration time arrangement (two weeks etc. weekly) or in (for example, 4 days) long term administration in continuous several days of 2-4 week.

The following example is intended to further specify some limited embodiment of the present invention, is not determinate.Yet these embodiment do not limit the present invention in any way, and are not intended to propose special active ingredient, carrier, secondary solubilizer, reinforcing agent, dosage range, testing procedure or other parameters with enforcement the application of unique use yet.Therefore, use paclitaxel with the various aspects of setting forth taxane on the whole purely for illustration purpose, and should not be understood that to limit the present invention.

Only with routine test those skilled in the art just can discern maybe can determine many at the particular matter of this record and the equivalent of step.These equivalents are considered within the scope of the invention, and are also included by following claim.

Embodiment 1

The representative drugs preparation of compositions

Those of ordinary skills judge that at an easy rate many kinds of approach can be used for preparing representative compositions of the present invention.The easy degree that below only shows representative compositions preparation of the present invention.Preparation as prescription I and IA designated representative property compositions.

Prescription I

Component %w/v U/ml

Paclitaxel 1.20 12.0mg

Vitamin E TPGS (*) 40.00 400.00mg

Propylene glycol USP 40.00 400.00mg

Ascorbyl palmitate NF 0.50 5.0mg

D1-alpha-tocopherol USP 0.50 5.0mg

Dehydrated alcohol in right amount to 100ml in right amount to 100ml

Prescription IA

Component Weight (gram)

Paclitaxel 1.2

Vitamin E TPGS 40.0

Propylene glycol 35.0

Ascorbyl palmitate 0.5

Vitamin E 0.5

Dehydrated alcohol-22.3 (28.1ml)

(*) d-alpha-tocopherol cetomacrogol 1000 succinate

Paclitaxel (NaPro BioTherapeutics, Inc., Boulder with above-mentioned specified amount, CO), ascorbyl palmitate NF (Aldrich Chemical Co., Milwaukee WI) and d1-alpha-tocopherol USP (Roche Vitamins, Nutley, NJ) place the container of an appropriate volume, and it is scattered in dehydrated alcohol (FloridaDistillers Co., the Lake Alfred of 2/3 total amounts, FL) in, (1.0 or 100ml) as mentioned above.Close on when finishing to disperse the propylene glycol of adding appropriate amount and mixing at least 30 minutes.Add liquefaction vitamin E TPGS (d-alpha-tocopherol cetomacrogol 1000 succinate (EastmanChemical Co., Kingsport, TN)) (and with its be heated to separately about 50-60 ℃ or to its liquefaction).The dehydrated alcohol that adds surplus then, final preparation slowly cools to about 25-30 ℃ (room temperature).In case solution reaches room temperature,, form shallow yellow transparent solution constantly adjusting solution to final volume with ethanol under the stirring condition.

Embodiment 2

Stability analysis

As previously mentioned, the present composition advantage is their stability.Following experiment has shown the stability of the present composition.Observing ICH instructs mensuration according to describing the representative compositions for preparing among the embodiment 1.Use the Eppendorf pipette of suitable size and have the 28/400 Black Phenolic Cap of PolySeal Liner, the solution of 10.2-10.5ml is moved into single 15cc Brown Glass Brown glass bottles and jars only.Write down the gross weight of each bottle, gross weight and net weight.The upright bottle of placing under 40 ℃ and 75% humidity subsequently.Remove and respectively organize bottle, with method test well known in the art (that is, testing the existence of known catabolite at each time point as follows (two weeks and 1-6 month) afterwards) by HPLC.As shown in table 2 below, find that compositions is stable, and based on CREMOPHOREEL ^TMThe negative control prescription of (not providing data) is compared, as the chemical compound such as the 7-table-paclitaxel C of degradation of paclitaxel sign, and 10-deacetylation paclitaxel, or Baccatine III has shown minimum level (representing with total impurities percentage ratio).In addition, reach 6 months and cultivate after impurity be lower than 3.5% (not providing data).

Table 2: stability analysis

Catabolite	Initially	2 weeks	1 month	2 months	3 months	6 months
							7-table-paclitaxel C	Do not find	Do not find	Do not find	Do not find	Do not find	??0.11
10-deacetylation paclitaxel	Do not find	??0.04	??0.04	??0.11	??0.12	??0.04
							7-table-paclitaxel	??0.06	??0.07	??0.06	??0.06	??0.06	??0.16
7-table-10-deacetylation paclitaxel	??0.14	??0.15	??0.17	??0.15	??0.14	??0.21
							Baccatine III	Do not find	??0.07	??0.09	??0.13	??0.14	??0.18
10-deacetylation baccatin III	Do not find	??0.02	??0.02	??0.04	??0.02	??0.02
							7-table-cephalomannine	Do not find	Do not find	Do not find	Do not find	Do not find	??0.05

Embodiment 3

Dissolubility is analyzed

Estimate the paclitaxel dissolubility in the representative compositions of the present invention, will have the paclitaxel ultimate density by the method preparation of prescription I and be 12,15,25 and the preparation of 50mg/ml be diluted with water to 1: 11 ratio (1ml paclitaxel and 10ml water).Use the HPLC analytical method to measure solution then.As shown in Figure 1, in other all preparations except the 50mg/ml preparation, paclitaxel has retained at least two hours (therefore having shown enough dissolubility for a long time) in solution.Significantly, the preparation that contains 12-20mg/ml remains in the solution in the overall process of research.

Embodiment 4

Pharmacokinetic analysis

In mammal, use the compositions and methods of the invention to obtain taxane target blood drug level, comprise the blood drug level of therapeutic dose.Be this aspect of illustration the present invention, at first give a kind of synergist, as 5mg/kg Neoral  (Cyclosporin A to two groups of patients (totally five people), Novartis Pharmaceuticals, Inc., Summit, New Jersey), giving single dose after 30 minutes is 60mg/m ²(n=2) and 180mg/m ²(n=3) prescription 1 medicine of paclitaxel.Frequent a series of blood samples, the mensuration paclitaxel of extracting in 30-48 hour.Table 3 has shown the individuality and the average pharmacokinetic parameter of paclitaxel.These results show the C behind the use prescription 1 _MaxWith the AUC value a little more than using CREMOPHOR EL ^TMPrescription.Two kinds of dosage have all reached the blood drug level of therapeutic dose, and relatively under two kinds of dosage during the following area of plasma concentration versus time curve, the interior paclitaxel of body has had about 2 times growth.The latter shows that compositions of the present invention can provide in the blood plasma paclitaxel of enough levels, and with based on CREMOPHOR EL ^TMPreparation compare the ethanol of taking in less amount.

Table 3: pharmacokinetic parameter relatively

The patient	??C max(ng/ml)	??AUC?last(ng·hr/ml)	??AUC inf(ng·hr/ml)
				????1	?????189.3	?????????929	????????1025
????2	?????226.6	?????????1126	????????1208
				On average	?????207.9	?????????1029	????????1159.5
????SD	?????26.3	?????????137.2	????????146.4
				????CV	?????19.6	?????????22.3	????????21.2

Table 4 has shown the EL based on CREMOPHOR ^TMThe write out a prescription comparison of 1 (n=4) preparation medicine kinetic parameter of (poly-ethoxyquin Oleum Ricini)/alcoholic acid preparation (n=9) and the present invention.

Table 4: pharmacokinetic parameter is (C/E compares with prescription 1) relatively

	????C/E	Prescription 1 (AUC IV=CE value 50%)
			Apparent Sheng Wuliyongdu @60MG/m 2	????42％	???????????69.1％
???AUC∞-60mg/m 2	????1409(56)	???????????1159.5
			???AUC∞-180mg/m 2	????2844(70)	???????????2474
The AUC ratio	????2.0	???????????2.1

Embodiment 5

The palatability test

Corresponding to them CREMOPHOR ^TMEL (poly-ethoxyquin Oleum Ricini)/alcoholic acid preparation is compared, and another characteristic of the present composition is their palatabilities.Having undesirable with the preparation of traditional stabilizing agent preparation may be because the bitterness that Oleum Ricini causes.Whole part prescription 1 (40% Vitamin E.TPGS+40% propylene glycol+20% ethanol is referring to embodiment 1) and the 75%CREMOPHOR of 5ml for this reason ^TMEL+25% ethanol places (another medicine bottle that does not add preparation is as negative control) in 17 vials.(commerce can derive from International Flavor ﹠amp to the various aromatic of these 16 medicine bottles of adding as shown in table 5; Fragrances, Inc., Dayton, NJ; Crompton ﹠amp; Knowles, Charlotte, N.C.and Virginia Dave, Brooklyn, NY) as follows: Fructus Musae (0.5%), Fructus Pruni pseudocerasi (0.2 and 0.5%), Fructus Vitis viniferae (0.5%), Fructus Vitis viniferae correctives (grape maskant) (0.5%), Herba Menthae (0.2 and 0.5%), lavender (0.2 and 0.5%), draft Herba Menthae (0.2 and 0.5%), pharmasweet (0.1%), prosweet (1%), rainbow sherbet (0.5%), Citrullus vulgaris (0.5%) and teaberry (0.5%).Preparation mixes and blindly to give that the tester tastes and marking is bad for (-), and (+) can accept/and passable, (++) is good, or (+++) very good.Mark is marked on the lid of the two groups of sample medicine bottles (prescription 1 or the 75%Cremophor EL/25% ethanol that contain the distinct fragrance agent) that comprise placebo.Use dropper random extraction solution from bottle.Taste through two chemists, the result keeps the score

As shown in table 5, the more corresponding preparation of different preparations of prescription 1 is more agreeable to the taste.And, be that the preparation of aromatic is particularly splendid with the Fructus Musae.

Table 5: flavor tests

	Prescription I	75%+25% ethanol
			Blank *	????+**	????????-
Fructus Musae (0.5%)	????+++	????????+
			Fructus Pruni pseudocerasi (0.2%)	????++	????????+
Fructus Pruni pseudocerasi (0.5%)	????++	????????+
			Fructus Vitis viniferae (0.5%)	????++	????????+
Fructus Vitis viniferae correctives (0.5%)	????++	????????+
			Herba Menthae (0.2%)	????++	????????+
Herba Menthae (0.5%)	????++	????????+
			Lavender (0.2%)	????++	????????+
Lavender (0.5%)	????++	????????+
			Draft Herba Menthae aromatic (0.2%)	????++	????????+
Draft Herba Menthae aromatic (0.5%)	????++	????????+
			Pharmasweet aromatic (0.1%)	????++	????????+
?Prosweet(1％)	????++	????????+
			Rainbow sherbet (0.5%)	????++	????????+
Citrullus vulgaris (0.5%)	????++	????????+
			Teaberry aromatic (0.5%)	????++	????????+

* do not add aromatic; Next column: * * ,-, bad ,+, it is acceptable/passable, ++, good, +++, outstanding

Embodiment 6

Relatively absorb test

The purpose of following experiment is to illustrate that representational compositions of the present invention and method have produced the higher absorption value that is observed than in the prior art IV method.Be one group with three male rats for this reason, giving ³The paclitaxel of H radioelement labelling is before with its fasting 16-18 hour.Before comprising the representative drugs compositions of the present invention of paclitaxel, make every treated animal accept the Ciclosporin A of oral dose (5mg/kg).After the ciclosporin administration one hour, make the paclitaxel in the present composition of every group of about 9mg/kg of oral acceptance.Every winding is subjected to different formula of oral.The blood sample of collecting every animal kind in 0.5,1,2,3,4,6,8,12 and 24 hours after dose of paclitaxel.Consume and measure the gross activity intensity of blood sample.Will with respect to the total blood radioactive intensity level behind the time dosage (corresponding to ³The blood level of H-paclitaxel) is plotted on the back time diagram of taking medicine.With average A UC, C _MaxAnd T _MaxThe collect data of every group of rat of form.By more every group average A UC value and accordingly to comprise CREMOPHOR ^TMEL, the PAXENE of ethanol and citric acid ^TM(Baker Norton Pharmaceuticals, Miami FL) form intravenously administrable ³The average A UC value of the reference group rat of H-paclitaxel (9mg/kg) is calculated every treated animal ³The percentage trap of H-paclitaxel.As shown in table 6, have now found that, compare with IV paclitaxel (not providing data), joined some carriers in the Orally administered composition that contains paclitaxel of the present invention and carrier/secondary solubilizer combination results 15% or higher percentage trap value by prescription.

Table 6: surpass carrier and carrier/secondary solubilizer conjugate that 15% paclitaxel absorbs

Carrier	Secondary solubilizer
								??TPGS	??Pharma- ??solve	Propylene glycol	??Mygliols	??Softigen	??PEG200&400	Propylene glycol/Pharma-solve	??PEG200&400 ??/Pharma- ??solve
??Gelucire ??44/14	??Pharma- ??solve	??Mygliols	Olive oil/Brij 97	Olive oil/Cremophor RH 40	Olive oil/TPGS	??Cremophor ??EL	??Cremophor ??RH?40
								??Gelucire ??44/14	??Labrasol	??TPGS/ ??Solutol ??HS?15	Tween 80	??PEG400
??Gelucire ??50/13	Tween 80	??PEG400	??Cremophor ??EL
								??Cremophor ??EL	??Pharma- ??solve	Citrate	??EtOH/H 2O	??EtOH
??Cremophor ??RH?40	??EtOH/ ??H 2O
								??Myrj?49	??Pharma- ??solve
??Myrj?52	??Pharma- ??solve	Propylene glycol
								??Myrj?53	??Pharma- ??solve
Polysorbate40 *
								Polysorbate60 *
Tween 80 *	??EtOH	Citrate	Olive oil	??PEG400	??H 2O
								??Crillet?6 *
??Emsorb ??2726	??Pharma- ??solve
								??Solutol ??HS ??15 *
??Brij?76	??Pharma- ??solve
								??Brij?78	??Pharma- ??solve
??Brij?98	??Pharma- ??solve
								??Crovol ??A40 *
??Crovol ??M40 *
								Cyclodextrin	??H 2O

^*Be proved and had solubilizing agent and two kinds of effects of carrier

Explain: all carriers listed above can surpass the paclitaxel of 25mg/ml 37 ℃ of dissolvings

Embodiment 7

Carrier is estimated

After this experiment of Miao Shuing understands that for example the representative Orally administered composition of oral different carriers configuration has the high ability of absorbance than its IV homologue separately.

Polyoxy ethylating (POE) sorbitan aliphatic ester is as carrier

Table 7 listed comprise certain POE sorbitan aliphatic ester separately or together solubilizing agent share prescription as carrier.There is more than one composition in the prescription and provided the weight ratio of each composition.Each prescription is tested in aforesaid animal model, and finds that the absorbance of paclitaxel has improved 15% when oral.Listed in the table and the actual accumulated dose that gives experimental animal of various carrier-bound paclitaxels, the concentration of paclitaxel in the compositions, the HLB value of carrier, accept preparation rat group average A UC value and compare the ratio of paclitaxel absorption with the rat of accepting the IV administration.

Table 7: polyoxy ethylization (POE) sorbitan

The fatty acid ester surfactant is as the absorption result of carrier

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	????HLB	????AUC ????μg. ??Eqxhr/ml	???％ABS *
						POE 20 sorbitan mono laurate salt (polysorbas20)	?????10.2	?????18	????16.7	????17.2	????54.6
POE 20 sorbitan list palmitates (polysorbate40)	?????10.2	?????18	????15.6	????17.6	????55.9
						POE 20 sorbitan Monostearates (polysorbate40)	?????8.9	?????25	????14.9	????17.1	????62.3
POE 20 sorbitans, three stearate (polysorbate65)	?????9.4	?????25	????10.5	????6.15	????21.1
						POE 20 sorbitan list oleates (Tween 80)	?????9.0	?????18	????15.0	????11.4	????40.9
POE 20 sorbitan list isostearates (Crillet 6)	?????9.3	?????20	????14.9	????13.6	????47.5
						POE 40 sorbitans two isostearates/Pharmasolve (3: 1) [Emsorb 2726]	?????10.2	?????25	????15.0*	????7.76	????24.6

* with respect to the percentage trap of paclitaxel IV AUC (4-11 is identical with table)

The POE alkyl ether is as carrier

Table 8 has been summarized and has been contained the formulation data of POE alkyl ether as carrier.The data of listing are corresponding with the data of preceding table.

Table 8: polyoxy ethylization (POE) alkyl ether surface active agent is as the absorption result of carrier

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	????HLB	????AUC ????μg. ??Eqxhr/ml	???％ABS
						POE
20 stearates/Pharmasolye (3: 1) [Myrj 49]	?????9.2	?????25	????15.0*	????10.3	????36.4
						POE 40 stearates/Pharmasolve (3: 1) [Myrj 52]	?????9.4	?????18	????16.9*	????16.2	????57.3
POE 20 stearates/Pharmasolve (3: 1) [Myrj 53]	?????10.0	?????25	????17.9*	????7.01	????22.3

* the actual HLB value that does not have mixture.The pure surfactant HLB of data representation value

The POE stearate is as carrier

Table 9 has been summarized and has been contained the formulation data of POE stearate as carrier.The data of listing are corresponding with the data of description among the embodiment 7.

Table 9: polyoxy ethylization (POE) stearate is as the absorption result of carrier

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	????HLB	????AUC ????μg. ??Eqxhr/ml	???％ABS
						POE
20 stearates/Pharmasolve (3: 1) [Myrj 49]	?????9.2	?????25	????15.0*	????10.3	????36.4
						POE 40 stearates/Pharmasolve (3: 1) [Myrj 52]	?????9.4	?????18	????16.9*	????16.2	????57.3
POE 20 stearates/Pharmasolve (3: 1) [Myrj 53]	?????10.0	?????25	????17.9*	????7.01	????22.3

* the actual HLB value that does not have mixture.The pure surfactant HLB of data representation value

Ethoxylation modified glycerol three esters are as carrier

Table 10 has been summarized and has been contained the formulation data of ethoxylation modified glycerol three esters as carrier.The data of listing are corresponding with the data of description among the embodiment 7.

Table 10: ethoxylation modified glycerol three esters are as the absorption result of carrier

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	???HLB	???AUC ???μg. ?Eqxhr/ml	???％ABS
						PEG-20 Semen Armeniacae Amarum glyceride (Crovol A-40)	?????9.5	??????20	???10	???8.06	???27.6
PEG-20 corn glyceride (Crovol M-40)	?????9.6	??????20	???10	???7.46	???25.3

The hard acid ester salt of POE 660 hydroxyls is as carrier

Table 11 has been summarized and has been contained the formulation data of the hard acid ester salt of POE 660 hydroxyls as carrier.The data of listing are corresponding with the data of description among the embodiment 7.

Table 11: the hard acid ester salt of polyoxy ethylization (POE) 660 hydroxyls is as the absorption result of carrier

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	???HLB	????AUC ????μg. ??Eqxhr/ml	???％ABS
						The hard acid ester salt of POE 660 hydroxyls (Solutol HS 15)	????9.1	?????25	???～14	????10.8	????38.4
?Gelucire?44/14+?Solutol ?HS+TPGS(2∶1∶1)	????9.3	?????25	???～14	????6.54	????22.8

The saturated glyceride of handling through Polyethylene Glycol is as carrier

Table 12 has been summarized and has been contained the formulation data of the saturated glyceride of handling through Polyethylene Glycol as carrier.The data of listing are corresponding with the data of description among the embodiment 7.

Table 12: the saturated glyceride of handling through Polyethylene Glycol is as the absorption result of carrier

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	????AUC ????μg. ??Eqxhr/ml	??％ABS
					??Gelucire?44/14+PEG400(6∶1)	?????10.3	??????25	????11.9	???37.4
??Gelucire?44/14+Labrasol(6∶1)	?????9.3	??????25	????12.1	???42.1
					??Gelucire?44/14+Mygliol?810(6∶1)	?????8.7	??????25	????4.75	???17.6
??Gelucire?44/14+Mygliol?818(6∶1)	?????10.3	??????25	????8.45	???26.6
					??Gelucire?44/14+Mygliol?840(6∶1)	?????9.5	??????25	????6.48	???22.0
??Gelucire?44/14+Cremophore?RH?40(6∶1)	?????9.5	??????25	????10.7	???36.6
					??Gelucire?44/14+Cremophor?EL(6∶1)	?????9.8	??????25	????11.5	???38.1
??Gelucire?44/14+ ??Solutol?HS+TPGS(2∶1∶1)	?????9.3	??????25	????6.54	???22.8
					Gelucire 44/14+ olive oil+Tween 80 (2: 1: 1)	?????9.6	??????20	????11.9	???39.9
Gelucire 44/14+ olive oil+TPGS (2: 1: 1)	?????9.6	??????20	????9.83	???33.2
					Gelucire 44/14+ olive oil+POE 10 Oleyl (2: 1: 1)	?????9.6	??????20	????9.07	???30.6
Gelucire 44/14+ olive oil+Cremophor RH 40 (2: 1: 1)	?????9.1	??????20	????7.73	???27.5
					Gelucire 44/14+ Tween 80 (6: 1)	?????9.7	??????25	????10.05	???33.5
Gelucire 50/13+ Tween 80 (5: 2)	?????9.4	??????25	????8.21	???28.4
					??Gelucire?50/13+PEG400(6∶1)	?????9.3	??????25	????6.46	???22.5
??Gelucire?50/13+Cremophor?EL(6∶1)	?????9.1	??????25	????8.11	???28.9

Labrasol: saturated C8-C10 glyceride (HLB=14) through the Polyethylene Glycol processing

Mygliols: neutral oil (saturated Cortex cocois radicis and Petiolus Trachycarpi nuclear fatty acid) is mainly the C8-nC10 fatty acid

Cremophor EL:Polyoxyl 35 Oleum Ricini (HLB 12-14)

Cremophor RH 40:Polyoxyl 40 castor oil hydrogenated (HLB 14-16)

Vitamin E TPGS system is as carrier

Table 13 has been summarized and has been contained the formulation data of vitamin E TPGS system as carrier.The data of listing are corresponding with the data of description among the embodiment 7.

Table 13:TPGS system is as the absorption result of carrier

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	???AUC ???μg. ?Eqxhr/ml	????％ABS
					?TPGS+Pharmasolve(1.5∶1)	?????8.2	??????25	???8.93	????35.2
?TPGS+Pharmasolve(1∶1)	?????9.5	??????25	???8.72	????29.8
					?TPGS+Pharmasolve(2∶1)	?????9.1	??????25	???8.83	????31.4
TPGS+ propylene glycol (1: 1)	?????8.5	??????20	???9.65	????36.9
					?TPGS+Pharmasolve+PEG200(2∶1∶1)	?????9.0	??????25	???8.31	????29.8
?TPGS+Pharmasolve+PEG400(2∶1∶1)	?????8.2	??????25	???6.62	????26.3
					?TPGS+Pharmasolve+PG(2∶1∶1)	?????8.9	??????25	???8.07	????29.3
?TPGS+Mygliol?810(1∶1)	?????9.1	??????25	???5.65	????20.0
					?TPGS+Softigen?767(1∶1)	?????10.2	??????25	???8.66	????27.5
?TPGS+PEG200(1∶1)	?????8.3	??????25	???7.75	????30.4
					?TPGS+PEG400(1∶1)	?????9.6	??????25	???7.32	????24.6

Softigen 767:PEG-6-caprylic/capric glyceride

POE and castor oil hydrogenated derivant are as carrier

Table 14 has been summarized and has been contained POE and the castor oil hydrogenated derivant formulation data as carrier.The data of listing are corresponding with the data of description among the embodiment 7.

Table 14: the absorption result of carrier is in polyoxyethylenated castor oil (Cremophor) derivant system

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	????AUC ????μg. ??Eqxhr/ml	???％ABS
					?IV?Panexe	?????10.0	??????6	????11.15	???37.2
Cremophor EL+ ethanol+water (1: 1: 8)	?????9.2	??????1.3	????6.07	???21.5
					IV Panexe+ water (1: 1)	?????8.9	??????3	????8.70	???31.8
IV Panexe+ water (1: 5)	?????9.1	??????1	????10.76	???38.5
					?Cremophor?EL+Pharmasolve(1∶1)	?????8.6	??????20	????6.74	???25.3
?Cremophor?EL+TBC(1∶1)	?????9.0	??????20	????9.35	???31.9
					?Cremophor?EL+Gelucire44/14(1∶6)	?????9.8	??????25	????11.5	???38.1
?Cremophor?EL+Gelucire50/13(1∶6)	?????9.1	??????25	????8.11	???28.9
					Cremophor RH 40+ ethanol+water (1: 1: 2)	?????9.0	??????3	????7.14	???25.7
?Cremophor?RH?40+Gelucire44/14(1∶6)	?????9.5	??????25	????10.7	???36.6
					Cremophor RH 40+ ethanol+olive oil (1: 2: 1)	?????9.1	??????20	????7.73	???27.5

The polyoxyethylene sorbitan monoleate carrier

Table 15 has been summarized and has been contained the formulation data of polyoxyethylene sorbitan monoleate as at least a carrier.The data of listing are corresponding with the data of description among the embodiment 7.

Table 15: the absorption result of carrier is in polyoxyethylene sorbitan monoleate (Tween 80) system

Prescription	Dosage [mg/kg]	Concentration [mg/ml]	????AUC ????μg. ??Eqxhr/ml	????％ABS
					Polyoxyethylene sorbitan monoleate	????9.0	??????18	????11.4	????40.9
Polyoxyethylene sorbitan monoleate+ethanol+water (1: 1: 8)	????8.0	??????1.2	????7.92	????31.2
					Polyoxyethylene sorbitan monoleate+ethanol (3: 1)	????8.9	??????18	????9.97	????36.3
Polyoxyethylene sorbitan monoleate+water (3: 1)	????8.2	??????18	????7.15	????28.3
					Polyoxyethylene sorbitan monoleate+TBC (1: 1)	????9.5	??????20	????9.12	????31.2
Polyoxyethylene sorbitan monoleate+ATEC (1: 1)	????9.1	??????20	????8.50	????30.3
					Polyoxyethylene sorbitan monoleate+olive oil (3: 1)	????9.0	??????20	????13.3	????43.7
Polyoxyethylene sorbitan monoleate+PEG400 (1: 1)	????9.7	??????20	????9.41	????31.5
					Polyoxyethylene sorbitan monoleate+Gelucire44/14+ olive oil (1: 2: 1)	????9.6	??????20	????11.9	????39.9
Polyoxyethylene sorbitan monoleate+Gelucire44/14 (1: 6)	????9.7	??????25	????10.05	????33.5

TBC=tributyl citrate (citrate)

ATEC=acetyl triethyl citrate (citrate)

Therefore the compositions and the method that can realize various objectives of the present invention and be applicable to practical situations preferably that provide also be provided.Because various possible embodiments can be made of above-mentioned invention, and various variation can carry out in embodiment set forth above, is appreciated that all the elements described herein may be interpreted as illustrative and nonrestrictive.

Terminology used here " approximately " means numerical value disclosed herein and scope is variable, and uses and to go beyond the scope or the temperature different with single numerical value, concentration, and quantity etc., practice of the present invention also can achieve the desired result.This term comprises that typically the numerical value of its modification has ± 10% deviation.

The present invention is useful clinical medicine, is used for the treatment of pernicious and nonmalignant disease especially.

Claims (21)

1. compositions, comprise and a kind of taxane, a kind of carrier that comprises vitamin E TPGS, a kind of comprising account for composition weight at least about 5% the ethanol and secondary solubilizer and a kind of stabilizing agent of propylene glycol, wherein said compositions is the form that is suitable for the mammal oral administration.

2. the compositions in the claim 1, wherein said taxane is paclitaxel or Ramulus et folium taxi cuspidatae terpene.

3. the compositions in the claim 1, the concentration of wherein said taxane is the about 100mg/ml of about 2-.

4. the compositions in the claim 3, the concentration of wherein said taxane is the about 50mg/ml of about 10-.

5. the compositions in the claim 1, wherein said carrier comprise that further saturated poly-dihydric alcohol separates glyceride, modified castor oil, polyoxy ethylization stearate, polyoxy ethylization sorbitol ester, polyoxy ethylization aliphatic ether, modification Semen Armeniacae Amarum and Semen Maydis oil glyceride, two isostearic acid sorbitol esters, polyoxy ethylization hydroxy stearic acid ester and cyclodextrin.

6. the compositions in the claim 1, ethanol wherein are for dehydration.

7. the compositions in the claim 1 further comprises a kind of surfactant.

8. the compositions in the claim 7, wherein said surfactant is dl-alpha-tocopherol or beta-carotene.

9. the compositions in the claim 8 comprises the dl-alpha-tocopherol of about 2mg/g (0.2%)-Yue 10mg/g (1.0%) weight.

10. the compositions in the claim 1, wherein said stabilizing agent is an ascorbyl palmitate.

11. the compositions in the claim 1, stabilizing agent wherein are the dl-alpha-tocopherols.

12. the compositions in the claim 1, stabilizing agent wherein is a free radical inhibitors.

13. the compositions in the claim 1 further comprises a kind of pharmaceutical excipient, diluent, sweeting agent, flavoring agent and/or coloring agent.

14. the compositions in the claim 1 further comprises a kind of bioavailability reinforcing agent.

15. the compositions in the claim 14, wherein said bioavailability reinforcing agent is a ciclosporin.

16. the compositions in the claim 1, wherein said ethanol dewaters.

17. the compositions in the claim 1, the content of wherein said polypropylene glycol is about 40% weight of about 35-.

18. the compositions in the claim 1, wherein said taxane comprises paclitaxel, its content is about 1.2% of described composition weight, wherein said vitamin E TPGS content is about 40% of described composition weight, wherein said alcoholic acid content is about 18% of described composition weight, described content of propylene glycol in this described compositions is about 40% weight, described stabilizing agent comprises ascorbyl palmitate, content is about 0.5% weight, wherein said compositions further comprises the dl-alpha-tocopherol, and its content is about 0.5% weight.

19. the compositions in the claim 1, wherein said taxane comprises paclitaxel, its content is about 1.2% of described composition weight, wherein said vitamin E TPGS content is about 40% of described composition weight, wherein said alcoholic acid content is about 22% of described composition weight, described content of propylene glycol in this described compositions is about 35% weight, described stabilizing agent comprises ascorbyl palmitate, content is about 0.5% weight, wherein said compositions further comprises the dl-alpha-tocopherol, and its content is about 0.5% weight.

20. method that in mammalian body, reaches taxane target blood drug level, comprise the Orally administered a kind of pharmaceutical composition of described mammal, its comprise a kind of taxane, a kind of carrier that comprises vitamin E TPGS, a kind of comprise account for composition weight at least about 5% the ethanol and secondary solubilizer and a kind of stabilizing agent of propylene glycol.

21. a treatment suffers taxane to reply the method for the mammalian subject of disease, comprise step to the Orally administered a kind of pharmaceutical composition of described mammal, said composition comprise a kind of taxane, a kind of carrier that comprises vitamin E TPGS, a kind of comprise account for composition weight at least about 5% the ethanol and secondary solubilizer and a kind of stabilizing agent of propylene glycol.

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