Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to pharmaceutical compositions comprising, in combination, an antitumor agent selected from an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, and a pharmaceutical agent that remarkably enhances the antitumor effect and methods of using such agents.
• an antitumor agent selected from an antitumor agent that forms a cross-link with DNA and shows an antitumor effect
• an antimetabolite antitumor agent and a taxane antitumor agent a pharmaceutical agent that remarkably enhances the antitumor effect and methods of using such agents.
• This combination therapy aims at alleviating side effects and enhancing antitumor action by combining antitumor agents having different action mechanisms, thereby to 1) decrease insensitive cell population, 2) prevent or delay development of drug resistance, 3) disperse toxicity by a combination of pharmaceutical agents with different toxicities and the like.
• random combinations of pharmaceutical agents with different action mechanisms for a combination therapy do not necessarily provide an antitumor effect-enhancing action or synerg .
• HDAC histone deacetylase
• Histone deacetylase inhibitors are also known as a potent anticancer agent (see JP-B-7-64872 , Experimental Cell Research, US (1998) , vol . 241 , pp . 126-133 ) .
• a compound represented by the formula (I) is also known as a potent anticancer agent.
• FK2278 or a pharmaceutically acceptable salt thereof are histone deacetylase inhibitors and reported to show a potent antitumor activity (see JP-B-7-64872 (corresponding to US Patent No. 4977138) , Experimental Cell Research, US (1998), vol. 241, pp. 126-133) .
• an antitumor agent comprising, in combination, an antitumor agent selected from an antitumor agent that forms a cross-link with DNA and shows, an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, and a pharmaceutical agent that remarkably enhances the antitumor effect, which reduces side effects and exhibits a superior antitumor activity.
• a histone deacetylase inhibitor particularly compound A known to have a potent histone deacetylase inhibitory activity, also remarkably enhances the antitumor effect of known antitumor agents : an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, which resulted in the completion of the present invention. Accordingly, the present invention provides the following.
• An antitumor agent and pharmaceutical compositions comprising, in combination, at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, and a histone deacetylase inhibitor and methods of treating patients comprising administering such compositions and agents.
• an antitumor agent according to the above-mentioned [1] , wherein the histone deacetylase inhibitor is a compound represented by the formula (I)
• the antitumor agent according to the above-mentioned [2] wherein the antitumor agent that forms a cross-link with DNA and shows an antitumor effect is a platinum compound antitumor agent or an alkylating antitumor agent.
• the an"titumor agent according to the above-mentioned [3] wherein the platinum compound antitumor agent is cisplatin.
• the antimetabolite antitumor agent is 5-fluorouracil .
• the antitumor agent according to the above-mentioned [2] wherein the taxane antitumor agent is at least one of paclitaxel and docetaxel.
• the enhancer according to the above-mentioned [8] wherein the histone deacetylase inhibitor is a compound represented by the formula (I)
• the enhancer according to the above-mentioned [9] wherein the antitumor agent that forms a cross-link with DNA and shows an antitumor effect is a platinum compound antitumor agent or an alkylating antitumor agent.
• the platinum compound antitumor agent is cisplatin.
• the enhancer according to any of the above-mentioned [8] to [13] which is an antitumor effect enhancer for lung cancer, malignant lymphoma, cancer of digestive organ, breast cancer, ovarian cancer, musculoskeletal sarcoma, bladder cancer, leukemia, kidney cancer or prostate cancer.
• a commercial package comprising a concomitant agent comprising at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a crosslink with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, and a written matter associated therewith, the written matter stating that the concomitant agent can or should be used as an antitumor agent with a histone deacetylase inhibitors.
• a commercial package comprising a preparation containing a histone deacetylase inhibitor and a written matter associated therewith, the written matter stating that the preparation can or should be used for enhancing an antitumor effect of at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a crosslink with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent.
• the histone deacetylase inhibitor is a compound represented by the formula (I)
• Fig. 1 is a graph showing the concept of the analysis.
• Fig. 2 is a graph showing the analysis of isobologram of combined use (simultaneous addition) of FK228 and cisplatin on DU-145 cells (Example 1) .
• Fig. 5 is a graph showing the analysis of isobologram of combined use (simultaneous addition) of FK228 and 5- fluorouracil on DU-145 cells (Example 3) .
• Histone deacetylase inhibitors remarkably enhance the antitumor effect of an antitumor agent (particularly platinum compound antitumor agent or alkylating antitumor agent) that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent or a taxane antitumor agent.
• the antitumor agent of the present invention comprising, in combination, at least one kind of antitumor agent selected from an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, and a histone deacetylase inhibitor affords a higher therapeutic effect against cancer at a smaller dose as compared to the administration of a single antitumor agent selected from an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, or a histone deacetylase inhibitor, and can suppress side effects to a lower level.
• the histone deacetylase inhibitor to be used in the present invention is a compound that binds to an active site of histone deacetylase competitively with substrates and/or shows an effect of decreasing the enzyme activity of histone deacetylase or otherwise inhibits enzyme activity and includes compounds known as histone deacetylase inhibitors.
• the aforementioned compound A, a salt thereof and a derivative thereof e.g., acetylated compound A, thiol form with reduced S-S bond etc. described in WO 02/06307) can be mentioned.
• Analogs of FK228 are described in US Patent No. 6403555.
• Trichostatin A sodium butyrate, suberoylanilide hydroxamic acid (SAHA) , MS-275, cyclic hydroxamic-acid-containing peptide, Apicidin, Trapoxin and the like are the compounds reported to have a histone deacetylase inhibitory activity.
• the histone deacetylase inhibitor may be one compound or a mixture of two or more compounds .
• compound A is preferably used as the histone deacetylase inhibitor.
• compound A may have a stereoisomer (e.g., FK228) based on an asymmetric carbon atom or a double bond, such as an optically active form, a geometric isomer and the like, all these isomers and mixtures thereof are also encompassed in the scope of compound A.
• solvates e.g., inclusion compounds (e.g., hydrates etc.)
• anhydrous forms and other polymorphic forms or pharmaceutically acceptable salts of the compounds described herein are also encompassed in the scope of the present invention.
• a mere reference to compound A means a compound group including FK228 and a pharmaceutically acceptable salt, irrespective of the stereoisomerism.
• the histone deacetylase inhibitors recited above include known and available substances.
• FK228, which is one of the stereoisomers of compound A can be obtained by culturing a strain belonging to the genus Chromobacterium , which is capable of producing FK228, under aerobic conditions, and harvesting the substance from its culture broth.
• the strain belonging to the genus Chromobacterium which is capable of producing FK228, for example, Chromobacterium violaceum WB968 (FERM BP-1968) can be mentioned.
• FK228 can be obtained from a FK228-producing strain as described in JP-B-7-64872 (corresponding to US Patent No. 4977138) .
• FK228 is preferably harvested from a strain belonging to the genus Chromojacteriu/n, which is capable of producing FK228, because it can be obtained more easily.
• Synthetic or semi-synthetic FK228 is also advantageous in that further purification step is not necessary or the number of steps can be reduced.
• compounds A other than FK228 can be also obtained by semi-synthesis or total synthesis by conventionally known methods. To be more specific, it can be produced according to the method reported by Khan W. Li,, et al.. (J. Am. Chem. Soc. , Vol. 118, 7237-7238(1996)).
• a pharmaceutically acceptable salt of compound A includes salts with a base or an acid addition salt such as salts with inorganic base (e.g., alkali metal salts such as sodium salt, potassium salt etc. , alkaline earth metal salts such as calcium salt, magnesium salt etc.
• organic base e.g., organic amine salts such as triethylamine salt, diisopropylethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt etc.
• organic acid addition salts e.g., hydrochloride, hydrobromide , sulfate, phosphate etc.
• organic carboxylic acid or sulfonic acid addition salts e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate etc.
• salts with a basic or acidic amino acid e.g., arginine, aspartic acid, glutamic acid etc.
• the antitumor agent that forms a cross-link with DNA and shows an antitumor effect to be used in the present invention may be any antitumor agent as long as it directly acts on DNA and forms a cross-link therewith to show an antitumor effect.
• antitumor agent examples thereof include known platinum compound antitumor agents, known alkylating antitumor agent and the like.
• the antitumor agent that forms a cross-link with DNA and shows an antitumor effect may be one kind of compound or two or more kinds of compounds in a mixture.
• the antimetabolite antitumor agent to be used in the present invention may be any antimetabolite known as an antitumor agent. Specific examples include 5-fluorouracil, tegaful and the like.
• the antimetabolite antitumor agent may be one kind of compound or two or more kinds of compounds in a mixture .
• the taxane antitumor agent used in the present invention includes various components or semisynthetic products thereof having, in the structure, a taxane skeleton isolated from Taxusbrevifolia or pure synthetic products having a taxane skeleton. Specifically, paclitaxel, docetaxel and the like can be mentioned.
• the taxane antitumor agent may be one kind of compound or two or more kinds of compounds in a mixture.
• the histone deacetylase inhibitor particularly compound A remarkably enhances at least one kind of antitumor agent selected from an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent.
• the antitumor agent and the antitumor effect enhancer of the present invention are useful as therapeutic agents for cancerous diseases including blood cancer, solid tumor etc. ; more specifically, lung cancer, malignant lymphoma (e.g., reticulosarcoma, lymphosarcoma,
• cancer of digestive organ e.g., gastric cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer etc.
• breast cancer ovarian cancer
• musculoskeletal sarcoma e.g., osteosarcoma etc.
• bladder cancer leukemia (e.g., acute leukemia including blast crisis of chronic myeloid leukemia etc.)
• kidney cancer prostate cancer and the like.
• the at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a crosslink with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent may be one kind of compound or two or more compounds administered separately or in a mixture.
• antitumor agent A is meant "at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent".
• the antitumor agent or pharmaceutical compositions of the present invention comprises a histone deacetylase inhibitor and an antitumor agent A in combination (i.e., concomitant agent) and may be any as long as it can comprise a histone deacetylase inhibitor and an antitumor agent A when in use for administration.
• the antitumor agent of the present invention may be a single preparation obtained by simultaneously preparing a histone deacetylase inhibitor and an antitumor agent A, or a combination of at least two preparations obtained by separately preparing a histone deacetylase inhibitor and an antitumor agent A.
• the mode of administration is not particularly limited, and, for example, (1) administration of a composition containing a b-istone deacetylase inhibitor and an antitumor agent A, namely, administration of a single preparation, (2) simultaneous administration of two preparations by the same administration route, which are obtained by separately preparing a histone deacetylase inhibitor and an antitumor agent A, (3) staggered administration of two preparations by the same administration route, which are obtained by separately preparing a histone deacetylase inhibitor and an antitumor agent A (e.g., administration in the order of a histone deacetylase inhibitor and an antitumor agent A, or administration thereof in reverse order) , (4) simultaneous administration of two preparations by different administration routes, which are obtained by separately preparing a histone deacetylase inhibitor and an antitumor agent A, (5) staggered administration of two preparations by different administration routes, which are obtained by separately preparing a histone deacetylase inhibitor and an antitumor agent A (e.
• the enhancer of the present invention contains a histone deacetylase inhibitor, and may be any as long as it can comprise a histone deacetylase inhibitor and an antitumor agent A in combination when in use for administration. Accordingly, as long as a histone deacetylase inhibitor is contained, the enhancer of the present invention may contain an antitumor agent A in a single preparation, and even if it does not contain an antitumor agent A, an antitumor agent A can be administered separately as a concomitant agent.
• the administration mode is not particularly limited and, for example, (1) administration of the enhancer of the present invention containing a histone deacetylase inhibitor and an antitumor agent A in a single preparation, (2) simultaneous administration of the enhancer of the present invention and an antitumor agent A by the same administration route, (3) staggered administration of the enhancer of the present invention and an antitumor agent A by the same administration route (e.g., administration in the order of an antitumor agent A and the enhancer of the present invention, or administration thereof in reverse order) , (4) simultaneous administration of the enhancer of the present invention and an antitumor agent A by different administration routes, (5) staggered administration of the enhancer of the present invention and an antitumor agent A by different administration routes (e.g.
• the mixing ratio of the histone deacetylase inhibitor and the antitumor agent A can be, whether they are formulated into a single preparation or separate preparations, in the range of generally 1:100 - 100:1, preferably 1:10 - 10:1, by weight ratio.
• the mixing ratio is not particularly limited.
• the mixing ratio is preferably in the range of
• the mixing ratio (weight ratio) is preferably in the range of 1:100 - 100:1; and when a mixture of an antimetabolite antitumor agent and a taxane antitumor agent is to be made, the mixing ratio (weight ratio) is preferably in the range of 1:100-100:1.
• compositions, antitumor agent A and/or histone deacetylase inhibitors of the present invention can be used in the form of a pharmaceutical preparation such as a solid, semisolid.
• liquid tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection etc.
• a histone deacetylase inhibitor and/or an antitumor agent A as active ingredient (s) , which is suitable for transrectal, intranasal, pulmonary, vaginal, external (topical) , oral or parenteral (including subcutaneous, implantation, intravenous and intramuscular) administration.
• the antitumor effect enhancer of the present invention can be used in the form of a pharmaceutical preparation such as a solid, semisolid or liquid (tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection etc.) containing a histone deacetylase inhibitor as an active ingredient, which is suitable for transrectal, intranasal, pulmonary, vaginal, external (topical), oral or parenteral (including subcutaneous, implantation, intravenous and intramuscular) administration.
• a pharmaceutical preparation such as a solid, semisolid or liquid (tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, liquid, emulsion, suspension, syrup, injection etc.) containing a histone deacetylase inhibitor as an active ingredient, which is suitable for transrectal, intranasal, pulmonary, vaginal, external (topical), oral or parenteral (including sub
• the antitumor agent and the antitumor effect enhancer of the present invention can be also produced by conventional methods using various organic or inorganic carriers conventionally used for forming pharmaceutical preparations, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate etc.), condensation agents (e.g., cellulose, methyl cellulose, hydroxypropyl cellulose, polypropylpyrrolidone, gelatin, gum arafcic, polyethylene glycol , sucrose, starch etc.), disintegrants (e.g., starch, carboxymethyl cellulose, carboxymethyl cellulose calcium salt, hydroxypropylstarch, sodium carboxy methyl starch, sodium hydrogen carbonate, calcium phosphate, calcium citrate etc.), lubricants (e.g., magnesium stearate, earosil, talc, sodium lauryl sulfate etc.), corrig
• the antitumor agent and the antitumor effect enhancer of the present invention can be administered to mammals inclusive of human in the form of the above-mentioned conventional pharmaceutical preparations without any particular limitation. In particular, intravenous, intramuscular or oral administration is preferable.
• the dose in the present invention can be set to a lower level than that for separate administration of each of the histone deacetylase inhibitor and the antitumor agent A.
• the dose is appropriately determined according to various factors such as body weight and/or age of patients and/or severity of disease and administration route.
• the daily dose of compound A and cisplatin in combination in the case of an intravenous administration is generally 1-1000 mg, preferably 5-100 mg, more preferably 10- 60 mg, per 1 m 2 of human body surface area, which is given for the treatment by continuous infusion.
• the daily dose of compound A is 0.1-100 mg, preferably 1-50 mg, more preferably 5-30 mg, in the amount of compound A, per 1 m 2 of human body surface area, and cisplatin is administered in the dose of [the aforementioned dose of a combination of compound A and cisplatin - the dose of compound A] .
• the present invention encompasses a commercial package comprising a concomitant agent comprising at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent and histone deacetylase inhibitor, and a written matter associated therewith, the written matter stating that the concomitant agent can or should be used as an antitumor agent; and a commercial package comprising a preparation containing a histone deacetylase inhibitor and a written matter associated therewith, the written matter stating that the preparation can or should be used for enhancing an antitumor effect of at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent .
• Experimental Example 1 effect of combined use (simultaneous addition) of FK228 and cisplatin Prostate cancer cells (6x10 cells/well) were cultured in a 96 well plate for 24 hr and FK228 (0.1 nM, 0.2 nM, 0.5 nM, 1 nM, 2 nM, 5 nM, 10 nM, 20 nM and 50 nM) , cisplatin (50 nM, 100 nM, 200 nM, 500 nM, 1000 nM, 2000 nM and 5000 nM) or both pharmaceutical agents (simultaneous addition of the combination at the aforementioned concentrations) was/were added to achieve various concentrations.
• FK228 0.1 nM, 0.2 nM, 0.5 nM, 1 nM, 2 nM, 5 nM, 10 nM, 20 nM and 50 nM
• cisplatin 50 nM, 100 n
• FBS Fetal Bovine Serum
• PBS phosphate-buffered saline (calcium magnesium free)
• the medium was changed to a drug-free medium and the cells were further cultured for 96 hr.
• FK228 was dissolved in ethanol and diluted with a medium before use, and cisplatin was diluted with a medium before use. The antitumor activity after each treatment was evaluated by MTT assay.
• 3- (4 , 5-dimethylthiazol-2-yl) - 2,5-diphenyltetrazonium bromide (MTT) was dissolved in PBS at a concentration of 2.5 mg/mL, 20 ⁇ l thereof was added to each well and cultured for 4 hr.
• Formazan formed by living cells was dissolved by adding acidic isopropanol (100 ⁇ l) and the absorbance of each well was measured at a wavelength of 580 nm. With the absorbance (OD) of non-treated cells as 100%, concentration—response curves of antitumor activity of a single pharmaceutical agent and a combination of pharmaceutical agents were drawn.
• the mixture was further cultured for 24 hr and washed twice with 1% FBS-containing PBS (-) .
• the medium was changed to a drug-free medium and the cells were further cultured for 72 hr.
• the effect of combined use was evaluated by a method similar to that in Experimental Example 1.
• Experimental Example 3 effect of combined use (simultaneous addition) of FK228 and 5-fluorouracil
• various concentrations of 5-fluorouracil 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, 50 ⁇ M, 100 ⁇ M, 200 ⁇ M and 500 ⁇ M
• 5- Fluorouracil was diluted with a medium before addition.
• the isobologram of Experimental Example 3 is shown in Fig. 5.
• the combined use (simultaneous addition) of FK228 and 5- fluorouracil enhanced the antitumor activity.
• Experimental Example 4 effect of combined use (continuous addition) of FK228 and 5-fluorouracil
• 5-Fluorouracil was diluted with a medium before addition.
• various concentrations of paclitaxel 0.2 nM, 0.5 nM, 1 nM, 2 nM, 5 nM, 10 nM and 20 nM
• Paclitaxel was dissolved in ethanol and diluted with a medium before addition.
• the isobologram of Experimental Example 5 is shown in Fig. 8.
• Formulation Example 1 FK228 20 mg ethanol 20 ml
• FK228 (20 mg) is dissolved in and diluted with ethanol (20 ml) to give a preparation for injection.
• Formulation Example 2 FK228 20 mg cisplatin 100 mg physiological saline 100 ml
• FK228 (20 mg) and 5-fluorouracil ( 500 mg) are dissolved in and diluted with ethanol ( 100 ml) to give a preparation for inj ection .
• FK228 (20 mg) and paclitaxel (20 mg) are dissolved in and diluted with ethanol (40 ml) to give a preparation for inj ection .

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