EP0876145A1 - Taxanzusammensetzung und verfahren - Google Patents

Taxanzusammensetzung und verfahren

Info

Publication number
EP0876145A1
EP0876145A1 EP96943805A EP96943805A EP0876145A1 EP 0876145 A1 EP0876145 A1 EP 0876145A1 EP 96943805 A EP96943805 A EP 96943805A EP 96943805 A EP96943805 A EP 96943805A EP 0876145 A1 EP0876145 A1 EP 0876145A1
Authority
EP
European Patent Office
Prior art keywords
solution
taxane
taxol
storage solution
castor oil
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP96943805A
Other languages
English (en)
French (fr)
Other versions
EP0876145A4 (de
Inventor
Bijan Almassian
William Choy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genelabs Technologies Inc
Original Assignee
Genelabs Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genelabs Technologies Inc filed Critical Genelabs Technologies Inc
Publication of EP0876145A1 publication Critical patent/EP0876145A1/de
Publication of EP0876145A4 publication Critical patent/EP0876145A4/de
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to formulations of taxol and related taxane compounds, which have improved safety, solubility and stability characteristics, and to methods of preparing such formulations.
  • Taxol also known as paclitaxel, is a compound extracted from the bark of the western yew, Taxus brevifolia. Much attention has been drawn to taxol for use as an antineoplastic agent. Taxol has shown good response rates in the treatment of ovarian and breast cancer pa ⁇ tients who did not respond to cisplatin or vinca alkaloid therapy. Taxol is also being examined for treating a variety of other cancers, such as melanoma, lymphoma and lung cancer. A major problem associated with taxol is its low solubility in aqueous solvents.
  • taxol lacks functional groups that are ionizable in a pharmaceutically acceptable range, manipulation of pH does not enhance solubility. Producing salts or adding charged complexing agents are also inapplicable (Straubinger, 1995, p. 238). Formulating taxol in a biocompatible carrier has thus been a challenge throughout its therapeutic development. In the search for taxol formulations having improved solubility and toxicity properties, a number of pharmaceutical vehicles have been investigated.
  • such vehicles have included a cosolvent, such as ethanol, dimethylsulfoxide (DMSO) or low molecular weight polyethylene glycol (e.g., PEG 400), with or without an oil or surfactant additive such as a polyoxyethylene sorbitan fatty acid ester (e.g., 'TWEEN 80", also known as polysorbate-80), polyethoxylated castor oil (e.g. , "CREMOPHOR EL”), soybean oil, or triacetin.
  • a cosolvent such as ethanol, dimethylsulfoxide (DMSO) or low molecular weight polyethylene glycol (e.g., PEG 400)
  • an oil or surfactant additive such as a polyoxyethylene sorbitan fatty acid ester (e.g., 'TWEEN 80", also known as polysorbate-80), polyethoxylated castor oil (e.g. , "CREMOPHOR EL”), soybean oil, or triacetin.
  • the present invention includes, in one aspect, a taxane storage solution for pharmaceutical use.
  • the storage solution comprises (a) a taxane compound in a pharmaceu ⁇ tically pure form, (b) a polyoxyethylene sorbitan fatty acid monoester, (c) polyethoxylated castor oil, and (d) ethanol.
  • the monoester and polyethoxylated castor oil are present together in amounts effective to reduce the toxicity of the solution relative to the toxicity observed when either the polyoxyethylene sorbitan fatty acid monoester or polyethoxyl ⁇ ated castor oil is used in the absence ofthe other.
  • the pH of the storage solution is preferably between about 1 and 8.
  • the taxane compound is preferably taxol or docetaxel.
  • the solution additionally includes a low molecular weight polyethylene glycol, such as PEG 300.
  • the solution may additionally include a pharmaceutically acceptable acid as a buffering agent, wherein the pH is maintained between about 4 and about 6.
  • the storage solution includes 4 mg/mL to 8 mg/mL of a taxane, such as taxol, 20 to 30% (v:v) polyethoxylated castor oil, 5 to 15% (v:v) polyoxyethyl ⁇ ene (20) sorbitan mono-oleate, 15 to 30% (v:v) ethanol, and 40 to 60% (v:v) low molecular weight polyethylene glycol.
  • a taxane such as taxol
  • 20 to 30% (v:v) polyethoxylated castor oil 5 to 15% (v:v) polyoxyethyl ⁇ ene (20) sorbitan mono-oleate
  • 15 to 30% (v:v) ethanol sorbitan mono-oleate
  • ethanol sorbitan mono-oleate
  • 40 to 60% (v:v) low molecular weight polyethylene glycol 40 to 60% (v:v) low molecular weight polyethylene glycol.
  • the invention includes a method of treating a cancer condition in a mammalian subject.
  • a taxane storage solution in accordance with the description above.
  • the storage solution is diluted with a diluent suitable for intrave ⁇ nous administration, to produce a dilute taxane solution.
  • the solution is then administered to the subject in a pharmaceutically acceptable amount effective to inhibit cancer growth in the subject.
  • the method is used to treat ovarian cancer or breast cancer.
  • the invention also includes a method of preparing a taxane solution for intravenous administration.
  • a taxane storage solution of the type described above is diluted with a diluent suitable for intravenous administration, to produce a dilute taxane solution.
  • the dilute taxane solution may be administered in a method of treating cancer, as noted above.
  • the invention includes a pharmaceutical vehicle for delivering a non- polar drug, such as taxol, to a subject.
  • the vehicle includes a polyoxyethylene sorbitan fatty acid monoester, and polyethoxylated castor oil.
  • the monoester and polyethoxylated castor oil are present in amounts effective to reduce the toxicity of the vehicle relative to the toxicity observed when either the monoester or the polyethoxylated castor oil is used in the absence of the other.
  • the vehicle is useful when a solubilizing agent is necessary to dissolve a non-polar drug in solution, and where using the polyoxyethylene sorbitan fatty acid monoester without the polyethoxylated castor oil, or oil without the monoester, produces toxic effects which limit the amount of drug that can be administered.
  • the vehicle addi ⁇ tionally includes a low molecular weight polyethylene glycol, such as PEG 300.
  • the invention also includes a drug composition comprising a non-polar drug in a vehicle of the type just de ⁇ scribed.
  • taxane is meant any compound (a) having the 6-8-6 fused ring backbone of taxol, including additional substituents or bonding necessary for taxol activity (e.g., 9-ketone or 9- hydroxyl, 4,5-oxetane ring, 4-acetoxy, and 2-benzoyloxy; see also Chapter 13 on taxane structure-activity relationships J ⁇ TAXOL: SCIENCE AND APPLICATIONS, cited above, particularly page 339), and (b) which inhibits depolymerization of microtubules.
  • Exemplary taxane com ⁇ pounds are taxol (paclitaxel) and docataxel ("TAXOTERE").
  • polyoxyethylene sorbitan fatty acid monoester is meant a compound having a sorbitan core (1,4-sorbitol cyclic ether), wherein the 2, 3, and 5-hydroxyl groups of the sorbitan core are each derivatized with one or more ethylene oxide monomers, and the 6- hydroxyl of the core is derivatized with one or more ethylene oxide monomers which terminate with a fatty acid ester group.
  • the number of ethylene oxide monomers in the compound will generally be between 10 and 50, and preferably between 10 and 30.
  • polyoxyethylene sorbitan fatty acid monoester is "TWEEN 80", also known as polyoxyethylene (20) sorbitan mono-oleate, wherein “(20)” indicates that the total number of ethylene oxide monomers attached to the sorbitan core is 20.
  • fatty acid is meant a C-16 to C-22 carboxylic acid which may be entirely aliphatic or may contain one or more carbon-carbon double bonds.
  • exemplary fatty acids include palmitic acid (C-16), stearic acid (C-18), and oleic acid (cis-9-octadecenoic acid).
  • polyoxyethylene sorbitan fatty acid monoester and polyethoxylated castor oil being "present together in amounts effective to reduce the toxicity of the solution relative to the toxicity observed when either the polyoxyethylene sorbitan fatty acid monoester or polyethoxyl- ated castor oil is used in the absence of the other" is meant that the monoester and oil are present together in amounts effective to reduce the toxicity of a taxane storage solution (after dilution for intravenous administration) relative to the toxicity that would be obtained if the monoester/oil combination of the invention were replaced with monoester compound alone or oil compound alone in an amount sufficient to achieve the same degree of solubilization of the taxane compound as achieved by the monoester/oil combination.
  • low molecular weight polyethylene glycol is meant polyethylene glycol (PEG) having an average molecular weight of 200 to 3000 daltons.
  • “Mammalian subject” is intended to have its traditional meaning, and encompasses cats, dogs, sheep, horses, and particularly humans, for example.
  • the present invention is directed to an improved composition and method for delivering high doses of taxanes to cancer patients using a vehicle with reduced toxicity.
  • the invention is based in part on the discovery that using a polyoxyethylene sorbitan fatty acid monoester in combination with a polyethoxylated castor oil, as solubilizing agents for a taxane compound, is effective to provide high taxol solubility and stability, but with reduced toxicity.
  • the storage solution of the invention includes a taxane in pharmaceutically pure form, which is solubilized at high concentration using a polyoxyethylene sorbitan fatty acid monoester and polyethoxylated castor oil in an ethanol base.
  • the taxane is present at a concentration of between about 2 and about 20 mg/mL, and typically between about 4 and about 8 mg/mL.
  • the monoester and polyethoxylated castor oil are present together in amounts effective to reduce the toxicity of the solution relative to the toxicity observed when either the polyoxy- ethylene sorbitan fatty acid monoester or the polyethoxylated castor oil is used in the absence of the other.
  • the polyethoxylated castor oil is from any pharmaceutically acceptable source.
  • CREMOPHOR EL Generally, the polyethoxylated castor oil is present at a concentration of about 10 to about 40% (v:v), and preferably between about 20 to about 30% .
  • the sorbitan fatty acid monoester is generally present at a concentration of about 5 to about 20% (v:v), preferably between about 5 and about 15% .
  • One preferred polyoxyethylene sorbitan fatty acid monoester is "TWEEN 80".
  • the polyethoxylated castor oil and sorbitan monoester are used in a ratio (oil:sorbitan monoester, v:v) of between about 0.5 to 6, preferably between about 1.3 and 6, and more preferably between about 2 and 3.
  • the poly ⁇ ethoxylated castor oil and polyoxyethylene sorbitan fatty acid monoester serve not only to enhance the solubility of the taxane, but also to enhance the anti-cancer potency of the taxane when administered against tumor cells.
  • the storage solution of the invention may also include a low molecular weight polyeth ⁇ ylene glycol (PEG) having an average molecular weight of 200 to about 3000 daltons, preferably between about 200 and about 1000 daltons.
  • PEG polyeth ⁇ ylene glycol
  • the PEG preparation is preferably one which is a liquid at a temperature above 15°C, e.g. , having an average molecular weight of between about 200 and about 1000 daltons, and preferably between about 200 and about 500.
  • PEG is optionally also included in the storage solution to improve the solubility and stability of the taxane.
  • the level of PEG is between 10 and 60%, more preferably between about 40 and about 60% .
  • the storage solution may also optionally include a buffering agent which maintains the pH of the storage solution between about 1 and about 8, preferably between about 4 and about 6.
  • the buffering agent is pharmaceutically acceptable acid, more preferably a carb ⁇ oxylic acid, such as citric acid, acetic acid, maleic acid, succinic acid, lactic acid, ascorbic acid, glutamic acid, or aspartic acid.
  • the buffering agent is anhydrous citric acid.
  • the buffering agent may be present at a concentration of between about 2 and about 200 mM, typically between about 5 and about 20 mM.
  • the remainder of the storage solution is preferably made up by ethanol.
  • the storage solution preferably does not contain water.
  • the storage solution of the invention is prepared by any method suitable to solubilize the taxane component, including the use of sonication and heating. Exemplary methods for preparing solutions in accordance with the invention are provided in Example 1.
  • the solution may be stored at room temperature, and preferably at 4°C or lower.
  • the solution is preferably treated to remove particulate matter by passage through a filter membrane, e.g. , a 0.22 ⁇ m pore-size membrane.
  • the solution may also be purged with nitrogen gas to remove oxygen.
  • the stability properties of the storage solution of the invention are illustrated by the studies described in Examples 2 and 3.
  • aliquots of two storage solutions in accordance with the invention were placed in an autoclave and heated under pressure at 250°C for 20 minutes. The samples were then diluted in acetonitrile and analyzed by HPLC. No sign of taxol degradation was detected.
  • Example 3 In the study described in Example 3, sample solutions were incubated at 37° C for 12 weeks, and aliquots were periodically removed and tested by HPLC for degradation of taxol.
  • the sample solutions tested included Formulations 1 and 2 from Example 1 , as well as a solu ⁇ tion containing taxol in a 1:1 mixture of polyethoxylated castor oil and ethanol (Formulation 3).
  • Formulations 1 and 2 from Example 1
  • a solu ⁇ tion containing taxol in a 1:1 mixture of polyethoxylated castor oil and ethanol (Formulation 3).
  • the taxol solutions in accordance with the present invention are at least as stable as Formulation 3, with less than 2% degradation after 12 weeks.
  • the storage solution of the invention is compatible with dilution into standard solutions for intravenous administration of drugs.
  • Example 4 In the study described in Example 4, the formulations from Example 1 were diluted in normal saline (0.9% NaCI in water) by dilution factors of 1:5, 1: 10, 1:25 and 1 :50 and were then examined for signs of precipitation or cloudiness after 1, 2, 4, 8, 24, and 48 hours. All dilutions remained clear for the first 24 hours for both formulations, and Formulation 1 remained clear for 48 hours. These results indicate that storage solutions in accordance with the invention are suitable for intravenous administration.
  • Example 5 In the study described in Example 5, the relative toxicities of .the storage vehicle alone (storage solution without taxol) were compared with a vehicle consisting of a 1:1 mixture of polyethoxylated castor oil and ethanol (Formulation 3).
  • groups of 2 or 3 mice were administered single dosages of test formulations in undiluted form, and the mice were monitored for 21 days for signs of intolerance of the administered dosages. Signs of intolerance included any ofthe following: (1) significant weight loss ( > 20%), (2) piloerection, (3) prolonged prostration, and (4) death.
  • the highest dosage volumes (MTD, maximum toler- ated dose) which could be administered without causing signs of intolerance were recorded.
  • the maximum tolerated dose for formulations in accordance with the present invention is twice that of the formulation which used polyethoxylated castor oil alone, without sorbitan monoester.
  • the invention includes a method of treating a cancer condition in a mammalian subject.
  • a taxane storage solution in accordance with the description above.
  • the storage solution is diluted with a diluent suitable for intrave- nous administration, to produce a dilute taxane solution.
  • the solution is then administered to the subject in a pharmaceutically acceptable amount effective to inhibit cancer growth in the subject.
  • the dilute taxane solution is administered to treat any cancer condition in which the taxane is effective to inhibit or destroy cancer growth.
  • cancer conditions may include ovarian cancer, breast cancer, bladder cancer, lung cancer, melanoma, and lymphoma, for example.
  • the diluent used in the method is any intravenous solution suitable for intravenous administration.
  • the diluent will include sodium chloride to establish a selected physiological osmolality, e.g., 0.9% (w/v) sodium chloride).
  • the diluent may additionally include suitable supplements, such as glucose, and/or an antimicrobial agent such as penicillin or tetracycline.
  • the solution is preferably dispensed using a non-plasticized container, to prevent leaching of placticizers into the solution.
  • the diluted taxane formulation is admin ⁇ istered at a selected rate until the desired amount of drug has been administered.
  • the formulation is administered periodically until remission has been achieved, or until it appears that proliferation of the target cancer is inhibited.
  • the formulation may also be administered following surgery to inhibit recurrence of the cancer, for a time sufficient to indicate that the cancer has been successfully removed.
  • the storage solution of the invention may be made in combination with any other anti-cancer regimen deemed appropriate for the patient.
  • the storage solution of the invention may be used in combination with cisplatin, edatrexate, L-buthionine sulfoxide, tiazofurin, gallium nitrate, doxorubicin, etoposide, or cyclo- phosphamide, for example, or may be used in combination with radiation therapy.
  • the preceding discussion describes the advantages of the vehicle of the invention in terms of utility with taxol, the invention contemplates use of the vehicle with other non-polar taxol/taxane derivatives, such as docetaxel, whether of synthetic or natural origin.
  • the following examples illustrate but are not intended in any way to limit the invention.
  • Example 1 Taxol Formulations For the studies described below, two formulations, were prepared in the following proportions.
  • the PEG 300, citric acid and ethanol (EtOH) were mixed with a high speed mixer or stir bar until the citric acid was completely dissolved. If necessary, the mixture was heated to 50°C or sonicated to complete dissolution. To the mixture was then added "CREMOPHOR EL" and “TWEEN 80", and the resultant mixture was stirred for 30 minutes with a high speed mixer. The taxol was then added, and mixing was continued until the taxol was completely dissolved. The resulting solution was purged with dry nitrogen and filtered through a 0.22 micron filter ("MILLIPACK" 200). In both formulations, the final concentration of taxol was 6 mg/mL.
  • EtOH ethanol
  • A. Toxicity of Undiluted Samples Samples of taxol Formulations 1, 2 and 3 were tested in undiluted form for acute toxicity in Balb/C mice. The samples were administered intravenously, over a range of administered volumes, to groups of 2 or 3 mice weighing 18- 20 grams. The mice were then monitored for signs of intolerance for 21 days after administration. Signs of intolerance included any one of the following: (1) significant weight loss ( > 20%), (2) piloerection, (3) prolonged prostration, and (4) death. The results are tabulated below, where MTD is the maximum tolerated dose expressed in units of mL/kg.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Epoxy Compounds (AREA)
EP96943805A 1995-12-21 1996-12-19 Taxanzusammensetzung und verfahren Ceased EP0876145A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US57620495A 1995-12-21 1995-12-21
US576204 1995-12-21
PCT/US1996/020187 WO1997023208A1 (en) 1995-12-21 1996-12-19 Taxane composition and method

Publications (2)

Publication Number Publication Date
EP0876145A1 true EP0876145A1 (de) 1998-11-11
EP0876145A4 EP0876145A4 (de) 1999-04-21

Family

ID=24303400

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96943805A Ceased EP0876145A4 (de) 1995-12-21 1996-12-19 Taxanzusammensetzung und verfahren

Country Status (6)

Country Link
EP (1) EP0876145A4 (de)
KR (1) KR970032859A (de)
CN (1) CN1209059A (de)
AU (1) AU724842B2 (de)
CA (1) CA2240595A1 (de)
WO (1) WO1997023208A1 (de)

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WO2010015400A2 (en) 2008-08-07 2010-02-11 Gp Pharm, S.A. Injectable taxane pharmaceutical composition

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WO1997023208A1 (en) 1997-07-03
EP0876145A4 (de) 1999-04-21
AU724842B2 (en) 2000-09-28
CA2240595A1 (en) 1997-07-03
KR970032859A (ko) 1997-07-22
AU1294997A (en) 1997-07-17
CN1209059A (zh) 1999-02-24

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