United States Patent [191
`Bastart et a].
`
`[54] COMPOSITIONS CONTAINING TAXANE
`DERIVATIVES
`
`[75] Inventors: Jean-Pierre Bastart, Lesigny; Thierry
`Dupechez, Villemoisson Sur Orge;
`Jean-Louis Fabre, Pan's, all of France
`
`[73] Assignee: Rhone-Poulenc Rorer S.A., Antony,
`France
`
`[*1 Notice:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat. No.
`5,403,858.
`
`[21] Appl. No.: 398,011
`[22] Filed:
`Mar. 3, 1995
`
`Related US. Application Data
`
`[63] Continuation-impart of Ser. No. 930,392, ?led as PCI‘I
`FR92/00624, Jul. 3, 1992, Pat. No. 5,403,858.
`Foreign Application Priority Data
`
`[30]
`
`Jul. 8, 1991 [FR]
`
`France ................................. .. 91 08527
`
`[51] Int. GL6 ..................... .. A61K 31/335; A61K 31/34;
`A61K 9/50
`[52] us. Cl. ........................ .. 514/449; 514/471; 514/408;
`424/502
`[5 8] Field of Search ................................... .. 514/471, 408,
`514/449; 424/502
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`US00569 85 82A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,698,582
`*Dec. 16, 1997
`
`4,960,790 10/1990 Stella et al. ........................... .. 514/441
`5,254,580 10/1993 Chen et a1. ..
`.. 514/449
`5,272,171 12/1993 Ueda et a1.
`.. 514/449
`
`FOREIGN PATENT DOCUMENTS
`
`WIPO .
`
`wrPo .
`
`02.53738
`1/1988 European Pat. 01f. .
`WO92/09589 6/1992
`W093/l6060 8/1993
`WO93/21l73 10/1993
`W094! 12484 6/1994
`
`WIPO .
`
`WIPO .
`
`OTHER PUBLICATIONS
`
`Chemical Abstract, vol. 106 (22) 1525810 Terry et a1.
`(1987).
`Merck Index, 11th Edition, #7559-(1987).
`B.D. Tarr, “A New Parenteral Vehicle for the Administration
`of Some Poorly Water Soluble Anti-Cancer Drugs,” J.
`Parenter. Sci. TechnoL, 41 (1), 31-33 (1987).
`
`Primary Examiner--'Iheodore J. Criares
`Attorney, Agent, or Firm--Finnegan, Henderson, Farabow,
`Garrett & Dunner, L.L.P.
`
`[57]
`
`ABSTRACT
`
`This invention relates to compositions containing taxane
`derivatives, consisting of a solution of such derivatives in a
`surfactant. These compositions can be used to prepare
`perfusion solutions.
`
`4,206,221
`
`6/1980 Miller et a1. .......................... .. 514/471
`
`53 Claims, No Drawings
`
`MYLAN - EXHIBIT 1081
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`

`

`1
`COMPOSITIONS CONTAINING TAXANE
`DERIVATIVES
`
`5,698,582
`
`This is a continuation-in-part of Ser. No. 07/930,392,
`?led Aug. 23, 1993, now US. Pat. No. 5,403,858 a national
`phase application of PCI‘IFR92/00624, ?led Jul. 3, 1992,
`hereby incorporated by reference.
`The present invention relates to compositions and espe
`cially pharmaceutical dosage forms containing therapeutic
`agents having antitumor and antileukemic activity. It relates
`more especially to compositions suitable for injection con
`taining taxane derivatives, such as, in particular, taxol or one
`of its analogues or derivatives of the formula (I)
`
`10
`
`25
`
`35
`
`45
`
`2
`Known taxane derivatives encompassed by the general
`formula (I) include two compounds which are known by the
`name of TAXOL and the name TAXOTERE.
`These products exhibit in vivo substantial activity against
`malignant tumors, which has enabled them to be studied in '
`the treatment of diseases resistant to other anticancer thera
`p1es.
`Unfortunately, these products possess such low solubility
`in water that it has been necessary to prepare formulations
`for injection containing surfactant and ethanol. Ethanol is
`the best solvent for dissolving compounds of formula (I).
`For example, according to the publication by Rowinsky,
`Lorraine, Cazenave and Donebower which appeared in the
`Journal of the National Cancer Institute, vol. 82, No. 15,
`pages 1247-1259 on 1st Aug. 1990, a ?rst solution, termed
`“stock solution”, containing approximately 6 mg/ml of taxol
`in a solvent mixture composed of:
`50% by volume of ethanol
`50% by volume of Cremophor EL,;
`is prepared On injection, this solution is mixed with a
`perfusion ?uid containing sodium chloride or dextrose
`(glucose). To obtain a mixture which is stable from both a
`physical standpoint and a chemical standpoint, the authors
`of this paper state that it is necessary to limit the concen
`tration of active principle in the perfusion solution to con
`centrations of approximately 0.03 to 0.6 mg/ml (see above
`publication, page 1251, column 1, third paragraph).
`Now, it is desirable to be able to inject su?icient doses of
`active principle; to this end, clinicians would like to inject
`concentrations of active principle of between approximately
`0.3 and 1 mg/ml in the perfusion ?uid; above these doses,
`anaphylactic shock phenomena which are dif?cult to
`control, due in the main to the Cremophor, are seen (see the
`publication by Rowinsky, page 1250, second column, last
`paragraph).
`Still according to this publication, to obtain such concen
`. trations (between 0.3 and 1 mg/ml), it is necessary to inject
`solutions containing, at the same time as the active principle,
`concentrations of each of the following compounds, ethanol
`and most especially Cremophor, of approximately 8 g per
`100 ml of solution. Since the treatment often requires the
`administration of high doses of active principle, and since
`the concentration of the active principle, and since the
`concentration of the active principle in the solution is
`relatively low, the injection of a large volume has the effect
`of causing, in addition to anaphylactic manifestations, mani
`festations of alcohol poisoning during the treatment.
`The present invention provides compositions that make it
`possible either to reduce the ethanol concentrations greatly,
`or to eliminate Cremophor and ethanol completely from the
`perfusions.
`For this purpose, according to a ?rst implementation of
`the present invention, a composition suitable for use as a
`stock solution is prepared, containing a compound of for
`mula I as de?ned above dissolved in a surfactant which may
`be a polysorbate, e.g. as marketed under the name ‘Tween”,
`a polyoxyethylated vegetable oil as marketed, e.g., under the
`name “Emulphor”, polyethoxylated castor oil, also known as
`glycerol polyethyleneglycol ricinoleate, as marketed, e.g.,
`under the name Cremophor, preferably CREMOPHOR ®
`EL, and virtually free from ethanol. CREMOPHOR ® EL is
`a non-ionic solubilizer and emulsi?er that can be obtained
`by reacting ethylene oxide with castor oil in a molar ratio of
`35—40 mol ethylene oxide to 1 mol glyceride and is com
`mercially available from BASF and has been assigned CAS
`Registry Number 61791-12-6. The main component of
`CREMOPHOR ® EL is glycerolpolyethyleneglycol
`
`50036115
`in which R1 and R2 each represent a hydrogen atom or one
`of R1 and R2 represents a hydrogen atom and the other
`represents a hydroxy, acyloxy, or acylcarbonyloxy radical,
`or R2 represents a hydrogen atom and R1 forms a single
`bond together with the methyl carbon atom situated in the or
`position, so they can fonn together a cyclopropane ring, one
`of R3 and R4 represents a hydrogen atom and the other
`represents a hydroxy radical, or R3 and R4 taken together
`form a 0x0 radical, R5 and R6 each represent each a
`hydrogen atom or one of Rs and R6 represents a hydrogen
`atom and the other represents a hydroxy, acyloxy, acylcar
`bonyloxy or a alkoxymethylcarbonyloxy radical, or R5 and
`R6 taken together form a 0x0 radical, R7 represents an
`alkoxy, alkenyloxy, cycloakyloxy or phenyl radical and Ar
`represents an aryl radical or preferably a phenyl radical
`optionally substituted by one or several atoms or radicals
`identical or different and selected from halogen, alkyl,
`alkoxy, dialkylarnino, acylamino, alkylcarbonylamino or
`tri?uoromethyl, or a 5 membered heterocyclic radical with
`one or more identical or dilferent heteroatoms chosen from
`nitrogen, oxygen or sulfur, it being understood that alkyl
`radicals are straight chain or branched chain and contain 1
`to 8 carbon atoms and the alkenyl radicals contain 2 to 8
`carbon atoms and provided that when R2 is a hydrogen atom
`and R1 is a hydroxy radical, R3 and R4 cannot be simulta
`neously an oxo radical when R6 is a hydrogen atom, R5 is
`a hydroxy, acetyloxyradical, R7 is a tbutoxy or a phenyl
`radical and Ar is a phenyl radical.
`Among the taxane derivatives of the formula (I) the most
`preferred ones are the following where R2 represents a
`hydrogen atom and R1 represents a hydrogen atom or a
`hydroxy radical, or R1 forms a single bond together with the
`methyl carbon atom situated in the on position, so they can
`form together a cyclopropane cycle, R3 and R4 taken
`together form an oxo radical, R,5 represents a hydrogen atom
`and R5 represents a hydrogen atom or a hydroxy, acetyloxy
`or methoxyacetyloxy radical, or R5 and R6 taken together
`form an oxo radical, R7 represents a t.butoxy or a phenyl
`radical and Ar is a phenyl radical, provided that when R2 is
`a hydrogen atom and R1 is a hydroxy radical, R3 and R4
`cannot be simultaneously an oxo radical when R5 is a
`hydrogen atom, R6 is a hydroxy, acetyloxy radical R7 is a
`t.butoxy or a phenyl radical and Ar is a phenyl radical.
`
`55
`
`60
`
`65
`
`

`

`3
`ricinoleate, which together with fatty acid esters of polyeth
`ylene glycol, represents the hydrophobic part of the product.
`The smaller, hydrophilic part consists of polyethylene gly
`cols and ethoxylated glycerol.
`The stock solution may be prepared by dissolving the
`active principle in ethanol, which is the best biocompatible
`solvent for the taxane derivatives, and then gradually adding
`the surfactant. Solutions containing 10 to 100 mg/ml of
`active principle in a mixture containing approximately 50%
`of surfactant can be prepared in this manner. The ethanol is
`then completely, or almost completely, eliminated.
`To prepare, according to the present invention, the solu
`tion having a low ethanol content, the taxane derivative is
`dissolved in ethanol, and the sm‘factant, which enables
`micelles to be formed in containing the taxane derivative
`encapsulated in the surfactant after dilution in an aqueous
`medium, is then added. The ethanol contained in this solu
`tion is then removed at least partially by evaporation under
`vacuum or by any other suitablemeans.
`According to a second method of preparing the stock
`solution, the taxane derivative is dissolved directly in the
`surfactant. According to a preferred method, a solution of
`surfactant containing, in particular, 1 to 2% of ethanol is
`prepared, and the taxane derivative is added continuously to
`this solution with stirring, e.g. using a helical grinder or a
`centrifugal disintegrator. The presence of a small amount of
`ethanol provides several advantages: the medium possesses
`a lower viscosity, and the wetting of the powder and the ?nal
`?ltration of the solution are improved
`The stock solution, having a low ethanol content, prefer
`ably contains less than 5% of ethanol; still more preferably,
`it contains less than 2% of ethanol. This solution is stable
`and can contain up to 200 rug/ml, preferably up to 80 mg/ml,
`of active principle in the surfactant.
`A stock solution of taxol possesses still more preferably a 0
`concentration of between 6 and 20 mg/ml of active principle
`in the surfactant. This solution can be mixed, in particular to
`provide a ?nal concentration of between 0.1 and 1 mg per
`milliliter, with the perfusion ?uid, which can be physiologi
`cal saline or a glucose solution. Perfusion prepared from the
`above stock solutions having a low ethanol content contain
`still more preferably between 0.3 and 0.5 mg/ml of taxol and
`less than 1 ml/l of ethanol.
`The taxol perfusion containing the active principle with
`out ethanol possesses a physical stability of between 8 and
`about one hundred hours. Physical stability is understood to
`mean that the solution does not exhibit any visible precipi
`tation after 8 to 10 hours of storage at room temperature.
`
`15
`
`20
`
`25
`
`35
`
`40
`
`5,698,582
`
`4
`from the above stock solutions having a low ethanol content
`contain still more preferably between 0.1 and 0.3 mg/ml of
`Taxotere; they preferably contain less than 15 ml/l of sur
`factant and less than 1 mlll of ethanol.
`The Taxotere perfusion containing the active principle
`without ethanol possesses a physical stability which can
`reach several months.
`The taxol or Taxotere perfusions may be injected into
`humans at a predetermined flow rate depending on the
`amount of active principle it is desired to inject. The
`anaphylactic shock phenomena which were observed with
`the solutions of the prior can be avoided with these solu
`tions.
`Thus, these perfusion have made it possible to reduce,
`relative to the prior art, the amount of surfactant injected into
`humans by approximately 80% and the amount of ethanol by
`almost 100%.
`The invention is illustrated by the following Examples.
`
`COMPARATIVE EXAMPLE ACCORDING TO
`THE PRIOR ARI‘
`
`Taxol (0.180 g) is dissolved in ethanol (15 ml). The
`mixture is made to volume with Cremophor to obtain a
`solution (30 ml) which contains taxol (6 mg/ml).
`This solution is diluted in a 5% glucose perfusion solution
`in a proportion of 1 mg/ml; the perfusion solution in a
`proportion of 1 mg/ml; the perfusion solution contains 87.7
`ml/l of Cremophor and 87 .7 mlll of ethanol. The perfusion
`solution is stable for more than 21 hours.
`
`EXAMPLES 1-7
`
`Taxoter'e (32 g) is dissolved in absolute ethanol (340 ml)
`and Polysorbate 80 (830 g) is then added. The ethanol is
`evaporated off in a rotary evaporator at 30° C. at a pressure
`of 15 mmHg for 2 hours. The solution obtained is stable; it
`contains Taxotere (40 mg/ml).
`After dilution is a 5% glucose perfusion solution at
`concentrations of 0.1, 0.3 and 0.5 mglml, the stability of the
`solutions obtained is observed.
`The same method is reproduced using a solution contain
`ing Taxotere (60 mg/ml).
`The same test is reproduced using taxol solutions con
`taining taxol (l2 and 20 mg/ml).
`The results are shown in Table 1.
`
`Product
`
`Solvent
`
`Stock solution Active principle
`concentration
`in the perfusion
`
`taxol
`taxol
`taxol
`Taxotere
`'I‘axotere
`Taxotere
`'I‘axotere
`
`Polysorbate 20 ing/ml
`Polysorbate 20 mg/ml
`Polysorbate
`12 mg/ml
`Polysorbate 40 mg/ml
`Polysorbate 40 mg/ml
`Polysorbate 40 mg/ml
`Polysorbate 60 mg/ml
`
`l mglml
`0.3 mglml
`1 myml
`0.5 mg/ml
`0.3 ing/ml
`0.1 mg/ml
`1.1 mglml
`
`Ethanol in
`Surfactant in the
`the perfusion perfusion Stability
`
`50 mlll
`15 mlll
`83.3 mlll
`11.6 mlll
`6.0 mlll
`2.3 mlll
`1.5 mlll
`
`<03 mlll >8 H
`4!.09 ml/l >24 H
`<05 mlll >48 H
`0.09 mlll 8H-23H
`0.05 mlll 8H-23H
`0.02 mlll 29H-45H
`43.01 ml/l 8H~23H
`
`A stock solution of Taxotere preferably possesses a con-
`centration of between 20 and 80 mg/ml of active principle in
`the surfactant. This solution can be mixed, in particular to
`provide a ?nal concentration of between 0.1 and 0.5 mg per
`milliliter, with the perfusion ?uid, which can be a physi
`ological saline or a glucose solution. Perfusion prepared
`
`EXAMPLE 8
`
`65
`
`Into a stainless steel reactor, Taxotere (258 g) is intro
`duced and dissolved in ethanol (2425 g) with mechanical
`stirring for 45 minutes. Polysorbate 80 (6156 g) is added and
`the mixture is homogenized with mechanical stirring for 15
`
`

`

`5
`minutes. The solution is transferred to a reactor and the
`alcohol is distilled oif under a reduced pressure of 10 to 50
`millibars (1000 to 5000 Pa), the temperature being main
`tained at between 18° and 28° C. The alcohol is stilled o?
`until its content is less than 2%.
`The solution obtained is ?ltered through a ?lter having a
`pore size of 0.2 pm. It contains:
`ethanol (1.3%)
`Taxotere (39.6 mglml).
`After dilution to mg/ml in a perfusion bag containing 5%
`glucose, the solution is stable without apparent precipitation
`for a period of more than two months.
`
`EXAMPLE 9
`
`Taxotere (160 mg) or taxol (160 mg) is dissolved in a
`mixture (10 ml) of absolute ethanol (2 ml) and Cremophor
`EL (218) (8 ml), and the ethanol is evaporated o? in a rotary
`evaporator at 30° C. at a pressure of 25 mmHg for three
`hours. The solutions obtained are stable. They contain 20
`mg/ml of Taxotere or taxol. After dilution in a 5% glucose
`perfusion solution at concentrations of 0.1 and 0.5 mg/ml,
`precipitation is observed at between 30 and 95 hours.
`
`EXAMPLE l0
`
`Polysorbate 80 (275.5 g) and absolute ethanol (5.4 g) are
`placed in a 500-ml Erlenmeyer ?ask, and the mixture is then
`stirred with a bar magnet until completely homogenized.
`The solution prepared above (26.13 g) in a 50 ml ?ask,
`placed in a water bath heated beforehand and maintained
`throughout the test period at 30° C., is stirred at approxi
`mately 600 rpm with a bar magnet With a spatula, Taxotere
`(1.076 g) is added in several portions so that the clumps
`disappear between two additions (the duration of the opera
`tion is approximately one hour). After incorporation of the
`last ?'action of Taxotere, stirring is maintained until the
`solution becomes clear (approximately two hours).
`
`25
`
`30
`
`35
`
`EXAMPLE 11
`4-acetoxy-20t-benzoyloxy-S [5,20-epoxy-1 ,7 [5, 10B
`trihydroxy-9-oxo-ll-taxen-130t-yl
`3-t
`butoxycarbonylamino-3-(2-?uorophenyl)-2-hydroxy-(2R,
`3S)-propionate (20 mg) is placed in round bottom ?ask and
`dissolved in absolute ethanol (0.4 ml). After dissolution,
`polysorbate 80 (0.5 ml) is added and the mixture is homog
`enized with the aid of a magnetic stirrer. The ?ask is placed
`in a vacuum using a rotary evaporator and the alcohol is
`distilled off under reduced pressure (10 mmHg) for one hour.
`The solution obtained is perfectly clear and contains 40
`mgml of 4-acetoxy-2ot-benzoyloxy-5[3,20-epoxy-1,713,100
`trihydroxy-9-oxo-11-taxen-13ot-yl
`3-t
`butoxycarbonylamino-3 -(2-?uorophenyl)-2-hydroxy-(2R,
`3S)-propionate. After dilution in a 0.9% aqueous sodium
`chloride perfusion solution to a concentration of 1 mg/ml,
`the solution obtained is stable for more than 24 hours.
`
`45
`
`50
`
`55
`
`EXANIPLE 12
`4-acetoxy-Zot-benzoyloxy-S B,20-epoxy-1,7 [3,1013
`trihydroxy-Q-oxo-ll-taxen-130t-yl
`3-t
`butoxycarbonylamino-3-(4-chlorophenyl)-2-hydroxy-(2R,
`3S)-propionate (20 mg) was placed in a round bottomed
`?ask and dissolved in absolute ethanol (0.4 ml). After
`dissolution, polysorbate 80 (0.5 ml) was added and the
`mixture was homogenized with the aid of magnetic stirrer.
`The ?ask was placed in a vacuum using a rotary evaporator
`and the alcohol was distilled oif under reduced pressure (10
`
`65
`
`5,698,582
`
`10
`
`15
`
`6
`mmHg) for one hour. The solution obtained is perfectly clear
`and contains 40 mg/ml of 4-acetoxy-2ot-benzoyloxy-S [5,20
`epoxy-lJB,10B-trihydroxy-9-oxo-ll-taxen-l30t-yl 3-t
`butoxycarbonylamino-3-(4-chlorophenyl)-2-hydroxy-(2R,
`3S)-propionate. After dilution in a 0.9% aqueous sodium
`chloride perfusion solution to a concentration of 1 mg/ml,
`the solution obtained was stable for more than 24 hours.
`EXAMPLE l3
`40L,10[3-diacetoxy-20t-benzoyloxy-5[5,20-epoxy-11$
`hydroxy-7[5,813-methylene-9-oxo-l9-nor-11-taxen-l30t-yl
`3-t-butoxycarbonylamino-2-hydroxy-3-phenyl-2-(2R,3S)
`propionate (20 mg) was placed in a round bottomed ?ask
`and dis solved in absolute ethanol (0.4 ml). After dissolution,
`polysorbate 80 (0.5 ml) was added and the mixture was
`homogenized with the aid of a magnetic stirrer. The ?ask
`was placed in a vacuum using a rotary evaporator and the
`alcohol was distilled o? under reduced pressure (10 mmHg)
`for one hour. The solution obtained is perfectly clear and
`contains 40 mg/ml of 40L,1OB-diacetoxy-Zwbenzoyloxy-S [3,
`20-epoxy- 1 B-hydroxy-713,8[5-methylene-9-oxo- l 9-n or- 1 1
`taxen-l3ot-yl 3-t-butoxycarbonylamino-2-hydroxy-3
`phenyl-(2R,3S)-propionate. After dilution in a 0.9% aqueous
`sodium chloride perfusion solution to a concentration of 1
`mg/ml, the solution obtained was stable for more than 24
`hours.
`Although the invention has been described in conjunction
`with speci?c embodiments, it is evident that many alterna
`tives and variations will be apparent to those skilled in the
`art in light of the foregoing description. Accordingly, the
`invention is intended to embrace all of the alternatives and
`variations that fall within the spirit and scope of the
`appended claims.
`We claim:
`1. A composition comprising a taxane derivative dis
`solved in a surfactant selected from polysorbate or poly
`ethoxylated castor oil, and essentially free or free of ethanol.
`2. The composition of claim 1, wherein said polyethoxy
`lated castor oil is a non-ionic solubilizer and emulsi?er
`containing glycerol-polyethylene glycol ricinoleate, fatty
`acid esters of polyethylene glycol, polyethylene glycols, and
`ethoxylated glycerol.
`3. The composition of claim 1, said composition being a
`stock solution and containing less than 5% by volume
`ethanol.
`4. The composition of claim 3, said composition contain
`ing less than 2% by volume ethanol.
`5. The composition of claim 1, said composition being a
`perfusion containing less than 0.5 mg/ml of said taxane
`derivative of claim 1, less than 1 mlll of said ethanol, and
`less than 15 mlll of said surfactant.
`6. The composition of claim 1, said composition being a
`perfusion containing less than or equal to 1 mg/ml of said
`taxane derivative of claim 1, and less than 1 mlll of said
`ethanol.
`7. A stock solution comprising a taxane derivative dis
`solved in a surfactant selected from polysorbate or poly
`ethoxylated castor oil, wherein said stock solution contains
`from 10 to 200 mglml of said taxane derivative, and wherein
`said stock solution is essentially free or free of ethanol.
`8. The stock solution of claim 7, wherein said stock
`solution contains from 10 to 80 mg/ml of said taxane
`derivative.
`9. The stock solution of claim 8, wherein said stock
`solution contains from 12 to 80 mg/ml of said taxane
`derivative.
`10. The stock solution of claim 9, wherein said stock
`solution contains from 20 to 80 mg/ml of said taxane
`derivative.
`
`

`

`7
`11. The stock solution of claim 7, wherein said surfactant
`is polysorbate.
`12. The stock solution of claim 7, wherein said surfactant
`is polyethoxylated castor oil.
`13. The stock solution of claim 12, wherein said poly
`ethoxylated castor oil is a non-ionic solubilizer and emul
`si?er containing glycerol-polyethylene glycol ricinoleate,
`fatty acid esters of polyethylene glycol, polyethylene
`glycols, and ethoxylated glycerol.
`14. A composition comprising the compound 4ot,10l3
`diacetoxy-2a-benzoyloxy-5[5,20-epoxy-1B-hydroxy-7B,8B
`methylene-9-oxo-19-nor-11-taxen-13ot-yl 3-t
`butoxycarbonylamino-2-hydroxy-3-phenyl-(2R,3S)—
`propionate dissolved in a surfactant selected from
`polysorbate or polyethoxylated castor oil, wherein said
`composition is essentially free or free of ethanol.
`15. The composition of claim 14, wherein said poly
`ethoxylated castor oil is a non-ionic solubilizer and emul
`si?er containing glycerol-polyethylene glycol ricinoleate,
`fatty acid esters of polyethylene glycol, polyethylene
`glycols, and ethoxylated glycerol.
`16. The composition of claim 14, said composition being
`a stock solution containing less than 5% by volume ethanol.
`17. The composition of claim 16, said composition con
`taining less than 2% by volume ethanol.
`18. The composition according to claim 16, said compo
`sition containing from 1 to about 2.5% by volume ethanol.
`19. The composition of claim 14, said composition being
`a stock solution and containing from 10 to 80 mg/ml of said
`compound of claim 14.
`20. The composition of claim 19, said composition con
`taining from 20 to 80 mg/ml of said compound.
`21. The composition of claim 14, said composition being
`a stock solution and containing from 6 to 20 mg/ml of said
`compound of claim 14.
`22. The composition of claim 14, said composition being
`a perfusion containing less than 0.5 mg/ml of said taxane
`derivative of claim 14, less than 1 ml/l of said ethanol, and
`less than 15 ml/l of said surfactant.
`23. The composition of claim 14, said composition being
`a perfusion containing less than or equal to l mglml of said
`taxane derivative of claim 14, and less than 1 ml/l of said
`ethanol.
`24. The composition of claim 14, wherein said surfactant
`is polysorbate.
`25. The composition of claim 14, wherein said surfactant
`is polyethoxylated castor oil.
`26. The composition of claim 25, wherein said poly
`ethoxylated castor oil is a non-ionic solubilizer and emul
`si?er containing glycerol-polyethylene glycol ricinoleate,
`fatty acid esters of polyethylene glycol, polyethylene
`glycols, and ethoxylated glycerol.
`27. A composition comprising the compound 4ot,l0[5
`diacetoxy-Zot-benzoyloxy-S [3,20-epoxy-lB-hydroxy-7B,8?
`methylene-Q-oxo-19-nor-11-taxen- l3ot-yl 3-t
`butoxycarbonylamino-Z-hydroxy-3-phenyl-(2R,3S)
`propionate dissolved in a surfactant selected from
`polysorbate or polyethoxylated castor oil, wherein said
`composition is a stock solution containing from 6 to 200
`mg/ml of said compound, and wherein said composition is
`essentially free or free of ethanol.
`28. The composition of claim 27, wherein said composi
`tion contains from 10 to 200 mg/ml of said compound.
`29. The composition of claim 28, wherein said surfactant
`is polysorbate.
`30. The composition of claim 28, wherein said surfactant
`is polyethoxylated castor oil.
`
`20
`
`25
`
`35
`
`50
`
`55
`
`65
`
`5,698,582
`
`8
`31. The composition of claim 30, wherein said poly
`ethoxylated castor oil is a non-ionic solubilizer and emul
`si?er containing glycerol-polyethylene glycol ricinoleate,
`fatty acid esters of polyethylene glycol, polyethylene
`glycols, and ethoxylated glycerol.
`32. A composition comprising a compound of formula (I):
`
`5
`
`(I)
`
`15
`
`in which R2 represents a hydrogen atom and R1 forms a
`single bond together with the methyl carbon atom
`situated in the (1 position, so they together form a
`cyclopropane ring,
`one of R3 and R4 represents a hydrogen atom and the
`other represents a hydroxy radical, or
`R3 and R4 taken together form an oxo radical,
`R5 and R5 each represents a hydrogen atom or one of R5
`and R6 represents a hydrogen atom and the other
`represents a hydroxy, acyloxy or an alkoxymethylcar
`bonyloxy radical, or
`R5 and
`taken together form an oxo radical,
`R7 represents an allroxy, alkenyloxy, cycloalkoxy or phe
`nyl radical and
`Ar represents
`a phenyl radical optionally substituted by one or several
`atoms or radicals which are identical or diiferent and
`are selected from halogen, alkyl, alkoxy,
`dialkylamino, acylamino, and tri?uoromethyl, or
`a S-membered heterocyclic radical with one or more
`identical or di?erent heteroatoms selected from
`nitrogen, oxygen and sulfur
`wherein said compound of formula (I) is dissolved in a
`surfactant selected from polysorbate or polyethoxy
`lated castor oil, and further wherein said composition is
`essentially free or free of alcohol.
`33. The composition of claim 32, wherein the alkyl radical
`and the alkyl portion of the radicals selected from
`alkoxymethylcarbonyloxy, alkoxy, and dialkylarnino are
`independently straight or branched and contain 1 to 8 carbon
`atoms and the alkenyloxy radical contains 2 to 8 carbon
`atoms.
`34. A perfusion comprising less than or equal to 1 mg/ml
`of said compound of formula (I) of claim 32, and less than
`1 ml/l ‘of said ethanol and less than l5"ml/l of surfactant
`35. The composition of claim 32, wherein R3 and R4 taken
`together form an 0x0 radical; either (i) R6 represents a
`hydrogen atom and R5 represents a hydrogen atom or a
`hydroxy, acetyloxy or methoxyacetyloxy radical, or (ii) Rs
`and R6 taken together form an oxo radical;
`R7 represents a t.butoxy or a phenyl radical; and
`Ar is a phenyl radical.
`36. The composition of claim 32, said composition being
`a stock solution containing less than 5% by volume ethanol.
`37. The composition of claim 36, said composition con
`taining less than 2% by volume ethanol.
`
`

`

`38. A composition comprising a compound of formula (I):
`
`5,698,582
`
`10
`
`bcocsHs
`
`in which R2 represents a hydrogen atom and R1 forms a
`single bond together with the methyl carbon atom situated in
`the on position, so they together form a cyclopropane ring,
`
`one of R3 and R4 represents a hydrogen atom and the
`other represents a hydroxy radical, or
`R3 and R4 taken together form an oxo radical,
`R5 and R6 each represents a hydrogen atom or one of R5
`and R6 represents a hydrogen atom and the other
`represents a hydroxy, acyloxy or an alkoxymethylcar
`bonyloxy radical, or
`R5 and R6 taken together form an oxo radical,
`R7 represents an alkoxy, alkenyloxy, cycloalkoxy or phe
`nyl radical and
`Ar represents
`a phenyl radical optionally substituted by one or several
`atoms or radicals which are identical or different and
`are selected from halogen, alkyl, alkoxy,
`dialkylarnino, acylamino, and tri?uoromethyl, or
`a S-membered heterocyclic radical with one or more
`identical or di?‘erent heteroatoms selected from
`nitrogen, oxygen and sulfur
`wherein said compound of formula (I) is dissolved in a
`surfactant selected from polysorbate or polyethoxy
`lated castor oil, and wherein said composition is a stock
`solution containing from 6 to 200 mg/ml of said
`compound of formula (I), and wherein said composi
`tion is essentially free or free of ethanol.
`39. The composition of claim 38, wherein said composi
`tion contains from 10 to 200 mg/ml of said compound of
`formula (I).
`40. The composition of claim 38, wherein said composi
`tion contains from 6 to 20 mg/ml of said compound of
`formula (I).
`41. The composition of claim 39, wherein said surfactant
`is polysorbate.
`42. The composition of claim 39, wherein said surfactant
`is polyethoxylated castor oil.
`43. The composition of claim 42, wherein said poly
`ethoxylated castor oil is a non-ionic solubilizer and emul
`si?er containing glycerol-polyethylene glycol ricinoleate,
`fatty acid esters of polyethylene glycol, polyethylene
`glycols, and ethoxylated glycerol.
`44. A stock solution comprising a compound of forrrulla
`(I):
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`bcocats
`in which R1 and R2 each represent a hydrogen atom or
`one of R1 and R2 represents a hydrogen atom and the
`other represents a hydroxy, acyloxy or acylcarbonyloxy
`radical, or
`R2 represents a hydrogen atom and R1 forms a single bond
`together with the methyl carbon atom situated in the (1
`position, so they together form a cyclopropane ring,
`one of R3 and R4 represents a hydrogen atom and the
`other represents a hydroxy radical,
`or R3 and R4 taken together form an oxo radical,
`Rs and R6 each represents a hydrogen atom 01' one of R5
`and R6 represents a hydrogen atom and the other
`represents a hydroxy, acyloxy or an alkoxymethylcar
`bonyloxy radical, or
`R5 and R6 taken together form an 0x0 radical,
`R7 represents an alkoxy, alkenyloxy, cycloalkoxy or phe
`nyl radical and
`Ar represents
`a phenyl radical optionally substituted by one or several
`atoms or radicals which are identical or ditferent and
`are selected from halogen, alkyl, alkoxy,
`dialkylarnino, acylamino, and tri?uoromethyl, or
`a S-membered heterocyclic radical with one or more
`identical or ditferent heteroatoms selected from
`nitrogen, oxygen and sulfur, and
`wherein said compound of formula (I) is dissolved in a
`surfactant selected from polysorbate or polyethoxy
`lated castor oil, and further wherein said composition is
`essentially free or free of alcohol.
`45. A composition comprising a taxane derivative dis
`solved in a polyethoxylated vegetable oil, wherein said
`composition is essentially free or free of ethanol.
`46. A stock solution comprising a taxane derivative dis
`solved in a polyethoxylated vegetable oil, wherein said stock
`solution contains from 10 to 200 mg/ml of said taxane
`derivative and is essentially free or free of ethanol.
`47. A composition comprising a compound of formula (I):
`
`(I)
`
`ococan
`in which R2 represents a hydrogen atom and R1 forms a
`single bond together with the methyl carbon atom
`situated in the on position, so they together form a‘
`cyclopropane ring,
`one of R3 and R4 represents a hydrogen atom and the
`other represents a hydroxy radical, or
`
`65
`
`

`

`5,698,582
`
`11
`R3 and R4 taken together form an oxo radical,
`R5 and R6 each represents a hydrogen atom or one of R5
`and R‘.3 represents a hydrogen atom and the other
`represents a hydroxy, acyloxy or an alkoxymethylcar
`bonyloxy radical, or
`R5 and R6 taken together form an oxo radical,
`R7 represents an alkoxy, alkenyloxy, cycloalkoxy or phe
`nyl radical and
`Ar represents
`a phenyl radical optionally substituted by one or several
`atoms or radicals which are identical or different and
`are selected from halogen, alkyl, alkoxy,
`dialkylamino, acylamino, and tri?uoromethyl, or
`a S-membered heteroc