United States Patent [191
`Bastart et al.
`
`USO05750561A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,750,561
`*May 12, 1998
`
`[54] COMPOSITIONS CONTAINING TAXANE
`DERIVATIVES
`
`[58] Field of Search ................................... .. 514/449. 471.
`5 14/408 ; 424/5 02
`
`[75] Inventors: J can-Pierre Bastart. Lesigny; Thierry
`Dupechez. Villemoisson Sur Orge;
`Jean-Louis Fabre. Paris. all of France
`
`[73] Assignee: Rhone-Poulenc Rorer, S.A.. Antony
`Cedex. France
`
`[*] Notice:
`
`The term of this patent shall not extend
`beyond the expiration date of Pat. No.
`5.403.858.
`
`[21] Appl. No.: 422,672
`[22] Filed:
`Apr. 12, 1995
`
`Related US. Application Data
`
`[63] Continuation of Ser. No. 930,393, Aug. 4, 1993, abandoned.
`[30]
`Foreign Application Priority Data
`
`Jul, 8, 1991 [FR]
`
`France .................................. .. 9108527
`
`[51] 1m. (:1.6 ...................... .. A61K 31/335; A61K 31/34;
`A61K 9/50
`[52] us. Cl. ........................ .. 514/449; 514/471; 514/408;
`424/502
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`424/278
`6/1980 Miller et a1. ..
`4,206,221
`514/449
`4,814,470 3/1989 Colin et a1.
`514/449
`4,960,790 10/1990 Stella et a1.
`5,403,858
`4/1995 Bastard et a]. ........................ .. 514/449
`
`OTHER PUBLICATIONS
`
`Merck Index. 11th Ed. #7559. (1989). p. 1207.
`CA. 106 (22): 182581c—Tarr et a1. (1987).
`
`Primary Examiner—Theodore J. Cn'ares
`Attomey, Agent, or Firm—-Finnegan. Henderson. Farabow.
`Garrett 8: Dunner. L.L.P.
`[57]
`ABSTRACT
`
`The invention provides new compositions containing taxane
`derivatives. consisting of solutions of such derivatives in a
`solvent mixture composed of ethanol and polysorbate. These
`compositions are used to prepare perfusionsi
`
`11 Claims, No Drawings
`
`MYLAN - EXHIBIT 1088
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`

`

`1
`COMPOSITIONS CONTAINING TAXANE
`DERIVATIVES
`
`5.750.561
`
`This is a continuation of application Ser. No. 07/930393.
`?led on Aug. 4. 1993. now abandoned.
`The present invention relates to compositions containing
`therapeutic agents having antitumour and antileukaemic
`activity. It relates more especially to pharmaceutical. and in
`particular injectable. dosage forms containing taxane
`derivatives. such as. in particular. taxol or one of its ana
`logues or derivatives of the following general formula:
`
`COO
`
`OAc
`
`15
`
`20
`
`30
`
`35
`
`Wherein R represents a hydrogen atom or an acetyl radical
`and R1 represents a tert-butoxycarbonylamino or benzoy
`lamino radical. The two derivatives in which R represents an
`25
`acetyl group and R1 at benzoylamino group or in which R
`represents a hydrogen atom and R1 a tert
`butoxycarbonylamino radical are preferred. The ?rst of
`these two compounds is better known by the name of taxol.
`and the second is known by the name of Taxotere.
`These products exhibit in vivo substantial activity against
`malignant tumours. which has enabled them to be studied in
`the treatment of diseases resistant to other anticancer thera
`pies.
`Unfortunately. these products possess such low solubility
`in water that it has been necessary to prepare a formulation
`for an injectable preparation based on surfactant and ethanol.
`Ethanol is the best solvent for dissolving compounds of the
`formula (I).
`As an example. according to the publication by Rowinsky.
`Lorraine. Cazenave and Donehower 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. For injection. this solution is mixed with a
`perfusion ?uid containing sodium chloride or dextrose. 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 concentration of
`active principle in the perfusion solution to concentrations 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 sufficient 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).
`This publication also discloses that. to obtain such con
`centrations (between 0.3 and 1 mg/ml). it is necessary to
`inject solutions containing. as well as the active principle.
`concentrations of each of the following compounds. ethanol
`
`55
`
`65
`
`2
`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 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 intoxication during the treatment.
`It has been discovered that. by the use of the pharmaceu
`tical dosage forms of the present invention. it is possible to
`avoid the use of Cremophor and greatly to reduce the ethanol
`concentrations used.
`For this purpose. a stock solution is prepared. containing
`the active principle of formula I in a solvent mixture
`composed of ethanol. which is the best biocompatible sol’
`vent for active principles of this class. and a polysorbate
`surfactant. e.g. as marketed. in particular. under the name
`‘"I‘ween”.
`The stock solution is prepared by dissolving the active
`principle in ethanol 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 present invention then makes it possible to replace
`the Cremophor. described in the publication of the Journal of
`National Cancer Institute. by a polysorbate. In effect. when
`an injectable solution containing ethanol and a polysorbate
`80 sm'factant in place of Cremophor was used in the clinical
`situation. it became apparent that the anaphylactic reactions
`were greatly reduced compared with the use of the same
`solution prepared with Cremophor. In addition to this con
`siderable advantage. it became apparent. most surprisingly.
`that. in the bottles of stock solution. the concentration of
`active principle can reach 15 mg/ml. The perfusion ?uid
`after dilution of these bottles contains an amount of ethanol.
`and also an amount of surfactant. which is reduced a little
`over twofold.
`The perfusions prepared from the above stock solutions.
`and containing a concentration of active principle of. e.g.. l
`myml. which is a preference. or less. contain less than 50
`mlll and preferably less than 35 mlll of surfactant and of
`ethanol. which represents a reduction of approximately 40%
`relative to the perfusions of the prior art.
`The new perfusions are stable from a physical standpoint.
`that is to say no precipitation phenomenon is seen to appear
`within approximately 8 hours.
`The taxol or Taxotere perfusions may be injected into
`humans at a predetermined ?ow 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 art are not observed with these
`solutions.
`The invention is described more completely in the
`Examples which follow. which are not to be considered as
`limiting the invention.
`
`EXAMPLES ACCORDING TO THE INVENTION
`
`EXAMPLE 1
`Taxotere (0.450 g) is dissolved in ethanol (15 ml). The
`mixture is made to 30 ml with polysorbate 80 to obtain a
`solution containing Taxotere (15 mg/ml). The physico
`chemical stability of this solution is satisfactory.
`After mixing with a 5% glucose solution so as to obtain
`a ?nal concentration of 1 mg/ml. this solution contains 33
`mlll of polysorbate 80 and 33 ml/l of ethanol.
`The perfusion is stable for more than 21 hours. i.e. no
`precipitation phenomenon is seen during this period.
`
`

`

`5.750.561
`
`3
`EXAMPLE 2
`
`Example 1 is reproduced with an initial concentration of
`10 mg/ml of Taxotere; the results are shown in Table l.
`
`COMPARATIVE EXAMPLE ACCORDING TO
`THE PRIOR ART
`
`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 the same perfusion solution as
`above to ?ve a ?nal concentration of 1 mgml; 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.
`
`15
`
`EXAMPLE 3
`
`4
`5. A perfusion. which contains approximately 1 mg/ml or
`less of co
`und of formula as e?ned in claim 1. and
`which contains less than 35 ml/l of ethanol and less than 35
`ml/l of polysorbate. wherein said perfusion is capable of
`being injected without anaphylactic or alcohol intoxication
`manifestations being associated therewith.
`6. A stock solution consisting essentially of a mixture of
`taxotere and ethanol in a ratio of about 3:100 by weight. and
`an amount of polysorbate to provide a solution containing
`about 10 to 15 mg/ml of taxotere. whereby said stock
`solution is used to form an injectable solution which con
`tains up to about 1 mg/ml of the compound of formula as
`de?ned in claim 1. said injectable solution being capable of
`being injected without anaphylactic or alcohol intoxication
`manifestations being associated herewith.
`7. A perfusion consisting essentially of the stock solution
`of claim 6 and an amount of glucose solution or dextrose
`solution to obtain a solution containing about 1 mg/ml of
`taxotere.
`8. A therapeutic composition consisting essentially of a
`taxane derivative dissolved in a mixture of ethanol and a
`polysorbate. whereby said therapeutic composition forms or
`is used to form an injectable solution which contains up to
`about 1 mg/ml of the compound of formula as de?ned in
`claim 1. said injectable solution being capable of being
`injected without anaphylactic or alcohol intoxication mani
`festations being associated herewith.
`9. The composition of claim 8 wherein said taxane
`derivative is taxol or an analogue or derivative thereof.
`
`Taxotere (65 g) is dissolved in ethanol (2083 ml). The
`volume is adjusted to 4147 ml by adding polysorbate 80
`(2083 ml). The mixture is homogenised by mechanical
`stirring. It is ?ltered through a ?lter of pore size 0.2 pm. A
`solution containing Taxotere (approximately 15 mg/ml) is
`obtained
`After dilution to a Taxotere content of 1 mg/ml in a
`perfusion bag containing 5% dextrose. this solution is stable
`for at least 96 hours.
`
`25
`
`TABLE 1
`
`Example
`
`Product
`
`Solvent
`
`Stock
`solution
`concentration
`
`Ethaml in
`Active
`Surfactant in the
`principle in
`the perfusion the perfusion perfusion Stability
`
`Comparative taxol
`taxol
`Taxotere
`Taxotere
`
`1
`2
`
`EtOH/Crern
`EtOH/Poly
`EtOH/Poly
`EtOH/Poly
`
`6 rug/ml
`6 myml
`15 mglml
`l0 mg/rnl
`
`1 mg/ml
`l rug/ml
`1 mg/ml
`l rug/ml
`
`87.7 ml/l
`83.3 rnl/l
`33.3 ml/l
`50 ml/]
`
`87.7 nil/l >21 H
`33.3 ml/l >21 H
`33.3 ml/l >21 H
`50 rnlll
`>21 H
`
`We claim:
`1. A composition consisting essentially of a compound of
`formula:
`
`40
`
`10. The composition of claim 8 wherein said taxane
`derivative is taxotere or an analogue or derivative thereof.
`11. A composition consisting essentially of a compound of
`formula
`
`(1)1
`
`COO
`
`45
`
`OAc
`
`in which R represents a hydrogen atom or an acetyl
`radical and R1‘ represents a tert-butoxycarbonylamino
`or benzloylammo radical. dissolved in a mixture of
`ethanol and a polysorbate whereby said composition is
`used to form an injectable solution which contains up
`to about 1
`ml of the compound of formula I. said
`injectable so ution being capable of being injected
`without anaphylactic or alcohol intoxication manifes
`tations being associated therewith.
`2. A composition according to claim 1. wherein. in the
`compound of formula (I). R represents a hydrogen atom and
`R1 represents a tert-butoxycarbonylamino radical.
`3. A composition according to claim 1. wherein. in the
`compound of formula (I). R represents an acetyl group and
`R1 represents a benzoylamino radical.
`4. A composition according to claim 1. which contains
`between 6 and 15 mgml of compound of formula (I).
`
`55
`
`65
`
`in which R represents a hydrogen atom or an acetyl radical
`and R1 represents a tert-butoxycarbonylamino or benzoy
`lamino radical.
`dissolved in a mixture of ethanol and polysorbate.
`wherein said ethanol is present in an amount of less
`than 5% and said polysorbate is present in an amount
`of less than 5%. said composition being used to forru an
`injectable solution capable of being injected without
`anaphylactic or alcohol intoxication manifestations
`being associated herewith.
`
`* * * *
`
`*
`
`

`

`UNITED ‘STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENTNO. ; 5,750,561
`DATED
`_ May12, 1998
`INVENTOWS) : BASTART et al.
`
`It is cer’tifled that error appears in the above~indenti?ed patent and that said Letters Patent is hereby
`corrected as shown below:
`
`Claim 1, column 3, lines 43-51, in the formula (I),
`
`" should read -—
`
`Signed and Sealed this
`Twenty-seventh Day of April, 1999
`
`Arresting OJWCEI‘
`
`Ac'ting Cummixu'oner of Parents and Trmlemurkx
`
`Q. TODD DICKINSON
`
`

`

`Disclaimer
`5,750,56l—Jean-Pierre, Bastart, Lesisn ; Thie?I Dugéachez, Villemoisson Sur Orge; Jean-Louis Fabre,
`Pans, all of France. COMPOSITIONS C hIITAINI G TA ANE DERIVATIVES. Patent Dated May 12, 1998.
`Dlsclalmer ?led November 8, 2007 by Assignee, Aventis Pharma SA.
`
`The term of this patent shall not extend beyond the expiration date of Patent No. 5,698,582.
`(O?lcial Gazette, November 24, 2009)
`
`