Document 1
Filed 11/09/2007
Page 1 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 2 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 3 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 4 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 5 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 6 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 7 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 8 of 9
Case 1:07-cv-00721-GMS
Document 1
Filed 11/09/2007
Page 9 of 9
Case 1:07-cv-00721-GMS
Document 1-2
Filed 11/09/2007
Page 1 of 8
Case 1:07-cv-00721-GMS
Document 1-2
~191 [ill [45] 1561
Filed 11/09/2007
Page 2 of 8
United States Patent
Bastart et al.
Patent Number: Date of Patent:
References Cited
5,714,512
Feb. 3, 1998
[54] NEW COMPOSITIONS CONTAINING TAXANE DERIVATIVES [75] Inventors: Jean-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
U.S. P m N T DO'CUMENTS
4,206221 6/1980 Miller et al. ............................ 4241278 4,960,790 1W1990 Stella et al. ............................. 5141449 5,403,858 41995 Bastart et al. .......................... 514/449
OTHER PUBLICATIONS
[21] Appl. No.: 568,760 [22] Filed:
Dec 7, 1995 Related U.S. Application Data
B.D. Tan, "A New Parenteral Vehicle for the Administration of Some Poorly Water Soluble Anti-Cancer Drugs," J. Parenter. Sci. Technol.. 41(1), 31-33 (1987). Merck Index. 11th ed. W559 (1989).
Primary Examiner-Amelia Owens Attorney, Agent, or Fi-Finnegan. Henderson. Farabow.
a. [63] Continuation-in-part of Ser. No. 398,011, M r 3, 1995,
which is a continuation-in-partof Sex No. 930,392,Aug. 23, 1993, Pat. No. 5,403,858.
Garrett & Dunner
POI
Foreign Application Priority Data
[571
ABSTRACT
Jut. 8, 1991
[51] [52] U.S. C1.
................................... 91 08527 Int. CL6 ................................................... A61K 31/335
France
m]
..........................514/449; 5491510; 514/471;
4241502
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.
[58] Field of Search
.............................. 5141449; 4241502
35 Claims, No Drawings
Case 1:07-cv-00721-GMS
Document 1-2
Filed 11/09/2007
Page 3 of 8
1
NEW COMPOSITIONS CONTAJNING TAXANE DERIVATNES
2
The preferred 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 This is a continuation-in-part of Ser. No. 081398,011. filed Mar. 3, 1995, which is a continuation-in-part of Ser. malignant tumors, which has enabled them to be studied in No. 071930,392. filed Aug. 23, 1993. now U.S. Pat. No. the treatment of diseases resistant to other anticancer thaa5,403.858 a national phase application of PCT/FR92/00624, pies. filed Jul. 3, 1992, hereby incorporated by reference. Unfortunately, these products possess such low solubility The present invention relates to compositions and espein water that it has been necessary to prepare formulations cially pharmaceutical dosage forms containing therapeutic for injection containing surfactant and ethanol. Ethanol is agents having antitumor and antileukemic activity. It relates the best solvent for dissolving compounds of formula (I). more especially to compositions suitable for injection conFor example, according to the publication by Rowinsky. taining taxane &rivatives, such as, in particular, taxol or one Lorraine, Cazenave and Donebower which appeared in the of its analogues or derivatives of the formula (I) Journal of the National Cancer Institute, vol. 82, No. 15, pages 1247-1259 on 1st Aug. 1990. a first solution, termed "stock solution". containing approximately 6 mghl 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 fluid 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 concentration of active principle in the perfusion solution to conin which R, and R, each represent a hydrogen atom or one centrations of approximately 0.03 to 0.6 mglrnl (see above of R, and R, represents a hydrogen atom and the other publication, page 1251. column 1. third paragraph). represents a hydroxy. acyloxy, or acylcarbonyloxy radical, Now, it is desirable to be able to inject sufficient doses of or R, represents a hydrogen atom and R, forms a single active principle; to this end, clinicians would like to inject bond together with the methyl carbon atom situated in the a concentrations of active principle of between approximately position. so they can form together a cyclopropane ring. one 0.3 and 1 mg/ml in the perfusion fluid; above these doses, of R, and R4 represents a hydrogen atom and the other anaphylactic shock phenomena which are difficult to represents a hydroxy radical, or R, and R4 taken together control, due in the main to the Cremophor. are seen (see the form a 0x0 radical, R, and & each represent each a hydrogen atom or one of R, and & represents a hydrogen publication by Rowinsky, page 1250, second column, last atom and the other represents a hydroxy, acyloxy, acylcarparagraph). bonyloxy or a alkoxymethylcarbonyloxyradical. or R, and Still according to this publication, to obtain such concen& taken together form a 0x0 radical, R7 represents an trations (between 0.3 and 1 mghl), it is necessary to inject alkoxy, alkenyloxy. cycloallcyloxy or phenyl radical and Ar solutions containing, at the same time as the activeprinciple, represents an aryl radical or preferably a phenyl radical concentrations of each of the following compounds. ethanol optionally substituted by one or several atoms or radicals and most especially Cremophor. of approximately 8 g per identical or different and selected from halogen. alkvl. l 100 m of solution. Since the treatment often requires the alkoxy, dialkylamino. acylamino, alkylcarbon$unino -or administration of high doses of active principle. and since ~ u o r o m e t h v l or a 5 membered heterocvclic radical with . the concentration of the active principle, and since the one or more identical or different heteroaioms chosen from concentration of the active principle in the solution is nitrogen, oxygen or sulfur, it being understood that alkyl relatively low, the injection of a large volume has the effect radicals are straight chain or branched chain and contain 1 of causing, in addition to anaphylactic manifestations, manito 8 carbon atoms and the alkenyl radicals contain 2 to 8 festations of alcohol poisoning during the treatment. carbon atoms. In one embodiment, it is preferred that when The present invention provides compositions that make it R, is a hydrogen atom and R, is a hydroxy radical, R, and possible either to reduce the ethanol concentrations greatly, R4 cannot be simultaneously an 0x0 radical when % is a or to eliminate Cremophor and ethanol completely from the hydrogen atom, R, is a hydroxy or acetyloxy radical, R7 is perfusions. a t.butoxy or a phenyl radical and Ar is a phenyl radical. For this purpose. according to a first implementation of I Representative taxane derivatives of the formula ( ) the present invention, a composition suitable for use as a include the following wherein R, represents a hydrogen stock solution is prepared, containing a compound of foratom and R, represents a hydrogen atom or a hydroxy mula I as defined above dissolved in a surfactant which may radical. or R, forms a single bond together with the methyl be a polysorbate, e.g. as marketed under the name 'Tween", carbon atom situated in the a position, so they can form a polyoxyethylatedvegetable oil as marketed. e.g., under the together a cyclopropane cycle, R, and R4 taken together polyethoxylated castor oil, also known as name "~ulphor", , form an 0x0 radical, % represents a hydrogen atom and R glycerol polyethyleneglycol ricinoleate. as marketed, e.g.. represents a hydrogei atom or a hydroxy, acetyloxy & under the name Cremophor preferably CREMOPHORB EL, methoxyacetyloxy radical, or R, and % taken together form and virtually free from ethanol. CREMOPHOR@ EL is a an 0x0 radical. R, represents a t.butoxy or a phenyl radical and non-ionic solubiliz~r emulsifier that can be obtained by and Ar is a phenyl radical. In one embodiment. it is preferred reacting ethylene oxide with castor oil in a molar ratio of that when R, is a hydrogen atom and R, is a hydroxy radical, 3 5 4 0 mol ethylene oxide to 1 mol glyceride and is comR, and R4 cannot be simultaneously an 0x0 radical when R, mercially available from BASF and has been assigned CAS is a hydrogen atom. % is a hydroxy or acetyloxy radical, R7 Registry Number 61791-12-6. The main component of is a t.butoxy or a phenyl radical and Ar is a phenyl radical. CREMOPHORB EL is glycerol-polyethyleneglycol
Case 1:07-cv-00721-GMS
Document 1-2
Filed 11/09/2007
Page 4 of 8
5,714,512
3
ricinoleate, which together with fatty acid esters of polyethylene glycol, represents the hydrophobic part of the product. The smaller, hydrophilic part consists of polyethylene glycols and ethoxylated glycerol. The stock solution may be prepared by dissolving the 5 active principle in ethanol, which is the best biocompatible solvent fa taxane derivatives, and then gradually adding the the surfactant. Solutions containing 10 to 100 m g / d of active principle in a mixture containing approximately 50% of surfactant can be prepared in this manner. The ethanol is 10 then completely. or almost completely. eliminated. To prepare. according to the present invention, the solution having a low ethanol content, the mane derivative is dissolved in ethanol. and the surfactant. 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 SO~Ution is then removed at least partially by evaporation under vacuum or by any other suitable means. According to a second method of preparing the stock solution. the taxane derivative is dissolved directly in the 20 surfactant. According to a prefmed 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 o a r centrifugal disintegrator. The presence of a small amount of 25 ethanol provides several advantages: the medium possesses a lower viscosity, and the wetting of the powder and the final filtration of the solution are improved The stock solution. having a low ethanol content. preferably contains less than 5% of ethanol; still more preferably. 30 it contains less than 2% of ethanol. This solution is stable and can contain up to 200 mg/ml, preferably up to 80 mgfml, of active principle in the surfactant. A stock sohtion of tax01 Possesses still more preferably a concentration of between 6 and20 mglml of active principle in the surfactant. This solution can be mixed, in particular to 35 provide a final concentration of between 0.1 and 1 mg per milliliter, with the perfusion fluid, which can be physiological 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 @ml of taxol and 40 less than 1 mV1 of ethanol. The tax01 perfusion containing the active principle without 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 ~ r e c i ~ 45 - itation after 8 to 10 hours of storage at r&m temperature.
a
4
Taxotere; they preferably contain less than 15 mVI of surfactant and less than 1 mV1 of ethanol. The Taxotae perfusion containing the active principle without ethanol possesses a physical stability which can several months. The taxol or Taxotere pdsions may be injected into humans at a predetermined flow rate depending on the amount of active principle it is desired to injeb. The anaphylactic shock phenomena which were observed with the solutions of the prior can be avoided with these solutions. 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%. invention is illustrated by the following Examples. COMF'ARKIWE EXAMPLE ACCORDING TO THE PRIOR AFS ~axol (0.180 g) is dissolved in ethanol (15 ml). The lnixture is to volume with cremophor to obtain a solution (30 which contains taxol (6 wml). This solution is diluted i a 5% glucose perfusion in a n proportion of 1mg/d; the perfusion solution in a proportion of 1 mglml; the perfusion solution contains 87.7 mVI of Cremophor and 87.7 ml/l of ethanol. The perfusion solution is stable for more than 21 hours.
EXAMPLES 1-7
Taxotae (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 mg 2 hmS. me solution obtained is for it contains T~~~~~ (40 mg/d). After dilution is a 5 % glucose perfusion solution at concentrations 0.l- 0-3 and 0.5 mgfml, the stability of the solutions obtained is ob~erved. The same method is reproduced using a solution containing Taxotme (60 m g / d ) . The same test is reproduced using taxol solutions containing taxol (12 and 20 mgld). The results are shown in Table 1.
Roduct
Solvent Polysorbate Polydate Polysorbate Polysorbatc Polysorbate Polysorbate Polysorbate
Stock solution concemration
20 mg/d 20 m g / d
Active principle Surfactant in Ethanol in in thc perfusion t e perfusion the perfusion Stability h
1
tax01 tax01 taxol Taxotm Taxoh Taxoten Taxoh
ms/ml
12 m g / d 40 @ml
40 @ l m
40 mg/ml 60 @ml
0.3 mglml 1 mglml 0.5 mglml
0.3 mglml 0.1 m g f d
0.1 @ml
5 mlll 0 1 mV1 5 83.3 mV1 11.6 mV1 6.0 mV1 23 mV1 .
1.5mV1
4.3 mV1 s8 H 4.09 mYI >24 H 4.5 mlll >48 H 0.09 mlll 8 H 2 H -3 0.05 d l 8 H 2 H -3 0.02 mlll 29 H 4 5 H 4.01mV1 8H-23H
EXAMPLE 8 A stock solution of Taxotere preferably possesses a con- 60 centration of b~tween and 80 WZdd of active principle in 20 Into a stainless steel reactor, Taxotere (258 g) is introthe surfactant. This solution can be mixed, in particular to duced and dissolved in ethanol (2425 g) with mechanical stirring for 45 minutes. Polysorbate 80 (6156 g) is added and provide a final concentration of between 0.1 and 0.5 mg per the mixture is homogenized with mechanical stirring for 15 milliliter. with the perfusion fluid, which can be a physiological saline or a glucose solution. Perfusion prepared 65 minutes. The solution is transferred to a reactor and the from the above stock solutions having a low ethanol content alcohol is distilled off under a reduced pressure of 10 to 50 contain still more preferably between 0.1 and 0.3 m g / d of millibars (1000 to 5000 Pa), the temperature being main-
Case 1:07-cv-00721-GMS
Document 1-2
5,714,512
Filed 11/09/2007
Page 5 of 8
5
6
tainedatbetween18"and28"C.Thealcoho1issti11edoff trihydroxy-9-0x0-11-taxen-13a-yl 3-tuntil its content is less than 2%. butoxycarbonylamino-3-(2-fluorophenyl)-2-hydroxy-(2R. 3S)-propionate. After dilution in a 0.9% aqueous sodium The solution obtained is filtered though a filter having a chloride perfusion solution to a concentration of 1 mg/ml. pore size of 0.2 p It contains: 5 the solution obtained is stable for more than 24 hours. ethanol (1.3%) Taxotere (39.6 mgtml). EXAMPLE 12 After dilution to mg/ml in a perfusion bag containing 5% glucose, the solution is stable without apparent precipitation 4-acetoxy-2a-benzoyloxy-5P,20-epoxy1,7P, lopfor a period of more than two months. trihydroxy-9-0x0-11-taxen- 13a-yl 3-tbutoxycarbonylamino-3-(4-chlorophenyl)-2-hy&oxy-(2R, EXAMPLE 9 3s)-propionate (20 mg) was placed in a round bottomed flask and dissolved in absolute ethanol (0.4 ml). After T~~~~~~ (160 mg) or taxol (160 is dissolved in a dissolution, polysorbate 80 (0.5 ml) was added and the mixture (10 ml) of absolute ethanol (2 ml) and Cremophor EL,(218) (8 ml). and the ethanol is evaporated off in a rotary 15 mixture was homogenized with the aid of magnetic stirrerThe flask was placed in a WcUm using a rotary evaporator evaporator at 30" C. at a pressure of 25 mmHg for three ~h~~ contain 20 and the alcohol was distilled off under reduced pressure (10 hours. ~h~ solutions obtained are of T~~~~~~~taxol, aer or dilutionin a 5% glucose mmHg) for one hour. The solution obtained is perfectly clear and contains 40 mglml of 4-acetoxy-201-benzoyloxy-5P.20perfusion solution at concentrations of 0.1 and 0.5 mg/ml, precipitation is observed at between 30 and 95 hours. 20 epoxy-1.7~.10~-trihydroxy-9-oxo-ll-taxen-13a-yl 3-tbutoxycarbonylamino-3-(4-chlorophenyl)-2-hydroxy-(2R, 3s)-propionate. After dilution in a 0.9% aqueous sodium EXAMPLE 10 chloride perfusion solution to a concentration of 1 m g m , ~ol~sorbate (275.5 g) and absolute ethanol (5.4 g) are 80 the solution obtained was stable for more than 2A hours. placed in a 500-mlErlenmeyer flask, and the mixture is then stirred with a bar magnet until completely homogenized. 25 EXAMPLE 13 The solution prepared above (26.13 g) in a 50 m flask, l 4a. 10~-diacetoxy-2a-benzo~ -5 P.20-epoxy- 1Ploxy placed in a water bath heated beforehand and maintained hydroxy-7P,8P-methylene-9 -oxo- 19-nor-11-taxen-13a-yl throughout the test period at 30' C.. is stirred at approxi3-t-butoxycarbonylamino-2-hydroxy-3-phenyl-2-(2R,3S)mately 600 rpm with a bat magnet. With a spatula,Taxotere (1.076 g) is added in several portions so that the clumps 30 propionate (20 mg) was placed in a round bottomed flask disappear between two additions (the duration of the operaand dissolved in absolute ethanol (0.4 ml). After dissolution, tion is approximately one hour). After incorporation of the polysorbate 80 (0.5 ml) was added and the mixture was last fraction of Taxotere. stining is maintained until the homogenized with the aid of a magnetic stirrer. The flask solution becomes clear (approximately two hours). was placed in a vacuum using a rotary evaporator and the 35 alcohol was distilled off under reduced pressure (10 rnmHg) EXAMPLE 11 for one hour. The solution obtained is perfectly clear and 4-acetoxy-2a-benzoyloxy-5P.20-epoxy-1,7, contains 40 @& of 4a.10P-diacetox~-2a-benzo~10x~-5$. trihydroxy-9-0x0-11-taxen-13a-yl 3- 20-epoxy-1~-hydroxy-7~.8~-methylene-9-oxo-19-nor-11butoxyc~bonylamino-3-(2-fluorophenyl)-2-y(, taxen-13a-~1 3-t-but0x~carb0n~1amin0-2-h~dr0x~-3)S)-popiionate (20 mg) is placed in round boftom flask a d 40 ~ h e n ~ ~ - ( 2 R 3 S ) - ~ ~ @ ~ in a 0.9% aqueous ~ ~~~~-Af~ sodium chloride perfusion solution to a concentration of 1 dissolved in absolute ethanol (0.4 m ~ , dissolution, m&d. the obtained was stable for more than 24 plysorbate 80 (0.5 d ) is ad&d and the mix- is homoghoursenized with the aid of a magnetic stirrer. The flask is placed in a vacuum using a rotary evaporator and the alcohol is 45 TAXOL is the compound of formula I in which Ar is distilled off under reducedpressure (10 d g ) for one hour. unsubstituted phenyl. R, is phenyl, R is acetyloxy. R is , , The solution obtained is perfectly clear and contains 40 hydrogen, R, and R taken together form an 0x0 radical, R, , m g l d of 4-acetoxy-2a-benzoyloxy-5~,20-epoxy-1,7~.10~ hydroxy, and R is hydrogen, as shown below: is ,
wd
-
Case 1:07-cv-00721-GMS
Document 1-2
Filed 11/09/2007
Page 6 of 8
2 0
TAXOTERE is the compound of formula I in which Ar is unsubstituted phenyl, R is t.butoxy. R is hydroxy. & is , , , hydrogen, R and % taken together form an 0x0 radical, R, , is hydroxy and R is hydrogen. as shown below:
5. The composition of claim 2. wherein said surfactant is polyethoxylated castor oil. 6. The composition of claim 1. wherein R is hydroxy and , R, is tbutoxy. 7. The composition of claim 6, wherein said surfactant is 25 0 poly sorbate. 8. The composition of claim 6. wherein said surfactant is polyoxyethylated vegetable oil. 9. The composition of claim 6, wherein said surfactant is 30 polyethoxylated castor oil. 10. The composition of claim 1, said composition being a 0 stock solution containing less than 5 volume % ethanol. 11. The composition of claim 10, said composition containing less than 2 volume 8 ethanol. 12. The composition of claim 10, said composition con35 taining from I to 2 volume % ethanol. 13. ?he composition of claim 1, said composition containing up to 200 mg/ml of the compound of formula (I). 14. The composition of claim 13, said composition containing from 10 to 80 mg/ml of the compound of formula (I). 40 15. The composition of claim 14, said composition containing from 20 to 80 mg/ml of the compound of formula (I). We claim: 16. The composition of claim 13, said composition con1. A composition comprising a compound of the formula taining from 6 to 20 mg/d of the compound of formula (I). (I) 17. The composition of claim 13. said composition con45 taining up to 80 m g h l of the compound of formula (I). 18. The composition of claim 1. said composition being a perfusion containing less than 0.5 mgtml of said compound R?C
do
Case 1:07-cv-00721-GMS
Document 1-2 5,714,512
Filed 11/09/2007
Page 7 of 8
9
10
26. The stock solution of claim 25, wherein said stock solution contains from 12 to 80 mg/ml of said compound of Q) formula (I). 2 . The stock solution of claim 26, wherein said stock 7 solution contains from 20 to 80 mg/ml of said compound of 1 2 1 formula (I). Ar 28. The stock solution of claim 24, wherein R, is acety4 o loxy and R7 is phenyl. b~ 14 1 29.The stock solution of claim 28. wherein said surfactant Ho 2 bc0c~~ is polysorbate. 'O 30. The stock solution of claim28, wherein said surfactant OCOCaHs is polyoxyethylated vegetable oil. in which Ar is unsubstituted phenyl, R, is phenyl or t.butoxy, 31.The stock solution of claim 28,wherein said surfactant , , , is polyethoxylated castor oil. &is hydrogen, R is acetyloxy or hydroxy, R and R taken 32. The stock solution of claim 24, wherein R is hydroxy , together form an 0x0 radical. R, is hydroxy and R, is hydrogen. said compound being dissolved in a surfactant 15 and R7 is t.butoxy. 33. stock solution of claim 32,wherein said surfactant The selected from polysorbate, polyoxyethylated vegetable oil. is pol~sorbate. and polyethoxylated castor oil, wherein said stock solution 34.The stock solution of claim 32,wherein said surfactant containsfrom 10 to 200 mg/ml said of of formula is polyoxyethylated vegetable oil. 0. 35. The stock solution of claim 32, wherein said surfactant 25. ~h~ stock solution of claim 24. wherein said stock 2 0 polyethoxylated castor solution contains from 10 to 80 mglrnl of said compound of formula (I). * * 3 * *
Case 1:07-cv-00721-GMS
Document 1-2 Filed 11/09/2007 Page 8 of 8 UNITED STATES PATENT AND TRADEMARK OFmCE
CERTIFICATE OF CORRECTION
PATENT NO. :
DATED
INVENTOR(S) :
5,714,512 February 3, 1998 Jean-Pierre Bastart et al.
It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:
Claim 1, Column 7, Line 56, "t.butoxyW should read --tert-butoxy--; Claim 6, Column 8, Line 24, "t.butoxy" should read --tert-butoxy--; should read --tert-butoxy--; Claim 24, Column 9, Line 12, "t.butoxyW Claim 32, Column 10, Line 15, "t.butoxyUshould read --tert-butoxy-.
Signed and Sealed this Twenty-firstDay of September, 1999
Attest:
Q. TODD DICKINSON
Attesting oficer
A c t i n x C o n r n ~ i s s i ~ ~ r orf rP i z r e n l s cord TrademorL~ r '
Case 1:07-cv-00721-GMS
Document 1-3
Filed 11/09/2007
Page 1 of 5
Case 1:07-cv-00721-GMS
Document 1-3
Filed 11/09/2007
Page 2 of 5
United States Patent
Bastart et al.
1191
[ill [a]
Patent Number: Date of Patent:
5,750,561
*May 12, 1998
5141449. 471. 5 141408; 4241502
[54] COMPOSITIONS CONTAINTNG TAXANE DERIVATIVES [75] Inventors: Jean-Pierre Bastart, Lesigny; Thierry Dupechez. Villernoisson Sur Orge; Jean-Louis Fabre, Paris, all of France [73] Assignee: RhonePoulenc Rorer, S.A., Antony Cedex. France
[* ]
[58] Field of Search
.....................................
1561
References Cited
U.S. PATENT DOCUMENTS
Notice:
The term of this patent shall not extend beyond the expiration date of Pat. No. 5,403.858.
4.206321 #I980 MiUer et al. ............................ 4,814,470 311989 Colin et al. ............................. 4,960,790 10/1990 Stellaetal. ............................. 5,403,858 4/1995 Bastard et al. ..........................
424Q78 514449 514449 514449
OTHER PUBLICATIONS Merck Index. 11th Ed.. #7559. (1989). p. 1207. C.A. 106 (22): 182581~-Tarr et al. (1987). Primary Examiner-Theodore J. Criares Attornex Agent, or Firm--Finnegan. Henderson. Farabow. Garrett & Dunner. L.L.P. [571
[21] Appl. No.: 422,672 [22] Filed:
Apr. 12, 1995 Related U.S. Application Data
[63] Continuation of Ser. No. 930,393, Aug. 4,1993, abandoned. Foreign Application Priority Data [301
Ju1. 8, 1991
ABSTRACT
m]
France
.................................... 9108527
A61K 9/50 4241502
[5 11 h. C1.6 t [52] U.S. C1.
........................ A61K 31/35; A61K 3 1/34;
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 perfusions.
..........................5141449; 5141471; 5141408;
11 Claims, No Drawings
Case 1:07-cv-00721-GMS
Document 1-3
5,750,561
Filed 11/09/2007
Page 3 of 5
1
COMPOSITIONS CONTAINING TAXANE DERIVATIVES
This is a continuation of application Ser. NO.071930393. filed on Aug. 4, 1993, now abandoned. The present invention relates to compositions containing therapeutic agents having antiturnour and antileukaemic activity. It relates more especially to pharmaceutical. and in particular injectable. dosage forms containing taxane derivatives* such as. in particular. Or One of its arialogues or derivatives of the following general formula:
0
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,inaddition to anaphylactic manifestations.rnanifestations of alcohol intoxication during the treatment. It has been discovered that, by the use of the pharmaceutical 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-
5
lo
O
~
o
o
HO
~
o
H
~15 vent for active as marketed. in particular, under the name surfactant. e.g. principles of this class. and a polysorbate "Neen".
The stock solution is prepared by dissolving the active principle in ethanol and then gradually adding the surfactant. Solutions containing 10 to 100 mglml 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 surfactant in place of Cremophorwas usedin 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 considerable 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 fluid 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.. 1 mglml, which is a preference, or less. contain less than 50 myl and preferably less than 35 ml/l of surfactant and of ethanol. which represents a reduction of approximately 40% relative to h e 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 tax01 or Taxotere perfusions may be injected into humans a a predetermined flow rate depending on the t 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.
\
b~z $
0Ac
20
Wherein R represents a hy&%en atom or an acetyl radical and R, represents a tert-butox~carbon~l-0 or benzoylamino rdkal. The two derivatives in which R rePresentsan 25 acewl group and R, a b e n z o ~ l d n o group or in which R represents a hydrogen atom and R I a tertbutox~carbon~lamino mdical are preferred. The first of these two compounds is better hewn by the name of -01and the second is known by the name of Taxotere. 30 substantial activity against These p r ~ d ~ cexhibit in V ~ V O ts malignant tumours. which has enabled them to be studied in the treatment of di~eases resistant to other anticancer thenpies. Unfortunately, these products Possess such low solubility 35 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 com~ounds the of formula (I). As an example. according to the publication by Rowinsky, M I Lorraine. Cazenave and I X m k ~ e which appeared in the r Journal of the National Cancer Institute, V O ~ . 82, NO. 15, 1990. a first solution, termed Pages 1247-1259 on 1st "stock solution", containing approximately 6 Wfml of tax01 in a solvent mixture composed of: 4s 50% by volume of ethanol 50% by volume of Cremophor EL. is prepared. For injection. this solution is mixed with a perfusion fluid containing sodium chloride or dextrose. To obtain a mixture which is stable from both a physical 50 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 m g / d (see above publication, 55 page 1251. column 1, third paragraph). EXAMPLES ACCORDING TO THE INVENTION Now. it is desirable to be able to iniect sufficient doses of active principle; to this end, clinicians would like to inject m P L E1 concentrations of active principle of between approximately Taxotme (0.450 g) is dissolved in ethanol (15 ml). The 0.3 and 1 mg/ml in the perfusion fluid; above these doses. l 80 anaphylactic shock phenomena which are difficult to 60 mixwe is made to 30 m with Pl~sorbate to obtain a control. due in the main to the Cremophor, are seen (see the solution containing Taxotere (15 mgld). The physicopublication by Rowinsky, page 1250. second column. last chemical stability of this solution is satisfactory. After mixing with a 5% glucose solution so as to obtain paragraph). a final concentration of 1 rng/ml, this solution contains 33 This publication also discloses that, to obtain such concentrations (between 0.3 and 1 mglml), it is necessary to 6s ml/l of polysorbate 80 and 33 mV1 of ethanol. The perfusion is stable for more than 21 hours, ire. no inject solutions containing. as well as the active principle, concentrations of each of the following compounds. ethanol precipitation phenomenon is seen during this period
Case 1:07-cv-00721-GMS
Document 1-3
Filed 11/09/2007
Page 4 of 5
3
EXAMPLE 2
4
5. A perfusion, which contains a roximately 1 mg/ml or less of compound of formula as %fined in claim 1. and which contams less than 35 mV1of ethanol and less than 35 mV1 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 m g h l of taxotere, whereby said stock solution is used to form an injectable solution which conof as tains up to about 1 mdml of the defined in claim 1. said injectable solution being capable of being injected without anaphylactic or alcohol intoxication
Example 1 is reproduced with an initial concentration of
10 m g h l of Taxotere; the results are shown in Table 1.
COMPARATIVE EXAMPLE ACCORDING TO THE PRIOR ART Tax01 (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 tax01 (6 mgfml). This solution is diluted in the same perfusion solution as above to five a final concentrationof 1 mg/ml; perfusion the solution contains mV1 of Cremophor and 87.7 mljl of ethanol. The perfusion solution is stable for more than 21 hours.
10
stock solution of claim and an amount of glucose solution or dexeose solution to obtain a solution containing about 1 mg/ml of EXAMPLE 3 taxotere, 8.A therapeutic composition consisting essentially of a (2083 ~h~ Taxotere (65 g) is dissolved in in a mixture Of and a volume is adjusted to 4147 ml by adding polysorbate 80 is homogenised by mechanical 20 polysorbate, whereby said therapeutic composition forms or (2083 *). The is used to form an injectable solution which contains up to stirring. It is filtered through a of pore size 0'2 A about 1 mgIml of the of formula as defined in is solution containing Taxotere (approximately claim 1, said injectable solution being capable of being obtained. injected without anaphylactic or alcohol intoxication maniAfter dilution to a Taxotere content of 1 m g / d in a festations being associated herewith. perfusion bag containing 5% dextrose. this solution is stable 25 9. The composition of claim 8 wherein said taxane derivative is tax01 or an analogue or derivative thereof. for at least 96 hours.
l5
m $ ~6 ~ ~ ~ $ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ $ ' ;
TABLE 1
Stock
Example
Roduct Solvent solution concentration
Ethanol in Active principle in Surfactant in the the perfusion the pedusial perhrsion Stability
1W m l 1 mg/ml 1 mghl 1 @ml
Comparative tax01 tax01 1 Taxotere 2 Taxotere
EtOWCrem
EtOHlPoly EtOWPoly EtOWPoly
6 @ml 6 @l m 15 @ml 10 &ml
87.7 mlll 83.3 d l 33.3 d l 50 d
87.7 mY1 >21 H 83.3 mV1 >21 H 33.3 mV1 >2l H 50 mV1 >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
in which R represents a hydrogen atom or an acetyl radical and R4 represents a tert-butoxycarbonylamino or benwylammo radical. dissolved in a mixture of ethanol and a polysorbate whereby said composition is 55 in which R represents a hydrogen atom or an acetyl radical and R, reqresents a tert-butoxycarbonylamino or benzoyused to form an injectable solution which contains up to about 1 mfml of the compound of formula I said . lamino radml. injectable so ution being capable of being injected dissolved in a mixture of ethanol and polysorbate. without anaphylactic or alcohol intoxication manifeswherein said ethanol is present in an amount of less tations being associated therewith. 6, than 5% and said polysorbate is present in an amount 2. A composition according to claim 1. wherein. in the of less than 5%. said composition being used to form an compound of formula (I).R represents a hydrogen atom and R, represents a tert-butoxycarbonylamino radical. injectable solution capable of being injected without 3. A composition according to claim 1. wherein. in the anaphylactic or alcohol intoxication manifestations Irepresents an acetyl group and 65 , compound of formula (R) being associated herewith. R, represents a benzoylamino radical. 4. A composition according to claim 1, which contains between 6 and 15 mglml of compound of formula (I).
Case 1:07-cv-00721-GMS
Document 1-3
Filed 11/09/2007
Page 5 of 5
UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT NO. : DATED INVENTOR(S) :
5,750,561 . May 12, 1998 BASTART et al.
It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby corrected as shown below:
Claim 1, column 3, lines 43-51, in the formula (I),
Signed and Sealed this
Twentyseventh Day of April, 1999
Arrest:
Q. TODD DICKINSON
Attesting Officer
A i 1111sC o o ~ r i ~ i s . $ r o ~ Pl~lt'llt.~ Trirdenri~i'k.~ rf ~ e r arrd
Case 1:07-cv-00721-GMS
Document 1-4
Filed 11/09/2007
Page 1 of 1
Case 1:07-cv-00721-GMS
Document 1-5
Filed 11/09/2007
Page 1 of 1
United States Free Forms
Canada Free Forms
United Kingdom Free Forms
Australia Free Forms