(12) United States Patent
`Brittain et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,895,756 B2
`*Nov. 25, 2014
`
`US008895756B2
`
`(54) BENDAMUSTINE PHARMACEUTICAL
`COMPOSITIONS
`.
`(71) Applicant: Cephalon, Inc., Frazer, PA (US)
`.
`Inventors: Jason Edward Brittain, El Cajon, CA
`(US); Joe Craig Franklin, Tulsa, OK
`(US)
`
`(72)
`
`(73) Assignee: Cephalon, Inc., Frazer, PA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`w4<b>
`This patent is subject to a terminal dis-
`
`(21) APP1,N0,I 13/719,409
`
`(22)
`
`Filed:
`
`Dec. 19, 2012
`
`5,413,995 A
`5,418,223 A
`5,750,131 A
`5,770,230 A
`5,776,456 A
`5,955,504 A
`5,972,912 A
`5,034,255 A
`6,077,850 A
`6,090,365 A
`
`6,492,390 B2
`6,545,034 B1
`5,559,402 B1
`2121252; 2:
`5,780,324 B2
`2152132 2:
`2002/0102215 A1
`2003/0232874 A1
`2004/0053972 A1
`2004/0058956 A1
`2004/0072889 A1
`
`5/1995 Alexander et al.
`5/1995 Palepu et al.
`5/1998 Wichert et al.
`1.
`6/1998 '1'
`d
`t
`7/1998 Aiadiirsoilei 3
`9/1999 Wechter et al.
`10/1999 Marek et a1.
`3/2000 Carter ct al,
`6/2000 Carter et al.
`7/2000 Kaminski et al.
`gigtiirlfrtlglét al.
`12/2002 Carter et al.
`4/2003 Carson et a1.
`5/2003 Chccsman ct a1,
`2/223:
`8/2004 Le Qarrec et a1,
`2/231: 1:11:1:.:::1
`8/2002 K1
`1‘
`12/2003 N:r:1:I111:SSe a
`3/2004 Nara
`3/2004 Akiyama et al.
`4/2004 Masferrer
`
`1.
`
`(65)
`
`Prior Publication Data
`
`2004/0096436 A1
`2004/0152672 A1
`
`5/2004 Carson et al.
`8/2004 Carson et al.
`
`US 2013/013113] A]
`
`May 23, 2013
`
`2004/0247600 A1
`2005/0020615 A1
`
`12/2004 Leoni
`1/2005 Rubino
`
`Related U.S. Application Data
`(63) Continuation of application No. 13/654,898, filed on
`
`HOIICS Ct 3.1.
`(commued)
`
`contmuatron of application No. 11/330,868, filed on
`Jan. 12, 2006, now Pat. No. 8,436,190.
`(60) Provisional application No. 60/644,354, filed on Jan.
`14,
`
`DE
`DE
`
`34727
`80967
`
`12/1964
`/
`6 1970
`.
`(COI1t1I111€d)
`OTHER PUBLICATIONS
`
`(51)
`
`Int. Cl.
`C07D 235/04
`A61K 9/19
`A61K 9/00
`A61K31/4184
`A 61K 47/10
`(52) U'S' Cl‘
`CPC ............... .. A61K 9/19 (2013.01); A61K 9/0019
`(2013~01)SA61K31/4184 (2013-01);/161K
`47/10 (2013.01)
`USPC ........................................ .. 548/304.7; 34/284
`(58) Field ofClassification Search
`USPC ........................................ .. 34/284; 548/304.7
`gee a
`“Cation me for Com lete gearch him)
`‘
`P
`‘
`‘
`References Cited
`U.S. PATENT DOCUMENTS
`
`pp
`
`(56)
`
`ry‘
`
`(200601)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`3,590,028 A
`4,012,448 A
`4,537,883 A
`4,659,699 A
`4,670,262 A
`5,036,060 A
`5,066,647 A
`5,130,305 A
`5,183,746 A
`5,192,743 A
`5,204,335 A
`5,227,373 A
`5,227,374 A
`5,268,368 A
`
`6/1971 Report et al.
`3/1977 Smith et al.
`8/1985 Alexander et al.
`4/1987 Francis
`6/1987 Battelli et al.
`7/1991 Alam et al.
`11/1991 Palepu et al.
`7/1992 Palepu et al.
`2/1993 Shaked et al.
`3/1993 Hsu et al.
`4/1993 Sauerbier et al.
`7/1993 Alexander et al.
`7/1993 Alexander et al.
`12/1993 Palepu
`
`Kanekal et al., Kanekal et al. (SDX-l05(Treanda) Enhances the
`Tumor Growth Inhibitory Effect of Rituximab in Daudi Lymphoma
`Xenografts, 2004, Blood (ASH Annual Meeting Abstracts), vol.
`113:3 T
`d 2013
`1 2 *
`is,
`rean a,
`,pp.
`-
`.
`Aivado et al ., “Bendamustine in tlie treatment ofchronic lymphocytic
`leukemia: Results and future perspectives”, Seminars in Oncology,
`Aug. 2002, 29(4), 1942, Suppl. 13.
`Barman Balfour et al., “Bendamustine”, Drugs, 2001, 61(5), 631-
`638, Auckland, New Zealand.
`Berge et a1., “Pharmaceutical Salts”, -I011fI1a1 Of Pharmaceutical Sci-
`encesslam197Za§6<1>a1-19~
`_
`_
`_
`Bremen K411’ Hlgh mes °f 1°“g".aS““g ““*“““‘°“S after 5'd"Y
`bendamustine chemotherapy cycles in pre-treated low-grade non-
`hodgkin’s-lymphomas”, Journal of Cancer Research and Clinical
`Oncology, 2002, 128(l1), 603-609.
`(Continued)
`
`Primary Examiner — Ali Soroush
`(74) Attorney, Agent, or Firm — Baker & Hostetler LLP
`
`(57)
`
`ABSTRACT
`
`The present invention provides pharmaceutical formulations
`of lyophilized bendamustine suitable for pharmaceutical use.
`The present invention further provides methods of producing
`lyophilized bendamustine. The pharmaceutical formulations
`can be used for any disease that is sensitive to treatment with
`bendamustine, such as neoplastic diseases.
`
`4 Claims, 6 Drawing Sheets
`
`FRESENIUS KABI 1001-OOO1
`
`

`
`US 8,895,756 B2
`Page 2
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`2005/0176678 A1
`2006/0051412 A1
`2006/0128777 A1
`2009/0264488 A1
`2011/0190363 A1
`2012/0071532 A1
`2013/0041003 A1
`
`8/2005 Horres et al.
`3/2006 Petereit et al.
`6/2006 Bendall et al.
`10/2009 Cooper et al.
`8/2011 Drager et al.
`3/2012 Cooper et al.
`2/2013 Brittain et al.
`
`FOREIGN PATENT DOCUMENTS
`
`159289
`DE
`159877
`DE
`3907079
`DE
`293808
`DE
`10016077
`DE
`10306724
`DE
`10304403
`DE
`334083 A1
`EP
`0656211
`EP
`0780386
`EP
`1354952
`EP
`1444989
`EP
`W0 96/28148
`W0
`W0 97/08174
`W0
`W0 99/42125
`W0
`W0 03/066027
`W0
`W0 03/077882 A2
`W0
`W0 03/081238
`W0
`W0 03/086470
`W0
`W0 03/094990
`W0
`W0 W0 2004/041118 A2
`W0 W0 2006/076620
`W0 W0 2009/120386
`
`3/1983
`4/1983
`9/1989
`9/1991
`12/2001
`9/2003
`8/2004
`9/1989
`6/1995
`6/1997
`10/2003
`8/2004
`9/1996
`3/1997
`8/1999
`8/2003
`9/2003
`10/2003
`10/2003
`11/2003
`5/2004
`7/2006
`10/2009
`
`OTHER PUBLICATIONS
`Byrn et al., “Pharmaceutical Solids: A Strategic Approach to Regu-
`latory Consideration”, Pharmaceutical Research, Jul. 1995, 12(7),
`945-954.
`rituximab)
`“Anti-CD20 antibody (IDEC-C2B8,
`Chow et al.,
`enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in
`vitro: role of cytokines complement, and caspases”, Haematologica,
`Jan. 2002, 87(1), 33-43.
`Chow et al., “In AML Cell Lines Ara-C Combined with Purine
`Analogues is Able to Exert Synergistic as Well as Antagonistic
`Effects on Proliferation, Apoptosis and Disruption of Mitochondrial
`Membrane Potential”, Leukemia & Lymphoma, 2003, 44(1), 165-
`173.
`Chow et al., “In vitro induction of apoptosis of neoplastic cells in
`low-grade non-Hodkin’ s lymphomas by combinations of established
`cytotoxic drugs with bendamustine”, Haematologica, May 2001,
`86(5), 485-493.
`Chow et al., “Synergistic effects of chemotherapeutic drugs in
`lymphoma cells are associated with down—regulation of inhibitor of
`apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4(Par-
`4), death-associated protein (Dazz) and with enforced caspase acti-
`vation”, Biochemical Pharmacology, Jan. 2003, 66(5), 711-724.
`Department of Health and Human Services, Food and Drug Admin-
`istration, “International Conference on Harmonisation; Guidance on
`Impurities: Residual Solvents,” Federal Register, Dec. 24, 1997,
`62(247), 67377-67388.
`Diehl et al., “Bendamustine in the Treatment of Hematologic Malig-
`nancies”, Semin. Oncol., Aug. 2002, 29(4), 1-3, Suppl. 13, Saundes,
`Philadelphia, PA.
`EC Safety Data Sheet: Ribomustin® in http://www.docstoc.com/
`doc s/2232323 1/EC-Safety-Data-Sheet-Bendamustin
`(published:
`Jul. 3, 1998; updated Mar. 1, 2007), 8 pages.
`Fichtner et al., “Antineoplastic activity and toxicity of some alkylat-
`ing cyto statics (cyclophosphamide, CCNU, cyto stasan) encapsulated
`in liposomes in different murine tumor models”,
`Journal of
`Microencapsulation, Jan. 1986, 3(2), 77-87.
`
`Gandhi, Varsha, “Metabolism and mechanisms of action of
`bendamustine: Rationales for combination therapies”, Seminars in
`Oncology, Aug. 2002, 29(4), 4-11, Suppl. 13.
`Goodman et al., The Pharmacological Basis of Therapeutics, 1985,
`7th edition, Macmillan publishing company, New York.
`Gust et al., “Investigations on the Stability of Bendamustin, a
`Cytostatic Agent of the Nitrogen Mustard Type, I. Synthesis, Isola-
`tion, and Characterization of Reference Substances”, Monatshefte
`fur Chemie, 1997, 128(3), 291-299.
`Heider et al., “Efficacy and toxicity of bendamustine in patients with
`relapsed low-grade non-Hodgkin’s
`lymphomas”, Anti-Cancer
`Drugs, 2001, 12(9), 725-729.
`Kath et al., “Bendamustine monotherapy in advanced and refractory
`chronic lymphocytic leukemia”, Journal of Cancer Research and
`Clinical Oncology, 2001, 127(1), 48-54.
`Koenigsman et al., “Fludarabine and Bendamustine in Refractory
`and Relapsed Indolent Lymphoma a Multicenter Phase IIII Trial of
`the East German Society of Hematology and Oncology (0SHO)”,
`Leukemia & Lymphoma, 2004, 45(9), 1821-1827.
`Kollmarmsberger et al., “Phase II study of bendamustine in patients
`with relapsed or cisplatin-refractory germ cell cancer”, Anti-Cancer
`Drugs, 2000, 11(17), 535-539.
`Konstantinov et al., Cytotoxic efficacy of bendamustine in human
`leukemia and breast cancer eel/lines, Journal of Cancer Research and
`Clinical Oncology, 2002, 128(5), 271-278.
`Koster et al., “Carboplatin in combination with bendamustine in
`previously untreated patients with extensive-stage small lung cancer
`(SCLC)”, Clinical Drug Investigation, 2004, 24(10), 611-618.
`Leoni et al., “Sdx-105 (Trenda), Active in Non-Hodgkins Lymphoma
`Cells, Induces the Mitotic Catastrophe Death Pathway”, Blood,
`104(11), 2004, Abs 4593, p. 232b.
`in
`Benamustinhydrochlorid
`Vlaas,
`“Stabilitat
`von
`Infusionslosungen”, Pharn1azie, 1994, 49(10), 775-777 (Translation
`Included).
`VIcKim et al., “Dimethyl Sulfoxide USP, PhEur in Approved Phar-
`maceutical Products and Medical Devices,” Pharmaceutical Technol-
`ogy, May 2, 2008, 1-7.
`\/Iottu et al., “Organic solvents for pharmaceutical parenterals and
`embolic liquids: A review of toxicity data,” PDA J. Pharma. Sci. &
`Tech. 54(6) Nov.-Dec. 2000, 456-469.
`\Ii et al., “Use of pure t-butanol as a solvent for freeze-drying: a case
`study”, International Journal of Pharmaceutics, Sep. 2001, 226(1-2),
`39-46.
`\Iiemeyer et al., “SDX-105 (bendamustine) is a clinically active
`chemotherapeutic agent with a distinct mechanism of action”, Proc
`Annu Meet Am Assoc Cancer Res, Mar. 2004, 45, 1st ed., 2 pages.
`\Iowak et al., “Upon Drug-Induced Apoptosis in Lymphoma Cells
`X-linked Inhibitor of Apoptosis (XIAP) Translocates from the
`Cytosol to the Nucleus”, Leukemia & Lymphoma, Jul. 2004, 45(7),
`1429-1436.
`“IMET 3393, gamma-(1-methyl-5-bis-([3-
`al.,
`et
`Ozegowski
`chlorathyl)-amino-benzimidazolyl(2)-buttersaure-hydrochlorid, ein
`neues Zytostatikum aus der Reihe der Benzimidazol-Loste”, Zbl
`Pharm., 1971;110, Heft 10, 1013-1019 (Translation Included).
`Ponisch et al., “Bendamustine in the treatment of Multiple Myeloma:
`Results and future perspectives”, Seminars in Oncology, Aug. 2002,
`29(4), 23-26, Suppl. 13.
`Preiss et al., “Pharmacokinetics of bendamustin (Cytostasan) in
`patients”, Pharmazie, Mar. 1985, 40(11), 782-784.
`Remington: Pharmaceutical Sciences, 1990, Mack Publishing com-
`pany, Easton, Pennsylvania.
`Ribomustin: Bendamustine Product Monograph, Jan. 2002, 3-58,
`Ribosepharm GmbH, Munchen, Germany.
`Ribomustin: Bendamustine Product Monograph, Mar. 2005, 3-73,
`Ribosepharm MBH, Munchen, Germany.
`Rummel et al., “Bendamustine in the treatment of non-Hodgkin’s
`lymphon1a: Results and future perspectives”, Seminars in Oncology,
`Aug. 2002, 29(4), 27-32, Suppl. 13.
`Rummel et al., “In Vitro Studies With Bendaustine: Enhanced Activ-
`ity in Combination With Rituxima ”, Seminars in Oncology, Aug.
`2002, 29(4), 12-14, Suppl. 13.
`
`FRESENIUS KABI 1001-0002
`
`

`
`US 8,895,756 B2
`Page 3
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Scasnar et al., “Radiochemical Assay of Stability of MC-Cytostasan
`Solutions During Preparation and Storage”, Journal of Radioanalyti-
`cal and Nuclear Chemistry, 1998, 121(2), 489-497.
`Scasnar et al., “Stability studies of 14C-Cytostasan solutions and its
`extraction using dicarbolide of cobalt,” Die Pharn1azie, Mar. 1988,
`43(3), 176-179.
`Schmidt-Hieber et al., “A phase II study of bendamustine chemo-
`therapy as second-line treatment in metastatic uveal melanoma”,
`Melanoma Research, 2004, 14(6), 439-442.
`Schoffski et al., “Repeated administration of short infusions of
`Bendamustine: a phase I study in patients with advanced progressive
`solid tumors”, Journal of Cancer Research and Clinical Oncology,
`2000, 126(1), 41-47.
`Schrijvers et al., “Phase I studies with bendamustine: An update”,
`Seminars in Oncology, 2002, 29(4), 15-18, Suppl. 13.
`Schwanen et al., “In Vitro Evaluation of Bendamustine Induced
`Apoptosis in B-Chronic Lymphocytic Leukemia”, Leukemia, Oct.
`2002, 16(10), 2096-2105.
`Strumberg et al., “Bendamustine hydrochloride activity against
`doxorubicin-resistant human breast carcinoma eel/lines”, Anti-Can-
`cer Drugs, 1996, 7(4), 415-421.
`Weide et al., “Bendamustine mitoxantrone and rituximab (BMR): A
`new effective
`regimen for
`refractory or
`relapsed indolent
`lymphomas”, Leukemia & Lymphoma, 2002, 43(2), 327-331.
`Weide et al., "Bendamustine/Mitoxantrone/Rituximab (BMR): A
`Very Effective, Well Tolerated Outpatient Chemoimmunotherapy for
`Relapsed and Refractory CD20-positive Indolent Malignancies.
`Final Results of a Pilot Study”, Leukemia & Lymphoma, 2004,
`45(12), 2445-2449.
`Weidmann et al., “Bendamustine is Effective in Relapsed or Refrac-
`tory Aggressive non-Hodgkin’s Lymphoma”, Annals of Oncology,
`Aug. 2002, 13(8), 1285-1289.
`Werner et al., “Hydrolyseprodukte des Cancerostaticums Cyto stasan
`(Bendamustin)”, Pharmazie, 1987, 42, 272-273.
`Zulkowski, et al., “Regression of brain metastases from breast carci-
`noma after chemotherapy with bendamustine”, Journal of Cancer
`Research and Clinical Oncology, 2002, 128(2), 111-113.
`Teagarden eta1., “Practical aspects of lyophilization using non-aque-
`ous co-solvent systems,” European Journal of Pharmaceutical Sci-
`ences, Mar. 2002, 15(2), 115-133.
`Wittaya-Areekul et al., “Freeze-drying of tert-butyl alcohol/water
`cosolvent systems: Effects of formulation and process variables on
`residual solvents,” Journal of Pharmaceutical Sciences, Apr. 1998,
`87(4), 491-495.
`U.S.App1.No. 13/719,379, filed Dec. 19, 2012, Cephalon, Inc.
`Mundipharma GmbH, Ribomustin EC Safety Data Sheet in accor-
`dance with 91/155/EEC. Eight Pages, Jan. 3, 2007.
`Ribosepharm. Fachinformation (Zusammenfassung der Merkrnale
`des Arzneimittels/SPC). Four Pages, Oct. 2005.
`Avis et al., “Pharmaceutical Dosage Forms: Parenteral Medications
`Volume 1” Marcel Dekker Inc, 1992, pp. 217-227.
`Excerpt
`from Rote Liste 2003, Arzneimittelverzeichnis
`Deutschland, 2 pages.
`Flamberg, et al., “Low Temperature Vacuum Drying of Sterile
`Parenterals from Ethanol” Bulletin of the Parenteral Drug Associa-
`tion, Sep.-Oct. 1970, 24(5), 209-217.
`IMET 3393”,
`Furst et al.,
`“The hydrolytic degradation of
`Pharmazeutische Zentralhalle fur Deutschland 1969, 108(9), 608-
`614.
`
`fur
`
`Gandhi et al., “Bendamustine in B Cell Malignancies: The New,
`46-year old kid on the Block” Clinical Cancer Research, Dec. 2009,
`15(24), 7456-7461.
`132 Jennings,Thomas A., “Extracts from Lyophilization. Introduc-
`tion and Basic Principles”. 2002, by CRC Press LLC, Boca Raton,
`Florida, 33431.
`Jonkmann-de Vries et al., “Pharmaceutical Development of (Inves-
`tigational) Anticancer Agents for Parenteral Use—A Review Drug
`Development and Industrial Pharmacy”, 1996, 22(6), 475-494.
`Kasraian et al., “The Effect Of Tertiary Butyl Alcohol On The Resis-
`tance Of The Dry Product Layer During Primary Drying”, 1995,
`Pharm. Res, 12(4), 491-495, hier: Zusammenfassung.
`Kasraian et al., “Thermal Analysis of the Tertiary Butyl Alcohol-
`Water System and its Implications on Freeze-Drying”, 1995, Pharm.
`Res, 12(4), 484-90, hier: Zusammenfassung.
`Kibbe, Arthur, H., Handbook Pharmaceutical Excipients, 3rd Edi-
`tion, 2000, Mannitol, American Pharmaceutical Association and
`Pharmaceutical Press.
`Kim, et al., “The Physical State of Marmitol after Freeze-Drying:
`Effects of Marmitol Concentration, Freezing Rate, and a Noncrystal-
`lizing Cosolute” Journal of Pharmaceutical Sciences, 87(8), Aug.
`1998, 931-935.
`a Parenteral
`“Pharmaceutical Development of
`Nuijen, B.,
`Lyophilized Formulation of the Novel Antitumor Agent Aplidine”,
`PDA Journal of Pharmaceutical Science and Technology, May/Jun.
`2000, 54(3), 193-208.
`Oesterle, et al., “The Influence Of Tertiary Butyl Alcohol And Vola-
`tile Salts On The Sublimation OfIce From Frozen Sucrose Solutions:
`Implications For Freeze-Drying” Pharmaceutical Development and
`Technology, 1998, 3(2), 175-183.
`Rey et al., "Freeze-Drying/Lyophilization of Pharmaceutical and
`Biological Products”, Second Edition, revised and expanded, New
`York, Taylor and Francis Group, 2004, Seiten 239-243.
`Rowe et al., “Handbook of Pharmaceutical Excipients” Fourth Edi-
`tion, The Royal Pharmaceutical Society of Great Britain, 2003, pp.
`373-377.
`Seager et al., Structure of Products Prepared by Freeze-Drying Solu-
`tions Containing Organic Solvents, PDA Journal of Pharmaceutical
`Science and Technology, Jul.-Aug. 1985, 39(4), 161-179, hier.
`Zusammenfassung.
`Tang, X. and Pikal, M. J., “Design of Freeze-Drying Processes for
`Pharmaceuticals: Practical Advice” Pharmaceutical Research, 21(2),
`Feb. 2004, 191-200.
`Telang, C. and Suryanarayanan, R., “Crystallization of Cephalothin
`Sodium During Lyophilization from Tert-Butyl Alcohol-Water
`Cosolvent System” Pharmaceutical Research, Jan. 2005, 22(1),153-
`160.
`Van Drooge et al., “Incorporation of Lipophilic Drugs in Sugar
`Glasses by Lyophilixation using a Mixture of Water and Tertiary
`Butyl Alcohol as Solven ” Journal of Pharmaceitical Sciences, Mar.
`2004, 93(3), 713-725.
`J., Handbook of Pharmaceutical
`Wade, A. and Weller, Paul
`Excipients, Second Edition, American Pharmaceutical Association,
`Washington and The Pharmaceutical Press, London, 1994, pp. 294-
`298.
`Wittaya-Areekul, Sakchai et al., Freeze-Drying of tert-Butanol/Wa-
`ter Cosolvent Systems: A Case Report on Formation of a Friable
`Freeze-Dried Powder of Tobramycin Sulfate Journal of Pharmaceu-
`tical Sciences, 91(4), Apr. 2002, 1147-1155.
`
`* cited by examiner
`
`FRESENIUS KABI 1001-0003
`
`

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`U.S. Patent
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`FRESENIUS KABI 1001-OOO4
`
`

`
`Bendamustine Purity after 24 hours at 5°C in Various
`Alcohol/Water Co-Solvents
`
`100.0
`
`————————————————————————————————————————————————————-
`
`__________
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`FRESENIUS KABI 1001-OOO5
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`Alcohol/Water Co—Solvents
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`
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`FRESENIUS KABI 1001-0006
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`FRESENIUS KABI 1001-0009
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`

`
`US 8,895,756 B2
`
`1
`BENDAMUSTINE PHARMACEUTICAL
`COMPOSITIONS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of U.S. application Ser.
`No. 13/654,898, filed Oct. 18, 2012, which is a continuation
`ofU.S. application Ser. No. 11/330,868, filed Jan. 12, 2006,
`which claims the benefit of U.S. Provisional Application No.
`60/644,354, filed Jan. 14, 2005, the entireties of which are
`incorporated herein for all purposes.
`
`FIELD OF THE INVENTION
`
`The present invention pertains to the field of pharmaceuti-
`cal compositions for the treatment of various disease states,
`especially neoplastic diseases and autoimmune diseases. Par-
`ticularly, it relates to pharmaceutical formulations compris-
`ing nitrogen mustards, particularly the nitrogen mustard ben-
`darnustine, e.g., bendamustine HCl.
`
`BACKGROUND OF THE INVENTION
`
`The present invention claims the benefit of and priority to
`U.S. Ser. No. 60/644,354, filed Jan. 14, 2005, entitled, “Ben-
`damustine Pharmaceutical Compositions,” which is incorpo-
`rated herein by reference in its entirety, including figures and
`claims.
`
`The following description includes information that may
`be useful in understanding the present invention. It is not an
`admission that any such information is prior art, or relevant, to
`the presently claimed inventions, or that any publication spe-
`cifically or implicitly referenced is prior art.
`Because oftheir high reactivity in aqueous solutions, nitro-
`gen mustards are difficult to formulate as pharmaceuticals
`and are often supplied for administration in a lyophilized
`form that requires reconstitution, usually in water, by skilled
`hospital personal prior to administration. Once in aqueous
`solution, nitrogen mustards are subject to degradation by
`hydrolysis, thus, the reconstituted product should be admin-
`istered to a patient as soon as possible after its reconstitution.
`Bendamustine,
`(4-{5-[Bis(2-chloroethyl)arnino]-1-me-
`thyl-2-benzimidazolyl}butyric acid, is an atypical structure
`with a benzimidazole ring, whose structure includes an active
`nitrogen mustard (see Formula I, which shows bendamustine
`hydrochloride).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Formula I
`
`50
`
`“W
`
`N
`
`O
`
`Bendamustine was initially synthesized in 1963 in the Ger-
`man Democratic Republic (GDR) and was available from
`1971 to 1992 in that location under the name Cytostasan®.
`Since that time, it has been marketed in Germany under the
`tradename Ribomustin®. It has been widely used in Germany
`to treat chronic lymphocytic leukemia, Hodgkin’s disease,
`non-Hodgkin’s lymphoma, multiple myeloma, and breast
`cancer.
`
`2
`
`Due to its degradation in aqueous solutions (like other
`nitrogen mustards), bendamustine is supplied as a lyophilized
`product. The current lyophilized formulation of bendarnus-
`tine (Ribomustin®) contains bendamustine hydrochloride
`and mannitol in a sterile lyophilized form as a white powder
`for intravenous use following reconstitution. The finished
`lyophilisate is unstable when exposed to light. Therefore, the
`product is stored in brown or amber-colored glass bottles. The
`current lyophilized formulation of bendamustine contains
`degradation products that may occur during manufacturing of
`the drug substance and/or during the lyophilization process to
`make the finished drug product.
`Currently bendamustine is formulated as a lyophilized
`powder for injection with 100 mg of drug per 50 mL vial or 25
`mg of drug per 20 mL vial. The vials are opened and recon-
`stituted as close to the time of patient administration as pos-
`sible. The product is reconstituted with 40 mL (for the 100 mg
`presentation) or 10 mL (for the 25 mg presentation) of Sterile
`Water for Injection. The reconstituted product
`is further
`diluted into 500 mL, q.s., 0.9% Sodium Chloride for Injec-
`tion. The route of administration is by intravenous infusion
`over 30 to 60 minutes.
`
`Following reconstitution with 40 mL Sterile Water for
`Injection, vials of bendamustine are stable for a period of 7
`hours under room temperature storage or for 6 days upon
`storage at 2-8° C. The 500 mL admixture solution must be
`administered to the patient within 7 hours of vial reconstitu-
`tion (assuming room temperature storage of the admixture).
`The reconstitution ofthe present bendamustine lyophilized
`powder is difiicult. Reports from the clinic indicate that
`reconstitution can require at least fifteen minutes and may
`require as long as thirty minutes. Besides being burdensome
`and time-consuming for the healthcare professional respon-
`sible for reconstituting the product, the lengthy exposure of
`bendamustine to water during the reconstitution process
`increases the potential for loss of potency and impurity for-
`mation due to the hydrolysis of the product by water.
`Thus, a need exists for lyophilized formulations of benda-
`mustine that are easier to reconstitute and which have a better
`
`impurity profile than the current lyophilate (lyophilized pow-
`der) formulations of bendamustine.
`German (GDR) Patent No. 34727 discloses a method of
`preparing oo-[5-bis-([3-chloroethyl)-amino-benzimidazolyl-
`(2)]-alkane carboxylic acids substituted in the 1-position.
`German (GDR) Patent No. 80967 discloses an injectable
`preparation of y-[1-methyl-5-bis-([3-chloroethyl)-amino-
`benzimaidazolyl-(2)] -butric acid hydrochloride.
`German (GDR) Patent No. 159877 discloses a method for
`preparing 4-[1-methyl-5 -bis(2-chloroethyl)amino -benzimi-
`dazolyl-2)-butyric acid.
`German (GDR) Patent No. 159289 discloses an injectable
`solution of bendamustine.
`
`55
`
`60
`
`65
`
`Ribomustin® bendamustine Product monograph (updated
`January 2002) http://www.ribosepharm.de/pdf/ribomustin_
`bendarnustin/productmonograph.pdf provides information
`about Ribomustin® including product description.
`Ni et al. report that the nitrosourea SarCNU was more
`stable in pure tertiary butanol than in pure acetic acid, dim-
`ethyl sulfoxide, methylhydroxy, water or in TBA/water mix-
`tures (Ni et al. (2001) Int]. J. Pharmaceutics 226239-46).
`Lyophilized cyclophosharnide is known in the art see e.g.,
`U.S. Pat. Nos. 5,418,223; 5,413,995; 5,268,368; 5,227,374;
`5,130,305; 4,659,699; 4,537,883; and 5,066,647.
`The lyophilized nitrogen mustard Ifosfamide is disclosed
`in International Publication No. WO 2003/066027; U.S. Pat.
`Nos. 6,613,927; 5,750,131; 5,972,912; 5,227,373; and 5,204,
`335.
`
`FRESENIUS KABI 1001-0010
`
`

`
`US 8,895,756 B2
`
`3
`Teagarden et al. disclose lyophilized formulations of pros-
`taglandin E-l made by dissolving PGE-l in a solution of
`lactose and tertiary butyl alcohol (U.S. Pat. No. 5,770,230).
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to stable pharmaceutical
`compositions of nitrogen mustards, in particular lyophilized
`bendamustine and its use in treatment of various disease
`
`states, especially neoplastic diseases and autoimmune dis-
`eases.
`
`An embodiment of the invention is a pharmaceutical com-
`position of bendamustine containing not more than about
`0.5% to about 0.9% (area percent of bendamustine) HPI, as
`shown in Formula II,
`
`Formula II
`
`T N
`
`0
`
`HO
`
`Cl
`
`at the time of release or where the HPI is the amount of HPI
`
`present at time zero after reconstitution of a lyophilized phar-
`maceutical composition ofbendamustine as described herein.
`In a preferred embodiment is a pharmaceutical composition
`of bendamustine containing not more than about 0.5% (area
`percent of bendamustine) HPI, preferably not more than
`about 0.45%, more preferably not more than about 0.40%,
`more preferably not more than about 0.35%, even more pref-
`erably not more than 0.30%.
`Another embodiment of the invention is a lyophilized
`preparation of bendamustine containing not more than about
`0.1% to about 0.3% bendamustine dimer as shown in Formula
`III at release or at time zero after reconstitution
`
`HO
`
`HO
`
`HO
`
`N\
`
`Yet another embodiment of the invention is a lyophilized
`preparation of bendamustine containing not more than about
`0.5%, preferably 0.15% to about 0.5%, bendamustine ethyl-
`ester, as shown in Formula IV at release or at time zero after
`reconstitution
`
`Cl
`
`Formula IV
`
`COOCHZCH3.
`
`Cl/\/N\EE:N>—/—/
`
`T
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`50
`
`55
`
`65
`
`4
`
`Yet another embodiment of the invention is a lyophilized
`preparation of bendamustine wherein the concentration of
`bendamustine ethylester (Formula IV) is no more than 0.2%,
`preferably 0.1%, greater than the concentration ofbendarnus-
`tine ethylester as found in the drug sub stance used to make the
`lyophilized preparation.
`In another embodiment of the invention is a lyophilized
`preparation of bendamustine containing not more than about
`0.5% to about 0.9% (area percent of bendamustine) HPI at
`the time of drug product release. In a preferred embodiment is
`a lyophilized preparation of bendamustine containing not
`more than about 0.50% (area percent of bendamustine) HPI,
`preferably not more than about 0.45%, more preferably not
`more than about 0.40%, more preferably not more than about
`0.35%, even more preferably not more than 0.30%. An aspect
`of this embodiment is lyophilized preparations of bendarnus-
`tine containing not more than about 0.5% to about 0.9%,
`preferably 0.5%, (area percent of bendamustine) HPI at the
`time of release of drug product where the lyophilized prepa-
`ration is packaged in a vial or other pharrnaceutically accept-
`able container.
`
`In yet another aspect of the invention, the lyophilized
`preparations of bendamustine are stable with respect to the
`amount of HPI for at least about 6 months, preferably 12
`months, preferably 24 months, to about 36 months or greater
`when stored at about 2° to about 30°. Preferred temperatures
`for storage are about 5° C. and about room temperature.
`Another embodiment of the invention is a pharmaceutical
`dosage form that includes a pharmaceutical composition of
`bendamustine containing not more than about 0.5% to about
`0.9% HPI, preferably not more than about 0.50%, preferably
`not more than about 0.45%, more preferably not more than
`about 0.40%, more preferably not more than about 0.35%,
`even more preferably not more than 0.30%, where the HPI is
`the amount of HPI present at release or at time zero after
`reconstitution of a lyophilized preparation of bendamustine
`ofthe present invention. In preferred aspects of the invention,
`the dosage form can be about 5 to about 500 mg of benda-
`
`Fonnula III
`
`\
`
`mustine, about 10 to about 300 mg ofbendamustine, about 25
`mg of bendamustine, about 100 mg of bendamustine, and
`about 200 mg of bendamustine.
`Yet another embodiment of the invention is a pharmaceu-
`tical dosage form that includes a lyophilized preparation of
`bendamustine containing not more than about 0.5% to about
`0.9%, preferably 0.5%, HPI. Preferred dosage forms can be
`about 5 to about 500 mg of bendamustine, about 10 to about
`300 mg of bendamustine, about 25 mg of bendamustine,
`about 100 mg of bendamustine, and about 200 mg of benda-
`mustine.
`
`In still another embodiment, the invention includes a phar-
`maceutical composition of bendamustine including benda-
`mustine containing not more than about 0.5% to about 0.9%
`(area percent of bendamustine), preferably not more than
`about 0.50%, preferably not more than about 0.45%, more
`preferably not more than about 0.40%, more preferably not
`
`FRESENIUS KABI 1001-0011
`
`

`
`US 8,895,756 B2
`
`5
`more than about 0.35%, even more preferably not more than
`0.30%, and a trace amount of one or more organic solvents,
`wherein said HP1 is the amount of HP1 present at release or
`time zero after reconstitution of a lyophilized pharmaceutical
`composition ofbendamustine as disclosed herein. In different
`aspects of this embodiment, the organic solvent is selected
`from one or more of tertiary butanol, n-propanol, n-butanol,
`isopropanol, ethanol, methanol, acetone, ethyl acetate, dim-
`ethyl carbonate, acetonitrile, dichloromethane, methyl ethyl
`ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate,
`carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone,
`chlorobutanol, dimethyl sulfone, acetic acid, and cyclohex-
`ane. Preferred organic solvents include one or more of etha-
`nol, methanol, propanol, butanol, isopropanol, and tertiary
`butanol. A more preferred organic solvent is tertiary butanol,
`also known as TBA, t-butanol, tert-butyl alcohol or tertiary
`butyl alcohol.
`The present invention involves a method for obtaining
`agency approval for a bendamustine product, the improve-
`ment which includes setting a release specification for ben-
`damustine degradants at less than about 4.0%, preferably
`about 2.0% to about 4.0%, (area percent bendamustine) or
`otherwise to achieve the pharmaceutical compositions
`described herein. An aspect of this embodiment is a method
`for obtaining agency approval for a bendamustine product
`which includes setting a release specification for HP1 to be
`less than or equal to 1.5% (area percent Bendamustine). The
`bendamustine product herein contains not more than about
`0.5% (area percent of bendamustine) HP1 at release.
`Another embodiment is a method for obtaining agency
`approval for a bendamustine product, the improvemen