US007888328B2
`
`(12) United States Patent
`B0dor et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,888,328 B2
`Feb. 15, 2011
`
`(54)
`(75)
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`(73)
`(*)
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`ORAL FORMULATIONS OF CLADRBINE
`
`Inventors: Nicholas S. Bodor, Bal Harbour, FL
`(US); Yogesh Dandiker, Toronto (CA)
`Assignee: Ares Trading S.A., Aubonne (CH)
`Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 16 days.
`10/551,205
`
`Appl. No.:
`
`PCT Fled:
`
`Mar. 26, 2004
`
`PCT NO.:
`
`PCT/US2004/009387
`
`S371 (c)(1),
`Nov. 14, 2006
`(2), (4) Date:
`PCT Pub. No.: WO2004/087101
`
`PCT Pub. Date: Oct. 14, 2004
`
`Prior Publication Data
`US 2007/O197468 A1
`Aug. 23, 2007
`
`Related U.S. Application Data
`Provisional application No. 60/458,922, filed on Mar.
`28, 2004, provisional application No. 60/484,756,
`filed on Jul. 2, 2003, provisional application No.
`60/541.247, filed on Feb. 4, 2004.
`
`(51)
`
`Int. C.
`A 6LX 3L/7076
`
`(2006.01)
`
`(2006.01)
`A6 IK3I/724
`U.S. Cl. ........................................... 514/46; 514/58
`Field of Classification Search ................... 514/46,
`514/58
`See application file for complete search history.
`References Cited
`
`(52)
`(58)
`
`(56)
`
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`8, 1969 Gramera et al.
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`6,174,873 B1* 1/2001 Wrenn, Jr. ................... 514/45
`6,194,395 B1
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`
`6,239,118 B1
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`6,699,849 B1*
`
`5, 2001 Schatz et al.
`6/2002 Miller et al.
`3/2004 Loftsson et al. ............... 514,58
`
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`DE
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`
`4f1982
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`eb.com/, accessed online on Dec. 31, 2008.
`Suzuki et al. Chem. Pharm. Bull., 1988, 36(2), p. 720-725.*
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`Loftsson et al. Journal of Pharmaceutical Sciences, 2002, 91 (11), p.
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`PCT International Preliminary Report on Patentability and Written
`Opinion for International Application No. PCT/US2004/009387,
`International filing date Mar. 26, 2004.
`Gao, Shen, New Dosage Form and New Technology of Modern
`Drugs, first edition, Jan. 2002, Chapter 6, Section 3 (III) Procedures,
`p. 105, lines 25-29 (published by People's Military Medical Pub
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`Albertioni et al., “On the bioavailability of 2-chloro-2'-
`deoxyadenosine (CdA), Eur JClin Pharmacol., vol. 44, pp. 579-582,
`1993, Springer-Verlag, Germany.
`Ahn et al., “Chiral Recognition in Gas-Phase Cyclodextrin: Amino
`Acid Complexes-Is the Three Point Interaction Still Valid in the Gas
`Phase?', J Am Soc Mass Spectrom, vol. 12, pp. 278-287. 2001,
`Elsevier Science, Inc., US.
`Bakthiar et al., “A study of the complexation between dimethyl-B-
`cyclodextrin and steroid hormones using electrospray ionization
`mass spectrometry”. Rapid Communications in Mass Spectrometry,
`vol. 11, pp. 1478-1481, 1997, John Wiley And Sons Ltd, England.
`Beutler et al., “The treatment of chronic progressive multiple sclero
`sis with cladribine'. Proc. Natl. Acad. Sci. USA, Medical Sciences,
`vol. 93, pp. 1716-1720, 1996, National Academy of Sciences, US.
`Cheng et al., “Measurement of chiral complexes of cyclodextrin and
`amino acids by electrospray ionization time-of-flight mass spectrom
`etry”. J. Mass Spectrom, vol. 36, pp. 834-836, 2001, John Wiley &
`Sons, Ltd., England.
`Choi et al., “FT-Raman and FT-IR Spectra of the Non-steroidal
`Anti-inflammatory Drug Ketoprofen Included in Cyclodextrins',
`Analytical Sciences, vol. 17 Supplement, pp. i785-1788, 2001. The
`Japan Society for Analytical Chemistry, Japan.
`Giordano et al., “Thermal analysis of cyclodextrins and their inclu
`sion compounds'. Thermochimica Acta 380, pp. 123-151, 2001,
`Elsevier Science B.V., The Netherlands.
`(Continued)
`Primary Examiner Shaojia Anna Jiang
`Assistant Examiner—Jonathan S Lau
`(74) Attorney, Agent, or Firm—Buchanan Ingersoll &
`Rooney PC
`
`(57)
`
`ABSTRACT
`
`Provided are compositions of cladribine and cyclodextrin
`which are especially suited for the oral administration of
`cladribine.
`
`55 Claims, 1 Drawing Sheet
`
`Petitioner TWi Pharms., Inc.
`EX 1029, Page 1 of 16
`
`

`

`US 7,888,328 B2
`Page 2
`
`OTHER PUBLICATIONS
`Hwang et al., “Water Suppression That Works. Excitation Sculpting
`Using Arbitrary Waveforms and Pulsed Field Gradients”, Journal of
`Magnetic Resonance, Series A. vol. 112, pp. 275-279, 1995, Aca
`demic Press, Inc., US.
`Lamcharfi et al., “Electrospray Ionization Mass Spectrometry in
`Supramolecular Chemistry: Characterization of Non-covalent
`Cyclodextrin Complexes”, Journal of Mass Spectrometry, vol. 31.
`pp. 982-986, 1996, John Wiley & Sons, Ltd., England.
`Loftsson et al., “Pharmaceutical Applications of Cyclodextrin. 1.
`Drug Solubilization and Stabilization”, Journal of Pharmaceutical
`Sciences, vol. 85, No. 10, pp. 1017-1025, 1996, American Pharma
`ceutical Association and the American Chemical Society, US.
`Meier et al., “The Influence of B- and Y-Cyclodextrin Cavity Size on
`the Association Constant with Decanoate and Octanoate Anions'.
`Journal of Inclusion Phenomena and Macrocyclic Chemistry, vol. 40,
`pp. 291-295, 2001, Kluwer Academic Publishers, The Netherlands.
`Mura et al., “Interactions of ketoprofen and ibuprofen with
`3-cyclodextrins in Solution and in the Solid state'. International Jour
`nal of Pharmaceutics, vol. 166, pp. 189-203, 1998, Elsevier Science
`B.V., The Netherlands.
`Nolan et al., “Preparation of Vesicles and Nanoparticles of
`Amphiphilic Cyclodextrins Containing Labile Disulfide Bonds',
`Langmuir, vol. 19, pp. 4469-4472, 2003, American Chemical Soci
`ety, US.
`Ramanathan et al., “Electrospray Ionization Mass Spectrometric
`Study of Encapsulation of Amino Acids by Cyclodextrins”. J. Am
`Soc Mass Spectrom, vol. 6, pp. 866-871, 1995, American Society for
`Mass Spectrometry, US.
`Redentietal., “Raman and Solid State 'C-NMR Investigation of the
`Structure of the 1: 1 Amorphous Piroxicam : B-Cyclodextrin Inclu
`sion Compound'. Biospectroscopy, vol. 5, pp. 243-251, 1999, John
`Wiley & Sons, Inc., US,
`Sipe et al., "Cladribine in treatment of chronic progressive multiple
`sclerosis'. The Lancet, vol. 344, pp. 9-13, 1994, Lancet Publishing
`Group, England.
`Szetli, “Introduction and General Overview of Cyclodextrin Chem
`istry”, Chem. Rev., vol. 98, pp. 1743-1753, 1998, American Chemi
`cal Society, US.
`Uekama et al., “Cyclodextrin Drug Carrier Systems”. Chem. Rev.
`vol. 98, pp. 2045-2076, 1998, American Chemical Society, US.
`Uekama et al., “Peracylated B-Cyclodextrins as Novel Sustained
`release Carriers for a Water-soluble Drug, Molsidomine”. J. Pharm.
`Pharmacol., vol. 46, pp. 714-717, 1994, Pharmaceutical Press,
`England.
`Taddei et al., “Influence of Environment on Piroxicam
`Polymorphism: Vibrational Spectroscopic Study”. Biopolymers
`(Biospectroscopy), vol. 62, pp. 68-78, 2001, John Wiley & Sons, Inc.,
`US.
`Tarasiuk et al., "Stability of 2-Chloro-2'-Deoxyadenosine at Various
`pH and Temperature'. Archivum Immunologiae et Therapiae
`Experimentalis, vol. 42, pp. 13-15, 1994, published by Birkhauser
`Publishers Ltd., Basel, Switzerland.
`Romine et al., “A Double-Blind, Placebo-Controlled, Randomized
`Trial of Cladribine in Relapsing-Remitting Multiple Sclerosis”. Pro
`
`ceedings of the Association of American Physicians, vol. 111, No. 1,
`pp. 35-44, 1999, published by Blackwell Publishing, Malden, MA.
`Tortorella et al., Current Opinion on Investigational Drugs, 2012), pp.
`1751-1756, 2001, published by PharmaPress Ltd., London, GB.
`Selby et al., “Safety and Tolerability of Subcutaneous Cladribine
`Therapy in Progressive Multiple Sclerosis”. Can. J. Neurol Sci., vol.
`25, pp. 295-299, 1998, published by Canadian Journal of Neurologi
`cal Science, Calgary, Canada.
`Rice et al., "Cladribine and progressive MS Clinical and MRI out
`comes of a multicenter controlled trial”. Neurology, vol. 54, pp.
`1145-1155, 2000, published by Lippincott Williams and Wilkins,
`Hagerstown, MD.
`Liliemark et al., “On the Bioavailability of Oral and Subcutaneous
`2-Chloro-2'-Deoxyadenosine in Humans. Alternative Routes of
`Administration”, Journal of Clinical Oncology, vol. 10, No. 10, pp.
`1514-1518, 1992, published by American Society of Clinicial Oncol
`ogy, Alexandria, VA.
`Karlsson et al., “Oral cladribine for B-cell chronic lymphocytic
`leukaemia. report of a phase II trial with a 3-d, 3-weekly schedule in
`untreated and pretreated patients, and a long-term follow-up of 126
`previously untreated patients”. British Journal of Haematology, vol.
`116, pp. 538-548, 2002, published by Blackwell Science Ltd.,
`Oxford, UK.
`Liliemark, “The Clinical Pharmacokinetics of Cladribine” Clin.
`Pharmacokinet, vol. 32 (2), pp. 120-131, 1997, published by Adis
`International Limited, Wolters Kluwer Health, Yardley, PA.
`Nakai et al., “Effects of Grinding On the Physical and Chemical
`Properties of Crystalline Medicinals with Microcrystalline Cellulose
`V: Comparison with Tri-O-methyl-3-cyclodextrin Ground Mixtures”.
`Chem. Pharm. Bulletin, vol. 28(5), pp. 1552-1558, 1980, published
`by Pharmaceutical Society of Japan, Tokyo, Japan.
`Saenger, "Clyclodextrin Inclusion Compounds in Research and
`Industry”. Angew. Chem. Int. Ed. Engl., vol. 19, pp. 344-362, 1980,
`published by Verlag Chemie, GmbH. Weinheim, Germany.
`Tang et al., “Design of Freeze-Drying Processes for Pharmaceuti
`cals. Practical Advice'. Pharmaceutical Research, vol. 21, No. 2, pp.
`191-200, 2004, Springer, The Netherlands.
`Van Axel Castelli et al. “Characterisation of an Inclusion Complex
`Between Cladribine and 2-Hydroxypropyl-B-Cyclodextrin.” J.
`Pharm. Sci., vol. 97, No. 9, Sep. 2008, pp. 3897-3906, Wiley
`InterScience and the American Pharmacists Association, US.
`Drugs.com, “Oral Investigational Treatment Cladribine Tablets for
`Multiple Sclerosis Significantly Reduced Relapse Rate in Phase III
`Pivotal Trial.” accessed online Feb. 3, 2009, at http://www.drugs.
`com/clinical trials/oral-investigational-cladribine-multiple-sclero
`SS.
`“Serono's Oral Cladribine for the Treatment of Multiple Sclerosis
`Awarded FastTrack Status by FDA', accessed online Feb. 3, 2009 at
`http://prnewswire.com.
`Merck Serono News Release, “Two-year Phase III Data Presented at
`AAN 61st Annual Meeting Show Positive Outcome of Cladribine
`Tablets in Patients with Multiple Sclerosis”, Apr. 29/30, 2009, avail
`able online.
`* cited by examiner
`
`Petitioner TWi Pharms., Inc.
`EX 1029, Page 2 of 16
`
`

`

`U.S. Patent
`
`Feb. 15, 2011
`
`US 7,888,328 B2
`
`0.08O
`
`0.070
`
`0.060
`
`0.050
`
`0.040
`
`0.030
`
`0.020
`
`0.010
`
`0.000
`0.000
`
`0.050
`
`0.100
`
`0.150
`CD conc. (M)
`
`0.200
`
`0.250
`
`O.300
`
`Petitioner TWi Pharms., Inc.
`EX 1029, Page 3 of 16
`
`

`

`US 7,888,328 B2
`
`1.
`ORAL FORMULATIONS OF CLADRBINE
`
`CROSS-REFERENCE TO EARLIER
`APPLICATIONS
`
`This application is the U.S. national stage of International
`Application No. PCT/US2004/009387, file Mar. 26, 2004,
`which claims benefit under 35 U.S.C. S 119(e) of U.S. Provi
`sional Application No. 60/458,922, filed Mar. 28, 2003; of
`U.S. Provisional Application No. 60/484,756, file Jul. 2,
`2003; and of U.S. Provisional Application No. 60/541.247,
`filed Feb. 4, 2004, all of said applications being hereby incor
`porated by reference herein in their entireties and relied upon.
`
`FIELD OF THE INVENTION
`
`10
`
`15
`
`The invention relates to a composition comprising a com
`plex cladribine-cyclodextrin complex formulated into a solid
`oral dosage form and to a method for enhancing the oral
`bioavailability of cladribine.
`
`BACKGROUND OF THE INVENTION
`
`Cladribine, which is an acid-labile drug, has the chemical
`structure as set forth below:
`
`25
`
`NH2
`
`2
`associated with oral administration versus parenteral admin
`istration costs gain importance. The cost of parenteral admin
`istration is much higher due to the requirement that a health
`care professional administer the cladribine in the health care
`provider setting, which also includes all attendant costs asso
`ciated with Such administration. Furthermore, in certain
`instances, therapeutic considerations such as the need for a
`slow release of cladribine over a prolonged period of time
`may be practically met only by oral or transmucosal delivery.
`However, to date the oral delivery of cladribine has been
`plagued by low bioavailability (see, e.g., J. Liliemarket al., J.
`Clin. Oncol., 10(10): 1514-1518, 1992), and suboptimal
`interpatient variation (see, e.g., J. Liliemark, Clin. Pharma
`cokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik, et al.
`reporting poor absorption and pH dependent lability (Arch.
`Immunol. et Therapiae Exper, 42: 13-15, 1994).
`Cyclodextrins are cyclic oligosaccharides composed of
`cyclic C-(1->4) linked D-glucopyranose units. Cyclodextrins
`with six to eight units have been named Cl-, 3- and Y-cyclo
`dextrin, respectively. The number of units determines the size
`of the cone-shaped cavity which characterizes cyclodextrins
`and into which drugs may be included to form stable com
`plexes. A number of derivatives of C.-, 3- and Y-cyclodextrin
`are known in which one or more hydroxyl groups is/are
`replaced with ether groups or other radicals. These com
`pounds are thus known complexing agents and have been
`previously used in the pharmaceutical field to form inclusion
`complexes with water-insoluble drugs and to thus solubilize
`them in aqueous media.
`Recently, Schultzetal., in U.S. Pat. No. 6,194,395 B1, have
`described complexing and solubilizing cladribine with cyclo
`dextrin. The Schultz et al. patent primarily addresses the
`problems inherent in previously described aqueous formula
`tions of cladribine, particularly for Subcutaneous and intra
`muscular injection. Schultz et al. have found that cladribine is
`not only significantly more soluble in aqueous media when
`formulated with cyclodextrin, but also is more stable against
`acid-catalyzed hydrolysis when combined with cyclodextrin.
`The latter finding is taught to be of particular benefit in the
`formulation of Solid oral dosage forms, where the compound
`would normally undergo hydrolysis in the acid pH of the
`stomach contents. Schultz et al. do not appear to have
`described any actual work in connection with Solid oral dos
`age forms. In fact, they describe only one method of preparing
`the Solid dosage form, which is a melt extrusion process, in
`which the cladribine and cyclodextrin are mixed with other
`optional additives and then heated until melting occurs. Fur
`thermore, the broad dosage ranges of 1 mg to 15 mg of
`cladribine and 100 mg to 500 mg of cyclodextrin listed in the
`patent Suggest no criticality to the particular amount of cyclo
`dextrin to be present with a given amount of cladribine in a
`Solid oral dosage form. Indeed, these dosage ranges include
`many combinations which may be suitable as mixtures but
`not for complex formation. For example, a ratio of 1 mg of
`cladribine to 500 mg of cyclodextrin contains too much
`cyclodextrin, so that the drug would not readily leave the
`complex and achieve its therapeutic function. On the other
`hand, 15 mg of cladribine and only 100 mg of cyclodextrin
`would not be enough to complex that amount of cladribine.
`The Schultz et al. patent does Suggest improving the sta
`bility of cladribine in oral dosage forms by combining/com
`plexing it with cyclodextrin, but does not suggest improving
`the drug’s oral bioavailability by such means; in fact, the
`patent does not describe or Suggest a method for enhancing or
`maximizing the bioavailability of cladribine from a solid oral
`dosage form of cladribine and cyclodextrin, or a composition
`specially designed to do so.
`
`N y
`l 2
`
`N
`
`N
`HOCH2
`O
`
`C
`
`OH
`
`It is also known as 2-chloro-2'-deoxyadenosine or 2-CdA.
`Cladribine exists as a white, nonhydroscopic, crystalline
`powder, consisting of individual crystals and of crystalline
`aggregates.
`Cladribine is an antimetabolite which has use in the treat
`ment of lymphoproliferative disorders. It has been used to
`treat experimental leukemias such as L1210 and clinically for
`hairy cell leukemia and chronic lymphocytic leukemia as well
`as Waldenstrom's macroglobulinaemia. It has also been used
`as an immunosuppressive agent and as a modality for the
`treatment of a variety of autoimmune conditions including
`rheumatoid arthritis, inflammatory bowel disease (e.g.,
`Crohn's disease, ulcerative colitis) and multiple Sclerosis (see
`e.g., J. Liliemark, Clin. Parmacokinet, 32(2): 120-131, 1997).
`It has also been investigated, either experimentally or clini
`cally in, for example, lymphomas, Langerhan's cell histiocy
`tosis, lupus erythematosus, chronic plaque psoriasis, Sezary
`syndrome, Bing-Neel syndrome, recurrent glioma, and Solid
`tumors.
`Oral delivery of drugs is often preferred to parenteral deliv
`ery for a variety of reasons, foremost patient compliance, or
`for cost or therapeutic considerations. Patient compliance is
`enhanced insofar as oral dosage forms alleviate repeated
`health care provider visits, or the discomfort of injections or
`prolonged infusion times associated with some active drugs.
`At a time of escalating health care costs, the reduced costs
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Petitioner TWi Pharms., Inc.
`EX 1029, Page 4 of 16
`
`

`

`US 7,888,328 B2
`
`3
`Many workers have studied the solubility of specific drugs
`in water containing various concentrations of selected cyclo
`dextrins in order to demonstrate that increasing concentra
`tions of cyclodextrins increase the solubility of the drugs at
`selected temperatures and pH levels, as for example reported
`in the Schultz et al. patent. Phase solubility studies have also
`been performed by various workers in order to elucidate the
`nature of the complex formation, for example, whether the
`cyclodextrin and drug form a 1:1 complex or a 1:2 complex;
`see, for example, Harada et al. U.S. Pat. No. 4,497.803, relat
`ing to inclusion complexes of lankacidin-group antibiotics
`with cyclodextrin, and Shinoda et al. U.S. Pat. No. 4,478,995,
`relating to a complex of an acid addition salt of (2'-benzy
`loxycarbonyl)phenyl trans-4-guanidinomethylcyclohexan
`ecarboxylate with a cyclodextrin.
`While Schultz et al. teach that a cladribine-cyclodextrin
`complex improves the water solubility and acid stability of
`cladribine, the art does not suggest how to maximize or
`enhance the benefits of the complexation in terms of bioavail
`ability and interpatient variation when the complex is to be
`administered in a solid oral dosage form.
`
`SUMMARY OF THE INVENTION
`
`4
`(ii) cooling the resultant aqueous solution to room tem
`perature; and
`(iii) lyophilizing the cooled solution to afford an amor
`phous product.
`In yet a further aspect the invention provides a pharmaceu
`tical composition obtainable by a process comprising the
`steps of:
`(i) combining cladribine and an amorphous cyclodextrin in
`water at a temperature of from about 40 to about 80° C. and
`maintaining said temperature for a period of from about 6 to
`about 24 hours;
`(ii) cooling the resultant aqueous solution to room tem
`perature;
`(iii) lyophilizing the cooled solution to afford an amor
`phous product; and
`(iv) formulating the amorphous product into a solid oral
`dosage form.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`A more complete appreciation of the invention and its
`many attendant advantages will be readily understood by
`reference to the following detailed description and the accom
`panying drawing, wherein the Sole FIGURE is a graphical
`representation of the results of a phase solubility study where
`various molar concentrations of hydroxypropyl-3-cyclodex
`trin (HPBCD) are plotted against various cladribine molar
`concentrations, with (O) representing the data points
`obtained for complexation under conditions specified in
`EXAMPLE 2 below.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Throughout the instant specification and claims, the fol
`lowing definitions and general statements are applicable.
`The patents, published applications, and Scientific litera
`ture referred to herein establish the knowledge of those with
`skill in the art and are hereby incorporated by reference in
`their entirety to the same extent as if each was specifically and
`individually indicated to be incorporated by reference. Any
`conflict between any reference cited herein and the specific
`teachings of this specification shall be resolved in favor of the
`latter. Likewise, any conflict between an art-understood defi
`nition of a word or phrase and a definition of the word or
`phrase as specifically taught in this specification shall be
`resolved in favor of the latter.
`The term “inclusion complex' as used herein refers to a
`complex of cladribine with the selected cyclodextrin wherein
`the hydrophobic portion of the cladribine molecule (the nitro
`gen-containing ring system) is inserted into the hydrophobic
`cavity of the cyclodextrin molecule. This is often referred to
`simply as a cyclodextrin complex of the drug.
`The term “non-inclusion complex’ refers to a complex
`which is not an inclusion complex; rather than the hydropho
`bic portion of cladribine being inserted in the cyclodextrin
`cavity, the non-inclusion complex is formed primarily by
`hydrogen-bonding of the hydroxyls and amino group on
`“free” cladribine, (i.e. cladribine not in the inclusion com
`plex) to the hydroxyls on the exterior of the cyclodextrintorus
`(e.g. in the case of hydroxypropyl-3-cyclodextrin, hydrox
`ypropyl and hydroxyl groups on the glucose rings). This is a
`more loosely-held association than an inclusion complex.
`As used herein, whether in a transitional phrase or in the
`body of a claim, the terms “comprise(s)' and “comprising
`are to be interpreted as having an open-ended meaning. That
`is, the terms are to be interpreted synonymously with the
`phrases “having at least” or “including at least'. When used in
`
`10
`
`15
`
`25
`
`30
`
`35
`
`It has now been found that amorphous cyclodextrins can be
`combined with cladribine to form aparticularly advantageous
`product which can be incorporated into a solid oral dosage
`form. This product is a complex cladribine-cyclodextrin com
`plex, and the Solid oral dosage form containing it improves
`oral bioavailability and/or achieves lower interpatient and/or
`intrapatient variation of the drug.
`The present invention provides a complex cladribine-cy
`clodextrin complex which is an intimate amorphous admix
`ture of (a) anamorphous inclusion complex of cladribine with
`an amorphous cyclodextrin and (b) amorphous free cladrib
`ine associated with amorphous cyclodextrin as a non-inclu
`sion complex, and a pharmaceutical composition comprising
`said complex, formulated into a Solid oral dosage form. Thus,
`the cyclodextrin itself is amorphous, the inclusion complex
`with cladribine is amorphous (and is preferably saturated
`40
`with cladribine) and the free cladribine which forms the non
`inclusion complex is amorphous.
`The invention also provides a method for increasing or
`enhancing the oral bioavailability of cladribine comprising
`orally administering to a subject in need thereof, a pharma
`ceutical composition comprising a complex cladribine-cyclo
`dextrin complex which is an intimate amorphous admixture
`of (a) an amorphous inclusion complex of cladribine with an
`amorphous cyclodextrin and (b) amorphous free cladribine
`associated with amorphous cyclodextrin as a non-inclusion
`complex, formulated into a solid oral dosage form which
`maximizes the amount of cladribine in the inclusion and
`non-inclusion complexes.
`The invention further provides for treatment of conditions
`responsive to administration of cladribine in mammals by
`administering thereto the composition of the invention. Use
`of cladribine in the preparation of the pharmaceutical com
`positions of the invention for administration to treat cladrib
`ine-responsive conditions and for enhancing the oral bio
`availability of cladribine is also provided.
`Still further, the invention provides a process for the prepa
`ration of a complex cladribine-cyclodextrin complex which
`comprises the steps of
`(i) combining cladribine and an amorphous cyclodextrin in
`water at a temperature of from about 40 to about 80° C. and
`maintaining said temperature for a period of from about 6 to
`about 24 hours;
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`Petitioner TWi Pharms., Inc.
`EX 1029, Page 5 of 16
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`US 7,888,328 B2
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`the context of a process, the term “comprising means that the
`process includes at least the recited steps, but may include
`additional steps. When used in the context of a composition,
`the term "comprising means that the composition includes at
`least the recited features or components, but may also include
`additional features or components.
`The terms “consists essentially of or “consisting essen
`tially of have a partially closed meaning, that is, they do not
`permit inclusion of steps or features or components which
`would substantially change the essential characteristics of a
`process or composition; for example, steps or features or
`components which would significantly interfere with the
`desired properties of the compositions described herein, i.e.,
`the process or composition is limited to the specified steps or
`materials and those which do not materially affect the basic
`and novel characteristics of the invention. The basic and novel
`features herein are the provision of a complex cladribine
`cyclodextrin complex which is an intimate amorphous
`admixture of (a) an amorphous inclusion complex of cladrib
`ine with an amorphous cyclodextrin and (b) amorphous free
`cladribine associated with amorphous cyclodextrinas a non
`inclusion complex, formulated into a solid oral dosage form,
`so as to provide improved bioavailability and/or lower inter
`patient and/or intrapatient variation following administration.
`Essential to the invention is the combination of the amor
`phous nature of the starting cyclodextrin, and the level of
`water solubility exhibited by cladribine (about 5 mg/ml at
`room temperature), and consequently its capability for hydro
`gen bonding, which can be taken advantage of underparticu
`lar conditions described hereinafter, and which afford a spe
`cial amorphous mixture uniquely well-suited for optimizing
`the oral bioavailability of cladribine.
`The terms “consists of and “consists' are closed termi
`nology and allow only for the inclusion of the recited steps or
`features or components.
`As used herein, the singular forms “a,” “an and “the
`specifically also encompass the plural forms of the terms to
`which they refer, unless the content clearly dictates other
`wise.
`The term “about is used hereinto means approximately, in
`the region of roughly, or around. When the term “about is
`used in conjunction with a numerical range, it modifies that
`range by extending the boundaries above and below the
`numerical values set forth. In general, the term “about' or
`“approximately” is used herein to modify a numerical value
`above and below the stated value by a variance of 20%.
`The term “amorphous” is used herein to refer to a noncrys
`talline Solid. The cyclodextrins encompassed herein them
`selves are amorphous because they are each composed of a
`multitude of individual isomers, and their complexes with
`cladribine are also amorphous. Further, conditions for com
`plexation can be selected (elevated temperature and pro
`longed complexation times, as described hereinafter) so that
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`a supersaturated cladribine solution will be formed. When
`cooled, because of the amorphous nature of the complex and
`the cyclodextrin, some excess free cladribine does not pre
`cipitate but rather is trapped in amorphous form in intimate
`admixture with the (preferably saturated) amorphous cladrib
`ine-cyclodextrin inclusion complex. This excess cladribine
`forms a loosely-held association, or non-inclusion complex,
`with the cyclodextrin through hydrogen bonding. This, then,
`further increases the amount of cladribine in the product; this
`additional cladribine, because it is amorphous and also
`because it is in intimate admixture with the amorphous inclu
`sion complex, is expected to be somewhat protected from
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`degradation by stomach acid (although it may not be as pro
`tected as the cladribine which is in the form of the inclusion
`complex).
`The term “saturated when used in conjunction with a
`complex of cladribine in amorphous cyclodextrin means that
`the complex is saturated with cladribine, that is, the complex
`contains the maximum amount of cladribine which can be
`complexed (by means of both inclusion and non-inclusion
`complexes) with a given amount of cyclodextrin under the
`conditions of complexation used. A phase solubility study can
`be used to provide this information, as described in more
`detail hereinafter. (Conditions for the complexation are also
`described in more detail below.) Alternatively, a saturated
`complex may be arrived at empirically by simply adding
`cladribine to an aqueous solution of the selected cyclodextrin
`until no more cladribine goes into solution; ultimately, excess
`cladribine, if any, is removed (by filtration or centrifugation)
`and the solution lyophilized to provide the dry saturated com
`plex.
`The expression “substantially, as in “substantially free”
`means within 20% of the exact calculated amount, preferably
`within 10%, most preferably within 5%.
`The term “interpatient variability” refers to variation
`among patients to which a drug is administered. The term
`“intrapatient variability” refers to variation experienced by a
`single patient when dosed at different times.
`As used herein, the recitation of a numerical range for a
`variable is intended to convey that the invention may be
`practiced with the variable equal to any of the values within
`that range. Thus, for a variable which is inherently discrete,
`the variable can be equal to any integer value of the numerical
`range, including the end-points of the range. Similarly, for a
`variable which is inherently continuous, the variable can be
`equal to any real value of the numerical range, including the
`end-points of the range. As an example, a variable which is
`described as having values between 0 and 2, can be 0, 1 or 2
`for variables which are inherently discrete, and can be 0.0,
`0.1, 0.01, 0.001, or any other real value for variables which
`are inherently continuous.
`In the specification and claims, the singular forms include
`plural referents unless the context clearly dictates otherwise.
`As used herein, unless specifically indicated otherwise, the
`word 'or' is used in the “inclusive' sense of “and/or” and not
`the “exclusive sense of “eitherfor
`Technical and Scientific terms used herein have the mean
`ing commonly understood by one of skill in the art to which
`the present invention pertains, unless otherwise defined. Ref
`erence is made hereinto various methodologies and materials
`known to those of skill in the art. Standard reference works
`setting forth the general principles of pharmacology include
`Goodman and Gilman's The Pharmacological Basis of
`Therapeutics, 10" Ed., McGraw Hill Companies Inc., New
`York (2001).
`Reference is made hereinafter in detail to specific embodi
`ments of the invention. While the invention will be described
`in conjunction with these specific embodiments, it will be
`understood that it is not intended to limit the invention to such
`specific embodiments. On the contrary, it is intended to cover
`alternatives, modifications, and equivalents as may be
`included within the spirit and scope of the invention as
`defined by the appended claims. In the following description,
`numerous specific details are set forth in order to provided a
`thorough understanding of the present invention. The present
`invention may be practiced without some or all of these spe
`cific details. In other instances, well-known process opera
`tions