PCT[usay/03387
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`reod 39 JUL 2004
`a
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`PA 1200271
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`TOALL,TOWHOMTHESE;PRESENTS) SHALE,COME
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`UNITED STATES DEPARTMENT OF COMMERCE
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`United States Patent and Trademark Office
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`July 23, 2004
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`ismy
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`THIS IS TO CERTIFY THAT ANNEXED HERETOIS A TRUE COPY FROM
`THE RECORDS OF THE UNITED STATES PATENT AND TRADEMARK
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`APPLICATION THAT MET THE REQUIREMENTSTO BE GRANTED A
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`APPLICATION NUMBER: 60/484,756
`FILING DATE: July 02, 2003
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`a,
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`_ PRIORITY
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`SUBMITTED OR TRANSMITTEDIN
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`on .|.COMMISSIONER OF PATENTS AND TRADE
`NY >
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`By Authority of the
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`Merck 2045
`Merck 2045
`Hopewell v Merck
`Hopewell v Merck
`IPR2023-00480
`IPR2023-00480
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`
`PATENT APPLICATION SERIAL NO.
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`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
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`07/09/2003 SZEWDIEL 00000087 500943
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`60484756
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`PTO-1556
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`*U.S. Government Printing Office: 2001 ~- 481-697/59173
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`PROVISIONAL APPLICATION COVER SHEET
`This is a requestforfiling a PROVISIONAL APPLICATION under 37 C.F.R. 1.53
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`BedaNicosSiri
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`TITLE OF THE INVENTION
`
`NOVEL CYCLODEXTRIN BASED FORMULATIONS
`
`CORRESPONDENCE ADDRESS
`
`Dennis A. Emma, Ph.D.
`
`IVAX CORPORATION
`4400 Biscayne Boulevard
`Miami, Florida 33137
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` ENCLOSED APPLICATION PARTS (check all that apply)
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`Theinventionwas made by anagencyoftheUnitedStates GovernmentorunderacontractwithanagencyoftheUnitedStates Government.
`dno
`Dyes, the name ofthe U.S. Governmentagency and the Government contractnumber are:
`SIGNATURE,
`{x
`)end, a: Enna
`DATE:July2,2003
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`TYPED orPRINTED NAME____DennisA.Emma,Ph.D.REGISTRATION NO: 50,980
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`Oo Additional inventors are being named on separately numbered sheets attachedhereto
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`Respectfully submitted,
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`

`

`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`PATENTS
`
`In re Application of:
`
`Nicholas S, Bodor
`
`Serial No.:
`
`Filing Date:
`
`Title:
`
`To be assigned
`
`HEREWITH
`
`NOVEL CYCLODEXTRIN BASED FORMULATIONS
`
`Attorney Docket No.:
`
`IVAX0012-P2-USA
`
`CERTIFICATION UNDER 37 C.E.R. § 1.10
`
`Thearby certify that the attached papers are being deposited with the United States Postal Service as "Express Mail
`Post Office to Addressee” Service of the United States Postal Service (UPS) under 37 C.E.R. § 1.10 ov July 2, 2003, and is addressed to:
`MAIL STOP PROVISIONAL PATENT APPLICATION, Commissionerfor Patents, P.O. Box 1450,
`Alexandria, VA 22313-1450
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`"Express Mail Label No."
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`EL 938625924 US
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`MAIL STOP PROVISIONAL PATENT APPLICATION
`Commissioner for Patents
`P.O. BOX 1450
`Alexandria, VA 22313-1450
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`Dear Sir:
`
`Enclosed herewith for filing with the United States Patent and Trademark Office in the above-identified
`Provisional Patent Application pursuantto 37 C.E.R. § 1.53 (c) are the following documents:
`
`1.
`2.
`3.
`
`Provisional Application Cover Sheet (one page);
`Provisional Patent Application (15 pages); and
`Return Postcard.
`
`Respectfully Submitted,
`
`aDewngEremd—
`
`Dennis A. Emma, Ph.D.
`Registration No. 50,980
`Attorney for Applicant
`
`IVAX CORPORATION
`4400 Biscayne Boulevard
`Miami, Florida 33137
`Tel. No.: 305 575 6061
`Fax. No.: 305 575 6064
`
`Date: July 2, 2003
`
`
`Copyprovided by USPTO from the PACH Image Database on 07/23/2004
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`NOVEL CYCLODEXTBENBASED FORMULATIONS
`(ArwomeyDocket: IVAX0012-P2-USA)
`
`nventor: Nicholas Bodor
`
`Theinvention relates to inclusion complexes of a drug and unsubstituted or substituted
`cyclodextrin, to pharmaceutical formulations containing the same for oral or transmucosal
`delivery, as well as to therapeutic uses of the same.
`
`Oral delivery of drugs is often preferred to parenteral delivery for a variety of reasons,
`foremost being patient compliance, or for cost or therapeutic considerations. Patient compliance
`is enhancedinsofar as oral dosage forms alleviate repeated health care providervisits, or the
`discomfort of injections or prolonged infusion times associated with someactive drugs. Ata
`time of escalating health care costs, the reduced costs associated with oral and buccal
`administration versus parenteral administration (requiring, at a minimum, a health care
`professional in the health care providersetting, with all attendant costs associated with such
`administration) are enhanced, In certain instances, therapeutic considerations (eg, the slow
`release of drug over a prolonged period) maydictate the need for oral and buccal delivery.
`
`However,oral delivery of some active agents is plagued bypoor absorption, drug lability
`(eg, pH dependent hability), low bioavailability, or interpatient variation. Additionally, age or the
`medical condition of a patient mayprevent the swallowingof the oral dosage drug form thereby
`requiring an alternative delivery method.
`
`‘Transmucosal deliveryof drugs offers a means of avoiding the disadvantages of the
`orogastric route as the drug reaches the systemic circulation directly. The mucosal routeis
`therefore a useful alternative comparable,if not preferred to the parenteral route, for a variety of
`" drugs where delivery by other routes are problematic due to a variety of factors (such as for
`example avoidanceof first pass metabolism, degradation, solubility, penetration, bioavailability, or
`therapeutic considerations). As exemplified herein, transmucosal delivery of drugs is an appealing .
`route for those drugs which are acid labile. However, to date transmucosal delivery has not been
`possible for many drugs. Therefore, there is a need to enhance drug solubiliryand penetration to
`improve bioavailabilityfor mucosal delivery.
`
`Theinventor has recognized that in most instances,there is an excess of cyclodextrin
`(“CD”) present in the dosage form, whichis generallyused as an aid to keeping the drug in
`solution, However, the presence of excess cyclodextrins is suspected to inhibit drug absorption
`once the drug has beendissociated from the drug/cyclodextrin complex. Whatis required then
`
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`is a means to maximize the concentration of drug within the particular CD complex to provide
`the best opportunity for maximal oral or transmucosal delivery.
`
`The inventor has discovered that using a saturated drug/CD complex solution in which
`the drugis in its highest thermodynamic activity state favors absorption. The saturated drug/CD
`complex provides the maximal amountof drug that can be solubilized with a minimal amountof
`cyclodextrin, thereby avoiding or minimizing absorption inhibition from an unnecessary excess of
`CD.
`
`As used herein, “saturated drug/CD complex”is meant the maximum amountof drug
`that can be complexed with a given amount of cyclodextrin under the conditions of complexation
`used, The amountof drug required for saturation for a given amount of cyclodextrin may be
`determined empirically, such as from phase solubility studies as described ing.
`
`By “mucosa”is meant the epithelial membraneslining the nasal, oral, vaginal or rectal
`cavities. As used herein, mucosal and transmucosal are used interchangeably. Mucosal delivery
`methods are well known in the art (see Remington’s Pharmaceutical Sciences, 18 Ed., Gennaro,
`Mack Publishing Co., Easton, PA 1990 and Remington: The Science and Practice of Pharmacy,
`Lippincott, Williams & Wilkins, 1995). These include buccal, sublingual, tablets, lozenges,
`adhesive patches, gels, solutions or sprays (powder,liquid or aerosol), and suppositories (eg, for
`rectal or vaginal administration),
`
`Theoral drug forms contemplated by the invention include saturated drug/CD
`complexes and pharmaceutically acceptable inert ingredients, eg, conventional excipients,
`vehicles,fillers, binders, disintegrants, solvents, solubilizing agents, sweeteners, coloring agents
`and any other inactive ingredients, which are regularly included in pharmaceutical dosage forms
`for oral administration. Suitable oral dosage forms includetablets, capsules, caplets, gelcaps,pills,
`liquid solutions, suspensions orelixirs, powders, lozenges, micronized particles and osmotic
`delivery systems.
`
`Theoral dosage form, for example a conventional tablet, according to the invention will
`dissolve, releasing the drug/CD complex followed bydissociation of the drug from the
`cyclodextrin. The saturated drug/CD complex provides a minimal amount of CD necessaryto
`solubilize the drug, thereby minimizing the potential that the dissociated drug will recomplex with
`CD. Minimizing complex reformation (eg, shifting the equilibrium towards dissociation) is
`believed to aid in avoiding or minimizing absorptioninhibition from the now uncomplexed CD.
`
`The drug/CD complex accordingto the invention may be formulated for transmucosal
`delivery. Hence, for example a buccal tablet accordingto the invention, upondissolution in the
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`small volume ofsaliva present produces a saturated drug solution in which the drug is in its
`highest thermodynamicactivity {ie, the solution contains the highest concentration of drug
`possible that can be complexed in the given CD) for maximizing drug delivery. One of skill in
`the art will appreciate that the same result may be achieved byusing a variety of delivery methods,
`some of which do not require dissolution (eg, drug/CD complex saturated liquid preparations
`putin direct contact with the mucosal tissue).
`
`Cyclodextrins are well known and are named by the number glucopyranose units in the
`cyclic ring (for a general overview see for example, Uekama et al, in CRC Critical Reviews in
`‘Therapeutic Drug Carrier Systems, vol. 3(1), 1-40 (1987).
`
`Commonly used cyclodextrins include «, 8, and y cyclodextrin and derivatives thereof, in
`particular, derivatives wherein one or more of the hydroxy groupsare substituted, eg by alkyl,
`hydroxyalkyl, carboxyalkyl, allsyicarbonyl, carboxyalkoxyalkyl,allylcarbonyloxyalkyl,
`alkoxycarbonylalkyl or hydroxy-(mono orpolyalkoxy) alkyl groups, wherein each alkyl or alkylene
`moietypreferablycontains up to six carbons. Substituted cyclodextrins which can also be used in
`the invention include polyethers, eg, as described in US. Pat. No. 3,459,731. Further examples of
`substituted cyclodextrins include ethers wherein the hydrogen of one or more cyclodextrin
`hydroxy groupsis replaced by C,, alkyl, hydroxy C,, alkyl, carboxy: C,alkyl or C,,,
`alkyloxycarbonyl- C,, alkyl groups or mixed ethers thereof. In particular, such substituted
`cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groupsis
`replaced by C,, alkyl, hydroxy C,_, alkyl or carboxy C,,, allyl or more particularly by methyl,
`ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl. The term “C,,
`alkyl” is meantto include straight and branched saturated hydrocarbonradicals, having from 1 to
`6 carbonatoms, such as methyl, ethyl 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl,
`butyl, pentyl, hexyl and thelike. Of particular utility in the present invention are the f-
`cyclodextrin ethers, eg dimethyl-6-cyclodextrin as described in Drugs of the Future, Vol. 9, No.
`8, p. 577-578 byM. Nogradi (1984) and polyethers, eg hydroxypropyl-p-cyclodextrin and
`hydroxyethyl-6-cyclodextrin. Besides simple cyclodextrins, branched cyclodextrins and
`cyclodextrin polymers mayalso be used. Other cyclodextrins are described for example in
`Chemical and Pharmaceutical Bulletin 28: 1552-1558 (1980), Yakugyo Jiho No. 6452 (28 March
`1983), Angew. Chem, Int. Ed. Engl, 19: 344-362 (1980), US. Pat. No. 3,459,731, EP-A-
`0,149,197, EP-A-0,197,571, ULS. Pat. No. 4,535,152, WO-90/12035 and GB-2,189,245, Other
`references describing cyclodextrins for use in the compositions accordingto the present
`invention, and which provide a guide for the preparation, purification and analysis of
`cyclodextrins includethe following: “Cyclodextrin Technology” byJozsef Szejtli, Kluwer
`
`
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`

`Academic Publishets (1988) in the chapter Cyclodextrins in Pharmaceuticals; “Cyclodextrin
`Chemistry” by M. L. Benderet al., Springer-Verlag, Berlin (1978); “Advances in Carbohydrate
`Chemistry”, Vol. 12, Ed. by M. L. Wolfrom, Academic Press, New York in the chapter The
`Schardinger Dextrins byDexter French at p. 189-260; “Cyclodextrins and their Inclusion
`Complexes”byJ. Szejtli, Akademiai Kiado, Budapest, Hungary (1982);I. 'Tabushi in Acc. Chem.
`Research, 1982, 15, p. 66-72; W. Sanger, Angewandte Chemie, 92, p. 343-361 (1981); A. P. Croft
`and R. A. Bartsch in Tetrahedron,39, p. 1417-1474 (1983); Irie et al. Pharmaceutical Research, 5,
`p- 713-716, (1988); Pitha et al. Int. J. Pharm. 29, 73, (1986); DE 3,118,218; DE-3,317,064; EP-A-
`94,157; U.S. Pat. No. 4,659,696; and U.S. Par. No. 4,383,992.
`
`Oneof skill in the art will appreciate that the choice of a specific cyclodextrin will vary
`uponthe route of administration, the drug of choice, a In certain embodiments, envisaged
`cyclodextrins include 2-hydroxypropyl-8-CD,2-hydroxypropyl-y-CD,y-CD, BCD,or
`sulfobutylcyclodextrins (see eg, US. Pat. Nos. 5,134,127 and 6,046,177),
`
`Solid mixtures of the cyclodextrins with the active ingredient may be prepared byavariety
`of methods known to those ofskill in the pharmaceutical arts, such as for example, via melt-
`extrusion (see eg, WO97/18839, hereby incorporated by reference). However, melt-extrusion
`may not be appropriate forall drugs or cyclodextrins inasmuch as the melting point for some
`active compounds maybe at a temperature which can cause decomposition of the cyclodextrins.
`
`It is possible in certain instances to have cyclodextrin in excess in these formulations, as
`the optimal drug/CD complex has not been formedprior to incorporation.
`
`Oral and transmucosal delivery forms are optionally formulated in a pharmaceutically
`acceptable vehicle with any of the well-known pharmaceutically acceptable carriers, including
`diluents and excipients (see Remington’s Pharmaceutical Sciences, supra).
`
`Tn an aspect of the invention, the drug/CD complexis a saturated drug/CD complex
`prepared priorto incorporation into the final drug form. A method envisioned for preparing a
`solid saturated drug/CD complex entails lyophilization of the complex from the complexion
`solution, However, those ofskill in the art will appreciate alternative methodologies for
`preparing a solid saturated drug/CD complex.
`
`In certain instances, oral or mucosal absorption may be furtherfacilitated bythe addition
`of various excipients, additives, etc (to increase solubility or to enhance penetration), bythe
`modification of the microenvironment(to favor the un-ionized form of the drug),or bythe
`addition of mucoadhesive excipients (to improve contact between the delivery system and the
`mucosal tissue).
`
`
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` Copy provided by USPTO from the PACR Image Database on 07/23/2004
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`

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`
`
`In some embodimentsofthe invention, the drug form is prepared with the minimal
`amountof excipient(s) necessaryfor shaping and producing the particulardrug form (eg tablet,
`patch, ec). In this embodiment, the excipients are chosenfromthose that do notinterfere with
`cyclodextrin orwith complex formation. In yet other embodiments, excipient(s) are chosen from
`those which complexwith cyclodextrins, eg, to facilitate dissolution of the drug/CD complex.
`"The invention is useful for the administration of anydrug capable of (a) oral deliveryby
`conventional routes, and (b) capable of forming a complex withCD.
`In certain embodiments,the inventionis particularlyuseful for the administration of any
`drug capableof (a) transmucosal delivery, and of (b) forming a complex with CD.
`Accordingly, the methods, formulations and pharmaceutical compositions described
`herein offer novel therapeutic modalities for the treatment ofpatients in need of treatmentwith
`the drug of choice. As such,the invention avoids the problems of poor absorption and
`bioavailabilityassociated with oral drug dosing byproviding a drugin its highest thermodynamic
`activity (ie, the solution contains the highest concentration of drug possible that can be
`complexed inthe given CD) for maximizing drug deliveryvia the orogastric route. Additionally,
`where necessaryfor some drugs, the orogastric route maybe avoided entirelybytransmucosal
`delivery.
`‘To exemplifythe advantages offered bytheinstant approaches, the non-limiting and
`representative example provided herein involvescladribine (“2-CdA”), a suspected acid labile
`drug. Cladribine is known as an antileukemic agent,(ie,in treating leukemias, such as, hairycell
`leukemia and L 1210 leukemia), as an immunosuppressive agent, and as a modalityuseful for the
`treatmentof rheumatoid arthritis and multiple sclerosis (see eg, Liliemark,J.,al., Clin. Cancer
`Res., 1:385-390, 1995). In somestudies, oral cladribineis plagued bythe combination of
`relativelylow bioavailabilitycombined with sub-optimal interpatient variation.
`(Seeeg,J.
`Liliemark in Clin, Pharmacokinet. 32(2): 120-131, 1997). These art recognized problems are
`addressed bythe instant invention and exemplified below.
`Example 1
`Phase Solubility Studies
`
`.
`
`Several processes for preparing cladribine are known intheart (see for example,
`European Patent ApplicationNo. 173,059 A2 and Robins etal.,J. Am. Chem. Soc., 106, 6379
`(1984), and US. Pat. No. 5,208,327).
`
`Copyprovided by USPTOfrom the PACRImage Database on 07/23/2004
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`

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`Various concentrations of cladribine were dissolved in hydroxypropyl-B cyclodextrin
`(HPSCD), HPSCD with 0.1% hydroxypropyl methylcellulose (HPMO), or y cyclodextrin (yCD)
`according to the Table I.
`
`Table I
`
`Phase Solubility Studies
`
`
`Cladribine -HP betaCD +
`
`
`Cladribine -HP betaCD
`HPMC(0.1%)
`Cladribine -gama- CD
`(Trial A)
`(Trial B)
`(Trial C)
`
`
`
`
`Molar
`Molar
`cD
`mea
`ae
`=
`a
`
`
`{ 000J0.140 2.550|0.00890.0091 0.137 0.132 2.459 |0,0086
`
`
`
`
`
`
`
`1
`°
`3.139
`0.011
`0,0095
`0.1352
`2.519
`{0.0088
`
`
`in
`Oo
`o
`
`Qo
`bh
`oor|0245|~4570|O16 [0203-4149|00145|0.152[2.873fora|
`012 621 [00217|0332|ees|00216|0.1965|3.461 [0.0138
`
`
`fozas|0514|9581|ooss|0259|ass1|o0i69|o4se8|8733 (0.0306
`
`
`cD
`
`
`
`
`
`Molar
`
`
`
`
`
`Methods of preparing drug/CD complex preparations are well known in the art (see
`supra). In the instant example, a saturated solution of cladribine was prepared bymixing excess
`cladribine with a 40% solution of the various CDs. Undissolved cladribine was removed by
`filtration. The resultant solution was then lyophilized and used to make solid forms.
`
`The molar concentration of cladribine in these solutions was then plotted andis
`presented graphicallyas Figure 1. The plotted line represents maximal drug solubilization for the
`conditions tested,thatis, the ratio of drug to cyclodextrin for highest thermodynamicactivity.
`The area above the plotted lines represents conditions where excess insoluble drug, here
`cladribine, is present. The area below theplotted line represents the conditions where
`cyclodextrin is in excess.
`
`Figure 1
`
`PHASE SOLUBILITY STUDIES
`
`CD- Malar Conc.
`
`
`
`CladribineMolarConc.
`
`——@—— HP-Beta-
`GD
`-- MF --HPCD+HP
`MC
`— *%&— Gama-Cd
`
`0.071
`
`0.142
`
`0.285
`
`
`
`Copy provided by USPTO from the PACR Image Database on 07/23/2004
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`

`

`If there is a linear plotforthe drug/complex tested, concentrating (or evaporating the
`frozen solution in vacuum)anyofthe solutions to dryness results in the unique mixture
`representing the maximumdrug concentration that can be incorporated into the cyclodextrin
`under those conditions. The dried drug/cyclodextrin complex can be used to producea tablet
`with a minimum of additives, such as, for example, 1% magnesium stearate or PEG,with a small
`amount of sorbitol. When this type oftablet is used for transmucosal deliveryand undergoes
`dissolution, forexample, inthe buccal area or sublingually, the dissolution produces the saturated
`drug solution of highest thermodynamic activity. This complex has the best chance of
`penetrating the mucosaltissue. Accordingly, solutions such as the one exemplified herein are
`expectedtofacilitate transmucosal absorption.
`However, a nonlinear drug/CD solubilization plot indicates multiple drug/CD
`complexes. The phase solubilitydata maythenbe usedto identifyspecific drug/CD ratios for
`use in the particular drug form.
`Example2
`Pharmacokinetic Studies
`
`The bioavailabilityof cladribine, when complexed with Gamma-CD or HPCDwas
`evaluated in a beagle dog model. ‘The data obtained from this modelare expected to be
`representative for the human experience.
`Cladribine was complexed with either hydroxypropyl-6-cyclodextrin (HPCD)oty-
`cyclodextrin (Gamma-CD)bythe following method.
`An aqueous solution of cladnbine,in excess, and CD was mixed with stirring at 44 - 50°C
`for nine hours. Excess, non-complexed cladribine was removed by filtration and the solution
`cooled to room temperature. The aqueous cladribine/CD complexes were taken to dryness by
`lyophilizationprior to incorporation into the solid buccal or oral tablets. The lyophilization
`procedureconsists of rapidlybringing the complexation solution to -45°C (ca. 200 min.) followed
`by lyophilization at -25°C for approximately 80 — 90 hours.
`Buccal and oral tablets accordingto the formulas presented in Table II belowwere
`prepared byblendingthelyophilized drug/cyclodextrin complex (containing 5 mg of cladribine)
`with magnesium stearate for 10 minutes at 12 rpm. Theresultant mixture was screened through
`
`Copy provided by USPTO from the PACRImage Database on 07/23/2004
`
`.
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`

`

`a # 18-mesh screen followed byasecond blending for 5 minutes at 12 rpm and screening. The
`resulting blend was then compressed into 100 mg tablets using a Manesty F3 single station punch.
`
`The physical properties of the tablets produced were:
`
`Diameter: 10 mm. Uppershallow concave tooling, lowerflat beveled edge tooling
`
`Average weight:
`
`237mg — Gamma-CD,
`
`217mg - HPCD
`
`Hardness:
`Friability:
`
`Thickness:
`
`Disintegration:
`
`4.0 Kp -Gamma-CD,
`0.5%
`
`.
`
`3.72 Kp - HPCD
`0.4%
`
`3.8mm
`
`6-8min
`
`3.3mm
`
`6-8min
`
`Table II
`
`Representative Drug Formulations
`
`Placebo (% w/w)
`
`HPCD (% w/w)
`
`Gamma-CD
`% w/w
`
`
`
`
`(contains 4.96 mg
`(contains 4.95 mg
`cladribine
`cladribine
`|Magnesiumstearate|10|
`omonpied)||
`Gamma-CD
`96.8
`|Sorbitah|2
`
`
`
`
`
`
`
`
`
`Bioavailabilityand pharmacokinetic studies were conducted in a beagle dog model as
`follows.
`
`Outbred male beagle dogs obtained from IDRI (Dunakeszi, Hungary) were housed in the
`animal facilityat the [VAX Institute for Drug Research, Hungary, and allowed laboratorydiet and
`water adlibitum. The same dogs were used throughoutthe study to minimize inter andintra
`subject variability.
`
`The bioavailability and pharmacokinetic studies were conducted as follows. In the first
`test period,cladribine was administered intravenously (5 mg, 0.25 mg/ml in isotonic saline) and
`blood samples collected at various time intervals over 48 hours. In the secondtest period, half of
`the test subjects received buccally either a Gamma-CD or HPCD tablet (see Table II sypxa); with
`serial blood samples collected over 48 hours, The third test period repeated the secondtest
`period with the exception that the subjects previouslyreceiving Gamma-CD were now given
`
`8
`
`nig!
`
`‘Copy provided by USPTO from the PACR Image Database on 07/23/2004
`
`

`

`HPCD buccal tablets, with HPCD recipients from the second period receiving Gamma-CD
`buccal tablets. The fourth and fifth test periods repeated test periods two and three with the
`exception that the tablets were given orally.
`
`Cladribine levels in the blood were measured byHPLC and an LC/MS/MS method. The
`TopFit 2.0 Pharmacokinetic and Pharmacodynamic Data Analysis System was used for the
`pharmacokinetic analysis of the data. The results of the bioavailabilitystudyfor control
`(intravenous) and cladribine/CD complexes are presented in Tables III — VIL and summarized in
`Table VII.
`
`
`
` Copy provided by USPTO from the PACR ImageDatabase on 07/23/2004
`
`

`

`
`
`0,40
`
`0,4
`
`193
`
`244
`
`192
`
`217
`
`247
`
`228
`
`432
`
`342
`
`433
`
`383
`
`10
`
`17,6|ve||vs
`
`Cltot/kg
`
`oe|99|948
`1077 2|98
`AUC/dose
`HIARMACOKINETICPARAMETERSINMALEDOGS
`
`
`0,35[ose_||ome|0,04[0|
`[dose_|[oss 0,36
`
`
`1,22fo|
`12,44[use|14,28|ise 12,75
`Bodyweight|1098 13,86
`
`
`
`
`Intravenousbolus,5mgcladribine/animal
`
`
`[art||ml[1312_|[a3|14[4s[13|[3 0,1[os|cltot|MRTtot
`
`
`
`220[as||
`ml/min
`
`TableIII
`
` 338|366_||_|fn|[avo|Aube.|_avc
`29*h/ail]
`37714pa|oa[ou|a»|CLADRIBINEP
`
`
`42614 7| os|1s_|yo|ts se|i|35919
`
`[ng*h/ml]{P%]
`10,4pgs
`
` ti/2terminal
`
`|Crs|[500_|[aie||oos_|[so|a7
`
`
`
`||CinitialLogt/amor|655pmo2_|
`
`525 pos|
`
`
`
`Copy provided by USPTOfrom the PACR Image Databaseon 07/23/2004
`
`113
`
`10,3
`
`10
`
`479
`
`103
`
`726
`
`
`
`

`

`
`
`(9/sth0-Lang)x21deI09ED-FUAUED1-49}9EL
`
`[eIINg AL192L
`
`jaunesamiqupel>Su¢voneNstupE
`
`
`
`
`
`
`
`Copyprovided by USPTOfrom the PACR Image Database on 07/23/2004
`
`UW
`
`

`

`
`
`
`
`
`1 n
`
`ima
`
`/a
`
`inelex(RD-0418/D)5mgcladsib
`
`
`Tablet-2:HPCDcomp
`
`inistration;
`Buccala
`
`
`
`
`%;excludedfrommean
`
`
`TableV
`
`12
`
`Copy provided by USPTO
`
`from the PAGR Image Database on 07/29/2004
`
`

`

`430
`
`484
`
`13
`
`|>|3|so|5|mo|96|567 a|es|#165
`
`
`
`
`
`
`
`tration;5mgcladribine/animal
`
`ex(RDT-0418/C)
`
`
`minisTablet-1:Gamma-CDcompl
`
`
`
`
`
`*,excludedfrommean
`
`
`USPTO from the PACRImage Database on 07/23/2004
`
`TableVI
`
`
`Oralad:
`
`Copy provided by
`
`

`

`
`
`Body
`imi.
`-0418/D)
`ribine/a:
`
`
`
`Tablet-2:HPCDcomplex(RD'
`Oraladministration;5mgclad
`
`TableVII
`
`
`
`
`1 n
`
`weight
`
`
`
`14
`
`pw?
`
`eetaylk”
`. Copy p
`
`rovided by USPTO from the PACR Image Database on 07/ 23/2004
`
`

`

`dose: 5 mg cladribine/ animal
`
`Table VIII Bioavailability of cladribine in dogs
`
`excluded from mean
`*; not characteristic for the group
`*#; the dog probablyswallowed the tablet
`
`15
`
` he PAGR Image Database on 07/23/2004
`
`Copy provided by USPTO from t
`
`