`
`10SLL,NOWALOMnHTHESE:ERESENES,suas,Comuns
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`July 23, 2004
`
`( THISISTOCERTIFYTHATANNEXEDHERETOISATRUECOPYFROM
`
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`
`Nie
`
`THE RECORDS OF THE UNITED STATES PATENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTS TO BE GRANTED A
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`APPLICATION NUMBER: 60/484,756
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`
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`PCT[usa/O3387
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`FILING DATE UNDER35 USC 111.
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`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`July 23, 2004
`
`APPLICATION NUMBER: 60/484,756
`FILING DATE: July 02, 2003
`
`_ PRIORITY
`DOCUMENT
`SUBMITTED OR TRANSMITTEDIN
`COMPLIANCE WITH RULE17.1(a) OR(b)
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`aa:sx CPOMMIBSIONESOFPATENTSANDTRADE
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`_ By Authority of the
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`M. BASSFORD
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`Certifying Offic
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`
`
` PATENT APPLICATION SERIAL NO.
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMARK OFFICE
`FEE RECORD SHEET
`
`07/09/2003 SZEWDIEL 00000087 500943
`
`60484756
`
`01 FCsi005
`
`160.00 DA
`
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`
`PTO-1556
`(5/87)
`
`“U.S. Government Printing Cffice: 2001 — 481-697/59173
`
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`
`INVENTOR(s)/APPLICANT(s)
`LAST NAME MIDDLE INITIAL|RESIDENCE (CITY& EITHERSTATE ORFIRST NAME
`
`
`FOREIGN COUNTRY)
`
`ol PNhoasLS—_| MiaFwi
`
`B
`
`+
`
`17613U.S.60,/404756NOMA
`
` PROVISIONAL APPLICATION COVER SHEET
`PTO
`This is a request forfiling a PROVISIONAL APPLICATIONunder 37 C.F.R. 1.53
`
`
`
`poe?(+|
`No.
`
`
`
`
`
`
`
`E OF THE INVENTION
`NOVEL CYCLODEXTRIN BASED FORMULATIONS
`CORRESPONDENCE ADDRESS
`
`Dennis A. Emma, Ph.D.
`IVAX CORPORATION
`
`4400 Biscayne Boulevard
`
`Miami, Florida 33137
`
`ENCLOSED APPLICATION PARTS (check all that apply)
`
`
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`SmallEntityStatement
`[XIspecification NumberofPages__—_—ES a}
`D
`O
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`
`(CO
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`prawing(s) NumberofSheets ____
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` $160,00
`
`[IreCommissioner is hereby authorized to charge the filing fee to Deposit AccountNumber: §0-0943
`
`Theinvention wasmadeby anagencyoftheUnitedStates Governmentorunderacontract withanagencyoftheUnitedStatesGoverment.
`Edlno
`ves, the name ofthe U.S. Government agency and the Governmentcontractnumber are:
`__
`wonanne(ennaAEnmnCC
`
`TYPED orPRINTED NAME___DennisA.Emma,Ph.D.REGISTRATIONNO: 50,980
`
`
`Respectfully submitted,
`
`oO ‘Additional inventors are being named on separately numbered sheets attachedhereto
`
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`Copy provided by USPTO from ihe PAGR Image Database on 07/23/2004
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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
`
`IN LUINDER 37 CER.§1.10
`
`
`I hear by 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.F.R. § 1.10 on 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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`EL 938625924 US
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`“Express Mail Label No.”
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`MAIL STOP PROVISIONAL PATENT APPLICATION
`Commissionerfor Patents
`P.O. BOX 1450
`Alexandria, VA 22313-1450
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`Dear Sir:
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`Enclosed herewith forfiling with the United States Patent and Trademark Office in the above-identified
`Provisional Patent Application pursuantto 37 C.F.R. § 1.53 (c) are the following documents:
`
`1.
`Zi
`3.
`
`Provisional Application Cover Sheet (one page);
`Provisional Patent Application (15 pages); and
`Return Postcard.
`
`Respectfully Submitted,
`
`ol eonng Exnnt—
`
`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 PACR Image Database on 07/23/2004
`
`

`

`NOVEL CYCLODEXTRIN BASED FORMULATIONS
`Inventor: Nicholas Bodor
`(AttomeyDocket: IVAX0012-P2-USA)
`
`‘The invention 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 varietyof reasons,
`foremost being patient compliance, or for cost or therapeutic considerations. Patient compliance
`is enhanced insofar as oral dosage forms alleviate repeated health care providervisits, or the
`discomfort ofinjections or prolonged infusion times associated with someactive drugs. Ata
`time ofescalating 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) may dictate the need for oral and buccal delivery.
`
`However,oral delivery of some active agents is plagued bypoorabsorption, drug lability
`(eg, pH dependent lability), low bioavailability, or interpatient variation. Additionally, age or the
`medical condition of a patient may prevent the swallowing of the oral dosage drug form thereby
`requiring an alternative deliverymethod,
`
`‘Transmucosal deliveryof drugs offers a means of avoiding the disadvantages of the
`orogastric route as the drug reaches the systemic circulation directly. The mucosal route is
`therefore a useful alternative comparable,if not preferred to the parenteral route,for a variety of
`~ drugs where deliveryby other routes are problematic due to a variety of factors (such as for
`example avoidance offirst 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 deliveryhas not been
`possible for many drugs. Therefore, there is a need to enhance drug solubility and penetration to
`improve bioavailabilityfor mucosal delivery.
`
`The inventor has recognized that in most instances, there is an excess of cyclodextrin
`(“CD”) present in the dosage form, which is 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
`
`
`
` Copy provided by USPTO from the PACR Image Database on 07/23/2004
`
`

`

`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 besolubilized with a minimal amount of
`cyclodextrin, thereby avoiding or minimizing absorption inhibition from an unnecessary excess of
`CD.
`
`As used herein, “saturated drug/CD complex”is meant the maximum amount ofdrug
`that can be complexed with a given amountof cyclodextrin underthe conditions of complexation
`used. The amount of drug required for saturation for a given amountof cyclodextrin maybe
`determined empirically, such as from phase solubility studies as described infra.
`
`By “mucosa” is meant the epithelial membraneslining the nasal, oral, vaginal orrectal
`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 andPractice 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 bythe 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,
`
`The oral dosage form, for example a conventional tablet, according to the invention will
`dissolve,releasing the drug/CD complex followed by dissociation 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
`believedto aid in avoiding or minimizing absorption inhibition from the now uncomplexed CD.
`
`The drug/CD complex according to the invention may be formulated for transmucosal
`delivery. Hence, for example a buccal tablet according to the invention, upondissolution in the
`
`.,. Copy provided by USPTO from the PACRImage Database on 07/23/2004
`
`
`
`

`

`small volume ofsaliva present produces a saturated drug solution in which the drug is in its
`highest thermodynamic activity (ie, the solution contains the highest concentration of drug
`possible that can be complexed in the given CD) for maximizing drug delivery. One ofskill 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 hydroxygroups are substituted, eg by alkyl,
`hydroxyally, carboxyalkyi, allytcarbonyl, carboxyalkoxyalky, alkylcarbonyloxyalkyl
`alkoxycarbonylalkyl or hydroxy-(mono orpolyalkoxy) alkyl groups, wherein each alkyl or alkylene
`moiety preferably contains 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
`hydroxygroupsis 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 methyi,
`ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl. The term “C,,
`alkyl” is meant to includestraight 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 inventionare the p-
`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--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, U.S. 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 include the following: “Cyclodextrin Technology” byJozsef Szejtli, Kluwer
`
`
`
` Copy provided by USPTO from the PACR Image Database on 07/23/2004
`
`

`

`Academic Publishers (1988) in the chapter Cyclodextrins in Pharmaceuticals; “Cyclodextrin
`Chemistry” by M. L. Bender et al., Springer-Verlag, Berlin (1978); “Advances in Carbohydrate
`Chemistry”, Vol. 12, Ed. by M. L. Wolftom, Academic Press, New York in the chapter The
`Schardinger Dextrins byDexter French at p. 189-260; “Cyclodextrins andtheir 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; USS. Pat. No. 4,659,696; and U.S. Pat. No. 4,383,992.
`
`One ofskill in the art will appreciate that the choice of a specific cyclodextrin will vary
`uponthe route of administration, the drug of choice, ec In certain embodiments, envisaged
`cyclodextrins include 2-hydroxypropyl-B-CD,2-hydroxypropyl-y-CD,y-CD, CD,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 bya variety
`of methods known to thoseofskill in the pharmaceutical arts, such as for example, via melt-
`extrusion (see eg, WO97/18839, hereby incorporated by reference). However, melt-extrusion
`maynot be appropriate for all drugs or cyclodextrins inasmuch as the melting point for some
`active compounds maybeat 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 formedpriorto 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,s#p7d).
`
`In an aspect of the invention, the drug/CD complex is a saturated drug/CD complex
`preparedpriorto incorporationinto the final drug form. A methodenvisioned for preparing a
`solid saturated drug/CD complex entails lyophilization of the complex from the complexion
`solution. However, thoseof skill in the art will appreciate alternative methodologies for
`preparing a solid saturated drug/CD complex.
`
`In certain instances, oral or mucosal absorption maybefurtherfacilitated bythe addition
`of various excipients, additives, etc (to increase solubility or to enhance penetration), by the
`modification of the microenvironment (to favor the un-ionized form of the drug), or by the
`addition of mucoadhesive excipients (to improve contact between the delivery system andthe
`mucosal tissue).
`
`
`
` Copy provided by USPTO from the PACR ImageDatabase on 07/23/2004
`
`

`

`In some embodiments ofthe invention, the drug form is prepared with the minimal
`amountof excipient(s) necessaryforshaping andproducingthe particular drug form (eg tablet,
`patch, ac). In this embodiment,the excipients are chosenfrom those that do notinterferewith
`cyclodextrin orwithcomplex formation. In yet otherembodiments, excipient(s) are chosen from
`those which complexwith cyclodextrins, eg, to facilitate dissolutionof the drug/CD complex.
`The inventionis useful for the administration of anydrug capable of(a) oral deliveryby
`conventional routes, and (b) capable of forming a complex with CD.
`In certain embodiments,theinvention is particularlyuseful for the administration of any
`drug capable of (a) transmucosal delivery, and of (b) forming a complex with CD.
`Accordingly, the methods, formulations and pharmaceutical compositions described
`herein offer noveltherapeutic modalities for the treatmentof patients in need of treatment with
`the drug of choice. As such, the invention avoids the problems of poor absorption and
`bioavailabilityassociated with oral drug dosing byprovidinga drug in 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 avoidedentirelybytransmucosal
`delivery.
`To exemplifythe advantages offered bythe instant approaches,the non-limiting and
`representative example provided herein involves cladribine (“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
`treatment of rheumatoid arthritis and multiple sclerosis (see eg, Liliemark,J.,al,, Clin. Cancer
`Res., 1:385-390, 1995). In some studies, oral cladribine is plagued by the combination of
`relativelylowbioavailabilitycombined 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 inthe art (see for example,
`European Patent Application No. 173,059 A2 and Robins etal.,J. Am. Chem. Soc., 106, 6379
`(1984), and US. Pat. No. 5,208,327).
`
`Copy provided by USPTO from the PACRImage Database on 07/23/2004
`
`

`

`Various concentrations of cladribine were dissolved in hydroxypropy/-® cyclodextrin
`(HPBCD), HPSCD with 0.1% hydroxypropyl methylcellulose (HPMQ),,or y cyclodextrin (yCD)
`according to the Table I.
`
`Table I
`Phase Solubility Studies
`iates +
`Cladribine-HP betaCD
`-HP betaCD
`is
`(TrialB)
`(Trial A)
`onl] SE[at
`on
`[aos|—oas7|-2350-|0008s|—0.02
`0.1352
`oie|083i
`gore [023|aa9|00145|—ose|~2.073
`oar|0332[aes|oonie|—0.1965|3001 0012
`ozs|o5ia|958i|0s|0259|aani|oie|o4688|8733 [0.0306
`
`i
`
`ibine
`
`Molar
`
`
`
`es
`
`Cladribine -gama- CD
`(Trial C)
`
`Molar
`
`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 by mixing excess
`cladribine with a 40%solution of the various CDs. Undissolved cladribine was removed by
`filtration. Theresultant solution was then lyophilized and used to make solid forms.
`
`The molar concentration of cladribine in these solutions was then plotted andis
`presented graphically as 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 theplottedlines represents conditions where excess insoluble drug,here
`cladribine,is present, The area below the plotted line represents the conditions where
`cyclodextrin is in excess.
`
`Figure 1
`
`PHASE SOLUBILITY STUDIES
`
`CD- Molar Conc,
`
`
`
`CladribineMolarConc.
`
`0.071
`
`0.142
`
`0.285
`
`
`
` Copy provided by USPTO from the PACR Image Database on 07/23/2004
`
`

`

`If there is a linear plot for the drug/complex tested, concentrating (or evaporating the
`frozen solution in vacuum) anyofthe solutions to dryness results in the unique mixture
`representingthe maximumdrug concentrationthat canbeincorporated intothe cyclodextrin
`under those conditions. The dried drug/cyclodextrin complex can be used to produce a tablet
`with a minimum ofadditives, such as, for example, 1% magnesium stearate or PEG, with a small
`amount of sorbitol. Whenthis type of tablet 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
`expected to facilitate transmucosal absorption.
`However, a nonlinear drug/CD solubilization plot indicates multiple drug/CD
`complexes. The phase solubilitydata maythenbe used to identifyspecific drug/CD ratios for
`use in the particular drug form.
`
`Example 2
`Pharmacokinetic Studies
`
`The bioavailabilityof cladribine, when complexed with Gamma-CD or HPCDwas
`evaluatedin a beagle dog model. The data obtained from this model are expected to be
`representative for the human experience.
`Cladribine was complexed with either hydroxypropyl-6-cyclodextrin (HPCD)or y-
`cyclodextrin (Gamma-CD)bythe following method,
`An aqueous solution of cladribine,in excess, and CD was mixed with stirring at 44 - 50°C
`for nine hours. Excess, non-complexedcladribine was removed by filtration and the solution
`cooled to room temperature. The aqueous cladribine/CD complexes were taken to dryness by
`lyophilizationprior to incorporationinto the solid buccal or oral tablets. ‘The lyophilization
`procedureconsists of rapidly bringing the complexation solution to -45°C (ca. 200 min.) followed
`bylyophilization at -25°C for approximately 80 — 90 hours.
`Buccal and oral tablets according to the formulas presented in Table II belowwere
`prepared byblendingthelyophilized drug/cyclodextrincomplex (containing 5 mg of cladribine)
`with magnesium stearate for 10 minutes at 12 rpm. The resultant mixture was screened through
`
`Copy provided by USPTO from the PAGR Image Database on 07/23/2004
`
`.
`
`

`

`a # 18-mesh screen followed bya second blending for 5 minutes at 12 rpm and screening. The
`resulting blend was then compressed into 100 mg tablets using a ManestyF3single station punch.
`
`The physical properties of the tablets produced were:
`
`Diameter: 10 mm. Upper shallow concave tooling, lower flat 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
`
`
`emcees Len
`
`Drug Complex
`
`% wihw
`99.0
`99.0
`(contains 4.96 mg
`(contains 4.95 mg
`cladribine
`cladribine
`|Magnesiumstearate[|1.0|TO
`
`uncomplexed
`|__Sorbital|
`pO
`2
`|100.0
`
`
`
`
`
`
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`
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`
`
`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 facility at the IVAX Institute for Drug Research, Hungary, and allowed laboratory diet and
`water adlibitum. The same dogs were used throughoutthe study to minimize inter and intra
`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 sypra); with
`serial blood samples collected over 48 hours. The third test period repeated the second test
`period with the exception that the subjects previously receiving Gamma-CD were now given
`
`8
`
`reat
`
`‘Copy provided by USPTOfrom 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 PAGRImage Database on 07/23/2004
`
`

`

`
`
`
`
`HARMACOKINETICPARAMETERSINMALEDOGS
`
` TableII
`
`
`Intravenousbolus,5mgcladribine/animal
`
`
`CLADRIBINEP
`
`10
`
`Copy provided by USPTO from the PACR Image Database on 07/23/2004
`
`
`
`

`

`11
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`Tablet-1;Gamma-
`
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`TableIV
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`CDcomplex(RDT-0418/C)
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`Copy provided by USPTO from the PACR Image Database on 07/23/2004
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`Oraladministration;5mgcladribine/animal
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`Tablet-2:HPCDcomplex(RDT-0418/D)
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` 14
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`
`
`Table VIIL
`
`Bioavailability of cladribine in dogs
`dose: 5 mgcladribine/animal
`
`
`
`mma-CD complex
`
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`
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`#4; the dog probablyswallowed the tablet
`
`15
`
` Copyprovided by USPTO from the PAGRHImage Database on 07/23/2004
`
`