US006194395B1
`(10) Patent No:
`a2) United States Patent
`US 6,194,395 B1
`Schultz et al.
`(45) Date of Patent:
`Feb. 27, 2001
`
`
`(54) CYCLODEXTRIN CLADRIBINE
`FORMULATIONS
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(75)
`
`Inventors: Thomas W. Schultz, Richboro, PA
`(US); Rainer Naeff, Langwiesen (CH)
`
`(*) Notice:
`
`(73) Assignee: Orthro-McNeil Pharmaceutical, Inc.,
`Raritan, NJ (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`ELS. 1544p) byl days.
`(21) Appl. No.: 09/257,809
`(22)
`Filed
`Keb, 25, 1999
`;
`iled:
`eb.
`25,
`
`(51)
`
`Int. Gl deneeresereeeeeeceeeeeeons AOIN 43/04; AOIN 43/90;
`A61K 31/715; A6IK 31/52
`
`(52) US. C]e cececeeescscesceesssesesessensceseneneees 514/58; 514/266
`
`4,719,295 *
`1/1988 Cook et al. ceccecsssessenees 536/26
`
`4,727,064 *
`2/1988 Pitha ........
`w. 514/58
`4,764,604
`8/1988 Muller vse...
`. 536/103
`
`5,641,757
`...
`.. 514/46
`6/1997 Bornstein et al.
`5,681,822 * 10/1997 Bornstein et al. wee 514/46
`FOREIGN EXTENT DOCUMENTS
`WO 97/18839
`11/1996 (EP).
`* cited by examiner
`Primary Examiner—Dwayne C. Jones
`(74) Attorney, Agent, or Firm—Kenneth J. Dow
`(57)
`ABSTRACT
`There is provided by the present invention liquid injectable
`and oral solid pharmaceutical dosage forms containing a
`mixture of cladribine (2-chloro-2'-deoxyadenosine; 2-CdA)
`and cyclodextrin.
`
`(58) Field of Search oo...ee 514/266, 58
`
`14 Claims, 1 Drawing Sheet
`
`1
`
`Hopewell EX1024
`
`Hopewell EX1024
`
`1
`
`

`

`U.S. Patent
`
`Feb. 27, 2001
`
`US 6,194,395 B1
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`US 6,194,395 B1
`
`1
`CYCLODEXTRIN CLADRIBINE
`FORMULATIONS
`
`This invention relates to pharmaceutically useful cyclo-
`dextrin formulations of cladribine (2-chloro-2'-
`deoxyadenosine; 2-CdA). More particularly, this invention
`relates to soluble aqueous formulations of cladribine with
`cyclodextrin solubilizers which are injectable in humans, as
`well as oral solid dosage forms containing a mixture of
`cladribine and cyclodextrins.
`
`BACKGROUND OF THE INVENTION
`
`The compound cladribine has the following formula:
`
`2
`route. Recrystallisation of cladribine in the tissue may occur
`and damage the surroundingtissue.
`Thus, there is a need for new formulations of cladribine
`whichallow the subcutaneous or intramuscular injection of
`more concentrated aqueoussolutions of cladribine which are
`isotonic and isohydric. Further,
`there is a need for oral
`formulations of cladribine which are stable against
`hydrolysis, particularly in an acid environment.
`6-cyclodextrin is a cyclic compound consisting of seven
`units of a-(1—4) linked D-gluco-pyranose units and is
`known as a complexing agent. Cyclodextrins are known in
`the art to possess the ability to form inclusion complexes and
`to have concomitant solubilizing properties. The properties
`of cyclodextrins and their properties have been reviewed in
`detail [see Szejtli, J. Cyclodextrin technology, (1988) Kdu-
`wer Academic Publishers, Dordrecht].
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`10
`
`15
`
`Cladribine is known as an antileukemic agent, ie., in
`treating leukemias, such as, hairy cell leukemia and L 1210
`leukemia, and as an immunosuppressive agent
`(D. A.
`Carson, D. Brucc Wasson, and Ernest Beutler, Proc. Soc.
`Acad. Sci. USA, Vol. 81, pp 2232-2236, 1984). More
`recently, cladribine has been disclosed as effective in the
`treatment of rheumatoidarthritis and multiple sclerosis, U.S.
`Pat. No. 5,310,732.
`To date, cladribine has been administered by intravenous
`injection of saline solutions presenting two problems for
`subcutaneousor intramuscular injection. First, cladribine is
`slightly soluble in water which requires a large volume of
`material to be injected subcutaneously or intramuscularly to
`achieve the required dose. Dilute solutions are acceptable for
`intravenous injection, but may create pain or inflammatory
`difficulties for subcutaneous or intramuscular injection.
`Secondly, cladribine has limited stability in simple saline
`solutions. Stability of the compound is hampered by its
`tendency to undergo hydrolysis, particularly under acidic
`conditions. Longer shelf-life is beneficial for extended stor-
`age at refrigerated or room temperature conditions. Use of
`the compound orally has been limited by the fact
`that
`cladribine is acid labile and wouldnotbestable in the acidic .
`environment of the gastro-intestinal system.
`US. Pat. No. 5,310,732, col. 8. teaches a 0.1 mg/mL
`isotonic saline solution of cladribine. There has been mar-
`
`40
`
`45
`
`keted a non-buffered solution containing 1.0 mg/mL of
`cladribine in 9.0 mg/mL Sodium Chloride Injection, USP.
`US. Pat. Nos. 5,641,757 and 5,681,822 describe inject-
`able aqueous formulations of cladribine in which the active
`cladribine material is solubilized with a cosolvent mixture of
`
`benzyl alcohol and propylene glycol and stabilized with
`m-cresol as a preservative. Use of the cosolvent mixtures
`disclosed therein enabled aqueous formulations of 2 to about
`8 mg/ml cladribine. However,
`the disadvantage of these
`formulations lies in the danger of supersaturation and the
`very high osmolality of the solution. The osmolality is
`between 1000 and 2000 mosm while physiological osmo-
`lality is around 290 mosm. The high osmolality may result
`in pain and irritation when injected by the subcutaneous
`
`60
`
`65
`
`FIG. 1 showsthe effect of hydroxypropyl-f-cyclodextrin
`on the stability of cladribine at pH 1.4
`
`SUMMARY OF THE INVENTION
`
`There is provided by the present invention a solution of
`cladribine in water comprising:
`a) from about 1 to about 15 mg/mLofcladribine orits
`pharmaceutically acceptable salts; and
`b) from about 1 to about 350 mg/ml cyclodextrin solu-
`bilizing agent.
`In a further aspect of the invention, there is provided a
`solid pharmaceutical oral dosage form of cladribine com-
`prising:
`a) from about 1 to about 15 mg cladribine or its pharma-
`ceutically acceptable salts; and
`b) from about 100 to about 500 mg of a cyclodextrin; in
`association with one or more pharmaccutically acceptable
`carriers.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Processes for preparing cladribine are known. European
`Patent Application No. 173,059 A2 and Robinset al., J. Am.
`Chem. Soc., 106, 6379(1984) disclose the preparation or
`cladribine. The preparation consists of the glycosylation of
`2,6-dichloropurine with 1-chloro-2'-deoxy-3',5'-di-O-p-
`toluoyl-b-D-erythropentofuranose to yield the N-9 glycosy-
`lated purine, 2,6-dichloro-9-deoxy-3, 5-di-0-p-toluoyl-b-D-
`erythropentofuranosyl)
`-purine. which is subsequently
`reacted with ammonia to yield cladribine. An alternative
`method to manufacture cladribine is taught in U.S. Pat. No.
`5,208,327 by Robert H. K. Chen.
`As the cyclodextrin in the compositions of the invention,
`there may be used any of the physiologically tolerable
`water-soluble substituted or unsubstituted cyclodextrins or
`physiologically tolerable derivatives thereof, e.g. a-, B- or
`y-cyclodextrins or derivatives thereof, in particular deriva-
`tives wherein one or more of the hydroxy groups are
`substituted, e.g. by alkyl, hydroxyalkyl, carboxyalkyl,
`alkylearbonyl, carboxyalkoxyalkyl, alkylcarbonyloxyalkyl,
`alkoxycarbonylalkyl or hydroxy-(monoor polyalkoxy)alkyl
`groups, wherein each alkyl or alkylene moiety preferably
`contains up to six carbons.
`Substituted cyclodextrins which can be used in the inven-
`tion include polyethers, e.g. as described in U.S. Pat. No.
`3,459,731. In general, to produce these, unsubstituted cyclo-
`
`3
`
`

`

`US 6,194,395 B1
`
`3
`dextrins are reacted with an alkylene oxide, preferably under
`superatmospheric pressure and at an elevated temperature,
`in the presence of an alkaline catalyst. Since a hydroxy
`moiety of the cyclodextrin can be substituted by an alkylene
`oxide which itself can react with yet another molecule of
`alkylene oxide, the average molar substitution (MS)is used
`as a measure of the average number of moles of the
`substituting agent per glucose unit. The MS can be greater
`than 3 and theoretically has no limit. In the cyclodextrin
`derivatives for use in the compositions according to the
`present invention the M.S is conveniently in the range of
`0.125 to 10, in particular of 0.3 to 3, or from 0.3 to 1.5.
`Preferably the M.S. ranges from about 0.3 to about 0.8, in
`particular from about 0.35 to about 0.5 and mostparticularly
`it
`is about 0.4. M.S. values determined by NMRor IR
`preferably range from 0.3 to 1, in particular from 0.55 to
`0.75.
`
`a
`
`10
`
`15
`
`-
`
`Further examples of substituted cyclodextrins include
`ethers wherein the hydrogen of one or more cyclodextrin
`hydroxy groupsis replaced by C,_,alkyl, hydroxyC,_,-alkyl,
`carboxy-C,_,alkyl or C,_,alkyloxycarbonyl-C,_,alkyl
`groups or mixedethers 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,_,alkyl or more particularly ?
`by methyl, ethyl, hydroxyethyl, hydroxypropyl,
`hydroxybutyl, carboxymethyl or carboxyethyl.
`In the foregoing definitions, the term “C,_,alkyl” is meant
`to include straight and branched saturated hydrocarbon
`radicals, having from 1 to 6 carbon atoms, such as methyl,
`ethyl 1-methylethyl, 1,1-dimethylethyl, propyl,
`2-methylpropyl, butyl, pentyl, hexyl and the like.
`Such ethers can be prepared by reacting a cyclodextrin
`with an appropriate O-alkylating agent or a mixture of such
`agents in a concentration selected such that the desired
`cyclodextrin ether is obtained. The reaction is preferably
`conducted in a solvent in the presence of a base. With such
`ethers, the degree of substitution (DS)is the average number
`of substituted hydroxy functions per glucose unit, the DS
`being thus 3 orless.
`In the cyclodextrin derivatives for use in the compositions
`according to the present invention, the DS preferably is in
`the range of 0.125 to 3,
`in particular 0.3 to 2, more
`particularly 0.3 to 1, and the MSis in the range of 0.125 to
`10, in particular 0.3 to 3 and more particularly 0.3 to 1.5.
`Of particular utility in the present
`invention are the
`B-cyclodextrin ethers, e.g. dimethyl-p-cyclodextrin as
`described in Drugs of the Future, Vol. 9, No. 8, p. 577-578
`by M. Nogradi (1984) and polyethers, e.g. hydroxypropyl-
`p-cyclodextrin and hydroxyethyl-f-cyclodextrin. Such alkyl
`ethers may for example be methyl ethers with a degree of
`substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a
`hydroxypropyl cyclodextrin may for example be formed
`from the reaction between [-cyclodextrin and propylene ,
`oxide and may have a MS value of about 0.125 to 10, e.g.
`about 0.3 to 3.
`
`40
`
`45
`
`Especially suitable cyclodextrins are B-CD, 2,6-dimethyl-
`P-CD, 2-hydroxyethyl-B-CD, 2-hydroxyethyl-B-CD,
`2-hydroxypropyl-B-CD and (2-carboxymethoxy)propyl-B-
`CD, and in particular 2-hydroxypropyl-B-CD.
`Besides simple cyclodextrins, branched cyclodextrins and
`cyclodextrin polymers may also be used.
`Other cyclodextrins are described for example in Chemi-
`cal and Pharmaceutical Bulletin 28: 1552-1558 (1980),
`Yakugyo Jiho No. 6452 (28 March 1983), Angew. Chem.
`Int. Ed. Engl. 19: 344-362 (1980), U.S. Pat. No. 3,459,731,
`
`60
`
`65
`
`4
`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 describ-
`ing cyclodextrins for use in the compositions according to
`the present invention, and which provide a guide for the
`preparation, purification and analysis of cyclodextrins
`include the following: “Cyclodextrin Technology” by Jozsef
`Szejtli, Kluwer Academic Publishers (1988) in the chapter
`Cyclodextrins in Pharmaceuticals; “Cyclodextrin Chemis-
`try” by M. L. Bender etal., 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 by Dexter French at p. 189-260;
`“Cyclodextrins and their Inclusion Complexes”by J. 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
`ct 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.
`Pat. No. 4,383,992.
`More recent examples of substituted cyclodextrins
`include sulfobutylcyclodextrins (U.S. Pat. No. 5,134,127-
`A). Their use is also envisaged in the present invention.
`The cyclodextrin used is preferably a B-cyclodextrin, in
`particular hydroxypropyl-B-cyclodextrin. The most pre-
`ferred cyclodextrin derivative for use in the compositions of
`the present invention is hydroxypropyl-B-cyclodextrin hav-
`ing a M.S. in the range of from 0.35 to 0.50 and containing
`less than 1.5% unsubstituted B-cyclodextrin. M.S. values
`determined by NMRor IR preferably range from 0.55 to
`0.75.
`
`The liquid dosage form contains from about 1 to about 15
`mg/mL of cladribine or its pharmaceutically acceptable
`salts, preferably from about 5 to about 12 mg/ml, most
`preferably about 10 mg/ml. The cyclodextrin is generally
`present in an amount necessary to solubilize the cladribine,
`1e., from about 1 to about 350 mg/ml, preferably from about
`200-300 mg/ml. The amount of cyclodextrin should be
`tailored to produce an isotonic and isohydric solution, gen-
`erally in the range of about 20% of the composition. The
`combination of cladribine and cyclodextrin in this
`concentration, preferably HPCD, results in a colorless, iso-
`tonic and isohydric solution.
`Alternatively, sufficient sodium chloride can be added to
`the solution to renderit isotonic.
`
`The liquid dosage form may also optionally contain a
`pharmaceutically acceptable buffer to maintain the pH at a
`range of about 5.5 to about 8.5. The preferred pH range for
`shelf stable solutions is about 6.0 and 8.0. Suitable buffers
`
`are any of those available for pharmaceutical application.
`Such butters include butare not limited to phosphate,citrate,
`acetate, borate and tris. The preferred buffer for use herein
`is a sodium phosphate buffer system containing a mixture of
`monobasic sodium dihydrogenphosphate dihydrate and
`dibasic di-sodium hydrogenphosphate dihydrate. The ratio
`of phosphate buffers is adjusted to achieve the pH desired,
`generally in about a 2 to 1 monobasic to dibasic phosphate
`buffer ratio. The amount of buffer generally range from
`about 0 to about 12 mg/ml monobasic phosphate buffer and
`about 0 to about 24 mg/ml dibasic phosphate buffer.
`The liquid dosage form may also optionally contain a
`preservative to prevent antimicrobial contamination.
`If
`employed, the preservative component maybe selected from
`any pharmaceutically acceptable preservative. M-cresol
`may be uscd as well as the alkyl esters of para-
`
`4
`
`

`

`US 6,194,395 B1
`
`5
`hydroxybenzoicacid (the parabens, e.g. butylparaben, meth-
`ylparaben and propylparaben), alone or in combination.
`Generally, the preservatives are used in a concentration of
`about 0.02% w/v. Other preservatives include ethylenedi-
`amine tetra-acetic acid, propyl-p-hydroxybenzoates or sor-
`bic acid.
`
`By employing the cyclodextrin liquid formulations of the
`present invention, the solubility of cladribine can be signifi-
`cantly enhanced. In this mannerthe injection volume can be
`reduced to less than 1 ml per injection. Irritation and pain
`due to high osmolality or large injection volumescan thus be
`reduced. In addition, cladribine is significantly more stable
`at lower pH when combined with cyclodextrins like HPCD.
`Further, due to the small volumes (0.5-1 ml) that can be
`achieved using the cyclodextrin liquid dosage forms of the
`present invention, patient friendly applicators or drug deliv-
`ery devices such as auto-injectors or pen injectors can be
`employed for subcutaneous administration of cladribine.
`Atypical liquid formulation of the present invention may
`for example comprise the following composition:
`
`Cladribine
`2-Hyroxypropyl-B-Cyclodextrin (parenteral grade)
`Sodium Dihydrogenphosphate Dihydrate
`di-Sodium Hydrogenphosphate Dihydrate
`Water for Injection
`
`1.0-15.0 mg/ml
`1.0-350.0 mg/ml
`0.0-24 mg/ml
`0.0-48 mg/ml
`ad 100.0
`
`6
`a) diluents such as lactose, kaolin, mannitol, crystalline
`sorbitol, tale and the like;
`
`b) binders such as sugars, microcrystalline cellulose,
`alginic acid, carboxymethyl cellulose, croscarmellose
`sodium, polyvinylpyrrolidone, crospovidone and the like;
`
`c) lubricants such as magnesiumstearate, talc, calcium
`stearate, zinc stearate, stearic acid, hydrogenated vegetable
`oil, leucine, glycerides and sodium stearyl fumarate;
`
`d) disintegrants such as starches, methylcellulose, agar,
`bentonite, alginic acid, carboxymethylcellulose, polyvi-
`nylpyrrolidone and the like;
`
`scavengers suchassilicon dioxide;
`€)
`f) flavoring agents such as mannitol, dextrose, fructose,
`sorbitol and the like; and
`
`10
`
`15
`
`g) coloring agents.
`
`Other suitable excipients can be found in the Handbook of
`Pharmaceutical Excipients, published by the American Phar-
`maceutical Association, herein incorporated by reference.
`
`A typical oral dosage form of the present invention may
`have a formulation containing various componentsin accor-
`dance with the following:
`Milled extrudate
`
`The use of the cyclodextrin formulations of the present
`invention also provide an additional benefit in that it has
`been found that cladribine is significantly more stable
`against hydrolysis when combined with cyclodextrins. This
`is 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. However,
`as shown in FIG. 1, the stability of cladribine at pH 1.4 is
`significantly enhanced when combined with cyclodextrins.
`The solid oral dosage forms of the present invention may
`be prepared in the formof tablets, caplets, gelcaps, capsules,
`chewable tablets, lozenges, fast dissolving wafers, and other
`known and effective delivery modes. The cladribine/
`cyclodextrin composition may be admixed with a variety of
`pharmaceutically acceptable excipients including fillers,
`binders, sweeteners, artificial sweeteners,
`lubricants,
`glidants, disintegrants, colors, adsorbents,acidifying agents,
`and flavoring agents. The choice of excipient will depend on
`the solid oral dosage form employed(i.e. tablets, caplets, or
`capsules) and whether the dosage form is chewable or a
`swallowable formulation. Swallowable oral tablets are pre-
`ferred.
`
`One method of preparing the solid oral dosage formsis
`disclosed in patent application WO97/18839, hereby incor-
`porated by reference. In this method, solid mixtures of the
`cyclodextrins with the active ingredient are prepared via
`melt-extrusion, where the active ingredient is embedded in
`the cyclodextrin carrier. In accordance with this technique,
`the cladribine active ingredient and the cyclodextrins are
`mixed with other optional additives and then heated until
`melting occurs. The mixture is then extruded through an
`extruder having one or more nozzles. The resulting mass is
`then cooled and prepared into pellets which can be used to
`prepare conventional solid pharmaceutical dosage forms. In
`doing so, the extrudate may be admixed with various excipi-
`ents commenly used in pharmaceutical tablets and coated in
`an art-known way.
`For example, suitable tablets may be prepared in the
`conventional way having one or more of the following
`excipients:
`
`40
`
`45
`
`60
`
`65
`
`Cladribine
`Cyclodextrin
`
`1mgto 15 mg
`100 to 500 mg
`
`Excipients
`
`Microcrystalline cellulose
`Crospovidone
`Colloidal silicon dioxide
`Sterotex
`
`100 to 300 mg
`10 to 200 mg
`1to5 mg
`2 to 10 mg.
`
`The cladribine/cyclodextrin formulation of the present
`invention is useful as an oral or parenteral formulation as a
`neoplastic in treating leukemias such as hairy cell leukemia
`and chronic myelogenous leukemia. It may also have appli-
`cation in the treatment of a variety of disease states and
`autoimmune disorders such as multiple sclerosis, autohe-
`molytic anemia,
`inflammatory bowel disease, rheumatoid
`arthritis, malignant astrocytoma andthe like. Effective dos-
`ayes are expected to vary considerably depending on the
`condition being treated and the route of administration. For
`treating hairy cell leukemia, the dosage is 0.09 mg/kg/day
`for 7 days. For treatment of multiple sclerosis the dosage can
`range from about 0.04 to about 1.0 mglkg of body weight per
`day, preferably from about 0.05 to about 0.15 mg/kg/day, as
`described in U.S. Pat. No. 5,506,214. Preferable doses for
`treatment of other disorders are described in U.S. Pat. Nos.
`5,106,837, 5,506,213, 5,310,732, 5,401,724 and 5,424,296.
`
`The invention is illustrated, but in no way limited, by the
`following examples.
`
`EXAMPLE1
`
`The formulation of Table 1 was prepared and foundto be
`suitable for use as an injectable and pharmaceutically useful
`solution. The pH of the solution is about 7.3.
`
`5
`
`

`

`US 6,194,395 B1
`
`Composition: (mg/ml)
`
`Table 1
`
`TABLE1
`
`Composition: (mg/ml)
`Cladribine
`2-Hyroxypropyl-B-Cyclodextrin (parenteral grade)
`Sodium Dihydrogenphosphate Dihydrate
`di-Sodium Hydrogenphosphate Dihydrate
`Water for Injection
`
`10.0
`275.0
`1.2
`24
`797.5
`
`Procedure:
`
`The cylodextrin and the buffer salts were solved in Water
`for Injection and an excess of Cladribine was added. The
`solution was shaken during 5 days at room temperature and
`4° C. The solution wasfiltered through a 0.2 wm filter.
`EXAMPLE2
`
`10
`
`15
`
`The solubility of cladribine in water at various concen-
`trations of 2-Hydroxypropyl-B-Cyclodextrin (HPCD) was
`measured by high performance liquid chromatography. The
`normalsolubility of cladribine in water is about 4.52 mg/ml.
`Table 2 sets forth the results of the solubility measurements
`for the HPCD/cladribine formulation of Example 1.
`
`‘
`
`TABLE 2
`
`% HP-B-CD (W/W)
`10
`15
`20
`25
`
`% HP-B-CD (W/W)
`10
`15
`20
`25
`
`pH
`7.3
`13
`7.3
`7.3
`
`pH
`13
`43
`73
`43
`
`Solubility of Cladribine at 4° C.
`4.93
`6.51
`8.27
`9.91
`
`Solubility of Cladribine (mg/ml) at RT
`6.4
`8.47
`10.48
`12.36
`
`The foregoing results demonstrate a greatly increased
`solubility of cladribine in water through use of the cyclo-
`dextrin formulation of the present invention.
`EXAMPLE3
`
`A solution of 10 mg/ml cladribine in 20% HPCD was
`prepared by heating the mixture to 80° C. for 5 minutes. A
`complex of caldribine/HPCD is formed at a 1:15 molar
`ratio. The effect of the HPCD onthe stability of cladribine
`at pH 1.4 and 8.2 at room temperature was measured. The
`results are shown in FIG. 1.
`
`As shown in FIG. 1, the cladribine/EPCD complex was
`significantly more stable at pH 1.4 than the cladribine
`solution prepared without HPCD.
`We claim:
`
`1. A solution of cladribine in water comprising:
`a) from about 1 to about 15 mg/mL ofcladribine orits
`pharmaceutically acceptable salts; and
`b) from about 1 to about 350 mg/ml cyclodextrin solu-
`bilizing agent.
`2. The solution of claim 1 wherein the cyclodextrin is
`selected from an a-cyclodextrin,
`a
`f-cyclodextrin, a
`y-cyclodextrin, and a derivative thereof.
`
`40
`
`45
`
`60
`
`8
`3. The solution of claim 1 wherein the cyclodextrin is
`selected from 2-Hydroxypropyl-f-Cyclodextrin.
`4. The solution of claim 1 comprising about 5 to about 12
`mg/ml cladribine.
`5. The solution of claim 1 comprising about 10 mg/ml
`cladribine.
`
`6. The solution of claim 1 comprising about 20% wiv
`2-Hydroxypropyl-f-Cyclodextrin.
`7. The solution of claim 1 comprising the following
`formula:
`
`Composition: (mg/ml)
`Cladribine
`2-Hyroxypropyl-B-Cyclodextrin (parenteral grade)
`Sodium Dihydrogenphosphate Dihydrate
`di-Sodium Hydrogenphosphate Dihydrate
`Water for Injection.
`
`10.0
`275.0
`122
`2.4
`197:
`
`8. A solid pharmaceutical oral dosage form of cladribine
`comprising:
`a) from about 1 to about 15 mg cladribine orits pharma-
`ceutically acceptable salts; and
`b) from about 100 mg to about 500 mgof a cyclodextrin;
`in association with one or more pharmaceutically accept-
`able carriers.
`
`9. The composition of claim 8 wherein the cyclodextrin is
`selected from an a-cyclodextrin, a B-cyclodextrin, a
`y-cyclodextrin, and a derivative thereof.
`10. The composition of claim 8 wherein the cyclodextrin
`is selected from 2-Hydroxypropyl-B-Cyclodextrin.
`11. ‘The composition of claim 8 comprising about 5 to
`about 15 mg cladribine.
`12. The composition of claim 8 comprising about 10 mg
`cladribine.
`
`13. The composition according to claim 8 prepared by
`melt-extrusion, where the cladribine is embeddedin a cyclo-
`dextrin carrier.
`
`14. Asolid composition according to claim 8 prepared by
`melt-extrusion having the following formula:
`Milled Extrudate
`
`Cladribine
`Cyclodextrin
`
`1 mg to 15 mg
`100 mg to 500 mg
`
`Excipients
`
`Microcrysstalline Cellulose
`Crospovidone Binders
`Colloidal Silicone Dioxide
`Sterotex
`
`100 mg to 200 mg
`10 mg to 200 mg
`1mg to 5 mg
`2 mg to 10 mg.
`
`6
`
`