(12) United States Patent
`Schultz et al.
`
`I 1111111111111111 11111 lllll 111111111111111 111111111111111 1111111111 11111111
`US006194395Bl
`US 6,194,395 Bl
`Feb.27,2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) CYCLODEXTRIN CLADRIBINE
`FORMULATIONS
`
`(75)
`
`(73)
`
`Inventors: Thomas W. Schultz, Richboro, PA
`(US); Rainer Naeff, Langwiesen (CH)
`
`Assignee: Orthro-McNeil Pharmaceutical, Inc.,
`Raritan, NJ (US)
`
`( *)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 09/257,809
`
`(22) Filed:
`
`Feb. 25, 1999
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,719,295 * 1/1988 Cook et al. ............................ 536/26
`4,727,064 * 2/1988 Pitha ...................................... 514/58
`4,764,604
`8/1988 Muller .................................. 536/103
`5,641,757
`6/1997 Bornstein et al.
`..................... 514/46
`5,681,822 * 10/1997 Bornstein et al.
`..................... 514/46
`FOREIGN PATENT DOCUMENTS
`
`11/1996 (EP) .
`WO 97/18839
`* cited by examiner
`Primary Examiner-Dwayne C. Jones
`(74) Attorney, Agent, or Firm-Kenneth J. Dow
`ABSTRACT
`
`(57)
`
`(51)
`
`Int. Cl.7 .......................... AOlN 43/04; AOlN 43/90;
`A61K 31/715; A61K 31/52
`
`(52) U.S. Cl. ............................................... 514/58; 514/266
`
`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 ........................................ 514/266, 58
`
`14 Claims, 1 Drawing Sheet
`
`Hopewell EX1075
`Hopewell v. Merck
`IPR2023-00480
`
`1
`
`

`

`FIG. 1
`
`100.tj! ~-==8=-~-~~1t:"li
`' ' ' ' ' '0.
`
`'
`
`',,'0----&
`
`%2-CdA
`Remaining
`
`50
`
`30
`
`20
`
`',,'0,,,,
`0,,
`''Q
`In HPf3CD Complex
`',,,
`ph 1.4
`e-
`In HPf3CD Complex
`ph 8.2
`-~-
`In Normal Saline (No CD)
`ph 1.4
`--0--
`In Normal Saline (No CD)
`phB.2
`10 ...__ _ _._ ____ _._ _ __. __ __._ _ __. __ _._ _ ___,.__ _ __._ _ __.
`
`0
`
`----0,,
`',0
`'-,,0,
`''-0,,
`'0
`',,_'El
`',,0_
`',,,
`0
`
`-•-
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`Time (hr)
`
`6
`
`7
`
`8
`
`9
`
`10
`
`d •
`r:JJ.
`•
`~
`~ .....
`~ = .....
`
`"'!"j
`~
`~
`N
`~-..J
`N
`0
`0
`'"""'
`
`e
`rJ'J.
`_,.a-...
`i,-
`
`'° ,I;;..
`~
`'° (It
`
`~
`i,-
`
`2
`
`

`

`US 6,194,395 Bl
`
`1
`CYCLODEXTRIN CLADRIBINE
`FORMULATIONS
`
`This invention relates to pharmaceutically useful cyclo(cid:173)
`dextrin formulations of cladribine (2-chloro-2'(cid:173)
`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 surrounding tissue.
`Thus, there is a need for new formulations of cladribine
`which allow the subcutaneous or intramuscular injection of
`5 more concentrated aqueous solutions 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.
`~-cyclodextrin is a cyclic compound consisting of seven
`10 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
`15 detail [see Szejtli, J. Cyclodextrin technology, (1988) Klu(cid:173)
`wer Academic Publishers, Dordrecht].
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`20
`
`FIG. 1 shows the effect of hydroxypropyl-~-cyclodextrin
`on the stability of cladribine at pH 1.4
`
`SUMMARY OF THE INVENTION
`
`There is provided by the present invention a solution of
`25 cladribine in water comprising:
`a) from about 1 to about 15 mg/mL of cladribine or its
`pharmaceutically acceptable salts; and
`b) from about 1 to about 350 mg/ml cyclodextrin solu-
`30 bilizing agent.
`In a further aspect of the invention, there is provided a
`solid pharmaceutical oral dosage form of cladribine com(cid:173)
`prising:
`a) from about 1 to about 15 mg cladribine or its pharma-
`35 ceutically acceptable salts; and
`b) from about 100 to about 500 mg of a cyclodextrin; in
`association with one or more pharmaceutically acceptable
`earners.
`
`Cladribine is known as an antileukemic agent, i.e., in
`treating leukemias, such as, hairy cell leukemia and L 1210
`leukemia, and as an immunosuppressive agent (D. A.
`Carson, D. Bruce 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 rheumatoid arthritis 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
`subcutaneous or intramuscular injection. First, cladribine is
`slightly soluble in water which requires a large volume of
`material to be injected subcutaneously or intramuscularly to 40
`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 45
`tendency to undergo hydrolysis, particularly under acidic
`conditions. Longer shelf-life is beneficial for extended stor(cid:173)
`age at refrigerated or room temperature conditions. Use of
`the compound orally has been limited by the fact that
`cladribine is acid labile and would not be stable in the acidic 50
`environment of the gastro-intestinal system.
`U.S. Pat. No. 5,310,732, col. 8. teaches a 0.1 mg/mL
`isotonic saline solution of cladribine. There has been mar(cid:173)
`keted a non-buffered solution containing 1.0 mg/mL of
`cladribine in 9.0 mg/mL Sodium Chloride Injection, USP.
`U.S. Pat. Nos. 5,641,757 and 5,681,822 describe inject(cid:173)
`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 60
`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- 65
`lality is around 290 mosm. The high osmolality may result
`in pain and irritation when injected by the subcutaneous
`
`55
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Processes for preparing cladribine are known. European
`Patent Application No. 173,059 A2 and Robins et al., J. Am.
`Chem. Soc., 106, 6379(1984) disclose the preparation or
`cladribine. The preparation consists of the glycosylation of
`2,6-dichloropurine with l-chloro-2'-deoxy-3' ,5'-di-O-p(cid:173)
`toluoyl-b-D-erythropentofuranose to yield the N-9 glycosy(cid:173)
`lated purine, 2,6-dichloro-9-deoxy-3, 5-di-0-p-toluoyl-b-D(cid:173)
`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-, ~- or
`y-cyclodextrins or derivatives thereof, in particular deriva(cid:173)
`tives wherein one or more of the hydroxy groups are
`substituted, e.g. by alkyl, hydroxyalkyl, carboxyalkyl,
`alkylcarbonyl, carboxyalkoxyalkyl, alkylcarbonyloxyalkyl,
`alkoxycarbonylalkyl or hydroxy-(mono or polyalkoxy)alkyl
`groups, wherein each alkyl or alkylene moiety preferably
`contains up to six carbons.
`Substituted cyclodextrins which can be used in the inven(cid:173)
`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 Bl
`
`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 most particularly
`it is about 0.4. M.S. values determined by NMR or IR
`preferably range from 0.3 to 1, in particular from 0.55 to
`0.75.
`Further examples of substituted cyclodextrins include
`ethers wherein the hydrogen of one or more cyclodextrin
`hydroxy groups is replaced by C1 _6 alkyl, hydroxyC1_calkyl,
`carboxy-C 1 _6 alkyl or C1 _6 alkyloxycarbonyl-C 1 _6 alkyl
`groups or mixed ethers thereof. In particular such substituted
`cyclodextrins are ethers wherein the hydrogen of one or
`more cyclodextrin hydroxy groups is replaced by C1 _3 alkyl,
`hydroxy-C2 _4 alkyl or carboxy-C1 _2 alkyl or more particularly 25
`by methyl, ethyl, hydroxyethyl, hydroxypropyl,
`hydroxybutyl, carboxymethyl or carboxyethyl.
`In the foregoing definitions, the term "C1 _6alkyl" 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 Q-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 or less.
`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 MS is in the range of 0.125 to 45
`10, in particular 0.3 to 3 and more particularly 0.3 to 1.5.
`Of particular utility in the present invention are the
`~-cyclodextrin ethers, e.g. dimethyl-~-cyclodextrin as
`described in Drugs of the Future, Vol. 9, No. 8, p. 577-578
`by M. Nogradi (1984) and polyethers, e.g. hydroxypropyl- 50
`p-cyclodextrin and hydroxyethyl-~-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 55
`oxide and may have a MS value of about 0.125 to 10, e.g.
`about 0.3 to 3.
`Especially suitable cyclodextrins are ~-CD, 2,6-dimethyl(cid:173)
`P-CD, 2-hydroxyethyl-~-CD, 2-hydroxyethyl-~-CD,
`2-hydroxypropyl-~-CD and (2-carboxymethoxy)propyl-~(cid:173)
`CD, and in particular 2-hydroxypropyl-~-CD.
`Besides simple cyclodextrins, branched cyclodextrins and
`cyclodextrin polymers may also be used.
`Other cyclodextrins are described for example in Chemi(cid:173)
`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,
`
`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(cid:173)
`ing cyclodextrins for use in the compositions according to
`the present invention, and which provide a guide for the
`5 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(cid:173)
`try" by M. L. Bender et al., Springer-Verlag, Berlin (1978);
`10 "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
`15 Acc. Chem. Research, 1982, 15, p. 66-72; W. Sanger,
`Angewandte Chemie, 92, p. 343-361 (1981); AP. 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,
`20 317,064; 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 ~-cyclodextrin, in
`particular hydroxypropyl-~-cyclodextrin. The most pre(cid:173)
`ferred cyclodextrin derivative for use in the compositions of
`the present invention is hydroxypropyl-~-cyclodextrin hav(cid:173)
`ing a M.S. in the range of from 0.35 to 0.50 and containing
`30 less than 1.5% unsubstituted ~-cyclodextrin. M.S. values
`determined by NMR or 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,
`i.e., 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(cid:173)
`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 render it 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 buffers include but are 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
`60 buffer ratio. The amount of buffer generally range from
`about O to about 12 mg/ml monobasic phosphate buffer and
`about O to about 24 mg/ml dibasic phosphate buffer.
`The liquid dosage form may also optionally contain a
`preservative to prevent antimicrobial contamination. If
`65 employed, the preservative component may be selected from
`any pharmaceutically acceptable preservative. M-cresol
`may be used as well as the alkyl esters of para-
`
`35
`
`40
`
`4
`
`

`

`US 6,194,395 Bl
`
`5
`hydroxybenzoic acid (the parabens, e.g. butylparaben, meth(cid:173)
`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(cid:173)
`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(cid:173)
`cantly enhanced. In this manner the injection volume can be
`reduced to less than 1 ml per injection. Irritation and pain 10
`due to high osmolality or large injection volumes can 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(cid:173)
`ery devices such as auto-injectors or pen injectors can be
`employed for subcutaneous administration of cladribine.
`A typical liquid formulation of the present invention may
`for example comprise the following composition:
`
`5
`
`15
`
`6
`a) diluents such as lactose, kaolin, mannitol, crystalline
`sorbitol, talc 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 magnesium stearate, 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(cid:173)
`nylpyrrolidone and the like;
`
`e) scavengers such as silicon dioxide;
`f) flavoring agents such as mannitol, dextrose, fructose,
`sorbitol and the like; and
`
`g) coloring agents.
`
`Other suitable excipients can be found in the Handbook of
`20 Pharmaceutical Excipients, published by the American Phar(cid:173)
`maceutical Association, herein incorporated by reference.
`
`Cladribine
`2-Hyroxypropyl-13-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
`
`A typical oral dosage form of the present invention may
`have a formulation containing various components in accor-
`25 dance with the following:
`
`Milled extrudate
`
`30
`
`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 35
`significantly enhanced when combined with cyclodextrins.
`The solid oral dosage forms of the present invention may
`be prepared in the form of tablets, caplets, gelcaps, capsules,
`chewable tablets, lozenges, fast dissolving wafers, and other
`known and effective delivery modes. The cladribine/ 40
`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 45
`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(cid:173)
`ferred.
`One method of preparing the solid oral dosage forms is
`disclosed in patent application WO97/18839, hereby incor(cid:173)
`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 60
`prepare conventional solid pharmaceutical dosage forms. In
`doing so, the extrudate may be admixed with various excipi(cid:173)
`ents commenly used in pharmaceutical tablets and coated in
`an art-known way.
`For example, suitable tablets may be prepared in the 65
`conventional way having one or more of the following
`excipients:
`
`Cladribine
`Cyclodextrin
`
`1 mg to 15 mg
`100 to 500 mg
`
`Excipients
`
`Microcrystalline cellulose
`Crospovidone
`Colloidal silicon dioxide
`Sterotex
`
`100 to 300 mg
`10 to 200 mg
`1 to 5 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(cid:173)
`cation in the treatment of a variety of disease states and
`autoimmune disorders such as multiple sclerosis, autohe(cid:173)
`molytic anemia, inflammatory bowel disease, rheumatoid
`arthritis, malignant astrocytoma and the like. Effective dos-
`so ages 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
`55 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.
`
`EXAMPLE 1
`
`The formulation of Table 1 was prepared and found to be
`suitable for use as an injectable and pharmaceutically useful
`solution. The pH of the solution is about 7.3.
`
`5
`
`

`

`Procedure:
`The cylodextrin and the buffer salts were solved in Water
`for Injection and an excess of Cladribine was added. The 15
`solution was shaken during 5 days at room temperature and
`4° C. The solution was filtered through a 0.2 µm filter.
`
`EXAMPLE 2
`The solubility of cladribine in water at various concen- 20
`trations of 2-Hydroxypropyl-~-Cyclodextrin (HPCD) was
`measured by high performance liquid chromatography. The
`normal solubility 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.
`
`25
`
`TABLE 2
`
`% HP-!3-CD (W/W)
`
`pH
`
`Solubility of Cladribine at 4° C.
`
`10
`15
`20
`25
`
`7.3
`7.3
`7.3
`7.3
`
`4.93
`6.51
`8.27
`9.91
`
`% HP-!3-CD (W/W)
`
`pH
`
`Solubility of Cladribine (mg/ml) at RT
`
`10
`15
`20
`25
`
`7.3
`7.3
`7.3
`7.3
`
`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(cid:173)
`dextrin formulation of the present invention.
`
`30
`
`35
`
`40
`
`8. A solid pharmaceutical oral dosage form of cladribine
`comprising:
`a) from about 1 to about 15 mg cladribine or its pharma(cid:173)
`ceutically acceptable salts; and
`b) from about 100 mg to about 500 mg of a cyclodextrin;
`in association with one or more pharmaceutically accept(cid:173)
`able carriers.
`9. The composition of claim 8 wherein the cyclodextrin is
`selected from an a-cyclodextrin, a ~-cyclodextrin, a
`y-cyclodextrin, and a derivative thereof.
`10. The composition of claim 8 wherein the cyclodextrin
`is selected from 2-Hydroxypropyl-~-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 embedded in a cyclo(cid:173)
`dextrin carrier.
`14. A solid composition according to claim 8 prepared by
`45 melt-extrusion having the following formula:
`Milled Extrudate
`
`US 6,194,395 Bl
`
`7
`Table 1
`
`Composition: (mg/ml)
`
`TABLE 1
`
`Composition: (mg/ml)
`
`Cladribine
`2-Hyroxypropyl-13-Cyclodextrin (parenteral grade)
`Sodium Dihydrogenphosphate Dihydrate
`di-Sodium Hydrogenphosphate Dihydrate
`Water for Injection
`
`10.0
`275.0
`1.2
`2.4
`797.5
`
`8
`3. The solution of claim 1 wherein the cyclodextrin is
`selected from 2-Hydroxypropyl-~-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% w/v
`2-Hydroxypropyl-~-Cyclodextrin.
`7. The solution of claim 1 comprising the following
`formula:
`
`5
`
`10
`
`Composition: (mg/ml)
`
`Cladribine
`2-Hyroxypropyl-13-Cyclodextrin (parenteral grade)
`Sodium Dihydrogenphosphate Dihydrate
`di-Sodium Hydrogenphosphate Dihydrate
`Water for Injection.
`
`10.0
`275.0
`1.2
`2.4
`797.5.
`
`EXAMPLE 3
`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 1:1.5 molar
`ratio. The effect of the HPCD on the stability of cladribine
`at pH 1.4 and 8.2 at room temperature was measured. The 50
`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 of cladribine or its
`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 ~-cyclodextrin, a
`y-cyclodextrin, and a derivative thereof.
`
`55
`
`60
`
`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
`1 mg to 5 mg
`2 mg to 10 mg.
`
`* * * *
`
`*
`
`6
`
`