United States Patent [191
`Shively
`
`[54] PHARMACEUTICAL SOLUTIONS AND
`EMULSIONS CONTAINING TAXOL
`[75] Inventor: MerrickL. Shively, Louisville, Colo.
`Assignee:
`[73]
`Research Corporation Technologies,
`Inc., Tucson, Ariz.
`955,282
`Oct. 1, 1992
`
`[21]
`[22]
`
`Appl. No.:
`
`Filed: \
`
`[63]
`
`[51]
`[52]
`
`[5 8]
`
`[56]
`
`Related US. Application Data
`Continuation-impart of Ser. No. 830,058, Feb. 3, 1992,
`abandoned, which is a continuation-in-part of Ser. No.
`531,847, Jun. 1, 1990, abandoned.
`
`Int. Cl.6 .................. .. A01N 65/00; C07D 305/00
`US. Cl. .................................. .. 424/439; 549/510;
`.
`424/195.1; 424/523
`Field of Search ................... .. 424/ 195.1, 520, 523,
`424/485, 484, 486, 439, 440, 409
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,723,134 3/1973 Cliivers ............................... .. 99/134
`5,011,532 4/1991 Fuisz ............ ..
`5,032,400 7/1991 Wiersum etal. ............... .. 424/1951
`
`OTHER PUBLICATIONS
`Chemical Abstracts l07(5):34441n.
`Russel et a1. (1987) “lntratesticular Injection as a
`Method to Assess the Potential Toxicity of Various
`Agents and Study Mechanisms of Normal Spermato
`genesis” Gamete Research 17(1): 43-56.
`Tarr et al. (1987) Pharm. Res. 4:162-165.
`
`USOO5407683A
`Patent Number:
`Date of Patent:
`
`[111
`[45]
`
`5,407,683
`Apr. 18, 1995
`
`Horwitz (1992) TIPS 13:134-136.
`Natl. Cancer Inst.
`Rowinsky et a1. (1990) J.
`82:1247-1259.
`Grem et a1. (1987) Cancer Treat. Rep. 71:1179-1184.
`Primary Examiner—Thurman K. Page
`Assistant Examiner-Peter F. Kulkosky
`Attorney, Agent, or Firm-Greenlee and Winner
`[57]
`ABSTRACT
`Compositions of matter are provided comprising a
`pharmaceutically effective amount of taxol or a tumor
`active analog thereof solubilized in a pharrnaceutically
`acceptable carrier comprising an oil having a dipole
`moment of between about 0.5 Debyes and about 2.0
`Debyes, and preferably between about 1.6 and about 1.7
`Debyes. Oils from marine organisms having an ether
`lipid as a major component thereof are preferred. Meth
`ods of solubilizing taxol or tumor-active taxol analogs in
`the pharmaceutically acceptable oils of this invention
`are provided comprising forming a ?rst solution by
`dissolving taxol in a preliminary solvent such as an
`anhydrous alcohol, then adding suf?cient oil to solubi
`lize said ?rst solution. Taxol-in-oil solutions are used to
`prepare oil-in-water emulsions for pharmaceutical use
`in anti-tumor therapy by means known to the art using
`known surfactants. Self-emulsifying glasses comprising
`taxol or tumor-active taxol analogs are also provided
`comprising a water-soluble, nonsurface active matrix
`compound and taxol-oil solutions. Emulsions are
`readily formed from such glasses by contacting the glass
`with an aqueous phase.
`
`8 Claims, No Drawings
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`1
`
`PHARMACEUTICAL SOLUTIONS AND
`EMULSIONS CONTAINING TAXOL
`
`This application is a C-I~P of Ser. No. 07/ 830,058,
`?led Feb. 3, 1992, which is a C-I-P of Ser. No.
`07/531,847, ?led Jun. 1, 1990, both now abandoned.
`
`FIELD OF THE INVENTION
`This invention is in the ?eld of pharmaceutical com
`positions, speci?cally compositions containing the anti
`cancer drug, taxol.
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`This application is a continuation-in-part of US. pa
`tent application Ser. No. 07/830,058, ?led Feb. 3, 1992,
`now abandoned, incorporated in its entirety by refer
`ence herein, which is a continuation-in-part of US.
`patent application Ser. No. 07/531,847, ?led Jun. 1,
`1990, also incorporated in its entirety by reference
`herein. Said Ser. No. 07/53l,847 is a continuation of
`International Patent Application PCT 91/03864, ?led
`May 31, 1991, and Applicant claims bene?t of the ?ling
`date of that application. PCT 91/03864 is incorporated
`in its entirety by reference herein. This application also
`incorporates by reference US. patent application Ser.
`' No. 07/954,817, ?led Oct. 1, 1992, which is a continua
`tion-in-part of U8. patent application Ser. No.
`07/ 830,058, now abandoned
`
`15
`
`25
`
`5,407,683
`2
`compounds that retain activity. Rowinsky et a1. (1990)
`J. Natl. Cancer Inst. 82:124-7-1259.
`Because of its poor solubility in water and many oils,
`taxol has been administered in formulations using
`Cremophors. Cremophors are polyoxyethylated castor
`oils. The current Sigma taxol formulation most widely
`used consists of ethanolzcremophor ELsisotonic saline
`(5:5:90). The drug’s solubility in this vehicle does not
`exceed 0.6 mg/ml and it remains physically stable only
`for a short time (3 hr). Therefore, large volumes of these
`formulations, with limited solubility, would have to be
`infused to obtain a desired total dose of 30 mg. Tarr et
`al. (1987) Pharm. Res. 4:162-165. The patient is usually
`required to check into a hospital and endure intrave
`nous infusion for an extended period, such as twenty
`four hours. Typically, taxol is administered intrave
`nously in a preparation containing 30 ug/ml over a
`period of twenty-four hours, followed by a week of rest
`and another dose. This is repeated two more times.
`Further, the BASF cremophor EL (polyoxye
`thylated castor oil), is extremely toxic and has been
`shown to produced vasodilation, labored breathing,
`lethargy, hypotension and death in dogs. Rowinsky et
`al. (1990) J. Natl. Cancer Inst. 82:1247-1259. Anaphy
`lactoid reactions attributed to the cremophor have also
`been observed. Green et al. (1987) Cancer Treat. Rep.
`71:1179-1184.
`Hypersensitivity reactions have been observed using
`the above formulation; one patient had a fatal reaction.
`It is unclear whether taxol itself or its cremophor vehi
`cle is principally responsible for the hypersensitivity
`reactions. Rowinsky et al. (1990) J. Natl. Cancer Inst.
`82:1247-1259.
`'
`Cosolvents have also been utilized in taxol prepara
`tions but require infusion times even longer than the
`currently-used formulation. Drugs with cosolvent for
`mulations may precipitate if infused too fast.
`In an attempt to overcome the taxol formulation
`problems using the toxic cremophor, and in an attempt
`to provide a formulation from which the active ingredi
`ent would not precipitate out from the aqueous solvent
`after IV administration, Tarr et al. (1987) Pharm. Res.
`4:162-165, attempted to formulate taxol with Intralipid
`(trademark of RabiVitrum (formerly Cutter Medical)
`comprising soybean oil, lecithin, egg yolk phospholip
`ids, and glycerol), a commonly used parenteral emul
`
`BACKGROUND OF THE INVENTION
`Taxol is a poorly water soluble alkaloid isolated from
`several species of Western Yew. Taxol exhibits antimi
`totic properties and is presently undergoing phase I
`clinical trials for the treatment of cancers. Taxol has
`been shown to be active against leukemia, colon, breast,
`melanoma, sarcomas, and Lewis lung tumor systems.
`Tarr et a1. (1987) Pharm. Res. 4:162-165; Horwitz
`(1992) TIPS 13:134~131. In vitro studies indicate that
`40
`concentrations of taxol (0.1-10.0 u g/ ml, stabilize micro
`' tubules, thus disrupting normal cell division. Rowinsky
`et al. (1990) J. Natl. Cancer Inst. 82:1247-1259.
`Taxol is a complex diterpene having a taxane ring
`system with a four-membered oxetane ring and an ester
`sidechain at position C-13, as follows:
`
`45
`
`35
`
`sion; however, the poor solubility of taxol in soybean oil
`In an attempt to increase taxol’s solubility and de- 65 (0.3 mg/ml) made this vehicle unsuitable.
`velop more feasible clinical formulations, investigators
`Tarr et a1. then made taxol emulsion formulations
`using triacetin, in which the solubility of taxol is 30
`have acylated carbons of taxol’s taxene ring at the 7
`mg/ml, along with emulsifying agents L-alpha-lecithin,
`position and 10-position. These efforts have yielded
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`pluronic F-86 of BASF company, polysorbate 80 of
`forming a ?rst solution by dissolving taxol in a prelimi
`Sigma Chemical Co., and ethyl oleate. Glyercol was
`nary solvent such as an anhydrous alcohol followed by
`also added to slow creaming. Toxicity of the formula
`mixing with the oil and evaporation of the solvent.
`tion was observed, including lethargy, ataxia and respi
`The solutions of taxol or tumor-active analogs of
`ratory depression in animal models, presumably due to
`taxol made by the methods of this invention are prefera
`the toxicity of the triacetin. The emulsion showed an
`bly used to prepare oil-in-water emulsions for pharma—
`intravenous LD5O of 1.3 ml/kg in mice. The tricetin
`ceutical use in anti-tumor therapy. Emulsions are pre
`emulsion initially gave a 1 urn average diameter droplet
`ferred vehicles for taxol for both intravenous and oral
`and exhibited instability, separating into two phases at
`administration, and can be prepared by means known to
`six months. Vigorous shaking again formed an emulsion
`the art using known surfactants from the solutions of
`having an average droplet size of 2 micrometers.
`taxol in oils of this invention.
`As taxol has been determined to be an especially
`Oil-in-water emulsions containing taxol can also be
`effective anti-cancer agent, formulations which do not
`made using self-‘emulsifying glasses prepared as dis
`contain toxic ingredients and which allow delivery of
`closed in abandoned U.S. Ser. No. 07/830,058 and sub
`pharmaceutically relevant dosages in a reasonable per
`sequent related applications. Such glass compositions
`iod of time, such as orally or by injection, are especially
`comprise a water-soluble, nonsurface active matrix
`needed. Such formulations have not been previously
`compound and an oil containing solubilized taxol from
`available.
`which emulsions can be readily formed by contacting
`Methods and compositions for solubilizing pharma
`the glass with an aqueous phase.
`ceutically relevant dosages of taxol in pharmaceutically
`The oil-in-water emulsions produced from these self
`20
`acceptable oils are therefore highly desirable objects of
`emulsifying glasses do not require art-recognized sur
`this invention.
`factants or emulsifying agents. The matrix compounds
`The use of oil-in-water emulsions for delivery of taxol
`are not surface active agents, surfactants or emulsifying
`and its active analogs are needed to avoid problems of
`agents. Among others, monosaccharides, disaccharides
`precipitation of 1".V. solutions at the time of administra
`and nonsugar sweeteners such as cyclamates, saccha
`25
`tion, increase bioavailability of orally administered
`rines and Water soluble polymers including polyvinyl
`taxol and prevent gastrointestinal upset. In nonemulsi
`pyrrolidones (PVP), cellulose derivatives, dextrans and
`fled form, taxol is degraded in the stomach. However,
`maltodextrins function as matrix compounds in the for
`prior efforts to ‘produce pharmaceutically-acceptable
`mation of such self-emulsifying glasses.
`emulsions containing the taxol have failed due both to
`A pharmaceutically effective emulsion containing
`the relative insolubility of taxol in typical pharmaceuti
`taxol is produced from the self-emulsifying glass by
`cally suitable oils and due to the need for the use of toxic
`mixing with suf?cient aqueous phase, to form an emul
`surface-active agents.
`sion. No emulsive mixing or surfactants are necessary.
`US. application Ser. No. 07/830,058 which is incor
`Such emulsions are administered to patients suffering
`' porated herein by reference, provides novel methods
`from cancers against which taxol is known to have a
`35
`' and compositions for forming pharmaceutical emulsions
`therapeutic effect in appropriate oral or intravenous
`without using conventional surfactants. The use of these
`dosages to effect reduction in the disease.
`novel emulsi?cation methods and compositions in com
`bination with the novel solutions of taxol and its active
`analogs provided herein are objects of this invention.
`Pharmaceutically acceptable oils useful in forming
`oil-in-water emulsions are well-known to the art and
`include vegetable, animal and marine oils. However, the
`poor solubility of taxol in most oils, such as safflower,
`olive and soybean oil (about 0.3-0.6 mg/ml), has pre
`vented the use of such oils in previously-known taxol
`formulations.
`Marine oils, especially those that are classi?ed as
`ether lipids as opposed to triglycerides, are known to
`the art and include orange roughy, squalane, squalene
`and shark liver oil.
`
`40
`
`45
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`A composition of matter is provided comprising a
`pharmaceutically effective amount of taxol or a tumor
`active analog thereof solubilized in a pharmaceutically
`acceptable carrier comprising an oil having a dipole
`moment of between about 0.5 Debyes and about 2.0
`Debyes, and preferably between about 1.6 and about 1.7
`Debyes.
`A pharmaceutically relevant dosage or pharmaceuti
`cally effective amount of taxol for humans is about 30
`mg per dose, repeated several times at weekly intervals.
`’ At solubilities of taxol in present formulations and be
`cause of the toxicity of the cremophor used in the for
`mulation, concentrations of only about 30 ug/ml are
`presently used to administer taxol, thus requiring a vol
`ume of 1,000 ml for a single dose. Concentrations of
`taxol in oil up to about 10 mg/ml are achievable
`through the use of this invention, thus allowing delivery
`of a pharmaceutically relevant dose in a signi?cantly
`lower amount of the pharmaceutical preparation. The
`?nal emulsions of this invention carry from 0.5-5
`mg/ml of taxol, thus allowing delivery of the drug in up
`to one one-hundredth‘ or less of the volume now used
`without toxic cosolvents or cremophores.
`Tumor-active analogs of taxol are known to the art
`and include analogs having acylated carbons of the
`taxene ring at the 7-position and l0-position.
`Pharmaceutically acceptable oils are known to the art
`and include vegetable, ?ower, animal and marine oils.
`
`55
`
`SUMMARY OF THE INVENTION
`This invention provides compositions of matter com
`prising a pharmaceutically effective amount of taxol or
`a tumor-active analog thereof solubilized in a pharma
`ceutically acceptable carrier comprising an oil having a
`dipole moment of between about 0.5 Debyes and about
`2.0 Debyes, and preferably between about 1.6 and about
`1.7 Debyes. Oils from deep-water marine organisms are
`preferred.
`The compositions of the present invention show a
`many-fold increase (up to ?ve hundred times) of oral
`absorption over the prior art formulation using the EL
`cremophor (Trademark of BASF).
`65
`Solutions of taxol or tumor-active taxol analogs in the
`pharmaceutically acceptable oils of this invention may
`be prepared by directly dissolving taxol in the oil or by
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`ing glasses. Water-soluble cellulose derivatives includ
`The oil used for solubilizing taxol is preferably a marine
`ing carboxymethyl-cellulose and hydroxyalkycellulo'ses
`oil, and more preferably, a deep-water marine oil. Oils
`including hydroxmethyl- and hydroxypropylcelluloses
`having ether lipid as a major component thereof are
`preferred. Orange roughy oil, shark liver oil, squalene
`can be processed by the methods described herein to
`or squalane oil are preferred.
`form self-emulsifying glasses. Useful maltodextrins are
`Dipole moment measurements of various oils are
`dextrose copolymers with starch, classi?ed as having
`readily available in the literature, (e.g., McClellan, A.
`dextrose equivalents from about 5 to about 25. Both
`L. (1963), “Table of Experimental Dipole Moments,”
`agglomerated and nonagglomerated forms of maltodex
`W. H. Freeman (publishers), San Francisco, Calif; and
`trin function in such self-emulsifying glasses.
`Smith, J. W. (1955) “Electric Dipole Moments,” But
`Molecules possessing a tripartite glucophore having
`tersworth Scienti?c Publications, London), and are
`the three structural features of a proton donor, an elec
`experimentally determined by the method of oscillome
`tronegative atom and a hydrophobic region are of par
`try (Reilley, C. N. (1954), in New Instrumental Methods
`ticular use as matrix compounds in the preparation of
`in Electrochemistry, P. Delahey (ed.), Interscience, New
`self-emulsifying glasses, especially where water is the
`York, NY. pp. 319-645) or comparison to drug solubil
`preferred solvent.
`ity (Gorman, W. G. and Ho] G. D. (1964) H01. J.
`The tripartite glucophore is a structural feature asso
`Pharm. Sci. 5321017).
`ciated with sweetness which consists of a polarizable
`The solutions of taxol or tumor-active analogs of
`bond, designated AH or A, an electronegative atom,
`taxol made by the methods of this invention are prefera
`designated B and a third feature. Initially two structural
`bly used to prepare oil-in-water emulsions for pharma
`features: a proton donor or more generally a polarizable
`ceutical use in antitumor therapy. Emulsions are pre
`bond and an electronegative atom separated in space by
`ferred vehicles for taxol for both intravenous and oral
`about 2.5 to 4.0 A were described as minimally required
`administration, and can be prepared by means known to
`for sweet taste (Shallenberger and Acree (1967) Nature
`the art using known surfactants from the solutions of
`216:480). Examples of AH include 0-H groups, N-H
`taxol in oils of this invention. Surfactants useful in the
`25
`groups and C-H groups of cycloalkyl groups or aro
`preparation of such emulsions include, e.g., Pluronic
`matic rings. Examples of B include oxygen atoms,
`F-86 TM (BASF), polysorbate Tween 80 TM , those
`oxime groups, nitro groups, carbonyl groups, and S-—O
`having HLB values between 10-13, and preferably Plu
`or SO; groups. The AH, B unit in the cyclamate and
`ronic F-86.
`saccharin sweeteners are assigned to the NH-SOZ
`This invention also includes self-emulsifying glasses
`moieties. The third feature, designated X herein, is asso
`prepared by the methods disclosed in abandoned U.S.
`ciated with increasing intensity of sweetness. The X
`Ser. No. 07/830,058, ?led Feb. 3, 1992, incorporated
`feature is described speci?cally as a lipophilic region or
`herein by reference, and related applications. Such glass
`hydrophobic bonding area (Deutsch and Hansch (1966)
`compositions comprise a water-soluble, nonsurface ac
`Nature 211:75), or more generally as a region capable of
`tive matrix compound and an oil containing solubilized
`dispersive bonding or a region susceptible to electro
`taxol or tumor-active taxol analog from which emul
`philic attack (Kier (1972) 1. Pharmaceutical Sci.
`sions can be readily formed by contacting the glass with
`61:1394-1397). Examples of the X feature include alkyl
`an aqueous phase.
`and alkenyl groups, cycloalkyl and cycloalkenyl
`No emulsive mixing or art-recognized surfactants are
`groups, aromatic rings, and the C-2 substituent in
`required to form emulsions from such self-emulsifying
`aminonitrobenzenes. All 'three'features are described as
`glasses. The matrix compounds are not surface active
`involved in binding of a sweet molecule to the taste
`agents, surfactants or emulsifying agents. Among oth
`ers, monosaccharides, disaccharides and nonsugar
`receptor.
`-
`The features of the tripartite glucophore form a trian
`sweeteners such as cyclamates, saccharines and water
`gle with the AH-B distance ranging from about 2.5-4.9
`soluble polymers including polyvinylpyrrolidones
`(PVP), cellulose derivatives, dextran, and maltodextrins
`
`A, the AH-X distance ranging from about 3.1 to 5.2 and the B-X distance ranging from about 5.2 to 7.4 A.
`function as matrix compounds in the formation of such
`The triangular tripartite glucophore structure is more
`self-emulsifying glasses. Saccharides including but not
`narrowly depicted with an AHO-B distance of about 2.6
`limited to sucrose, fructose and trehalose function as
`A, a B-X distance of about 5.5 A and an X-AH distance
`matrix compounds in the subject glasses. Preferred non
`of about 3.5 A. Intensity of sweetness is associated with
`polymeric matrix compounds are molecules which taste
`better ?t or improved binding in the receptor. Sweet
`sweet, more preferred are molecules which are at least
`tasting compounds which possess a tripartite gluco
`about as sweet as sucrose. Saccharides, monosaccha~
`phore, particularly in which the X feature is a region
`rides, disaccharides, sugar alcohols and sugar deriva
`capable of hydrophobic bonding, are useful in the prep
`tives, like chlorinated sugars, which are at least about as
`aration of self-emulsifying glasses via the water solvent
`sweet as sucrose, are useful as matrix compounds. Non
`method as described herein. Those compounds possess
`sugar sweeteners useful as matrix compounds include
`ing the tripartite glucophore which are sweeter than
`various sweet tasting molecules including but not lim
`sucrose are preferred matrix compounds for use in the
`ited to amino acids, amino acid derivatives, Aspartame
`compositions and methods of the present invention.
`(Trademark) and derivatives thereof, and sulfamates
`The tripartite glucophore structure is found not only
`including cyclamates, saccharines, acesulfams and de
`rivatives thereof.
`in sweet molecules,.but also as a feature of the mono
`mers which make up the polymeric matrix materials
`Polymeric matrix compounds that are useful in self
`emulsifying glasses include among others, PVPs, dex
`useful in this invention, such as PVP.
`The weight ratio of matrix compound to oil phase in
`tran, maltodextrins and cellulose derivatives. Cross~
`a self-emulsifying glass is more preferably between
`linked and noncrosslinked PVPs ranging in molecular
`about 2:1 and 20:1 and most preferably between about
`weight from about 15 to 70 thousand can be processed
`2:1 and 10:1.
`. by the methods described herein to form self-emulsify
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`The compositions of the present invention are also
`Self-emulsifying glasses containing taxol and tumor
`termed “inclusion compounds” herein. Matrix materials
`active taxol analogs are preferably prepared by combin
`ing the tumor~active ingredient and oil solution de
`used herein may also be described in terms of their
`ability to form inclusion compounds or aggregates in
`scribed above, With or without the presence of the pre
`corporating the oleaginous materials of this invention.
`liminary solvent, with a nonsurface active matrix mate
`Such matrix materials are capable of forming chains of
`rial, as de?ned above, and a suf?cient amount of a sol
`inde?nite length, either due to the fact that they are
`vent for the matrix material, such that substantially all
`polymeric materials or by intermolecular hydrogen
`of the matrix compound is dissolved to form a combina
`bonds in the presence of oil, such chains having surfaces
`tion such that the combination is not a stable emulsion,
`that are relatively hydrophobic and surfaces that are
`followed by removing the solvent for the matrix com
`relatively hydrophilic. The oleaginous material is en
`pound, along with any preliminary solvent that may be
`closed within the cavities or interstices formed by lipo
`present, from the combination such that a glass results.
`philic regions of the chains (Harata, K. and Vedaira, K.
`The solvent for the matrix material employed can
`(1975) Bull. Chem. Soc. Jap. 48:375). When the solvent
`include but is not limited to water, aqueous solvents,
`used to form the self-emulsifying glass is removed the
`aqueous alcohols, ethanol, methanol, and organic sol
`matrix material forms a structure which “includes” the
`vents in which the matrix compound is soluble, includ
`oleaginous material within it in discretely separated
`ing among others, chloroform. Water and aqueous sol
`aggregates or small portions. The use of the word
`vents including aqueous alcohols are preferred.
`“compound” does not imply a de?nite stoiehiometry.
`The matrix material and oil solution containing taxol
`The molar ratio of oil to matrix may vary, as may the
`or tumor-active taxol analog are preferably combined
`size of the matrix chains.
`such that the weight ratio of the matrix compound to
`In general, the various matrix compounds can be
`the oil solution is at least about 2:1. Solvent removal is
`preferably done by evaporation by application of a
`admixed to form glasses of the present invention. Em
`vacuum accompanied by nonvigorous mixing, i.e.,
`ploying a mixture of matrix components can, for exam
`ple, lead to self-emulsifying glasses with higher glass
`nonemulsive mixing, most preferably by rotoevapora
`transition temperatures. The higher the glass transition
`tion. Solvent is removed until a dry-appearing solid,
`temperature, the more kinetically stable the glass.
`solid foam or ?lm is produced. Rotoevaporation results
`Glasses with higher glass transition temperatures will
`in bubbling of the combination and the solid resulting
`be generally more stable to storage and have longer
`from removal of solvent has the appearance of a solid
`shelf-lives. It is generally preferable that glass transition
`foam. Substantially all the solvent is removed, leaving
`temperatures be about 20° C. or'more above room tem
`trace amounts of solvent, i.e., around 0.2 to about 0.5
`perature. Mixtures of nonpolymeric matrix compounds,
`percent.
`such as sucrose, with polymeric matrix compounds,
`The solid left after removal of substantially all the
`such as maltodextrin, result in glasses with higher tran
`solvent is a glass. Glasses formed using nonpolymeric
`sition temperatures compared to glasses formed with
`matrix compounds or mixtures of polymeric and non
`the nonpolymeric matrix compound alone. In particu
`polymeric matrix compounds often retain some level of
`lar, the use of a mixture of sucrose and maltodextrin as
`short or medium range molecular order, designated
`the matrix compound results in glasses havinghigher
`microcrystallinity herein, as measured by differential
`glass transition temperatures than sucrose-based glasses.
`scanning calorimetry (DSC). Glasses which are fully
`It is preferred in the subject self-emulsifying glasses
`amorphous, as measured by X-ray diffraction and DSC
`that the weight ratio of the matrix compound to the oil
`can be prepared, but fully amorphous glasses may be
`phase is at least about 2:1.
`very hygroscopic and the absorption of signi?cant
`Solutions of taxol or tumor-active taxol analogs in the
`amounts of water into glasses is detrimental to their
`pharmaceutically acceptable oils of this invention may
`functionality and shelf-life. Thus, glasses retaining some
`be prepared by dissolving taxol crystals directly in the
`level of microcrystallinity, from about 10% to 60%
`45
`oil, preferably with the application of heat. More rapid
`microcrystallinity as measured by DSC, are preferred.
`dissolution is obtained by ?rst dissolving the taxol in a
`The subject glasses do not retain more than about 10%
`more volatile, less viscous preliminary solvent such as
`long range molecular order as measured by X-ray dif
`anhydrous alcohol, e.g., ethanol or methanol. The pri
`fraction.
`mary solution is then mixed with an oil of this invention
`In the casein which a nonpolymer is employed as or
`having a dipole moment of between about 0.5 and about
`in the matrix compound, it is preferred that the solvent
`2.0 Debyes to form a second solution. This second solu—
`be removed at a rate that is fast enough to prevent the
`tion may at this point he treated to remove the prelimi
`formation of signi?cant, i.e., greater than about 10%,
`nary solvent, preferably by heating. Alternatively, the
`long range molecular order via crystallization of the
`nonpolymer component of the matrix compound. This
`solvent may be removed later in the process as de
`scribed below.
`can generally be achieved if the rate of solvent removal
`Solutions comprising taxol or a tumor-active taxol
`is faster than the rate of crystallization of any matrix
`analog in a preferred oil can be emulsi?ed by means
`component from the solvent solution.
`known to the art to form pharmaceutical 10% w/v oil
`The process steps can in many cases be performed at
`compositions having concentrations of the tumor-active
`about room temperaturelt is preferred that the process
`ingredient of at least about 0.5 mg/ml up to about 5
`steps are performed at the lowest temperatures possible
`mg/ ml. Useful emulsions of this invention have concen
`which allow generation of a dry-appearing solid, still
`trations of the tumor-active ingredient of about 3
`keeping the taxol or tumor-active taxol analog in solu
`mg/ml.
`tion. The process steps should be performed to avoid
`melting or decomposition of the matrix compound, i.e.,
`To avoid the use of surfactants which may be toxic or
`cause undesirable side-effects, it is preferred that such
`the process should be performed at temperatures less
`emulsions be produced using the self-emulsifying
`than about the melting point or decomposition point of
`glasses described above.
`the matrix compound, generally about 140° C. or less.
`
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`5,407,683
`9
`Taxol is stable for at least about two hours at 130° C.
`Under vacuum taxol tends to precipitate from the oil
`solution at bath temperatures less than 50° to 60° C.
`Thus preferred temperatures for performing the process
`steps are about 60° C. to about 130° C.
`If preliminary solvent is present, and if it is desired to
`remove it prior to adding matrix materials, preferred
`temperatures for removing the preliminary solvent
`from the taxol and oil solution are between about 60° C.
`and about 70° C., preferably about 60° C. This step is
`preferably done by heating under a nitrogen blanket for
`a suf?cient period to remove substantially all the sol
`vent, typically about 20 minutes.
`»
`The matrix material, preferably sucrose, is mixed
`with the taxol and oil solution, which may also contain
`preliminary solvent, at a preferred ratio of between
`about 2:1 and about 20:1:zmatrixzoil solution. The sol
`vent for this composition, preferably water, is then
`added, preferably using the smallest amount of solvent
`which will dissolve the composition, i.e., about 2:l::sol
`ventzmatrix/ oil phase. The solvent may be heated to aid
`in dissolution, preferably to about 80° C., for a suf?cient
`period of time to dissolve the composition, i.e. about
`five minutes.
`Solvent is then removed from the solubilized compo
`sition, preferably by rotoevaporation, under vacuum,
`preferably starting at about 500 mbar and increasing to
`maintain bubbling. The vapor temperature should be
`kept at about 30° C. or higher. When the vapor temper
`ature no longer increases, usually after about half an
`hour, maximum vacuum is applied. The self-emulsifying
`glass is collected from the ?lm or foam formed in the
`reaction vessel as a dry-appearing solid. The glass
`should be stored at room temperature at less than about
`30% relative humidity.
`A pharmaceutically effective emulsion containing
`taxol is produced from the self-emulsifying glass by
`mixing with suf?cient aqueous phase, preferably an
`isotonic solution such as Normal Saline or 5% dextrose
`(DSW), to form an emulsion. No emulsive mixing or
`surfactants are necessary. The aqueous phase is added
`to the glass preferably at a ratio of between about 1 inlzl
`g, and about 5 mlzl gzzaqueous phasezglass, to form a
`composition having a pharmaceutically-effective con
`centration of the tumor-active ingredient.
`The emulsion so formed, after storage for several
`45
`hours without agitation, has a particle size between
`about 5 pm and about 1 pm and remains stable at room
`temperature for periods of three weeks or more. Drop
`let size decreases over time. Droplet size of the emul
`sion as initially formed may be larger, e.g., between
`about 10 um and about 2 um.
`For therapeutic use, emulsions containing between
`about 0.5 and about 5 mg/ ml taxol or tumor-active taxol
`analog are prepared by the foregoing methods and ad
`ministered orally or intravenously.
`
`50
`
`EXAMPLES
`Example 1
`Taxol (Sigma T-7402), 4.0 mg, was dissolved in anhy
`drous methanol. The taxol solution was added to 0.400
`ml squalane oil (Sigma S-45 10, lot 88F3528). The meth
`anol was then removed with heating and nitrogen blan
`ket at about 60° C. for 10 minutes. The taxol was com
`pletely solubilized in the squalane oil.
`Example 2
`The taxol-in-oil solution of Example 1 was added to
`1.62 g of sucrose in a 100 ml vacuum ?ask. Suf?cient
`water to just dissolve the