`I
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`Page 2 of 2
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`the examiner's decision of rejection or
`
`application converted registration]
`
`[Date of final disposal for application]
`
`[Patent number]
`
`[Date of registration]
`
`[Number of appeal against examiner's
`
`decision of rejection]
`
`[Date of requesting appeal against examiner's
`
`decision of rejection]
`
`[Date of extinction of right]
`
`AQUESTIVE EXHIBIT 1007 page 2401
`http://www19.ipd1.ncipi.go.jp/PA1/resu1t/detail/main/wAAAxlsSéBBflbYfilgégrlilfilfll 10078/1m2401
`
`
`
`
`
`5
`
`10
`
`15
`
`Japanese Publication No. 1-151528
`
`CLAIMS
`
`1. An agent for accelerating transmucosal absorption of a poorly absorbable drug, wherein the
`
`agent comprises one or more ether or thioether compounds of C6-C13 aliphatic hydrocarbon and
`
`monosaccharide or disaccharide.
`
`2. The agent of claim} 1, wherein the ether or thioether compound of aliphatic hydrocarbon and
`
`monosaccharide is represented by Formula (1):
`
`Cl‘le”
`
`0
`
`OH
`
`Ho
`
`’
`
`on
`
`A—R
`
`(1)
`
`wherein A represents an oxygen atom or sulfur atom; and R represents a C5-Clg aliphatic
`
`hydrocarbon group.
`
`' 3. The agent of claim 1, wherein the ether or thioether compound of aliphatic hydrocarbon and
`
`disaccharide is represented by Formula (2):
`
`CH,OH
`
`CH,OH
`
`o
`
`on
`
`p
`
`0H
`
`0
`
`A-—R
`
`(2)
`
`H0
`
`0
`
`OH
`
`on
`
`wherein A represents an oxygen atom or sulfur atom; and R represents a C6-C18 aliphatic
`
`hydrocarbon group.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2402
`
`page 2402
`
`
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`AQUESTIVE EXHIBIT 1007 page 2403
`
`AQUESTIVE EXHIBIT 1007
`
`page 2403
`
`
`
`33 Bil-131151528 (2)
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`—226—
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2404
`
`page 2404
`
`
`
`HrH1-151528 (8)
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`—227—
`
`AQUESTIVE EXHIBIT 1007 page 2405
`
`AQUESTIVE EXHIBIT 1007
`
`page 2405
`
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`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 2406
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`AQUESTIVE EXHIBIT 1007 page 2407
`
`AQUESTIVE EXHIBIT 1007
`
`page 2407
`
`
`
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`AQUESTIVE EXHIBIT 1007 page 2408
`
`AQUESTIVE EXHIBIT 1007
`
`page 2408
`
`
`
`3“
`
`
`
`1m'P83IB.‘_(Ils/al)
`
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`
`PCI‘
`
`International Bureau
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 1
`
`(11) International Publication Number:
`
`W0 91/19481
`
`A61K 9/107
`
`(43) International Publication Date:
`
`26 December 1991 (26.12.91)
`
`(21) International Application Number:
`
`PCT/US91/O4104
`
`(22) International Filing Date:
`
`11 June 1991 (11.06.91)
`
`(74) Agents :1 BARAN, Robert, J. et al.; Allergan, Inc., 2525 Du—
`pont Drive, Post Office Box
`19534,
`Irvine, CA
`92713-9534 (US).
`
`(30) Priority data:
`539,061
`
`15 June 1990 (15.06.90)
`
`US
`
`(71) Applicant: ALLERGAN, INC. [US/US]; 2525 Dupont
`Drive, Post Office Box 19534, Irvine, CA 92713-9534
`(US).
`
`(72) Inventors: JOSHI, Abhay ; 120 Monroe, Irvine, CA 92720
`(US). DING, Shulin ; 14641 Fir Avenue, Irvine, CA
`92714 (US). HIMMELSTEIN, Kenneth, James ; 217
`Gilbert Avenue, Pearl River, NY 10965 (US).
`
`(81) Designated States: AT (European patent), AU, BB, BE
`(European patent), BF (OAPI patent), BG, BJ (OAPI
`patent), BR, CA, CF (OAPI patent), CG (OAPI patent),
`CH (European patent), CI (OAPI patent), CM (OAPI
`patent), DE (European patent), DK (European patent),
`ES (European patent), FI, FR (European patent), GA
`(OAPI patent), GB (European patent), GN (OAPI pa-
`tent), GR (European patent), HU, IT (European patent),
`JP, KP, KR, LK, LU (European patent), MC, MG, ML
`(OAPI patent), MR (OAPI patent), MW, NL (European
`patent), NO, PL, RO, SD, SE (European patent), SN
`(OAPI patent), SU, TD (OAPI patent), TG (OAPI pa-
`tent).
`
`Published
`With international search report.
`
`
`
`which will gel following administration to a physiological system for the sustained delivery of such pharmaceutical compounds.
`
`(54) Title: REVERSIBLE GELATION COMPOSITIONS AND METHODS OF USE
`
`(57) Abstract
`
`Reversibly gelling aqueous compositions are disclosed which undergo significant changes in viscosity in response to sub-
`stantially simultaneous changes in both temperature and pH. The compositions are formed of relatively low concentrations of a
`stable combination of at least one pH-sensitive reversibly gelling polymer and at least one temperature—sensitive reversibly gelling
`polymer. The compositions can be formulated to exhibit a sol-gel transition over a wide range of conditions and viscosities and
`may be modified to incorporate a pharmaceutical compound for utilization as droppable or injectable drug delivery systems
`
`AQUESTIVE EXHIBIT 1007 page 2409
`
`AQUESTIVE EXHIBIT 1007
`
`page 2409
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing international
`applications under the PCI‘.
`
`Monaco
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Guinea
`Greece
`Hungary
`Italy
`Japan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Liechtenstein
`Sri Lanka
`Luxembourg
`
`AT
`AU
`BB
`BE
`BF
`36
`3.!
`BR
`CA
`CF
`CG
`CH
`Cl
`CM
`CS
`DE
`DK
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Canada
`Central African Republic
`Congo
`Switzerland
`can: d'lvoire
`Cameroon
`Gechoslovakia
`Germany
`Denmark
`
`Madagascar
`Mali
`Mongolia
`Mauritania
`Malawi
`Netherlands
`Norway
`Poland
`Romania
`Sudan
`Sweden
`Senegal
`Soviet Union
`Chad
`Togo
`United States of America
`
`AQUESTIVE EXHIBIT 1007 page 2410
`
`AQUESTIVE EXHIBIT 1007
`
`page 2410
`
`
`
`W0 91/1948]
`
`'fl
`
`PCT/US9l/04104
`
`REVERSIBLE GELATION COMPOSITIONS AND METHODS OF USE
`
`FIELD OF THE INVENTION
`
`The present invention relates in general to macromolecular polymer
`
`mixtures exhibiting reversible gelation properties. More particularly,
`
`the present invention is directed to aqueous compositions that revers—
`
`ibly gel in response to simultaneous variations in at least two physical
`
`parameters
`
`such as
`
`temperature and pH or
`
`ionic strength.
`
`These
`
`compositions can be designed to reversibly gel at varying viscosities
`
`10
`
`over a relatively wide range of conditions, making them particularly
`
`suitable for use as droppable, oral, or inj ectable drug delivery systems
`
`for the sustained and controlled delivery of pharmaceutical medicaments
`
`and diagnostic agents.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`Various
`
`approaches
`
`to the production of
`
`reversibly gelling
`
`solutions have been developed over the years. Principal efforts have
`
`been devoted to the development of gelatinous drug delivery systems for
`
`20
`
`topical
`and subcutaneous applications and, more
`recently,
`for
`the
`administration of ophthalmic drugs to the eye.
`'In general, sustained
`
`25
`
`30
`
`35
`
`release drug delivery systems incorporate pharmaceutical agents in solid
`
`or semi-solid vehicles which are applied to or implanted under the skin
`
`of a patient by medical personnel. Additionally, unlike conventional
`
`drug delivery systems. ocular drug delivery systems also must address
`
`the additional problem of drug loss through the lacrimal drainage system
`
`as well as the needs of patient comfort and ease of administration.
`
`Early approaches to the solution of the problems associated with
`
`ocular drug delivery systems utilized semi-solid ointments or gels
`
`applied directly to the conjunctiva or cul—de—sac of the eye to retain
`
`the pharmaceutical agents contained therein on the ocular surface
`
`against such physiological factors as
`
`tear turnover,
`
`tear drainage,
`
`blinking. and other mechanical losses.
`
`For example. U.S. Patents Nos.
`
`3,944,427 and 3,700,451 disclose gelatinous drug delivery compositions
`
`containing agar, xanthine gum, and carob gum in liquid mediums in order
`
`to enhance their residence time upon the skin or mucosae and the
`
`resultant bioavailability of the medicinal products contained therein.
`
`Similarly. European Patent Application No. 0 300 888 Al, filed July 18,
`
`1988, recently disclosed the use of rhamsan gum to thicken ophthalmic
`
`compositions for droppable and topical application.
`
`AQUESTIVE EXHIBIT 1007 page 2411
`
`AQUESTIVE EXHIBIT 1007
`
`page 2411
`
`
`
`WO 91/19481
`
`PCT/US91/04104
`
`-2-
`
`Though effectiva at
`
`increasing drug retention times,
`
`lack of
`
`patient acceptability remains as a significant drawback to the use of
`
`such known viscous drug delivery compositions in the eye. Many patients
`
`experience difficulty in applying the appropriate amount of
`
`such
`
`compounds to the eye and resist the unpleasant side effects of eyelid
`crusting and vision blurring. As a result,
`these compounds may only be
`suitable for use in the evening or during non—active hours.
`
`A known alternative approach to these problems was the use of a
`
`formulation which is liquid at room temperature but which forms a semi-
`
`solid when warmed to body temperature.
`
`Such a thermally triggered
`
`system is disclosed in U.S. Patent No. 4,474,751, where an aqueous drug
`
`delivery system that forms a semi-solid "gel" at body temperature is
`
`formed
`
`from proprietary polymers
`
`known
`
`as
`
`"Tetronico"
`
`polyols.
`
`Generally speaking, these compositions are formed from approximately 10%
`
`to 50% of the specific polymers in an aqueous base.
`
`By adjusting the
`
`pH of these drug delivery systems through the addition of buffering
`
`agents,
`
`the gelling transition temperature can be raised to physiologi—
`
`cal temperatures on the order of 35'C.
`
`Similar drug delivery systems which can be injected subcutaneously
`
`or intramuscularly are disclosed in United States Patent No. 4,474,752.
`
`These compounds also contain from 103
`
`to 50% by weight Tetronico
`
`polymers and gel at temperatures from about 30'
`
`to 10°C.
`
`A thermal setting gel drug delivery system is also described in
`
`0.5. Patent No. 4,188,373, utilizing "Pluronico polyols"
`
`as
`
`the
`
`thermally gelling polymer. Adjusting the concentration of the polymer
`
`gives the desired l'sol--gel" transition temperature. However, producing
`
`a compound which sets at physiologically useful
`
`temperature ranges
`
`limits the available viscosity of the gelled product.
`
`Alternatively, it has been proposed to utilize formulations which
`
`gel
`
`in response to changes
`
`in pH as drug delivery vehicles.
`
`By
`
`carefully controlling the pH of such mixtures. a solution which forms
`
`a gel upon mixing with aqueous
`
`tear
`
`fluid could theoretically be
`
`produced. However, it is believed that the relatively high buffering
`
`capacity of such pH responsive compositions can lead to slow gelling,
`
`irritation and discomfort in patient eyes.
`
`Though successful at achieving increased drug retention times,
`
`the
`
`relatively high polymer concentrations required by such formulations
`
`undesirably increase both the buffering capacity and the amount of
`
`thermal energy necessary to induce gelation of the compounds which may
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`AQUESTIVE EXHIBIT 1007 page 2412
`
`AQUESTIVE EXHIBIT 1007
`
`page 2412
`
`
`
`WO 91/19481
`
`_3_
`
`PCT/US91/04104
`
`lead to irritation and discomfort when used in the eye. What is more,
`
`the high polymer concentrations also contribute to unacceptably high
`
`product costs and generally slow the gelling process as well,
`
`leading
`
`to migration of the compounds from the site of application or injection.
`
`Accordingly, it is a principal object of the present invention to
`
`provide a reversibly gelling polymer solution having significantly lower
`
`polymer concentrations than has previously been attainable by the prior
`
`art in order to reduce both the buffering and thermal capacities of the
`
`solution to ensure its rapid and complete transition from liquid to gel
`
`upon application to a physiological system such as an oral dosage,
`
`the
`
`surface of the eye, or an injectable drug depot.
`
`It is a further object of the present
`
`invention to provide a
`
`reversibly gelling solution which can be utilized as a drug delivery
`
`vehicle or wetting solution that can easily be administered by a patient
`
`in the form of a freely fIOWing liquid or drops which gel
`
`immediately
`
`following administration with minimal side effects,
`
`thereby providing
`
`ready patient control of drug dosage and improved patient acceptability.
`
`It is a further object of the present invention to provide an oral
`
`dosage, drop-instillable,
`
`injectable or other depot form drug delivery
`
`vehicle which will prolong drug contact
`
`time for
`
`improved bioavail—
`
`ability and for sustained drug release.
`
`SUMMARY OF THE INVENTION
`
`Generally stated,
`
`the present invention accomplishes the above-
`
`described objectives by providing aqueous compositions that reversibly
`
`gel in response to substantially simultaneous variations in at least two
`
`physical parameters such as temperature, pH, or ionic strength. What
`
`is more,
`
`the compositions of the present invention can be tailored to
`
`exhibit a specific sol-gel transition over predetermined temperature and
`
`pH ranges to make the compositions particularly well suited for use as
`
`drop—instillable aqueous wetting agents and drug delivery systems, as
`
`well as for use as injectable sustained release drug delivery systems.
`
`More particularly,
`
`it has been surprisingly discovered that
`
`superior reversibly gelling compositions can be produced from unusually
`
`low concentrations of uniquely synergistic polymer systems which stably
`
`exist in aqueous solutions.
`
`In contrast to prior art gelation systems
`
`that rely on only a single triggering mechanism which may be either
`
`changes in pH,
`
`ionic strength. or changes in temperature,
`
`the compo—
`
`sitions of the present
`
`invention reversibly gel
`
`in response to sub-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`AQUESTIVE EXHIBIT 1007 page 2413
`
`AQUESTIVE EXHIBIT 1007
`
`page 2413
`
`
`
`WO 91/19481
`
`-4-
`
`PCT/US91/04104
`
`and pH over
`in both temperature
`changes
`stantially simultaneous
`predetermined ranges. What is more,
`the synergistic gelation action of
`the compositions of the present
`invention produces rapid and complete
`viscosity changes of an order of magnitude without the undesirable side
`
`5
`
`effects associated with the high polymer concentration, single gelation
`mechanism compositions of the prior art.'
`
`These properties make the compositions of the present invention
`
`particularly well suited for uses as topically applied lubricants and
`
`wetting agents as well as for drug delivery vehicles where sustained and
`
`10
`
`controlled delivery of bioactive agents
`
`is desired.
`
`For example,
`
`‘
`
`‘
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`wetting agents, ocular drug delivery vehicles, oral and injectable drug
`delivery compositions can be produced in accordance with the teachings
`of the present invention.which exhibit steady state flow characteristics
`
`at or near room temperature and a pH range of 2.5 to 6.5, yet almost
`instantaneously transform to highly visco-elastic gels when exposed to
`
`physiological conditions of pH and temperature on the order of pH 7.4
`and 37°C.
`
`Exemplary compositions are formed in accordance with the teachings
`of the present
`invention from aqueous solutions containing effective
`concentrations of a stable physical admixture or combination of at least
`
`one thermally—sensitive gelling polymer and at least one pH-sensitive
`
`gelling polymer. Thermally—sensitive gelling polymers for practicing
`the present
`invention can be selected from the group including alkyl
`
`cellulose, hydroxyalkyl cellulose, cellulosic ethers, Pluronic0 polymers
`and Tetronico polymers, with methylcellulose being particularly
`preferred.
`Exemplary pH—triggered gelling polymers
`that produce
`
`thickening at increased pH are preferably acidic polymers such as those
`
`containing carboxyl groups.
`
`Those skilled in the art will appreciate
`
`that small amounts of crosslinking agents such as divinyl benzene,
`divinyl glycol and polyalkenyl polyethers will facilitate the formation
`
`of three dimensional polymer network structures in the resultant cross-
`
`linked polyacrylates. Carboxy vinyl linear or branched or crosslinked
`
`polymers of the monomers, such as methacrylic acid, ethacrylic acid, 3-
`
`trans-a-methylcrotonic
`methylacrylic acid, cis-a—methylcrotonic acid,
`acid. a—butylcrotonic acid, a—phenylacrylic acid. a—benzylacrylic acid,
`a-cyclohexylacrylic acid, and the like are examples of such acidic pH-
`
`sensitive gelling polymers. Conversely, where thickening is desired at
`
`decreased pH, polymers containing weakly basic pendant groups such as
`
`poly—N—N—dimethylaminoethylmethacrylate may be employed.
`
`AQUESTIVE EXHIBIT 1007 page 2414
`
`AQUESTIVE EXHIBIT 1007
`
`page 2414
`
`
`
`W0 91/1948]
`
`-5-
`
`PCT/US91/04104
`
`In contrast to the relatively high polymer concentrations required
`
`by the individually triggered prior art compositions (on the order of
`
`10% or more by weight),
`
`the reversibly gelling compositions of
`
`the
`
`present invention preferably contain only approximately 0.25% to 5% by
`
`weight
`
`thermally—sensitive gelling polymer and only 0.1% to 0.5% by
`
`weight pH—sensitive gelling polymer. This substantially lower polymer
`
`concentration significantly reduces
`
`the
`
`amount of
`
`thermal
`
`energy
`
`required to induce gelation as well as reducing the buffering capacity
`
`of
`
`the compositions of
`
`the present
`
`invention, making them markedly
`
`superior topical wetting agents and drug delivery compounds.
`
`When
`
`utilized in the ocular milieu,
`
`the compositions of the present invention
`
`eliminate the discomfort, vision blurring and crusting produced by the
`
`known prior art compositions yet produce rapid conformational changes
`
`to high viscosity.
`
`However,
`
`it is contemplated as being within the scope of
`
`the
`
`present
`
`invention to utilize thermally-sensitive gelling polymer
`
`concentrations ranging from approximately 0.1% to 30% by weight and pH—
`
`sensitive gelling polymer concentrations ranging from approximately
`
`0.01% to 10% by weight. As discussed in detail below,
`
`these relatively
`
`broader polymer concentration ranges increase the scope of the available
`
`viscosities and sol-gel transition temperatures that may be produced in
`
`accordance with the teachings of the present invention. Thus, viscosi—
`
`ties ranging from 200 to approximately 1 million cP at sol-gel transi—
`
`tion temperatures ranging from 0°C to 60'C can be attained with the
`
`present
`
`invention. Nonetheless.
`
`for ophthalmic uses,
`
`the previously
`
`described polymer concentration ranges are preferred.
`
`For use as drug delivery vehicles,
`
`the aqueous compositions of the
`
`present
`invention can be modified through the incorporation of
`a
`suitable pharmaceutical medicament or diagnostic compound in a concen-
`
`tration ranging from approximately 0.00018 to 50% by weight. As those
`
`skilled in the art will appreciate, when compatible medicaments and/or
`
`diagnostic compounds are incorporated into the aqueous compositions of
`
`the present
`
`invention,
`
`the drugs will also be incorporated into the
`
`gelling matrix following delivery to the target site. As a result,
`
`the
`
`drug containing visco—elastic gel will reside at the applied location{
`
`thereby prolonging the retention and delivery of the incorporated drug.
`
`Similarly,
`
`fine suspensions of solid drug compositions or particulate
`
`drug containing delivery systems may also be incorporated into the
`
`reversibly gelling compositions of the present
`
`invention.
`
`Injection
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`AQUESTIVE EXHIBIT 1007 page 2415
`AQUESTIVE EXHIBIT 1007
`page 2415
`
`
`
`W0 91/1948]
`
`—6-
`
`PCT/US91/04104
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`'
`
`’
`
`topical delivery by drop
`into subcutaneous drug delivery depots or
`installation of the solutions will then position such delivery systems
`at
`the site of choice for sustained bioavailability.
`This enhanced
`
`bioavailability and improved duration of action may lead to overall
`lower drug dosages being required with resultant improved side effect
`profiles.
`I
`
`Modifications to the viscosity ranges, pH ranges and temperatures
`at which the sol-gel
`transition takes place can be produced in the
`
`compositions of the present.invention by varying the polymer concentra—
`tions as well as through the incorporation of small amounts of univalent
`
`or divalent salt. Typically,
`
`the addition of small quantities of salt
`
`giving a salt-to—combined polymer ratio up to 0.5 and preferably on the
`order of 0.045 to 0.075 will decrease the viscosity of the composition
`in the ungelled state if desired. Alternatively, it is contemplated as
`being within the scope of the present
`invention to incorporate up to
`approximately 0.2% to 0.9% by weight salt.
`
`Further objects and advantages of the reversibly gelling composi-
`tions of
`the present
`invention,
`as well as a better understanding
`thereof, will be afforded to those skilled in the art from a consider-
`ation of
`the following detailed explanation of preferred exemplary
`embodiments thereof. Reference will be made to the appended sheets of
`
`drawings which will now be first described briefly.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`illustration showing the viscosity of a
`is a graphical
`1
`FIG.
`Methocel/Carbopol
`(Carbopol concentration fixed at 0.3% by‘ weight)
`mixture as a function of
`the concentration of a Methocel at
`room
`
`temperature and pH 4.0 Carbopol;
`
`illustration showing the viscosity of a
`is a graphical
`2
`FIG.
`Methocel/Carbopol
`(Carbopol concentration fixed at 0.38 by weight)
`mixture as a function of the concentration of a Methocel at 37'C and pH
`7.4 Carbopol;
`
`is a graphical illustration showing the viscosity of a
`3
`FIG.
`Methocel (1%)/Carbopol (0.3‘) mixture as a function of salt concentra— -
`tion at room temperature and pH 4.0;
`
`illustration showing the viscosity of a
`FIG. 4 is a graphical
`Methocel (l%)/Carbopol
`(0.3%) mixture as a function of salt concentra-
`
`‘
`
`tion at 37'C and pH 7.4;
`
`AQUESTIVE EXHIBIT 1007 page 2416
`
`AQUESTIVE EXHIBIT 1007
`
`page 2416
`
`
`
`W0 91/1948]
`
`-7-
`
`PCT/US9l/04104
`
`is a graphical illustration showing the viscosity of a
`5
`FIG.
`PluronicQ/Carbopol
`(Carbopol concentration fixed at 0.3% by weight)
`
`mixture as
`
`a
`
`function of
`
`the concentration of PluronicO at
`
`room
`
`temperature and pH 5.0 Carbopol;
`FIG.
`6
`is a graphical
`illustration showing the viscosity of a
`PluronicG/Carbopol
`(Carbopol concentration fixed at 0.3% by weight)
`
`mixture as a function of the concentration of Pluronic® at 37°C and pH
`
`7.4 Carbopol;
`
`FIG.
`
`7
`
`is a graphical
`
`illustration showing the viscosity of a
`
`Tetronico/Carbopol
`
`(Carbopol concentration fixed at 0.3% by weight)
`
`mixture as a function of the Tetronico concentration at room temperature
`
`and pH 5.0 Carbopol; and
`FIG.
`8
`is a graphical illustration showing the viscosity of a
`Tectonics/Carbopol
`(Carbopol concentration fixed at 0.3% by weight)
`
`mixture as a function of the .Tetronico concentration at 37°C and pH 7.4
`
`Carbopol.
`
`DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
`
`The
`
`reversibly gelling aqueous
`
`compositions of
`
`the present
`
`invention are primarily intended for use as drop insti‘llable, oral and
`
`injectable drug delivery vehicles as well as
`for
`1ubricants,. wetting agents
`and cleaning agents.
`
`topically applied
`Accordingly,
`the
`
`preferred exemplary embodiments of the present invention exhibit good,
`usable flow characteristics at
`room temperature, yet rapidly gel
`to
`highly visco-elastic compounds exhibiting viscosities several orders of
`
`magnitude greater at physiological
`
`temperatures and pH.
`
`Thus,
`
`the
`
`preferred exemplary embodiments
`
`exhibit
`
`significant
`
`increases
`
`in
`
`viscosity in response to substantially simultaneous upshifts in both
`
`temperature and pH to those conditions encountered in the ocular milieu
`
`or at typical injectsble drug delivery sites. However,
`
`those skilled
`
`in the art will appreciate that alternative compositions which gel
`
`in
`
`response to simultaneous increases in temperature and decreases in pH
`
`or the converse may also be produced in accordance with the teachings
`
`of
`
`the present
`
`invention where desired.
`
`Similarly,
`
`alternative
`
`compositions which gel at
`
`temperatures significantly above or below
`
`those encountered in physiologi