United States Patent 19
`4,249,531
`{iq
`
`(45) * Feb. 10, 1981
`Heller et al.
`
`5/1974 Heller et al. oo... eseeeeeee 128/260
`3,811,444
`[54] BIOERODIBLE SYSTEM FOR DELIVERING
`.. 128/260
`6/1975
`Ramwell ......
`3,888,975
`DRUG MANUFACTURED FROM
`
`.. 128/260
`8/1975
`Zaffaroni
`..
`3,898,986
`POLY(CARBOXYLIC ACID)
`
`
`3,914,402 10/1975=Shell ........ « 128/260
`
`3,971,367
`7/1976
`Zaffaroni .....
`. 128/260
`Jorge Heller, Palo Alto, Calif.;
`[75]
`Inventors:
`
`10/1976 Higuchi etal.
`. 128/260
`3,986,510
`Richard W. Baker, Bend, Oreg.
`3/1977) Heller et al. oo... teens 128/260
`4,014,987
`
`
`
`[73] Assignee:
`
`Alza Corporation, Palo Alto, Calif.
`
`[*] Notice:
`
`The portion of the term of this patent
`subsequent to May 21, 1991, has been
`disclaimed.
`
`[21] Appl. No.: 54,788
`
`[22]
`
`Filed:
`
`Jul, 5, 1979
`
`Related U.S. Application Data
`
`[60]
`
`Continuation of Ser. No. 750,701, Dec. 15, 1976, Pat.
`No. 4.180.064, which is a division of Ser. No. 591,443,
`Jun. 30, 1975, Pat. No. 4,014,987, which is a continua-
`tion-in-part of Ser. No. 467,246, Jun. 4, 1974, aban-
`doned, which is a continuation-in-part of Ser. No.
`318,831, Dec. 27, 1972, abandoned.
`
`FOREIGN PATENT DOCUMENTS
`
`1124115
`
`8/1968 United Kingdom ... 128/260
`OTHER PUBLICATIONS
`
`Lappas,L.et al., J. Pharm. Set., vol. 56, pp. 1257-1261,
`1967.
`Heyd, A. et al., < Pharm. Sci, vol. 58, No. 5, pp.
`586-588, 1969; vol. 59, No. 7, pp. 947-949, 1970.
`
`Primary Examiner—Robert W. Michell
`Assistant Examiner—C. F, Rosenbaum
`Altorney, Agent, or Firm—Paul L. Sabatine; Thomas E.
`Ciotti; Edward L. Mandell
`
`ABSTRACT
`[57]
`A device for the controlled continuous administration
`of an active agent to an environment ofuse is disclosed.
`The device comprises a body of erodible agent release
`rate controlling material containing an agent dispersed
`therethrough; the rate controlling material is a hydro-
`phobic poly(carboxylic acid) having one ionizable car-
`boxylic hydrogen for each 8 to 12 carbon atoms, which
`material erodes at a controlled and continuousrate over
`a prolonged period of time in response to the environ-
`2,066,105
`12/1936 Hagedorn et al. oc 424/33
`ment by a process of carboxylic hydrogen ionization,
`2.897.121
`7/1959) Wagner.............
`. 424/33
`thereby releasing the dispersed agent at a controlled
`3.080.346
`3/1963
`Schellenberg etal. .
`a. 424/81
`rate over a prolonged period of time.
`S.081,233
`371963
`ENz «0.0... eee
`wee 424/33
`
`
`
`3,143,472 8/1964—Lappaset al. » 424/33
`
`Banker ceccscesssssssssvcsseseceeseeen
`3.608.063
`9/1971
`424/33
`15 Claims, 9 Drawing Figures
`
`[S]] Unt, Cho oes eenesereses) AGIM 7/00
`[52] US. Ch. cc eeteteeeeeeee: 128/260; 128/271;
`424/33
`Field of Search .......cccccceceserrees 128/260, 271;
`424/19-22, 33; 71/1, 65, 3, 64 F
`
`[58]
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`
`
`
`
`Dr. Reddy's - EX1017
`Page 1
`
`Dr. Reddy's - EX1017
`Page 1
`
`

`

`U.S. Patent
`
`Feb. 10, 1981
`
`Sheet 1 of 4
`
`4,249,531
`
`FIG. |
`
`FIG. 2
`
`‘)
`
`
`
`SyYLSSeS
`
`
`
`
`22—C
`
`
`
`Page 2
`
`Page 2
`
`

`

`
`
`Page 3
`
`

`

`
`
`Page 4
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`

`

`U.S. Patent
`
`Feb. 10, 1981
`
`Sheet 4 of 4
`
`4,249,531
`
`1007
`
`TEST MEDIUM
`ph8.0,0.1m
`BUFFER
`
`lz,
`
`k
`
`o—
`
`6
`
`o/
`
`TEST MEDIUM
`phf0.0.lm
`BUFFER
`
`Ap
`
`A
`
`5
`
`_, 80
`
`S 64
`~
`re
`= 40
`
`=i
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`ELAPSED TIME, MINUTES
`
`Page 5
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`Page 5
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`

`

`1
`
`4,249,531
`
`BIOERODIBLE SYSTEM FOR DELIVERING
`DRUG MANUFACTURED FROM
`POLY(CARBOXYLIC ACID)
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of United States
`Patent Application Ser. No. 750,701 filed on Dec. 15,
`1976 and now U.S. Pat. No. 4,180,064 issued on Dec. 25,
`1979, which application is a division of United States
`Patent Application Ser. No. 591,443 filed on June 30,
`1975 and now US. Pat. No. 4,014,987 issued on Mar. 29,
`1977, which division is a continuation-in-part of our
`copending United States Patent Application Ser. No.
`467,246 filed on June 4, 1974, now abandoned, which
`latter application is a continuation-in-part of United
`States Patent Application Ser. No. 318,831 filed on Dec.
`27, 1972 and now abandoned. This application and the
`earlier applications are assigned to the same assignee
`and benefit of their filing dates is claimed.
`BACKGROUNDOF THE INVENTION
`1. Field of the Invention
`This invention relates to device which dispense ac-
`tive agents to an environmentof use at a controlled and
`continuous rate over a prolonged period of time. In a
`preferred embodiment,it relates to delivery devices for
`the sustained release of an agent to a substantially con-
`stant pH environment, such as an agent to a mammalian
`patient, and the like.
`2. The Prior Art
`The use of poly(carboxylic acids) as enteric coatings
`has been reported by Lappas and McKeehanat 5] J.
`Pharm. Sci. 808 (1962), at 54 J. Pharm. Sci. 176 (1965)
`and at 56 J. Pharm, Sci. 1257 (1967).
`Asis well known, enteric coatings are special coat-
`ings applied to ingestible tablets or capsules which pre-
`vent release and absorption of their contents until the
`tablets reach the intestines.
`The poly(carboxylic acids) are well suited to this
`application and the widely varying pH conditionsof the
`gastrointestinal tract. In the highly acidic stomach (pH
`2) poly(carboxylic acids) are present completely as
`unionized hydrophobic species which are water insolu-
`ble and which preventthe release of any enclosed drug.
`As the poly(carboxylic acids) move on to the intestine,
`they are exposed to alkaline conditions (pH of up to 9)
`in which they ionize to soluble hydrophilic species and
`release the enclosed drug.
`With these prior enteric coating teachings, the release
`of drug is merely delayed. The release is essentially a
`pH-dependent step function.
`There is no release of drug in the acidic stomach;
`there is release ofall the drug as the encapsulated drug
`enters the intestine and the pH of the environment
`changes to an alkaline value.
`STATEMENT OF THE INVENTION
`
`It has now been found that poly(carboxylic acids)
`may be used to form a device giving a controlled and
`continuous release of an active agent over a prolonged
`period of time under conditions of essentially constant
`pH. This is in direct contrast to the teachings of the
`prior art of the use of these materials in enteric coated
`pills which gave a step function release of drug under
`conditions of changing pH.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`60
`
`65
`
`2
`In accordance with this invention, a device is pro-
`vided which permits the controlled and continuous
`administration of active agent to an essentially constant
`pH environment. Such a device comprises a body of
`erodible release rate controlling material containing the
`active agent dispersed therethrough. The release rate
`controlling material comprises a hydrophobic poly(car-
`boxylic acid) having an averageof one ionizable hydro-
`gen for each8 to 22 total carbon atoms. These polyacids
`erode in response to the environment of use at a con-
`trolled and continuous rate by a process of carboxylic
`hydrogen ionization. This erosion extends over a pro-
`longed period of time and causes the dispersed agent to
`be released at a controlled and continuous rate over a
`prolonged period oftime.
`In a preferred embodiment, the invention involves a
`device for delivering drugs to a substantially constant
`pH environment within the body of a mammalian pa-
`tient, with the device eroding when placed in the body
`in response to the environment.
`Such a device comprises a body of the hydrophobic
`poly(carboxylic acid) having drug dispersed there-
`through. When this device is placed in a substantially
`constant pH environment within the body of a mamma-
`lian patient, the poly(carboxylic acid) bioerodes by a
`process of carboxylic hydrogen ionization in response
`to the mammalian environment and gradually releases
`drug at a controlled and continuous rate over a pro-
`longed period of time.
`The invention further makes possible a process for
`the controlled and continuous administration of drugs
`to a mammalian patient over prolonged periodsoftime.
`This process involves employing the drugs in a certain
`form, and applying this form to an environmentin the
`mammalian patient which is characterized as having an
`essentially constant pH throughoutthe period of admin-
`istration of drug. The drug form employed in this pro-
`cess comprises a body of drug release rate controlling
`hydrophobic poly(carboxylic acid) having one ioniz-
`able carboxylic hydrogen atom for each 8 to 22 carbon
`atoms and having the drug dispersed throughout, that
`bioerodes in response to the environment.
`In another embodiment, the invention provides de-
`vices for the local delivery of drug to the uterus and
`vagina which devices are of simple operation, give a
`reliable delivery of drug over a prolonged period of
`time, and bioerode in the uterus or vagina in response to
`the environmentthereof.
`Theinvention also provides devices for the local and
`systemic delivery of drug wherein the device is a nasal,
`anal, buccal,
`topical,
`implant, body passageway, or
`non-reproductive body cavity device for the controlled
`and continuous delivery of drug as the device erodes in
`response to the environment wherein the device is
`placed for release of drug thereto.
`The invention also provides for devices for the re-
`lease of an active agent to a non-biological environment
`with the device releasing active agent at a controlled
`and continuous rate as the device erodes in response to
`the environment.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`In the drawings:
`FIG.1 is a cross sectional view of a device in accord
`with this invention for releasing active agent at a con-
`trolled rate over a prolonged period of time.
`
`Page 6
`
`Page 6
`
`

`

`3
`FIG. 2 is’a cross sectional view of a multi-layered
`device in accord with the invention which releases
`active agent at a varying rate.
`FIGS. 3-7 inclusive areillustrative of the many em-
`bodiments the present invention may take. -
`FIG. 3 is a perspective view of a disc-shaped tablet
`suitable for releasing drugs perorally or subcutaneously
`or for releasing other active agents to other constant pH
`environments.
`FIG.4 illustrates in perspective a device of this in-
`vention adaptedto release a controlled amountof active
`agent into a liquid medium.
`:
`FIG. 5 is a cross-sectional view of a suppository em-
`bodying the present invention.
`FIG.6 is a partially cut away elevational view of an
`intrauterine device formed of two connecting rings.
`FIG. 7 is a partially cut away elevational view of an
`intrauterine device shapedlike a ‘‘T”, adapted 'to release
`a controlled amount of active agent into the uterus.
`FIG. 8 is a partially sectional elevational view of a
`device of this invention adapted for placement in the
`cervical canal of a pregnant femalc.
`FIG. 9 is a graph illustrating the linear release of
`active agent achieved with devices of this invention.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`In accord with this invention, agents may be most
`advantageously delivered to the environment of use
`over a prolonged period of time by being incorporated
`in a body of hydrophobic poly(carboxylic acid) of from
`8 to 22 carbons per ionizable hydrogen. This body
`slowlyerodesin the environmentof use and is incorpo-
`rated in a device adapted and sized for insertion, posi-
`tioning and placement
`in the environment of use
`throughout the period of agent administration.
`The terms “hydrophobic” and “hydrophobicity”
`broadly refer to the property of a substance to not ab-
`sorb or adsorb appreciable amounts of water. As used in
`this specification and claims, a more precise meaning of
`these terms is intended; a hydrophobic materialis de-
`fined as one which absorbs or adsorbs water in a maxi-
`mum amount not exceeding 10% of its dry weight.
`The phrase “active agent” and the term “agents” as
`used in this specification and accompanying claims
`comprise any compound, or mixture of compounds,
`composition of matter or mixture thereof which when
`dispensed producesa beneficial result for man, animals
`or the environmentofuse.
`As uscd herein, the phrase “a prolonged period of
`time”shall have different meanings with respect to the
`various delivery devices and the environment of use to
`whichit is applied. Normally,it will mean a time period
`of at least 4 hour to 180 days, and it includes one hour
`of higher, up to two years or more.
`there is
`In accordance with the present invention,
`provided a device for the conrolled continuous dispens-
`ing of a predetermined amount of active agent over a
`prolonged period oftime.
`Such a device is shown as device 10 in FIG. 1. In
`FIG. 1, device 10 comprises an active agent 21 dis-
`persed throughout a body 22 of hydrophobic poly(car-
`boxylic acid). When placed in an environment having a
`controlled and essentially constant pH, poly(carboxylic
`acid) body 22 bioerodes concommitantly. releasing the
`active agent which is dispersed therethrough.
`The polyacids employed are characterized as being
`hydrophobic when unionized and as having a specified
`
`25
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`35
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`40
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`45
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`50
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`55
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`60
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`65
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`4,249,531
`
`4
`proportion of carboxylic hydrogens. They. are substan-
`tially impermeable to the passage of agent and biologi-
`cal fluids and release entrapped agent by an erosion
`control process, since these poly(acids) gradually erode
`in the environment; preferably a biological environ-
`ment, at a controlled rate by a process of carboxylic
`hydrogen ionization. These poly(acids) and their ero-
`sion products are nontoxic and non-irritation to biologi-
`cal tissues such as the endometrium and other uterine
`and vaginal tissues.
`Suitable poly(carboxylic acids) are the hydrophobic
`poly(acids) which are represented by the general for-
`mula:
`
`
`
`ReversesR"
`R!
`|
`|
`|
`C—OH C—OH C+OH
`ll
`I
`tl
`oO
`o
`oO
`
`(I)
`
`the R’s are organic radicals independently
`wherein:
`selected to provide, on average, from 8 to 22 total car-
`bon atoms for each carboxylic hydrogen. Variations of
`this ratio within this range can vary the erosion and
`active agent release rates to devices prepared from
`these polymeric acids. Organic radicals represented by
`R!, R2,...R” may be selected from hydrocarbonradi-
`cals and hetero-atom containing organic radicals. Suit-
`able hetero atoms for employment in R!, R2,... R”
`include oxygen, nitrogen, sulfur, and phosphorous as
`well as other hetero atoms so long as the required hy-
`drophobicity and carbon to carboxylic hydrogen aver-
`age ratio is maintained. The value of n and hence the
`average molecular weight of the polymer is notcritical
`and may vary over a wide range. Suitable molecular
`weights, for example, range from about 10,000 to about
`800,000, Materials within this range erode to products
`which may be easily and innocuously passed from the
`environment of use. Preferred molecular weights are
`from about 15,000 to about 500,000.
`While not wishing to limit the scope of the poly(a-
`cids) intended to be employed in accord withthis inven-
`tion, and while alternative materials and preparative
`schemes are set forth in the description of suitable
`poly(acids) which follows, practically speaking,
`the
`most commonand widely applied method for introduc-
`ing a carboxylic acid function, as well as other hetero
`atom functions, into a polymeric material of the type
`employedin this invention, is to proceed through mon-
`omers having a carbon skeleton of at least two carbon
`atoms. These monomerscontain polymerizable olefinic
`carbon-carbon double bonds. At least a portion of these
`monomers will have appended thereto one or more
`carboxyl radicals, or suitable precursors thereof and
`optionally also other hetero atom radicals. The polymer
`is formed by effecting addition of these monomers, one
`to another, across the polymerizable double bonds. This
`general method for forming poly(acids) is well known
`and does not comprise a part of the present invention.
`This preparative method may be generally represented
`by the reaction:
`|
`
`i i
`=—O
`wg + CMEC + CH2=C
`y—
`IloO
`
`A
`
`—OH
`
`¥
`
`>
`
`Page 7
`
`Page 7
`
`

`

`5
`-continued
`A
`8
`Cc
`|
`|
`|
`At -
`TENG CHTENCE
`|
`oH
`Y
`Z
`ItoO
`
`4,249,531
`
`6
`acid (or substituted acrylic acid) with a polymerizable
`hydrocarbon. These acids may be represented by the
`general formula:
`
`(Iv)
`
`wherein A represents hydrogen or a hydrocarbon and
`
`represents a carboxy! group (or carboxy group precur-
`sor) containing monomeralso containing a polymeriz-
`able olefinic double bond. Such monomersinclude, for
`example, acrylic acid, substituted acrylic acid, maleic
`acid, maleic anhydride, crotonic acid and the like.
`
`c
`B
`|
`1
`CH}=C and CH2=C
`|
`|
`Y
`Zz
`
`10
`
`20
`
`25
`
`represent organic monomers containing a polymeriz-
`able double bond which may be the same or different
`than
`
`30
`
`35
`
`40
`
`45
`
`350
`
`55
`
`60
`
`65
`
`This preparative technique can be employed to pre-
`pare poly(carboxylic acids)
`in accord with General
`Formula I having hydrocarbon R's either by polymeriz-
`ing suitable hydrocarbon substituted olefinically unsatu-
`rated acids such as substituted acrylic acids and cro-
`tonic acids or by copolymerizing olefinically unsatu-
`rated acids, such as acrylic acid or hydrocarbon-sub-
`stituted acrylic acids or the crotonic acids, with unsatu-
`rated hydrocarbons. Suitable poly(carboxylic acids)
`having hydrocarbon R's prepared by polymerizing sub-
`stituted acrylic acids may be represented by the general
`formula:
`
`(HEY
`
`Rue
`
`te
`
`CH2—C
`C—OH
`if
`oO
`
`.
`
`wherein Ric represents hydrocarbon substitutes aver-
`aging from 5 to 15 carbon atoms in size, for example
`n-pentyl, cyclohexyl, pehnyl, n-decyl, 2,2-diethyldecyl,
`combinations of butyl and hexyl, and the like. Such
`materials may be prepared by polymerizing the corre-
`sponding hydrocarbon substituted acrylic acid mono-
`mers with free radical initiators as described in U.S. Pat.
`No. 2,904,541 issued Sept. 15, 1959.
`Also useful are poly(carboxylic acids) prepared by
`copolymerizing unsaturated carboxylic acids as acrylic
`
`eee
`
`Ruro
`Recm—CH2—C
`C—-OH
`ul
`o
`
`eee
`
`a
`
`wherein Rwic isa Apdrocarbon radical of up to abour 12 carbons
`or hydrogen; and Ricpyis a copolymerized hydrocarbon
`group. The hydrocarbons which may be copolymerized
`with unsaturated carboxylic acids include terminally
`olefinically unsaturated hydrocarbons and olefinically
`unsaturated hydrocarbons having a conjugated carbon-
`carbon double bond. Thus, typical hydrocarbon groups
`represented by Rycp) include ethyl, propyl, butyl, iso-
`pentyl, and phenylethyl as result when ethylene, propy-
`lene, butadiene, isoprene and styrene, respectively, are
`copolymerized with unsaturated acids. Such prepara-
`tions are set forth in 10 J. Polp. Sci. 441 (1946 Series) and
`10 J. Poly. Sei. 597 (1946 Series).
`Poly(carboxylic acids) in accord with General For-
`mula I having hydrocarbon R’s mayalso be prepared by
`other known techniques, such as for example by oxidiz-
`ing terminal methyl groups on suitable hydrocarbon
`polymers to carboxy] groups with alkaline permanate as
`described in Cram and Hammond Organic Chemistry,
`2nd Ed., pages 525-6; or by carboxylating olefinically
`unsaturated hydrocarbon polymers by contacting them
`with carbon monoxide, water and optionally some hy-
`drogen under conditions of elevated temperature and
`pressure in the presence of stongly acidic catalysts, for
`example HF, BF3, H2SOq and thelike.
`Poly(carboxylic acids) useful in the devices of the
`invention and illustrated by General Formula I may
`suitably incorporate oxygen atomsin their R’s. Oxyhy-
`drocarbon R’s include ester groups or ether groups.
`Poly(carboxylic acids) represented by Formula [ incor-
`porating ester groups, as R's, are especially suitable in
`devices of this invention. They may be readily prepared
`by partially esterifying acid polymers or copolymers,
`which are themselves easily obtained. They offer the
`advantage of permitting simple variation of the ratio of
`carbons to ionizable carboxylic hydrogens by varying
`the extent of partial esterification or the esterifying
`alcohol employed. As a result, easy adjustment of ero-
`sion characteristics of the poly(carboxylic acid) product
`and hence active agent release rate, is obtained.
`As an example of this easy control, consider the case
`of poly(carboxylic acid). Poly(acrylic acid) is available
`commercially or may be easily prepared such as by
`mixing 167 parts of 60% acrylic acid, 232 parts of water,
`0.50 parts of potassium peroxydisulfate and 0.25 parts of
`potassium metabisulfite and heating the mixture to 60°
`C. Poly(acrylic acid) per se, however, is not a suitable
`poly(carboxylic acid) for use in devices of this invention
`as it is substantially hydrophilic and water soluble and
`does not have the carbon to ionizable hydrogen ratio
`necessary to give suitable erosion and active agent re-
`lease characteristics.
`7
`When half the carboxyl groups of poly{acrylic acid)
`are esterified by reaction with an alkanol such as hexa-
`nol, the resulting partial ester is hydrophobic and has a
`carbon to ionizable hydrogen ratio within the range
`
`Page 8
`
`Page 8
`
`

`

`4,249,531
`
`7
`necessary for materials employed in the devices of this
`invention (i.e., 12:1). A similarly suitable material would
`result if § of the poly(acrylic acid) carboxyl groups
`were esterified with ethanol.
`This partial esterification technique is of course not
`limited to treatment of acrylic acids. Any organic lower
`poly(carboxylic acid) may be partially esterified when
`necessary to achieve the required hydrophobicity and
`carbon to acidic hydrogen ratio. Other poly(acids)
`which often benefit from esterification include homo-
`polymers of unsaturated lower carboxylic acids such as
`the lower alkyl acrylic acids, for example methacrylic
`and ethacrylic acid; crotonic and propiolic acid; maleic
`acid and fumaric acid. Polymers of acid precursors such
`as poly(maleic anhydride) may be hydrolyzed and par-
`tially esterified as well. Also suitable for esterification
`are acids or precursors copolymerized with lower un-
`saturated hydrocarbons of from 2 to 8 carbons such as
`ethylene, propylene, butadiene, styrene and the like, or
`with lower unsaturated oxyhydrocarbonssuchas unsat-
`urated ethers of from 3 to 8 carbon atoms. Many of
`these polymers and copolymers are available commer-
`cially. Others can be prepared by bulk, solution, emul-
`sion or suspension polymerization using free radical
`initiators at 40°-100° C., all methods well knownin the
`art. The partial esterification may be conveniently ef-
`fected by contacting the acid-containing polymers with
`a controlled quantity of the esterifying alcohol at ele-
`vated temperature, optionally in the presence of an
`acidic esterification catalyst. Alcohols suitable for par-
`tially esterifying the above-noted poly(acids) include
`the hydrocarbon alcohols, preferably the alkanols of
`from about one to about 16 carbon atoms; for example,
`methanol, ethanol, isopropanol, n-butanol, cyclohexa-
`nol, octanol, the decanols, and n-dodecanol. Combina-
`tions of alcohols may also be employed.
`In addition to being included in partially esterified
`poly(carboxylic acids), as noted above, ether linkages
`may be included generally in the polymers employed in
`this invention; that is, they may be oxyhydrocarbon R’s
`in General Formula I. Ether groups may be incorpo-
`rated by copolymerizing an unsaturated carboxylic acid
`with an unsaturated ether, for example, acrylic acid,
`maleic acid, crontonic acid and the like with the vinyl
`ethers of from about 3 to about 10 carbon atoms such as
`methyl vinyl ether, ethyl vinyl ether, butyl vinyl ether,
`hexyl vinyl ether, and the like; for example, by the
`method described in U.S. Pat. No. 2,927,911. Because of
`the small number of carbon atoms in many of these
`unsaturated ethers and acids,
`it may be desirable,
`to
`achieve the required carbon/acid hydrogen ratio,
`to
`terpolymerize these materials with a non-carboxylic
`hydrogén-containing material, most suitably an unsatu-
`rated terpolymerizable unsaturated hydrocarbon of
`from 2 to 8 carbon atomssuch as ethylene, butadiene, or
`styrene. Examples of terpolymers are presented herein-
`after.
`The R’s of General Formula I, as oxyhydrocarbons,
`may contain alcohollinkages. The employment of alco-
`hol
`linkage-containing oxyhydrocarbons as R’s can
`pose a problem, however,as the alcohollinkages gener-
`ally decrease the hydrophobicity of the poly(acid),
`often to below the extent of hydrophobicity required of
`poly(acids) for employmentin this invention. It is usu-
`ally possible to incorporate up to about 10%, basis total
`polymer, of alcohol
`linkage-containing R’s
`in
`the
`poly(acids).
`
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`8
`Nitrogen, sulfur and phosphorous atoms may also be
`incorporated in R groups employed in the polymers
`represented by General Formula I. Nitrogen may be
`present as cyano groups, amide groups or imide groups.
`Amine groups are generally not suitable as they can
`result in internal salts being formed between the poly-
`merized acid and amine groups. Sulfur atoms may be
`present as mercaptan or disulfide linkage, while phos-
`phorous atoms may be present as phosphate linkages.
`A preferred group of materials from which to fabri-
`cate the dispensing devices of this invention comprise
`hydrophobic polymers of an acid selected from acrylic
`acid, lower alkyl acrylic acids of from 4 to 6 carbon
`atoms per monomeric unit, and maleic acid; either alone
`or copolymerized with up to about 2 moles, per mole of
`acid of a copolymerizable olefinically unsaturated
`group such as ethylene or lower (1 to 4 carbon) alkyl
`vinyl ethers wherein from about 20% to 90% of the
`acid groups have beenesterified with an alkanol of from
`1 to about 10 carbon atoms and wherein the ratio of
`total carbon atomsto acidic carboxylic hydrogensis in
`the range of from about about 9:1 to about 20:1.
`An even more preferred group of poly(carboxylic
`acids) comprise the hydrophobic partially esterified
`copolymersof acrylic acid, methacrylic acid or maleic
`acid with from 0.2 to 1.5 moles, per mole of acid of
`ethylene or lower (1-4 carbon) alkyl vinyl ether having
`from about 35% to about 70% oftheir total carboxylic
`groupsesterified with lower alkanol of from about 3 to
`about 10 carbon atoms, said copolymers having a car-
`bon to acidic carboxylic hydrogen ratio of from about
`10:1 to about 15:1,
`A group of poly(carboxylic acids) most preferred for
`use in accord with the present invention comprise hy-
`drophobic copolymers of maleic acid with about one
`mole, per mole of maleic acid, of ethylene or methyl
`vinyl ether, said copolymer having abouthalf ofits total
`carboxylic groupsesterified with a lower monoalkanol
`of from 4 to 8 carbon atoms, wherein the carbon to
`acidic carboxylic hydrogen ratio has a value of from
`about 10:1 to about 14:1.
`A presently preferred group of poly(carboxylic
`acids) are terpolymers of at least one a,@-unsaturated
`aliphatic acid of 3 to 8 carbons, an alkyl ester of such
`a,8-unsaturated aliphatic acids in which said alkyl is of
`2 to 8 carbon atoms. Typical terpolymers include one
`acid monomerand two ester monomers, two acid mon-
`omers and an ester monomerof the acid functionality,
`an acid monomer, an ester monomerof the acid func-
`tionality and an acid monomer having a lower alkyl
`group, and the like. A particularly preferred terpolymer
`is comprised of 60 to 75 mol % of a loweralkyl acrylate
`of the formula CH2—CH—COORowhere Rogis analkyl
`of 2 to 8 carbons, from 15 to 30 mol % ofan acid of the
`formula CH2=CR 19—COOHwhereR jois an alkyl of 1
`to 8 carbons, and from 5 to 15 mol % of an acid of the
`formula CH2—=CHCOOH, and thelike. A terpolymer
`includedin this preferred group is comprised of 60 to 75
`mol % butyl acrylate, 15 to 30 mol % methacrylic acid
`and 5 to 15 mol % acrylic acid. The terpolymers have a
`molecular weight
`range of 10,000 to 1,000,000 or
`higher.
`Typical carboxylic acid monomersuseful for produc-
`ing the terpolymerare the olefinically unsaturated car-
`boxylic acid containing at least one activated carbon-to-
`carbon olefinic double bond, and at least one carboxyl
`group,
`that is, an acid containing an olefinic double
`bond which functions in polymerization because ofits
`
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`

`9
`presence in the monomer molecule either in the alpha-
`beta position with respect to the carboxyl group, such
`as
`
`4,249,531
`
`{1—C=C—COOH,
`
`terminal methylene grouping
`or as a part of a
`CH2=C <. Olefinically unsaturated acids of this broad
`class include acrylic acids such as acrylic acid itself,
`methacrylic acid, ethacrylic acid, crotonic acid, sorbic
`acid, cinnamic acid, beta-styryl acrylic acid, hydromu-
`conic acid, itaconic acid, citraconic acid, and the like.
`As used for the terpolymer herein, the term carboxylic
`acid includes poly(carboxylic acids) and those acid
`anhydrides, such as maleic anhydride, wherein the an-
`hydride groupis formed by the elimination of one mole-
`cule of water from two carboxyl groups located on the
`same poly(carboxylic acid} molecule. The anhydrides
`have the general formula
`
`(Vv)
`
`Ry—c—-C
`
`|
`
`Ryp—c-—c
`
`o
`
`yo
`\Oo
`
`20
`
`25
`
`35
`
`wherein Rj2 are selected from the group consisting of 30
`hydrogen, halogen, cyanogen, hydroxyl, lactam, alkyl
`and the like. The term alkyl! as used herein includes the
`straight and branched chain alkyl groups such as
`methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl,
`2-methyhexyl, heptyl, and the like.
`Representative esters suitable for synthesizing the
`terpolymer include without limitation methyl methac-
`rylate, ethyl methacrylate, n-butyl methacrylate, isobu-
`tyl methacrylate, t-butyl methacrylate, hexyl methacry-
`late,
`lauryl methacrylate, and other acrylates such as
`cyclohexyl methacrylate, dimethylaminomethacrylate,
`2-hydroxymethylmethacrylate, and the like. Acrylic
`esters of the formula CH:)—CHCOORincludes the
`n-alkyl esters methyl, ethyl, propyl, butyl, pentyl, hexyl
`and heptyl, the secondary and branched chain alkyl
`esters isopropyl,
`isobutyl, sec-butyl, 2-methylbutyl,
`3-methylbutyl, 1-ethylpropyl,
`!-methylhexyl and the
`like. Acrylic acid, its esters and other derivatives are
`commercially available and knownto theart in Encyclo-
`pedia of Chemical Technology, Kirk-othmer, Vol.
`1,
`pages 285 to 313, 1963; Encyclopedia of Polymer Science
`and Technology, Vol. 1 pages 197 to 226 and 246 to 328,
`1964, in U.S. Pat. No. 3,137,660, and the like.
`The poly(carboxylic acids) employed in the device of
`this invention are soluble in organic solvents. Accord-
`ingly, the poly{acids) may be conveniently formed by
`film casting techniques. An organic solvented solution
`of the poly(acid), optionally containing active agent, is
`prepared and cast or drawn to a flim. The solvent is
`then evaporated to yield a continuousfilm of the poly(a-
`cid). The devices may them be punched orcut from this
`film. Alternatively, the devices may be molded from
`such a solution.
`A wide range of organic solvents may be used for the
`casting solutions. With poly(carboxylic acid} materials
`having total carbon to carboxylic hydrogenratiosat the
`lower end of the range specified for this invention, such
`as ratios in the range of from about 8:1 to about 11:1, it
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`is generally preferred to use relatively polar organic
`solvents, that is, organic solvents having dielectric con-
`stants, as listed in the 51st Edition of the Chemical Rub-
`ber Company ‘Handbook of Chemistry and Physics”at
`pages E-62 through E-64, of greater than about 15, for
`example, lwoer alkanols such as methanol, ethanol, the
`propanols, l- and 2-butanol, Ilwoer alkanones such as
`acetone, diethy] ketone, ethyl methyl ketone and cyclo-
`hexanone and halogenated and nitrogenated solvents
`such as 2-chloroethanol, and nitrobenzene. With poly(-
`carboxylic acids) having higher ratio of total carbon
`atoms to ionizable hydrogens, such as from about 14:1
`to 22:1, it is generally preferred to use less polar organic
`solvents, such as those having dielectric constants of
`less than about 15, especially less than about 10, for
`example, ethers such as diethyl ether, isopropyl ether
`and the like, hydrocarbons such as cyclohexane, ben-
`zene and toluene, and other low dielectric materials
`such as ethyl acetate. With the intermediate ratio poly(-
`carboxylic acids) either group of solvents may be used
`with the alkanols and alkenones generally being fa-
`vored.
`:
`The casting and drying are carried out at moderate
`conditions such as at ambient temperature and pressure.
`Solvent removal may be facilitated by the use of vac-
`uum orslightly elevated temperatures. However, sub-
`stantially elevated temperatures, such as about 100° C.,
`for lengthy periods, such as for several hours, may be
`deleterious to some agents or poly(carboxylic acids).
`It is often desired to incorporate plasticizers in the
`poly(carboxylic acid) materials to improve or vary their
`physical properties, such as to make them moreflexible.
`Exemplary plasticizers suitable for employmentfor the
`present purpsoe are the pharmaceutically acceptable
`plasticizers conventionally used, such as acetyl tri-n-
`butyl citrate, epoxidized soy beanoil, glycerol monoac-
`etate, polyethylene glycol, propylene glycol dilaurate,
`decanol, dodecanol, 2-ethy] hexanol, 2,2-butoxye