4,249,531 '
`o 1]
`United States Patent {19]
`r:
`
`Heller et al.
`[45]
`Feb. 10, 1981
`
`128/260
`5/1974 Heller el al.
`3.811.444
`
`128/260
`6/1975
`Ramwell .... ..
`3,888,915
`“u 128/260
`BIIQTS
`Znfihroni.
`3.39&986
`10/1975
`Shell
`118/260
`3,914,402
`3,9?L36? mm Zaffaroni
`123/250
`3.986.510
`111/1916 Higuchi et 21.
`. 123/260
`4,014.93?
`3x191? H 11
`12.1.
`. 123/250
`FORE} N
`6 H e
`G FAWN-r DOCUMENTS
`1124115 8/1968 United Kingdom
`OTHER PUBLICATIONS
`
`
`
`..
`
`128/260
`
`Lappas. L. et at, J. Pharm. sot, vol. 56, pp. 1251—1251,
`1967.
`_
`Heyd. A. at 3.1., J: Pharm. Set, vol. 58. No. 5, pp.
`586—588. 1959; V01. 59, No. 7, pp. 947—949, 1970.
`Pn'rfmry Examirfer—Robert W- Michell
`Asmara: Exammernc F. Roscnbaum
`Attorney, Agent, or Firm—Paul L. Sahatine; Thomas E
`Ciotti; Edward L Mandell
`
`[57}
`
`ABSTRACT
`
`A devicc for the Controlled continuous adminismfion
`of an active agent to an environment of use is disclosed.
`The device comprises a body of erodible agent release
`rate controlling material containing an agent dimmed
`therethrough; the rate controlling 1113181131 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 continuous rate over
`a prolonged period of time in response to the environ-
`ment by a procas of carboxyiic hydrogen ionization,
`were”? releasing the disPcrsed i’ge'“ 3‘ a “nmfled
`me 0"“ 3 91010113“ Fem" or “me-
`
`15 Claims, 9 Drawing Figures
`
`[54} BIOERODIBLE SYSTEM FOR DELIVERING
`DRUG MANUFACTURED FROM
`
`[75]
`
`POIJHCARBOXYLIC ACID)
`Inventors:
`Jorge Heller, Palo Alto. Calif.;
`Richard W. Baker, Bend, Oreg,
`[73} Assignoe: Alza Corporation, Palo Alto, Calif.
`[ * ] Notice:
`The portion of the term ofthis patent
`subsequent to May 21’ '99], has been
`disc'simd-
`
`[211 Appl- No: 54.783
`[22] Filed:
`Jul. 5. 1979
`
`I60]
`
`Related U3. Application Data
`:5, 19m. Pat.
`Continuation ofSer. No. 750,101. Dec.
`No. 4.130.064. which is a division of Ser. No. 591.443.
`Jun. 30. 1975. Pat. No. 4.014.931, which is a continua-
`t‘mn-in-part of Ser. No. 461.246. Jun. 4. 1914, ahan-
`doned. which is a continuationoin-part of Ser. No.
`313,331. Dec. 21. 1972. abandoned.
`
`ASIM 7/00
`Int (:1.‘1
`[51]
`[52] U
`CL ................................" 123/260. 123/271.
`'
`424/33:
`'
`'
`[53; Field of Search ............................. .. 128/260, 271;
`424/19_22. 33. 71/1, 65, 3' 64 F
`_
`'
`Katerina C1194
`US. pATENT DOCUMENTS
`
`1561
`
`:agendgm El al‘ """""""""""
`sci‘ilono'eig‘éi'.
`I: 424/31
`Shaina moo}
`En:
`3.031233
`3il963
`424/33
` 9/1911
`3.14J.472 @1964
`Lappas etal.
`424/33
`3.608.063
`Banker ................................. .. 424/33
`
`
`
`
`
`Dr. Reddy's — EX1017
`
`Page 1
`
`Dr. Reddy's - EX1017
`Page 1
`
`

`

`U.S. Patent
`
`Feb. 10,1981
`
`Sheet 1 of4-
`
`4,2499531
`
`
`
`20
`
`i §
`
`
`
`k
`
`
`
`
`
`22
`
`5|
`
`
`.
`.
`WWII/I'll! %
`.5. §
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`22o
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`2Ie
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`Page 2
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`Page 2
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`Page 3
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`Page 4
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`Page 4
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`

`

`U.S. Patent
`
`Feb. 10, 1981
`
`Sheet 4 of 4
`
`4,249,531
`
`
`
`CUMULATIVEDRUGRELEASE,"IoOFTOTAL
`
`
`
`
`
`TEST MEDIUM
`ph3.0,0.lrn
`BUFFER
`
`I00
`
`mC:
`
`6'3CD
`
`.5:-CD
`
`N0
`
`TEST MEDIUM
`phTOfl. II'I'I
`BUFFER
`
`IO
`
`20
`
`30
`
`40
`
`50
`
`60
`
`ELAPSED TIME, MINUTES
`
`Page 5
`
`Page 5
`
`

`

`1
`
`4,249,531
`
`BIOERODIBLE SYSTEM FOR DELIVERING
`DRUG MANUFACTURED FROM
`POLYlCARBOXYLIC AC1 D)
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`IO
`
`15
`
`This application is a continuation of United States
`Patent Application Ser. No. 750,701 filed on Dec. 15,
`1976 and now US. Pat. No 4,130,064 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 {1.5. Pat. No. 4,014,987 isatled 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. 19'”, 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.
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`
`This invention relates to device which dispense ac-
`tive agents to an environment of 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
`
`‘
`
`30
`
`35
`
`The use of polytcarboxylic acids) as enteric coatings
`has been reported by Lappas and McKeehan at 51 J.
`Pharm. Sci. 308 (1962), at 54 J. Phomz. Sci. 176 (l965)
`and at 56.1. Pharm. Sci. l257 (1967).
`As is well known, enteric coatings are spacial coat-
`ings applied to ingestthe tablets or capsules which pre-
`vent release and absorption of their contents until the
`tablets reach the intestines.
`The pcly(carboxylic acids) are well suited to this
`application and the widely varying pH conditions of the
`gastrointestinal tract. In the highly acidic stomach (pl-I
`2) poly{carboxylic acids) are present completely as 45
`unionized hydrophobic species which are water insolu-
`ble and which prevent the release of any enclosed drug.
`As the poly(carboxylic acids) move on to the intestine,
`they are exposed to alkaline conditions (pl-I 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
`pit—dependent step function.
`There is no release of drug in the acidic stomach;
`there is release of all the drug as the encapsulated drug
`enters the intestine and the pH of the environment
`changes to an alkaline value.
`STATEMENT OF THE INVENTION
`
`50
`
`SS
`
`It has now been found that polytcarboxylic 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.
`
`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
`pI-l environment. Such a device comprises a body of
`credible release rate controlling material containing the
`active agent dispersed therethrough. The release rate
`controlling material comprises a hydrophobic poly(car—
`boxylic acid) having an average of one ionizable hydro-
`gen for each 8 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 carbonylic
`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 of time.
`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
`polytcarboxylic 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) hioerodes by a
`process of carbonylic 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 periods of time.
`This process involves employing the drugs in a certain
`form, and applying this form to an environment in the
`mammalian patient which is characterized as having an
`essentially constant pH throughout the period of admin-
`istration ofdrug. The drug form employed in this pro-
`cess comprises a body of dntg release rate controlling
`hydmphobic poly(carboxylic acid) having one ioniz-
`able carbonylic 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 loonl 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 hioenode in the uterus or vagina in response to
`the environment thereof.
`The invention 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 cit-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
`
`

`

`4,249,53 l
`
`3.
`FIG. 2 is'a cross sectional viewof a multi-Iayered
`device in accord with the invention which releases
`active agent at a varying rate.
`=
`_
`_
`FIGS. 3—7 inclusive are illustrative 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 or this in-
`vention adapted to release a controlled amount of active
`agent into a liquid medium.
`'
`'
`'
`FIG. 5 is a cross-sectional view of a suppdsitory ern-
`bodying the present invention.
`-'
`FIG. 6 is a partially cutaway elevational view of an
`intrauterine device formed of two connecting rings.
`FIG. 7 is a partially cut away elevational view of an
`intrauterine device shaped like 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 fer placement in the
`cervical canal of a pregnant female.
`-
`FIG. 9 is a graph illustrating the. linear release of
`active agent achieved with devices of this invention.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`I0
`
`I5
`
`25
`
`30
`
`35
`
`4
`proportion of carbonylic hydrogens. They. are substan-
`tially impermeable to the passage of agent and biologi-
`cal fluids and release entrapped agent by an erosion
`centre} process, since these poly(acids) gradually erode
`in the environment; preferably a biological environ-
`ment, at a controlled rate by a process of carbonylic
`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:
`-
`
`
`
`I
`Rina-rune?"
`R2
`|
`l
`C"0H C—OH C-DH
`1]
`ll
`II
`0
`O
`0
`
`_
`'
`
`I
`
`_
`
`(I)
`
`the R‘s are organic radicals independently
`wherein:
`selected to provide, on average, from 8 to 22 total car-
`bon atoms for each carbonylic 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 hydrocarbon radi-
`cals and hetero-atom containing organic radicals. Suit-
`able hetero atoms for employment in R1, R1,
`.
`.
`. R."
`include oxygen, nitrogen. sulfur, and phosphorous as
`well as other hetero atoms so long as the required hy-
`drophobicity and carbon to carbonylic hydrogen aver-
`age ratio is maintained. The value of n and hence the
`average molecular weight of the polymer is not critical
`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 15.800 to about 500,000.
`'
`While not wishing to limit the scope of the poly(a-
`cids} intended to be employed in accord with this inven-
`tion, and while alternative materials and preparative
`schemes are set forth in the description of suitable
`poly(acids) which follows, practiwa speaking,
`the
`most common and widely applied method for introduc-
`ing a carboxylic acid function, as well as other hetero
`atom functions, into a polymeric material of the type
`craployed in this invention, is to proceed through mon-
`omers having a carbon skeleton of at least two cart-0n
`atoms. These monomers contain polymerizable oiefinic
`carbon-carbon double bonds. At least-a portion of these
`monomers will have appended thereto one or more
`carbonyl 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:
`-
`..
`.
`
`a
`l
`
`'c'.'
`a
`l
`'
`'
`-
`|
`+CH3=tE +_cn;=-l: %
`_0H
`‘t’
`7.
`l!
`-
`O
`
`(in:
`A'
`
`n
`
`Page 7
`
`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
`slowly erodes in the environment of use andis 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 “hydrophobieity”
`broadly refer to the prOperty of a substance to not ab-
`sorber adsorb appreciable amounts of water. As used in
`this specification and claims, a more precise meaning of 40
`these terms is intended; a hydrophobic material, is de-
`fined as one which absorbs or adsorbs water in a maxi-
`mum amount not exceeding 10% ofrits dry weight.
`The phrase “active agent" and the term “agents” as
`used in this specification and accompanying _cIairns
`comprise any compound, or mixture of compounds,
`composition of matter or mixture thereof which when
`dispensed produces a beneficial result for man, animals
`or the environment of use.
`_
`As used 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
`which it is applied. Normally, it will mean a time period
`of at least i hour to 130 days, and it includes one hour
`of higher, up to two years or more.
`,
`In accordance with the present invention, there is
`provided a device for the conrolled continuous dispens-
`ing of a predetermined amount of active agent over a
`prolonged period of time.
`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 environmenthaving 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
`
`45
`
`SD
`
`55
`
`65
`
`Page 7
`
`

`

`5
`-continued
`rt
`l
`
`C
`|
`
`-CH_~-t|.‘-'CHg-—(l:--- =
`._DH ‘1'
`Z
`
`A
`l
`
`1
`
`- - -v—c|‘—-
`A‘
`
`4,249,531
`
`6
`acid {or substituted acrylic acid) with a polymerizable
`hydrocarbon. These acids may be represented by the
`general formula:
`-
`
`(W)
`
`in!
`
`-
`
`1ftth
`
`u.-
`
`C—OH
`ll
`0
`
`PI
`
`Wharf-ll“ RtHCI r'sa hydrocarbon radical ofap to about 12 carbons
`or hydrogen; and Rm” is a copolymerized hydrocarbon
`group. The hydrocarbons which may be cepolymerized
`with unsaturated carbonylic acids include terminally
`oiefinically unsaturated hydrocarbons and olefinically
`unsaturated hydrocarbons having a conjugated carbon-
`carbon double bond. Thus, typical hydrocarbon groups
`represented by chm 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. P00}. 5ch 441 (1946 Series} and
`10 J. Poly. Sci: 597 (1946 Series).
`Poly(carboxylic acids) in accord with General For-
`mula I having hydrocarbon R‘s may aIso be prepared by
`other knewn techniques, such as for example by oxidiz-
`ing terminal methyl groups on suitable hydrocarbon
`polymers to carbony groups with alkaline permanate as
`described in Cram and Hammond Organic Chemistry
`2nd Ed, pages 525-6; or by carbonylating olefinically
`unsaturated hydroan polymers by contacting them
`with carbon monoxide, water and optionally some hy-
`drogen under conditions of elevated temperature and
`premure in the presence of stongly acidic catalysts. for
`example HF, BF}, H280: and the like.
`Poly(carbortylic acids) useful in the devices of the
`invention and illustrated by General Formula I may
`suitably incorporate oxygen atoms in their R’s. Oxyhy-
`drocarbon R’s include ester groups or ether groups.
`Poly(carb0xylic acids) represented by Formula I incor-
`porating ester groups. as R‘s. are especially suitable in
`devices of this invention. They may be readily prepared
`by partially aterifying acid polymers or copolymers,
`which are themselves easily obtained. They offer the
`advantage of permitting simple variation of the ratio of
`carbons to ionizable carbonylic hydrogens by varying
`the extent of partial esterification or the esterifying
`alcohol employed. As a result, easy adjustment of ero~
`sion characteristics of the polytcarboxylic 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 pcroxydisulfate and 0.25 parts of
`potassium metabisulfite and heating the mixture to 60'
`C. Polytacrylic 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.
`'
`‘
`When half“ the carboxyl groups of poly(acrylic acid)
`are esterii'ted 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
`
`10
`
`15
`
`20
`
`25
`
`wherein A represents hydrogen or a hydrocarbon and
`
`A|
`
`CH:
`
`E
`i—ot—t
`
`l0
`
`'-
`4*
`
`represents a carbonyl group (or carboxy group precur~
`sor) containing monomer also containing a polymeriz-
`able olefinic double bond. Such monomers include. for
`example. acrylic acid. substituted acrylic acid, maleic
`acid. maleic anhydride. crotonic acid and the like.
`
`rcpresent organic monomers containing a polymeriz-
`able double bond which may be the same or different
`than
`
`30
`
`35
`
`45
`
`50
`
`55
`
`Al
`
`C‘H=
`'-
`A
`
`i
`-0H
`ito
`
`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 pol y(carboxylic acids)
`having hydrocarbon R's prepared by polymerizing sub-
`stituted acrylic acids may be represented by the general
`formula:
`
`(Ill)
`
`lllmc‘l
`CH1—?
`C—OH
`II
`o
`
`u u n
`
`“
`
`wherein Rum represents hydrocarbon substitutes aver-
`aging frorn 5 to [5 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.
`
`65
`
`No. 2,904,541 issued Sept. 15. [959.
`Also useful are polyfcarboxylic acids) prepared by
`copolymerizing unsaturated carbonylic acids as acrylic
`
`Page 8
`
`

`

`4,249, 5 3 1
`
`7
`necessary for materials employed in the devices of this
`invention (i.e., 12:1). A similarly suitable material would
`result if E 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 lbwer 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 3 carbons such as
`ethylene, pr0pylene, butadiene. styrene and the like, or
`with lower unsaturated oxyhydrocarbons such as unsat-
`urated ethers of from 3 to 8 carbon atoms. Many of
`these polymers and capolymers 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 known in the
`art. The partial esterification may be canveniently ef-
`fected by contacting the acid-containing polymers with
`a controlled quantity of the esteril'ying 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-
`no], 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,
`heayl 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-carbonylic
`hydrogen-containing material, most suitably an unsatu-
`rated terpolymerizable unsaturated hydrocarbon of
`from 2 to 3 carbon atoms such as ethylene, butadiene, or
`styrene. Examples of terpolymers are presented herein-
`after.
`
`The R’s of General Formula I, as oxyhydrocarbons,
`may contain alcohol linkages. The employment of alco-
`hol
`linkage-containing oxyhydrocarbons as R's can
`pose a problem, however, as the alcohol linkages gener-
`ally decrease the hydrophobicity of the poly(acid),
`often to below the extent of hydrophobicin required of
`poly(acids) for employment in 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).
`
`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 been esterified with an alkanol of from
`1 to about 10 carbon atoms and wherein the ratio of
`total carbon atoms to acidic carbonylic hydrogens is in
`the range of from about about 9:1 to about 20:].
`An even more preferred group of poly(carboity1ic
`acids) comprise the hydrophobic partially esterified
`copolymers of 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% of their total carbonylic
`groups esterified with lower alkanol of from about 3 to
`about 10 carbon atoms, said copolymers having a car-
`bon to acidic carbonylic 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 about half of its total
`carboxyIic groups esterified with a 10wer 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:].
`'
`A presently preferred group of poly(carboxylic
`acids) are terpolymers of at least one mil-unsaturated
`aliphatic acid of 3 to B carbons, an alkyl ester of such
`afi-unsaturated aliphatic acids in which said alkyl is of
`2 to 8 carbon atoms. Typical terpolymers include one
`acid monomer and two ester monomers, two acid mon-
`omers and an ester monomer of the acid functiOnality,
`an acid monomer. an ester monomer of 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 lower alkyl acrylate
`of the formula CHz=CH-—COOR9 where R9 is an alkyl
`of 2 to 8 carbons, from 15 to 30 mol % of an acid of the
`formula CH2=CRm—C00H where Rlois an alkyl of 1
`to 8 carbOns, and from 5 to 15 mol % of an acid of the
`formula CH3=CHCOOH. and the like. A terpolymer
`included in this preferred group is comprised of 60 to TS
`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 carbonylic acid monomers useful for produc-
`ing the terpolymer are 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 of its
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`Page 9
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`Page 9
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`

`9
`presence in the monomer molecule either in the alpha-
`beta position with reSpect to the carbonyl group, such
`as
`
`4,249.53 1
`
`l
`I
`-c=c—coon.
`
`or as a part of a terminal methylene grouping
`CH3=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 carbonylic
`acid includes polytcarboxylic acids) and those acid
`anhydrides, such as maleic anhydride, wherein the an-
`hydride group is formed by the elimination of one mole-
`cule of water from two carbonyl groups located on the
`same poly(carboxylic acid) molecule. The anhydrides
`have the general formula
`
`10
`
`15
`
`R I1—C-C
`ll
`Ru-C-C
`
`0
`
`['0
`
`0
`
`(V)
`
`25
`
`35
`
`wherein R1; 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, isoba-
`tyl methacrylate, t-butyi methacrylate, hexyl methacry-
`late. lauryl methacrylate, and other acrylates such as
`cyclohexyl methacrylate. dimethylaminomethacrylate.
`2-hydroxymethylmethacrylate, and the like. Acrylic
`esters of the formula CH1=CHCOOR includes the
`Milky] esters methyl, ethyl, propyl. butyl, pentyl, hesyl
`and heptyl. the secondary and branched chain alkyl
`esters isoprOpyl.
`isobutyl,
`sec—butyl. 2-methylbutyl.
`3-methylbutyl,
`l-ethylpropyl,
`l-methylhexyl and the
`like. Acrylic acid. its esters and other derivatives are
`commercially available and known to the art in Ell-rewin-
`perils of Chemical Technology. Kirk-othmer, Vol. 1,
`pages 285 to 313, 1963; Encyclopedia ofPobrmer 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. Accotd- 55
`ingly, the poly(acids) may be conveniently formed by
`film casting techniques. An organic solvented solution
`of the polytacid). optionally containing active agent. is
`prepared and cast or drawn to a flint. The solvent is
`then evaporated to yield acontinuous film of the poly(a- 60
`old}. The devices may them be punched or cut 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(carbosylic acid} materials 65
`having total carbon to carbonylic hydrogen ratios at the
`lower end of the range specified for this invention, such
`as ratios in the range or from about 8:1 to about 11:1, it
`
`45
`
`SO
`
`10
`is generally preferred to use relatively polar organic
`solvents, that is, organic solvents having dielectric con-
`stants. as listed in the Slst Edition of the Chemical Rub-
`ber Company “Handbook of Chemistry and Physics" at
`pages 5-62 through 564, of greater that! about 15, for
`example, lwoer alkanols such as methanol, ethanol, the
`propanols, _l- and 2-butanol. lwoer alkauoues such as
`acetone, diethyl ketone, ethyl methyl ketone and cyclo-
`hexanone and halogenated and nitrogenated solvents
`such as z-chloroethanol, and nitrobenzeue. With poly(-
`carbonylic acids) having higher ratio of total carbon
`atoms to ionizable hydrogens, such as fmm 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 cyclohesane, 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 alkeuones 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 or slightly 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 impmve or vary their
`physical properties. such as to make them more flexible.
`Exemplary plasticizers suitable for employment for the
`present purpsoe are the pharmaceutically acceptable
`plasticizers conventionally used, such as acetyl tri-n-
`butyl