United States Patent [19]
`United States Patent [19]
`Heller et ai.
`Heller et al. (cid:9)
`
`[11]
`[11] (cid:9)
`[45]
`[45] (cid:9)
`
`4,249,531
`4,249,531
`* Feb. 10, 1981
`* Feb. 10, 1981
`
`
`
`[54] BIOERODIBLE SYSTEM FOR DELIVERING
` 128/260
`5/ 1 974 (cid:9) Heller et al. (cid:9)
`3,811,444 (cid:9)
`3,811,444
`5/1974 Heller et al. ......................... 128/260
`[54] BIOERODIBLE SYSTEM FOR DELIVERING
`DRUG MANUFACTURED FROM
`6/1975 Ramwell (cid:9)
` 128/260
`3,888,975 (cid:9)
`3,888,975
`6/1975 Ramwell .............................. 128/260
`DRUG MANUFACTURED FROM
`POLY(CARBOXYLIC ACID)
`8/1975 Zaffaroni (cid:9)
` 128/260
`3,898,986 (cid:9)
`3,898,986
`8/1975 Zaffaroni ............................. 128/260
`POLY(CARBOXYLIC ACID)
`3,914,402 10/1975 Shell ..................................... 128/260
`Shell (cid:9)
` 128/260
`3,914,402 10/1975 (cid:9)
`[75] Inventors: Jorge Heller, Palo Alto, Calif.;
`3,971,367
`7/1 976 Zaffaroni (cid:9)
`7/1976 Zaffaroni ............................. 128/260
`3,971,367 (cid:9)
` 128/260
`[75] Inventors: Jorge Heller, Palo Alto, Calif.;
`Richard W. Baker, Bend, Oreg.
`3,986,510 10/1976 Higuchi et al. ...................... 128/260
`3,986,510 10/1976 (cid:9) Higuchi et al. (cid:9)
` 128/260
`Richard W. Baker, Bend, Oreg.
`-
`3/1 977 (cid:9) Heller et al. (cid:9)
`4,014,987 (cid:9)
` 128/260
`-
`4,014,987
`3/1977 Heller et al. ......................... 128/260
`[73] Assignee: Aiza Corporation, Palo Alto, Calif.
`[73] Assignee: Alza Corporation, Palo Alto, Calif.
`[*] Notice:
`FOREIGN PATENT DOCUMENTS
`The portion of the term of this patent
`FOREIGN PATENT DOCUMENTS
`The portion of the term of this patent
`[ * ] Notice:
`subsequent to May 21, 1991, has been
`| 1241.15 8/1968 United Kingdom ..................... 128/260
` 128/260
`1124115 8/1968 United Kingdom (cid:9)
`subsequent to May 21, 1991, has been
`disclaimed.
`disclaimed.
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`[21] Appl. No.: 54,788
`[21] Appl. No.: 54,788
`Lappas, L. et al., J. Pharm. Sci., vol. 56, pp. 1257–1261,
`Lappas, L. et al., J. Pharm. Sci., vol. 56, pp. 1257-1261,
`1967.
`22] Filed:
`Jul. 5, 1979
`Jul. 5, 1979
`[22] Filed:
`1967.
`Heyd, A. et al., J. Pharm. Sci., vol. 58, No. 5, pp.
`Heyd, A. et al., J. Pharm. Sci., vol. 58, No. 5, pp.
`Related U.S. Application Data
`586-588, 1969; vol. 59, No. 7, pp. 947-949, 1970.
`586–588, 1969; vol. 59, No. 7, pp. 947–949, 1970.
`Related U.S. Application Data
`continuation of ser. No. 750,701, Dec. 15, 1976, Pat.
`Primary Examiner—Robert W. Michell
`Primary Examiner—Robert W. Michell
`Continuation of Ser. No. 750,701. Dec. 15, 1976, Pat.
`No. 4,180,064, which is a division of Ser. No. 591,443,
`Assistant Examiner—C. F. Rosenbaum
`Assistant Examiner—C. F. Rosenbaum
`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-
`Attorney, Agent, or Firm—Paul L. Sabatine; Thomas E.
`Jun. 30. 1975, Pat. No. 4,014,987, which is a continua-
`Attorney, Agent, or Firm—Paul L. Sabatine; Thomas E.
`tion-in-part of Ser. No. 467,246, Jun. 4, 1974, aban-
`tion-in-part of Ser. No. 467,246, Jun. 4, 1974, aban-
`Ciotti; Edward L. Mandell
`Ciotti; Edward L. Mandell
`doned, which is a continuation-in-part of Ser. No.
`doned. which is a continuation-in-part of Ser. No.
`[57] (cid:9)
`318,831, Dec. 27, 1972, abandoned.
`ABSTRACT
`[57]
`318,831, Dec. 27, 1972, abandoned.
`ABSTRACT
`[51] Int. Cl." ............................................... A61M 7/00 A device for the controlled continuous administration
`A device for the controlled continuous administration
`A61M 7/00
`[51] Int. O. (cid:9)
`[52] U.S. Cl. .................................... 128/260; 128/271,
`of an active agent to an environment of use is disclosed.
`of an active agent to an environment of use is disclosed.
` 128/260; 128/271;
`[52] U.S. Cl. (cid:9)
`424/33
`The device comprises a body of erodible agent release
`The device comprises a body of erodible agent release
`424/33
`[58] Field of Search ............................... 128/260, 271;
`rate controlling material containing an agent dispersed
`rate controlling material containing an agent dispersed
` 128/260, 271;
`[58] Field of Search (cid:9)
`424/19–22, 33; 71/1, 65, 3, 64 F therethrough; the rate controlling material is a hydro
`therethrough; the rate controlling material is a hydro-
`424/19-22, 33; 7111, 65, 3, 64 F
`phobic poly(carboxylic acid) having one ionizable car
`phobic poly(carboxylic acid) having one ionizable car-
`References Cited
`boxylic hydrogen for each 8 to 12 carbon atoms, which
`References Cited
`boxylic hydrogen for each 8 to 12 carbon atoms, which
`U.S. PATENT DOCUMENTS
`material erodes at a controlled and continuous rate over
`material erodes at a controlled and continuous rate over
`U.S. PATENT DOCUMENTS
`2,066. 105 i2/1936 Hagedorn et al
`a prolonged period of time in response to the environ-
`424/33
`a prolonged period of time in response to the environ
`424/33
`
`2,066.105 12/1936 Hagedorn et al. (cid:9)
`3.39.ji 7/1959 §:Ther
`- --------------------- 424/33
`ment by a process of carboxylic hydrogen ionization,
`ment by a process of carboxylic hydrogen ionization,
`5.6; ;6; jº. ºf thereby releasing the dispersed agent at a controlled
`424/33
`7/1959 Wagner (cid:9)
`
`2,897,121
`thereby releasing the dispersed agent at a controlled
`424/81
`3/1963 Schellenberg et al. (cid:9)
`
`3.080.346
`3,081,233
`3/1963 Enz ........................,
`... 424/33
`rate over a prolonged period of time.
`rate over a prolonged period of time.
`424/33
`3/1963 Enz (cid:9)
`
`3.081,233
`3,143,472
`424/33
`8/1964 Lappas et al.
`3.143,472
`8/1964 Lappas et al. (cid:9)
`
`... 424/33
`3,608.063
`Banker ................................... 424/33
`15 Claims, 9 Drawing Figures
`424/33
`9/1971 Banker (cid:9)
`
`3,608.063
`15 Claims, 9 Drawing Figures
`9/1971
`
`[60]
`[60]
`
`[56]
`[56] (cid:9)
`
`
`
`50
`
`22
`21
`
`Par Pharm., Inc., et al.
`Exhibit 1017
`Page 001
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`U.S. Patent Feb. 10, 1981
`U.S. Patent Feb. 10, 1981
`
`Sheet 1 of 4
`Sheet 1 of 4
`
`4,249,531
`4,249,531
`
`FIG. I
`
`
`
`
`
`FIG. 2
`
`
`
`21
`
`
`
`20
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`22
`
`31
`
`22a (cid:9)
`
`21a
`
`G. 3
`
`50
`
`22
`21
`
`FIG. 5
`
`Par Pharm., Inc., et al.
`Exhibit 1017
`Page 002
`
`(cid:9)
`(cid:9)
`

`

`(cid:9) (cid:9)
`
`U.S. Patent Feb. 10, 1981
`
`Sheet 2 of 4
`
`4,249,531
`
`tig
`
`t
`
`/ 91
`31
`r(I
`36
`
`10
`
`FIG. 7
`
`Par Pharm., Inc., et al.
`Exhibit 1017
`Page 003
`
`(cid:9)
`(cid:9)
`

`

`U.S. Patent Feb. 10, 1981
`
`Sheet 3 of 4 (cid:9)
`
`4,249,531
`
`FIG. 8
`
`Par Pharm., Inc., et al.
`Exhibit 1017
`Page 004
`
`

`

`U.S. Patent Feb. 10, 1981
`U.S. Patent Feb. 10, 1981 (cid:9)
`
`Sheet 4 of 4
`Sheet 4 of 4 (cid:9)
`
`4,249,531
`4,249,531
`
`"1 TEST MEDUM
`100-
`TEST MEDIUM
`ph8.0,0.1m
`ph 80,0lm
`BUFFER
`BUFFER
`
`_, 80
`80-
`
`?e—
`&\
`
`O-C
`
`Ç
`
`22
`
`..?
`
`3.
`
`º
`
`TEST MEDIUM
`TEST MEDIUM
`ph100 lm
`phi0,0.1m
`BUFFER
`BUFFER
`
`5
`sº
`cfe 60-
`,
`:
`cc,
`U-J
`£ 40
`'Etc' 40-
`
`1=3
`
`# 20: A .
`
`20-
`
`LL-1
`
`-J
`
`=
`
`C
`
`0
`0
`
`I
`|0
`I0 (cid:9)
`
`I
`20
`30
`30
`20 (cid:9)
`'
`ELAPSED TIME, MINUTES
`ELAPSED TIME, MINUTES
`
`40
`401
`
`50
`50
`
`601
`60
`
`Par Pharm., Inc., et al.
`Exhibit 1017
`Page 005
`
`(cid:9)
`(cid:9)
`

`

`1
`1
`
`60
`60
`
`BIOERODIBLE SYSTEM FOR DELIVERING
`BIOERODIBLE SYSTEM FOR DELIVERING
`DRUG MANUFACTURED FROM
`DRUG MANUFACTURED FROM
`POLY(CARBOXYLIC ACID)
`POLY(CARBOXYLIC ACID)
`
`4,249,531
`4,249,531
`2
`2
`In accordance with this invention, a device is pro
`In accordance with this invention, a device is pro-
`vided which permits the controlled and continuous
`vided which permits the controlled and continuous
`administration of active agent to an essentially constant
`administration of active agent to an essentially constant
`pH environment. Such a device comprises a body of
`pH environment. Such a device comprises a body of
`erodible release rate controlling material containing the
`5 erodible release rate controlling material containing the
`CROSS-REFERENCE TO RELATED
`active agent dispersed therethrough. The release rate
`CROSS-REFERENCE TO RELATED
`active agent dispersed therethrough. The release rate
`controlling material comprises a hydrophobic poly(car
`APPLICATIONS
`APPLICATIONS
`controlling material comprises a hydrophobic poly(car-
`boxylic acid) having an average of one ionizable hydro
`This application is a continuation of United States
`boxylic acid) having an average of one ionizable hydro-
`This application is a continuation of United States
`gen for each 8 to 22 total carbon atoms. These polyacids
`Patent Application Ser. No. 750,701 filed on Dec. 15,
`gen for each 8 to 22 total carbon atoms. These polyacids
`Patent Application Ser. No. 750,701 filed on Dec. 15,
`erode in response to the environment of use at a con
`10 erode in response to the environment of use at a con-
`1976 and now U.S. Pat. No. 4, 180,064 issued on Dec. 25,
`1976 and now U.S. Pat. No. 4,180,064 issued on Dec. 25,
`trolled and continuous rate by a process of carboxylic
`1979, which application is a division of United States
`trolled and continuous rate by a process of carboxylic
`1979, which application is a division of United States
`hydrogen ionization. This erosion extends over a pro
`Patent Application Ser. No. 591,443 filed on June 30,
`hydrogen ionization. This erosion extends over a pro-
`Patent Application Ser. No. 591,443 filed on June 30,
`longed period of time and causes the dispersed agent to
`1975 and now U.S. Pat. No. 4,014,987 issued on Mar. 29,
`longed period of time and causes the dispersed agent to
`1975 and now U.S. Pat. No. 4,014,987 issued on Mar. 29,
`1977, which division is a continuation-in-part of our
`be released at a controlled and continuous rate over a
`be released at a controlled and continuous rate over a
`1977, which division is a continuation-in-part of our
`15
`15
`prolonged period of time.
`copending United States Patent Application Ser. No.
`prolonged period of time.
`copending United States Patent Application Ser. No.
`In a preferred embodiment, the invention involves a
`467,246 filed on June 4, 1974, now abandoned, which
`467,246 filed on June 4, 1974, now abandoned, which
`In a preferred embodiment, the invention involves a
`latter application is a continuation-in-part of United
`device for delivering drugs to a substantially constant
`latter application is a continuation-in-part of United
`device for delivering drugs to a substantially constant
`States Patent Application Ser. No. 318,831 filed on Dec.
`pH environment within the body of a mammalian pa
`States Patent Application Ser. No. 318,831 filed on Dec.
`pH environment within the body of a mammalian pa-
`27, 1972 and now abandoned. This application and the
`tient, with the device eroding when placed in the body
`27, 1972 and now abandoned. This application and the
`20 tient, with the device eroding when placed in the body
`20
`earlier applications are assigned to the same assignee
`earlier applications are assigned to the same assignee
`in response to the environment.
`in response to the environment.
`.
`Such a device comprises a body of the hydrophobic
`and benefit of their filing dates is claimed.
`and benefit of their filing dates is claimed.
`Such a device comprises a body of the hydrophobic
`poly(carboxylic acid) having drug dispersed there
`poly(carboxylic acid) having drug dispersed there-
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`through. When this device is placed in a substantially
`through. When this device is placed in a substantially
`1. Field of the Invention
`constant pH environment within the body of a mamma
`1. Field of the Invention
`25 constant pH environment within the body of a mamma-
`25
`This invention relates to device which dispense ac
`lian patient, the poly(carboxylic acid) bioerodes by a
`This invention relates to device which dispense ac-
`lian patient, the poly(carboxylic acid) bioerodes by a
`tive agents to an environment of use at a controlled and
`process of carboxylic hydrogen ionization in response
`tive agents to an environment of use at a controlled and
`process of carboxylic hydrogen ionization in response
`continuous rate over a prolonged period of time. In a
`continuous rate over a prolonged period of time. In a
`to the mammalian environment and gradually releases
`to the mammalian environment and gradually releases
`preferred embodiment, it relates to delivery devices for
`preferred embodiment, it relates to delivery devices for
`drug at a controlled and continuous rate over a pro
`drug at a controlled and continuous rate over a pro-
`the sustained release of an agent to a substantially con
`the sustained release of an agent to a substantially con-
`longed period of time.
`30 longed period of time.
`30
`stant pH environment, such as an agent to a mammalian
`stant pH environment, such as an agent to a mammalian
`The invention further makes possible a process for
`The invention further makes possible a process for
`patient, and the like.
`patient, and the like.
`the controlled and continuous administration of drugs
`the controlled and continuous administration of drugs
`2. The Prior Art
`2. The Prior Art
`to a mammalian patient over prolonged periods of time.
`to a mammalian patient over prolonged periods of time.
`The use of poly(carboxylic acids) as enteric coatings
`The use of poly(carboxylic acids) as enteric coatings
`This process involves employing the drugs in a certain
`This process involves employing the drugs in a certain
`has been reported by Lappas and McKeehan at 51 J.
`has been reported by Lappas and McKeehan at 51 J.
`form, and applying this form to an environment in the
`35 form, and applying this form to an environment in the
`35
`Pharm. Sci. 808 (1962), at 54.J. Pharm. Sci. 176 (1965)
`Pharm. Sci. 808 (1962), at 54 J. Pharm. Sci. 176 (1965)
`mammalian patient which is characterized as having an
`mammalian patient which is characterized as having an
`and at 56 J. Pharm. Sci. 1257 (1967).
`and at 56 J. Pharm. Sel. 1257 (1967).
`essentially constant pH throughout the period of admin
`essentially constant pH throughout the period of admin-
`As is well known, enteric coatings are special coat
`As is well known, enteric coatings are special coat-
`istration of drug. The drug form employed in this pro
`istration of drug. The drug form employed in this pro-
`ings applied to ingestible tablets or capsules which pre
`ings applied to ingestible tablets or capsules which pre-
`cess comprises a body of drug release rate controlling
`cess comprises a body of drug release rate controlling
`vent release and absorption of their contents until the
`vent release and absorption of their contents until the
`hydrophobic poly(carboxylic acid) having one ioniz
`40 hydrophobic poly(carboxylic acid) having one ioniz-
`tablets reach the intestines.
`tablets reach the intestines.
`able carboxylic hydrogen atom for each 8 to 22 carbon
`able carboxylic hydrogen atom for each 8 to 22 carbon
`The poly(carboxylic acids) are well suited to this
`The poly(carboxylic acids) are well suited to this
`atoms and having the drug dispersed throughout, that
`atoms and having the drug dispersed throughout, that
`application and the widely varying pH conditions of the
`application and the widely varying pH conditions of the
`bioerodes in response to the environment.
`bioerodes in response to the environment.
`gastrointestinal tract. In the highly acidic stomach (pH
`gastrointestinal tract. In the highly acidic stomach (pH
`In another embodiment, the invention provides de
`In another embodiment, the invention provides de-
`2) poly(carboxylic acids) are present completely as
`2) poly(carboxylic acids) are present completely as
`45
`vices for the local delivery of drug to the uterus and
`45 vices for the local delivery of drug to the uterus and
`unionized hydrophobic species which are water insolu
`unionized hydrophobic species which are water insolu-
`vagina which devices are of simple operation, give a
`vagina which devices are of simple operation, give a
`ble and which prevent the release of any enclosed drug.
`ble and which prevent the release of any enclosed drug.
`reliable delivery of drug over a prolonged period of
`reliable delivery of drug over a prolonged period of
`As the poly(carboxylic acids) move on to the intestine,
`As the poly(carboxylic acids) move on to the intestine,
`time, and bioerode in the uterus or vagina in response to
`time, and bioerode in the uterus or vagina in response to
`they are exposed to alkaline conditions (pH of up to 9)
`they are exposed to alkaline conditions (pH of up to 9)
`the environment thereof.
`the environment thereof.
`in which they ionize to soluble hydrophilic species and
`in which they ionize to soluble hydrophilic species and
`50
`50
`The invention also provides devices for the local and
`The invention also provides devices for the local and
`release the enclosed drug.
`release the enclosed drug.
`systemic delivery of drug wherein the device is a nasal,
`systemic delivery of drug wherein the device is a nasal,
`With these prior enteric coating teachings, the release
`With these prior enteric coating teachings, the release
`anal, buccal, topical, implant, body passageway, or
`anal, buccal, topical, implant, body passageway, or
`of drug is merely delayed. The release is essentially a
`of drug is merely delayed. The release is essentially a
`non-reproductive body cavity device for the controlled
`non-reproductive body cavity device for the controlled
`pH-dependent step function.
`pH-dependent step function.
`and continuous delivery of drug as the device erodes in
`55 and continuous delivery of drug as the device erodes in
`There is no release of drug in the acidic stomach;
`There is no release of drug in the acidic stomach;
`55
`response to the environment wherein the device is
`response to the environment wherein the device is
`there is release of all the drug as the encapsulated drug
`there is release of all the drug as the encapsulated drug
`placed for release of drug thereto.
`placed for release of drug thereto.
`enters the intestine and the pH of the environment
`enters the intestine and the pH of the environment
`The invention also provides for devices for the re
`The invention also provides for devices for the re-
`changes to an alkaline value.
`changes to an alkaline value.
`lease of an active agent to a non-biological environment
`lease of an active agent to a non-biological environment
`STATEMENT OF THE INVENTION
`STATEMENT OF THE INVENTION
`with the device releasing active agent at a controlled
`with the device releasing active agent at a controlled
`and continuous rate as the device erodes in response to
`It has now been found that poly(carboxylic acids)
`and continuous rate as the device erodes in response to
`It has now been found that poly(carboxylic acids)
`may be used to form a device giving a controlled and
`the environment.
`the environment.
`may be used to form a device giving a controlled and
`continuous release of an active agent over a prolonged
`continuous release of an active agent over a prolonged
`BRIEF DESCRIPTION OF THE DRAWINGS
`BRIEF DESCRIPTION OF THE DRAWINGS
`period of time under conditions of essentially constant
`period of time under conditions of essentially constant
`In the drawings:
`pH. This is in direct contrast to the teachings of the
`In the drawings:
`pH. This is in direct contrast to the teachings of the 65
`65
`FIG. 1 is a cross sectional view of a device in accord
`prior art of the use of these materials in enteric coated
`FIG. 1 is a cross sectional view of a device in accord
`prior art of the use of these materials in enteric coated
`with this invention for releasing active agent at a con
`pills which gave a step function release of drug under
`with this invention for releasing active agent at a con-
`pills which gave a step function release of drug under
`trolled rate over a prolonged period of time.
`conditions of changing pH.
`conditions of changing pH.
`trolled rate over a prolonged period of time.
`
`Par Pharm., Inc., et al.
`Exhibit 1017
`Page 006
`
`

`

`environments.
`
`-
`
`. . "
`
`RI— R' (cid:9)
`R"
`R!
`R2. . . . . . . Rn -
`|
`|
`|
`I (cid:9)
`I (cid:9)
`I
`C—OH C—OH C—OH
`|
`|
`|
`II (cid:9)
`II (cid:9)
`II
`O
`O
`O
`
`(I)
`(I)
`
`25
`25
`
`55
`55
`
`4,249,531
`4,249,531
`3
`3
`4
`4
`FIG. 2 is a cross sectional view of a multi-layered
`proportion of carboxylic hydrogens. They are substan
`FIG. 2 is' a cross sectional view of a multi-layered
`proportion of carboxylic hydrogens. They are substan-
`tially impermeable to the passage of agent and biologi
`device in accord with the invention which releases
`device in accord with the invention which releases
`tially impermeable to the passage of agent and biologi-
`cal fluids and release entrapped agent by an erosion
`active agent at a varying rate.
`.
`active agent at a varying rate.
`cal fluids and release entrapped agent by an erosion
`FIGS. 3–7 inclusive are illustrative of the many em
`control process, since these poly(acids) gradually erode
`FIGS. 3-7 inclusive are illustrative of the many em-
`control process, since these poly(acids) gradually erode
`bodiments the present invention may take. (cid:9)
`bodiments the present invention may take.
`5
`in the environment; preferably a biological environ
`5
`in the environment; preferably a biological environ-
`FIG. 3 is a perspective view of a disc-shaped tablet
`FIG. 3 is a perspective view of a disc-shaped tablet
`ment, at a controlled rate by a process of carboxylic
`ment, at a controlled rate by a process of carboxylic
`suitable for releasing drugs perorally or subcutaneously
`suitable for releasing drugs perorally or subcutaneously
`hydrogen ionization. These poly(acids) and their ero
`hydrogen ionization. These poly(acids) and their ero-
`or for releasing other active agents to other constant pH
`or for releasing other active agents to other constant pH
`sion products are nontoxic and non-irritation to biologi
`sion products are nontoxic and non-irritation to biologi-
`environments.
`cal tissues such as the endometrium and other uterine
`cal tissues such as the endometrium and other uterine
`FIG. 4 illustrates in perspective a device of this in- 10
`FIG. 4 illustrates in perspective a device of this in- 10
`and vaginal tissues.
`and vaginal tissues.
`-
`vention adapted to release a controlled amount of active
`vention adapted to release a controlled amount of active
`Suitable poly(carboxylic acids) are the hydrophobic
`Suitable poly(carboxylic acids) are the hydrophobic
`agent into a liquid medium.
`agent into a liquid medium.
`.
`. . .
`poly(acids) which are represented by the general for
`poly(acids) which are represented by the general for-
`FIG. 5 is a cross-sectional view of a suppository em
`FIG. 5 is a cross-sectional view of a suppository em-
`mula:
`mula:
`-
`bodying the present invention.
`bodying the present invention.
`FIG. 6 is a partially cut away elevational view of an 15
`FIG. 6 is a partially cut away elevational view of an 15
`intrauterine device formed of two connecting rings.
`intrauterine device formed of two connecting rings.
`FIG. 7 is a partially cut away elevational view of an
`FIG. 7 is a partially cut away elevational view of an
`intrauterine device shaped like a “T”, adapted to release
`intrauterine device shaped like a "T", adapted to release
`a controlled amount of active agent into the uterus.
`a controlled amount of active agent into the uterus.
`FIG. 8 is a partially sectional elevational view of a 20
`FIG. 8 is a partially sectional elevational view of a 20
`device of this invention adapted for placement in the
`device of this invention adapted for placement in the
`cervical canal of a pregnant female.
`cervical canal of a pregnant female.
`FIG. 9 is a graph illustrating the linear release of
`FIG. 9 is a graph illustrating the linear release of
`active agent achieved with devices of this invention.
`active agent achieved with devices of this invention.
`DETAHLED DESCRIPTION OF THE
`DETAILED DESCRIPTION OF THE
`INVENTION
`INVENTION
`In accord with this invention, agents may be most
`In accord with this invention, agents may be most
`advantageously delivered to the environment of use
`advantageously delivered to the environment of use
`over a prolonged period of time by being incorporated 30
`over a prolonged period of time by being incorporated 30
`in a body of hydrophobic poly(carboxylic acid) of from
`in a body of hydrophobic poly(carboxylic acid) of from
`8 to 22 carbons per ionizable hydrogen. This body
`8 to 22 carbons per ionizable hydrogen. This body
`slowly erodes in the environment of use and is incorpo
`slowly erodes in the environment of use and is incorpo-
`rated in a device adapted and sized for insertion, posi
`rated in a device adapted and sized for insertion, posi-
`tioning and placement in the environment of use 35
`tioning and placement in the environment of use 35
`throughout the period of agent administration. .
`throughout the period of agent administration.
`The terms “hydrophobic” and “hydrophobicity”
`The terms "hydrophobic" and "hydrophobicity"
`broadly refer to the property of a substance to not ab
`broadly refer to the property of a substance to not ab-
`sorb or adsorb appreciable amounts of water. As used in
`sorb or adsorb appreciable amounts of water. As used in
`this specification and claims, a more precise meaning of 40
`this specification and claims, a more precise meaning of 40
`these terms is intended; a hydrophobic material is de
`these terms is intended; a hydrophobic material is de-
`fined as one which absorbs or adsorbs water in a maxi
`fined as one which absorbs or adsorbs water in a maxi-
`mum amount not exceeding 10% of its dry weight.
`mum amount not exceeding 10% of its dry weight.
`The phrase “active agent” and the term “agents” as
`The phrase "active agent" and the term "agents" as
`used in this specification and accompanying claims 45
`used in this specification and accompanying claims 45
`comprise any compound, or mixture of compounds,
`comprise any compound, or mixture of compounds,
`composition of matter or mixture thereof which when
`composition of matter or mixture thereof which when
`dispensed produces a beneficial result for man, animals
`dispensed produces a beneficial result for man, animals
`or the environment of use.
`or the environment of use.
`As used herein, the phrase “a prolonged period of 50
`As used herein, the phrase "a prolonged period of 50
`time” shall have different meanings with respect to the
`time" shall have different meanings with respect to the
`various delivery devices and the environment of use to
`various delivery devices and the environment of use to
`which it is applied. Normally, it will mean a time period
`which it is applied. Normally, it will mean a time period
`of at least hour to 180 days, and it includes one hour
`of at least z hour to 180 days, and it includes one hour
`of higher, up to two years or more. (cid:9)
`of higher, up to two years or more.
`In accordance with the present invention, there is
`In accordance with the present invention, there is
`provided a device for the conrolled continuous dispens
`provided a device for the conrolled continuous dispens-
`ing of a predetermined amount of active agent over a
`ing of a predetermined amount of active agent over a
`prolonged period of time.
`prolonged period of time.
`Such a device is shown as device 10 in FIG. 1. In 60
`Such a device is shown as device 10 in FIG. 1. In 60
`FIG. 1, device 10 comprises an active agent 21 dis
`FIG. 1, device 10 comprises an active agent 21 dis-
`persed throughout a body 22 of hydrophobic poly(car
`persed throughout a body 22 of hydrophobic poly(car-
`boxylic acid). When placed in an environment having a
`boxylic acid). When placed in an environment having a
`controlled and essentially constant pH, poly(carboxylic
`controlled and essentially constant pH, poly(carboxylic
`acid) body 22 bioerodes concommitantly releasing the 65
`acid) body 22 bioerodes concommitantly releasing the
`65 (cid:9)
`active agent which is dispersed therethrough.
`active agent which is dispersed therethrough.
`The polyacids employed are characterized as being
`The polyacids employed are characterized as being
`hydrophobic when unionized and as having a specified
`hydrophobic when unionized and as having a specified
`
`wherein: the R’s are organic radicals independently
`wherein: the R's are organic radicals independently
`selected to provide, on average, from 8 to 22 total car
`selected to provide, on average, from 8 to 22 total car-
`bon atoms for each carboxylic hydrogen. Variations of
`bon atoms for each carboxylic hydrogen. Variations of
`this ratio within this range can vary the erosion and
`this ratio within this range can vary the erosion and
`active agent release rates to devices prepared from
`active agent release rates to devices prepared from
`these polymeric acids. Organic radicals represented by
`these polymeric acids. Organic radicals represented by
`R!, R2, . . . R* may be selected from hydrocarbon radi
`RI, R2, .. . Rh may be selected from hydrocarbon radi-
`cals and hetero-atom containing organic radicals. Suit
`cals and hetero-atom containing organic radicals. Suit-
`able hetero atoms for employment in R, R2, . . . R*
`able hetero atoms for employment in RI, R2, . . . Rn
`include oxygen, nitrogen, sulfur, and phosphorous as
`include oxygen, nitrogen, sulfur, and phosphorous as
`well as other hetero atoms so long as the required hy
`well as other hetero atoms so long as the required hy-
`drophobicity and carbon to carboxylic hydrogen aver
`drophobicity and carbon to carboxylic hydrogen aver-
`age ratio is maintained. The value of n and hence the
`age ratio is maintained. The value of n and hence the
`average molecular weight of the polymer is not critical
`average molecular weight of the polymer is not critical
`and may vary over a wide range. Suitable molecular
`and may vary over a wide range. Suitable molecular
`weights, for example, range from about 10,000 to about
`weights, for example, range from about 10,000 to about
`800,000. Materials within this range erode to products
`800,000. Materials within this range erode to products
`which may be easily and innocuously passed from the
`which may be easily and innocuously passed from the
`environment of use. Preferred molecular weights are
`environment of use. Preferred molecular weights are
`from about 15,000 to about 500,000.
`from about 15,000 to about 500,000.
`While not wishing to limit the scope of the poly(a
`While not wishing to limit the scope of the poly(a-
`cids) intended to be employed in accord with this inven
`cids) intended to be employed in accord with this inven-
`tion, and while alternative materials and preparative
`tion, and while alternative materials and preparative
`schemes are set forth in the description of suitable
`schemes are set forth in the description of suitable
`poly(acids) which follows, practically speaking, the
`poly(acids) which follows, practically speaking, the
`most common and widely applied method for introduc
`most common and widely applied method for introduc-
`ing a carboxylic acid function, as well as other hetero
`ing a carboxylic acid function, as well as other hetero
`atom functions, into a polymeric material of the type
`atom functions, into a polymeric material of the type
`employed in this invention, is to proceed through mon
`employed in this invention, is to proceed through mon-
`omers having a carbon skeleton of at least two carbon
`omers having a carbon skeleton of at least two carbon
`atoms. These monomers contain polymerizable olefinic
`atoms. These monomers contain polymerizable olefinic
`carbon-carbon double bonds. At least a portion of these
`carbon-carbon double bonds. At least a portion of these
`monomers will have appended thereto one or more
`monomers will have appended thereto one or more
`carboxyl radicals, or suitable precursors thereof and
`carboxyl radicals, or suitable precursors thereof and
`optionally also other hetero atom radicals. The polymer
`optionally also other hetero atom radicals. The polymer
`is formed by effecting addition of these monomers, one
`is formed by effecting addition of these monomers, one
`to another, across the polymerizable double bonds. This
`to another, across the polymerizable double bonds. This
`general method for forming poly(acids) is well known
`general method for forming poly(acids) is well known
`and does not comprise a part of the present invention.
`and does not comprise a part of the present invention.
`This preparative method may be generally represented
`This preparative method may be generally repres