CA1087345A - Orthoester polymers - Google Patents
Orthoester polymersInfo
- Publication number
- CA1087345A CA1087345A CA243,429A CA243429A CA1087345A CA 1087345 A CA1087345 A CA 1087345A CA 243429 A CA243429 A CA 243429A CA 1087345 A CA1087345 A CA 1087345A
- Authority
- CA
- Canada
- Prior art keywords
- carbon atoms
- polymer
- alkoxy
- alkyl
- mer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G4/00—Condensation polymers of aldehydes or ketones with polyalcohols; Addition polymers of heterocyclic oxygen compounds containing in the ring at least once the grouping —O—C—O—
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G67/00—Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S71/00—Chemistry: fertilizers
- Y10S71/904—Carrier
Abstract
ABSTRACT
The invention concerns orthoester and orthocarbonate polymers comprising a repeating mer of the general formula:
wherein R1 is a multivalent radical derived from a polyol;
and the group
The invention concerns orthoester and orthocarbonate polymers comprising a repeating mer of the general formula:
wherein R1 is a multivalent radical derived from a polyol;
and the group
Description
~ ¦¦ Pn 5066 . i~87345 `
.-. . . .. , ., ".
1 . ~PECI~IC~TION . .
.-. . . .. , ., ".
1 . ~PECI~IC~TION . .
2 ` .
3 ~he reaction of orthoesters with glycols leading to non-polymeric and other diverse products is known to the -art in the references such as Ind. J. ~ppl. Chem., Vol. 28, 6 No. 2, pages 53 to 58, 1965 wherein Mehrota, et al obtained 7 monoethoxy-monoglycolate and triglycoxy-bisorthoformate 3 by reacting orthoformate with hexamethylene glycol in molar 9 ratios of one to one, and two to three. Similarly, Crank, et al in Aust. J. Chem., vol. 17, pages 1392 to 1394, 1964, disclose the reaction of triols with orthoesters including 12 ethyl orthoformate with butane-1,2,4-triol, pentane-1,2,5-t3 triol and pentane-1,3,5-~riol to form monomeric bicyclic 14 compounds. During the preparation of the bicyclic ortho-esters by reacting ethyl orthoformate wi~h triols, Crank, 16 et al found that compounds produced from starting materials 17 having a 1,2-diol structure also contained compounds having ~8 ethylene linkages. In a subsequent ~aper, Crank, et al, 19 Aust. J. Chem., Vol. 17, pages 1934 to 19~8, 1964, developed this reaction into a synthetic procedure for the conversion 21 of 1,2-diols into olefins. Later, DeWolfe in Carboxylic 22 Ortho Acid Derivatives, 1970, published by Academic Press, 23 Inc., New York, noted that carboxylic orthoesters are 24 more reactive toward acid hydrolysis than almost any other class of compounds, and this high hydrolytic reactivity 26 complicates their synthesis and storage. DeWolf, supra, reported that the conversion of diols to cyclic orthoesters ~,. 2g . ' . , : , 1087~5 P~ 506G
I including alkoxydioxolane or alkoxydioxane, followed .. by acid hydrolysis, provides a method for monoacy].ating : 3 diols. More recently, Bailey reported in Polym. Prepr.
Amer. Chem. Soc. Dlv. Polym. Chem., vol. 13, No. i, .
S pages 281 to 286, 1972, that the polymerization of spiro : . 6 orthoesters at ambient and elevated temperatures led 7 to polye~ters and-polycarbbnates having the repeating 8 units ~-CH 2CH2CH2COOC~12CH2 O-] and t-O,CH;!OCOOCH2CH2CH 2-];
9 The invention provides a polymer comprising a repeating mer the general formula '' 11 ........... ... '.. ~ .
2 I ~ ~
characterized in that: Rl is polyvalent and is alkylene 16 of 2 to 10 carbon atoms; alkenylene of 2 to 10 carbon 17 atoms; oxaalkylene of 2 to 6 carbon atoms and 1 or 2 internal oxa groups; cycloalkylene of 3 to 7 annular .
I9 carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl 21 of 2 to 7 carbon atoms; cycloalkenylene of 4 to 7 annular ' 22 carbon atoms optionally substituted with alkyl of 1 to ..
23 7 carbon atoms, alkoxy of 1 of 7 carbon atoms, or alkenyl 24 of 2 to 7 carbon atoms; cycloalkanedi-aliphatic hydrocar- .
bylene of 3 to 7 annular carbon atoms wherein the hydro-26 carbylene groups are of 1 to 7 carbon atoms and the ring 27 is optionally substituted with alkyl of 1 to 7 carbon 29 . ~ . .
-3- . -. .
:~ 32 .
, .
1~87345 atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms;
cycloalkenedi-aliphatic hydrocarbylene of 4 to 7 annular carbon atoms where-in the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; phenylene optionally sub- -stituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, i or alkenyl of 2 to 7 carbon atoms; or phenyldi-aliphatic hydrocarbylene -~
wherein the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; R2 and R3 when taken independently are alkyl of 1 to 7 carbon atoms; alkenyl of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms; alkenyloxy of 2 to 7 carbon atoms; or monocyclic aryloxy of 6 to 12 carbon atoms; or -ORlO-, with the proviso that at least one of R2 and R3 is said alkoxy, alkenyloxy, aryloxy, or -ORlO-;
R2 and R3 when taken together with the dioxycarbon atom of the polymer backbone forms a heteromonocyclic group of 5 to 8 annular members with 1 or 2 - oxygen heteroatom linkages to the dioxycarbon atom of the polymer backbone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; or a fused heteropolycyclic group of 7 to 12 annular members with 1 or 2 oxygen heteroatom linkages to the dioxycarbon atom of the polymer backbone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 `, carbon atoms, . ., , , ~
~ ~ , . ,
I including alkoxydioxolane or alkoxydioxane, followed .. by acid hydrolysis, provides a method for monoacy].ating : 3 diols. More recently, Bailey reported in Polym. Prepr.
Amer. Chem. Soc. Dlv. Polym. Chem., vol. 13, No. i, .
S pages 281 to 286, 1972, that the polymerization of spiro : . 6 orthoesters at ambient and elevated temperatures led 7 to polye~ters and-polycarbbnates having the repeating 8 units ~-CH 2CH2CH2COOC~12CH2 O-] and t-O,CH;!OCOOCH2CH2CH 2-];
9 The invention provides a polymer comprising a repeating mer the general formula '' 11 ........... ... '.. ~ .
2 I ~ ~
characterized in that: Rl is polyvalent and is alkylene 16 of 2 to 10 carbon atoms; alkenylene of 2 to 10 carbon 17 atoms; oxaalkylene of 2 to 6 carbon atoms and 1 or 2 internal oxa groups; cycloalkylene of 3 to 7 annular .
I9 carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl 21 of 2 to 7 carbon atoms; cycloalkenylene of 4 to 7 annular ' 22 carbon atoms optionally substituted with alkyl of 1 to ..
23 7 carbon atoms, alkoxy of 1 of 7 carbon atoms, or alkenyl 24 of 2 to 7 carbon atoms; cycloalkanedi-aliphatic hydrocar- .
bylene of 3 to 7 annular carbon atoms wherein the hydro-26 carbylene groups are of 1 to 7 carbon atoms and the ring 27 is optionally substituted with alkyl of 1 to 7 carbon 29 . ~ . .
-3- . -. .
:~ 32 .
, .
1~87345 atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms;
cycloalkenedi-aliphatic hydrocarbylene of 4 to 7 annular carbon atoms where-in the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; phenylene optionally sub- -stituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, i or alkenyl of 2 to 7 carbon atoms; or phenyldi-aliphatic hydrocarbylene -~
wherein the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; R2 and R3 when taken independently are alkyl of 1 to 7 carbon atoms; alkenyl of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms; alkenyloxy of 2 to 7 carbon atoms; or monocyclic aryloxy of 6 to 12 carbon atoms; or -ORlO-, with the proviso that at least one of R2 and R3 is said alkoxy, alkenyloxy, aryloxy, or -ORlO-;
R2 and R3 when taken together with the dioxycarbon atom of the polymer backbone forms a heteromonocyclic group of 5 to 8 annular members with 1 or 2 - oxygen heteroatom linkages to the dioxycarbon atom of the polymer backbone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; or a fused heteropolycyclic group of 7 to 12 annular members with 1 or 2 oxygen heteroatom linkages to the dioxycarbon atom of the polymer backbone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 `, carbon atoms, . ., , , ~
~ ~ , . ,
-4-' Pm 5066 .
~ . ~087345 `
., . ,- . .
.. or alkenyl of 2 to 7 carbon atoms; and n is an integer .
2 and is at least 10.
. 3 The invention also provldes a process for making 4 the above described polymers characterized by reacting at least a stoichiometric amount of a polyol of the 6 formula ~10-Rl-08 wherein Rl is as defined above (when the valency of Rl is greater than two the polyol has 8 additional reactive hydroxyl groups that are removed in~
. the process to provide additional valencies that serve as cross-linking sites) with a compound of the formula '' 1'1 . . . - : . ' 12 ~ "
lS wherein R 2 and R 3 are as defined above and R~ is alkyl of 1 to 7 carbon atoms in the presence of a transesterifica-17 tion catalyst and optionally in the presence of an inert 18 solvent.
;:, 19 The invention also provides an active agent dis-. 20 penser comprising an active agent confined within a ' .
: 21 bioerodible polymer that bioerodes in the environment ~' 22 of use of the dispenser to release the active agent ; 23 characterized in that the bioerodible polymer is the :~ 24 above described polymer. .
The polymers provided by the invention include homo-; 26 polymers, copolymers of the random and block types formed 28 ~ by react monomers or mixtares of preformed homopolymers
~ . ~087345 `
., . ,- . .
.. or alkenyl of 2 to 7 carbon atoms; and n is an integer .
2 and is at least 10.
. 3 The invention also provldes a process for making 4 the above described polymers characterized by reacting at least a stoichiometric amount of a polyol of the 6 formula ~10-Rl-08 wherein Rl is as defined above (when the valency of Rl is greater than two the polyol has 8 additional reactive hydroxyl groups that are removed in~
. the process to provide additional valencies that serve as cross-linking sites) with a compound of the formula '' 1'1 . . . - : . ' 12 ~ "
lS wherein R 2 and R 3 are as defined above and R~ is alkyl of 1 to 7 carbon atoms in the presence of a transesterifica-17 tion catalyst and optionally in the presence of an inert 18 solvent.
;:, 19 The invention also provides an active agent dis-. 20 penser comprising an active agent confined within a ' .
: 21 bioerodible polymer that bioerodes in the environment ~' 22 of use of the dispenser to release the active agent ; 23 characterized in that the bioerodible polymer is the :~ 24 above described polymer. .
The polymers provided by the invention include homo-; 26 polymers, copolymers of the random and block types formed 28 ~ by react monomers or mixtares of preformed homopolymers
-5- .
"
~ ¦¦ Pm 5066 10~37345 .. . . , . , .. .,.
,, 1 and/or copolymers, branched polymers and cross-linked 2 polymers (when R~ is polyvalent to an extent greater than 3 divalency or R 2 or R 3 iS a cross-linking group). The 4 invention also makes available to the art thermoplastic S linear polymers when R~ is divalent! R2 and R3 are
"
~ ¦¦ Pm 5066 10~37345 .. . . , . , .. .,.
,, 1 and/or copolymers, branched polymers and cross-linked 2 polymers (when R~ is polyvalent to an extent greater than 3 divalency or R 2 or R 3 iS a cross-linking group). The 4 invention also makes available to the art thermoplastic S linear polymers when R~ is divalent! R2 and R3 are
6 noncross-linking groups or are bonded together; thermo-
7 setting cross-linked polymers when Rl is div-alent and R2 or R 3 iS a cross-linking gr;oup; and, thermosetting 9 cross-linked polymers when R, is polyvalent to an extent greater than divalency and R2 and R 3 are noncross-11 linking gro~ps, or are bonded together.
12 Preferred polymers are homo-, co- and terpolymers 13 wherein Rl is divalen~t and is cycloalkanedialkylene of 14 4 to 6 annular carbon atoms wherein the alkylene groups are of 1 to 4 carbon atoms; said alkylene; or said 16 oxaalkylene; and R2 and R3 are taken together with the 17 dioxycarbon atom of the polymer backbone to form a 18 heteromonocyclic ring of 5 to 6 members with one oxygen heteroatom link to the dioxycarbon atom o~ the polymer backbone and the remaining members of the ring being 21 carbon atoms. Preferably n is an integer from 10 to 22 1000. .
The term alkylene used in this specification for R~
24 denotes straight or branched chain divalent, trivalent or tetravalent radicals such as 1,2-ethylene; 1,2-26 propylene; 1,7-heptylene; 2,3,5-trimethyl-1,7-heptylene;
27 and l,10-decylene. The term alkenylene used for Rl denotes 29 . .
-6- . -. .
32 . . .
~ . 1087~45 Pm 5066 I unsaturated straight or branched chain multivalent radicals such as vinylene; 2,5-dimethyl-1,8-oct-3-enylene; and 1,10-dec-3-enylene. The term cycloalkylene as used for Rl in-cludes monocyclic radicals such as cyclopropylene and cyclo-heptylene. Exemplary cycloalkenylenes represented by R
6 are 1,3-cyclobut-2-enylene and 1,6-cyclohept-2-enylene.
Exemplary phenylene, phenyldialkylene and phenyldialkenylene
12 Preferred polymers are homo-, co- and terpolymers 13 wherein Rl is divalen~t and is cycloalkanedialkylene of 14 4 to 6 annular carbon atoms wherein the alkylene groups are of 1 to 4 carbon atoms; said alkylene; or said 16 oxaalkylene; and R2 and R3 are taken together with the 17 dioxycarbon atom of the polymer backbone to form a 18 heteromonocyclic ring of 5 to 6 members with one oxygen heteroatom link to the dioxycarbon atom o~ the polymer backbone and the remaining members of the ring being 21 carbon atoms. Preferably n is an integer from 10 to 22 1000. .
The term alkylene used in this specification for R~
24 denotes straight or branched chain divalent, trivalent or tetravalent radicals such as 1,2-ethylene; 1,2-26 propylene; 1,7-heptylene; 2,3,5-trimethyl-1,7-heptylene;
27 and l,10-decylene. The term alkenylene used for Rl denotes 29 . .
-6- . -. .
32 . . .
~ . 1087~45 Pm 5066 I unsaturated straight or branched chain multivalent radicals such as vinylene; 2,5-dimethyl-1,8-oct-3-enylene; and 1,10-dec-3-enylene. The term cycloalkylene as used for Rl in-cludes monocyclic radicals such as cyclopropylene and cyclo-heptylene. Exemplary cycloalkenylenes represented by R
6 are 1,3-cyclobut-2-enylene and 1,6-cyclohept-2-enylene.
Exemplary phenylene, phenyldialkylene and phenyldialkenylene
8 groups represented by R~ are 1~4-phenylene; 1,4-phenyldi-
9 methylene; 1,4-phenyldiheptylene; 1,4-phenyldivinylene; and i,4-phenyldihept-3-enylene. Exemplary cycloalkanedialkylene, l cycloalkanedialkenylene, cycloalkenedialkylene, and cyclo-12 alkenedlalkenylene radicals represented by R~ are cyclo-13 propanedimethylene; 1,4-cycloheptanediheptylene, cyclopro- .
14 panedivinylene; 1,5-cycloheptanedihept-4-enylene; 1,3-cyclobut-2-enedimethylene; 1,3-cyclohept-5-enediheptylene;
16 1,3-cyclobut-2-enedivinylene; and 1,4-cyclohept-6-17 enedihept-4-enylene. Oxaalkylene radicals represented 18 by Rl are exemplified by oxaethylene; 3-oxahexylene; and 9 2,4-dioxahexylene.
The t/erm alkyl appearing herein for R2 and R3, and 21 as an optional substituent(s) on various Rl radicals and 22 heteromonocyclic and fused heteropolycyclic groups 23 represented by the combination of R2, R3, and the dioxy-24 carbon atom of the polymer backbone, embraces straight .
and branched chain radicals such as methyl; n-heptyl;
26 isopropyl; and t-heptyl. Exemplary alkenyls as used for 27 R2 and R3, and as an optional substituent(s) on various 2~ . . .
29 . . .
-7- .
32 ~ .
¦~ Pm 50~6 ~)87345 .-Rl groups and heteromonocyclic and fused heteropolycyclicgroups represented by the combination of R2, R3, and the dioxycarbon atom of the polymer backbone, include 4 the straight and branched chain groups such as vinyl;
5 2-propenyl; l-heptenyl; and 3-methyl-4-hexenyl. The 6 term alkoxy as used for R2 and R3,-and as an optional 7 substituent(s) on various R~ groups and heteromonocyclic 8 and fused heteropolycyclic groups represented by the combination of R2, R3, and the dioxycarbon atom of the : polymer backbone, include the straight and branched chain 11 ~roups such as methoxy; n-heptoxy; isopropoxy; and 2-l2 methylhexoxy. The term alkenyloxy as used for R~ and 13 R3 embraces the straight and branched chain groups such 14 as isopropenoxy; hept-3-enoxy; and 2,3-dimethyl-hept-5-IS enoxy. Examples of monocyclicaryloxy radicals represented by R2 and R3 are phenoxy; p-tolyloxy; xylyloxy; p-hexyl-17 phenoxy; benzyloxy; and phenylhexoxy. Heteromonocyclic I8 rings represented by the combination of R2, R3 and the 19 dioxycarbon atom of the polymer backbone are exemplified - 20 by furyl and its hydro derivatives; dioxolanyl; oxocinyl 21 and its hydro derivatives; and dioxocinyl and its hydro r 2a derivat-ives. Fused heteropolycyclic rings represented by 23 the combination of R2, R3 and the dioxycarbon atom of the 24 polymer backbone are those in which a heterocyclic and an aryl ring have two atoms in common, for example, 26 benzfuryl and its hydro derivatives; 4,5-benz-1,3-. 27 dioxolanyl; 4,5-benz-1,3-dioxocinyl and its position ,' ~ m 5066 . ' 1087345 . . ' ' isomers and hydro derivatives thereof; and ~,5-benz-2 oxacinyl and its position~isomers and hydro derivatives.
3 Alkyl groups represented by R 6 may be straight or branched chain and are exemplified by methyl; isopropyl;
butyl; heptyl; and 3-methylhexyl. Preferably R 6 represents 6 an alkyl of l to 4 carbon atoms, i.e., methyl-butyl. The 7 individual groups represented by R6 may be the same or 8 different.
9 The term mer as used herein denotes the member unit or the monomeric unit of- the polymeE. For example, in -11 a homopolymer, the mer units are the same. In a copolymer, 12 the mer units are different and can be ordered in the 13 polymer chain in a random fashion when the original units 14 are copolymerized in a common reaction vessel, or they can be ordered in block fashion when the polymers are 16 formed after an initial homopolymerization of each o~
17 the different monomeric units. A terpolymer is a copoly-18 mer of three diffe~ent mers.
- As indicated above, the novel polymers of the invention can be synthesized by reacting a polyol 21 monomer with an ester or carbonate monomer. The 22 polymerization reaction is carried out by reacting 23 stoichiometric amounts of the monomers or an excess of 24 polyol, that is, about l to lO moles of polyol to l mole of ester or carbonate monomer.
26 The polymerization of the monomers may be carried 27 out in a reaction vessel equipped with a stirrer and 29 .
331 _9-¦ ' ~m 5066 I vacuum attachment with continuous mixing of the monomers in the presence of a transesterification catalyst. The 3 polymerization comprises an initial transesterification reaction followed by a polycondensation reaction with the complete polymerization performed at a temperature of 6 60C to 220C and over a reaction time of 1 hour to 96 7 hours. The transesterification step of the reaction con-8 sists of mixing the monomers and catalyst, and while 9 continuously stirring the mixture, gradually raising the temperature to 180C. The transesterification reaction ll for most monomers, occurs at i50C to 180C over a 1 to ~ ¦ 12 hour reaction period and at normal atmospheric pressure 13 ¦ with continuous distillation of the alcohol. The poly-14 ¦ condensation reaction is commenced by reducing the pressure ~s ¦ to 0.10 to 0.0001 mm of mercury and, while maintaining 16 I the elevated temperature and reduced pressure, continuously 17 ¦ mixing the reactants for 12 to 96 hours.
18 ¦ The polymer may be recovered under anhydrous condi-~9 I tions from the reaction vessel by conventional isolation 20 ¦ and recovery techniques. For example, the polymer may 21 I be recovered while hot by extruding or pouring, or the 22 ¦ polymer may be isolated after cooling, by dissolving it 23 ¦ in a dry organic solvent such as benzene, carbon tetra-24 I chloride, methylene chloride, dioxane, toluene, or xylene, 25 ¦ followed by the addition of an organic liquid in which 26 ¦ the polymer is insoluble or has limited solubility to 28 ! precipita the polymer. Orqanic liquids for thls 33l ` -10-'32 ~ lo~7345 P. 5066 1 latter purpose include ether, hexane, pentane, petrolcum 2 ether, and hexane-heptane mixtures. The polymer is 3 isolated by filtering and drying under anhydrous condi-4 tions. Other methods for recovering the polymer include lyophilizing from a solvent.
6 Representative transesterification catalysts for 7 performing the polymerization reaction are Lewis acids .
8 such as boron trifluoride, boron trichloride, boron 9 trichloride etherate, boron trifluoride etherate, stannic oxychloride, phosphorous oxychloride, zinc chloride, 11 phosphorous. pentachlorid.e, calcium acetate, antimonous 12 oxide mixture, antimony pentachloride, antimony penta-13 fluoride, stannous octoate, stannic chloride, diethyl zinc, 14 n-butyl lithium, and mixtures thereof; Bronsted catalysts such as p-toluene sulfonic acid, polyphosphoric acid, cross-16 linked polystyrene sulfonic acid, acidic silica gel, and 17 mixtùres thereof; organotitanates such as tetrabutyl tita-18 nate, and titanium sodium hydrogen hexabutoxide; oxides, 19 carbonates and acetates of zinc, calcium, lead, magnesium, manganese, and cobalt; alkanoates, hydrides and alkoxides 21 of sodium, lithium, zinc, calcium, magnesium and aluminum;
22 antimony trioxide; complex alkoxide, and organomagnesium 23 halides. The preferred amount of catalyst used is about 24 one part catalyst to about 500 parts of the ester or car-2S bonate monomer. Smaller or larger amounts can also be used, 26 such as 0.005% to about 2.0~ based on the weight of the 27 ester or carbonate monomer.
29 . .
31 ~ .
'32 , - ~45 Pm 5066 1 The polymerization optionally can be carried out in the presence of an added inert organic solvent that does not ad-versely affect the reaction. When no added solvent is used one of the reactants, for example, the polyol initially serves as a solvent. As the polymerization proceeds, solvent 6 by-product is removed from the reaction ~y conventional dis-7 tillation, azeotropic distillation, or by distillation under 8 vacuum. Suitable azeotropic solvents include toluene, ben-zene, m-xylene, cumene, pyridine, and n-heptane.
tO The following examples are illustrative of the invention 11 polymers and their synthesis. These examples are not to limit ~2 the scope of the invention in any manner.
To 45 grams (0.312 moles~ of anhydrous trans-1,4-16 cyclohexane dicarbinol and 0.05 grams of polyphosphoric 17 acid in a commercialiy available polymerization reactor i8 was added with constant stirring under an inert nitrogen 19 environment and normal atmospheric pressure 50 grams (0.312 moles) of anhydrous 2,2-diethoxytetrahydrofuran. Next, 21 the mixture was heated to 110-115C and held at thi$
22 temperature for. 1-1/2 to 2 hours, with slow distillation 23 of any liquid formed. Then, while maintaining the 24 temperature, the pressure was gradually reduced to 0.01 mm of mercury and at this reduced pressure the temperature 26 was slowly increased to 1~0C. The reaction was continued 27 at this temperature for 24 hours. The polymer was isolated ~9 . , '. , -12- .
1~ ~ .P-5r)(i6 10873~S
1 by extruding it from the reactor. The polymer had the 2 following structure, where n is the degree of polymeriza-tion and n is from 10 to 1000.
. 4 . ' S ., .............. .... ' 6 ~ ~2~>-1l2~-8 n ''' 9 .~, , 10 ' .'' ,~` :. ... ' , 11 . , . -:~ 13 .
. 1~ . ..
17 Following the procedure of Example 1, but replacing ~ 18 trans-1,4-cyclohexane dicarbinol and 2,2-diethoxytetra-: 19 hydrofuran with: .
trans-2-methyl-1,4-cyclohexane diethanol and 2,2-21 dimethoxytetrahydrofuran;
22 trans-2-methyl-1,4-cyclohexane dipropanol and 23 2,2-dibutoxytetrahydrofuran; and, 24 trans-2-ethyl-1,4-cyclohexane dicarbinol and 2,2-2S diethoxy-5-methyl-3,4-dihydrofuran; the following 26 polymers are formed:
28 .. .
31 -13- .
32 .
1087~5 Pm 5066 ¦¦ ~CBz}~Q--(C~lz~ l ,., . ,.
: S `. , , ' , . .
6 ~ Z~c~12~ l ' ' ,. .' . , . .,' I2 ~ ~ H j~~5z-J
13 . .. ..... ... ;~ ~ ... .
) IS wherein n is from lO to 1000, :
; l6 . EXAMPLE 5 .
17 Repeating the procedure of Example 1, but replacing 2,2-18 diethoxytetrahydrofuran with a 2,2-di-alkoxytetrahydrofuran 19 selected from the group of 2,2-dimethoxytetrahydrofuxan; 2,2-dipropoxytetrahydrofuran; and 2,2-dibutoxytetrahydrofuran; and ~ 21 the dicarbinol with 1,6-hexanediol the corresponding polymer 23 ¦~ of the fo wing formala is obtain-d (n i5 10-1000).
26 .
28 .
29 . .
31 -14- . .
32 .
.- . .
1087345 pm 506G
''~................... . ' ' '~ ", `i 1 EXAMPLE 6 To 45 grams ~0.312 moles) of dry cis-trans-1,4-4 cyclohe~ane dicarbinol and 0.05 grams of p-toluene S sulfonic acid was added with constant agitation, 50.5 6 grams (0.312 moles) of 2,2-dimethoxy-5-methyl-1,3-7 dioxolane and the polymerization reaction of Example 1 8 was repeated to yield the polym;er shown below (n is
14 panedivinylene; 1,5-cycloheptanedihept-4-enylene; 1,3-cyclobut-2-enedimethylene; 1,3-cyclohept-5-enediheptylene;
16 1,3-cyclobut-2-enedivinylene; and 1,4-cyclohept-6-17 enedihept-4-enylene. Oxaalkylene radicals represented 18 by Rl are exemplified by oxaethylene; 3-oxahexylene; and 9 2,4-dioxahexylene.
The t/erm alkyl appearing herein for R2 and R3, and 21 as an optional substituent(s) on various Rl radicals and 22 heteromonocyclic and fused heteropolycyclic groups 23 represented by the combination of R2, R3, and the dioxy-24 carbon atom of the polymer backbone, embraces straight .
and branched chain radicals such as methyl; n-heptyl;
26 isopropyl; and t-heptyl. Exemplary alkenyls as used for 27 R2 and R3, and as an optional substituent(s) on various 2~ . . .
29 . . .
-7- .
32 ~ .
¦~ Pm 50~6 ~)87345 .-Rl groups and heteromonocyclic and fused heteropolycyclicgroups represented by the combination of R2, R3, and the dioxycarbon atom of the polymer backbone, include 4 the straight and branched chain groups such as vinyl;
5 2-propenyl; l-heptenyl; and 3-methyl-4-hexenyl. The 6 term alkoxy as used for R2 and R3,-and as an optional 7 substituent(s) on various R~ groups and heteromonocyclic 8 and fused heteropolycyclic groups represented by the combination of R2, R3, and the dioxycarbon atom of the : polymer backbone, include the straight and branched chain 11 ~roups such as methoxy; n-heptoxy; isopropoxy; and 2-l2 methylhexoxy. The term alkenyloxy as used for R~ and 13 R3 embraces the straight and branched chain groups such 14 as isopropenoxy; hept-3-enoxy; and 2,3-dimethyl-hept-5-IS enoxy. Examples of monocyclicaryloxy radicals represented by R2 and R3 are phenoxy; p-tolyloxy; xylyloxy; p-hexyl-17 phenoxy; benzyloxy; and phenylhexoxy. Heteromonocyclic I8 rings represented by the combination of R2, R3 and the 19 dioxycarbon atom of the polymer backbone are exemplified - 20 by furyl and its hydro derivatives; dioxolanyl; oxocinyl 21 and its hydro derivatives; and dioxocinyl and its hydro r 2a derivat-ives. Fused heteropolycyclic rings represented by 23 the combination of R2, R3 and the dioxycarbon atom of the 24 polymer backbone are those in which a heterocyclic and an aryl ring have two atoms in common, for example, 26 benzfuryl and its hydro derivatives; 4,5-benz-1,3-. 27 dioxolanyl; 4,5-benz-1,3-dioxocinyl and its position ,' ~ m 5066 . ' 1087345 . . ' ' isomers and hydro derivatives thereof; and ~,5-benz-2 oxacinyl and its position~isomers and hydro derivatives.
3 Alkyl groups represented by R 6 may be straight or branched chain and are exemplified by methyl; isopropyl;
butyl; heptyl; and 3-methylhexyl. Preferably R 6 represents 6 an alkyl of l to 4 carbon atoms, i.e., methyl-butyl. The 7 individual groups represented by R6 may be the same or 8 different.
9 The term mer as used herein denotes the member unit or the monomeric unit of- the polymeE. For example, in -11 a homopolymer, the mer units are the same. In a copolymer, 12 the mer units are different and can be ordered in the 13 polymer chain in a random fashion when the original units 14 are copolymerized in a common reaction vessel, or they can be ordered in block fashion when the polymers are 16 formed after an initial homopolymerization of each o~
17 the different monomeric units. A terpolymer is a copoly-18 mer of three diffe~ent mers.
- As indicated above, the novel polymers of the invention can be synthesized by reacting a polyol 21 monomer with an ester or carbonate monomer. The 22 polymerization reaction is carried out by reacting 23 stoichiometric amounts of the monomers or an excess of 24 polyol, that is, about l to lO moles of polyol to l mole of ester or carbonate monomer.
26 The polymerization of the monomers may be carried 27 out in a reaction vessel equipped with a stirrer and 29 .
331 _9-¦ ' ~m 5066 I vacuum attachment with continuous mixing of the monomers in the presence of a transesterification catalyst. The 3 polymerization comprises an initial transesterification reaction followed by a polycondensation reaction with the complete polymerization performed at a temperature of 6 60C to 220C and over a reaction time of 1 hour to 96 7 hours. The transesterification step of the reaction con-8 sists of mixing the monomers and catalyst, and while 9 continuously stirring the mixture, gradually raising the temperature to 180C. The transesterification reaction ll for most monomers, occurs at i50C to 180C over a 1 to ~ ¦ 12 hour reaction period and at normal atmospheric pressure 13 ¦ with continuous distillation of the alcohol. The poly-14 ¦ condensation reaction is commenced by reducing the pressure ~s ¦ to 0.10 to 0.0001 mm of mercury and, while maintaining 16 I the elevated temperature and reduced pressure, continuously 17 ¦ mixing the reactants for 12 to 96 hours.
18 ¦ The polymer may be recovered under anhydrous condi-~9 I tions from the reaction vessel by conventional isolation 20 ¦ and recovery techniques. For example, the polymer may 21 I be recovered while hot by extruding or pouring, or the 22 ¦ polymer may be isolated after cooling, by dissolving it 23 ¦ in a dry organic solvent such as benzene, carbon tetra-24 I chloride, methylene chloride, dioxane, toluene, or xylene, 25 ¦ followed by the addition of an organic liquid in which 26 ¦ the polymer is insoluble or has limited solubility to 28 ! precipita the polymer. Orqanic liquids for thls 33l ` -10-'32 ~ lo~7345 P. 5066 1 latter purpose include ether, hexane, pentane, petrolcum 2 ether, and hexane-heptane mixtures. The polymer is 3 isolated by filtering and drying under anhydrous condi-4 tions. Other methods for recovering the polymer include lyophilizing from a solvent.
6 Representative transesterification catalysts for 7 performing the polymerization reaction are Lewis acids .
8 such as boron trifluoride, boron trichloride, boron 9 trichloride etherate, boron trifluoride etherate, stannic oxychloride, phosphorous oxychloride, zinc chloride, 11 phosphorous. pentachlorid.e, calcium acetate, antimonous 12 oxide mixture, antimony pentachloride, antimony penta-13 fluoride, stannous octoate, stannic chloride, diethyl zinc, 14 n-butyl lithium, and mixtures thereof; Bronsted catalysts such as p-toluene sulfonic acid, polyphosphoric acid, cross-16 linked polystyrene sulfonic acid, acidic silica gel, and 17 mixtùres thereof; organotitanates such as tetrabutyl tita-18 nate, and titanium sodium hydrogen hexabutoxide; oxides, 19 carbonates and acetates of zinc, calcium, lead, magnesium, manganese, and cobalt; alkanoates, hydrides and alkoxides 21 of sodium, lithium, zinc, calcium, magnesium and aluminum;
22 antimony trioxide; complex alkoxide, and organomagnesium 23 halides. The preferred amount of catalyst used is about 24 one part catalyst to about 500 parts of the ester or car-2S bonate monomer. Smaller or larger amounts can also be used, 26 such as 0.005% to about 2.0~ based on the weight of the 27 ester or carbonate monomer.
29 . .
31 ~ .
'32 , - ~45 Pm 5066 1 The polymerization optionally can be carried out in the presence of an added inert organic solvent that does not ad-versely affect the reaction. When no added solvent is used one of the reactants, for example, the polyol initially serves as a solvent. As the polymerization proceeds, solvent 6 by-product is removed from the reaction ~y conventional dis-7 tillation, azeotropic distillation, or by distillation under 8 vacuum. Suitable azeotropic solvents include toluene, ben-zene, m-xylene, cumene, pyridine, and n-heptane.
tO The following examples are illustrative of the invention 11 polymers and their synthesis. These examples are not to limit ~2 the scope of the invention in any manner.
To 45 grams (0.312 moles~ of anhydrous trans-1,4-16 cyclohexane dicarbinol and 0.05 grams of polyphosphoric 17 acid in a commercialiy available polymerization reactor i8 was added with constant stirring under an inert nitrogen 19 environment and normal atmospheric pressure 50 grams (0.312 moles) of anhydrous 2,2-diethoxytetrahydrofuran. Next, 21 the mixture was heated to 110-115C and held at thi$
22 temperature for. 1-1/2 to 2 hours, with slow distillation 23 of any liquid formed. Then, while maintaining the 24 temperature, the pressure was gradually reduced to 0.01 mm of mercury and at this reduced pressure the temperature 26 was slowly increased to 1~0C. The reaction was continued 27 at this temperature for 24 hours. The polymer was isolated ~9 . , '. , -12- .
1~ ~ .P-5r)(i6 10873~S
1 by extruding it from the reactor. The polymer had the 2 following structure, where n is the degree of polymeriza-tion and n is from 10 to 1000.
. 4 . ' S ., .............. .... ' 6 ~ ~2~>-1l2~-8 n ''' 9 .~, , 10 ' .'' ,~` :. ... ' , 11 . , . -:~ 13 .
. 1~ . ..
17 Following the procedure of Example 1, but replacing ~ 18 trans-1,4-cyclohexane dicarbinol and 2,2-diethoxytetra-: 19 hydrofuran with: .
trans-2-methyl-1,4-cyclohexane diethanol and 2,2-21 dimethoxytetrahydrofuran;
22 trans-2-methyl-1,4-cyclohexane dipropanol and 23 2,2-dibutoxytetrahydrofuran; and, 24 trans-2-ethyl-1,4-cyclohexane dicarbinol and 2,2-2S diethoxy-5-methyl-3,4-dihydrofuran; the following 26 polymers are formed:
28 .. .
31 -13- .
32 .
1087~5 Pm 5066 ¦¦ ~CBz}~Q--(C~lz~ l ,., . ,.
: S `. , , ' , . .
6 ~ Z~c~12~ l ' ' ,. .' . , . .,' I2 ~ ~ H j~~5z-J
13 . .. ..... ... ;~ ~ ... .
) IS wherein n is from lO to 1000, :
; l6 . EXAMPLE 5 .
17 Repeating the procedure of Example 1, but replacing 2,2-18 diethoxytetrahydrofuran with a 2,2-di-alkoxytetrahydrofuran 19 selected from the group of 2,2-dimethoxytetrahydrofuxan; 2,2-dipropoxytetrahydrofuran; and 2,2-dibutoxytetrahydrofuran; and ~ 21 the dicarbinol with 1,6-hexanediol the corresponding polymer 23 ¦~ of the fo wing formala is obtain-d (n i5 10-1000).
26 .
28 .
29 . .
31 -14- . .
32 .
.- . .
1087345 pm 506G
''~................... . ' ' '~ ", `i 1 EXAMPLE 6 To 45 grams ~0.312 moles) of dry cis-trans-1,4-4 cyclohe~ane dicarbinol and 0.05 grams of p-toluene S sulfonic acid was added with constant agitation, 50.5 6 grams (0.312 moles) of 2,2-dimethoxy-5-methyl-1,3-7 dioxolane and the polymerization reaction of Example 1 8 was repeated to yield the polym;er shown below (n is
10 10-1000).
¦ ~ 2 ~ 2 13 ! - :
15 .'''- , . '' '- '' .
l6 EXAMPI.E 7 17 To 54.7 grams (0.312 mole) of l,10-decane diol 18 and 0.05 grams of polyphosphoric acid in a reactor 19 vessel under ,a nitrogen environment and at atmospheric pressure was added with constant stirring 50.0 grams 21 (0.312 mole) of 2,2-diethoxytetrahydrofuran. Next, 22 the mixture was heated to 110 to 115C and held at 23 this temperature for 1.5 to 2 hours as ethanol gently 24 distilled from the reactor. Then, while maintaining this temperature, the pressure was reduced to 0.01 mm 26 of mercury and at this reduced pressure the temperature 27 was raised to 180C. The polycondensation was continued '32 10~37345 Plll 5066 .
,.,. . ,' .j for 24 hours to yield the polymer with the structure 2 shown below and with a degree of polymerization of 10 3 to 1000. . .
; 6 ~ ~
7 . . n : 8 . ,. ` . . ;
,'',.' ~ 9 . .. , ' ~ .
IO . EXAMPLE 8 . Repeating the procedure of Example 7, but replacing : l2 l,10-decane diol and 2,2-diethoxytetrahydrofuran with 13 stoichiometric amounts of the monomers 1,4,7-heptanetriol 1~ and 2,2-diethoxy-1,3-dioxolane, the following polymer lS (n is 10 to 1000) is obtained.
l6 _ . ~ . ......... . ... ........
"I .~. ~(r~3r~(c~
21 . .
26 . ' .
28 ~.
29 .-3~ -16- .
32 . .
' ~087345 Pm St)6G
' . . .
., ., ,. '',.
1 , EXAMP~JE 9 .
2 To 7.38 grams (0.625 mole) of 1,6-hexane diol and 3 0.10 grams of polyphosphoric aeid was added 100.0 grams 4 (0.625 mole~ of 2,2-diethoxytetrahydrofuran and 81.0 gram S (0.562 mole) of trans-eyelohexane diearbinol, and the 6 polymerization earried out according to the procedure of 7 Example 1. The random copoiymer obtained had a molecular 8 weight, (Mw) of 11,500 and the following structure, 9 wherein n is 10 to 1000.
~ 10 ......... . . . ~ -1l ~ 2 ~ 2 ~ t 2 ~
14 ; .
~5 16 EXAMP~E 10 17 The procedure of Example 9 was repeated in this 18 example, and all conditions and reagents were as described 19 except that in this example, 1,7-heptane diol was used instead of 1,6-hexane diol. The random copolymer recovered 21 had the indicated structure, wherein n i-s 10 to 1000.
22 ' -224 ~ Z ~ --Cl~2 - ~ tCI12)7 27 .
29 . ' .
10~7345 Pm S066 : .' .'' .
: 1 ~ . EXAMPL~ 11 ~ 2 . . .
.. ^ 3To 66.3 grams (0.62S moles) of diethylene glycol .. and 0.1 gram of polyphosphoric acid in a stainless steel 5polymerization reactor was added 100 grams (0.62S moles) 6 of 2,2-diethoxytetrahydrofuran with constant stirring 7 under an argon backflow, and the reactants heated to 110-¦ 8115DC for 2 hours with distillatio.n of ethanol formed dur-. 9.ing the transesterification step. Then, while.holding the temperature constant, the pressure was reduced from atmos-
¦ ~ 2 ~ 2 13 ! - :
15 .'''- , . '' '- '' .
l6 EXAMPI.E 7 17 To 54.7 grams (0.312 mole) of l,10-decane diol 18 and 0.05 grams of polyphosphoric acid in a reactor 19 vessel under ,a nitrogen environment and at atmospheric pressure was added with constant stirring 50.0 grams 21 (0.312 mole) of 2,2-diethoxytetrahydrofuran. Next, 22 the mixture was heated to 110 to 115C and held at 23 this temperature for 1.5 to 2 hours as ethanol gently 24 distilled from the reactor. Then, while maintaining this temperature, the pressure was reduced to 0.01 mm 26 of mercury and at this reduced pressure the temperature 27 was raised to 180C. The polycondensation was continued '32 10~37345 Plll 5066 .
,.,. . ,' .j for 24 hours to yield the polymer with the structure 2 shown below and with a degree of polymerization of 10 3 to 1000. . .
; 6 ~ ~
7 . . n : 8 . ,. ` . . ;
,'',.' ~ 9 . .. , ' ~ .
IO . EXAMPLE 8 . Repeating the procedure of Example 7, but replacing : l2 l,10-decane diol and 2,2-diethoxytetrahydrofuran with 13 stoichiometric amounts of the monomers 1,4,7-heptanetriol 1~ and 2,2-diethoxy-1,3-dioxolane, the following polymer lS (n is 10 to 1000) is obtained.
l6 _ . ~ . ......... . ... ........
"I .~. ~(r~3r~(c~
21 . .
26 . ' .
28 ~.
29 .-3~ -16- .
32 . .
' ~087345 Pm St)6G
' . . .
., ., ,. '',.
1 , EXAMP~JE 9 .
2 To 7.38 grams (0.625 mole) of 1,6-hexane diol and 3 0.10 grams of polyphosphoric aeid was added 100.0 grams 4 (0.625 mole~ of 2,2-diethoxytetrahydrofuran and 81.0 gram S (0.562 mole) of trans-eyelohexane diearbinol, and the 6 polymerization earried out according to the procedure of 7 Example 1. The random copoiymer obtained had a molecular 8 weight, (Mw) of 11,500 and the following structure, 9 wherein n is 10 to 1000.
~ 10 ......... . . . ~ -1l ~ 2 ~ 2 ~ t 2 ~
14 ; .
~5 16 EXAMP~E 10 17 The procedure of Example 9 was repeated in this 18 example, and all conditions and reagents were as described 19 except that in this example, 1,7-heptane diol was used instead of 1,6-hexane diol. The random copolymer recovered 21 had the indicated structure, wherein n i-s 10 to 1000.
22 ' -224 ~ Z ~ --Cl~2 - ~ tCI12)7 27 .
29 . ' .
10~7345 Pm S066 : .' .'' .
: 1 ~ . EXAMPL~ 11 ~ 2 . . .
.. ^ 3To 66.3 grams (0.62S moles) of diethylene glycol .. and 0.1 gram of polyphosphoric acid in a stainless steel 5polymerization reactor was added 100 grams (0.62S moles) 6 of 2,2-diethoxytetrahydrofuran with constant stirring 7 under an argon backflow, and the reactants heated to 110-¦ 8115DC for 2 hours with distillatio.n of ethanol formed dur-. 9.ing the transesterification step. Then, while.holding the temperature constant, the pressure was reduced from atmos-
11 pheric to 0.01 mm Hg and held there with the temperature
12 slowly elevated to l~O~C. The polycondensation was allowed : 13. to proceed for 24 hours under these conditions to yield the 14polymer (n is 10-1000) shown below. .
6~ l~2cr2CII2C 2 . . j ~, ,,,.,. ................ ... _ ,:'' 19 . ' ' ' ' . .
. ~XAMPLES 12 - 16 21 The procedure of Example 11 was followed in these - 22 examples, with all the reaction conditions as described, 23 except the monomers of the previous example were replaced 24 with stoichiometric amounts of the following monomers:
a) 1,5-pentylene glycol and 2,2-dipropoxy-4-methyltetra-26 hydrofuran;
27 ll b) 2, imethyl-1,6-hexylene glycol and 2,2-dipropoxy--18- .
3 .
1 , . ., .,.. ~ .. .. .... .. . . .. .
0 W a 5 , P 5066 1 5-heptyltetrahydrofuran;
2 c) 3,6-dimethyl-1,9-nonylene glycol and 2,2-dipropoxy-5-ethoxy tetrahydrofuran;
4 d) 1,6-hexylene glycol and 2,2-diethoxy-3,4-dihydro-S furan; and 6 e) 1,6-hexylene glycol and 2,2-diethoxy-5-vinyl-3,4-7 dihydrofuran; to yield the following polymers (n is . 8 10-lOOO.in each instance): - - b) ~ C~ CII (CH 3 ) CH ( C~13 ) ( C ~2 14 ¦ ~2 2 ) 2 (C~13 ) ( ~H2 ) 2CH ~ CH3 ) ( CH
6 ~ 3 ~CH2 18 n S andH=CH2 n . .. .. .... . .... , ,, _ ,,,, .. , .. _ 19 ~ EXAMPLES 17 - 19 20 The procedure employed in Example 11 was followed 21 in these examples with all the reaction conditions as ' 22 previously described. The starting monomers listed 23 below were used in equivalent amounts for those of 24 Example 11.
25 2~2~4~4-tetramethylcyclobutane-l~3-diol and 26 2,2-diethoxytetrahydrofuran;
: .. 27 28 . .
2g 32 . .
. . ,.
10g7345 - Pm SOG6 ., , . .
' ' .'-1 triethylene glycol and 2,2-diethoxy-5,5-dimethyl-2 tetrahydrofuran;
3 triethylene glycol and 2,2-diethoxy-4-methoxy-4 tetrahydrofuran. The following polymers result, - wherein y is 3 and n is 10 to 1000.
'1~ , ~' .
6~ l~2cr2CII2C 2 . . j ~, ,,,.,. ................ ... _ ,:'' 19 . ' ' ' ' . .
. ~XAMPLES 12 - 16 21 The procedure of Example 11 was followed in these - 22 examples, with all the reaction conditions as described, 23 except the monomers of the previous example were replaced 24 with stoichiometric amounts of the following monomers:
a) 1,5-pentylene glycol and 2,2-dipropoxy-4-methyltetra-26 hydrofuran;
27 ll b) 2, imethyl-1,6-hexylene glycol and 2,2-dipropoxy--18- .
3 .
1 , . ., .,.. ~ .. .. .... .. . . .. .
0 W a 5 , P 5066 1 5-heptyltetrahydrofuran;
2 c) 3,6-dimethyl-1,9-nonylene glycol and 2,2-dipropoxy-5-ethoxy tetrahydrofuran;
4 d) 1,6-hexylene glycol and 2,2-diethoxy-3,4-dihydro-S furan; and 6 e) 1,6-hexylene glycol and 2,2-diethoxy-5-vinyl-3,4-7 dihydrofuran; to yield the following polymers (n is . 8 10-lOOO.in each instance): - - b) ~ C~ CII (CH 3 ) CH ( C~13 ) ( C ~2 14 ¦ ~2 2 ) 2 (C~13 ) ( ~H2 ) 2CH ~ CH3 ) ( CH
6 ~ 3 ~CH2 18 n S andH=CH2 n . .. .. .... . .... , ,, _ ,,,, .. , .. _ 19 ~ EXAMPLES 17 - 19 20 The procedure employed in Example 11 was followed 21 in these examples with all the reaction conditions as ' 22 previously described. The starting monomers listed 23 below were used in equivalent amounts for those of 24 Example 11.
25 2~2~4~4-tetramethylcyclobutane-l~3-diol and 26 2,2-diethoxytetrahydrofuran;
: .. 27 28 . .
2g 32 . .
. . ,.
10g7345 - Pm SOG6 ., , . .
' ' .'-1 triethylene glycol and 2,2-diethoxy-5,5-dimethyl-2 tetrahydrofuran;
3 triethylene glycol and 2,2-diethoxy-4-methoxy-4 tetrahydrofuran. The following polymers result, - wherein y is 3 and n is 10 to 1000.
'1~ , ~' .
13~ ~ ~ 3)~ ]~ ~ wnd
14 ~ ~ ~ cU~
I8 To a mixture of polyol monomers consisting of l9 41.58 grams (0.284 moles) of trans-cyclohexane dicarbinol;
7.53 grams (0.071 moles) of the oxyalkylene glycol;
21 diethylene glycol and 0.057 grams of polyphosphoric acid 22 was added 56.7 grams (0.355 moles) of diethoxytetrahydro-23 furan under the inert gas argon and the mixture heated 24 to 115C for 2 hours with continuous distillation of the liquid organic by-product. Then, while keeping 26 the temperature constant, the pressure was reduced to 27 0.01 mm of Hg and at this reduced pressure the tempera-29 .
'32 ~ 10~7345 .................... s06~
1 ture was raised to 180C. The reaction was continued at this temperature and vacuum for 24 hours. The 3 random copolymer was isolated by extruding it from the 4 reactor and it had the following configuration where n is 10 to 1000.
. ..... ~ ,. , .,...................... r~ ..
: ~ t ~112CH20CU2CH2~ ~1 ~ J
1l .;
~3 The procedure used for preparing the copolymer in 16 Example 20 was repeated in this polymerization; all 17 conditions were as described. The monomerS used in this example were 2,2-diethoxytetrahydrofuran, 1,6-hexanediol 19 and a mixture of cis-trans-1,4-cyclohexane dicarbinol.
The structure of the copolymer (n is 10-1000) obtained is as follows:
23 ~ 2 ~ --n , ` ~m 50G6 n87345 . ' ',' I EX~MPLE 22 2 To 14.77 grams (0.125 moles~ of 1,6-hexanediol was 3 added 20.0 g (0.125 moles) of 2,2-diethoxytetrahydrofuran 4 and 20 mg of p-toluene sulfonic acid and the monomers reacted according to the procedure of Example 1 to yield 6 poly(2,2-dioxohexamethylene tetrahydrofuran) having a 7 molecular weight of 15,700. Separately, 45 grams (0.3i2 8 moles) of cis-trans-1,4-cyclohexane dicarbinol and 0.05 grams of p-toluene sulfonic acid was added to 50 I0 grams ~0.312 moles) of 2,2-diethoxytetrahydrofuran and II the monomer reacted according to the procedure of 12 Example 1 to yield poly(2,2-dioxo-cis,trans-cyclohexane-13 dimethylene tetrahydrofuran) having a molecular weight 14 of 24,700. Then, 9.5 grams (0.051 moles) of the poly(2,2-dioxohexymethylene tetrahydrofuran) was copolymerized with 10.76 grams (0.051 moles) of poly(2,2-dioxo-cis,trans-17 cyclohexanedimethylene tetrahydrofuran) for 43 hours at l8 180~C under 0.01 mm Hg in the presence of trace amounts of acid catalyst to yield the block copolymer of the following formula, where the ratio of m to n is 1 to 1, 21 and the degree of polymerization is 10 to 1000. -.
24 ~ H2 ~ H2 ~ 2 ! m n ~6 29 .
. '.
... . . ... ..
. 1087345 Pm 506~
1 EX~MPL~ 23 13.26 grams (0.125 moles) of diethylene glycol was - 3 added to 20.0 grams (0.125 moles) of 2,2-diethoxytetra-hydrofuran, and the monomers reacted in the presence of a Lewis acid catalyst for 42 hours according to the 6 general procedure in Examples 11 and 12 to yield a 7 polymer having a molecular weight of about 20,000.
8 Separately, 50.0 grams (0.312 moles) of trans-1,4-cyclo-9 hexane dicarbinol and 50 grams ~0.312 moles) of 2,2-10 diethoxytetrahydrofuran were reacted according to the - 11 procedure of Example 1 to yield another polymer. Next, 12 5.94 grams ~0.0341 moles) of the former polymer was 13 mixed with 14.5 grams (0.0682 moles) of the latter poly-14 mer and the reaction carried out at 180C, and under 0.01 mm Hg for four days to yield a block copolymer.
16 The copolymer was dissolved in benzene and lyophilized 17 for later use. The structure of the copolymer where 18 the ratio of m to n is 2 to 1 and the degree of poly-merization is 10-1000 is as follows:
23 ¦ ~ ~ 2 ~ i2 ~ 2CH2OCN2C~i2~ .¦
_ _ '32 . ':
..
~m 5066 1 A ~ EXAMPLES 24 - 27 2 The procedure of Example 1 was followed in this example, with all the reaction conditions identical to 4 those as previously set forth; however, the monomers.
of Example 1 were replaced with the monomers set forth 6 below:
7 a) 2,2-dimethoxy-4,5-benz-1,3-dioxolane (61.5 grams, 8 0.3 moles) and 1,6-hexamethylene diol (39.5 grams, 0.3 9 moles);
b) 2,2-dimethoxy-4,5-benz-1,3-dioxane (66.3 grams, 11 0.3 moles) and 3-hexenylene-1,6-diol (48.3 grams, 0.3 12 moles);
13 c) 2,2-diethoxy-4,5 benz-1,3-dioxolane (106 grams, 0.5 14 moles) and diethylene glycol (41 grams, 0.5 moles); and d) 2,2-diethoxy-l,methylcyclohexyl ortho carbonate 16 (73 grams, 0.3 moles) and 1,6-hexamethylene diol (39.3 17 grams, 0.3 moles); to yield the following polymers ~n is 1810-1000): . ;
l9 a) b) 20 ~ (cll2~2 c~=C8-lC~2 24 . d) U ~ nd 29 n ¦ Im 501i6 ~(~87345 2 136 grams (1.0 moles) of anhydrous 1,3,3,5-pentane . 3 tetraol and 0.075 grams of titanium sodium hydrogen hexabutoxide are added to 162 grams (1.0 moles) of anhydrous 2,2-diethoxy-1,3-dioxolane and the reactants 6 stirred to produce a homogenous mixture. Next, the 7 mixture is heated to 115C for 2 hours with distilla-8 tion of the continuous forming liquid into a side-arm 9 collector. Then, with the temperature constant, the pressure is reduced to 0.01 mm Hg and at this pressure 11 the temperature is raised to 180C, with the reac ion 12 continued at the raised temperature for 48 hours to 13 yield the polymer below (n is 10-1000).
s ~ ~ ~a~ 2 ~ j . , , ~ . ~
`24 . .
~227 28 ;~ .
29 . .
3l -25- .
3~ . . .
,, 10~7345 Pm 9066 1 ~ EXAMPLES 29 - 32 . Following the procedure of Example 28, with all 3 reaction conditions as described, except tha~ the . . polyol and heterocyclic ester of the example are re-S placed with the following monomeric pairs:
6 a) 1,3,5-pentane triol, 120 grams, and asymetrical 7 2-propoxy-2-ethoxy-5-methyl-1,3-dioxolane, 178 grams;
8 b) l,10-decanediol, 174 grams, and 2,2-diethoxy-5-. g methyl-1,3-dioxane, 180 grams;
-- 10 c) l,10-decanediol, 174 grams, and 2,2-diethoxy-1,3-11 dioxepane, 178 grams; and, 12 d) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-1,3-13 dioxocane, 218 grams; the following polymers are prepared (n is 10-1000 in each case):
i5 .... . . . ...... .. -... . ~ .... ..... . . ~... ...
7 ~ 2 21 a) 22 c) . _ -~ p~-~cl ~- _.
24 ~ 2 ~ l ~ 2 6J
: 25 n ~ and n 26 . . .
27 . .
28 . .
-26- .
32 . .
., ~ .
10 ~345 Pm 5066 . .1 EXAMPLES 33 - 36 2 Repeating the procedure of Example 28, the trans-. esterification and polycondensation steps are repeated 4 with the following reactive monomers:
a) 1,6-hexanediol, 122 grams, and 2,2-diethoxytetra-.6 hydropyran, 174 grams;
7 b) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-5,s-8 dimethyl-tetrahydropyran, 202 grams;
9 c) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-1-oxepane, 188 grams; and, . :
Ii d) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-~3-12 oxyepin, 172 grams; to yield the following polymers 13 where n is 10 to 1000:
17 I ~ J
~ 22 ~ }~n ~ 2nd . 224 "226 29 .' . . .
31 -27- . .
32 . .
¦¦ Pm 506~
1 , EXAMPLES 37 - 4l In Table l below, copolymers prepared according to 3 the general procedure of Example 22 are struc~urally .
4 illustrated. In the table, "No." refers to the polymer;
"Ratio" is the ratio of "m" and "n"; "Type" is ''B" for 6 block copolymer and "R" is for random copolymer and the 7 degree of polymerization is lO to lOOO.
8 Table l 10 ll No. litio Type Polyme 12 37 :1 , ~112~CH2~[~Cl12Cil20cH2 2~ i 16 3B i 2 N ~Cll2{~cl12~0 CHzCil 19 ~ 2~CH~H2CHzOCH2CH
22 ¦¦ 40 11 R ~ 2~[~ 2 2 2CN2 224 ¦ 41 :1 R ~(CN2~ 2~
~,', 226 I . ' ' " .
29 . ¦, 31 -28 .
~3 . .
` Pm 5066 10~7345 .
¦¦ - . EXAMPLES 42 - 44 3 In Table 2, polymers prepared according to Example l 4 from the monomers 2,2-diethoxytetrahydropyran, 2,2-: 5 diethoxyoxepane, 2,2-diethoxyoxecane and trans-cyclohexane 6 dicarbinol are illustrated ~n is lO-1000).
~oll Table 2 .,, . . . - . .
11 No. Monomer Monomer Polymer 6 , ~ 115C2 ~C2K5 ua~2C ~ 20K ~ ~c 2~ > , 2J
43 ~ C2115 j 2 ~ _~12OH ~ 2 { ~--c 2 ~~ ! 44 ~ ~ ~2 5 ~ K01~2C--a ~l~2 .J~' , 27 ... ... . .
228 ' ' ,, '. , 31 -29- . .
32~
:., .. ,, ,, . ~. , .
. . .
1087345 rm 50G6 1 . . E~AMPr.E 45 2 50 ~rams of 2,2-diethoxytetrahydrofuran and 28.1 grams of 1,4-butanediol previously mixed with 0.05 grams of polyphosphoric acid, were reacted for 3.25 hours over an S increasing temperature span of 70 to 130C, and under 6 atmospheric pressure according to Example 1. Then the 7 reactants were heated under reduced pressure of 120 mm to .
8 2.4 mm Hg for 4 hours at llO to.125C to yield 1,6,8-9 trioxa-spiro(4,6)undecane. The spiro compound was poly-merized in a sealed tube at 125C in the presence of a Il Lewis acid catalyst to yield the polymer, where n is 10 .x l2 to 1000, as illustrated below.
17 ~ + DO(CH2~ ~(C 12lA~
9 , EX~MPLE _4 6 The polycondensation of 2,2-diethoxytetrahydrofuran 21 and 30/70 cis/trans-cyclohexanedimethanol with poly-22 phosphoric acid. was carried out as follows: the 23 catalyst's weight ratio to diethoxytetrahydrofuran was 24 1/500, the monomer ratio of cyclohexanedicarbinol to tetrahydrofuran was 2.2/1, and the cyclohexanedicarbinol 26 was introduced into the reactor as a 68% weight solution .
27 in methanol. The methanol was distilled from the diol 29 . . .
-30- .
'32 . . .
" ,~ ' ', . .
¦¦ ~ Pm 5066 . ,, '' ',.
1 in situ, and toluene was added to azeotrope water from 2 the system. The tetrahydrofuran was then added and transesterification and polycondensation carried out at 4 180C and at a vacuum of 24 mm over a 24 hour period.
The recovered yield was 82%. GPC analysis was as 6 follows: Mw = 36,000, Mn = 8,500, Mw/Mn = 4.3. The 7 polymer had the specific formula as follows (n is 10 8 to 1000):
9 . . _ ,; , 10 . ... ~2~ 2 _ .
11 ! . _ n - .
)2 . ..... ..... . :.,.. .....
, 13 . .
;j 14 EXAMPLES 47 - 49 ~ .J .
The procedure set forth in ExampIe 1 is repeated 16 in these examples, with all reaction conditions as pre-17 viously described, except the following monomers are substituted for those previously set forth:
Ig 2,2-diethoxytetrahydrofuran and 5-methyl-1,6-cyclohex-~2-enedicarbinol;
21 2,2-dipropoxy-1,3-dioxolane and 2-vinyl-1,6-22 cyclohexanedipropanol; and 23 2,2-diethoxy-5-methyl-1,3-dioxolane and 3-methyl-24 1,5-cyclopentanediethanol, to yield, respectively, the .
following polymers:
26 . ~.
28 . . . .
2g . . .
3l -31- .
32 . , . ' . .
Pm 5066 .
2 . ; ~ ~ .
76 ! ~ 2C 2C ,~ 2 2 2}
9 n ~ and -' , 11 I ' " ,' ,_ ' -13 ~ ~ CH3 16 , - -18 where n is 10-1000.
Ig ~ EXAMPLE 50 13.26 grams (0.125 moles) of diethylene glycol was 21 added to 20.0 grams (0.125 moles) of 2,2-diethoxytetra-22 hydrofuran and the monomers reacted in the presence of 23 a Lewis acid for 42 hours according to Example 11 to 24 yield poly(2,2-dioxodiethylene glycol tetrahydrofuran).
2S Separately, 50.0 grams (0.312 moles) of trans-1,4-26 cyclohexane dicarbinol and 50.0 grams (0.312 moles) of 27 2,2-diethoxytetrahydrofuran was reacted according to ~2 ' ¦ Pm 5066 1 ~087345 I ", ," ' .
I ¦ Example 1 to yield poly(2,2-dioxo-trans-cyclohexane a ¦ dimethylene tetrahydrofuran~. Separately, 14.77 grams 3 ¦ tO.125 molcs) of 1,6-hexanediol was added to 20.0 grams 4 ¦ (0.125 moles) of 2,2-diethoxytetrahydrofuran and 20 mg S ¦ of p-toluene sulfonic acid, and the monomers reacted 6 ¦ according to Example 5, to yield poly(2,2-dioxohexa-7 ¦ methylene tetrahydrofuran). Then, 0.51 moles of poly(2,2-8 ¦ dioxodiethylene glycol tetrahydrofuran), 0.51 moles of 9 ¦ poly~2,2-dioxo-trans-cyclohexane dimethylene tetra-10 ¦ hydrofuran) and 0.51 moles of poly(2,2-dioxohexamethylene 11 ¦ tetrahydrof~ran) were polymerized for 50 hours at 180C
l2 ¦ under 0.01 mm Hg in thé presence of trace amounts of 13 acid catalyst to yield the terpolymer (the ratio of 14 ¦ m, n and p was 1:1:1 and the degree of polymerization
I8 To a mixture of polyol monomers consisting of l9 41.58 grams (0.284 moles) of trans-cyclohexane dicarbinol;
7.53 grams (0.071 moles) of the oxyalkylene glycol;
21 diethylene glycol and 0.057 grams of polyphosphoric acid 22 was added 56.7 grams (0.355 moles) of diethoxytetrahydro-23 furan under the inert gas argon and the mixture heated 24 to 115C for 2 hours with continuous distillation of the liquid organic by-product. Then, while keeping 26 the temperature constant, the pressure was reduced to 27 0.01 mm of Hg and at this reduced pressure the tempera-29 .
'32 ~ 10~7345 .................... s06~
1 ture was raised to 180C. The reaction was continued at this temperature and vacuum for 24 hours. The 3 random copolymer was isolated by extruding it from the 4 reactor and it had the following configuration where n is 10 to 1000.
. ..... ~ ,. , .,...................... r~ ..
: ~ t ~112CH20CU2CH2~ ~1 ~ J
1l .;
~3 The procedure used for preparing the copolymer in 16 Example 20 was repeated in this polymerization; all 17 conditions were as described. The monomerS used in this example were 2,2-diethoxytetrahydrofuran, 1,6-hexanediol 19 and a mixture of cis-trans-1,4-cyclohexane dicarbinol.
The structure of the copolymer (n is 10-1000) obtained is as follows:
23 ~ 2 ~ --n , ` ~m 50G6 n87345 . ' ',' I EX~MPLE 22 2 To 14.77 grams (0.125 moles~ of 1,6-hexanediol was 3 added 20.0 g (0.125 moles) of 2,2-diethoxytetrahydrofuran 4 and 20 mg of p-toluene sulfonic acid and the monomers reacted according to the procedure of Example 1 to yield 6 poly(2,2-dioxohexamethylene tetrahydrofuran) having a 7 molecular weight of 15,700. Separately, 45 grams (0.3i2 8 moles) of cis-trans-1,4-cyclohexane dicarbinol and 0.05 grams of p-toluene sulfonic acid was added to 50 I0 grams ~0.312 moles) of 2,2-diethoxytetrahydrofuran and II the monomer reacted according to the procedure of 12 Example 1 to yield poly(2,2-dioxo-cis,trans-cyclohexane-13 dimethylene tetrahydrofuran) having a molecular weight 14 of 24,700. Then, 9.5 grams (0.051 moles) of the poly(2,2-dioxohexymethylene tetrahydrofuran) was copolymerized with 10.76 grams (0.051 moles) of poly(2,2-dioxo-cis,trans-17 cyclohexanedimethylene tetrahydrofuran) for 43 hours at l8 180~C under 0.01 mm Hg in the presence of trace amounts of acid catalyst to yield the block copolymer of the following formula, where the ratio of m to n is 1 to 1, 21 and the degree of polymerization is 10 to 1000. -.
24 ~ H2 ~ H2 ~ 2 ! m n ~6 29 .
. '.
... . . ... ..
. 1087345 Pm 506~
1 EX~MPL~ 23 13.26 grams (0.125 moles) of diethylene glycol was - 3 added to 20.0 grams (0.125 moles) of 2,2-diethoxytetra-hydrofuran, and the monomers reacted in the presence of a Lewis acid catalyst for 42 hours according to the 6 general procedure in Examples 11 and 12 to yield a 7 polymer having a molecular weight of about 20,000.
8 Separately, 50.0 grams (0.312 moles) of trans-1,4-cyclo-9 hexane dicarbinol and 50 grams ~0.312 moles) of 2,2-10 diethoxytetrahydrofuran were reacted according to the - 11 procedure of Example 1 to yield another polymer. Next, 12 5.94 grams ~0.0341 moles) of the former polymer was 13 mixed with 14.5 grams (0.0682 moles) of the latter poly-14 mer and the reaction carried out at 180C, and under 0.01 mm Hg for four days to yield a block copolymer.
16 The copolymer was dissolved in benzene and lyophilized 17 for later use. The structure of the copolymer where 18 the ratio of m to n is 2 to 1 and the degree of poly-merization is 10-1000 is as follows:
23 ¦ ~ ~ 2 ~ i2 ~ 2CH2OCN2C~i2~ .¦
_ _ '32 . ':
..
~m 5066 1 A ~ EXAMPLES 24 - 27 2 The procedure of Example 1 was followed in this example, with all the reaction conditions identical to 4 those as previously set forth; however, the monomers.
of Example 1 were replaced with the monomers set forth 6 below:
7 a) 2,2-dimethoxy-4,5-benz-1,3-dioxolane (61.5 grams, 8 0.3 moles) and 1,6-hexamethylene diol (39.5 grams, 0.3 9 moles);
b) 2,2-dimethoxy-4,5-benz-1,3-dioxane (66.3 grams, 11 0.3 moles) and 3-hexenylene-1,6-diol (48.3 grams, 0.3 12 moles);
13 c) 2,2-diethoxy-4,5 benz-1,3-dioxolane (106 grams, 0.5 14 moles) and diethylene glycol (41 grams, 0.5 moles); and d) 2,2-diethoxy-l,methylcyclohexyl ortho carbonate 16 (73 grams, 0.3 moles) and 1,6-hexamethylene diol (39.3 17 grams, 0.3 moles); to yield the following polymers ~n is 1810-1000): . ;
l9 a) b) 20 ~ (cll2~2 c~=C8-lC~2 24 . d) U ~ nd 29 n ¦ Im 501i6 ~(~87345 2 136 grams (1.0 moles) of anhydrous 1,3,3,5-pentane . 3 tetraol and 0.075 grams of titanium sodium hydrogen hexabutoxide are added to 162 grams (1.0 moles) of anhydrous 2,2-diethoxy-1,3-dioxolane and the reactants 6 stirred to produce a homogenous mixture. Next, the 7 mixture is heated to 115C for 2 hours with distilla-8 tion of the continuous forming liquid into a side-arm 9 collector. Then, with the temperature constant, the pressure is reduced to 0.01 mm Hg and at this pressure 11 the temperature is raised to 180C, with the reac ion 12 continued at the raised temperature for 48 hours to 13 yield the polymer below (n is 10-1000).
s ~ ~ ~a~ 2 ~ j . , , ~ . ~
`24 . .
~227 28 ;~ .
29 . .
3l -25- .
3~ . . .
,, 10~7345 Pm 9066 1 ~ EXAMPLES 29 - 32 . Following the procedure of Example 28, with all 3 reaction conditions as described, except tha~ the . . polyol and heterocyclic ester of the example are re-S placed with the following monomeric pairs:
6 a) 1,3,5-pentane triol, 120 grams, and asymetrical 7 2-propoxy-2-ethoxy-5-methyl-1,3-dioxolane, 178 grams;
8 b) l,10-decanediol, 174 grams, and 2,2-diethoxy-5-. g methyl-1,3-dioxane, 180 grams;
-- 10 c) l,10-decanediol, 174 grams, and 2,2-diethoxy-1,3-11 dioxepane, 178 grams; and, 12 d) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-1,3-13 dioxocane, 218 grams; the following polymers are prepared (n is 10-1000 in each case):
i5 .... . . . ...... .. -... . ~ .... ..... . . ~... ...
7 ~ 2 21 a) 22 c) . _ -~ p~-~cl ~- _.
24 ~ 2 ~ l ~ 2 6J
: 25 n ~ and n 26 . . .
27 . .
28 . .
-26- .
32 . .
., ~ .
10 ~345 Pm 5066 . .1 EXAMPLES 33 - 36 2 Repeating the procedure of Example 28, the trans-. esterification and polycondensation steps are repeated 4 with the following reactive monomers:
a) 1,6-hexanediol, 122 grams, and 2,2-diethoxytetra-.6 hydropyran, 174 grams;
7 b) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-5,s-8 dimethyl-tetrahydropyran, 202 grams;
9 c) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-1-oxepane, 188 grams; and, . :
Ii d) 1,6-hexanediol, 122 grams, and 2,2-diethoxy-~3-12 oxyepin, 172 grams; to yield the following polymers 13 where n is 10 to 1000:
17 I ~ J
~ 22 ~ }~n ~ 2nd . 224 "226 29 .' . . .
31 -27- . .
32 . .
¦¦ Pm 506~
1 , EXAMPLES 37 - 4l In Table l below, copolymers prepared according to 3 the general procedure of Example 22 are struc~urally .
4 illustrated. In the table, "No." refers to the polymer;
"Ratio" is the ratio of "m" and "n"; "Type" is ''B" for 6 block copolymer and "R" is for random copolymer and the 7 degree of polymerization is lO to lOOO.
8 Table l 10 ll No. litio Type Polyme 12 37 :1 , ~112~CH2~[~Cl12Cil20cH2 2~ i 16 3B i 2 N ~Cll2{~cl12~0 CHzCil 19 ~ 2~CH~H2CHzOCH2CH
22 ¦¦ 40 11 R ~ 2~[~ 2 2 2CN2 224 ¦ 41 :1 R ~(CN2~ 2~
~,', 226 I . ' ' " .
29 . ¦, 31 -28 .
~3 . .
` Pm 5066 10~7345 .
¦¦ - . EXAMPLES 42 - 44 3 In Table 2, polymers prepared according to Example l 4 from the monomers 2,2-diethoxytetrahydropyran, 2,2-: 5 diethoxyoxepane, 2,2-diethoxyoxecane and trans-cyclohexane 6 dicarbinol are illustrated ~n is lO-1000).
~oll Table 2 .,, . . . - . .
11 No. Monomer Monomer Polymer 6 , ~ 115C2 ~C2K5 ua~2C ~ 20K ~ ~c 2~ > , 2J
43 ~ C2115 j 2 ~ _~12OH ~ 2 { ~--c 2 ~~ ! 44 ~ ~ ~2 5 ~ K01~2C--a ~l~2 .J~' , 27 ... ... . .
228 ' ' ,, '. , 31 -29- . .
32~
:., .. ,, ,, . ~. , .
. . .
1087345 rm 50G6 1 . . E~AMPr.E 45 2 50 ~rams of 2,2-diethoxytetrahydrofuran and 28.1 grams of 1,4-butanediol previously mixed with 0.05 grams of polyphosphoric acid, were reacted for 3.25 hours over an S increasing temperature span of 70 to 130C, and under 6 atmospheric pressure according to Example 1. Then the 7 reactants were heated under reduced pressure of 120 mm to .
8 2.4 mm Hg for 4 hours at llO to.125C to yield 1,6,8-9 trioxa-spiro(4,6)undecane. The spiro compound was poly-merized in a sealed tube at 125C in the presence of a Il Lewis acid catalyst to yield the polymer, where n is 10 .x l2 to 1000, as illustrated below.
17 ~ + DO(CH2~ ~(C 12lA~
9 , EX~MPLE _4 6 The polycondensation of 2,2-diethoxytetrahydrofuran 21 and 30/70 cis/trans-cyclohexanedimethanol with poly-22 phosphoric acid. was carried out as follows: the 23 catalyst's weight ratio to diethoxytetrahydrofuran was 24 1/500, the monomer ratio of cyclohexanedicarbinol to tetrahydrofuran was 2.2/1, and the cyclohexanedicarbinol 26 was introduced into the reactor as a 68% weight solution .
27 in methanol. The methanol was distilled from the diol 29 . . .
-30- .
'32 . . .
" ,~ ' ', . .
¦¦ ~ Pm 5066 . ,, '' ',.
1 in situ, and toluene was added to azeotrope water from 2 the system. The tetrahydrofuran was then added and transesterification and polycondensation carried out at 4 180C and at a vacuum of 24 mm over a 24 hour period.
The recovered yield was 82%. GPC analysis was as 6 follows: Mw = 36,000, Mn = 8,500, Mw/Mn = 4.3. The 7 polymer had the specific formula as follows (n is 10 8 to 1000):
9 . . _ ,; , 10 . ... ~2~ 2 _ .
11 ! . _ n - .
)2 . ..... ..... . :.,.. .....
, 13 . .
;j 14 EXAMPLES 47 - 49 ~ .J .
The procedure set forth in ExampIe 1 is repeated 16 in these examples, with all reaction conditions as pre-17 viously described, except the following monomers are substituted for those previously set forth:
Ig 2,2-diethoxytetrahydrofuran and 5-methyl-1,6-cyclohex-~2-enedicarbinol;
21 2,2-dipropoxy-1,3-dioxolane and 2-vinyl-1,6-22 cyclohexanedipropanol; and 23 2,2-diethoxy-5-methyl-1,3-dioxolane and 3-methyl-24 1,5-cyclopentanediethanol, to yield, respectively, the .
following polymers:
26 . ~.
28 . . . .
2g . . .
3l -31- .
32 . , . ' . .
Pm 5066 .
2 . ; ~ ~ .
76 ! ~ 2C 2C ,~ 2 2 2}
9 n ~ and -' , 11 I ' " ,' ,_ ' -13 ~ ~ CH3 16 , - -18 where n is 10-1000.
Ig ~ EXAMPLE 50 13.26 grams (0.125 moles) of diethylene glycol was 21 added to 20.0 grams (0.125 moles) of 2,2-diethoxytetra-22 hydrofuran and the monomers reacted in the presence of 23 a Lewis acid for 42 hours according to Example 11 to 24 yield poly(2,2-dioxodiethylene glycol tetrahydrofuran).
2S Separately, 50.0 grams (0.312 moles) of trans-1,4-26 cyclohexane dicarbinol and 50.0 grams (0.312 moles) of 27 2,2-diethoxytetrahydrofuran was reacted according to ~2 ' ¦ Pm 5066 1 ~087345 I ", ," ' .
I ¦ Example 1 to yield poly(2,2-dioxo-trans-cyclohexane a ¦ dimethylene tetrahydrofuran~. Separately, 14.77 grams 3 ¦ tO.125 molcs) of 1,6-hexanediol was added to 20.0 grams 4 ¦ (0.125 moles) of 2,2-diethoxytetrahydrofuran and 20 mg S ¦ of p-toluene sulfonic acid, and the monomers reacted 6 ¦ according to Example 5, to yield poly(2,2-dioxohexa-7 ¦ methylene tetrahydrofuran). Then, 0.51 moles of poly(2,2-8 ¦ dioxodiethylene glycol tetrahydrofuran), 0.51 moles of 9 ¦ poly~2,2-dioxo-trans-cyclohexane dimethylene tetra-10 ¦ hydrofuran) and 0.51 moles of poly(2,2-dioxohexamethylene 11 ¦ tetrahydrof~ran) were polymerized for 50 hours at 180C
l2 ¦ under 0.01 mm Hg in thé presence of trace amounts of 13 acid catalyst to yield the terpolymer (the ratio of 14 ¦ m, n and p was 1:1:1 and the degree of polymerization
15 ¦ was 10-1000). ..
l7 ~ [ ~ ~ ~ 2 ~ C Z)6 EX~MPLE 51 68.2 grams of trans-cyclohexane dicarbinol and 0.1 ¦ grams of polyphosphoric acid were added to 50 grams of ¦ 5-methyl-2,2-diethoxytetrahydrofuran, that was previously ¦ treated with sodium to remove any traces of ethanol and 24 ~ the polymer polymerized according to Example 1 to yield 25 ¦ 46.2 grams of polymer. The polymer had a Mn of 10,000, 226 ¦ an Mw of 36,000, an Mw/Mn of 3.6 and a structural formula 28 as follows: . .
ll 10~7345 ~m 5066 ,. ' I ~., ...... .. ' . ' 2 ¦ ~ ~ 2 ~ }
` 5 .. ~
: 6 . . ~ .
. 7 Examples o~ other polymers that may be made by the .~ . 8 above procedures are: `
g poly(2,2-dioxohexamethylene-1,3-dioxolane);
poly(2,2-dioxo-1,4-phenyldimethylene-1,3-dioxolane);
- 11 poly(2,2-dioxo-2-methyl-cis,trans-1,6-cyclohexane-12 dipropylene-1,3-dioxepane);
13 ~ poly(2,2-dioxo-3-ethyl-1,5-cyclopentane diethylene-:~ 14 1,3-dioxocane);
i poly(2,2-dioxo-1,6-hex-3-enelene-1,3-dioxolane);
l7 ~ [ ~ ~ ~ 2 ~ C Z)6 EX~MPLE 51 68.2 grams of trans-cyclohexane dicarbinol and 0.1 ¦ grams of polyphosphoric acid were added to 50 grams of ¦ 5-methyl-2,2-diethoxytetrahydrofuran, that was previously ¦ treated with sodium to remove any traces of ethanol and 24 ~ the polymer polymerized according to Example 1 to yield 25 ¦ 46.2 grams of polymer. The polymer had a Mn of 10,000, 226 ¦ an Mw of 36,000, an Mw/Mn of 3.6 and a structural formula 28 as follows: . .
ll 10~7345 ~m 5066 ,. ' I ~., ...... .. ' . ' 2 ¦ ~ ~ 2 ~ }
` 5 .. ~
: 6 . . ~ .
. 7 Examples o~ other polymers that may be made by the .~ . 8 above procedures are: `
g poly(2,2-dioxohexamethylene-1,3-dioxolane);
poly(2,2-dioxo-1,4-phenyldimethylene-1,3-dioxolane);
- 11 poly(2,2-dioxo-2-methyl-cis,trans-1,6-cyclohexane-12 dipropylene-1,3-dioxepane);
13 ~ poly(2,2-dioxo-3-ethyl-1,5-cyclopentane diethylene-:~ 14 1,3-dioxocane);
i poly(2,2-dioxo-1,6-hex-3-enelene-1,3-dioxolane);
16 poly(2,2-dioxo-1,6-cyclohexane dibut-2-eneylene-1,3-
17 dioxolane);
18 poly(methylorthoacetate-1,6-hexylene);
l9 poly(vinylorthoacrylate-1,4-phenylene);
: poly(heptylorthoheptanoate-1,4-cyclohexyldimethylene);
; 21 poly(methylorthohept-3-enoate-1,4-cyclohexylene);
-' 22 poly(hept 3-enylorthoacetate-1,4-phenyldiethylene);
.23 poly(dimethylorthocarbonate-1,3-propylene);
24 poly~methylheptylorthocarbonate-1,7-hept-3-enylene);
poly(diheptylorthocarbonate-3-methyl-1,4-phenylene);
26 poly(methylvinylorthocarbonate-2-heptyl-1,4-cyclo-27 hexylene);
28 . -:~- .
29 .
''32 . . .
~' 1087345''' , ' '' -` Pm 5066 ., . ' ' ' , poly(dihept-2-enylorthocarbonate-1,10-decylene);
poly(methylphenylorthocarbonate-2-vinyl-1,4-phenyl-3 dimethylene);
poly(vinylbenzylorthocarbonate-1,4-butyl~ne);
poly~allyl-3,5-dipropylphenylorthocarbonate-1,6-hex-6 3-enylene); and poly(diphenylorthocarbonate-1,6-hexylene).
8 The polymers of the invention are useful for making 9 devices and compositions for dispensing an active agent to an aqueous environment, as they have a controlled 11 degree of hydrophobicity in such environments and because ~2 they erode therein into innocuous products at a continuous 13 rate which exhibit no known deleterious effects. As 14 used herein "device" includes articles that have a unit IS structure as well as articles such as ointments, that 16 do not have a unit structure. The polymers can be pro-17 cessed into such devices and coated onto an agent by 18 standard manufacturing techniques. For example, the ~
l9 poly(vinylorthoacrylate-1,4-phenylene);
: poly(heptylorthoheptanoate-1,4-cyclohexyldimethylene);
; 21 poly(methylorthohept-3-enoate-1,4-cyclohexylene);
-' 22 poly(hept 3-enylorthoacetate-1,4-phenyldiethylene);
.23 poly(dimethylorthocarbonate-1,3-propylene);
24 poly~methylheptylorthocarbonate-1,7-hept-3-enylene);
poly(diheptylorthocarbonate-3-methyl-1,4-phenylene);
26 poly(methylvinylorthocarbonate-2-heptyl-1,4-cyclo-27 hexylene);
28 . -:~- .
29 .
''32 . . .
~' 1087345''' , ' '' -` Pm 5066 ., . ' ' ' , poly(dihept-2-enylorthocarbonate-1,10-decylene);
poly(methylphenylorthocarbonate-2-vinyl-1,4-phenyl-3 dimethylene);
poly(vinylbenzylorthocarbonate-1,4-butyl~ne);
poly~allyl-3,5-dipropylphenylorthocarbonate-1,6-hex-6 3-enylene); and poly(diphenylorthocarbonate-1,6-hexylene).
8 The polymers of the invention are useful for making 9 devices and compositions for dispensing an active agent to an aqueous environment, as they have a controlled 11 degree of hydrophobicity in such environments and because ~2 they erode therein into innocuous products at a continuous 13 rate which exhibit no known deleterious effects. As 14 used herein "device" includes articles that have a unit IS structure as well as articles such as ointments, that 16 do not have a unit structure. The polymers can be pro-17 cessed into such devices and coated onto an agent by 18 standard manufacturing techniques. For example, the ~
19 polymers can be extruded into filaments, spun into fibers, pressed into shaped articles, solvent film cast, coated 21 onto an agent by solvent evaporation, coated by using a 22 fluidized bed, or compression and transfer molded, and 23 processed by like standard methods of manufacture.
24 The term "hydrophobicity" as used above and in the remainder of the specification refers to the property of 26 the polymers not to absorb appreciable amounts of water.
27 The hydrophobic polymers of the invention do not absorb 29 .
3 _35_ .~ .' . .
,: , .' 1087345 Plll 5066 I water in an amount exceedin~ 5 percent of their dry weight.
3 Th~ terms "erodible" and "bioerodible" as used herein define the property of the polymers to break down as a unit structure or entity in an aqueous non-6 biological or aqueous biological environment over a 7 period of time to innocuo~s products. The terms "erosion", "bloerode" and "bioerosion" generally define 9 the method whereby breakdown or degradation of the polymer occurs.
11 The term "active agent" as used in the specification 12 and accompanying claims includes any composition of matter 13 which when released from a device produces a beneficial 14 and useful result, for example pesticides, herbicides, IS biocides, aigicides, rodenticides, fungicides, insecti-cides, plant growth inhibitors, preservatives, cosmetics, 17 drugs, fertility inhibitors, fertility promoters, air l8 purifiers, and nutrients. The term "drug" includes 19 physiologically or pharmacologically active substances for producing a localized or systemic effect or effects 21 in mammals.
22 The active agènt formulation within the device can 23 be in various forms such as solution, dispersion, paste, 24 cream, particle, microcapsules, emulsions, and suspen-2S sions.
26 The devices can be made to release an active agent 27 at a zero order rate or at a variable rate depending -36- ;
. . ,",,,,""""",',,,,,,,,,,'.
: ¦ 1087345 Pm 5066 , , , ' '.
. . ~ , .
1 upon the molecular weight and composition of the poly-2 mer, the concentration of the active agent in the poly-3 mer, and the surface area of the device tilat is exposed 4 to the environment. ~ariable release rate devices may S also be made by using different polymers that bioerode 6 at different rates or by using various structures, such 7 as laminates of different polymer-drug content.
8 Examples of such devices for dispensing active agents 9 are described below.
tO A parallelipiped-shaped device (7.5 cm x 7.5 cm x 250 11 microns) for dispensing hydrocortisone was made by mixing 12 hydrocortisone into poly(2,2-dioxo-trans-1,4-cyclohexane-13 dimethylene tetrahydrofuran) as follows: 2.375 grams of 14 the polymer was heated in a laboratory pan to about 150C, and then 0.125 grams of micronized hydrocortisone was 16 added to the polymer. Next, the polymer and hydrocorti-17 sone were thoroughly mixed to produce a good dispersion ~8 of the drug in the polymer. After the pan cooled to 19 room temperature, the polymer-drug formulation was re-moved from the pan and a device was made from it by 21 pressing it at 121C, 700 kg/cm2 for 5 minutes with a 22 250 micron, 7.5 cm x 7.5 cm spacer, positioned between 23 Teflon~ sheets. The device was prepared under an essen-24 tially dry, inert atmosphere using oven dried apparatus.
This device's surface bioerodes in an aqueous environment 26 at a controlled and continuous rate of about two microns 27 of depth per hour. Concurrently, hydrocortisone is ~8 . .
31 _~7_ ¦ lOB7345 Pm 5066 1 released at a like controlled and continuous, but pro-portional rate. ~his device can be used for the manage-3 ment of inflammation, and bursitis when applied to the 4 skin or mucosa.
A drug dispensing ointment was prepared as follows:
6 to 2.37S grams of the viscous polymer poly(2,2-dioxo-1,6-7 hexamethylelle tetrahydrofuran), having a molecular weight of about 25,000, was added 0.125 grams of hydrocortisone 9 and the ingredients thoroughly mixed for 5 minutes. The mixing was done with standard laboratory blending equip-11 ment, at room temperature, and in a dry, inert atmosphere.
12 The ointment is useful as a topically applied anti-13 inflammatory.
14~ The device may be in the form of a solid implant, such as an implant that dispenses an analgesic and is 16 used in surgical operations accompanied by severe pain 17 after the operation. In these cases, when the body is 18 opened for the operation, an implant containing an 19 analgesic can be implanted into the body during the operation to ease pain as the implant bioerodes and 21 releases the analgesic throughout the recovery period.
22 Injectable (for instance by trochar injection) implants 23 may also be made. An injectable implant comprising a 24 polymer having an erosion-rate of about 2 microns per hour in a biological aqueous environment with a physio-2~ logical p~3 of 6 to 8 and a drug concentration of 5~
27 was prepared as ~ollows: To 2.375 g of poly(2,2-dioxo-1087345 Plo 5066 1 trans-1,4-cyclohexane dimethylene tetrahydrofuran) was 2 added 0.125 g of hydrocortisone and the ingredients 3 heated to 150C to give a melt. The drug was dispersed 4 throughout the melt by mixing the ingredients for 5 minutes to give a good dispersion. The mixing was per-6 formed in a dry, inert environment, at atmospheric 7 pressure, and with dry equipment. Next, after the 8 polymer cooled to room temperature, it was transferred 9 to a press and injection molded into a solid, cylindri-cal shaped implant, 3 mm in diameter by g mm long. The 11 implant was positioned in a muscle of an animal by tro-12 char injection where it bioeroded and released steroid 13 for the treatment of inflammation.
14 A similar implant containin~ 20% progesterone in IS poly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetra-16 hydrofuran) having an original weight of about 114 mg, 17 had an in vivo release rate of progesterone, expressed l8 in mg per day over a 7 day period, as follows: 3.7;
19 3.2; 2.9; 2.2; 2.5; and 3.8 respectively.
Another injectable implant containing norethis-21 terone was prepared by dispensing the drug in poly(2,2-22 dioxo-trans-1,4-cyclohexane dimethylene tetrahydro-23 furan) according to the procedure set forth above, 24 except that drug and polymer were blended at 130C
2S in a dry helium atmosphere. The implant formed had 26 a drug concentration of 20~ and a cylindrical shape.
27 The implant was placed bilaterally in the paravertebral 29 . ~
33 -39- :
..
~ Pm 5066 I ~0~7345 I muscles of rabbits by trochar injection where it bio-2 1 eroded at a controlled and continuous rate concomitantly 3 1 with the release of norethisterone at a rate of 600 ~g 4 ¦ per day.
S ¦ Ocular inserts in forms such as an 8 mm disc, and 6 ¦ a 6 mm by 12 mm ellipsoid, each 0.4 mm thick were also 7 ¦ made by dissolving both the drug and the polymer in a 8 ¦ dry solvent, benzene or 1,4-dioxane, and the mixture 9 ¦ lyophilized; then the dry mixture was pressed at 100C
10 ¦ and 1050 kg/cm 2 to give a drug-containing polymer ¦ sheet. Ocular inserts prepared by this procedure in-; 12 ¦ clude 10~ pilocarpine nitrate and poly(2,2-dioxo-trans-13 ¦ 1,4-cyclohexane dimethylene tetrahydrofuran); 5~ pilo-14 ¦ carpine free base and poly(2,2-dioxo-trans-1,4-cyclo-15 ¦ hexane dimethylene tetrahydrofuran); 10~ hydrocortisone 16 ¦ alcohol and poly(2,2-dioxo-trans-1,4-cyclohexane dimeth-17 ¦ ylene tetrahydrofuran); 10% idoxuridine and poly(2,2-1 l8 ¦ dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran-.. ;.19 ¦ 2,2-dioxo-oxadimethylene-tetrahydrofuran); and 10~ .
24 The term "hydrophobicity" as used above and in the remainder of the specification refers to the property of 26 the polymers not to absorb appreciable amounts of water.
27 The hydrophobic polymers of the invention do not absorb 29 .
3 _35_ .~ .' . .
,: , .' 1087345 Plll 5066 I water in an amount exceedin~ 5 percent of their dry weight.
3 Th~ terms "erodible" and "bioerodible" as used herein define the property of the polymers to break down as a unit structure or entity in an aqueous non-6 biological or aqueous biological environment over a 7 period of time to innocuo~s products. The terms "erosion", "bloerode" and "bioerosion" generally define 9 the method whereby breakdown or degradation of the polymer occurs.
11 The term "active agent" as used in the specification 12 and accompanying claims includes any composition of matter 13 which when released from a device produces a beneficial 14 and useful result, for example pesticides, herbicides, IS biocides, aigicides, rodenticides, fungicides, insecti-cides, plant growth inhibitors, preservatives, cosmetics, 17 drugs, fertility inhibitors, fertility promoters, air l8 purifiers, and nutrients. The term "drug" includes 19 physiologically or pharmacologically active substances for producing a localized or systemic effect or effects 21 in mammals.
22 The active agènt formulation within the device can 23 be in various forms such as solution, dispersion, paste, 24 cream, particle, microcapsules, emulsions, and suspen-2S sions.
26 The devices can be made to release an active agent 27 at a zero order rate or at a variable rate depending -36- ;
. . ,",,,,""""",',,,,,,,,,,'.
: ¦ 1087345 Pm 5066 , , , ' '.
. . ~ , .
1 upon the molecular weight and composition of the poly-2 mer, the concentration of the active agent in the poly-3 mer, and the surface area of the device tilat is exposed 4 to the environment. ~ariable release rate devices may S also be made by using different polymers that bioerode 6 at different rates or by using various structures, such 7 as laminates of different polymer-drug content.
8 Examples of such devices for dispensing active agents 9 are described below.
tO A parallelipiped-shaped device (7.5 cm x 7.5 cm x 250 11 microns) for dispensing hydrocortisone was made by mixing 12 hydrocortisone into poly(2,2-dioxo-trans-1,4-cyclohexane-13 dimethylene tetrahydrofuran) as follows: 2.375 grams of 14 the polymer was heated in a laboratory pan to about 150C, and then 0.125 grams of micronized hydrocortisone was 16 added to the polymer. Next, the polymer and hydrocorti-17 sone were thoroughly mixed to produce a good dispersion ~8 of the drug in the polymer. After the pan cooled to 19 room temperature, the polymer-drug formulation was re-moved from the pan and a device was made from it by 21 pressing it at 121C, 700 kg/cm2 for 5 minutes with a 22 250 micron, 7.5 cm x 7.5 cm spacer, positioned between 23 Teflon~ sheets. The device was prepared under an essen-24 tially dry, inert atmosphere using oven dried apparatus.
This device's surface bioerodes in an aqueous environment 26 at a controlled and continuous rate of about two microns 27 of depth per hour. Concurrently, hydrocortisone is ~8 . .
31 _~7_ ¦ lOB7345 Pm 5066 1 released at a like controlled and continuous, but pro-portional rate. ~his device can be used for the manage-3 ment of inflammation, and bursitis when applied to the 4 skin or mucosa.
A drug dispensing ointment was prepared as follows:
6 to 2.37S grams of the viscous polymer poly(2,2-dioxo-1,6-7 hexamethylelle tetrahydrofuran), having a molecular weight of about 25,000, was added 0.125 grams of hydrocortisone 9 and the ingredients thoroughly mixed for 5 minutes. The mixing was done with standard laboratory blending equip-11 ment, at room temperature, and in a dry, inert atmosphere.
12 The ointment is useful as a topically applied anti-13 inflammatory.
14~ The device may be in the form of a solid implant, such as an implant that dispenses an analgesic and is 16 used in surgical operations accompanied by severe pain 17 after the operation. In these cases, when the body is 18 opened for the operation, an implant containing an 19 analgesic can be implanted into the body during the operation to ease pain as the implant bioerodes and 21 releases the analgesic throughout the recovery period.
22 Injectable (for instance by trochar injection) implants 23 may also be made. An injectable implant comprising a 24 polymer having an erosion-rate of about 2 microns per hour in a biological aqueous environment with a physio-2~ logical p~3 of 6 to 8 and a drug concentration of 5~
27 was prepared as ~ollows: To 2.375 g of poly(2,2-dioxo-1087345 Plo 5066 1 trans-1,4-cyclohexane dimethylene tetrahydrofuran) was 2 added 0.125 g of hydrocortisone and the ingredients 3 heated to 150C to give a melt. The drug was dispersed 4 throughout the melt by mixing the ingredients for 5 minutes to give a good dispersion. The mixing was per-6 formed in a dry, inert environment, at atmospheric 7 pressure, and with dry equipment. Next, after the 8 polymer cooled to room temperature, it was transferred 9 to a press and injection molded into a solid, cylindri-cal shaped implant, 3 mm in diameter by g mm long. The 11 implant was positioned in a muscle of an animal by tro-12 char injection where it bioeroded and released steroid 13 for the treatment of inflammation.
14 A similar implant containin~ 20% progesterone in IS poly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetra-16 hydrofuran) having an original weight of about 114 mg, 17 had an in vivo release rate of progesterone, expressed l8 in mg per day over a 7 day period, as follows: 3.7;
19 3.2; 2.9; 2.2; 2.5; and 3.8 respectively.
Another injectable implant containing norethis-21 terone was prepared by dispensing the drug in poly(2,2-22 dioxo-trans-1,4-cyclohexane dimethylene tetrahydro-23 furan) according to the procedure set forth above, 24 except that drug and polymer were blended at 130C
2S in a dry helium atmosphere. The implant formed had 26 a drug concentration of 20~ and a cylindrical shape.
27 The implant was placed bilaterally in the paravertebral 29 . ~
33 -39- :
..
~ Pm 5066 I ~0~7345 I muscles of rabbits by trochar injection where it bio-2 1 eroded at a controlled and continuous rate concomitantly 3 1 with the release of norethisterone at a rate of 600 ~g 4 ¦ per day.
S ¦ Ocular inserts in forms such as an 8 mm disc, and 6 ¦ a 6 mm by 12 mm ellipsoid, each 0.4 mm thick were also 7 ¦ made by dissolving both the drug and the polymer in a 8 ¦ dry solvent, benzene or 1,4-dioxane, and the mixture 9 ¦ lyophilized; then the dry mixture was pressed at 100C
10 ¦ and 1050 kg/cm 2 to give a drug-containing polymer ¦ sheet. Ocular inserts prepared by this procedure in-; 12 ¦ clude 10~ pilocarpine nitrate and poly(2,2-dioxo-trans-13 ¦ 1,4-cyclohexane dimethylene tetrahydrofuran); 5~ pilo-14 ¦ carpine free base and poly(2,2-dioxo-trans-1,4-cyclo-15 ¦ hexane dimethylene tetrahydrofuran); 10~ hydrocortisone 16 ¦ alcohol and poly(2,2-dioxo-trans-1,4-cyclohexane dimeth-17 ¦ ylene tetrahydrofuran); 10% idoxuridine and poly(2,2-1 l8 ¦ dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran-.. ;.19 ¦ 2,2-dioxo-oxadimethylene-tetrahydrofuran); and 10~ .
20 ¦ chloramphenicol and poly(2,2-dioxo-trans-1,4-cyclohexane
21 ¦ dimethylene tetrahydrofuran-2,2-dioxo-oxadimethylene-
22 ¦ tetrahydrofuran). These ocular inserts continuously
23 ¦ bioerode and dispense a metered amount of ophthalmic
24 ¦ drug(s) to the eye and its surrounding tissue over a
25 ¦ prolonged period of time.
26 ¦ Additional ocular devices comprising zinc bacitracin
27 ¦ and the random copolymer poly(2,2-dioxo-trans-1,4-cyclo-
28
29 . .
33l -40- .
10~7345 Pm 5066 ¦ hexane dimethylene tetrahydrofuran-2,2-dioxo-1,6-hexameth-¦ ylene tetrahydrofuran) were prepared by mixing and dis-3 ¦ persing at 120C for 5 minutes the bacitracin into the hot 4 ¦ melt of the polymer. After cooling to room temperature, S ¦ the drug polymer formulation was pressed into a film at 6 ¦ 120C under 700 Icg/cm 2 for 5 minutes; and then it was 7 ¦ templated into ocular devices. The release rate for 3 8 ¦ day ocular devices made from the above drug~polymer formu-9 ¦ lation is set forth in the table below:
I _ _ -11 I Dimension and Surface area Zn bacitracin ~g/hr for ~2 ¦ Shape (cm2) content (mg) 72 hrs I
13 ¦ 6 mm circular 0.56 1.5 21 ¦ 5 x 8 mm ellipse 0.62 1.6 22 14 ¦ 5.6 x 12.7 mm ellipse 1.1 2.9 40 15 ¦ Also, appliques of active agent-polymer compositions 16 ¦ such as those used for burn and wound treatment may be made 17 ~ by incorporating the composition into an absorbent suppor-l8 ¦ tive carrier. Carriers such as a fabric, plastic fiber, 19 ¦ a section of porous foamed rubber or paper may be used.
20 ¦ Typical active agents that might be used in such appliques 21 ¦ are the various sulfa drugs, salicylic acid derivatives 22 ¦ and other antiobiotic agents. For example, a circular 23 ¦ section of double knit polyester fabric is charged with 24 4 grams of poly(2,2-dioxohexamethylene tetrahydrofuran) containing 0.1~ to 30~, usually 2~ to 15~ ~-amino-p-toluene 26 sulfonamide by working the polymer-agent into the fabric 27 with a laboratory spatula. Similarly, the hydrophobic . . Pm ~066 .
l polymer can be charged with other agents such as 1% to 2 1 1/2% silver nitrate in poly(2,2-dioxohexamethylene tetrahydrofuran), from 0.001% to 2% by weight of collage-4 nase mixed with.1% to 1 1/2% by weight of silver nitrate in poly(2,2-dioxohexamethylene tetrahydrofuran), and~1 g of poly~2,2 dioxohexamethylene tetrahydrofuran) containing 7 82 x 103 casein units of a protease such as streptokinase, 8 or sutilains.
'9 . ' '' , .
,10~
l6 ~ . 187 -~: 19 . , ' '.
21 ..
22 j 26 ~ .
28 . .
2~
31 -~2- .
'32 . .
33l -40- .
10~7345 Pm 5066 ¦ hexane dimethylene tetrahydrofuran-2,2-dioxo-1,6-hexameth-¦ ylene tetrahydrofuran) were prepared by mixing and dis-3 ¦ persing at 120C for 5 minutes the bacitracin into the hot 4 ¦ melt of the polymer. After cooling to room temperature, S ¦ the drug polymer formulation was pressed into a film at 6 ¦ 120C under 700 Icg/cm 2 for 5 minutes; and then it was 7 ¦ templated into ocular devices. The release rate for 3 8 ¦ day ocular devices made from the above drug~polymer formu-9 ¦ lation is set forth in the table below:
I _ _ -11 I Dimension and Surface area Zn bacitracin ~g/hr for ~2 ¦ Shape (cm2) content (mg) 72 hrs I
13 ¦ 6 mm circular 0.56 1.5 21 ¦ 5 x 8 mm ellipse 0.62 1.6 22 14 ¦ 5.6 x 12.7 mm ellipse 1.1 2.9 40 15 ¦ Also, appliques of active agent-polymer compositions 16 ¦ such as those used for burn and wound treatment may be made 17 ~ by incorporating the composition into an absorbent suppor-l8 ¦ tive carrier. Carriers such as a fabric, plastic fiber, 19 ¦ a section of porous foamed rubber or paper may be used.
20 ¦ Typical active agents that might be used in such appliques 21 ¦ are the various sulfa drugs, salicylic acid derivatives 22 ¦ and other antiobiotic agents. For example, a circular 23 ¦ section of double knit polyester fabric is charged with 24 4 grams of poly(2,2-dioxohexamethylene tetrahydrofuran) containing 0.1~ to 30~, usually 2~ to 15~ ~-amino-p-toluene 26 sulfonamide by working the polymer-agent into the fabric 27 with a laboratory spatula. Similarly, the hydrophobic . . Pm ~066 .
l polymer can be charged with other agents such as 1% to 2 1 1/2% silver nitrate in poly(2,2-dioxohexamethylene tetrahydrofuran), from 0.001% to 2% by weight of collage-4 nase mixed with.1% to 1 1/2% by weight of silver nitrate in poly(2,2-dioxohexamethylene tetrahydrofuran), and~1 g of poly~2,2 dioxohexamethylene tetrahydrofuran) containing 7 82 x 103 casein units of a protease such as streptokinase, 8 or sutilains.
'9 . ' '' , .
,10~
l6 ~ . 187 -~: 19 . , ' '.
21 ..
22 j 26 ~ .
28 . .
2~
31 -~2- .
'32 . .
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A polymer comprising a repeating mer of the general formula characterized in that R1 is polyvalent and is alkylene of 2 to 10 carbon atoms; alkenylene of 2 to 10 carbon atoms; oxaalkylene of 2 to 6 carbon atoms and 1 or 2 internal oxa groups; cycloalkylene of 3 to 7 annular carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; cycloalkenylene of 4 to 7 annular carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; cycloalkanedi-aliphatic hydrocarbylene of 3 to 7 annular carbon atoms wherein the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; cycloalkenedi-aliphatic hydrocarbylene of 4 to 7 annular carbon atoms wherein the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms;
phenylene optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; or phenyldi-aliphatic hydrocar-bylene wherein the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms;
R2 and R3 when taken independently are alkyl of 1 to 7 carbon atoms; alkenyl of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms; alkenyloxy of 2 to 7 carbon atoms;
or monocyclic aryloxy of 6 to 12 carbon atoms; or -OR1O-, with the proviso that at least one of R2 and R3 is said alkoxy, alkenyloxy, aryloxy, or -OR1O-;
R2 and R 3 when taken together with the dioxycarbon atom of the polymer backbone forms a heteromonocyclic group of 5 to 8 annular members with 1 or 2 oxygen hetero-atom linkages to the dioxycarbon atom of the polymer back-bone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; or a fused heteropolycyclic group of 7 to 12 annular members with 1 or 2 oxygen heteroatom linkages to the dioxy-carbon atom of the polymer backbone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; and n is an integer and is at least 10.
phenylene optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; or phenyldi-aliphatic hydrocar-bylene wherein the hydrocarbylene groups are of 1 to 7 carbon atoms and the ring is optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms;
R2 and R3 when taken independently are alkyl of 1 to 7 carbon atoms; alkenyl of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms; alkenyloxy of 2 to 7 carbon atoms;
or monocyclic aryloxy of 6 to 12 carbon atoms; or -OR1O-, with the proviso that at least one of R2 and R3 is said alkoxy, alkenyloxy, aryloxy, or -OR1O-;
R2 and R 3 when taken together with the dioxycarbon atom of the polymer backbone forms a heteromonocyclic group of 5 to 8 annular members with 1 or 2 oxygen hetero-atom linkages to the dioxycarbon atom of the polymer back-bone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; or a fused heteropolycyclic group of 7 to 12 annular members with 1 or 2 oxygen heteroatom linkages to the dioxy-carbon atom of the polymer backbone and the remaining annular members being carbon atoms optionally substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or alkenyl of 2 to 7 carbon atoms; and n is an integer and is at least 10.
2. The polymer as claimed in claim 1 further characterized in that n is an integer from 10 to 1000.
3. The polymer as claimed in claims 1 or 2 further characterized in that the polymer is a homo-polymer, copolymer or terpolymer; R1 is divalent and is cycloalkyldialkylene of 4 to 6 annular carbon atoms wherein the alkylene groups are of 1 to 4 carbon atoms;
alkylene of 2 to 10 carbon atoms, or oxaakylene of 2 to 6 carbon atoms and 1 or 2 internal oxa groups; and R2 and R3 are taken together with the dioxycarbon atom of the polymer backbone to form a heteromonocyclic ring of 5 to 6 members with one oxygen heteroatom link to the dioxycarbon atom of the polymer backbone and the remaining members of the ring being carbon atoms.
alkylene of 2 to 10 carbon atoms, or oxaakylene of 2 to 6 carbon atoms and 1 or 2 internal oxa groups; and R2 and R3 are taken together with the dioxycarbon atom of the polymer backbone to form a heteromonocyclic ring of 5 to 6 members with one oxygen heteroatom link to the dioxycarbon atom of the polymer backbone and the remaining members of the ring being carbon atoms.
4. The polymer as claimed in claim 2 wherein the polymer is a homopolymer further characterized in that R, is tetramethylene, hexamethylene, decamethylene, 1,4-cyclohexanedimethylene, 2,2,4,4-tetramethyl-1,3-cyclobutylene, or 2-oxa-1,4-butylene and R2 and R3 are taken together with the dioxycarbon atom of the polymer backbone to form a tetrahydrofuryl group.
5. The polymer as claimed in claim 2 wherein the polymer is a random copolymer of two mers further char-acterized in that in each mer R2 and R3 are taken together with the dioxycarbon atom of the polymer backbone to form a tetrahydrofuryl group and in one of the mers R1 is 1,4-cyclohexanedimethylene and in the other mer R1 is hexamethylene or 2-oxa-1,4-butylene.
6. The polymer as claimed in claim 2 wherein the polymer is a block copolymer of two mers further characterized in that in each mer R 2 and R 3 are taken together with the dioxycarbon atom of the polymer back-bone to form a tetrahydrofuryl group and in one of the mers R 1 is 1,4-cyclohexanedimethylene and in the other mer R 1 is hexamethylene or 2-oxa-1,4-butylene.
7. The polymer as claimed in claim 2 wherein the polymer is a block terpolymer further characterized in that in each mer R 2 and R 3 are taken together with the dioxycarbon atom of the polymer backbone to form a tetrahydrofuryl group and in one mer R1 is 1,4-cyclo-hexanedimethylene, in the second mer R1 is hexamethylene, and in the third mer R1 is 2-oxa-1,4-butylene.
8. The polymer as claimed in claim 2 wherein the polymer is a homopolymer further characterized in that R1 is 1,4-cyclohexanedimethylene and R2 and R3 are taken together with the dioxycarbon atom of the polymer backbone to form a tetrahydropyranyl group.
9. The polymer as claimed in claim 2 wherein the polymer is a homopolymer further characterized in that R1 is 1,4-cyclohexanedimethylene and R2 and R3 are taken together with the dioxycarbon atom of the polymer backbone to form a 5-methyltetrahydrofuryl group.
10. A process for making the polymers claimed in claim 1 characterized by reacting at least a stoichio-metric amount of a polyol of the formula wherein R1 is as defined in claim 1 with a compound of the formula wherein R2 and R3 are as defined in claim 1 and R6 is alkyl of 1 to 7 carbon atoms in the presence of a Lewis acid, Bronsted or organotitanate catalyst and option-ally in the presence of an inert solvent.
11. The process as claimed in claim 10 further characterized in that the reaction is initially carried out at 75 to 180°C at atmospheric pressure to effect a transesterification and is then carried out at 75 to 180°C at a pressure of 0.0001 to 0.10 mm Hg to effect a polycondensation.
12. The process as claimed in claims 10 and 11 further character-ized in that the amount of said catalyst is 0.005% to about 2.0% based on the weight of said compound of the formula
13. An active agent dispenser comprising an active agent confined within a bioerodible polymer that bioerodes in the environment of use of the dispenser to release the active agent characterized in that the polymer is the polymer of any of claims 1, 2 or 4.
14. An active agent dispenser comprising a drug confined within a bioerodible polymer that bioerodes in the environment of use of the dispen-ser to release the active agent characterized in that the polymer is the polymer of any of claims 1, 2 or 4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/544,808 US4093709A (en) | 1975-01-28 | 1975-01-28 | Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates) |
| US544,808 | 1975-01-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1087345A true CA1087345A (en) | 1980-10-07 |
Family
ID=24173683
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA243,429A Expired CA1087345A (en) | 1975-01-28 | 1976-01-13 | Orthoester polymers |
Country Status (19)
| Country | Link |
|---|---|
| US (2) | US4093709A (en) |
| JP (1) | JPS5410037B2 (en) |
| AR (1) | AR213619A1 (en) |
| AT (1) | AT356903B (en) |
| BE (1) | BE837935A (en) |
| BR (1) | BR7600499A (en) |
| CA (1) | CA1087345A (en) |
| CH (1) | CH635355A5 (en) |
| DE (1) | DE2602994C2 (en) |
| DK (1) | DK166360C (en) |
| ES (1) | ES444484A1 (en) |
| FR (1) | FR2299356A1 (en) |
| GB (1) | GB1502082A (en) |
| IL (1) | IL48799A (en) |
| IT (1) | IT1057070B (en) |
| MX (1) | MX142986A (en) |
| NL (1) | NL174728C (en) |
| SE (1) | SE418189B (en) |
| ZA (1) | ZA76493B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4131648A (en) * | 1975-01-28 | 1978-12-26 | Alza Corporation | Structured orthoester and orthocarbonate drug delivery devices |
| US4150108A (en) * | 1975-12-29 | 1979-04-17 | Graham Neil B | Injectable medicinal compositions |
| US4070347A (en) * | 1976-08-16 | 1978-01-24 | Alza Corporation | Poly(orthoester) co- and homopolymers and poly(orthocarbonate) co- and homopolymers having carbonyloxy functionality |
| US4115544A (en) | 1976-08-18 | 1978-09-19 | Alza Corporation | Ocular system made of bioerodible esters having linear ether |
| US4259102A (en) * | 1979-02-02 | 1981-03-31 | Alza Corporation | Composition comprising useful agent such as fertilizers, housed in heterocyclic polymer |
| US4282201A (en) * | 1979-02-02 | 1981-08-04 | Alza Corporation | Pharmaceutical comprising drug and polymer |
| US4246397A (en) * | 1979-02-02 | 1981-01-20 | Alza Corporation | Polymers comprising heterocyclic system |
| US4304767A (en) * | 1980-05-15 | 1981-12-08 | Sri International | Polymers of di- (and higher functionality) ketene acetals and polyols |
| US4346709A (en) * | 1980-11-10 | 1982-08-31 | Alza Corporation | Drug delivery devices comprising erodible polymer and erosion rate modifier |
| US4675189A (en) * | 1980-11-18 | 1987-06-23 | Syntex (U.S.A.) Inc. | Microencapsulation of water soluble active polypeptides |
| US4764380A (en) * | 1982-03-22 | 1988-08-16 | Alza Corporation | Drug delivery system comprising a volume increasing matrix containing a plurality of tiny pills |
| US4484923A (en) * | 1982-03-25 | 1984-11-27 | Alza Corporation | Method for administering immunopotentiator |
| US5248700A (en) * | 1982-05-14 | 1993-09-28 | Akzo Nv | Active agent containing solid structures for prolonged release of active agents |
| JPS5931701A (en) * | 1982-08-16 | 1984-02-20 | Nitto Electric Ind Co Ltd | Membrane containing liquid active substance and its preparation |
| US4489056A (en) * | 1982-06-30 | 1984-12-18 | Merck & Co., Inc. | Acid anhydrides as rate controlling agent for the erosion of polymers which latter polymers have beneficial substances dispersed throughout their matrix or where the polymer matrix surrounds the beneficial substance |
| CH660488A5 (en) * | 1982-12-17 | 1987-04-30 | Sandoz Ag | (Co)oligomeric hydroxycarboxylic acid derivatives, the preparation thereof, and the use thereof in pharmaceutical compositions |
| JPS59155451A (en) * | 1983-02-22 | 1984-09-04 | Asahi Glass Co Ltd | Perfume-containing resin |
| US4576604A (en) * | 1983-03-04 | 1986-03-18 | Alza Corporation | Osmotic system with instant drug availability |
| US4673405A (en) * | 1983-03-04 | 1987-06-16 | Alza Corporation | Osmotic system with instant drug availability |
| JPS6075476A (en) * | 1983-10-03 | 1985-04-27 | Toagosei Chem Ind Co Ltd | Cyclic compound |
| US5855908A (en) * | 1984-05-01 | 1999-01-05 | University Of Utah Research Foundation | Non-dissolvable drug-containing dosage-forms for use in the transmucosal delivery of a drug to a patient |
| US4863737A (en) * | 1985-05-01 | 1989-09-05 | University Of Utah | Compositions and methods of manufacture of compressed powder medicaments |
| US5456663A (en) * | 1984-05-25 | 1995-10-10 | Lemelson; Jerome H. | Drugs and methods for treating diseases |
| US4639366A (en) * | 1984-06-06 | 1987-01-27 | Merck & Co., Inc. | Polymers containing pendant acid functionalities and labile backbone bonds |
| US4880635B1 (en) * | 1984-08-08 | 1996-07-02 | Liposome Company | Dehydrated liposomes |
| US5132114A (en) * | 1985-05-01 | 1992-07-21 | University Of Utah Research Foundation | Compositions and methods of manufacture of compressed powder medicaments |
| US4885173A (en) * | 1985-05-01 | 1989-12-05 | University Of Utah | Methods and compositions for noninvasive dose-to-effect administration of drugs with cardiovascular or renal vascular activities |
| US5122127A (en) * | 1985-05-01 | 1992-06-16 | University Of Utah | Apparatus and methods for use in administering medicaments by direct medicament contact to mucosal tissues |
| US4671953A (en) * | 1985-05-01 | 1987-06-09 | University Of Utah Research Foundation | Methods and compositions for noninvasive administration of sedatives, analgesics, and anesthetics |
| US5288497A (en) * | 1985-05-01 | 1994-02-22 | The University Of Utah | Compositions of oral dissolvable medicaments |
| US4780319A (en) * | 1985-07-08 | 1988-10-25 | Merck & Co., Inc. | Organic acids as catalysts for the erosion of polymers |
| US4764364A (en) * | 1986-02-25 | 1988-08-16 | S R I International | Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product |
| US4855132A (en) * | 1986-02-25 | 1989-08-08 | S R I International | Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product |
| ATE97929T1 (en) * | 1986-05-15 | 1993-12-15 | Hoechst Ag | BIODEGRADABLE POLYMERS FOR CONTROLLED RELEASE DELIVERY PREPARATION. |
| USRE33976E (en) * | 1986-05-16 | 1992-06-30 | Sumitomo Chemical Co., Ltd. | Granular fertilizer compositions |
| JPH0798713B2 (en) * | 1986-05-16 | 1995-10-25 | 住友化学工業株式会社 | Granular fertilizer composition and method for producing the same |
| US4841968A (en) * | 1986-09-26 | 1989-06-27 | Southern Research Institute | Antithrombotic/thrombolytic suture and methods of making and using the same |
| DE3700128A1 (en) * | 1987-01-03 | 1988-07-14 | Hoechst Ag | BIODEGRADABLE POLY- (HYDROXYALKYL) - AMINODICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF FOR DEPOT PREPARATIONS WITH CONTROLLED ACTIVE SUBSTANCE DELIVERY |
| US4913903A (en) * | 1987-02-04 | 1990-04-03 | Alza Corporation | Post-surgical applications for bioerodible polymers |
| US4851232A (en) * | 1987-02-13 | 1989-07-25 | Alza Corporation | Drug delivery system with means for obtaining desirable in vivo release rate pattern |
| US5985354A (en) | 1995-06-07 | 1999-11-16 | Brown University Research Foundation | Preparation of multiwall polymeric microcapsules from hydrophilic polymers |
| US4897268A (en) * | 1987-08-03 | 1990-01-30 | Southern Research Institute | Drug delivery system and method of making the same |
| US4950795A (en) * | 1987-08-27 | 1990-08-21 | Ciba-Geigy Corporation | Oligomeric benzil ketals and their use as photoinitiators |
| JP2563814B2 (en) * | 1987-11-12 | 1996-12-18 | 日東電工株式会社 | Liquid active substance sustained release device |
| US4957998A (en) * | 1988-08-22 | 1990-09-18 | Pharmaceutical Delivery Systems, Inc. | Polymers containing acetal, carboxy-acetal, ortho ester and carboxyortho ester linkages |
| US4990336A (en) * | 1989-02-08 | 1991-02-05 | Biosearch, Inc. | Sustained release dosage form |
| US5278142A (en) * | 1989-03-20 | 1994-01-11 | Orbon Corporation | Systemic delivery of polypeptides through the eye |
| US5182258A (en) * | 1989-03-20 | 1993-01-26 | Orbon Corporation | Systemic delivery of polypeptides through the eye |
| US5108755A (en) * | 1989-04-27 | 1992-04-28 | Sri International | Biodegradable composites for internal medical use |
| US5013821A (en) * | 1989-06-15 | 1991-05-07 | Pharmaceutical Delivery Systems, Inc. | Ortho and thio-ortho ester polymer |
| US5660851A (en) * | 1989-12-26 | 1997-08-26 | Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem | Ocular inserts |
| DE4002736A1 (en) * | 1990-01-31 | 1991-08-01 | Hoechst Ag | Poly-amino-di:carboxylic acid co-anhydro-amino-di:carboxylic derivs. - bio:degradable polymeric peptide(s) for controlled release of pharmaceuticals |
| US5126147A (en) * | 1990-02-08 | 1992-06-30 | Biosearch, Inc. | Sustained release dosage form |
| NZ239370A (en) * | 1990-08-22 | 1994-04-27 | Merck & Co Inc | Bioerodible implantable controlled release dosage form comprising a poly(ortho ester) or a polyacetal with an active agent incorporated into the chain backbone |
| US5232705A (en) * | 1990-08-31 | 1993-08-03 | Alza Corporation | Dosage form for time-varying patterns of drug delivery |
| US5156850A (en) * | 1990-08-31 | 1992-10-20 | Alza Corporation | Dosage form for time-varying patterns of drug delivery |
| US5620700A (en) * | 1990-10-30 | 1997-04-15 | Alza Corporation | Injectable drug delivery system and method |
| WO1992011843A1 (en) * | 1991-01-09 | 1992-07-23 | Alza Corporation | Bioerodible devices and compositions for diffusional release of agents |
| US5993805A (en) * | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
| GB9107628D0 (en) | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
| EP0514790A2 (en) * | 1991-05-24 | 1992-11-25 | Hoechst Aktiengesellschaft | Polycondensates containing tartaric acid derivatives, process for preparation thereof and their use |
| WO1993000383A1 (en) * | 1991-06-20 | 1993-01-07 | Pharmaceutical Delivery Systems, Inc. | Pulsed release of high molecular weight therapeutic agents from bioerodible polymer compositions |
| US5160744A (en) * | 1991-06-27 | 1992-11-03 | Alza Corporation | Verapmil therapy |
| US5190765A (en) * | 1991-06-27 | 1993-03-02 | Alza Corporation | Therapy delayed |
| US6764697B1 (en) | 1991-06-27 | 2004-07-20 | Alza Corporation | System for delaying drug delivery up to seven hours |
| US5252338A (en) * | 1991-06-27 | 1993-10-12 | Alza Corporation | Therapy delayed |
| JPH05202177A (en) * | 1991-09-06 | 1993-08-10 | Teijin Ltd | Biodegradable copolymer and medicinal composition containing the same |
| US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5254345A (en) * | 1991-10-11 | 1993-10-19 | Merck & Co., Inc. | Poly(orthocarbonate acetal) bioerodible polymers |
| WO1993015767A1 (en) * | 1992-02-05 | 1993-08-19 | Merck & Co., Inc. | Implant therapy for bone growth stimulation |
| WO1993019739A1 (en) * | 1992-03-30 | 1993-10-14 | Alza Corporation | Viscous suspensions of controlled-release drug particles |
| EP0633907A1 (en) * | 1992-03-30 | 1995-01-18 | Alza Corporation | Additives for bioerodible polymers to regulate degradation |
| MX9301817A (en) * | 1992-03-30 | 1994-01-31 | Alza Corp | POLYMERIC SYSTEM CONTAINING A PARTIALLY SOLUBLE COMPOUND. |
| US5518730A (en) | 1992-06-03 | 1996-05-21 | Fuisz Technologies Ltd. | Biodegradable controlled release flash flow melt-spun delivery system |
| EP0659073B1 (en) * | 1992-09-10 | 2001-12-19 | Children's Medical Center Corporation | Biodegradable polymer matrices for sustained delivery of local anesthetic agents |
| US5922340A (en) | 1992-09-10 | 1999-07-13 | Children's Medical Center Corporation | High load formulations and methods for providing prolonged local anesthesia |
| US5700485A (en) * | 1992-09-10 | 1997-12-23 | Children's Medical Center Corporation | Prolonged nerve blockade by the combination of local anesthetic and glucocorticoid |
| US5378468A (en) * | 1992-09-22 | 1995-01-03 | The Mennen Company | Composition containing body activated fragrance for contacting the skin and method of use |
| EP1826280A3 (en) | 1992-09-25 | 2007-12-05 | Boston Scientific Limited | Therapeutic conjugates inhibiting vascular smooth muscle cells |
| US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US5770609A (en) * | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US6306421B1 (en) | 1992-09-25 | 2001-10-23 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6395494B1 (en) | 1993-05-13 | 2002-05-28 | Neorx Corporation | Method to determine TGF-β |
| CA2153063A1 (en) * | 1992-12-29 | 1994-07-07 | Lyle M. Bowman | Bioerodible controlled delivery system |
| MY113268A (en) | 1992-12-29 | 2002-01-31 | Insite Vision Incorporated | Plasticized bioerodible controlled delivery system |
| DE69435318D1 (en) | 1993-01-28 | 2010-12-09 | Boston Scient Ltd | THERAPEUTIC INHIBITORS OF THE CELLS OF THE SMOOTH VASCULAR MUSCULAR |
| US6663881B2 (en) | 1993-01-28 | 2003-12-16 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5595722A (en) * | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
| US5981568A (en) | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| WO1996040098A2 (en) | 1995-06-07 | 1996-12-19 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
| US6440457B1 (en) * | 1993-05-27 | 2002-08-27 | Alza Corporation | Method of administering antidepressant dosage form |
| US5431630A (en) * | 1993-09-07 | 1995-07-11 | Surgic-Acid, Inc. | Needle guard and nonreusable syringe |
| DE4407898A1 (en) * | 1994-03-09 | 1995-09-14 | Hoechst Ag | Nanoparticles containing an active ingredient and a polyketalic acid amide, process for their preparation and use thereof |
| US5626862A (en) | 1994-08-02 | 1997-05-06 | Massachusetts Institute Of Technology | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
| US6063396A (en) * | 1994-10-26 | 2000-05-16 | Houston Biotechnology Incorporated | Methods and compositions for the modulation of cell proliferation and wound healing |
| US6063116A (en) * | 1994-10-26 | 2000-05-16 | Medarex, Inc. | Modulation of cell proliferation and wound healing |
| US6262115B1 (en) | 1995-05-22 | 2001-07-17 | Alza Coporation | Method for the management of incontinence |
| US5631024A (en) * | 1995-05-22 | 1997-05-20 | Enviroquest, Ltd. | Medicaments for beneficial insects and method |
| US5912268A (en) * | 1995-05-22 | 1999-06-15 | Alza Corporation | Dosage form and method for treating incontinence |
| US7611533B2 (en) * | 1995-06-07 | 2009-11-03 | Cook Incorporated | Coated implantable medical device |
| AU706541B2 (en) | 1995-06-09 | 1999-06-17 | Euro-Celtique S.A. | Formulations and methods for providing prolonged local anesthesia |
| US5736152A (en) * | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
| US5968543A (en) * | 1996-01-05 | 1999-10-19 | Advanced Polymer Systems, Inc. | Polymers with controlled physical state and bioerodibility |
| US6440460B1 (en) | 1996-03-05 | 2002-08-27 | Allergan Sales, Inc. | Pharmaceutical compositions containing buffered ortho ester polymers |
| US6096339A (en) * | 1997-04-04 | 2000-08-01 | Alza Corporation | Dosage form, process of making and using same |
| AU733867B2 (en) | 1996-06-24 | 2001-05-31 | Euro-Celtique S.A. | Methods for providing safe local anesthesia |
| US6046187A (en) * | 1996-09-16 | 2000-04-04 | Children's Medical Center Corporation | Formulations and methods for providing prolonged local anesthesia |
| EP1690531A3 (en) * | 1996-09-30 | 2010-01-20 | Alza Corporation | Dosage form and method for administering drug |
| US6919373B1 (en) * | 1996-11-12 | 2005-07-19 | Alza Corporation | Methods and devices for providing prolonged drug therapy |
| US5788987A (en) | 1997-01-29 | 1998-08-04 | Poli Industria Chimica Spa | Methods for treating early morning pathologies |
| BR9808109A (en) | 1997-03-31 | 2000-03-08 | Neorx Corp | Therapeutic smooth muscle vascular cell inhibitor |
| AU739384B2 (en) * | 1997-07-02 | 2001-10-11 | Euro-Celtique S.A. | Prolonged anesthesia in joints and body spaces |
| US20040062799A1 (en) * | 1997-09-29 | 2004-04-01 | Ayer Atul D. | Therapeutic composition and delivery system for administering drug |
| US6787157B1 (en) * | 1998-03-10 | 2004-09-07 | Abbott Laboratories | Multiphase active ingredient-containing formulations |
| WO2000002564A1 (en) * | 1998-07-10 | 2000-01-20 | The University Of Sydney | Prophylactic treatments of neovascularisation in macular degeneration |
| EP1141011A2 (en) | 1999-01-12 | 2001-10-10 | Neorx Corporation | Compounds and methods to inhibit or augment an inflammatory response |
| AUPQ496500A0 (en) * | 2000-01-06 | 2000-02-03 | University Of Sydney, The | Kit |
| WO2001080831A2 (en) | 2000-04-27 | 2001-11-01 | Verion Inc. | Zero order release and temperature-controlled microcapsules and process for the preparation thereof |
| US6613355B2 (en) | 2000-05-11 | 2003-09-02 | A.P. Pharma, Inc. | Semi-solid delivery vehicle and pharmaceutical compositions |
| US20050042194A1 (en) | 2000-05-11 | 2005-02-24 | A.P. Pharma, Inc. | Semi-solid delivery vehicle and pharmaceutical compositions |
| CA2410887C (en) | 2000-06-02 | 2012-07-24 | Bracco Research Usa | Compounds for targeting endothelial cells, compositions containing the same and methods for their use |
| EP1315777B1 (en) * | 2000-09-06 | 2007-10-31 | AP Pharma, Inc. | Degradable polyacetal polymers |
| WO2004026111A2 (en) | 2000-11-16 | 2004-04-01 | Microspherix Llc | Flexible and/or elastic brachytherapy seed or strand |
| JP2004521111A (en) * | 2001-01-25 | 2004-07-15 | ユーロ−セルティーク，エス．エイ． | Local anesthetics and usage |
| US6962071B2 (en) * | 2001-04-06 | 2005-11-08 | Bracco Research S.A. | Method for improved measurement of local physical parameters in a fluid-filled cavity |
| US6613083B2 (en) | 2001-05-02 | 2003-09-02 | Eckhard Alt | Stent device and method |
| US6590059B2 (en) * | 2001-05-11 | 2003-07-08 | Ap Pharma, Inc. | Bioerodible polyorthoesters from dioxolane-based diketene acetals |
| US20030152630A1 (en) * | 2001-05-11 | 2003-08-14 | Ng Steven Y. | PEG-POE, PEG-POE-PEG, and POE-PEG-POE block copolymers |
| WO2002100344A2 (en) * | 2001-06-11 | 2002-12-19 | Xenoport, Inc. | Amino acid conjugates providing for sustained systemic concentrations of gaba analogues |
| US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| WO2002100392A1 (en) * | 2001-06-11 | 2002-12-19 | Xenoport, Inc. | Orally administered dosage forms of gaba analog prodrugs having reduced toxicity |
| US7232924B2 (en) * | 2001-06-11 | 2007-06-19 | Xenoport, Inc. | Methods for synthesis of acyloxyalkyl derivatives of GABA analogs |
| US6524606B1 (en) * | 2001-11-16 | 2003-02-25 | Ap Pharma, Inc. | Bioerodible polyorthoesters containing amine groups |
| US20030125714A1 (en) * | 2001-12-18 | 2003-07-03 | Edgren David Emil | Dosage form for time-varying patterns of drug delivery |
| US7794693B2 (en) * | 2002-03-01 | 2010-09-14 | Bracco International B.V. | Targeting vector-phospholipid conjugates |
| CA2513044A1 (en) | 2002-03-01 | 2004-08-05 | Dyax Corp. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
| US7261876B2 (en) | 2002-03-01 | 2007-08-28 | Bracco International Bv | Multivalent constructs for therapeutic and diagnostic applications |
| US7211240B2 (en) * | 2002-03-01 | 2007-05-01 | Bracco International B.V. | Multivalent constructs for therapeutic and diagnostic applications |
| ES2398393T3 (en) | 2002-03-01 | 2013-03-15 | Dyax Corp. | KDR and VEGF / KDR binding peptides and their use in diagnosis and therapy |
| US8623822B2 (en) * | 2002-03-01 | 2014-01-07 | Bracco Suisse Sa | KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy |
| US20040043070A1 (en) * | 2002-05-14 | 2004-03-04 | Ayres James W. | Hot melt coating by direct blending and coated substrates |
| US20040001889A1 (en) | 2002-06-25 | 2004-01-01 | Guohua Chen | Short duration depot formulations |
| US20050232995A1 (en) * | 2002-07-29 | 2005-10-20 | Yam Nyomi V | Methods and dosage forms for controlled delivery of paliperidone and risperidone |
| US20050208132A1 (en) * | 2002-07-29 | 2005-09-22 | Gayatri Sathyan | Methods and dosage forms for reducing side effects of benzisozazole derivatives |
| JP4959133B2 (en) | 2002-09-09 | 2012-06-20 | ネクター セラピューティックス | Method for preparing water-soluble polymer derivative having terminal carboxylic acid or ester thereof |
| US7354574B2 (en) * | 2002-11-07 | 2008-04-08 | Advanced Ocular Systems Limited | Treatment of ocular disease |
| US7045589B2 (en) * | 2002-11-15 | 2006-05-16 | A.P. Pharma, Inc. | Bioerodible poly(ortho esters) from dioxane-based di(ketene acetals), and block copolymers containing them |
| WO2004052841A1 (en) | 2002-12-06 | 2004-06-24 | Xenoport, Inc. | Carbidopa prodrugs and uses thereof |
| US20040162351A1 (en) * | 2002-12-11 | 2004-08-19 | Gallop Mark A. | Orally administered dosage forms of fused GABA analog prodrugs having reduced toxicity |
| ES2396368T3 (en) | 2003-03-03 | 2013-02-21 | Dyax Corporation | Peptides that specifically bind to the HGF receptor (CMET) and uses thereof |
| US20040254246A1 (en) * | 2003-03-31 | 2004-12-16 | Barrett Ronald W. | Treating or preventing hot flashes using prodrugs of GABA analogs |
| ATE461681T1 (en) * | 2003-04-29 | 2010-04-15 | Gen Hospital Corp | METHODS AND DEVICES FOR SUSTAINED RELEASE OF MULTIPLE DRUGS |
| US20070141071A1 (en) * | 2003-05-14 | 2007-06-21 | Oregon State University | Hot melt coating by direct blending and coated substrates |
| US7083802B2 (en) * | 2003-07-31 | 2006-08-01 | Advanced Ocular Systems Limited | Treatment of ocular disease |
| EP2354120A1 (en) | 2003-08-20 | 2011-08-10 | XenoPort, Inc. | Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof |
| WO2005019163A2 (en) * | 2003-08-20 | 2005-03-03 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis and use |
| US7700652B2 (en) * | 2003-09-11 | 2010-04-20 | Xenoport, Inc. | Treating urinary incontinence using prodrugs of GABA analogs |
| KR101157436B1 (en) * | 2003-09-17 | 2012-07-05 | 제노포트 인코포레이티드 | Treating or preventing restless legs syndrome using prodrugs of gaba analogs |
| AU2004274026A1 (en) * | 2003-09-18 | 2005-03-31 | Macusight, Inc. | Transscleral delivery |
| US7083803B2 (en) * | 2003-09-19 | 2006-08-01 | Advanced Ocular Systems Limited | Ocular solutions |
| US20050181018A1 (en) * | 2003-09-19 | 2005-08-18 | Peyman Gholam A. | Ocular drug delivery |
| US7087237B2 (en) * | 2003-09-19 | 2006-08-08 | Advanced Ocular Systems Limited | Ocular solutions |
| US7329413B1 (en) * | 2003-11-06 | 2008-02-12 | Advanced Cardiovascular Systems, Inc. | Coatings for drug delivery devices having gradient of hydration and methods for fabricating thereof |
| JP2007520496A (en) * | 2004-02-04 | 2007-07-26 | レットメッド ピーティーワイ リミテッド | Sustained release steroid composition |
| US20050192257A1 (en) * | 2004-02-26 | 2005-09-01 | Peyman Gholam A. | Predictors for patients at risk for glaucoma from steroid therapy |
| WO2005082380A1 (en) * | 2004-02-26 | 2005-09-09 | Advanced Ocular Systems Limited | Heparin for the treatment of ocular pathologies |
| PL1755616T3 (en) * | 2004-04-08 | 2014-10-31 | Eye Co Pty Ltd | Treatment of exudative retinopathy with mineralcorticoids |
| US20050261243A1 (en) * | 2004-04-21 | 2005-11-24 | Peyman Gholam A | Antiprostaglandins for the treatment of ocular pathologies |
| WO2005121070A1 (en) * | 2004-06-04 | 2005-12-22 | Xenoport, Inc. | Levodopa prodrugs, and compositions and uses thereof |
| PT1751087E (en) * | 2004-06-04 | 2012-09-10 | Xenoport Inc | Levodopa derivatives, and compositions and uses thereof |
| US20060128676A1 (en) * | 2004-07-13 | 2006-06-15 | Pharmacofore, Inc. | Compositions of nicotinic agonists and therapeutic agents and methods for treating or preventing diseases or pain |
| ES2432556T3 (en) | 2004-08-04 | 2013-12-04 | Evonik Corporation | Methods for manufacturing supply devices and their devices |
| US7566738B2 (en) | 2004-11-03 | 2009-07-28 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs of sulfinic acids, methods of synthesis, and use |
| WO2006050472A2 (en) * | 2004-11-03 | 2006-05-11 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs of 3-aminopropylphosphonous and -phosphinic acids |
| NZ554737A (en) * | 2004-11-04 | 2011-04-29 | Xenoport Inc | Gabapentin prodrug sustained release oral dosage forms |
| US20060122152A1 (en) * | 2004-12-03 | 2006-06-08 | Peyman Gholam A | Heparin for the treatment of ocular pathologies |
| US8663639B2 (en) * | 2005-02-09 | 2014-03-04 | Santen Pharmaceutical Co., Ltd. | Formulations for treating ocular diseases and conditions |
| ES2564194T3 (en) * | 2005-02-09 | 2016-03-18 | Santen Pharmaceutical Co., Ltd. | Liquid formulations for the treatment of diseases or ailments |
| EP1853560A1 (en) | 2005-02-23 | 2007-11-14 | Psychenomics, Inc. | Dopamine transporter inhibitors for use in treatment of movement disorders and other cns indications |
| WO2006091790A1 (en) * | 2005-02-23 | 2006-08-31 | Xenoport, Inc. | Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use |
| US20060235084A1 (en) * | 2005-03-31 | 2006-10-19 | Jorge Heller | PEG-polyacetal diblock and triblock copolymers and pharmaceutical compositions |
| KR20070122522A (en) * | 2005-03-31 | 2007-12-31 | 에이피 파마, 인코포레이티드 | Peg-poly(ortho ester) graft copolymers and pharmaceutical compositions |
| AU2006243960A1 (en) * | 2005-05-10 | 2006-11-16 | Emory University | Strategies for delivery of active agents using micelles and particles |
| US7616111B2 (en) | 2005-06-20 | 2009-11-10 | Carestream Health, Inc. | System to monitor the ingestion of medicines |
| US7782189B2 (en) * | 2005-06-20 | 2010-08-24 | Carestream Health, Inc. | System to monitor the ingestion of medicines |
| DE602006014694D1 (en) | 2005-06-20 | 2010-07-15 | Xenoport Inc | ACYLOXYALKYL CARBAMATE PRODRUGS OF TRANEXAN ACID AND APPLICATION |
| WO2007011880A2 (en) | 2005-07-18 | 2007-01-25 | Minu, L.L.C. | Enhanced ocular neuroprotection/neurostimulation |
| US20070014760A1 (en) * | 2005-07-18 | 2007-01-18 | Peyman Gholam A | Enhanced recovery following ocular surgery |
| WO2007027476A2 (en) * | 2005-08-26 | 2007-03-08 | Xenoport, Inc. | Treating premature ejaculation using gabapentin and pregabalin prodrugs |
| US7563821B2 (en) * | 2005-12-05 | 2009-07-21 | Xenoport, Inc. | Levodopa prodrug mesylate, compositions thereof, and uses thereof |
| WO2007076462A2 (en) * | 2005-12-22 | 2007-07-05 | Oakwood Laboratories, Llc | Sublimable sustained release delivery system and method of making same |
| KR20140093764A (en) | 2006-02-09 | 2014-07-28 | 산텐 세이야꾸 가부시키가이샤 | Stable formulations, and methods of their preparation and use |
| EP1854477B9 (en) | 2006-03-16 | 2018-03-14 | Dyax Corp. | Peptides inhibiting plasma kallikrein for use in the treatment of ophthalmic disorders. |
| DK2001466T3 (en) | 2006-03-23 | 2016-02-29 | Santen Pharmaceutical Co Ltd | LOW-DOSAGE RAPAMYCINE FOR TREATMENT OF VASCULAR PERMEABILITY-RELATED DISEASES |
| US20070265329A1 (en) * | 2006-05-12 | 2007-11-15 | Devang Shah T | Methods for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) |
| US20070264338A1 (en) * | 2006-05-12 | 2007-11-15 | Shah Devang T | Base-stabilized polyorthoester formulations |
| US20070264339A1 (en) * | 2006-05-12 | 2007-11-15 | Ap Pharma, Inc. | Base-stabilized polyorthoester formulations |
| EP2046393B1 (en) | 2006-05-26 | 2014-02-12 | Signature Therapeutics, Inc. | Controlled release of phenolic opioids |
| US7458953B2 (en) * | 2006-06-20 | 2008-12-02 | Gholam A. Peyman | Ocular drainage device |
| EP2044142A2 (en) | 2006-06-29 | 2009-04-08 | Medtronic, Inc. | Poly(orthoester) polymers, and methods of making and using same |
| CN101505794B (en) * | 2006-07-10 | 2013-09-04 | 艾斯巴技术,爱尔康生物医药研究装置有限责任公司 | scFV antibodies which pass epithelial and/or endothelial layers |
| US9744137B2 (en) * | 2006-08-31 | 2017-08-29 | Supernus Pharmaceuticals, Inc. | Topiramate compositions and methods of enhancing its bioavailability |
| WO2008033572A1 (en) * | 2006-09-15 | 2008-03-20 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis and use |
| BRPI0718696A2 (en) | 2006-11-09 | 2013-12-31 | Alcon Res Ltd | WATER INSOLUBLE POLYMER MATRIX FOR PHARMACEUTICAL RELEASE. |
| US20080114076A1 (en) * | 2006-11-09 | 2008-05-15 | Alcon Manufacturing Ltd. | Punctal plug comprising a water-insoluble polymeric matrix |
| EP1973528B1 (en) | 2006-11-17 | 2012-11-07 | Supernus Pharmaceuticals, Inc. | Sustained-release formulations of topiramate |
| JP2010512314A (en) * | 2006-12-08 | 2010-04-22 | ゼノポート，インコーポレーテッド | Use of GABA analog prodrugs to treat disease |
| TW200843731A (en) * | 2006-12-21 | 2008-11-16 | Xenoport Inc | Catechol protected levodopa diester prodrugs, compositions, and methods of use |
| TW200843732A (en) * | 2006-12-21 | 2008-11-16 | Xenoport Inc | Levodopa dimethyl-substituted diester prodrugs, compositions, and methods of use |
| US20080265343A1 (en) * | 2007-04-26 | 2008-10-30 | International Business Machines Corporation | Field effect transistor with inverted t shaped gate electrode and methods for fabrication thereof |
| EP2222281B1 (en) | 2007-12-20 | 2018-12-05 | Evonik Corporation | Process for preparing microparticles having a low residual solvent volume |
| US8940315B2 (en) * | 2008-04-18 | 2015-01-27 | Medtronic, Inc. | Benzodiazepine formulation in a polyorthoester carrier |
| US8956642B2 (en) * | 2008-04-18 | 2015-02-17 | Medtronic, Inc. | Bupivacaine formulation in a polyorthoester carrier |
| JP2011519638A (en) * | 2008-05-07 | 2011-07-14 | オービージェイ・リミテッド | Method and apparatus for promoting transdermal diffusion |
| AU2009270695A1 (en) | 2008-07-17 | 2010-01-21 | Ap Pharma | Methods for enhancing the stability of polyorthoesters and their formulations |
| EP2147684A1 (en) | 2008-07-22 | 2010-01-27 | Bracco Imaging S.p.A | Diagnostic Agents Selective Against Metalloproteases |
| CN102186804A (en) * | 2008-10-20 | 2011-09-14 | 克塞诺波特公司 | Methods of synthesizing a levodopa ester prodrug |
| US8399513B2 (en) * | 2008-10-20 | 2013-03-19 | Xenoport, Inc. | Levodopa prodrug mesylate hydrate |
| WO2010068827A1 (en) * | 2008-12-11 | 2010-06-17 | A.P. Pharma, Inc. | Methods for enhancing stability of polyorthoesters and their formulations |
| EP2437684B1 (en) | 2009-06-03 | 2022-06-15 | ForSight Vision5, Inc. | Anterior segment drug delivery |
| WO2011028234A1 (en) * | 2009-09-04 | 2011-03-10 | Xenoport, Inc. | Uses of acyloxyalkyl carbamate prodrugs of tranexamic acid |
| US8709489B2 (en) * | 2009-09-30 | 2014-04-29 | Surmodics, Inc. | Emulsions containing arylboronic acids and medical articles made therefrom |
| EP2488640B1 (en) | 2009-10-14 | 2018-09-26 | Nanyang Technological University | Antiproliferative agent |
| JP2013520521A (en) | 2009-11-09 | 2013-06-06 | ゼノポート，インコーポレーテッド | Pharmaceutical composition and oral dosage form of levodopa prodrug and method of use |
| EP2343046A1 (en) | 2010-01-08 | 2011-07-13 | Nirvana's Tree House B.V. | Functionalised triblock copolymers and compositions containing such polymers |
| US9452037B2 (en) | 2010-05-25 | 2016-09-27 | International Scientific Pty Ltd | Delivery of oral care products |
| US9463330B2 (en) | 2010-06-17 | 2016-10-11 | International Scientific Pty Ltd | Delivery of skin care products |
| WO2012050907A2 (en) | 2010-09-28 | 2012-04-19 | The Regents Of The University Of California | Gaba agonists in the treatment of disorders associated with metabolic syndrome and gaba combinations in treatment or prophylaxis of type i diabetes |
| US8580294B2 (en) | 2010-10-19 | 2013-11-12 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
| WO2012116209A1 (en) | 2011-02-23 | 2012-08-30 | Ams Research Corporation | Drug releasing pelvic treatment system and method |
| EP2677960A4 (en) | 2011-02-23 | 2016-11-16 | Boston Scient Scimed Inc | Pelvic implant and therapeutic agent system and method |
| WO2013040426A2 (en) | 2011-09-14 | 2013-03-21 | Forsight Labs, Llc | Ocular insert apparatus and methods |
| WO2013078422A2 (en) | 2011-11-23 | 2013-05-30 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US9115066B2 (en) | 2011-12-14 | 2015-08-25 | Indicator Systems International, Inc. | Trisubstituted methyl alcohols and their polymerizable derivatives |
| US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
| US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
| US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| DK2911623T3 (en) | 2012-10-26 | 2019-10-28 | Forsight Vision5 Inc | Ophthalmic system for long-term release of drug into the eye |
| US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
| US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10220093B2 (en) | 2013-02-28 | 2019-03-05 | Mira Pharma Corporation | Long-acting semi-solid lipid formulations |
| US9849180B2 (en) | 2014-09-15 | 2017-12-26 | Hui Rong Shen | Long-acting semi-solid lipid formulations |
| KR102370470B1 (en) | 2013-03-15 | 2022-03-04 | 헤론 테라퓨틱스 인코포레이티드 | Compositions of a polyorthoester and an aprotic solvent |
| US10137031B2 (en) | 2013-11-14 | 2018-11-27 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
| JP6702882B2 (en) | 2014-04-21 | 2020-06-03 | ヘロン セラピューティクス， インコーポレイテッドＨｅｒｏｎ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． | Long-acting polymer delivery system |
| EP3785700A1 (en) | 2014-04-21 | 2021-03-03 | Heron Therapeutics, Inc. | Compositions of a polyorthoester and an organic acid excipient |
| US9801945B2 (en) | 2014-04-21 | 2017-10-31 | Heron Therapeutics, Inc. | Long-acting polymeric delivery systems |
| EP3509601A1 (en) | 2014-04-21 | 2019-07-17 | Heron Therapeutics, Inc. | A pharmaceutical composition comprising a delivery system, an amide-type local anesthetic, and meloxicam |
| US10206932B2 (en) | 2014-05-22 | 2019-02-19 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| WO2015188223A1 (en) | 2014-06-11 | 2015-12-17 | International Scientific Pty Ltd | Device and method to treat or prevent joint degeneration |
| CA2936748C (en) | 2014-10-31 | 2017-08-08 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
| US20160296532A1 (en) | 2015-04-13 | 2016-10-13 | Forsight Vision5, Inc. | Ocular Insert Composition of a Semi-Crystalline or Crystalline Pharmaceutically Active Agent |
| US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
| CA2998708C (en) | 2015-10-01 | 2019-09-03 | Elysium Therapeutics, Inc. | Polysubunit opioid prodrugs resistant to overdose and abuse |
| US10335406B2 (en) | 2015-10-01 | 2019-07-02 | Elysium Therapeutics, Inc. | Opioid compositions resistant to overdose and abuse |
| US10519442B2 (en) | 2016-02-11 | 2019-12-31 | City Of Hope | Twist signaling inhibitor compositions and methods of using the same |
| AU2017239645A1 (en) | 2016-04-01 | 2018-10-18 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical composition |
| US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
| US11779657B2 (en) | 2016-06-10 | 2023-10-10 | City Of Hope | Compositions and methods for mitochondrial genome editing |
| US10646540B2 (en) | 2016-11-18 | 2020-05-12 | City Of Hope | Peptide inhibitors of twist |
| CA3056239C (en) | 2017-03-17 | 2023-09-12 | Elysium Therapeutics, Inc. | Polysubunit opioid prodrugs resistant to overdose and abuse |
| SG11201909478UA (en) | 2017-04-24 | 2019-11-28 | Cocrystal Pharma Inc | Pyrrolopyrimidine derivatives useful as inhibitors of influenza virus replication |
| CA3067558A1 (en) | 2017-06-16 | 2018-12-20 | Avery Therapeutics, Inc. | Three dimensional tissue compositions and methods of use |
| US11426418B2 (en) | 2017-12-06 | 2022-08-30 | Mira Pharma Corporation | Injectable long-acting semi-solid gel formulations |
| US10561606B2 (en) | 2017-12-06 | 2020-02-18 | Mira Pharma Corporation | Injectable long-acting local anesthetic semi-solid gel formulations |
| WO2020023813A1 (en) | 2018-07-27 | 2020-01-30 | Cocrystal Pharma, Inc. | Pyrrolo[2,3-b]pyridin derivatives as inhibitors of influenza virus replication |
| TW202023566A (en) | 2018-09-10 | 2020-07-01 | 美商共結晶製藥公司 | Inhibitors of influenza virus replication |
| EP3866778B1 (en) | 2018-10-17 | 2022-11-30 | Cocrystal Pharma, Inc. | Combinations of inhibitors of influenza virus replication |
| US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
| US20220048897A1 (en) | 2018-11-26 | 2022-02-17 | Cocrystal Pharma, Inc. | Inhibitors of influenza virus replication |
| WO2021146215A1 (en) | 2020-01-13 | 2021-07-22 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
| US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
| WO2021188620A1 (en) | 2020-03-17 | 2021-09-23 | Cocrystal Pharma Inc. | Peptidomimetic n5-methyl-n2-(nonanoyl-l-leucyl)-l-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds as inhibitors of norovirus and coronavirus replication |
| JP2023521116A (en) | 2020-04-10 | 2023-05-23 | コクリスタル ファーマ，インコーポレイテッド | Inhibitors of norovirus and coronavirus replication |
| IL310394A (en) | 2021-08-03 | 2024-03-01 | Cocrystal Pharma Inc | Inhibitors for coronaviruses |
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| US3252786A (en) * | 1962-09-28 | 1966-05-24 | Sun Oil Co | Slow release fertilizers and method of making |
| US3887699A (en) * | 1969-03-24 | 1975-06-03 | Seymour Yolles | Biodegradable polymeric article for dispensing drugs |
| US3960150A (en) * | 1971-09-09 | 1976-06-01 | Alza Corporation | Bioerodible ocular device |
| US4001388A (en) * | 1973-06-14 | 1977-01-04 | Alza Corporation | Ophthalmological bioerodible drug dispensing formulation |
| US4014987A (en) * | 1974-06-04 | 1977-03-29 | Alza Corporation | Device for delivery of useful agent |
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- 1975-01-28 US US05/544,808 patent/US4093709A/en not_active Expired - Lifetime
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- 1976-01-26 SE SE7600760A patent/SE418189B/en not_active IP Right Cessation
- 1976-01-27 AT AT55276A patent/AT356903B/en not_active IP Right Cessation
- 1976-01-27 DK DK032076A patent/DK166360C/en not_active IP Right Cessation
- 1976-01-27 BR BR7600499A patent/BR7600499A/en unknown
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- 1976-01-27 CH CH100376A patent/CH635355A5/en not_active IP Right Cessation
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- 1976-01-28 MX MX163296A patent/MX142986A/en unknown
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- 1976-01-28 NL NLAANVRAGE7600881,A patent/NL174728C/en not_active IP Right Cessation
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| FR2299356A1 (en) | 1976-08-27 |
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| ZA76493B (en) | 1977-07-27 |
| IL48799A0 (en) | 1976-03-31 |
| CH635355A5 (en) | 1983-03-31 |
| MX142986A (en) | 1981-02-03 |
| NL174728B (en) | 1984-03-01 |
| ES444484A1 (en) | 1977-09-16 |
| GB1502082A (en) | 1978-02-22 |
| DK166360B (en) | 1993-04-13 |
| NL7600881A (en) | 1976-07-30 |
| SE7600760L (en) | 1976-09-20 |
| US4138344A (en) | 1979-02-06 |
| IT1057070B (en) | 1982-03-10 |
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