CA1185048A - Polymerization process and product - Google Patents
Polymerization process and productInfo
- Publication number
- CA1185048A CA1185048A CA000360018A CA360018A CA1185048A CA 1185048 A CA1185048 A CA 1185048A CA 000360018 A CA000360018 A CA 000360018A CA 360018 A CA360018 A CA 360018A CA 1185048 A CA1185048 A CA 1185048A
- Authority
- CA
- Canada
- Prior art keywords
- copolymer
- weight percent
- lactic acid
- glycolic acid
- acid
- 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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
- C08G63/82—Preparation processes characterised by the catalyst used
- C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
Abstract
Abstract of the Disclosure Lactic-glycolic copolymers having weight average molecular weights of about 6000 to about 35000 are prepared by condensation of lactic acid and glycolic acid in the presence of readily removable strong acid ion-exchange resins. The invention provides a polymerization process which permits the substantially total removal from the copolymer of polymerization catalysts, so that the copolymers so produced can be utilized as drug delivery systems, thereby permitting the complete biodegradation of the system with no residual toxic foreign substances remaining in animal tissues.
Description
,Y-5064 -1-POLYMERIZA~ION PROCESS AND PRODUCT
Polymers and copolymers are widely used in a variety of fields. One reason for the e~pansive appli-cation of polymers is due to the uniquely differing physical properties which are e~hibited by various polymers. Numerous different polymers, all e~hibiting varying physical properties, can be obtained from the same monomers by altering the method of preparation, the polymeri~ation catalysts, the quantities of monomers utilized and related factors.
The prior art teaches a number of polymers and copolymers of lactic acid and glycolic acid.
Schmitt et 21., in U.S. Patent Nos. 3,739,773, 3,736,646 and 3,875,937, cite and discuss a great deal of art directed to polymers and copolymers in general, as well as specific lactic acid and glycolic acid copolymers.
As pointed out by Yolles in ~I.S. Patent No.
3,887,699, much interest has been focused on the possibility of incorporating drugs into polymeric materials in order to obtain a controlled and sustained release of such drug to a living system. ~any problems, however, are associated with the use o~ polymers and copolymers for the slow release of drugs into a living system. For e~ample, Schmitt et al., in U.S. Patent 25 No. 3,982,543, points out that copolymers in general have a rela-tively slow hydrolysis rate in the acid environment in the stomach but a much high-r hydrolysis rate in the more alkaline environment of the intestine.
Siegrist et al., in U.S. Patent No. 3,535,419, disclose a sustained release drug and polymer formulation that ~ ~ ~ 3 ~
X-5064 -2~
ls suitable for the administra-tion of steroidal drugs via the rumeno-reticular portions of the stomach of ruminants. Such formulations require the use of at least one hig~ly water insoluble wax, fat, oil, fatty acid, fatty acid ester, fatty acid amide, fatty acid alcohol or polymer. Reuter et al., in U.S. Patent No.
4,011,312, describe a prolonged release drug dosage form for the treatment of bovine mastitis consisting of an antimicrobial agent dispersed in a matrix of a poly-ester of glycolic and lactic aeids having a molecularweight of less than 2000.
Numerous referenees teach that an advantage of utilizing copolymers comprised of glycolic acid and laetic acid is the fact -that the hydrolysis products are constituents in normal me-tobolic pathways and consequently are nontoxic and harmless when exposed to human or animal tissues. One drawback assoeiated with the prior art copolymers, however, is the presence of polymexization catalysts sueh as a polyvalent metal oxide or metal nalide. Upon biodegradation of the eopolymer-drug matrix, a finite quantity of such toxic polymerization catalyst remains in the animal tissue and is not subject to biodegradation. Moreover, catalysts utilized to promote polymerization also cause ~5 breakdown of -the polymer when eontaet i5 maintained.
Therefore, polymers containing polymerization eatalysts as impurities are subjeet to unpredietable degradation.
This inven-tion relates to a proeess for polymerizing glyeolie aeid and laetie aeid via eon-densation~ such that copolymers having a weight average molecular weight of about 6000 to abou-t 35000 are obtained. Also this invention provides a polymeriza-tion process which permits the substantially total removal from the copolymer of polymerization catalysts, so that the copolymers so produced can be utilized as drug delivery systems, thereby permitting the complete biodegradation of the system with no residual toxlc foreign substances remaining in animal tissues. This invention additionally provides unique copolymers derived from lactic and glycolic acid which are capable of biodegradation over a predetermined period of time, thus allowing -the controlled release of a drug dispersed therein at a predetermined rate over the period of time necessitated by the particular treatment being af~orded.
Further, this invention provides a method for polymeriz-ing lactic acid and glycolic acid via direct condensa~
tion, thereby obviating the need to first prepare cyclic lactides and glycolides as preerred by the prior art. The invention thererore offers significant economic advantages over prior art polymerization processes.
Thus, this invention concerns a process for the polymerization of lactic acid and glycolic acid via direct conden5ation, and to the copolymers prepared by such process. More particularly, the invention provides a copolymer derived from the polymerization of lactic acid and glycolic acid, which comprises the amount of about 60 to about 95 weight percent of lactic acid and about ~0 to about 5 weight percent of glycolic acid, said copolymer having an inherent viscosity in chloro-X-5064 -~-form of about 0.08 to about 0.30 and a weight average molecular weight of about 6000 to about 35,000, said copolymer being substantially free of polymerization catalyst. The inherent viscosity was measured a-t a concentration of 0.50 g. of copolymer in 100 ml. of chloroform at 25C.
A process for preparing a copolymer derived by the polymerization of about 60 to about 95 weight percent of lactic acid and about 40 to about 5 weight percent of glycolic acid, said copolymer having a weight average molecular weight of about 6000 to about 35000, with an inherent viscosity in chloroform of about 0.08 to about 0.30, wherein the polymerization of the lactic acid and glycolic acid is effected in the presence of a readily removable strong acid ion-exchange resin, said resin being subsequently removed therefrom.
This polymerization is preferrably effected at a tempera-ture from about 100 to about 250C. for about 3 to about 172 hours.
Preferred copolymers prepared according to the process of this invention are derived from about 60 -to about 90 weight percent lactic acid and about 40 to about 10 weight percent glycolic acid. The copolymers of the invention ideally have a viscosity of àbout 0.10 to about 0.25, and a weight average molecular weight of about 15,000 to about 30,000. Especially preferred copolymers are those derived from about 70 to about 80 weight percent lactic acid and about 30 to about 20 weight percent glycolic acid with an inherent viscosity 30 of about 0.10 to about 0.25.
According to the process of this inventlon, glycolic acid is condensed with lactic acid by reaction in the presence of a readily removable strong acid ion exchange resin. Preferred catalysts are those in the ~orm of beads or similar solid compositions which facilitate removal, for example by filtration. Pre-ferred catalysts include~commercial resins o~ the gel type, [such as Amberlite IR-118(H) and Dowex HCR-W
(formerly Dowex 50W)] as well as resins of the macro-reticular type, [such as Amberly~t~15 and Dowex~MSC-l].
According to the process of this invention, lactic acid is condensed ~ith glycolic acid in such a manner that a copolymer is formed which is derived from about 60 to about 95 weight percent of lactic acid and from about 40 to about 5 weight percent of glycolic acid. The polymerization process is carried out by condensing lactic acid and glycolic acid in the presence of a strong acid ion-exchange resin catalyst that is subject to convenient removal by standard methods such as filtration. The catalyst can be prepared by poly-merizing styrene with any of a number of cross-linking agents such as divinylbenzene or similar agentsO
Such resin polymer is reacted with a strong acid such as sulfuric, phosphoric, tetrafluoroboric, paratoluene sulfonic, and related acids, so as to obtain a strong acid substituted cross-linked polystyrene. Such strong acid ion-exchange resins are commercially available in the form of beads and similar solid articles. Examples of commercially available strong acid ion-exchange resins useful in the present process include Amberlite ~3 IR-118(H), Amberlite~ IR--120 Amberlite~ I~F-66(~1), Dowex~ ElCR-W (formerly Dowe ~ 50W), Duolite~ C-20, Amberlyst~ 15, Dowex~ MSC-l, Duolite~ C-25D, Duolite~ ES-26 and related strong acid ion-exchange resins. Various forms of these catalysts can be utilized, for example Dowex HCR-W2-H. Amberlyst 15 is a macroreticular ion-exchange resin which is of a strongly acidic cation exchange type.
Dowex HCR-W2-H is a strongly acidic cation resin with cross-linking made from styrene-divinylbenzene copolymers, having a large number of ionizable or functional groups attached.
According to the present process, the strong acid ion-exchange resin is added to a mixture of lactic acid and glycolic acid. The polymerization reaction generally is carried out in the absence of reaction solvent. How-ever, reaction solvents such as N,N-dimethylformamide, dimethylsulfoxide, and others, can be utilized if desired.
The amount of strong acid ion-exchange resin utilized in the condensation process is not critical to the process.
Typically, the quantity of resin catalyst utilized will be an amount sufficient to effectively initiate and main-tain the polymerization process. Such effective amounts routinely vary from about 0.1 to about 20 percent by weight relative to the total amount of glycolic acid and lactic acid in the reaction mixture.
Once the strong acid ion-exchange resin and glycolic and lactic acids are mixed, the reaction mixture is heated to a temperature from about 100C. to about 250C. Ideally the reaction is carried out in such a manner that water which is formed during the polymerization is conveniently removed, for instance by distillation. Water removal can be facilitated if desired by the application of a vacuum to the ~eaction vessel. Typically, any lactide and glycolide that is formed also is removed by such distillation. The polymerization reaction is driven to completion by the continuous heating and concomittant removal of water from the reaction mixture as it is formed. When the reaction is carried out at a temperature of about 100 to about 250C., ideally from about 130 to about 190C., the polymerization generally is substantially complete after about 48 to about 96 hours.
Isolation and purification of the copolymer thus formed are accomplished by routine methods. The strong acid ion-exchange resin can be substantially removed from the copolymer product by simply filtering the molten reaction mixture, for instance through a metal sieve of appropriate mesh size, for example rnesh 20 to about 50. Alternatively, the reaction mixture can be cooled to room temperature and the copolymer can be dissolved in any of a number of organic solvents in which the ion~exchange resin is insoluble. Such solvents include chloroform, dichloromethane, benzene, xylene and others. Once the copolymer is substantially dissolved in such organic solvent, normal filtration effects removal of the insoluble strong acid ion-exchange resin. Removal of the organic solvent from the filtrate, for instance by evaporation under reduced pressure, then affords the desired copolymer of the lnvention, substantially free of polymerization catalyst. If needed, the copolymer can be redissolved in a suitable solvent and again filtered, thereby substantially eliminatin~ all traces of ion-exchange resin which might be present.
The copolymers comprehended by this inventionand prepared according to the novel process described hereinabove are charac-terized by routine methods commonly utilized in the identification o polymers and copolymers. The relative composition of the copolymers is determined by proton nuclear ma~netic resonance spectrometry. By determining the ratio of methylene protons attributable to glycolic acid units to methine protons attributable to lactic acid units, the relatlve ratio of total glycolic units to total lactic units is determined.
The inherent viscosity of the copolymers of this invention is determined by standard procedures utilizing an Ubbelohde viscometer. The copolymer to be analyzed is dissolved in chloroform at a concentration of 0.50 g./100 ml. The term inherent viscosity (ninh) used herein is defined by the following equation:
inh ln nrel wherein ln is the natural logarithm, C is concen-tration in grams/100 ml. of solution, and nrel is relative viscosity as defined by the equation:
nrel - tt wherein to is the efflux time of pure solvent (chloro-form herein) and t is the efflux time of the solution containing the copolymer.
The copolymers derived from lactic acid and glycolic acid which are provided by this invention and prepared according to the novel process described hereinabove are particularly well suited for use in the formulation of medlcaments deslgned to provide a prolonged, controlled and unlform release of active agent to a biologic~l system. Such formulations are especially useful in the therapeutic and prophylactic trea-tment of diseases occurring in animals which are not subject to daily treatment by conventional me-thods.
rrhe copolymers of the invention have the unique physical properties which permit their con-trolled and uniform degradation into non-toxic and readily metabolized substances ~hen placed in contact with animal tissue and body fluids. For example, to allow the controlled release of the drug from the co-polymer/ the copolymer must be p~ soluble in the envi-ronment used, e.g. -the rumen of an animal, the body tissues contacted by injection, and other such areas.
Thus, the instant copolymer is pH soluble from a~out 5.0 to about 7.3. Moreover, bscause the copolymers are prepared by the novel process provided herein which permits the substantially complete removal of polymeri-zation catalysts, no foreign substances of a toxic nature are available for absorption by body tissue.
Furthermore, because the copolymers have the ability to undergo uniform biodegradation determined in part by the relative proportions of lactic acid and glycolic acid present, the particular period required for total biodegradation can be predetermined and adjusted as desired by varying the relative ~uantities of the respective constituents of the copolymer~ To determine the dissolutior. rate of the instant copolymers; the a~
~-5064 -10-copolymer was placed n ar-tificial rumen conditions (pH about ~.8) for a 63 day period and the mg./day dissolution rate determined. Range about 350 to about 500 mg./day.
~inh1mg./day~
0.20 ~00 0.19 415 0.17 475 lis the inherent viscosity and all copolymers were 80 weight percent lactic acld and 20 weight percent glycolic acid.
2is dissolution rate determined as an average of three seperate runs.
As contemplated herein, the copolymers pro-vided by this invention can be utilized in the formula-tion of various drugs for the controlled release of such drug into a biological system. Druys which can be incorporated into such formulations containing the copolymers of this invention include any such dxug useful in the therapeutic or prophylactic treatment of a mammal, including humans and animals. The copolymers are particularly useful in the preparation of con-trolled release formulations for the treatment of animals raised for their meat or other food products to be consumed by humans, for example farm animals such ascattle, swine and the like.
Typical drugs which are ideally suited ~or the treatment of animals via a controlled release formulation utllizing a copolymer of this invention include an-tibiotics such as any of the well known penicillins, cephalosporins, tetracyclines, as well as speeific agents such as streptomycin A and streptomycin B, aureom~ein, tylosin and simllar antibiotics.
Another elass of drugs whieh are well suited to formulation with the eopolymers of this invention for eontrolled release over a prolonged period of time are agents used to improve feed efficieney in animals such as feeder ealves. Such agents currently are administered primarily as feed additives. Sueh method of administration suffers from the faet that the aetual and effeetive dose of active agent is dependent upon the feeding habits OL the animal, thus permitting uneontrolled overdosing and underdosing. Moreover, feeder stoek whieh is range fed are unable to be treated b~ feed additives, whereas a formulation eomprised of a suitable drug dispersed throughout a copolymer of this invention can be administered in the form of a bolus whieh is retained in the rumen, thus permitting the eontrolled release of an effective amount of aetive agent over a prolonged period of time lasting several weeks or months. Typieal feed effi-eieney enhaneing agents and growth promoters whieh ean be formulated with the eopolymers of this invention inelude monensin, lasaloeid, apramycin, narasin, salinomyein and the like.
~ L~V~8 Another class or pharmocodynamic agents which can be formulated with the copolymers of this invention for con-trolled release include natural and synthetic hormones and related agents that function as fertility-control agents. Such drugs include estrogens, androgens,progestogens, corticoids, anabolic agents and the like.
The copolymers of this invention can be used to formulate an active agent for convenient oral or parenteral administration. For example, a c~polymer derived from about 30 weight percent glycolic acid and about 70 weight percent lactic acid and having an inh~rent viscosity of about 0.13 can be dissolved in a suitable organic solvent such as dichloromethane. A
suficient quantity of an antibacterial agent such as tylosin or the like can be added to the copolymer solution, and the organic solvent can then be removsd by evaporation so as to provide a uni~orm mixture com-prised of about 30 weight percent active agent and about 70 weight percent copolymer. Such mixture can be extruded so as to form glass-type rods. The glass rods thus ormed can be ground, powdered and suspended in a suitable oil such as sesame oil and injected subcutane-ousl~ to an animal such as a young calf for the effec-tive prolonged treatment of infections caused by diseases such as pneumonia. By utilizing such formulation/ the animal can recei~e a uniform dose of active agent, such as about 5 mg. per head per day, following a single injection. Total payout can occur within about seven days, or longer depending upon the particular copolymer and antibiotic utilized.
a~
~-5~64 -13-As noted above, the active agents can be formulated with -the copolymers of the invention ~or convenlent oral administration. For example, a feed enhancing agen-t such as monensin or the like can be intimately dispersed -throughout a copolymer matrix.
Such mixture can be molded into a bolus and adjusted so that once orally administered to a feeder calf, such formulation will lodge in the rumeno-reticular portions of the stomach, and thereby provide a gradual and con-trolled release of the feed utilization enhancing agentto the calf over an extended period of time. Such formulation thus permits young calves to be range fed throughout the entire range feeding season, with the net result that such animals more effectively produce more usuable meat than heretofore possible.
The use of strong acid ion-exchange resins, as hereinbefore pointed out, permits the substantially total removal (i.e. greater than ninety-five percent) of polymerization catalyst from the copolymers formed.
This offers an additional advantage over the prior art since the complete removal of catalyst allows the production or copolymers having greatly enhanced stability. It i5 well known that catalysts which promote polymerization also promote decompositon.
Accordingly, polymers prepared by standard processes utilizing non-removable catalysts such as ferric sulfate and the like are somewhat unstable and are subject to degradation upon formulation with active drugs, and additionally have a shortened shelf life once formulated. In contrast, the substantial removal '~~
x-5064 -14-of polymerization catalyst according to the process of this invention permits the production of unusually s~able copolymers which are substantially resistant to degradation during formulation processing, and addi-tionally have longer shelf lives than the polymers madeby prior art methods.
In an effort to more fully describe the polymerization process and the product of this in-vention, the following detailed examples are provided by way of illustration.
Example 1 -To a 3-neck round bottom flask equipped with a condenser and thermometer were added 864.0 g. of lactic acid, 201.0 g. of glycolic acid and 12.0 g. of Dowex HCR-W2-H ion exchange resin. The mixture was stirred and heated to 130C. for three hours, during which time 400 ml. o water were distilled and collected.
After discarding the water thus produced, stirring and heating were continued and the pressure was gradually reduced by vacuum over three hours, after which time the temperature of the reaction mixture had increased to 150C. at a final pressure of 5 torr. An additional 12.0 g. o Dowex HCR-W2-H catalyst was added to the reaction mixture, and the mixtur~ then was heated to 170C. at 5.0 torr for twenty-four hours, and then at 185C. at 5.0 torr for an additional 48 hours. The molten reaction mixture next was filtered to remo~e most of the ion exchange polymerization catalyst, and the filtrate was allowed to cool to room temperature to give 700 g. of 80 percent lactic--20 percent glycolic copolymer. The copolymer was analyzed by proton nuclear magnetic resonance spectrometry and shown to be comprised of 76 percent by weight of lactic units.
The viscosity of the copolymer was determined in a Ubbelohde viscometer in which chloroform had an eEflux time of 51 seconds at 25C. The copolymer was dissolved in chloroform at a concentration of 0.50 g.
per 100 ml. o solvent. Inherent viscosity of the copolymer was then determined according to the formulas:
~rel = tt ninh - ln~rel o wherein:
nrel = relative viscosity to = erflux time of solvent (C~C13) t = efflux time of solution ninh = inherent viscosity C = conc. in grams/100 ml.
The inherent viscosity of the copolymer thus prepared was determined to be 0.19 dl/gO
E ~
Following the general procedure set forth in Example 1, 432 g. of lactic acid and 101 g. of glycolic acid were condensed in the presence of a total of 12.0 g. of Amberlyst 15 ion exchange polymerization catalyst to afford 350 g. of a copolymer comprised of about 80 percent lactic units and about 20 percent glycolic units. The copolymer had the following inherent viscosity: 0.18 dl/g.
3~3 Example 3 _ Following the general procedure of Example 1, 422.0 g. of lactic acid were condensed with 144.0 g. of glycolic acid in the presence of a total of 12.0 q. of Dowex HCR-W2-H ion exchange polymerization catalyst.
After removing the catalyst by filtration of the molten reaction mi~ture, there was provided 350 g. of a copol~mer derived from about 75 percent by weight of lactic acid and a~out 25 percent by weight of glycolic acid. The copol~mer exhibited the following inherent viscosity: 0.19 dl/g.
Example 4 Following the general procedure of Example 1, 15 1080 g. of lactic acid were condensed with 252 g. of glycolic acid in the pre~ence o a total of 30.0 gO of Dowex HCR-W2-H ion exchange polymerization catalys-t to give, after removal of the catalyst, 750 g. of a copolymer which was shown by proton NMR to contain about 79 percent of lactic units and about 21 percent of glycolic units. The copolymer exhibited the following inherent viscosity: 0.20 dl/g.
Example 5 Following the procedure of Example 1, 1080 g.
oî lactic acid were condensed with 1~0 g. of glycolic acid in the presence of a total of 15.0 g. of Dowex HCR-W2-H ion exchange polymerization catalyst to provide, after work-up, 630 g. of a copolymer derived 9~
x-5064 -17-from abou-t 90 weight percent of lactic acid and about 10 weight percent of glycolic acid. The copolymer had a~ inherent viscosity of 0.20 dl/g.
Example 6 Following the procedure of Example 1, 710 g.
of lactic acld were condensed with 190 g. of glycolic acid in the presence of a total of 12.0 g. of Dowex ~CR-W2-H ion exchange polymeri~ation catalyst to provide 500 g. of a copolymer comprised of about 70 percent lactic units and about 30 percent glycolic units. The copolymer had an inherent viscoslty of: 0.12 after 24 hours at 175C.
Example 7 The procedure of Example 1 was followed to condense 1080 g. of lactic acid with 120 g. of glycolic acid in the presence o a total of 30.0 g. of Dowex ~CR-W2-H ion exchange polymeriza-tion catalyst. After workup, there was recovered 750 g. of a copolymer derived of about 89 weight percent of lactic acid and about 11 weight percent of glycolic acid having an inherent viscosity of 0.20 dl/g.
The copolymers provided by this invention additionally have been characterized by gel permea~ion chromatography (high pressure liquid chromatography) and subsequent determination of molecular weight. Gel permeation chromatography separates sample molecules by differences in effective molecular size in solution.
Separation is accomplished as a result of the pore size 3 distribution in the packing material. This analytical x-5~6~ -18-technique allows determinations of wei~ht-average molecular weight, number average molecular weight, molecular weight distribution, and dispersity for polymeric materials.
Several such experiments have been carried out on the copolymers of this invention. Standard gel permeation chromatographic columns were used, and the support in each case was commercial ~Styragel. All samples and standards were dissolved in a solution of 80 parts tetrahydrofuran and 20 parts dichloromethane.
The indirect method (i.e. the "Q-Factor Method") of calibrating the gel permeation chromatographic columns was used to obtain molecular weight averages for -the copolym~rs of the invention. Commercial polystyrene, with a Q Factor of 41.3, was used in the calibrations.
The following Table presents several determinations of - molecular weight by standard gel permeation chromato-graphic techniques as outlined above. A more detailed discussion of the technique utilized is presented by Slade in Polymer Molecular Wei~hts, Marcel Deckker, Inc., 1975.
In the Table, column I presents the relative proportions of lactic units and glycolic units making up the copolymer analyzed. Column II gives the inherent viscosity of each copolymer analyzed. Column III
reports the strong acid ion exchange resin utilized to prepare the copolymer being analyzed. Column IV presents the weight average angstrom si2e as determined from the gel permeation chromatographic retention time for the particular copolymer. Column V presentq the weight average molecular weights for the various copolymers prepared by the process of this invention. The weight average molecular weights are determined by multiplying the Q-Factor for polystyrene (4~.3) times the weight average angstrom size for the particular copolymer being analy~ed. Column VI is the relevant Example number.
As demonstrated in the Table, the preferred copolymers of this invention have a molecular weight from about 15,000 to about 35,000, and ideally from about 15,000 to about 30,000.
oo o o~ o a~ ~ u7 _ o ~ O ~D ~
S
3 . . . . .
:> ~ ~ U~ r~ ~ o C~l ~I H f`') .--1 0 1` ~r O ~I
g ~1 o I
a) :~ ,1 ~ 3: 3 3 I I I I
H ~ U~ ) C.) V C.) H ~--I
X S~ X X X X X
3 5~ 3 3 3 3 3 :~ o ~ O o o o o a ~ ~ ~ a a ~
~H
o ~, 0 ~ o o ~ o ;~l H
O O O O O O O
o o ~ o o o o ,~ .. .. .. .. .. .. ..
o o o U~ o o o C~
Polymers and copolymers are widely used in a variety of fields. One reason for the e~pansive appli-cation of polymers is due to the uniquely differing physical properties which are e~hibited by various polymers. Numerous different polymers, all e~hibiting varying physical properties, can be obtained from the same monomers by altering the method of preparation, the polymeri~ation catalysts, the quantities of monomers utilized and related factors.
The prior art teaches a number of polymers and copolymers of lactic acid and glycolic acid.
Schmitt et 21., in U.S. Patent Nos. 3,739,773, 3,736,646 and 3,875,937, cite and discuss a great deal of art directed to polymers and copolymers in general, as well as specific lactic acid and glycolic acid copolymers.
As pointed out by Yolles in ~I.S. Patent No.
3,887,699, much interest has been focused on the possibility of incorporating drugs into polymeric materials in order to obtain a controlled and sustained release of such drug to a living system. ~any problems, however, are associated with the use o~ polymers and copolymers for the slow release of drugs into a living system. For e~ample, Schmitt et al., in U.S. Patent 25 No. 3,982,543, points out that copolymers in general have a rela-tively slow hydrolysis rate in the acid environment in the stomach but a much high-r hydrolysis rate in the more alkaline environment of the intestine.
Siegrist et al., in U.S. Patent No. 3,535,419, disclose a sustained release drug and polymer formulation that ~ ~ ~ 3 ~
X-5064 -2~
ls suitable for the administra-tion of steroidal drugs via the rumeno-reticular portions of the stomach of ruminants. Such formulations require the use of at least one hig~ly water insoluble wax, fat, oil, fatty acid, fatty acid ester, fatty acid amide, fatty acid alcohol or polymer. Reuter et al., in U.S. Patent No.
4,011,312, describe a prolonged release drug dosage form for the treatment of bovine mastitis consisting of an antimicrobial agent dispersed in a matrix of a poly-ester of glycolic and lactic aeids having a molecularweight of less than 2000.
Numerous referenees teach that an advantage of utilizing copolymers comprised of glycolic acid and laetic acid is the fact -that the hydrolysis products are constituents in normal me-tobolic pathways and consequently are nontoxic and harmless when exposed to human or animal tissues. One drawback assoeiated with the prior art copolymers, however, is the presence of polymexization catalysts sueh as a polyvalent metal oxide or metal nalide. Upon biodegradation of the eopolymer-drug matrix, a finite quantity of such toxic polymerization catalyst remains in the animal tissue and is not subject to biodegradation. Moreover, catalysts utilized to promote polymerization also cause ~5 breakdown of -the polymer when eontaet i5 maintained.
Therefore, polymers containing polymerization eatalysts as impurities are subjeet to unpredietable degradation.
This inven-tion relates to a proeess for polymerizing glyeolie aeid and laetie aeid via eon-densation~ such that copolymers having a weight average molecular weight of about 6000 to abou-t 35000 are obtained. Also this invention provides a polymeriza-tion process which permits the substantially total removal from the copolymer of polymerization catalysts, so that the copolymers so produced can be utilized as drug delivery systems, thereby permitting the complete biodegradation of the system with no residual toxlc foreign substances remaining in animal tissues. This invention additionally provides unique copolymers derived from lactic and glycolic acid which are capable of biodegradation over a predetermined period of time, thus allowing -the controlled release of a drug dispersed therein at a predetermined rate over the period of time necessitated by the particular treatment being af~orded.
Further, this invention provides a method for polymeriz-ing lactic acid and glycolic acid via direct condensa~
tion, thereby obviating the need to first prepare cyclic lactides and glycolides as preerred by the prior art. The invention thererore offers significant economic advantages over prior art polymerization processes.
Thus, this invention concerns a process for the polymerization of lactic acid and glycolic acid via direct conden5ation, and to the copolymers prepared by such process. More particularly, the invention provides a copolymer derived from the polymerization of lactic acid and glycolic acid, which comprises the amount of about 60 to about 95 weight percent of lactic acid and about ~0 to about 5 weight percent of glycolic acid, said copolymer having an inherent viscosity in chloro-X-5064 -~-form of about 0.08 to about 0.30 and a weight average molecular weight of about 6000 to about 35,000, said copolymer being substantially free of polymerization catalyst. The inherent viscosity was measured a-t a concentration of 0.50 g. of copolymer in 100 ml. of chloroform at 25C.
A process for preparing a copolymer derived by the polymerization of about 60 to about 95 weight percent of lactic acid and about 40 to about 5 weight percent of glycolic acid, said copolymer having a weight average molecular weight of about 6000 to about 35000, with an inherent viscosity in chloroform of about 0.08 to about 0.30, wherein the polymerization of the lactic acid and glycolic acid is effected in the presence of a readily removable strong acid ion-exchange resin, said resin being subsequently removed therefrom.
This polymerization is preferrably effected at a tempera-ture from about 100 to about 250C. for about 3 to about 172 hours.
Preferred copolymers prepared according to the process of this invention are derived from about 60 -to about 90 weight percent lactic acid and about 40 to about 10 weight percent glycolic acid. The copolymers of the invention ideally have a viscosity of àbout 0.10 to about 0.25, and a weight average molecular weight of about 15,000 to about 30,000. Especially preferred copolymers are those derived from about 70 to about 80 weight percent lactic acid and about 30 to about 20 weight percent glycolic acid with an inherent viscosity 30 of about 0.10 to about 0.25.
According to the process of this inventlon, glycolic acid is condensed with lactic acid by reaction in the presence of a readily removable strong acid ion exchange resin. Preferred catalysts are those in the ~orm of beads or similar solid compositions which facilitate removal, for example by filtration. Pre-ferred catalysts include~commercial resins o~ the gel type, [such as Amberlite IR-118(H) and Dowex HCR-W
(formerly Dowex 50W)] as well as resins of the macro-reticular type, [such as Amberly~t~15 and Dowex~MSC-l].
According to the process of this invention, lactic acid is condensed ~ith glycolic acid in such a manner that a copolymer is formed which is derived from about 60 to about 95 weight percent of lactic acid and from about 40 to about 5 weight percent of glycolic acid. The polymerization process is carried out by condensing lactic acid and glycolic acid in the presence of a strong acid ion-exchange resin catalyst that is subject to convenient removal by standard methods such as filtration. The catalyst can be prepared by poly-merizing styrene with any of a number of cross-linking agents such as divinylbenzene or similar agentsO
Such resin polymer is reacted with a strong acid such as sulfuric, phosphoric, tetrafluoroboric, paratoluene sulfonic, and related acids, so as to obtain a strong acid substituted cross-linked polystyrene. Such strong acid ion-exchange resins are commercially available in the form of beads and similar solid articles. Examples of commercially available strong acid ion-exchange resins useful in the present process include Amberlite ~3 IR-118(H), Amberlite~ IR--120 Amberlite~ I~F-66(~1), Dowex~ ElCR-W (formerly Dowe ~ 50W), Duolite~ C-20, Amberlyst~ 15, Dowex~ MSC-l, Duolite~ C-25D, Duolite~ ES-26 and related strong acid ion-exchange resins. Various forms of these catalysts can be utilized, for example Dowex HCR-W2-H. Amberlyst 15 is a macroreticular ion-exchange resin which is of a strongly acidic cation exchange type.
Dowex HCR-W2-H is a strongly acidic cation resin with cross-linking made from styrene-divinylbenzene copolymers, having a large number of ionizable or functional groups attached.
According to the present process, the strong acid ion-exchange resin is added to a mixture of lactic acid and glycolic acid. The polymerization reaction generally is carried out in the absence of reaction solvent. How-ever, reaction solvents such as N,N-dimethylformamide, dimethylsulfoxide, and others, can be utilized if desired.
The amount of strong acid ion-exchange resin utilized in the condensation process is not critical to the process.
Typically, the quantity of resin catalyst utilized will be an amount sufficient to effectively initiate and main-tain the polymerization process. Such effective amounts routinely vary from about 0.1 to about 20 percent by weight relative to the total amount of glycolic acid and lactic acid in the reaction mixture.
Once the strong acid ion-exchange resin and glycolic and lactic acids are mixed, the reaction mixture is heated to a temperature from about 100C. to about 250C. Ideally the reaction is carried out in such a manner that water which is formed during the polymerization is conveniently removed, for instance by distillation. Water removal can be facilitated if desired by the application of a vacuum to the ~eaction vessel. Typically, any lactide and glycolide that is formed also is removed by such distillation. The polymerization reaction is driven to completion by the continuous heating and concomittant removal of water from the reaction mixture as it is formed. When the reaction is carried out at a temperature of about 100 to about 250C., ideally from about 130 to about 190C., the polymerization generally is substantially complete after about 48 to about 96 hours.
Isolation and purification of the copolymer thus formed are accomplished by routine methods. The strong acid ion-exchange resin can be substantially removed from the copolymer product by simply filtering the molten reaction mixture, for instance through a metal sieve of appropriate mesh size, for example rnesh 20 to about 50. Alternatively, the reaction mixture can be cooled to room temperature and the copolymer can be dissolved in any of a number of organic solvents in which the ion~exchange resin is insoluble. Such solvents include chloroform, dichloromethane, benzene, xylene and others. Once the copolymer is substantially dissolved in such organic solvent, normal filtration effects removal of the insoluble strong acid ion-exchange resin. Removal of the organic solvent from the filtrate, for instance by evaporation under reduced pressure, then affords the desired copolymer of the lnvention, substantially free of polymerization catalyst. If needed, the copolymer can be redissolved in a suitable solvent and again filtered, thereby substantially eliminatin~ all traces of ion-exchange resin which might be present.
The copolymers comprehended by this inventionand prepared according to the novel process described hereinabove are charac-terized by routine methods commonly utilized in the identification o polymers and copolymers. The relative composition of the copolymers is determined by proton nuclear ma~netic resonance spectrometry. By determining the ratio of methylene protons attributable to glycolic acid units to methine protons attributable to lactic acid units, the relatlve ratio of total glycolic units to total lactic units is determined.
The inherent viscosity of the copolymers of this invention is determined by standard procedures utilizing an Ubbelohde viscometer. The copolymer to be analyzed is dissolved in chloroform at a concentration of 0.50 g./100 ml. The term inherent viscosity (ninh) used herein is defined by the following equation:
inh ln nrel wherein ln is the natural logarithm, C is concen-tration in grams/100 ml. of solution, and nrel is relative viscosity as defined by the equation:
nrel - tt wherein to is the efflux time of pure solvent (chloro-form herein) and t is the efflux time of the solution containing the copolymer.
The copolymers derived from lactic acid and glycolic acid which are provided by this invention and prepared according to the novel process described hereinabove are particularly well suited for use in the formulation of medlcaments deslgned to provide a prolonged, controlled and unlform release of active agent to a biologic~l system. Such formulations are especially useful in the therapeutic and prophylactic trea-tment of diseases occurring in animals which are not subject to daily treatment by conventional me-thods.
rrhe copolymers of the invention have the unique physical properties which permit their con-trolled and uniform degradation into non-toxic and readily metabolized substances ~hen placed in contact with animal tissue and body fluids. For example, to allow the controlled release of the drug from the co-polymer/ the copolymer must be p~ soluble in the envi-ronment used, e.g. -the rumen of an animal, the body tissues contacted by injection, and other such areas.
Thus, the instant copolymer is pH soluble from a~out 5.0 to about 7.3. Moreover, bscause the copolymers are prepared by the novel process provided herein which permits the substantially complete removal of polymeri-zation catalysts, no foreign substances of a toxic nature are available for absorption by body tissue.
Furthermore, because the copolymers have the ability to undergo uniform biodegradation determined in part by the relative proportions of lactic acid and glycolic acid present, the particular period required for total biodegradation can be predetermined and adjusted as desired by varying the relative ~uantities of the respective constituents of the copolymer~ To determine the dissolutior. rate of the instant copolymers; the a~
~-5064 -10-copolymer was placed n ar-tificial rumen conditions (pH about ~.8) for a 63 day period and the mg./day dissolution rate determined. Range about 350 to about 500 mg./day.
~inh1mg./day~
0.20 ~00 0.19 415 0.17 475 lis the inherent viscosity and all copolymers were 80 weight percent lactic acld and 20 weight percent glycolic acid.
2is dissolution rate determined as an average of three seperate runs.
As contemplated herein, the copolymers pro-vided by this invention can be utilized in the formula-tion of various drugs for the controlled release of such drug into a biological system. Druys which can be incorporated into such formulations containing the copolymers of this invention include any such dxug useful in the therapeutic or prophylactic treatment of a mammal, including humans and animals. The copolymers are particularly useful in the preparation of con-trolled release formulations for the treatment of animals raised for their meat or other food products to be consumed by humans, for example farm animals such ascattle, swine and the like.
Typical drugs which are ideally suited ~or the treatment of animals via a controlled release formulation utllizing a copolymer of this invention include an-tibiotics such as any of the well known penicillins, cephalosporins, tetracyclines, as well as speeific agents such as streptomycin A and streptomycin B, aureom~ein, tylosin and simllar antibiotics.
Another elass of drugs whieh are well suited to formulation with the eopolymers of this invention for eontrolled release over a prolonged period of time are agents used to improve feed efficieney in animals such as feeder ealves. Such agents currently are administered primarily as feed additives. Sueh method of administration suffers from the faet that the aetual and effeetive dose of active agent is dependent upon the feeding habits OL the animal, thus permitting uneontrolled overdosing and underdosing. Moreover, feeder stoek whieh is range fed are unable to be treated b~ feed additives, whereas a formulation eomprised of a suitable drug dispersed throughout a copolymer of this invention can be administered in the form of a bolus whieh is retained in the rumen, thus permitting the eontrolled release of an effective amount of aetive agent over a prolonged period of time lasting several weeks or months. Typieal feed effi-eieney enhaneing agents and growth promoters whieh ean be formulated with the eopolymers of this invention inelude monensin, lasaloeid, apramycin, narasin, salinomyein and the like.
~ L~V~8 Another class or pharmocodynamic agents which can be formulated with the copolymers of this invention for con-trolled release include natural and synthetic hormones and related agents that function as fertility-control agents. Such drugs include estrogens, androgens,progestogens, corticoids, anabolic agents and the like.
The copolymers of this invention can be used to formulate an active agent for convenient oral or parenteral administration. For example, a c~polymer derived from about 30 weight percent glycolic acid and about 70 weight percent lactic acid and having an inh~rent viscosity of about 0.13 can be dissolved in a suitable organic solvent such as dichloromethane. A
suficient quantity of an antibacterial agent such as tylosin or the like can be added to the copolymer solution, and the organic solvent can then be removsd by evaporation so as to provide a uni~orm mixture com-prised of about 30 weight percent active agent and about 70 weight percent copolymer. Such mixture can be extruded so as to form glass-type rods. The glass rods thus ormed can be ground, powdered and suspended in a suitable oil such as sesame oil and injected subcutane-ousl~ to an animal such as a young calf for the effec-tive prolonged treatment of infections caused by diseases such as pneumonia. By utilizing such formulation/ the animal can recei~e a uniform dose of active agent, such as about 5 mg. per head per day, following a single injection. Total payout can occur within about seven days, or longer depending upon the particular copolymer and antibiotic utilized.
a~
~-5~64 -13-As noted above, the active agents can be formulated with -the copolymers of the invention ~or convenlent oral administration. For example, a feed enhancing agen-t such as monensin or the like can be intimately dispersed -throughout a copolymer matrix.
Such mixture can be molded into a bolus and adjusted so that once orally administered to a feeder calf, such formulation will lodge in the rumeno-reticular portions of the stomach, and thereby provide a gradual and con-trolled release of the feed utilization enhancing agentto the calf over an extended period of time. Such formulation thus permits young calves to be range fed throughout the entire range feeding season, with the net result that such animals more effectively produce more usuable meat than heretofore possible.
The use of strong acid ion-exchange resins, as hereinbefore pointed out, permits the substantially total removal (i.e. greater than ninety-five percent) of polymerization catalyst from the copolymers formed.
This offers an additional advantage over the prior art since the complete removal of catalyst allows the production or copolymers having greatly enhanced stability. It i5 well known that catalysts which promote polymerization also promote decompositon.
Accordingly, polymers prepared by standard processes utilizing non-removable catalysts such as ferric sulfate and the like are somewhat unstable and are subject to degradation upon formulation with active drugs, and additionally have a shortened shelf life once formulated. In contrast, the substantial removal '~~
x-5064 -14-of polymerization catalyst according to the process of this invention permits the production of unusually s~able copolymers which are substantially resistant to degradation during formulation processing, and addi-tionally have longer shelf lives than the polymers madeby prior art methods.
In an effort to more fully describe the polymerization process and the product of this in-vention, the following detailed examples are provided by way of illustration.
Example 1 -To a 3-neck round bottom flask equipped with a condenser and thermometer were added 864.0 g. of lactic acid, 201.0 g. of glycolic acid and 12.0 g. of Dowex HCR-W2-H ion exchange resin. The mixture was stirred and heated to 130C. for three hours, during which time 400 ml. o water were distilled and collected.
After discarding the water thus produced, stirring and heating were continued and the pressure was gradually reduced by vacuum over three hours, after which time the temperature of the reaction mixture had increased to 150C. at a final pressure of 5 torr. An additional 12.0 g. o Dowex HCR-W2-H catalyst was added to the reaction mixture, and the mixtur~ then was heated to 170C. at 5.0 torr for twenty-four hours, and then at 185C. at 5.0 torr for an additional 48 hours. The molten reaction mixture next was filtered to remo~e most of the ion exchange polymerization catalyst, and the filtrate was allowed to cool to room temperature to give 700 g. of 80 percent lactic--20 percent glycolic copolymer. The copolymer was analyzed by proton nuclear magnetic resonance spectrometry and shown to be comprised of 76 percent by weight of lactic units.
The viscosity of the copolymer was determined in a Ubbelohde viscometer in which chloroform had an eEflux time of 51 seconds at 25C. The copolymer was dissolved in chloroform at a concentration of 0.50 g.
per 100 ml. o solvent. Inherent viscosity of the copolymer was then determined according to the formulas:
~rel = tt ninh - ln~rel o wherein:
nrel = relative viscosity to = erflux time of solvent (C~C13) t = efflux time of solution ninh = inherent viscosity C = conc. in grams/100 ml.
The inherent viscosity of the copolymer thus prepared was determined to be 0.19 dl/gO
E ~
Following the general procedure set forth in Example 1, 432 g. of lactic acid and 101 g. of glycolic acid were condensed in the presence of a total of 12.0 g. of Amberlyst 15 ion exchange polymerization catalyst to afford 350 g. of a copolymer comprised of about 80 percent lactic units and about 20 percent glycolic units. The copolymer had the following inherent viscosity: 0.18 dl/g.
3~3 Example 3 _ Following the general procedure of Example 1, 422.0 g. of lactic acid were condensed with 144.0 g. of glycolic acid in the presence of a total of 12.0 q. of Dowex HCR-W2-H ion exchange polymerization catalyst.
After removing the catalyst by filtration of the molten reaction mi~ture, there was provided 350 g. of a copol~mer derived from about 75 percent by weight of lactic acid and a~out 25 percent by weight of glycolic acid. The copol~mer exhibited the following inherent viscosity: 0.19 dl/g.
Example 4 Following the general procedure of Example 1, 15 1080 g. of lactic acid were condensed with 252 g. of glycolic acid in the pre~ence o a total of 30.0 gO of Dowex HCR-W2-H ion exchange polymerization catalys-t to give, after removal of the catalyst, 750 g. of a copolymer which was shown by proton NMR to contain about 79 percent of lactic units and about 21 percent of glycolic units. The copolymer exhibited the following inherent viscosity: 0.20 dl/g.
Example 5 Following the procedure of Example 1, 1080 g.
oî lactic acid were condensed with 1~0 g. of glycolic acid in the presence of a total of 15.0 g. of Dowex HCR-W2-H ion exchange polymerization catalyst to provide, after work-up, 630 g. of a copolymer derived 9~
x-5064 -17-from abou-t 90 weight percent of lactic acid and about 10 weight percent of glycolic acid. The copolymer had a~ inherent viscosity of 0.20 dl/g.
Example 6 Following the procedure of Example 1, 710 g.
of lactic acld were condensed with 190 g. of glycolic acid in the presence of a total of 12.0 g. of Dowex ~CR-W2-H ion exchange polymeri~ation catalyst to provide 500 g. of a copolymer comprised of about 70 percent lactic units and about 30 percent glycolic units. The copolymer had an inherent viscoslty of: 0.12 after 24 hours at 175C.
Example 7 The procedure of Example 1 was followed to condense 1080 g. of lactic acid with 120 g. of glycolic acid in the presence o a total of 30.0 g. of Dowex ~CR-W2-H ion exchange polymeriza-tion catalyst. After workup, there was recovered 750 g. of a copolymer derived of about 89 weight percent of lactic acid and about 11 weight percent of glycolic acid having an inherent viscosity of 0.20 dl/g.
The copolymers provided by this invention additionally have been characterized by gel permea~ion chromatography (high pressure liquid chromatography) and subsequent determination of molecular weight. Gel permeation chromatography separates sample molecules by differences in effective molecular size in solution.
Separation is accomplished as a result of the pore size 3 distribution in the packing material. This analytical x-5~6~ -18-technique allows determinations of wei~ht-average molecular weight, number average molecular weight, molecular weight distribution, and dispersity for polymeric materials.
Several such experiments have been carried out on the copolymers of this invention. Standard gel permeation chromatographic columns were used, and the support in each case was commercial ~Styragel. All samples and standards were dissolved in a solution of 80 parts tetrahydrofuran and 20 parts dichloromethane.
The indirect method (i.e. the "Q-Factor Method") of calibrating the gel permeation chromatographic columns was used to obtain molecular weight averages for -the copolym~rs of the invention. Commercial polystyrene, with a Q Factor of 41.3, was used in the calibrations.
The following Table presents several determinations of - molecular weight by standard gel permeation chromato-graphic techniques as outlined above. A more detailed discussion of the technique utilized is presented by Slade in Polymer Molecular Wei~hts, Marcel Deckker, Inc., 1975.
In the Table, column I presents the relative proportions of lactic units and glycolic units making up the copolymer analyzed. Column II gives the inherent viscosity of each copolymer analyzed. Column III
reports the strong acid ion exchange resin utilized to prepare the copolymer being analyzed. Column IV presents the weight average angstrom si2e as determined from the gel permeation chromatographic retention time for the particular copolymer. Column V presentq the weight average molecular weights for the various copolymers prepared by the process of this invention. The weight average molecular weights are determined by multiplying the Q-Factor for polystyrene (4~.3) times the weight average angstrom size for the particular copolymer being analy~ed. Column VI is the relevant Example number.
As demonstrated in the Table, the preferred copolymers of this invention have a molecular weight from about 15,000 to about 35,000, and ideally from about 15,000 to about 30,000.
oo o o~ o a~ ~ u7 _ o ~ O ~D ~
S
3 . . . . .
:> ~ ~ U~ r~ ~ o C~l ~I H f`') .--1 0 1` ~r O ~I
g ~1 o I
a) :~ ,1 ~ 3: 3 3 I I I I
H ~ U~ ) C.) V C.) H ~--I
X S~ X X X X X
3 5~ 3 3 3 3 3 :~ o ~ O o o o o a ~ ~ ~ a a ~
~H
o ~, 0 ~ o o ~ o ;~l H
O O O O O O O
o o ~ o o o o ,~ .. .. .. .. .. .. ..
o o o U~ o o o C~
Claims (12)
1. A copolymer derived from the polymeriza-tion of lactic acid and glycolic acid, which comprises the amount of about 60 to about 95 weight percent of lactic acid and about 40 to about 5 weight percent of glycolic acid, said copolymer having an inherent viscosity in chloroform of about 0.08 to about 0.30 and a weight average molecular weight of about 6000 to about 35000, said copolymer being substantially free of polymerization catalyst.
2. The copolymer of claim 1, said copolymer derived from about 60 to about 90 weight percent lactic acid and about 40 to about 10 weight percent glycolic acid, having an inherent viscosity of about 0.10 to about 0.25 and a weight average molecular weight of about 15,000 to about 30,000.
3. The copolymer of claim 1, said copolymer derived from about 65 to about 80 weight percent lactic acid and about 35 to about 20 weight percent glycolic acid, having an inherent viscosity of about 0.10 to about 0.25 and a weight average molecular weight of about 15000 to about 30000.
4. The copolymer of claim 1, said copolymer derived from about 70 to about 80 weight percent lactic acid and about 30 to about 20 weight percent glycolic acid, having an inherent viscosity of about 0.10 to about 0.25.
5. The copolymer of claim 1, said copolymer derived from about 70 weight percent lactic acid and about 30 weight percent glycolic acid, having an inherent viscosity of about 0.10 to about 0.15.
6. The copolymer of claim 1, said copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid, having an inherent viscosity of about 0.15 to about 0.25.
7. A copolymer of claim 1, said copolymer being pH soluble in the range from about 5.0 to about 7.3.
8. A copolymer of claim 1, said copolymer dis-solution occurring at the rate of about 350 to about 500 mg./day.
9. A process for preparing a copolymer as claimed in claim 1, wherein the polymerization of the lactic acid and glycolic acid is effected in the presence of a readily removable strong acid ion-exchange resin, said resin being subsequently removed therefrom.
10. A process of claim 9 wherein the polymeriza-tion is effected at a temperature from about 100 to about 250°C. for about 3 to about 172 hours.
11. The process of claim 9 wherein about 70 weight percent of lactic acid are reacted with about 30 weight percent of glycolic acid in the presence of a macroreticu-lar ion-exchange resin of a strongly acidic cation exchange type or a strongly acidic cation resin with cross-linking made from styrene-divinylbenzene copolymers, having a large number of ionizable or functional groups attached, for about 48 to about 96 hours to give a copolymer derived from about 70 weight percent lactic acid and about 30 weight percent glycolic acid, having an inherent viscosity of about 0.10 to about 0.25.
12. The process of claim 9 wherein about 80 weight percent of lactic acid are reacted with about 20 weight percent of glycolic acid in the presence of a macroreticu-lar ion-exchange resin of a strongly acidic cation exchange type or a strongly acidic cation resin with cross-linking made from styrene-divinylbenzene copolymers, having a large number of ionizable or functional groups attached, for about 48 to about 96 hours to give a copolymer derived from about 80 weight percent lactic acid and about 20 weight percent glycolic acid, having an inherent viscosity of about 0.10 to about 0.25.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/075,296 US4273920A (en) | 1979-09-12 | 1979-09-12 | Polymerization process and product |
| US75,296 | 1979-09-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1185048A true CA1185048A (en) | 1985-04-02 |
Family
ID=22124778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000360018A Expired CA1185048A (en) | 1979-09-12 | 1980-09-10 | Polymerization process and product |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US4273920A (en) |
| EP (1) | EP0026599B1 (en) |
| JP (2) | JPS5645920A (en) |
| AR (1) | AR221173A1 (en) |
| AT (1) | AT380689B (en) |
| AU (1) | AU539130B2 (en) |
| BE (1) | BE885182A (en) |
| BG (1) | BG41132A3 (en) |
| CA (1) | CA1185048A (en) |
| CH (1) | CH648048A5 (en) |
| CS (1) | CS221979B2 (en) |
| DD (1) | DD153125A5 (en) |
| DE (1) | DE3068116D1 (en) |
| DK (1) | DK155093C (en) |
| EG (1) | EG14381A (en) |
| ES (1) | ES8106542A1 (en) |
| FI (1) | FI66412C (en) |
| FR (1) | FR2464973A1 (en) |
| GB (1) | GB2058808B (en) |
| GR (1) | GR69961B (en) |
| GT (1) | GT198065361A (en) |
| HU (1) | HU191807B (en) |
| IE (1) | IE50236B1 (en) |
| IL (1) | IL61024A (en) |
| IT (1) | IT1141040B (en) |
| NZ (1) | NZ194902A (en) |
| PH (1) | PH15272A (en) |
| PL (1) | PL129779B1 (en) |
| PT (1) | PT71794B (en) |
| RO (1) | RO80864A (en) |
| ZA (1) | ZA805629B (en) |
Families Citing this family (88)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4333919A (en) * | 1979-09-12 | 1982-06-08 | Eli Lilly And Company | Growth promotant controlled release formulations and method of treatment |
| IE52535B1 (en) * | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
| US4716964A (en) * | 1981-08-10 | 1988-01-05 | Exxon Production Research Company | Use of degradable ball sealers to seal casing perforations in well treatment fluid diversion |
| US4523591A (en) * | 1982-10-22 | 1985-06-18 | Kaplan Donald S | Polymers for injection molding of absorbable surgical devices |
| FR2537980B1 (en) * | 1982-12-17 | 1986-12-19 | Sandoz Sa | OLIGOMERIC HYDROXYCARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE |
| US4470416A (en) * | 1983-06-17 | 1984-09-11 | Ethicon, Inc. | Copolymers of lactide and/or glycolide with 1,5-dioxepan-2-one |
| CH656884A5 (en) * | 1983-08-26 | 1986-07-31 | Sandoz Ag | POLYOLESTERS, THEIR PRODUCTION AND USE. |
| US4594407A (en) * | 1983-09-20 | 1986-06-10 | Allied Corporation | Prosthetic devices derived from krebs-cycle dicarboxylic acids and diols |
| JPS60100516A (en) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
| ES2091185T3 (en) * | 1984-03-06 | 1996-11-01 | United States Surgical Corp | A PROCEDURE FOR THE PREPARATION OF TWO-PHASE COMPOSITIONS FOR ABSORBABLE SURGICAL DEVICES. |
| US4649042A (en) * | 1984-05-31 | 1987-03-10 | Eli Lilly And Company | Rumen delivery device |
| JPH0678425B2 (en) * | 1984-07-06 | 1994-10-05 | 和光純薬工業株式会社 | New polymer manufacturing method |
| CA1256638A (en) * | 1984-07-06 | 1989-06-27 | Motoaki Tanaka | Polymer and its production |
| DE3428640A1 (en) * | 1984-08-03 | 1986-02-06 | Akzo Gmbh, 5600 Wuppertal | MICROPOROUS, POWDER-SHAPED POLYLACTIDES |
| US4595713A (en) * | 1985-01-22 | 1986-06-17 | Hexcel Corporation | Medical putty for tissue augmentation |
| ATE61935T1 (en) * | 1985-02-07 | 1991-04-15 | Takeda Chemical Industries Ltd | PROCESS FOR PRODUCTION OF MICROCAPSULES. |
| JP2551756B2 (en) * | 1985-05-07 | 1996-11-06 | 武田薬品工業株式会社 | Polyoxycarboxylic acid ester and method for producing the same |
| US5618547A (en) * | 1985-05-20 | 1997-04-08 | British Technology Group Limited | Control of ectoparasites |
| JPH0610252B2 (en) * | 1985-08-21 | 1994-02-09 | 和光純薬工業株式会社 | Polymer manufacturing method |
| US5061281A (en) * | 1985-12-17 | 1991-10-29 | Allied-Signal Inc. | Bioresorbable polymers and implantation devices thereof |
| GB8609537D0 (en) * | 1986-04-18 | 1986-05-21 | Ici Plc | Polyesters |
| US4744365A (en) * | 1986-07-17 | 1988-05-17 | United States Surgical Corporation | Two-phase compositions for absorbable surgical devices |
| DE3641692A1 (en) * | 1986-12-06 | 1988-06-09 | Boehringer Ingelheim Kg | CATALYST-FREE RESORBABLE HOMOPOLYMERS AND COPOLYMERS |
| SE8701479L (en) * | 1987-04-09 | 1988-10-10 | Carbomatrix Ab | METHOD FOR CONTAINING BIOLOGICALLY EFFECTIVE PREPARATIONS AND USE THEREOF |
| US4804691A (en) * | 1987-08-28 | 1989-02-14 | Richards Medical Company | Method for making a biodegradable adhesive for soft living tissue |
| MA21697A1 (en) * | 1988-12-19 | 1990-07-01 | Dow Agrosciences Llc | MACROLIDE COMPOUNDS. |
| JP2986509B2 (en) * | 1989-05-26 | 1999-12-06 | 三井化学株式会社 | Modified polyester resin composition, method for producing the same, and use thereof |
| DE4005415C2 (en) * | 1990-02-21 | 1996-04-11 | Boehringer Ingelheim Kg | Process for the preparation of polyesters based on hydroxycarboxylic acids |
| US5302694A (en) * | 1990-02-21 | 1994-04-12 | Boehringer Ingelheim Gmbh | Process for preparing polyesters based on hydroxycarboxylic acids |
| ATE168391T1 (en) * | 1990-04-13 | 1998-08-15 | Takeda Chemical Industries Ltd | BIODEGRADABLE HIGH MOLECULAR POLYMERS, THEIR PRODUCTION AND THEIR USE |
| MY108621A (en) * | 1990-08-01 | 1996-10-31 | Novartis Ag | Polylactide preparation and purification |
| US6353030B1 (en) * | 1990-08-01 | 2002-03-05 | Novartis Ag | Relating to organic compounds |
| US5593423A (en) * | 1990-10-22 | 1997-01-14 | United States Surgical Corporation | Skin fastener |
| US5108422A (en) * | 1990-10-22 | 1992-04-28 | United States Surgical Corporation | Skin fastener |
| US5320624A (en) * | 1991-02-12 | 1994-06-14 | United States Surgical Corporation | Blends of glycolide and/or lactide polymers and caprolactone and/or trimethylene carbonate polymers and absorbable surgical devices made therefrom |
| US6228954B1 (en) | 1991-02-12 | 2001-05-08 | United States Surgical Corporation | Blends of glycolide and/or lactide polymers and caprolactone and/or trimethylene carbonate polymers and absorabable surgical devices made therefrom |
| IT1249045B (en) * | 1991-02-21 | 1995-02-11 | Himont Inc | SOLID STATE SYNTHESIS PROCESS OF LACTIC ACID POLYMERS AND PRODUCTS SO OBTAINED |
| US5232648A (en) * | 1991-07-19 | 1993-08-03 | United States Surgical Corporation | Bioabsorbable melt spun fiber based on glycolide-containing copolymer |
| US5206341A (en) * | 1991-11-21 | 1993-04-27 | Southern Research Institute | Polymers from hydroxy acids and polycarboxylic acids |
| KR970007322B1 (en) * | 1991-12-19 | 1997-05-07 | 미쓰이도오아쓰 가가쿠 가부시키가이샤 | Polyhydroxy carboxylic acid and production thereof |
| US5142023A (en) * | 1992-01-24 | 1992-08-25 | Cargill, Incorporated | Continuous process for manufacture of lactide polymers with controlled optical purity |
| US6005067A (en) * | 1992-01-24 | 1999-12-21 | Cargill Incorporated | Continuous process for manufacture of lactide polymers with controlled optical purity |
| US6326458B1 (en) | 1992-01-24 | 2001-12-04 | Cargill, Inc. | Continuous process for the manufacture of lactide and lactide polymers |
| US5247059A (en) * | 1992-01-24 | 1993-09-21 | Cargill, Incorporated | Continuous process for the manufacture of a purified lactide from esters of lactic acid |
| US5247058A (en) * | 1992-01-24 | 1993-09-21 | Cargill, Incorporated | Continuous process for manufacture of lactide polymers with controlled optical purity |
| US5258488A (en) * | 1992-01-24 | 1993-11-02 | Cargill, Incorporated | Continuous process for manufacture of lactide polymers with controlled optical purity |
| ES2123668T3 (en) * | 1992-10-02 | 1999-01-16 | Cargill Inc | PAPER WHICH HAS A STABLE CAST LACTIDE POLYMER COATING AND PROCEDURE FOR ITS MANUFACTURE. |
| DK0615555T3 (en) * | 1992-10-02 | 2001-07-09 | Cargill Inc | Textile material of melt-stable lactide polymer and process for preparation thereof |
| US6005068A (en) * | 1992-10-02 | 1999-12-21 | Cargill Incorporated | Melt-stable amorphous lactide polymer film and process for manufacture thereof |
| US5338822A (en) * | 1992-10-02 | 1994-08-16 | Cargill, Incorporated | Melt-stable lactide polymer composition and process for manufacture thereof |
| US5591606A (en) * | 1992-11-06 | 1997-01-07 | Dowelanco | Process for the production of A83543 compounds with Saccharopolyspora spinosa |
| TW333456B (en) | 1992-12-07 | 1998-06-11 | Takeda Pharm Ind Co Ltd | A pharmaceutical composition of sustained-release preparation the invention relates to a pharmaceutical composition of sustained-release preparation which comprises a physiologically active peptide. |
| US5444143A (en) * | 1992-12-25 | 1995-08-22 | Mitsui Toatsu Chemicals, Inc. | Preparation process of polyhydroxycarboxylic acid |
| DK0688332T3 (en) * | 1993-03-12 | 1997-10-13 | Dowelanco | New A83543 compounds and processes for their preparation. |
| KR970002523B1 (en) * | 1993-04-24 | 1997-03-05 | Korea Inst Sci & Tech | Biodegradable polylactic acid having improved properties and method for manufacturing the same |
| US5403347A (en) * | 1993-05-27 | 1995-04-04 | United States Surgical Corporation | Absorbable block copolymers and surgical articles fabricated therefrom |
| US5522841A (en) * | 1993-05-27 | 1996-06-04 | United States Surgical Corporation | Absorbable block copolymers and surgical articles fabricated therefrom |
| JPH09505615A (en) * | 1993-10-15 | 1997-06-03 | エイチ．ビイ．フラー ライセンシング アンド ファイナンシング インク | Biodegradable / fertilizable hot melt adhesive containing lactic acid polyester |
| US5431679A (en) * | 1994-03-10 | 1995-07-11 | United States Surgical Corporation | Absorbable block copolymers and surgical articles fabricated therefrom |
| US5543202A (en) * | 1994-03-14 | 1996-08-06 | Kimberly-Clark Corporation | Process for producing a crimp-bonded fibrous cellulosic laminate |
| CN1058736C (en) * | 1994-05-27 | 2000-11-22 | 北京市星辰现代控制工程研究所 | Preparing method for biodegradation compound and its use |
| US5578662A (en) | 1994-07-22 | 1996-11-26 | United States Surgical Corporation | Bioabsorbable branched polymers containing units derived from dioxanone and medical/surgical devices manufactured therefrom |
| US6339130B1 (en) * | 1994-07-22 | 2002-01-15 | United States Surgical Corporation | Bioabsorbable branched polymers containing units derived from dioxanone and medical/surgical devices manufactured therefrom |
| CA2158420C (en) | 1994-09-16 | 2007-05-01 | Mark S. Roby | Absorbable polymer and surgical articles fabricated therefrom |
| US6206908B1 (en) | 1994-09-16 | 2001-03-27 | United States Surgical Corporation | Absorbable polymer and surgical articles fabricated therefrom |
| US5618313A (en) * | 1994-10-11 | 1997-04-08 | United States Surgical Corporation | Absorbable polymer and surgical articles fabricated therefrom |
| US5770683A (en) * | 1994-11-02 | 1998-06-23 | Mitsui Toatsu Chemicals, Inc. | Preparation process of polyhydroxycarboxylic acid |
| EP0786259B1 (en) * | 1996-01-19 | 2004-03-31 | United States Surgical Corporation | Absorbable polymer blends and surgical articles fabricated therefrom |
| US6001981A (en) * | 1996-06-13 | 1999-12-14 | Dow Agrosciences Llc | Synthetic modification of Spinosyn compounds |
| US5756651A (en) * | 1996-07-17 | 1998-05-26 | Chronopol, Inc. | Impact modified polylactide |
| US6191236B1 (en) | 1996-10-11 | 2001-02-20 | United States Surgical Corporation | Bioabsorbable suture and method of its manufacture |
| US6007565A (en) * | 1997-09-05 | 1999-12-28 | United States Surgical | Absorbable block copolymers and surgical articles fabricated therefrom |
| US6277927B1 (en) | 1997-11-26 | 2001-08-21 | United States Surgical Corporation | Absorbable block copolymers and surgical articles fabricated therefrom |
| JPH11203837A (en) | 1998-01-16 | 1999-07-30 | Sony Corp | Editing system and method therefor |
| AR023940A1 (en) | 2000-05-03 | 2002-09-04 | Eriochem Sa | PROCEDURE FOR THE PRODUCTION OF PROLONGED WATERPROOF PEPTIDE MICROCAPSULES IN WATER |
| PT1310517E (en) * | 2000-08-07 | 2006-05-31 | Wako Pure Chem Ind Ltd | LACTICAL ACID POLYMER AND PROCESS FOR ITS PRODUCTION |
| CA2418347C (en) | 2000-08-16 | 2010-03-30 | Tyco Healthcare Group Lp | High consistency absorbable polymeric resin |
| TW200526267A (en) | 2001-06-29 | 2005-08-16 | Takeda Chemical Industries Ltd | Controlled release composition and method of producing the same |
| JP4612239B2 (en) * | 2001-07-18 | 2011-01-12 | 三井化学株式会社 | Process for producing bioabsorbable polyhydroxycarboxylic acid |
| US7163545B2 (en) * | 2002-07-29 | 2007-01-16 | Mayo Foundation For Medical Education And Research | Spinal cord surgical implant |
| KR100684682B1 (en) * | 2002-09-24 | 2007-02-22 | 아사히 가세이 케미칼즈 가부시키가이샤 | Glycolic Acid Copolymer and Method for Production Thereof |
| EP1440992A1 (en) * | 2003-01-21 | 2004-07-28 | Société de Conseils de Recherches et d'Applications Scientifiques ( S.C.R.A.S.) | Catalyst composition for (co)polymerisation of lactide and glycolide |
| FR2867698B1 (en) * | 2004-03-16 | 2007-11-16 | Beaufour Ipsen S C R A S | CATALYTIC SYSTEM FOR (CO) OLIGOMERIZATION OF LACTIDE AND GLYCOLIDE |
| DE112005000965T5 (en) * | 2004-04-28 | 2007-03-22 | Keio University | Depolymerization process for ester bond-containing polymers in the backbone and process for preparing ester linkage polymers in the backbone of the depolymerization product |
| CA2671670C (en) * | 2006-12-18 | 2015-02-10 | Takeda Pharmaceutical Company Limited | Sustained-release composition and method for producing the same |
| CN101284883B (en) * | 2008-05-14 | 2011-02-16 | 西北大学 | Preparation method of polylactic acid-chitose graft copolymer |
| CN103300120B (en) * | 2013-06-25 | 2015-04-22 | 南京工业大学 | Environment-friendly hair removal agent for poultry and livestock and preparation method of hair removal agent |
| EP3675921A1 (en) | 2017-08-31 | 2020-07-08 | Evonik Corporation | Improved resorbable polymer purification process |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2362511A (en) * | 1939-11-21 | 1944-11-14 | Du Pont | Modified glycolide resins |
| US2703316A (en) * | 1951-06-05 | 1955-03-01 | Du Pont | Polymers of high melting lactide |
| US2758987A (en) * | 1952-06-05 | 1956-08-14 | Du Pont | Optically active homopolymers containing but one antipodal species of an alpha-monohydroxy monocarboxylic acid |
| US3268487A (en) * | 1963-12-23 | 1966-08-23 | Shell Oil Co | Process for polymerization of lactides |
| US3535419A (en) * | 1965-12-15 | 1970-10-20 | Syntex Corp | Veterinary compositions and methods |
| US3442871A (en) * | 1966-05-04 | 1969-05-06 | American Cyanamid Co | Process for polymerizing a glycolide |
| US3458622A (en) * | 1967-04-07 | 1969-07-29 | Squibb & Sons Inc | Controlled release tablet |
| US3887699A (en) * | 1969-03-24 | 1975-06-03 | Seymour Yolles | Biodegradable polymeric article for dispensing drugs |
| US3773919A (en) * | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
| BE758156R (en) * | 1970-05-13 | 1971-04-28 | Ethicon Inc | ABSORBABLE SUTURE ELEMENT AND ITS |
| US3736646A (en) * | 1971-10-18 | 1973-06-05 | American Cyanamid Co | Method of attaching surgical needles to multifilament polyglycolic acid absorbable sutures |
| US3839297A (en) * | 1971-11-22 | 1974-10-01 | Ethicon Inc | Use of stannous octoate catalyst in the manufacture of l(-)lactide-glycolide copolymer sutures |
| JPS4936597A (en) * | 1972-08-07 | 1974-04-04 | ||
| US3982543A (en) * | 1973-04-24 | 1976-09-28 | American Cyanamid Company | Reducing capillarity of polyglycolic acid sutures |
| US3991766A (en) * | 1973-05-31 | 1976-11-16 | American Cyanamid Company | Controlled release of medicaments using polymers from glycolic acid |
| US4144317A (en) * | 1975-05-30 | 1979-03-13 | Alza Corporation | Device consisting of copolymer having acetoxy groups for delivering drugs |
| US4011312A (en) * | 1975-06-25 | 1977-03-08 | American Home Products Corporation | Prolonged release drug form for the treatment of bovine mastitis |
| US4010196A (en) * | 1975-06-25 | 1977-03-01 | American Home Products Corporation | Linear polyester salts |
| ZA782039B (en) * | 1977-05-23 | 1979-09-26 | American Cyanamid Co | Surgical articles |
-
1979
- 1979-09-12 US US06/075,296 patent/US4273920A/en not_active Expired - Lifetime
-
1980
- 1980-09-09 NZ NZ194902A patent/NZ194902A/en unknown
- 1980-09-09 PL PL1980226653A patent/PL129779B1/en unknown
- 1980-09-09 AR AR282459A patent/AR221173A1/en active
- 1980-09-09 PH PH24558A patent/PH15272A/en unknown
- 1980-09-09 RO RO80102132A patent/RO80864A/en unknown
- 1980-09-09 AU AU62166/80A patent/AU539130B2/en not_active Expired
- 1980-09-09 GR GR62846A patent/GR69961B/el unknown
- 1980-09-10 CH CH6807/80A patent/CH648048A5/en not_active IP Right Cessation
- 1980-09-10 FR FR8019582A patent/FR2464973A1/en active Granted
- 1980-09-10 FI FI802840A patent/FI66412C/en not_active IP Right Cessation
- 1980-09-10 GT GT198065361A patent/GT198065361A/en unknown
- 1980-09-10 AT AT0455380A patent/AT380689B/en not_active IP Right Cessation
- 1980-09-10 CA CA000360018A patent/CA1185048A/en not_active Expired
- 1980-09-10 IL IL61024A patent/IL61024A/en not_active IP Right Cessation
- 1980-09-10 EG EG559/80A patent/EG14381A/en active
- 1980-09-10 CS CS806134A patent/CS221979B2/en unknown
- 1980-09-11 ZA ZA00805629A patent/ZA805629B/en unknown
- 1980-09-11 IT IT24607/80A patent/IT1141040B/en active
- 1980-09-11 DK DK387380A patent/DK155093C/en not_active IP Right Cessation
- 1980-09-11 GB GB8029392A patent/GB2058808B/en not_active Expired
- 1980-09-11 EP EP80303198A patent/EP0026599B1/en not_active Expired
- 1980-09-11 PT PT71794A patent/PT71794B/en not_active IP Right Cessation
- 1980-09-11 BE BE1/9957A patent/BE885182A/en not_active IP Right Cessation
- 1980-09-11 ES ES494974A patent/ES8106542A1/en not_active Expired
- 1980-09-11 HU HU802235A patent/HU191807B/en not_active IP Right Cessation
- 1980-09-11 DE DE8080303198T patent/DE3068116D1/en not_active Expired
- 1980-09-11 BG BG8049032A patent/BG41132A3/en unknown
- 1980-09-11 IE IE1902/80A patent/IE50236B1/en not_active IP Right Cessation
- 1980-09-11 JP JP12664280A patent/JPS5645920A/en active Granted
- 1980-09-12 DD DD80223870A patent/DD153125A5/en not_active IP Right Cessation
-
1988
- 1988-04-26 JP JP63107377A patent/JPH0198617A/en active Granted
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1185048A (en) | Polymerization process and product | |
| CA1158553A (en) | Controlled release formulations and method of treatment | |
| US4859763A (en) | Preparation process of dl-lactic acid-glycolic acid-copolymer | |
| DE69837443T2 (en) | DEGRADABLE POLYETHYLENEGLYCOLHYDROGELE WITH CONTROLLED HALF TIME AND ITS PREPARED PRODUCTS | |
| US4130639A (en) | Absorbable pharmaceutical compositions based on isomorphic copolyoxalates | |
| EP0171907B2 (en) | Use of a copolymer in a controlled drug release composition | |
| FI80594B (en) | FOERFARANDE FOER FRAMSTAELLNING AV EN KOMPOSITION SOM FRIGOERS KONTINUERLIGT POLYPEPTID, POLY (LACTIDKOGLYCOLID) POLYMER OCH FOERFARANDE FOER DESS FRAMSTAELLNING. | |
| US4333919A (en) | Growth promotant controlled release formulations and method of treatment | |
| CA1158552A (en) | Controlled release parasitic formulations and method | |
| GB1592829A (en) | Absorbable pharmaceutical compositions based on poly (alkylene oxalates) | |
| US6455665B1 (en) | Polymers and polymerization processes | |
| US7297347B2 (en) | Polyanhydrides | |
| IE50198B1 (en) | Growth promotant controlled release formulations and method of treatment | |
| KR840001675B1 (en) | Polymerization proces | |
| CH666406A5 (en) | METHOD FOR PRODUCING microcapsules BROMOKRIPTINMESYLAT AS PHARMACOLOGICAL ACTIVE INCLUDED. | |
| DE3642662A1 (en) | PARENTERAL DEPOT PREPARATIONS OF REGULATORY PEPTIDES CONTAINING CALCIUM ACETATE-GLYCERIN ADDUCT, METHOD FOR THE PRODUCTION THEREOF AND THE USE OF THE ADDUCT | |
| JPH07223908A (en) | Slow releasing antibacterial component |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |