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Patent US4118470 - Normally-solid, bioabsorbable, hydrolyzable, polymeric reaction product - Google Patents
A normally-solid, bioabsorbable, hydrolyzable, polymeric reaction product of (A) a polyglycolic acid composition and (B) a polyester of diglycolic acid and an unhindered glycol and to the process of preparing the same and the use of said polymeric reaction product as a sterile surgical element and as...http://www.google.ca/patents/US4118470?utm_source=gb-gplus-sharePatent US4118470 - Normally-solid, bioabsorbable, hydrolyzable, polymeric reaction product
Publication number US4118470 A
Application number US 05/793,986
Filing date 5 May 1977
Priority date 1 Jun 1976
Publication number 05793986, 793986, US 4118470 A, US 4118470A, US-A-4118470, US4118470 A, US4118470A
Inventors Donald James Casey, Martin Epstein
Patent Citations (2), Referenced by (101), Classifications (19)
Normally-solid, bioabsorbable, hydrolyzable, polymeric reaction product
US 4118470 A
A normally-solid, bioabsorbable, hydrolyzable, polymeric reaction product of (A) a polyglycolic acid composition and (B) a polyester of diglycolic acid and an unhindered glycol and to the process of preparing the same and the use of said polymeric reaction product as a sterile surgical element and as a device for the controlled continuous administration of a predetermined dosage of a drug to a living animal.
1. A device for the controlled continuous administration of a predetermined dosage of a drug to a living animal comprising the polymeric reaction product of (A) a polyglycolic acid composition and (B) a polyester of diglycolic acid and an unhindered glycol; wherein the amount of (B) used is between about 2% and 50%, by weight, based on the total weight of (A) and (B); wherein (A), before reaction with (B), has a molecular weight of at least 30,000 and (B), before reaction with (A), has a molecular weight sufficiently high so as to provide a polymeric material possessing self-supporting film-forming properties, which has dispersed uniformly throughout said polymeric reaction product, a drug formulation.
2. A device according to claim 1 in the form of a self-supporting film.
This is a division, of application Ser. No. 691,749 filed June 1, 1976, now U.S. Pat. No. 4,048,256.
This application is related to the U.S. application Ser. No. 418,138, filed Nov. 21, 1973, (Attorney's Docket 24,395) entitled HIGH MOLECULAR WEIGHT POLYESTER RESIN, THE METHOD OF MAKING THE SAME AND THE USE THEREOF in the names of Donald J. Casey and George C. Gleckler wherein the Donald J. Casey is the same Donald J. Casey who is a co-inventor in the instant application. The aforementioned U.S. patent application (now abandoned) is incorporated herein by reference as is the streamlined continuation thereof Ser. No. 648,988, filed Jan. 14, 1976, (Attorney's Docket 26,122).
Polyester resins have been prepared in the past by reacting such carboxylic acids as diglycolic acid with a dihydric alcohol such as a glycol but these polyester resins of the prior art were comparatively low molecular weight materials such as those having a molecular weight of about 3,000 to about 8,000 and many had an inherent viscosity of only about 0.25. These low molecular weight polyesters of diglycolic acid and glycols were not capable of forming self-supporting films and had been suggested for use as a propellant plasticizer, among other things. The Casey and Gleckler applications referred to hereinabove produce polyester resins from diglycolic acid and an unhindered glycol which have a molecular weight sufficiently high so as to provide a polymeric material possessing self-supporting, film-forming properties. Those polyester resins are normally solid, biodegradable, hydrolyzable polyester resins.
The present invention is in the field of polymeric reaction products and, more particularly, a normally-solid, bioabsorbable, hydrolyzable, polymeric reaction product which can be prepared by heating a polyglycolic acid having a molecular weight of at least 30,000 at its melting point and adding to the molten polyglycolic acid selected amounts of a polyester of diglycolic acid and an unhindered glycol. The product thus produced can be converted into self-supporting films and fibrous materials which could find utility in the surgical field either as a sterile surgical element such as a suture or a ligature or as a device for the controlled continuous administration of a predetermined dosage of a drug to a living animal.
The instant Applicants are aware of a publication entitled "Polyesters of Diglycolic Acid", Korshak et al., Academy of Sciences, USSR, Bulletin: Div. Chem. Sci. 1957, 889-93. Attention is also directed to the U.S. Pat. Nos. 2,668,162; 2,683,136; 2,676,945 and the U.S. Pat. No. 3,297,033, all of which patents are incorporated herein by reference as well as the literature reference by Korshak et al.
This invention relates to a normally-solid, bioabsorbable, hydrolyzable, polymeric reaction product of (A) a polyglycolic acid composition and (B) a polyester of diglycolic acid and an unhindered glycol wherein the amount of (B) used is between about 2% and 50%, by weight, based on the total weight of (A) and (B) and wherein (A), before reaction with (B), has a molecular weight of at least 30,000 and, preferably, between about 50,000 and 60,000 and (B), before reaction with (A), has a molecular weight sufficiently high so as to provide a polymeric material possessing self-supporting, film-forming properties. This invention also relates to a process for preparing said polymeric reaction product wherein the polyglycolic acid is heated at its melting point and there is added to the molten polyglycolic acid selected amounts of the polyester resin prepared from the diglycolic acid and the unhindered glycol and the heating of the blend is continued at or above the melting temperature of the resulting polymeric reaction product until the transesterification reaction is completed. This invention also relates to self-supporting films and filamentary materials produced from the transesterification product. This invention also relates to the use of such a transesterification product in the form of a device for the controlled continuous administration of a predetermined dosage of a drug to a living animal wherein the drug formulation is dispersed uniformly throughout said transesterification product.
The polyglycolic acid is generally prepared from a substantially pure composition that consists essentially of α-glycolide and/or β-glycolide. The α-glycolide and its method of preparation are fully described in U.S. Pat. No. 3,457,280. The β-glycolide and its method of preparation are disclosed in the U.S. Pat. No. 3,435,008. The method for the purification of glycolide is disclosed in the U.S. Pat. No. 3,597,450. Each of these patents is incorporated herein by reference to avoid any unnecessary redundancy.
In order to get even higher molecular weights than about 50,000-60,000, one can produce polyglycolic acid compositions that have chemical modification such as those shown in the U.S. Pat. No. 3,912,692 in which the modifier is inositol. The inherent viscosities of these modified polymers, when measured on a 0.5% solution of the polymer in hexafluoroactone sesquihydrate at 30° C., may vary between about 0.8 and 1.6. This patent is also incorporated herein by reference.
PREPARATION OF THE DIGLYCOLIC ACID POLYESTERS
The polyester resins used to produce the polymeric reaction products of the present invention are prepared by esterifying diglycolic acid and an unhindered glycol which polyesters are disclosed and claimed in the U.S. patent application Ser. No. 418,138, filed Nov. 21, 1973, which application is now abandoned but has been refiled as a streamlined continuation application having the Ser. No. 648,988, filed Jan. 14, 1976. Among the glycols which may be used to esterify the diglycolic acid to prepare the polyesters used in the present invention are ethylene glycol; diethylene glycol; 1,2-propylene glycol; 1,3-propylene glycol; 1,4-butylene glycol; dipropylene glycol; 1,5-pentanediol; 1,6-hexanediol; 1,7-heptanediol; 1,8-octanediol and the like. These and other glycols may be used individually or in combination with one another. These glycols when reacted with the diglycolic acid should be used in molar amounts substantially equivalent to the dicarboxylic acid although in order to achieve substantially full esterification, it is frequently desirable to use an excess of the glycol components in an amount of about 10 to 150 mole percent over and beyond the stoichiometrically calculated amount necessary to esterify all of the carboxyl groups of the diglycolic acid. As the molecular weight of the polyester increases during the esterification reaction, excess glycol is removed. When the esterification reaction is completed, the excess glycol, if any, can be removed.
In preparing the polyester resin used in preparing the transesterification product of the present invention, one can utilize as the catalytic material antimony trioxide in an amount varying between about 0.01% and 0.5%, by weight, based on the weight of the diglycolic acid. It is preferred to use between about 0.05% and 0.25%, by weight, of the antimony trioxide, based on the weight of diglycolic acid. The esterification reaction may be carried out at a temperature between about 125° C. and 250° C. and preferably between about 150° C. and 225° C. In order to achieve the desired high molecular weight polyester, the esterification reaction is carried out in three steps. The temperature ranges set forth hereinabove are applicable to all three steps. In the first step, the heating can be carried out over a period of about 1 to 5 hours at about 175° C. under an atmosphere of an inert gas such as nitrogen or carbon dioxide. In this first step, atmospheric pressure is generally used. In the second step, the pressure in the system is reduced to about 1.5 mm. of mercury and the heating is carried out for a period of from about 8 hours to about 24 hours. Ordinarily, the temperature would be about 175° C. In the third step, a higher vacuum (lower pressure) is applied in the order of magnitude of about 0.4 mm. of mercury and the period of time is generally between about 2 hours and 36 hours until a very viscous melt is produced. In the first step it is preferred to continue the heating for a period varying between about 2 hours and 31/2 hours. In the second step it is preferred to use the heating time of between about 15 hours and 18 hours and in the third step it is preferred to use a heating time of between about 6 hours and 24 hours. The temperature selected will vary inversely with time, i.e., the higher the temperature, the shorter time interval and vice-versa.
Into a suitable polymerization reactor, fitted with a T-tube so that a capillary bubbler could be inserted through one port and the volatiles removed through the other port, there was introduced a blend of 26.8 parts of diglycolic acid (0.20 mol) (recrystallized from water using decolorizing charcoal) and 0.040 part of antimony trioxide. The blend of these two components was rinsed into the polymerization vessel with 24.8 parts of ethylene glycol (0.40 mol) that had been purified by treatment with sodium under nitrogen followed by distillation. A capillary bubbler was inserted into the polymerization reactor through a rubber seal so that the bottom of the bubbler was above the liquid in the reaction vessel. The system was purged with argon and then was immersed in a fluidized bed sand bath heated to 175° C. The vessel was adjusted until the sand was just above the level of the reactants, and then the capillary tube was pushed to the bottom of the liquid. The volatiles were distilled out of the reactor through the side port and collected in a trap. After 23/4 hours at 175° C., the pressure was gradually reduced so that after 45 minutes the pressure had reached 1.5 mm. of mercury. The reaction was continued for 161/2 hours under these conditions. Thereupon the reaction vessel was immersed up to its neck, and the pressure was further reduced to about 0.4 mm. of mercury. After 81/2 hours under these conditions, the reaction was discontinued. The product produced was a dark brown, clear, rubbery material having an inherent viscosity in hexafluoroacetone sesquihydrate of 0.78 (0.5% conc., 30° C.). The polymer was also soluble in chloroform. Analysis: Calculated for C6 H8 O5 :C,45.00; H,5.04; Found: C,44.61; H,5.04.
Into a suitable polymerization vessel equipped as in Polyester Resin 1, there was introduced a mixture of 26.8 parts (0.20 mol) of diglycolic acid, 0.040 part of antimony trioxide and 30 parts of 1,3-propylene glycol (0.40 mol) which had been distilled under vacuum. The system was purged with argon and the mixture was heated for 2 hours at 175° C. whereupon the pressure was reduced over a 25 minute period to 1 mm. The reaction was continued for 151/2 hours under these conditions. The tube was then inserted in the bath as far as possible and the presssure was further reduced to 0.4-0.5 mm. Heating was continued at about 175° C. under these reduced pressure conditions for an additional 241/2 hours to produce a very viscous, amber product. After cooling the reaction mixture, 24.2 parts of a tough, flexible and opaque polymer was recovered. This material had an inherent viscosity of 0.85 in hexafluoroacetone sesquihydrate (0.5% conc., 30° C.). Analysis: Calculated for C7 H10 O5 :C,48.27; H,5.79; Found: C,48.18, 47.71; H,5.52,5.77.
POLYESTER RESIN 3
The procedure of Polyester Resin 1 was followed again but in this case 13.4 parts (0.10 mol) of diglycolic acid, 0.020 part of antimony trioxide and 16.7 parts of 1,2-propanediol (0.22 mol, treated with sodium under argon and distilled) were introduced into the polymerization reaction vessel. After 3 hours at 175° C. and atmospheric pressure under a blanket of argon gas, the pressure was gradually reduced and the reaction was continued for an additional 24 hours at 0.3 mm. of mercury with the argon slowly bubbled through the reaction mixture. The product was an amber, rubbery and transparent material with an inherent viscosity of 0.68 in hexafluoroacetone sesquihydrate (0.5% conc., 30° C.). Analysis: Calculated for C7 H10 O5 : C,48.27; H,5.79; Found: C,48.15; H,5.75. A solution of this polyester was prepared by dissolving 0.9 part of the polyester and 0.045 part of benzophenone in 3 volumes of hexafluoroacetone sesquihydrate. A film was cast from this solution, air-dried and then irradiated for 12 hours with a Hanovia 100 watt ultraviolet lamp at a distance of 3.25 inches. After irradiation, the tough, self-supporting film became highly swollen in hexafluoroacetone sesquihydrate but did not redissolve.
POLYESTER RESIN 4
The procedure of Polyester Resin 1 was followed in all essential details except that the side port was heated to facilitate the removal of the butanediol used in this example. Into the reaction vessel there was introduced 26.8 parts of diglycolic acid (0.20 mol), 0.040 part of antimony trioxide and 36.0 parts of 1,4-butanediol (0.40 mol, redistilled). The charge was heated under a nitrogen purge for 2 hours at 175° C. before the pressure was gradually reduced to 0.8 mm. of mercury. The reaction was permitted to continue at 175° C. and 0.5-0.8 mm. for 231/2 hours. During the last 71/2 hours, the polymerization vessel was immersed up to its neck in the 175° C. bath. At the end of the reaction the polymerization mixture was allowed to cool to room temperature under a nitrogen atmosphere. Further cooling in liquid nitrogen freed most of the polymer amounting to 36.5 parts (theoretically 37.6 parts) from the glass container; some additional polymer adhered strongly to the glass container and was not recovered. The polymer thus recovered was dissolved in chloroform and the solution was filtered. After the filtered solution was diluted seven-fold with acetone, the precipitated polymer was recovered by filtration, washed with acetone and dried to a constant weight at 40°-45° C. under reduced pressure. The polymer had an inherent viscosity of 0.65 (0.5% concentration in chloroform at 30° C.) and a melting point of 77° C. (differential thermal analysis). Analysis: Calculated for C8 H12 O5 :C, 51.06; H,6.43; Found: C,51.03; H,6.17
POLYESTER RESIN 5
In this example the reaction vessel used in Polyester Resin 1 was modified with a heated wide-bore side-arm tube so that the exit port would not become plugged with excess diol. There was introduced into this modified reaction vessel a mixture composed of 16.8 parts of diglycolic acid, (0.125 mol), 29.5 parts of hexamethylene glycol, (0.25 mol) and 0.025 part of antimony trioxide. After the reaction mixture had been heated for 2 hours at 175° C. the pressure was gradually reduced to 0.8 mm. of mercury and the polymerization vessel was slowly lowered into the sand bath so as to maintain a steady evolution of excess diol. After the bulk of the excess diol had been removed, the pressure was reduced further to 0.2-0.3 mm. and the reaction was continued until a very viscous melt was achieved. The resulting cloudy, tough, amber polymer had an inherent viscosity of 0.70 in chloroform (0.5% conc., 30° C.). Reprecipitation of this material was effected by cooling an acetone solution of the polymer to -78° C. and then removing the acetone under reduced pressure at -50°--60° C. The caked residue was further dried under reduced pressure at room temperature. Analysis: Calculated for C10 H16 O5 :C,55.54; H,7.46; Found: C,54.97; H,7.43.
EXAMPLE 1 (PART 1)
Into a suitable reaction vessel preheated to 140° C., that has been purged with nitrogen gas, there is charged a mixture consisting of 160 parts of molten glycolide into which was placed 0.0032 part (0.002%) of stannous chloride dihydrate and 0.128 part (0.08%) of lauryl alcohol. The reaction vessel is heated to 218° C. with constant stirring for 60 minutes after charging the molten glycolide to the reactor. The system is then placed under a 40 mm. vacuum for about 30 minutes. The polyglycolic acid at this point has an inherent viscosity in hexafluoroacetone sesquihydrate of 0.94 when measured on a 0.5% solids solution at 30° C.
EXAMPLE 1 (PART 2)
While maintaining the polyglycolic acid at about 218° C. under a blanket of nitrogen, 40 parts of poly(1,4-butylene diglycolate), having an inherent viscosity in chloroform of 0.43 when measured on a 0.5% solids solution at 30° C., is added to the molten polyglycolic acid with constant stirring. Samples of the transesterified copolymer were removed from the reaction vessel at intervals of 40 minutes, 80 minutes and 120 minutes after the addition of the poly(butylene diglycolate). The samples all had inherent viscosities of about 0.68-0.69 when measured on a 0.5% solids solution in hexafluoroacetone sesquihydrate at 30° C. and the samples when analyzed by nuclear magnetic resonance showed a content of 20.5 weight percent of the poly(1,4-butylene diglycolate) and 79.5% weight percent of the polyglycolic acid. The samples of the transesterified product were ground to a ten mesh size in a Wiley mill and dried in a vacuum oven at less than 1 mm. of mercury and at 135° C. for about 24 hours before being fabricated into a film and also into a fiber.
EXAMPLES 2-13 INCLUSIVE
The basic procedure of Example 1 (part 2) was followed with the exceptions noted hereinbelow. In the Examples 2, 3 and 4 a polyglycolic acid material was used having an inherent viscosity of 1.12 when measured on a 0.5% solids solution in hexafluoroacetone sesquihydrate at 30° C. The amount of the poly(1,4-butylene diglycolate) was 5%. In Examples 5, 6 and 7 the polyglycolic acid had an inherent viscosity of 0.91, same basis of measurement, and the amount of the poly(1,4-butylene diglycolate) was 10%. In Examples 8, 9 and 10 the inherent viscosity of the polyglycolic acid was 1.03, same basis of measurement, and the amount of the poly(1,4-butylene diglycolate) was 15%. In Examples 11, 12 and 13 the polyglycolic acid used had an inherent viscosity of 0.94, same basis of measurement, and the amount of the poly(1,4-butylene diglycolate) was 20%. These percentages are by weight based on the total weight of (A) and (B), namely, the polyglycolic acid and the polyester. The transesterification time for the Examples 2, 5, 8 and 11 was 40 minutes. The transesterification time for the Examples 3, 6, 9 and 12 was 80 minutes. The transesterification time for the Examples 4, 7, 10 and 13 was 120 minutes. Further details of these Examples are set forth in Table I hereinbelow. These examples were carried out in a cone-vertical mixer manufactured by Atlantic Research. The inherent viscosity of the poly(1,4-butylene diglycolate) in all of these examples was 0.43 when measured on a 0.5% solids solution in chloroform at 30° C. The polyglycolic acid homopolymer when subjected to the same heating conditions for varying periods of time in the absence of any poly(alkylene diglycolate) would undergo a diminution of the inherent viscosity. For instance, a PGA having a starting inherent viscosity of 1.01 would show a decrease in inherent viscosity to 0.99 in 30 minutes; to 0.98 in 60 minutes; to 0.98 in 90 minutes and to 0.94 in 120 minutes if held under a blanket of nitrogen at 222° C. for these periods of time.
TABLE I______________________________________TRANSESTERIFICATION COPOLYMER    NMR    Wt %           DSC Endotherm, ° C.Examples  η inh          1,4-BDG  tg ° C.                         Start  Peak End.______________________________________2      0.94    4.8       37°                         196    223  2283      0.88    5.0       37°                         194    221  2284      0.87    4.8      --    196    221  2295      0.81    9.3      --    189    220  2266      0.78    9.0      34    181    217  2257      0.77    9.3      34    181    215  2218      0.76    15.2     29    185    215  2229      0.73    15.0     29    172    204  21010     0.72    14.4     --    162    199  20411     0.69    20.3     25    170    208  21312     0.68    20.8     25    152    196  20313     0.68    20.5     25    130    185  196______________________________________
Example 1 (part 2) is repeated in all essential details except that there is used a polyglycolic acid having an inherent viscosity of 0.85, measured as before, and the modifier was 10% by weight of poly(1,4-butylene diglycolate) having an inherent viscosity of 0.43 when measured on a 0.5% solids solution in chloroform. The transesterification was carried out in a cone-vertical mixer and the transesterification time was 25 minutes at about 222° C. The resulting transesterification product had an inherent viscosity of 0.75 when measured on a 0.5% solids solution of the copolymer in hexafluoroacetone sesquihydrate. The resulting copolymer had a melting point range of from 194° C. to 229° C. when measured on a differential scanning calorimeter.
Example 14 is repeated in all essential details except that the transesterification time was 240 minutes and the inherent viscosity of the resulting copolymer was 0.66 as measured on the same solids solution in hexafluoroacetone sesquihydrate. The melting point range as measured on a differential scanning calorimeter was 173°-213° C.
EXAMPLES 16, 17, AND 18
Example 14 is repeated in all essential details except that there was used a polyglycolic acid having an inherent viscosity of 1.12 and 10% of poly(1,3-propylene diglycolate) having an inherent viscosity of 0.65 when measured on a 0.5% solids solution in chloroform at 30° C. The results of these examples are set forth hereinbelow in Table II.
TABLE II______________________________________           DSC        NMR3           Endotherm, ° C.2                      wt %Examples  Time     η inh1                   tg                       Start                            Peak End  1,3-PDG______________________________________16      40 min. 0.75    34  195  224  233  9.817     120 min. 0.69    36  189  218  225  9.918     240 min. 0.63    34  179  211  216  10.5______________________________________ 1 Inherent viscosity of the transesterified copolymer in hexafluoroacetone sesquihydrate. 2 Differential scanning calorimeter. 3 NMR = Nuclear Magnetic Resonance.
Into a suitable reaction vessel equipped with a stirrer there was introduced simultaneously 70 parts of a polyglycolic acid, having an inherent viscosity of 1.05 when measured on a 0.5% solids solution in hexafluoroacetone sesquihydrate at 30° C., and 30 parts of a poly(1,4-butylene diglycolate) having an inherent viscosity of 0.81 when measured on a 0.5% solids solution in hexafluoroacetone sesquihydrate at 30° C. The two materials are melted together for 30 minutes and the heating was continued at about 235° C. under a blanket of nitrogen gas for an additional 50 minutes. The resultant copolymer had an inherent viscosity of 0.73 when measured as before, a weight % content of 29.3% of poly(1,4-butylene diglycolate), when measured by nuclear magnetic resonance; a glass transition temperature of 18° C. and a melting point of 183° C. when measured by differential scanning calorimetry and 180°-190° by hot stage microscopy. When the transesterified copolymer was reprecipitated from hexafluoroacetone sesquihydrate into dioxane, the inherent viscosity was 0.74 and the weight % of the poly(1,4-butylene diglycolate) was 27.7% when measured by nuclear magnetic resonance.
EXAMPLES 20-29 INCLUSIVE
Varying amounts of polyglycolic acid were transesterified at 235° C. under a blanket of nitrogen with poly(1,3-propylene diglycolate). The polyglycolic acid, in each instance, had an inherent viscosity of 1.05 as measured before. The poly(1,3-propylene diglycolate) used in Examples 20, 24 and 25 had an inherent viscosity of 0.58 when measured on a 0.5% solids solution in chloroform at 30° C. The remaining examples, namely, Examples 21, 22, 23, 26, 27, 28 and 29 contained a poly(1,3-propylene diglycolate) having an inherent viscosity of 0.65 when measured on a 0.5% solids solution in chloroform at 30° C. The resultant transesterified copolymer was dissolved in hexafluoroacetone sesquihydrate and cast films were prepared therefrom by depositing the solution on a substrate and evaporating the solvent. Tensile properties of the cast films were determined and the results are set forth in Table III hereinbelow.
TABLE III__________________________________________________________________________PGA/Poly(1,3-Propylene diglycolate) Copolymers                            Tensile Properties of Cast Films1,3-PDG       Reaction             Copolymer                   1 H-NMR                            Tens. Str.,                                  Elong,                                      Sec. Mod.ExamplesCharged, %       Time, min.             η inh                   Wt % 1,3-PDG1                            psi   %   at 10%, psi__________________________________________________________________________20   40     25    0.69  42.6     2300  102 20,60021   30     25    0.64  30.0     1580   8  --22   40     25    0.58  44.1     1400  27  12,60023   50     25    0.44  52.8     1750  27  14,00024   30     50    0.53  31.5      903   3  --25   50     50    0.49  60.0      564  18   4,80026   30     50    0.65  27.3     --    --  --27   40     50    0.62  41.8     2800  91  24,70028   50     50    0.46  56.4     1650  50  12,20029   40     120   0.52  36.8     --    --  --__________________________________________________________________________ 1 Copolymers prepared with 30% and 40% of the modifier were purified by dissolving the "as-made" compositions in hexafluoroacetone sesquihydrate and reprecipitating the copolymers into dioxane. The purified samples were used for 7 inh, NMR, and tensile measurements. Copolymers containing 50% of the 1,3-PDG were not reprecipitated.
Into a suitable reaction vessel there was introduced 90.9 parts of a dried polyglycolic acid material having an inherent viscosity of 1.05 and 9.1 parts of poly(1,2-propylene diglycolate) having an inherent viscosity of 0.40 as measured previously on a chloroform solution. The two component mix is melted at 235° C. using a continuous nitrogen blanket purge. After the melt has been completed, the mixture is stirred for a reaction time of about 25 minutes. The mass is then cooled under nitrogen and the solid is ground in a Wiley mill. An inherent viscosity of 0.92 is measured on the copolymer.
Example 30 is repeated in all essential details except that the amount of the polyglycolic acid used was about 83.3 parts and the poly(1,2-propylene diglycolate) was about 16.7 parts. An inherent viscosity of 0.81 was measured for this copolymer.
Example 1 (part 1) is repeated in all essential details except that there is used 144 parts of the glycolide and 16 parts of lactide to produce a copolymer of glycolide and lactide in a 90/10 weight ratio. Example 1 (part 2) was then repeated in all essential details using 160 parts of the copolymer and 40 parts of poly(1,4-butylene diglycolate). A transesterification copolymer was produced having properties similar to those produced in Example 1.
Example 32 was repeated in all essential details except that there was used, to produce the copolymer of the glycolide and the lactide, 136 parts of the glycolide and 24 parts of the lactide to provide an 85/15 weight ratio. The ultimate transesterification copolymer with the poly(1,4-butylene diglycolate) was lower melting than the copolymer produced according to Example 32.
Example 32 is repeated in all essential details except that the copolymer was composed of about 152 parts of the glycolide and 8 parts of the lactide to provide a 95/5 weight ratio. The ultimate transesterification copolymer had properties similar to those produced in Examples 32.
The transesterification reactions set forth in the examples hereinabove have been carried out for varying periods of time. Longer reaction times result in increased transesterification as indicated by the steadily decreasing melting points for copolymers of identical composition. Similarly, as the degree of transesterification is increased, a greater number of carbonyl carbon signals are detected in 13 O-NMR spectra of the copolymers. Depending on the polymer properties desired, the transesterification reaction can be carried out for a period of time varying between about 25 minutes and 240 minutes.
The film from the solution method set forth hereinabove was cut into large pieces and put between aluminum foils separated by 6 mil shims. The "sandwich" was pressed between chrome plated steel plates at a platen temperature of about 100° C. for 30 seconds after preheating for 3 minutes. The sandwich was allowed to stand overnight in a desiccator to give the polyester transesterification reaction product time to crystallize.
Various other delivery devices may be manufactured from these transesterification compositions to administer drugs via a number of routes. For example, an intrauterine device for releasing an anti-fertility agent at a controlled rate for a prolonged period of time; a medical bandage for use in the continuous administration of controlled quantities of systemically active drugs over a prolonged period of time by absorption through the external body skin or mucosa; a strip which could be inserted between the gum and the cheek so that absorption of the medicament at a predetermined interval through the buccal mucosa into the bloodstream may take effect. Drugs could also be incorporated into fine particles of these polyester resin transesterification reaction products and subsequently a dispersion of these particles could be injected parenterally, subcutaneously, intramuscularly, etc., at which site the polymeric material would slowly biodegrade and release the drug over a prolonged period of time. Other methods of drug administration can be envisaged and those skilled in the art can manufacture controlled release device from these compositions in accordance with the present invention.
Polyglycolic acid filamentary braid was dip coated with the transesterification reaction product consisting of 50% PGA and 50% poly(1,3-propylene diglycolide) [Ex. 28] by passing the braid through either a 1%, 2% or 4% (wt./vol.) solution of the transesterification product in dioxane. The wet braid was dried at room temperature to volatilize the solvent and leave a 0.93% to 4.6%, by weight, coating (based on the weight of the braid) of the transesterification reaction product deposited on the braid surface.
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U.S. Classification 514/772.1, 525/444, 528/301, 528/354
International Classification C08G63/664, A61L15/12, A61L17/12, A61K9/70, A61L15/64
Cooperative Classification A61L17/12, A61K9/7007, C08G63/664, A61L15/12, A61L15/64
European Classification A61L15/12, A61L17/12, A61K9/70B, A61L15/64, C08G63/664