CS277545B6 - Process for preparing hydroxy carboxylic acid oligoesters - Google Patents

Abstract

Process for preparing hydroxy acid oligoesters by dehydration dehydrated hydroxy acids, optionally mixtures thereof in the presence of an acid catalyst at gradually decreasing pressure and gradually as the temperature rises, it is while raising the temperature to 90-210 ° Ck reaction alcohol with the number of carbons 8 to 24, preferably at a stage of 60 to 99% of the desired conversion rates, after 2 to 5 hours are collected from the reaction mixture sample and alcohol concentration in the reaction mixture is adjusted in the range 0.001 to 0.3 wt.

Description

Field of technology

The invention relates to a process for the preparation of biocompatible oligoesters of aliphatic hydroxy acids.

Prior art

By heating some hydroxy acids under reduced pressure, polyesterification occurs. The first polyester to be examined in more detail of this type is a lactic acid-derived product called polylactic acid or polylactide. The existing knowledge about the course of the reaction was summarized as early as 1944. Increased attention was paid to polylactic acid and similar polyesters from the early 70's, after the elaboration of its two-step synthesis from the cyclic dimer - lactide. Ring-opening polymerization results in high molecular weight polymers with molecular weights of up to several hundred thousand Daltons. The reaction of this type takes place in the presence of catalysts, most often tin compounds.

The polycondensation reaction, which starts from hydroxy acids, takes place at a temperature higher than 100 ° C. By continuously removing water from an aliphatic hydroxy acid having up to 6 carbon atoms under reduced pressure and extending the reaction time to several tens of hours, a maximum weight average molecular weight of up to 10,000 at a dehydration degree of 99.28% can be achieved. The reaction proceeds in low yield, depending on the type and purity of the starting monomers. The products are non-standard, they have a high dispersion of molecular weights. Acid catalysts are preferably used to achieve higher molecular weights of the polycondensation reaction products. Using cations, polymers with a weight average molecular weight of up to 35,000 were prepared. (Pat. Franc. FR 2 464 973, Ogawa, Y. et al., Chem. Pharm. Bull., 36, 1988, p. 1095). The addition of pyrophosphoric acid to the reaction system in the advanced stage of the reaction leads to an increase in the maximum achievable molecular weight (Pat. Jap. JP 62 25, 121) at a temperature of 245 ° C.

To increase the rate of the single-stage polycondensation reaction, mixtures of different catalysts are preferably used. A mixture of antimony trioxide and phosphoric acid was added at the beginning of the reaction (Cohn, D. et al., Adv. Biomater., 7, 1987, p. 503). The use of a mixture of stannous chloride and pyrophosphoric acid added gradually over several hours is described (Pat. Jap. JP 62 25, 121. In: Chem. Abstr., 107, P 78 491 h).

Mixtures of zinc or stannous chloride with cetolal alcohol have been successfully used in lactator-based ring-opening polymerization (Barskaya, J. G. et al., Vysokomolekul. Soedin., Ser. A, 25, 1983, p. 1289). High molecular weight ternically resistant polymers specifically suitable for the production of prosthetic fibers have been prepared in the presence of tinctoate with layrul alcohol (up to 10%) in the presence of tinctoate with layrul alcohol (Pat. Europ. EP 241 252).

CS 277545 B6 2

The essence of the invention

Process for the preparation of oligoesters of aliphatic hydroxy acids. or mixtures thereof under reduced pressure by dehydration in the presence of an acid catalyst, the invention consists in adding an alcohol having a carbon number of 8 to 24, preferably at a stage of 60 to 99% of the desired degree of conversion, at a gradually increasing temperature to 90 to 210 ° C. After 2 to 5 hours, samples are taken from the reaction mixture and the concentration of alcohols is adjusted in the range of 0.001 to 0.3% by weight.

The reaction is stopped several times as needed by increasing the pressure, the reaction system can be left under a desiccant ( ^p 2 ° 5 'silica gel, CaCl ₂ ) for a longer time without heating. The total duration of the vacuum and elevated temperature is from 6 to 120 hours.

After reaching the required parameters, the vacuum is stopped, the melt is poured into molds, cooled, crushed, dissolved in a suitable solvent (dichloromethane, chloroform, acetone, ethanol, benzene, toluene, ethyl acetate, ether or mixtures thereof), the ion exchanger particles are filtered off , the polyester is purified by precipitation or other suitable means, separated by decantation, filtration or centrifugation, dried in vacuo, stored at reduced temperature under a desiccant.

According to the process of the invention, the reaction is accelerated and the yield of the polyesterification is increased, in particular by the synergistic action of the acid catalyst mixture with the alcohol. The activated ion exchanger binds monovalent cations and at the same time releases traces of acid, fatty alcohol supports the course of the reaction. Interrupting the synthesis by increasing the pressure allows the gradual addition of catalyst and alcohol according to the analysis of the samples. The reactions can be monitored continuously. With varying amount and quality of monomers, different purity of monomers, inaccuracies in maintaining pressure and temperature, and changing parameters of the apparatus, it is possible to standardize the product. By successive addition of catalyst and alcohol, sufficiently high molecular weight values of oligoesters with a low degree of polydispersity can be achieved. The low degree of polydispersity of products with esterified terminal carboxyl groups becomes an essential qualitative factor in terms of standardization of hydrolysis behavior. The rate of hydrolysis of oligoesters is highly dependent on their molecular weight. The variance of the mean molecular weights of the products obtained in repeated syntheses and the high degree of polydispersity of the products cause the non-standard behavior of the oligomers during their hydrolysis.

Examples of embodiments of the invention

Example 1, X

In a vacuum distillation flask, 100.0 g of L-lactic acid are mixed with 10.5 g of α-hydroxybutyric acid. Water (11 g) was removed at 3.0 kPa by gradually heating to 80 ° C. The system temperature is raised to 115 DEG C. after pouring off the water, 3.0 g of Dowex and 0.02 g of cetyl stearate are added. The mixture is heated at 1.5 kPa for 10 hours, the vacuum is broken or reduced and 0.6 g of Dowex · CS 277545 B6 and 0.03 g of cetystearyl alcohol are added. The pressure is reduced to 0.3 kPa and samples are taken at intervals of 2 to 5 hours, the whole being heated at this pressure for 5 to 30 hours. 85.0 g of melt are obtained, which is poured into molds, allowed to cool, crushed, dissolved, and the ion exchanger is removed by filtration. The product is purified by precipitation or other suitable means, separated from the liquid phase and dried. 75 g of copolymer are obtained, which has a number average molecular weight of 2060, a degree of polydispersity of 1.91 and a m.p. 125 ° C.

Example 2

250 g of water are separated from 1,170.0 g of 90% DL-lactic acid and 530.0 g of 85% glycolic acid. 0.2 g of cetyl alcohol and 20.0 g of Dowex are added, the vacuum is reduced to 0.8 kPa and the temperature is raised to 120 ° C. After 15 hours, a sample was taken and another 20.0 g of Dowex and 0.2 g of cetyl alcohol were added and the temperature was raised to 175 ° C. After 10 hours, a sample is taken and 5.0 g of Dowex is added. A sample is taken every 3 hours, after reaching the required properties the temperature is reduced to 100 ° C. , the melt is poured into molds and further processed. The product obtained has a number average molecular weight of 5210 and a weight average molecular weight of 10,590, m.p. 60 ° C, the reaction yield is 68% copolymer.

Example 3

In a vacuum distillation flask, 100.0 g of L-lactic acid are mixed with 10.5 g of α-hydroxybutyric acid. Water (11 g) was removed at 3.0 kPa by gradually heating to 80 ° C. The system temperature is raised to 115 ° C after pouring off the water, 0.5 g of a cation exchange type ion exchanger (Ostion LG KS 0805) is added. The mixture is heated at 0.3 kPa for 10 hours. The vacuum is broken and 0.8 g of Ostion and 0.15 lauryl alcohol are added, the pressure is reduced to 0.3 kPa at 115 DEG C. and molecular weight samples are taken at 2-4 hour intervals. After reaching M _n 2000, 0.50 g of cetylstearyl alcohol is added and the mixture is heated at 0.3 kPa and 115 ° C for 6 hours. After the vacuum is released, the melt is poured into molds, allowed to cool, crushed and dissolved in dichloromethane. The ion exchanger particles are removed by filtration. The product is purified by precipitation or other suitable means, separated from the liquid phase and dried. 75 g of copolymer are obtained, which has a number average molecular weight of 2060, a degree of polydispersity of 1.39 and a melting point of 125 ° C.

Cylindrical bodies of 2 mm diameter and 10 mm length prepared by melt casting into molds were tested for degradation rate in phosphate buffer pH 7.4, conc. 0.154 mol.l “ ¹ at 37 ° C. The average weight loss of bodies was 20% in 20 days, 50% 0 in 29 days with a deviation not exceeding 10% of the limit in the number of samples 4.

Example 4

53 g of water are distilled off from a mixture of 440 g of L-lactic acid and 45 g of DL-lactic acid. 5 g of Dowex are added and the temperature is raised to 140 [deg.] C. at a pressure of 1 kPa. After 10 hours, an additional 5 g of Dowex was added and the temperature was raised to 170 ° C. The pressure is reduced to 0.3 kPa. After another 10 hours, another 5 g of Dowex was added and the temperature was raised to 170 ° C. The pressure is reduced to 0.3 kPa. After a further 10 hours, a sample is taken and 5 g of Dowex and 0.3 g of lauryl alcohol are added. Samples are taken every 2 hours and analyzed by a suitable method for the molecular weight parameter. After reaching a molecular weight of M _n 2800, 2.9 g of cetyl alcohol are added and the system is heated for 5 hours, then the temperature is reduced to 140 ° C, the vacuum is released and the melt is allowed to solidify after pouring into a mold. The copolymer is pulverized, dissolved and precipitated by reducing the polarity of the solvent. After separation, the precipitate is dried or repurified by repeated precipitation and dried. 298.5 g of product are obtained, having a number average molecular weight of 2965 and a degree of polydispersity of 1.44.

Microspheres prepared from copolymer by emulsion evaporation in size fraction 80 to 140 disintegrated in distilled water in 65 days, in isosmotic buffer with blood plasma pH 6.0 in 53 days, in isoosmotic buffer with blood plasma pH 7.4 in 43 days .

Example 5

250 g of water are separated from 1170.0 g of 90% DL-lactic acid and 530.0 g of 85% glycolic acid. 8.5 g of Dowex MSC-1 are added, the vacuum is reduced to 0.8 kPa and the temperature is raised to 120 ° C. After 20 hours, a sample is taken and a further 8.5 g of Dowex are added and the temperature is raised to 175 DEG C. at a pressure of 0.8 kPa. After 10 hours, 0.75 g of cethanol is added and samples are taken every 2 hours and analyzed for molecular weight parameters. After reaching 90% of the desired degree of conversion (M 5000), 8.3 g of cethanol are added and the system is heated for 4 hours. After cooling to 120 ° C and releasing the vacuum, the melt is poured into molds and further processed. The product obtained has a number average molecular weight of 5210 and a weight average molecular weight of 8330, m.p. 62 ° C. The reaction yield is 68% of copolymer. The film prepared by evaporating the acetone solution of the copolymer immersed in phosphate buffer pH 7.4 at 37 ° C disintegrated in 57 days.

Example 6 '·

200 g of water are removed from 2000.0 g of DL-lactic acid at 80 [deg.] C. and 3 kPa. After breaking the vacuum, 10 g of ostion are added. The temperature is raised to 130 ° C and the pressure is reduced to 0.5 kPa in 1 hour. After 15 hours, 10 g of Ostion and 0.3 g of decanol are added. The vacuum is reduced to 0.2 kPa and the system is further heated. Samples are taken every 3 hours until M _n 5000 is reached. 3.5 g of decanol are added and the system is heated at 130 DEG C. and 2 kPa for 10 hours. After the vacuum is released, the melt is immediately poured into molds and further processed. The product has a number average molecular weight of 5,055, a weight average molecular weight of 8,900, a glass transition temperature of 56 ° C. The reaction yield is 76%.

Cylindrical plates, 6 mm in diameter, 2 mm high, prepared by pressing the reaction product with 10% cholesterol are model substances continuously liberated cholesterol at 70 ° C. 20% of cholesterol was liberated in 9 days, 50% in 26 days, 80% in 41 days.

ft

The presence of alcohol and its gradual addition during the reaction has a significant effect on the degree of polydispersity and the value of molecular weights, which significantly affect the properties of the obtained oligoesters.

In Table 1 are the number average molecular weight M _n values for the repeated synthesis according to Example 3. Products prepared without cetylstearyl alcohol had greater variability in the molecular weight parameter expressed by the standard deviation n-1 than products synthesized with cetylstearyl alcohol. M _n values were determined by gel permeation chromatography (GPC).

Table 2 shows the values of the degree of polydispersity of products prepared by repeated synthesis in the presence of lauryl alcohol, which have a lower average value of X than samples prepared without lauryl alcohol. The values of the degree of polydispersity p were calculated from the ratio of the weight-average relative molecular weight and the number-average relative molecular weight determined by GPC with calibration to polystyrene standards. Samples were prepared according to the procedure of Example 6. In Table 3, the synthesis products according to the procedure of Example 5 are presented in terms of loss of shape integrity (disintegration). Samples were prepared by melting the ethers, pouring the melt into a mold and cooling them. The bodies had the shape of a cylinder 10 mm long and 2 mm in diameter. It was immersed in phosphate buffer pH 7.4, conc. 0.154 mol.I ” ¹ at 37 ° C.

Table 3 shows that cetyl alcohol hydrophobizes the synthesis product, prolongs the decay time of bodies prepared by melting (x values) and reduces the volatility of this decay time (S _n -i values) ·

Table 1: Numerical mean relative molecular weight values - influence of the presence of cetylstearyl alcohol (Example 3)

Mn 1 Mn2 Mn3 Mn4 6n-l without alcohol 2150 2340 1920 2450 232.4 with alcohol 2030 1990 2120 2100 60.6 Table 2: Values of the degree of lauryl alcohol polydispersity P - influence of presence (example 6) PI P2 P3 P4 X without alcohol 2.15 1.95 2.76 2.12 2.24 with alcohol 1.78 1.57 1.84 1.85 1.76

Table 3: Disintegration time (days) of bodies from oligomers of DL-lactic acid and glycolic acid, phosphate buffer pH 7.4, conc. 0.154 mol.I ^-1 (example 5)

tl t2 t3 t4 X ^S n-1 without alcohol 25 28 30 35 29.5 4.2. with alcohol 36 40 37 37 37.5 0.7

Industrial applicability

There are currently several hundred works dealing with the properties and uses of biodegradable polyesters. The importance of this material lies in its high biocompatibility with the biological environment. The final decomposition product of polyesters is water-soluble non-toxic monomer units, in the case of poly-L-lactic acid the metabolism may end in carbon dioxide and water. Polyesters decompose by non-enzymatic hydrolysis. Thus, with the stability of the surrounding tissue, the polyester hydrolysis process is standard.

The use of biodegradable materials as drug carriers is important. Microspheres, microcapsules, micropellets, nanoparticles intended for application to oral, intravenous, intramuscular, subcutaneous, ocular, paritoneal, cerebral cavities, inter-articular cavities, etc. are the subject of research into particulate dosage forms. Matrix systems are prepared from monolithic-type dosage forms. containing dissolved or particulate dispersed drug substance in the form of platelets, films, rollers, rods, needles and fibers and rigid foam porous formations. They can be implanted, eg in the subcutaneous tissue or in tumor tissue.

Systems containing oligoesters or polyesters in the function of carriers and a drug substance, for the action of which a long-term transfer to the organism is advantageous, are used in human and veterinary medicine. A potential sphere of usability of the mentioned systems are agrochemicals intended for the treatment and protection of plants.

Liberation by hydrolytic erosion is a specific property of oligoesters and polyesters of aliphatic hydroxy acids. By choosing suitable conditions, which include parameters of molecular weight and polar character, it is possible to optimize the behavior of materials of this type after their application to the environment of the organism. The release time of the substances contained in the mixture with oligomers and polymers of aliphatic hydroxy acids can be modified in the range from a few hours to several months.

Claims (1)

Process for the preparation of hydroxy oligoesters dehydrating the mixture dewatered hydroxyacids or mixtures thereof in the presence of an acidic catalyst at a progressively decreasing pressure gradually zvyšující- temperature characterized in that the temperature is increased to 90 to 210 C, ^e added to the mixture with alcohol number of carbons from 8 to 24, and preferably at the stage of 60 to 99% of the desired degree of conversion, after 2 to 5 hours, samples are taken from the reaction mixture and the concentration of alcohols in the reaction mixture is adjusted to between 0.001 and 0.3% by weight.