TW200521154A - Thermosensitive biodegradabel copolymer - Google Patents

Abstract

A thermo-sensitve copolymer of following formula; is disclosed; wherein R1 is hydrogen, or -C(=O)-R2; R2 is C7-30 alkyl substituted or unsubstituted with functional groups; R3 is hydrogen, or C1-6 alkyl; and x, y or z individually is an integer greater than 0. The thermo-sensitive copolymers disclosed here are easy to be implanted into a human body through injection. The biodegradability is greatly improved and the cytotoxicity of the copolymers is low.

Description

200521154 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to a medical temperature-sensitive biodegradable hydrocolloid copolymer, especially a temperature-sensitive 5 biodegradable water suitable for drug release or embolization. Gum copolymer. [~ Previous technology] In the past decades, a variety of biodegradable polymers have been developed for use in drug release systems to treat chronic diseases in humans. 10 previously proposed a dispersed polymer (dispersed polymer) to increase the solubility of the polymer in the liquid phase and stabilize the biodegradable polymer in a drug release system. However, in order to take into account the requirements of dispersibility, the application of these biodegradable polymers is limited. In order to make biodegradable polymers easier to prepare and improve their softness, a composite 15 ^ biodegradable polymer has also been disclosed; ㈣ Because organic solvents are used in complex processes, these biodegradable polymers The scope of application of degradable polymers still needs to be further explored. Recently, a temperature-sensitive biodegradable terpolymer has appeared. Due to its good biodegradability and high temperature sensitivity, it is not suitable for drug delivery; however, in this temperature-sensitive biodegradable 〇Toxic monomers (such as diisocyanates, Dllsocyanates) are used in the process of decomposable dipolymers. Therefore, the use of such terpolymers is still limited in the human body. In addition, the temperature-sensitive biodegradable copolymers described above all prevent the drug from being released in the drug release system containing the co-substance continuously in a short period of time during the initial period of administration. Therefore, these are used as Temperature-sensitive copolymers of the drug release system 200521154 are still not commonly used. On the other hand, some biodegradable copolymers are used as embolic agents to block the required nutrients from passing through arterial blood vessels into lesion tissue or cancer cells. However, non-toxic biodegradable copolymers suitable as embolic agents are often rare. . In addition, due to the limitation of implantation methods, the application of biodegradable copolymers as embolic agents is also limited. So far, temperature-sensitive copolymers have been proposed as a suitable embolic agent because of their ease of implantation (such as injection) and easy gelation; however, this temperature-sensitive copolymer is still toxic And new issues of biodegradability remain to be resolved. At the same time, temperature-sensitive copolymers can also be used as carriers for biological materials. For example, N-isopropylacrylamide and acrylic monomers have been proposed as a carrier with a seal. Artificial pancreas of pancreatic islets. However, isopropylacrylamide (NIPAAm) itself is not a biodegradable polymer, and its application in the human body is even more scarce. In order to achieve the application of temperature-sensitive polymers in drug delivery systems and as embolic agents, it is urgent to develop a temperature-sensitive biodegradable polymer to overcome the above disadvantages. [Summary of the Invention] The main purpose of the present invention is to provide a temperature-sensitive biodegradable hydrocolloid copolymer, which can have biodegradability and a suitable low criticality> Lower critical solution temperature (LCST) range Characteristics to reduce damage to the tissue, simplify implantation procedures, preparation procedures 200521154, and dose surges when drug is released. In order to achieve the above object, the temperature-sensitive biodegradable hydrocolloid copolymer of the present invention is a compound of the following formula (I): 〇ch3 0 is called a CH2-c | izt〇R3 (I); 5 wherein Ri is a hydrogen atom, Or -C (= 0) -R2; & is an alkyl group containing 7-30 carbons with a replaceable or non-substitutable functional group; & is a hydrogen atom or an alkyl group containing 6 carbons' and X, y Or z is an integer greater than zero each. R, is preferably a hydrogen atom in the copolymer of the present invention, or is selected from the group consisting of cholic acid, fauyacid, 10 folic acid, cholesterol and cholesterol. Vitamin E; more preferably, Ri in the copolymer of the present invention is a hydrogen atom or bile acid (such as the formation of heart

(Π). ) When it is a hydrogen atom, the copolymer of the present invention forms a two-component copolymer, and the two-component soldier polymer is suitable as a drug release system or an embolic agent. A carbon-containing alkyl group is preferably a methyl group. The molecular weight of the copolymer of the present invention is not limited. Basically, the molecular weight calculation of the copolymer of the present invention includes the sum of hydrophobic groups, hydrophilic groups, and acid groups. The hydrophobic part of the hydrocolloid copolymer:

CHg—

The molecular weight of t- is preferably from 1,000 to 6,000; the hydrophilic part of the hydrocolloid copolymer:

The molecular Xia # 5 is 5 to 5 0 0; the ratio of the three parts (in X: y: z) is not limited, preferably 3-18: 11_66: 4_114; the hydrocolloid copolymerization of the present invention 3. Low Critical SQlut '

Temperature (LCST) range is not limited, preferably in the range of 15-30 ° C. The method for preparing the temperature-sensitive copolymer of the present invention includes the following steps: 10 steps: co-polymerizing a mixed solution including at least one hydrophilic monomer, at least one hydrophobic monomer, and optionally a carboxylic acid functional group; Polymerization reaction or selective coupling reaction (coupling reactio); wherein the hydrophilic single system methoxy polyethylene glycol (polyethylene glycol); the hydrophobic The single-system lactic acid dimer is 15 dimmer and glycerolide dimer; the functional group with carboxyl group is 7 to 3 carbon acid. X, y or z are each an integer greater than zero, preferably, X is an integer between 3-18; ^^ is an integer greater than zero, preferably, an integer between 11-66; z Is an integer greater than zero. Preferably, z is an integer between 20 and 114. The content of the hydrophilic monomer used in the method of the present invention is not limited. The “preferred” is that the weight percentage of the hydrophilic monomer in the hydrophilic monomer, the hydrophobic monomer, and the acid-based mixture is 20 wt. % _60 ％%; the content of the hydrophobic monomer used in the method of the present invention is not limited, preferably 200521154, 'the hydrophobic monomer has a hydrophilic monomer, a hydrophobic monomer, and an acid-based mixture The weight percentage is between 80% and 40% by weight. Other features, objects, and advantages of the invention will be apparent from the description herein and the scope of the claims. 5 [Embodiment] The temperature-sensitive biodegradable hydrocolloid copolymer of the present invention includes three main parts, a hydrophobic group, a hydrophilic group, and a hydrophobic carboxylic acid group; used to polymerize the hydrocolloid copolymer The molecular weight of the hydrophilic group is not limited, 10 is preferably 20 to 5000, and more preferably, the molecular weight of the hydrophilic group is 200 to 5000. In addition, the hydrophilic group is used to improve the hydrocolloid copolymer of the present invention. The water-bathability of the hydrocolloid copolymer of the present invention can also help to increase the temperature range of the low critical solution of the hydrocolloid copolymer. 15 percent. Most of the time, the low critical solution temperature of the copolymer of the present invention can be made lower than the human body temperature by adjusting the percentage of hydrophilic groups. The hydrophobic group part of the copolymer of the present invention is derived from poly (lactide-co-glycolide) (PLGA), and the molecular weight of the hydrophobic group part of the copolymer of the present invention is 8000. In the following, the preferred molecular weight is between 1000 and 6000. The hydrophobic group can improve the hydrophobicity and biodegradability of the copolymer, and therefore, the temperature-sensitive biodegradable hydrogel copolymer of the present invention has good biodegradable characteristics. In addition, the hydrophobic group can also help lower the low critical solution temperature of the copolymer of the present invention, so the range of the low critical solution temperature of the hydrocolloid copolymer of the present invention can be 25 by changing the percentage of the hydrophobic group or the hydrophilic group, And adjusted to be lower than 200521154 at or near body temperature; even most of the hydrophobic groups will be hydrolyzed and excreted from the body. The functional group having a carboxyl group provides the hydrophobic property of the copolymer of the present invention, and greatly improves the affinity of the polymer of the present invention with a hydrophobic drug. 5 The functional group having a carboxyl group may be a conventionally used carboxylic acid containing 7 to 33 carbons. Preferably, the functional group having a carboxyl group is derived from a compound such as bile acid, fatty acid, folic acid or cholesterol. In order to make your reviewing committee better understand the technical content of the present invention, the nine preferred embodiments are described below. The following embodiments are merely examples for the convenience of description. The scope of rights claimed in the present invention should be based on the scope of the patent application, rather than being limited to the following embodiments. Example 1: Preparation method of AB two-component copolymer (PEG-PLGA) First, set up a 250 ml four-necked flask (24/40) and a mechanical stirrer, pass N2 (g) for 15 minutes before the reaction, and then set the reaction device After heating to 110 ° C, 50.0g of monomer lactide and 11.36g of glycolide and 24.02g of initiator m-PEG (MW 550) were added to the reaction flask and heated to melt. After the monomer and the initiator have completely melted, add the catalyst 0.05% Sn + 2, and then gradually increase the reaction temperature (10 ° C each time) until the temperature of the reaction flask 20 is 160 ° C. The reaction time is 9 hours. After the reaction, the product was cooled to room temperature, and the product was light yellow gum. 80ml of CH2C12 was added to stir, the product was completely dissolved, and the CH2C12 solution of the product was gradually dropped into a hexane / ether (9 / l) mixed solvent, and stirred by magnetic stirring Stir thoroughly with the machine for 3 hours. The product will sink in the lower layer, then drain the upper layer and replace with a new solvent 25 (hexane / ether). Repeat this cleaning step 3 times. After finishing the cleaning steps such as Shen Dian 200521154, place the product on a hot plate and heat it at 45 ° C for about 2 hours. Then move the product to a vacuum oven and heat it (45 ° C) for 1 day to evacuate the remaining Removal of organic solvents. 500 MHz 1H-NMR, d-chloroform 5 δ 1.58 (d, J = 6_5 Hz, H-4), 3.39 (s, -OCH3), 4.29 (m, H_l, 2), 4.80 (m, H-5) The polymerization reaction of 5.14 (m, H-3) · AB two-component copolymer is shown in the first flowchart: 〇0 ch3 ο ch3o- (ch2ch2) oh Tl r-. ^ ≫ ch3o {ch2ch2o ^ c-ch- o ^ (cch ^ oh Flowchart 10 Example 2 Preparation method of ABC three-component copolymer (PEG-PLGA-FA (C12)) Hold a 250 ml three-necked reaction flask, and pass N2 (g) 30 before reaction Minutes, 1.53 g Laurie acid was dissolved in 30 ml CHC13, and 1.58 g 15 DCC (dicyclohexyl carbodiimide) was dissolved in 20 ml CHC13. Then the prepared DCC solution was slowly added to the Laurie acid solution in an isocratic funnel and reacted. 30 minutes. In addition, 10 g of AB-diblock was dissolved in 50 ml of CHCl3, and 1.5 ml of TEA (triethylamine) was added to stir the reaction for 30 minutes. Then, the AB-diblock solution was slowly dropped into the Laurie 20 acid solution through an isocratic funnel and reacted. 24 hours. After the reaction is completed, 'DCU (dicyclohexylurea) insoluble matter is removed by a transition method, and then the crossing liquid is slowly poured into a hexane / ether solvent for stirring and washing. This step is repeated. Finally, place the cleaned product on 12 200521154 hot plate and heat it at 45 ° C for about 2 hours, then move the product to a vacuum oven and heat it (45 ° C) for 1 day to remove the residual organic solvent. 5 00 MHz 1H-NMR, d-chloroform δ 0 · 86 (t, J = 6.8 Ηζ, Η-8), 1.23 (m, H_7), 1.58 (d, J = 6.5 Hz, 5 H-4), 2 · 38 (m, H-6), 3.39 (s, -OCH3), 4.29 (m, Hl, 2), 4.80 (m, H_5), 5.14 (m, H_3), ABC three-component copolymer ( The polymerization reaction of PEG-PLGA-FA (C12)) is shown in the second scheme: o ch3 〇

CH30 ^ CH2CH2 (^ C-CH- ^ CCH2) -0H

CH3 (CH2) i〇COOH chci3

DCC / TEA 〇ch3 oo CH3〇 (CH2CH2 (^-iH-^ (JcH2 ^ 〇-i;-(CH2) 10CH3 10 Flowchart 2 Example 3, ABC three-component copolymer preparation method (PEG-PLGA-CA ) Set up a 250ml three-necked reaction flask. Pass N2 (g) for 30 minutes before the reaction, dissolve 6.27 g of Cholic acid in 30 ml l, 4-dioxane, and dissolve 3.16 15 g of DCC in 20 ml l In 4-dioxane, the prepared DCC solution was slowly added to the Laurie acid solution in an isostatic funnel and reacted for 30 minutes. In addition, 10 g of AB-diblock was dissolved in 100 ml of 1,4-dioxane, and 2.0 mi was added. TEA was stirred for 30 minutes in advance. 13 200521154 After the reaction was completed, Dcu insoluble matter was removed by filtration, and the solvent was removed by concentration under reduced pressure. The product was dissolved in CHCl3, and then filtered. The lower filtrate was slowly poured into hexane. This step is repeated three times. Finally, the washed product is placed on a hot plate (hot plate) and heated at 45 ° C for about 2 hours. Then the product is moved to a vacuum oven and heated (45 〇 Vacuum for 1 day to remove residual organic solvents. 500 MHz 1H-NMR, d-chloroform 60.67 (s, H-8) , 0.87 (s, H-9), 0.97 (d, J = 6.8 Hz, H-7), 1.58 (d, J = 6.5 Hz, H-4), 2.38 (m, H-6), 3.39 (s } -OCH3), 4.29 (m, 10 Hl, 2), 4.80 (m5 H-5), 5.14 (m, H-3). Example 4. Preparation of hydrocolloid copolymer / protein solution The gum copolymer is dissolved in pure water. Pour fetal bovine serum albumin 15 (BSA-FITC) 100 mg / mi with FITC fluorescent dye into the hydrogel polymer solution, and shake the protein and hydrogel slightly. The dissolving solution is mixed uniformly; the final concentration range of the hydrocolloid copolymer is 10-50%, and the post-concentration concentration range of protein shells is 0 01 ng / mL to 50 mg / mL. Used in the above experimental steps All materials need to be cooled down to 4 ° C first, and all are operated at low temperature to avoid unnecessary gelation during operation. 20 Example 5 Drug release test 0.2 mL of hydrogel prepared in Example 4 The copolymer / protein solution is placed at the bottom of the release cell, see Figure 3. The release unit 10 is first placed at 37.0 ± 1.0. (: 10 minutes in the thermostat, at this time the hydrocolloid copolymer / 25 The protein solution will quickly gel, pre-heated at 5mi (37. (]) The salt-buffering buffer 14 200521154 The solution is added to the release unit and is in direct contact with the surface of the gel. A galvanized iron mesh and a stir bar were placed in the upper part of the release unit; the release test was performed at 37.0 ° C, and the speed of the stir bar was 100 rpm. After a certain period of time, a new phosphate buffer solution was replaced; the concentration of protein released from the phosphate buffer solution was measured by a fluorescence spectrophotometer. According to Figure 4 and Figure 5, the results of two or three experiments were carried out respectively. It was found that the burst release effect of protein can be observed in the ΑΒΑ three-component hydrogel polymer system, but this phenomenon is being implemented by Obvious improvements were observed in the AB two-component hydrogel polymers prepared in Examples 1 to 3. The 10 and ABC three-component hydrogel polymers were obtained. Example 6 15 Two types of synthetic hydrocolloid copolymers were provided. Suspension 0.01g / ml (AB two-component hydrogel and ABC three-component hydrogel), the hydrogel copolymer was diluted with cell culture solution to a concentration of 50 (^ g / ml, adjusted with a 1N NaOH solution The pH value is 7.4. Fibroblasts (L-929 fibroblast) 5x104 cells / well are seeded into a 24-well cell culture plate. After one day of culture, lml each of the prepared water 20 gel copolymer suspension is put into Cultivate for one day in the holes of a 24-well plate; take out the hydrocolloid copolymer suspension from each hole with a micro-dispenser, then add MTT (5 mg / ml) solution and incubate for another 2-4 hours; Remove the MTT from each hole; add DMSO to The blue particles are dissolved in each hole; after the blue particles are completely dissolved, the 25 absorbance value is measured at OD570 nm to measure the cell survival rate in each hole. The results are shown in Figure 6, which shows the material synthesized by the invention of this 15 200521154 invention and No cytotoxicity. In the figure, the 'culture medium represents the cell culture solution of the non-aqueous gum copolymer solution; sample 1 represents the mixed solution of the pEG_pLGA hydrogel copolymer and the cell culture solution prepared in Example 1; sample 2 represents the embodiment The mixed solution of 5 PEG_PLGA_FA (C12) hydrogel copolymer and cell culture fluid prepared in Example 2. Example 7 Preparation of hydrogel copolymer samples of different concentrations (AB two-component hydrogel copolymer prepared in Example 1) on the sample In the bottle (di_9n227 represents 25wt%, 10 d, 911227 represents 33wt%, and di-FA represents 20wt%), each hydrocolloid copolymer sample is stored for a different period of time (0 days, 1 day, 3 days, 5 days, 7 days, 9 days, 13 days, 16 days, 20 days, 25 days, 31 days, 38 days, 46 days); after the storage time is over, remove 0.2 blood samples from each different hydrogel copolymer sample bottle Into another large vial (4ml); stored During the process, the solid gel will be accompanied by 15 with the hydrocolloid copolymer liquid. The weight of the solid gel and hydrogel copolymer liquid (excluding the solid gel) of each sample can be obtained by weighing and calculation. Add 3ml of water to the large sample bottle and shake at 37 rpm in a 37 C water bath; the upper layer of the large sample bottle will be removed during shaking, and the solid gel left in the bottle will be carefully washed with pure water. Collect and freeze-dry for 20 days; weigh the freeze-dried solid gel and calculate the weight loss due to degradation. This result is shown in Figure 7. Example 8. Measurement of gelation time in vitro and evaluation of gelation temperature The measurement of gelation time was performed using a Brookfield DVIII + Cone and Plate Geometer; before using the rheometer, A variety of 16 200521154 are calibrated with the standard solutions (100, 5000 and 1000 cP) before measuring; the measuring method is to first test the hydrogel sample (0.5 ml) below 1 (The rc temperature is placed in the center of the measurement board. There is a thermocouple sensor directly below the measurement board to detect the temperature in the center of the measurement board. The cone-plate rheometer uses 5 cone # CPD52 as a probe. At the beginning of the test, 'warm water of about 3rc (or higher than 3 generations but lower than the thief) is added to the measuring board, at this time the measuring board temperature # will quickly rise to 36-grip; measure From the beginning to the relevant data such as viscosity, time thermocouple / plate degree and rheometer rotation speed and torque are recorded by the rheometer, software Rheocal, and recorded; in order to make the experimental data more The speed of the rheometer should be adjusted so that the torque value is between 80.%; The setting is based on the time it takes for the viscosity of the sample to increase to 10000CP. / 0 ′ 20 wt%, 25 wt%, and 33 wt% of various hydrogel samples are shown in Figure 10. The relationship between water viscosity and time can be seen in the graph; the gelation time can be estimated from the viscosity time graph of the AB two-component water-glue copolymer. As shown in Figure i, the gelation time is between seconds. As shown in Figure 2, the LCST is between 15HC. 20 Example 9. Establishing a rabbit renal artery embolization experiment Because the diameter of the catheter used by the human body is larger than the diameter of the rabbit hepatic artery, embolization of the rabbit renal artery is used to confirm the warmth The polymer is enough to be used to embolize the renal arterial blood vessels as an embolic agent. The renal artery hemorrhagic embolism model is established by the following steps. First, a 22 G 25 pingmai remote needle (ΐ.ν · mail is aimed at the femoral artery of the rabbit Stuck in, withdraw 17,200521154 After passing the hard needle, insert the guide wire into the indwelling needle, wait for the wire to enter the femoral artery, and then enter the renal artery. An angiographic catheter enters the renal artery through the wire; add contrast agent Upiodol ® 2 ml / kg, along The angiography catheter was poured in; under x-ray photography, it can be clearly seen that the contrast agent from 2 = 5: the arteries enter the aorta and then the renal arteries. Staying in the kidneys, the renal veins return to the heart with the blood flowing back to the heart With the assistance of angiography and X-ray photography, the distribution of blood vessels can be clearly seen; a PBS solution containing the 25% temperature-sensitive hydrocolloid copolymer of the present invention is provided, and the solution is provided. It is implanted at a predetermined position in the renal artery by injection to block blood flow. After the 25% PBS solution of the temperature-sensitive hydrocolloid copolymer of the present invention is injected, the embolization experiment is completed by using computer tomography to observe Rabbit's renal artery. When the temperature-sensitive hydrocolloid copolymer is injected through a catheter, the solution immediately transforms into a gel and blocks blood flow. Fig. 8 shows the results of a computed tomography scan, in which the darker region of the left kidney, that is, 15 represents that there is no blood inflow in that region, that is, by injection into the temperature-sensitive hydrocolloid copolymer of the present invention, it can be successfully used in animal blood vessels To achieve the purpose of embolization. The temperature-sensitive hydrocolloid copolymers of the present invention include AB two-component hydrocolloid co-polymers and ABC three-component hydrocolloid copolymers. Due to the appropriate LCST, they can be easily implanted into the human body by injection. In addition, since the hydrocolloid copolymer of the present invention has high biodegradability and low cytotoxicity, it can be used as a good embolic agent or as a drug delivery system. Therefore, the hydrocolloid copolymer of the present invention has good biodegradable name 25 and low cytotoxicity, and is suitable for drug release or embolization. 18 200521154 Several embodiments of the invention have been described in detail above. And without departing from the spirit and scope of the present invention, various changes and modifications can be made to the present invention to be suitable for various uses and situations. Therefore, other specific embodiments are also within the scope of this application. [Brief description of the drawings] FIG. 1 is a time-temperature curve diagram of the eighth embodiment of the present invention. FIG. 2 is a graph showing the results of the viscosity and temperature of the hydrogel according to the eighth embodiment of the present invention. 3 is a cross-sectional view of a release unit used in a fifth embodiment of the present invention. Fig. 4 is a time chart of the cumulative release of substances in the copolymers made from the data in Example 5 of the present invention. Fig. 5 is another time chart of the cumulative release of substances in the copolymers made from the data in Example 5 of the present invention. Figure 001 shows the absorption values of OD 57 of several samples in Example 6. 7 is a sample according to the sixth embodiment of the present invention, the weight of the sample before and after the release of the dry weight is also η β B β β! 15 Figure ratio of the ratio of time and time Figure 8 is a test of rabbit renal artery embolization in Example 9 of the present invention Computer (CT) Photography _ 20 [Illustration of the drawing number] 10 Release unit 20 Release interstitial fluid 30 Galvanized iron mesh 4 40 Stirrer 50 Hydrogel copolymer / protein solution 19

Claims (1)

200521154 Scope of patent application: 1. A temperature-sensitive biodegradable hydrocolloid copolymer, which is a compound of formula (I): Wherein R 2 is a hydrogen atom, or C 0 = 0) _R 2; R 2 is an alkyl group containing 7 to 30 carbons with a replaceable or non-substitutable functional group is a hydrogen atom or an alkyl group containing 6 carbons; and X,; ^ or 2 are each an integer greater than zero. ίο 2 · The hydrocolloid copolymer described in item 1 of the scope of the patent application, wherein the Ri is a group consisting of the following materials: · cholic acid ^ In the sentence, fatty acid, folic acid (folic acid) and cholesterol (choloster〇1) 0 3 · The hydrocolloid copolymer according to item 1 of the scope of patent application, wherein R2 is a compound of the following formula (Π): (Π) 〇 4. The hydrocolloid copolymer according to item 1 of the scope of the patent application, wherein the R3 is a methyl group. 5. The hydrocolloid copolymer according to item 1 of the scope of the patent application, wherein the R2 is a hydrogen atom, and the hydrocolloid copolymer is used for drug release or embolization as 200521154 6 · As described in the scope of the patent application, item 1 Hydrocolloid copolymer, wherein the hydrophobic part of the hydrocolloid copolymer: 7. The hydrocolloid copolymer according to item 1 of the scope of the patent application, wherein the hydrophilic part of the hydrocolloid copolymer: The molecular weight is 200 to 5000. 8. The hydrocolloid copolymer according to item 2 of the scope of the patent application, wherein the ratio of X: y: ζ is 3-18: 11-66: 4-114. 9. The hydrocolloid copolymer according to item 丨 in the scope of application patent, wherein the hydrocolloid copolymer has a low critical solution temperature (Lówer plus 〇solotin Temperature, LCST) in the range of 15-30 ° C . 10 · The hydrocolloid copolymer according to item 1 of the scope of patent application, wherein the hydrocolloid copolymer is used as a suppository. twenty one