KR101454597B1 - Manufacturing method of hydrogel having mucosadhesive property and thus prepared hydrogel having mucosadhesive property - Google Patents

Abstract

The present invention provides a method for preparing a mucoadhesive hydrogel by adding a diacrylated poloxamer and a carbowol having a functional group capable of crosslinking to a poloxamer introduced into an aqueous solution and irradiating the same.

Description

Technical Field [0001] The present invention relates to a method for producing a mucoadhesive hydrogel and a mucoadhesive hydrogel prepared thereby,

The present invention relates to a method for producing a mucoadhesive hydrogel and a mucoadhesive hydrogel prepared thereby. More particularly, the present invention relates to a mucoadhesive hydrogel cross-linked using radiation, and a mucoadhesive hydrogel .

Mucoadhesive drug delivery technology is a system that delivers drugs through the mucosa. It improves the drug absorption rate by increasing the residence time of the drug in the body and improving contact with the drug-absorbing membrane, .

In addition, it is possible to control the release rate and the rate of drug by changing the composition of the drug by means of mucous membrane. Unlike the oral administration, since the drug is hydrolyzed in the body and does not disappear or the hepatic effect is not exerted, have.

The mucosal adhesion is formed when the polymer is in contact with the mucous membrane and is bound to the mucin, which is the main component of the mucosa, and a weak chemical bond such as a hydrogen bond between the chains is temporarily formed between the contact surfaces. Therefore, in order for a polymer to have an effective mucosal adhesion to a mucous membrane, it is necessary to have a hydrophilic functional group such as a hydroxyl group, a carboxyl group or an amine group so that a hydrogen bond can be formed in the molecular molecular structure, Should be flexible enough to take place.

Among the various mucous membranes distributed in various parts of the body such as mouth, eye, nasal cavity, vagina, anus and gastrointestinal tract, the oral mucosa is a relatively non-keratinized structure, Absorption is relatively easy. It also has the advantage of being easy to administer the drug or remove the formulation. Formulations suitable for delivery of drugs through such oral mucosa should be small enough to be used once in the mouth and the formulation itself should be soft and flexible. It is also desirable to have a formulation that is excellent in mucoadhesive power of the formulation, easy to use, and capable of controlling drug release. Formulations for drug delivery include tablets, patches, films, gels, and ointments. Of these, hydrogels are composed of hydrophilic polymers that hydrate in aquatic environments and are easily controlled by physicochemical properties according to the composition and manufacturing conditions of the polymer. To be useful as a formulation for oral delivery.

It is also suitable for use in oral mucous membranes which can control drug release and hydrogel itself is soft and flexible, which is highly mobile.

However, hydrogels, which are easy to disperse through the mucous membrane, have a disadvantage in that the application time is shortened at the application site. Therefore, the hydrogels have a disadvantage in that they can not be used with carbomers, chitosan, sodium alginate, Studies have been conducted to overcome short duration by using a polymer having excellent adhesion property (Korea Patent Publication No. 0299231).

Poloxamer (hereinafter referred to as Pol) is a nonionic PEO-PPO-PEO triblock copolymer composed of hydrophilic polymer poly (ethylene oxide) (PEO) and hydrophobic polymer poly (propylene oxide) It is known as hydrogel. At a certain temperature (about 18 wt%) or more, the aqueous solution of Pol is in a solution state (sol) of low viscosity at room temperature. However, when the temperature is above a certain temperature, the relatively weak hydrogen bond between PPO and water molecules is broken, and hydrophobic interaction between PPO blocks Gel phase transformation phenomenon which is converted into a gel form by secondary association and packing of the micellar structure.

Pol is divided into various kinds according to the composition ratio and molecular weight of PEO and PPO, and Pol Hydrogel exhibits phase transition according to temperature change. Because of physical crosslinking structure in which micelle is packed constantly, it is easily decomposed when excess water exists have.

In addition, the mechanical properties are very weak, and when the gel is attached to the oral cavity, the concentration of the gel may be diluted by body fluids or other food or the like, which may cause the phase transition to the solution (sol) again.

Therefore, studies are needed to improve the physical stability and mechanical properties of hydrogels in order to overcome these problems.

Korean Registered Trademark Bulletin No. 0299231 (Registered on June, 2001)

The present invention provides a method for manufacturing a mucoadhesive hydrogel which can improve physical stability and mechanical properties of a hydrogel by a simple process.

The present invention also provides a method for producing a mucoadhesive hydrogel in which a process is simplified since it is not necessary to remove unreacted residual materials without using a harmful chemical crosslinking agent or an initiator, and the sterilization treatment can be performed simultaneously with crosslinking.

The present invention also provides a mucoadhesive hydrogel prepared according to the process of the present invention.

The present invention relates to a method for producing a mucoadhesive hydrogel having improved mechanical properties, mucoadhesiveness and drug release rate characteristics, and a method for producing the hydrogel of the present invention comprises

Reacting poloxamer with (meth) acryloyl chloride to prepare di (meth) acrylated poloxamer;

(Meth) acrylated poloxamer, and a step

And irradiating the mixed aqueous solution with radiation to prepare a mucoadhesive hydrogel.

The mucoadhesive hydrogel according to the present invention does not require a cross-linking agent and an initiator used in a general chemical crosslinking method by irradiating and irradiating radiation, so that there is no need to remove a crosslinking agent and an initiator remaining as unreacted materials, And the sterilization process does not require a separate sterilization process.

In addition, according to the present invention, it is possible to irradiate a specimen irradiated with radiation irrespective of a solid or a liquid, to examine whether the specimen is in a cooled state, It is not necessary.

Also, the crosslinking time is short, and the physical properties of the mucoadhesive hydrogel can be controlled by radiation irradiation.

In particular, the method for preparing a mucoadhesive hydrogel of the present invention can solve the drawbacks of low stickiness, low mechanical strength, and short duration of the mucoadhesive hydrogel by adding carbopol.

The poloxamer according to an embodiment of the present invention may have a weight average molecular weight of 9,840 to 14,600 and may have a low toxicity and a high solubility and preferably 11,000 to 13,000 in terms of drug release effect.

The mixed aqueous solution according to an embodiment of the present invention may contain less than 0.01 to 2% by weight of carpol, and preferably 0.01 to 1.5% by weight in terms of swelling degree, mucoadhesiveness, and delayed drug release rate.

The radiation according to one embodiment of the present invention may be an electron beam, an ion beam or a gamma ray, preferably an electron beam, the total dose may be 1 to 50 kGy, and the mucoadhesive hydrogel may have enhanced mucoadhesion For example, 10 to 30 kGy.

In the mixed aqueous solution according to an embodiment of the present invention, a drug for treating mucosal diseases may be further added in an amount of 0.01 to 0.5% by weight, and the drug for treating mucosal diseases is not limited, but the di (meth) acrylate It may be naproxen or triamcinolone acetonide in terms of preferred combination with poloxamer.

The mucoadhesive high-road gel according to one embodiment of the present invention may contain 60 to 90 parts by weight of water relative to 100 parts by weight of the mucoadhesive hydrogel, preferably in the aspect of increasing swelling degree and mucoadhesion 75 to 90 parts by weight.

The mixed aqueous solution according to an embodiment of the present invention may contain 10 to 30% by weight, preferably 15 to 23% by weight of di (meth) acrylated poloxamer, 0.01 to 2% by weight of carbolol, 0.01 to 2% 0.5% by weight and a balance of purified water.

In the step of preparing di (meth) acrylated poloxamer by reacting poloxamer and (meth) acryloyl chloride according to an embodiment of the present invention, the reaction may be carried out at 50 to 90 ° C for 2 to 6 hours The solvent to be used at this time is not limited, but benzene can be used.

The molar ratio of the polychlorosilicate and the (meth) acryloyl chloride according to one embodiment of the present invention can be reacted in a molar ratio of 1: 2 to 8, and after the reaction, impurities are removed and separated. For one day.

The present invention also provides a mucoadhesive hydrogel prepared according to the present invention.

The mucoadhesive hydrogel prepared according to the present invention has high mechanical properties and has an effect of retarding the drug release rate. In view of this, it is preferable that water is 75 to 90 weight parts per 100 weight parts of the mucoadhesive hydrogel Lt; RTI ID = 0.0 > hydrogel < / RTI >

The method for preparing a mucoadhesive hydrogel according to the present invention can improve the mechanical properties of a mucoadhesive hydrogel prepared by introducing functional groups capable of crosslinking to poloxamer and cross-linking by irradiation with radiation.

Further, in the method of preparing the mucoadhesive hydrogel of the present invention, it is necessary to separately remove the unreacted residual material because the cross-linking agent and the initiator used for the chemical crosslinking are not separately used in order to improve the conventional mechanical properties by irradiating the cross- It has the advantage of simple process, easy to cross-link, and sterilized. It can be cross-linked regardless of solid or liquid. It does not require any heat for cross-linking, Investigation is possible regardless.

Further, unlike the conventional method in which the crosslinking is performed for a long time, crosslinking takes place in a relatively short time, and the physical properties of the hydrogel can be freely controlled by adjusting only the radiation intensity of the radiation. There is an advantage that it can be freely manufactured in various ways according to the shape.

In addition, the manufacturing method of the mucoadhesive hydrogel according to the present invention overcomes the weak physical stability and mechanical properties of the hydrogel having a physically crosslinked structure through radiation crosslinking. In particular, the mechanical properties of the hydrogel are improved by adding a sticky polymer, , And the rate of drug release can be controlled.

1 shows FTIR and ¹ H NMR graphs of the diacrylated poloxamer prepared in Example 1, and FIG.
2 is a diagram showing the phase transition states of the diacrylated poloxamer and poloxamer prepared in Example 1 in a solution state,
3 is a graph showing swelling degree of the mucoadhesive hydrogel prepared in Examples 2 to 4 and Comparative Example 9,
4 is a graph showing the mucoadhesiveness of the mucoadhesive hydrogel prepared in Examples 2 to 7 and Comparative Examples 1 to 10,
FIG. 5 is a graph showing drug release effects of the mucoadhesive hydrogel prepared in Examples 2 to 3 and Comparative Examples 1 to 3 and 9 over time,
6 is a graph showing the drug release effect of the mucoadhesive hydrogel prepared in Example 8 with time,
FIG. 7 is a graph showing tissue recovery when applied to a skin wound in an animal test of the mucoadhesive hydrogel prepared in Example 8 and the control group,
FIG. 8 is a chart showing histopathological changes in tissue repair when applied to skin wounds of the mucoadhesive hydrogel prepared in Example 8 and control groups,
FIG. 9 is a chart showing histopathological changes in tissue repair upon application to wound of oral mucosa during animal experiment of mucoadhesive hydrogel prepared in Example 8 and control groups.

Hereinafter, the present invention will be described in more detail in the following non-limiting examples, but the claims of the present invention are not limited to these examples. Unless otherwise defined, technical terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the following description, And a description of the known function and configuration will be omitted.

[Example 1] Production of diaclitated poloxamer

Poloxamer 407 (Pol, Lutrol F 127, weight average molecular weight 12,600, polypropylene oxide content 30% by weight, BASF) (12.6 g, 1 mmol) was vacuum dried at 80 ° C for 25 hours. The dried poloxamer 407 was dissolved in benzene (35 mL) under a stream of nitrogen, then triethylamine (0.41 mg, 4 mmol) was slowly added dropwise thereto, and the mixture was heated to 75 ° C and stirred for 1 hour. To this was added acryloyl chloride (0.36 mg, 4 mmol) dissolved in 10 mL of benzene, and the reaction was allowed to proceed at 75 DEG C for 4 hours. Triethylamine hydrochloride was removed by filtration using a centrifugal separator, precipitated with normal hexane, and dried at 40 DEG C for 3 days to obtain diacrylated poloxamer (hereinafter referred to as D -Pol) was prepared.

The chemical composition and substitution ratio of synthesized D-Pol were analyzed by ¹ H NMR (JNM-AL400 spectrometer, Jeol Ltd., Akishima, Japan) and CDCl ₃ was used as a sample solvent.

In order to investigate the structural change of the molecular bond before and after the synthesis, FTIR (MAGNA 560 spectrometer, USA) was used. The KBr pellet was prepared and the specimen was measured in the range of 500-4000 cm ^-1 . And < ¹ > H NMR.

As shown in FIG. 1 (b), the peak of the methyl group (-CH ₃ ) of PPO of Pol was found to be about 1.1 ppm and the ethylene (-CH ₂ CH ₂ -) peak of PEO was found to be about δ = 3.7 ppm, respectively. As shown in FIG. 1 (a), the vinyl groups substituted at both terminals of the modified Pol were confirmed to be substituted through three small peaks at about δ = 5.8 to 6.4 ppm, and the vinyl groups of -CH ₃ and acrylate groups of PPO It was confirmed that the substitution ratio was about 85% by comparing the proton area ratio of the peak, and consequently, the diacrylated poloxamer was produced.

[Example 2] Production of mucoadhesive hydrogel 1

D-Pol (20, 23 wt%) and naproxen (0.1 wt%) prepared in Example 1 were completely dissolved in distilled water, and then 0.5 wt% of carbopol was dispersed in the distilled water for characterization according to the amount of carbo- And dissolved to prepare a reaction solution. The reaction solution was placed in a petri dish (35 ㅧ 10 mm), covered with a lid, and irradiated with an electron beam accelerator (UELV-10 ~ 10S, Russia, Korea Atomic Energy Research Institute, Korea, dose: 0.1 kGy / Irradiated with a dose of 25 kGy to synthesize a mucoadhesive hydrogel.

[Examples 3 to 4] Preparation of mucoadhesive hydrogel 2

A mucoadhesive hydrogel was prepared in the same manner as in Example 2, except that the carbopol was used in an amount of 1 wt% and 2 wt%, respectively, in Example 2.

[Example 5] Production of mucoadhesive hydrogel 3

A mucoadhesive hydrogel was prepared in the same manner as in Example 2 except that 23% by weight of poloxamer was used in Example 2.

[Examples 6 to 7] Preparation of mucoadhesive hydrogel 4

The mucoadhesive hydrogel was prepared in the same manner as in Examples 3 to 4 except that 23% by weight of poloxamer was used in Examples 3 to 4.

[Comparative Examples 1 to 10]

As shown in the following Table 1, except that Poloxamer 407 was used instead of the diacrylated poloxamer prepared in Example 1, and the content of carbopol was changed, the same procedure as in Example 2 was carried out to obtain a mucoadhesive hydrogel .

D-Pol or Pol (wt.%) Carbopol (% by weight) D-Pol or Pol (wt% Carbopol (% by weight) Example 2 D-Pol 20 0.5 Comparative Example 3 Pol 20 One Example 3 D-Pol 20 One Comparative Example 4 Pol 20 2 Example 4 D-Pol20 2 Comparative Example 5 Pol 23 - Example 5 D-Pol 23 0.5 Comparative Example 6 Pol 23 0.5 Example 6 D-Pol 23 One Comparative Example 7 Pol 23 One Example 7 D-Pol 23 2 Comparative Example 8 Pol 23 2 Comparative Example 1 Pol 20 - Comparative Example 9 D-Pol 20 - Comparative Example 2 Po1 20 0.5 Comparative Example 10 D-Pol 23 -

The gel prepared from the aqueous solution of Pol did not have a uniform shape even after irradiating it and had a flowing property like a solution. Thus, it was found that the chemical crosslinking was not performed properly. This seems to be due to the structure of the polymer, which is difficult to form radicals for crosslinking. In contrast, D-Pol in which a vinyl group is introduced at the terminal of Pol has a structure in which a terminal vinyl group easily generates radicals by radiation to form a covalent bond, resulting in chemical crosslinking, A gel was prepared. The crosslinking method using radiation is relatively simple compared to the method using a chemical crosslinking agent, the process for preparing the hydrogel is relatively simple, the heat for the reaction is not needed, and the reaction is performed in a short time, The hydrogels of various types could be prepared according to the method.

In addition, the mechanical strength was increased compared to the case where the carbopls were not added, but the concentration of 2 wt% or more was poor in the manufacture of the mucoadhesive hydrogel because of the high viscosity of the carpol, .

[Example 8]

A mucoadhesive hydrogel was synthesized in the same manner as in Example 2, except that triamcinolone acetonide was used instead of naproxen in Example 2.

<Experiment 1> Sol-gel phase transition

The phase transition temperature was measured by inverting method in order to confirm the sol-gel transition according to the temperature after various concentrations of Pol and D-Pol aqueous solutions were prepared.

The samples were prepared with Pol or D-Pol concentrations of 18, 20, 25 and 30 wt%, respectively. The samples were stored at a refrigeration temperature of 4 ° C for at least 24 hours, and dissolved sufficiently until the solution became transparent. The transition temperature was measured at 15 ° C using a constant temperature water bath.

From the temperature above room temperature, the temperature was ascertained by heating block (Barnstead International, USA, 2000-1) at 0.5 ° C increments up to 80 ° C.

In general, Pol shows a sol-gel phase transition phenomenon when the concentration of aqueous solution is 18 wt% or more. As a result of inversion measurement of the phase transition temperature when the concentrations of Pol and D-Pol were changed to 18, 20, 25 and 30 wt%, Pol exhibited a typical sol-gel phase transition with increasing temperature in the whole concentration range And it was found. The gelation temperature of D-Pol was almost the same at 30 wt%, and the temperature was about 1.5 ℃ for 25 wt% and 3.3 ℃ for 20 wt%. wt.%, and 20 wt.%, respectively, exhibited phase transition at a lower temperature than before the reforming. The aqueous solution of 18wt% of D-Pol maintained the sol state without gel phase transition despite the increase of temperature. It is considered that acrylate substitution at both ends affected the formation and packing of micelles. In addition, the 30 wt% aqueous solution of D-Pol was gel-like, but the gel remained unchanged at high temperatures up to 80 ° C. This is probably because the vinyl group at the end formed a chemical gel before reaching the temperature at which it forms a crosslinked structure by heat generated by the temperature increase and becomes a sol. As can be seen from FIG. 2, the phase transition phenomenon before and after the reforming was compared, and it was found that the region where the D-Pol phase transition was slightly reduced overall.

Gel formation was confirmed by the temperature increase even after the reforming. The temperature difference before and after the reforming was not large, indicating that the diacrylated composition did not greatly affect the phase transition.

Experiment 2 Swelling behavior of Examples 2 to 7 and Comparative Examples 1 to 10

The adhesive hydrogel was synthesized by irradiation and dried thoroughly in a vacuum oven at 40 ° C for 3 days. The swelling degree of each sample was measured by immersing a disk shaped sample of a certain size in PBS of pH 7.4. The dried samples were weighed before soaking and the weights were measured at regular intervals after soaking. The measurement was carried out at room temperature and the swelling ratio was calculated by the following formula.

Swelling ratio = (Ws-Wd) / Wd

Ws: Weight of swelled hydrogel

Wd: Weight of dried hydrogel

The weight of the hydrogel was measured by removing the flowing water when the sample was taken out, and measuring the weight to eliminate the influence of the excessively accumulated water on the surface and inside of the swelled hydrogel. Samples were measured for each condition and the average value of the weights was used.

The results are shown in Fig. As a result, the swelling degree of hydrogel containing no carbopol was the highest at 17.7, and the hydrogel containing 0.5 wt% of carbopol showed similar swelling degree. In addition, hydrogels containing 1 wt% and 2 wt% of carbopole exhibited a lower swelling degree, because the chain entanglement of the polymer chains increases as the content of carbopol increases, and the degree of swelling Respectively.

<Experiment 3> Evaluation of mucoadhesive properties of Examples 2 to 7 and Comparative Examples 1 to 10

The mucosal adhesion was evaluated by measuring the tensile strength, which is the force required to remove the mucosa from the hydrogel after contact. The mucosa for mucoadhesion test was collected from the oral cavity of pigs. The adhesion of samples of various composition ratios prepared by Pol and D-Pol was measured.

Adhesion was measured using an Instron (5569 premium 5800 series). The hydrogel sample was adhered to a stainless steel circular test bench, and the oral mucosa was fixed in a 10 mL disposable syringe and fixed on a table placed on a circular test bench. At this time, the initial contact time was 5 minutes, and 5 times for each concentration condition, and it was shown as an average value. The sample and the mucosa were once discarded and replaced with a new sample and a mucosa. D-Pol concentration after the reaction with Pol before the diacrylation reaction Were fixed at 20 wt% and 23 wt%, respectively, and 16 kinds of samples were prepared by varying the contents of carbopol at 0, 0.5, 1 and 2 wt%.

The hydrogels prepared from Pol were almost free of chemical crosslinking, so that 23 wt% of Pol and 2 wt% of carbopol showed the smallest value of 6.24 kPa. It was observed that separation occurred.

The adherence of the hydrogel prepared by D-Pol after the end modification was higher than 90 kPa, and it showed up to 120 kPa, and it was observed that the hydrogel separated from the interface between the hydrogel and the oral mucosa. Fig. 4 shows the results of the adhesion measurement for 16 samples. The physical properties and elasticity of the hydrogels were improved by the crosslinking by the radiation by modifying the ends, and the adherence was increased about 40 times as compared with that before the modification. Thus, it was confirmed that the adhesion of the mucosa was remarkably improved.

Samples with a concentration of 23 wt% of Pol were slightly higher than those of 20 wt%, but the difference was not significant. Also, as the content of the carbopol increases, the adhesion of the hydrogel increases due to the excellent adhesion of the carbol. However, hydrogels composed of 23 wt% of D-Pol and 2 wt% of carbopol, which were expected to have the highest tackiness due to the highest polymer concentration, showed a significant decrease in adhesiveness, It is considered that the carbopol is not uniformly mixed in the solution due to the high viscosity, so that a heterogeneous sample is prepared. Therefore, it is understood that the carbonpol content for improving the adhesion is preferably less than 2 wt%.

<Experiment 5> Evaluation of drug release in Examples 2 to 7 and Comparative Examples 1 to 10

For the drug release evaluation, a hydrogel formulation made of Pol and D-Pol was placed in a molecular porous membrane tube and the release experiment was performed. A hydrogel sample containing naproxen was placed on the membrane of MWCO3500, and the prepared membrane was placed in a conical tube containing 40 mL of PBS. The sample was placed in a 37 ° C thermostat (SI-300, Lab Companion, Korea) and the release test was performed. Hydrogel samples were prepared with 0, 0.5 and 1 wt% carbopol in 20 wt% of Pol or D-Pol, respectively. The membrane containing the drug was withdrawn from the tube at a fixed time interval and transferred to a conical tube containing 40 mL of fresh PBS. The release test was continued until the next measurement time. The absorbance of the drug was measured at 230 nm by taking the sample solution from the previous conical tube. And the emission amount was calculated.

FIG. 5 (a) shows the release behavior of the hydrogel prepared from Pol, and FIG. 5 (b) shows the hydrogel release behavior of D-Pol.

The burst effect of the drug was not observed even in the initial conditions, both of the Pol sample not crosslinked and the D-Pol crosslinked sample. It is considered that this is due to the property of gel forming the micellar structure at body temperature due to the temperature sensitivity of Pol. The Pol sample without carbopol was able to release more than 95% of the drug in 8 hours, but the D-Pol sample showed about 87% release behavior. The end modification of Pol resulted in a stronger density of the hydrogel matrix and the diffusion rate of the drug was lowered due to the strengthening of the cross-linking structure. Carbopol also has the effect of delaying drug release in proportion to concentration due to its own stickiness. As can be seen from FIG. 5 (b), about 87% of the drug was released in 8 hours without the addition of carbopol, but the release was almost complete within 4 hours. The addition of carbopol 0.5 and 1 wt% resulted in 83% and 78% of drug release over 8 hours, respectively, and the half - life of drug release was around 3.5 hours and was continuously released throughout the observation period. These results are believed to be due to the enhanced density of the hydrogel matrix due to the addition of carbopol. It is thought that the continuous treatment effect can be obtained by attaching the gel prepared with D-Pol and carbopol to the wound site to have a slow releasing behavior and then repeatedly replacing the drug every 8 hours. From the experimental results, it can be seen that when Pol is a thermosensitive hydrogel, it plays a role of a slow release drug substance, and when the mucosal topical formulation is designed by adding a sticking polymer, Carbopol, after strengthening the crosslinking structure of the gel through modification, The gel formulation with adequate release characteristics could be designed.

<Experiment 6> Evaluation of Drug Release in Example 8

Drug release assays were performed at 37 占 폚 for 48 hours using a Franz diffusion cell (Logan Instruments, Somerset, NJ). The mucoadhesive hydrogel prepared in Example 8 was placed in a Franz diffusion cell having a penetration area of 0.785 cm 2, and 10 ml of PBS (pH 7.4) was added thereto.

The Franz diffusion cell was maintained at 37 ° C and a sample in which triamcinolone acetonide was released in 1 mL increments at predetermined intervals (30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 1 day, 2 days) One mL of fresh PBS was added to the collected samples. The concentration of triamcinolone acetonide in each hourly solution was measured by absorbance at a wavelength of 240 nm. The drug release showed the concentration of triamcinolone acetonide released in% compared to the concentration of triamcinolone acetonide injected into the Franz diffusion cell for the first time. The measurement results are shown in Table 2 and FIG. As shown in the following Table 2 and FIG. 6, the initial rapid release was not observed, and it is considered that the continuous treatment effect can be obtained.

time Amount of triamcinolone released (%) 30 minutes 8.48 1 hours 13.98 2 hours 23.68 4 hours 33.41 8 hours 49.12 12 hours 61.12 1 day 76.05 2 days 92.60

<Experiment 7> Animal experiment evaluation of the mucoadhesive hydrogel prepared in Example 8

Twenty-six Sprague-Dawley rats (Orient Bio Inc, Korea) were used for experiments under aseptic conditions to be freely fed with water.

To compare the effect of tissue restoration on the skin, 18 rats were anesthetized and the area to be applied was shaved and disinfected with iodine tincture. A 6 mm diameter wound was made on both sides using a biopsy punch on the back of the rat. Skin tissue was removed with surgical scissors. For 3 days, the injured area was treated with physiological saline (control, control), 0.1% triamcinolone acetonide solution (0.1% sol'n), 0.1% triamcinolone acetonide hydrogel (0.1% patch), blank ) Hydrogel (Blank Patch) was applied for 8 hours every day. Histopathological changes of wound tissues were observed at days 1, 2, 5, 8, 11 and 15. The measurement results are shown in Fig. 7 and Fig.

As shown in FIG. 7, there was no significant difference in tissue recovery on days 1 and 2, and bleeding and edema were observed near the wound. Wound surface was formed on day 5, and wound size on days 8 and 11 was the most significant decrease in triamcinolone acetonide hydrogel treated group. On day 15, tissue repair in all groups recovered and wound size decreased.

In Fig. 8, histological changes of the skin according to each treatment group can be observed. On days 1 and 2, there was no significant difference in histopathologically treated groups, and inflammatory cells, hemorrhage and fibrin were observed. On day 5, histopathologic changes in wound tissues were observed in all groups and recovery of epithelial tissue was observed. On days 8 and 11, recovery of wound tissues was most significant in triamcinolone acetonide hydrogel treated group. On the fifteenth day, the organization in all the armies was restored.

From the results shown in FIGS. 7 and 8, it can be seen that the mucoadhesive hydrogel according to one embodiment of the present invention is very effective for repairing the epithelial tissue, as well as having the smallest wound size, which is very effective for the wound of the mucosa.

<Experiment 8> Animal experiment evaluation of the mucoadhesive hydrogel prepared in Example 8

To compare the tissue restorative effect in the oral mucosa, eight rats were anesthetized and a 4 mm diameter wound was made on both sides of the buccal mucosa of the rat using a biopsy punch. For 2 days, the injured area was treated with physiological saline (control, control), 0.1% triamcinolone acetonide solution (0.1% sol'n), 0.1% triamcinolone acetonide hydrogel (0.1% patch) ) Hydrogel (Blank Patch) was applied for 8 hours every day. On days 2 and 8, histopathological changes of wound tissues were observed and the results are shown in FIG.

As shown in FIG. 9, no significant difference was observed in terms of histopathological aspects, inflammatory cells, edema, and fibrin among the treatment groups on day 2, but inflammation reaction was weaker in triamcinolone acetonide hydrogel treated group . On the 8th day, it recovered to the wound surface, and inflammation cells were increased, and recovery was observed to proceed rapidly.

Claims (9)

Reacting poloxamer with (meth) acryloyl chloride to prepare di (meth) acrylated poloxamer;
Preparing a mixed aqueous solution comprising a carbonpol and the di (meth) acrylated poloxamer, wherein the carbonpol comprises from 0.5 to 1% by weight;
Further comprising a triamcinolone acetonide, which is a drug for treating mucosal diseases, in said mixed aqueous solution; And
And irradiating the mixed aqueous solution with radiation to prepare a mucoadhesive hydrogel. The method according to claim 1,
Wherein the poloxamer has a weight average molecular weight of 9,840 to 14,600. delete The method according to claim 1,
Wherein the radiation is an electron beam, an ion beam or a gamma ray. The method according to claim 1,
Wherein the radiation has a total irradiation dose of 1 to 50 kGy. The method according to claim 1,
Wherein the mixed aqueous solution further comprises 0.01 to 0.5% by weight of a drug for treating mucosal diseases. delete The method according to claim 1,
Wherein the mucoadhesive hydrogel comprises 60 to 90 parts by weight of water relative to 100 parts by weight of the mucoadhesive hydrogel. A mucoadhesive hydrogel prepared according to any one of claims 1 to 2, 4 to 6 and 8.

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