KR102444452B1 - temperature sensitive polymer composition - Google Patents

Abstract

The present invention is one type (poloxamer 407) containing at least 50% by weight of polyethylene oxide (PEO), and two types containing at least 10% by weight of polyethylene oxide (PEO), hyaluronic acid (Hyaluronic acid) acid) and carboxymethyl cellulose, and relates to an anti-adhesion agent with improved stability and safety in the body by chemical crosslinking.
In addition, it relates to a temperature-sensitive polymer composition, and to an anti-adhesion agent composition having excellent stability having a property of reacting sensitively to temperature changes. Due to the sol-gel transition phenomenon that gels quickly when injected into the body, it is attached to the surgical site and does not require sutures for fixation. It is a formulation that is easy to handle during invasive surgery and laparoscopic surgery.

Description

temperature sensitive polymer composition

The present invention relates to a temperature-sensitive polymer composition, and to an anti-adhesion agent composition having excellent stability having a property of reacting sensitively to temperature changes.

Post-surgery adhesion (post-sugical adhesion) is a typical problem that occurs during the recovery process of a patient after surgery, and refers to abnormal connection of normally separated living tissues with adjacent living tissues due to a surgical operation or the like. This adhesion is a natural phenomenon that occurs during self-healing after surgical operations such as incision or suture.

When a living tissue such as the peritoneum is damaged in the course of surgery, the permeability of blood vessels increases, inflammatory exudate is secreted, and fibrin is deposited and dissolved, then dissolution is inhibited and fixed, resulting in adhesion. These postoperative adhesions cause various medical problems. Postoperative adhesions are the most common cause of small bowel obstruction, accounting for 65-75% of all small bowel obstruction causes, and about 50 It is reported that adhesions occur in ~95% of cases. In addition, postoperative adhesions are attracting attention as a cause of chronic pain, secondary infertility, and sexual dysfunction. Adhesion is also emerging as a problem in terms of social cost. According to statistical data, it was reported that about $1.3 billion a year is spent for hospitalization in the United States due to adhesions.

In order to remove tissue adhesions that have occurred after surgery, surgical treatment is considered, and in this case, it places a lot of burden on patients and surgeons.

For this reason, methods for preventing tissue adhesion that occur during surgery are being studied. To prevent tissue adhesion, minimize wounds during surgery, use anti-inflammatory drugs such as aspirin and ibuprofen that can suppress inflammation, and administer tissue plasminogen activator to prevent the formation of fibrin. , and methods that create physical barriers between organizations are being used.

Anti-adhesion agents must be safe and effective, do not cause inflammatory or immune responses, exist in the body during the healing period, do not require sutures for attachment to the body, maintain activity in the blood, decompose in vivo, and separate removal It can be said that it is the most ideal anti-adhesion agent when there is no need.

The anti-adhesion agent blocks contact with the wound area and surrounding tissues by covering or covering the wound area by blocking the area where adhesion is expected during the surgical procedure with a physical barrier. It should not cause an inflammatory or immune response, and should not require suturing and should remain active in the blood. In addition, while remaining during the healing period of the damaged tissue and preventing adhesion, it is decomposed or absorbed after a certain period of time, so there is no need for separate removal. Discharged substances must also be harmless to the human body and have excellent biocompatibility.

One of the methods to prevent adhesions is to minimize the damage during surgery. Second, there is a method of reducing inflammation by administering steroids and anti-inflammatory drugs, there is a method of increasing tPA (tissue plasminogen activator) activity, and finally, a physical barrier is used to separate the wound surface of the tissue from the surrounding tissue. will do

However, it has not been widely used clinically due to concerns of various complications including inconvenience of use (Eur J Ophthalmology, 15:530-535), lack of verification of drug toxicity, inconsistent success rates, and displacement of the anti-adhesion barrier. (Ophthalmology, Vol.118, 1754-1759.), and in actual clinical practice, when suturing and disinfecting the surgical site, a lot of solution-type anti-adhesion agent leaks out, and there are many doubts about the anti-adhesion effect.

Currently commercially available anti-adhesion agents can be divided into solution and gel forms, and most adhesion-blocking agents are in the form of films and membranes. Adept (4% icodextrin solution), Ringer's lactate solution (Compound sodium lactate), Hyskon Dextran 70 (32% dextrin 70 solution), CMC solution (Carboxy methylcellulose), Sepracoat (Sodium hyaluronate sodium) , Saline (0.9% sodium chloride), etc., and the gel form is an injectable preparation, Intragel (Ferric hyaluronate gel), Spray gel (In situ crosslinkable polyethlene glycol), Intercoat (CMC+hyaluronate gel), Guardix-Sol (Gel of Hyaluronic acid + Sodium carboxymethyl cellulose), Adcon (Gelatin / Proteoglycan), Incert (Chemically crosslinked hyaluronic acid), Sepragel (Hyalronic acid-carboxymethylcellulose gel), etc. + carboxmethylcellulose membrane), Interceed (Oxidezed regenerated cellulose), Surgiwrap (70:30 poly (L-lactide-co-D-L-lactide)), etc.

The solution form has the disadvantages that it flows down in the body even if the viscosity is high, is easily decomposed and absorbed, and it is difficult to apply when the surgical site is wide.

Among film and membrane products, Interceed ^™ and Seprafilm ^™ use the properties of gelation in the body, whereas Sugicalwrap ^™ products do not gel and act as an impermeable barrier during the healing period. There is a problem that may obstruct the flow.

In addition, since it is difficult to attach to the affected part due to its poor hygroscopicity, it has to be sutured, and since it is a relatively recently released product, it is a preparation that requires further research in the field of efficacy, safety and manipulation.

Korean Patent Registration No. 10-1389831 uses amphiphilic copolymers having different ratios of polyethylene oxide in the copolymer, in a sol state outside the body and in a gel state in the body. It shows the effect of maintaining stability, preventing tissue adhesion and maintaining physical properties. Alginic acid aqueous solution using ionic crosslinking has a problem in that it is rapidly decomposed in the body because the residence time is short due to the ionic bond of alginic acid.

Korean Patent Publication No. 10-2013-0098768 uses a bio-derived polymer such as chitosan or gelatin as an anti-adhesion agent to exhibit an anti-adhesion function and to have adhesion, antibacterial and hemostatic properties. However, if the above method is used, it is possible to suppress the inflammatory reaction or foreign body reaction in the living body as much as possible, but it is easily decomposed by hydrolysis and has a disadvantage that it can easily flow down from the applied site in actual use.

The applicant of the present invention is a temperature-sensitive hydrogel showing sol-gel transition by temperature change using poloxamers 407, 188, etc. The material consisting of coalescing) was prepared so that when the temperature was increased, it was converted into a hydrogel at 4-30 °C.

The poloxamer gel used in the present invention is a ter-block copolymer, and the anti-adhesion agent in the form of a gel is an injectable formulation and was developed to overcome the disadvantages of film and solution form. There is a problem of falling.

Korean Patent 10-1389831 Korean Patent 10-2012-0020554

The Laryngoscope, 114, 1668-1673 (2004), Efficacy of antiadhesivebarrier in secondary thyroidectomy: an experimentalstudy The Open Drug Delivery Journal, 2008, 2, 61-70, Designing of a Thermosensitive Chitosan/Poloxamer In Situ Gel for OcularDelivery of Ciprofloxacin Eur J Ophthalmology, 15:530-535., Comparison of the effectiveness of mitomycin-C and Viscoat on delayed adjustable strabismus surgery in rabbits Ophthalmology, Vol.118, 1754-1759., Outcomes in 15 patients with conjunctival melanoma treated with adjuvant topical mitomycin C: complications and recurrences

The present invention provides a crosslinking agent BDDE (1,4-) in a network of hyaluronic acid and carboxymethyl cellulose in order to solve the problems of the prior art as described above and meet the needs of the present invention in this technical background Butanediol diglycidyl ether) is used to chemically combine and convert to a derivative, and by binding a thermosensitive hydrogel, it can remain safely at a desired position in the derivative for a certain period of time, and when decomposed in the body, the decomposition products are released into the body. To provide a temperature-sensitive polymer composition that is easily absorbed and decomposed in There is a purpose.

According to the present invention to achieve the above object, hyaluronic acid (Hyaluronic acid) and carboxymethyl cellulose (Carboxymethyl cellulose) 1 to 20%; and 15 to 40 wt% of a temperature-sensitive polymer.

One type (poloxamer 407) containing 50 to 90% by weight or more of the temperature-sensitive polymer polyethylene oxide (PEO), and two types containing 10 to 50% by weight of polyethylene oxide (PEO) (polox) Samer 188), including a mixture of biocompatible polymers hyaluronic acid and carboxymethyl cellulose (hydroxy group), carboxyl group (Carboxyl group) of BDDE (1,4-Butanediol diglycidyl ether) ) is a composition comprising an epoxy functional group crosslinked.

The polymer composition according to the present invention changes the gelling temperature and viscoelasticity according to the content of the poloxamer and the ratio of the polymer (hyaluronic acid/carboxymethyl cellulose).

For example, poloxamer 407 and poloxamer 188 are in a solution state at a low temperature at a certain mixing ratio, have temperature sensitivity to gel when the temperature rises to a certain temperature, and remain at a desired location for a certain period of time by using a polymer It was confirmed that the time was increased. An embodiment according to the present invention is characterized in that the poloxamer of the polymer composition contains 28% by weight or less of a mixture of poloxamer 407 and poloxamer 188, and the polymer content is within 15%.

In addition, the present invention, in particular, by using a polymer such as poloxamer 407 and poloxamer 188 in combination, increases the binding force between the polymers and improves the stability in the body and uses a material with excellent biocompatibility, so there is no inflammation and foreign body reaction in the body, so safety also It was confirmed that it can be secured, and the present invention was completed.

According to the present invention, an adhesive hydrogel formulation based on the adhesiveness and temperature sensitivity of poloxamer is designed and the weak physical stability of a hydrogel of a physically crosslinked structure is overcome through chemical crosslinking.

Due to the sol-gel transition phenomenon that gels quickly when injected into the body, it is attached to the surgical site and does not require sutures for fixation. It is a formulation that is easy to handle during minimally invasive surgery and laparoscopic surgery.

In addition, according to the present invention, the composition is a temperature-sensitive anti-adhesion composition with improved convenience of operation (Convenience), internal stability (Stability) and safety (Safety), and tissue adhesion.

1 is a view showing hydrogen bonding of a poloxamer gel as a conventional polymer composition.
2 is a view showing a covalent bond between a poloxamer gel and a polymer as a temperature-sensitive polymer composition of the present invention.
3 is a view confirming the phase transition of the polymer composition.
4 is a view showing the stability evaluation results.
5 is a view showing the results of evaluation of effectiveness (grade, strength, area) through animal experiments.

The injection containing the poloxamer according to the present invention gels quickly when injected into the body, so that the maintenance time at the surgical site is extended compared to conventional anti-adhesion products, and the injection operability is excellent to prevent adhesions to various surgical sites can be used for

The anti-adhesion polymer according to the present invention serves as a temperature-sensitive anti-adhesion agent that improves the convenience (convenience), internal stability (Stability) and safety (Safety), and tissue adhesion.

Anti-adhesion agents block contact with surrounding tissues by covering or covering the wounded area to prevent adhesions. The ideal anti-adhesion agent is a physical barrier that can be used even between narrow surfaces to prevent adhesions, must form an exact barrier film at the location where adhesion is expected, and act as a barrier film for a certain period after surgery. In addition, after a certain period of time has elapsed, all of them must be discharged or absorbed, so that they do not remain as foreign substances in the body. It should also be safe, non-inflammatory, suture-free, and easy to use.

From the above point of view, those well-known as the main ingredients of the temperature-sensitive anti-adhesion agent include gelatin, chitosan, and the like. Gelatin or chitosan has the advantage that it may have an additional hemostatic or antibacterial effect. However, as described above, it is easily decomposed by hydrolysis, so there is a high risk of separation from the applied treatment site in actual use.

The present invention has a poloxamer-based polymer as a main component. Poloxamer is a temperature-sensitive component and is liquid at room temperature, so it is easy to inject and gels quickly at body temperature, so it has the advantage of being fixed in the area where adhesion is expected.

When poloxamer is sprayed into the body in a liquid form, for example, after surgery, it changes into a gel form due to a temperature difference and quickly forms a barrier film. When sprayed in liquid form, there are fewer problems such as dripping, so it has the advantage of being able to continuously remain in the desired area.

However, a single component of poloxamer may have a problem that the anti-adhesion effect decreases due to insufficient time to stay in the tissue when applied to the wound site.

Accordingly, in the present invention, additional components are further included.

The anti-adhesion agent according to the present invention comprises a poloxamer composition, which is a temperature-sensitive polymer, and a polymer derivative by crosslinking. Specifically, the present invention can be prepared by preparing a polymer derivative solution by crosslinking and mixing the poloxamer composition thereto. Hereinafter, a polymer derivative solution by crosslinking is also referred to as a polymer solution.

The present inventors do not know the exact mechanism, but surprisingly, when a poloxamer composition and a specific polymer are mixed to induce mutual covalent bonding, the poloxamer can be easily attached to the wound site with a higher viscosity than a single component or a single component of the composition. , the decomposition period is long, so it can stay in the wound site for a longer period of time, and the effect of more stable sol-gel transition appears.

The temperature-sensitive polymer composition is characterized in that it is a poloxamer composition, and the poloxamer composition contains a species containing 50 to 90% by weight of polyethylene oxide (PEO) and 10 to 50 polyethylene oxide (PEO). % by weight. Preferably, it may include a mixture of a species containing 60 to 90% by weight or more of PEO and a mixture of a species containing 10 to 40% by weight of PEO. Examples include poloxamer 407 (>50% by weight PEO) and poloxamer 188 (less than 50% by weight PEO). At this time, the species containing 50 to 90% by weight or more of polyethylene oxide (PEO) and the species containing 10 to 50% by weight of polyethylene oxide (PEO) are 50-90: 10-50 in a weight ratio of It shows the properties of an anti-adhesion agent, which are excellent in blending, in vivo persistence and tissue adhesion. In particular, mixing poloxamer 407 and poloxamer 188 in a ratio of 70:30 may exhibit a more preferable anti-adhesion effect.

The polymer solution may include hyaluronic acid and carboxymethyl cellulose at a concentration of 1 to 20% based on the solution. For example, a derivative solution formulated with hyaluronic acid 10% and carboxymethyl cellulose 5% can exhibit the most excellent clinical effect. The molecular weight of hyaluronic acid can be appropriately selected in consideration of the desired viscosity and elasticity, and a generally adopted range can be selected. For example, the molecular weight of hyaluronic acid may be selected from 1,000 to 3,000,000 g/mol.

If necessary, the polymer solution may further include a crosslinking agent for the purpose of increasing the time for decomposition in the body. The crosslinking agent may be an epoxide-based crosslinking agent. In an embodiment of the present invention, BDDE may be considered, and the amount of BDDE may be included in a content ratio appropriately selected by a person skilled in the art. In particular, mixing the crosslinking agent in an amount of 10 mol% or less based on the polymer may be preferable in terms of minimizing toxicity.

The hyaluronic acid may be selected from hyaluronic acid or a salt thereof, and carboxymethyl cellulose may also be selected from carboxymethyl cellulose or a salt thereof. Salts include, but are not limited to, sodium salts, calcium salts, zinc salts, and the like.

The weight ratio of the poloxamer composition added to the polymer solution may be 10-60 wt% based on the total weight of the anti-adhesion agent. Preferably, it may be 10-40 wt% in consideration of the improvement of convenience in use.

The temperature-sensitive composition according to the present invention may be prepared in the form of a solution, bead, sponge, powder or membrane, and if necessary, pharmacologically active ingredients or other additives may be optionally added.

The temperature-sensitive composition according to the present invention becomes a gel at body temperature, and becomes a sol at other temperatures. For example, it becomes a gel in the body (30-40°C), and becomes a solution outside the body (20-30°C). In addition, it does not cause an adverse reaction in the body, is not easily decomposed, and can be easily removed after a desired function is exhibited, so it can be used in various fields where such a function is required. For example, it can be used as a medical device for human insertion, a cell support, a medical dressing, or a pharmaceutical matrix, and specifically, it can be used as a drug carrier, a filler for plastic surgery, a dental filler, an orthopedic adjuvant or an anti-adhesion agent, etc. .

When the temperature-sensitive composition according to the present invention is used as a pharmaceutical matrix, a hydrophobic drug, a hydrophilic drug, or a protein drug may be included as the amphiphilic property of the poloxamer.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only for illustrating the present invention, and the present invention is not limited thereto.

[Experimental Example 1]

It was prepared by varying the total weight of poloxamer and mixing ratios of poloxamer 407 and poloxamer 188.

sample preparation

As shown in Table 1 below, samples were prepared in which the weight of poloxamer was 25 to 28% by weight based on the total weight.

Poloxamer total weight (%) Poloxamer 407 (%) / Poloxamer 188 (%) 25
(Purified water: 5g) A-1
(1.5g/0.17g) A-2
(1.33g/0.33g) A-3
(1.17g/0.5g) A-4
(1g/0.67g) A-5
(0.83g/0.83g) 26
(Purified water: 5g) B-1
(1.58g/0.18g) B-2
(1.41g/0.35g) B-3
(1.24g/0.53g) B-4
(1.05g/0.7g) B-5
(0.88g/0.88g) 27
(Purified water: 5g) C-1
(1.66g/0.18g) C-2
(1.48/0.37g) C-3
(1.29g/0.55g) C-4
(1.11g/0.74g) C-5 (0.92g/0.92g) 28
(Purified water: 5g) D-1
(1.75g/0.19g) D-2
(1.56g/0.39g) D-3
(1.36g/0.58g) D-4
(1.17g/0.78g) D-5
(0.97g/0.97g)

* Poloxamer weight 25%

A-1 to A-5: Weigh poloxamer 407 and poloxamer 188, add 5 g of purified water, and dissolve completely in a refrigerator at 4°C.

* Poloxamer weight 26%

B-1~B-5: Weigh poloxamer 407 and poloxamer 188, add 5g of purified water, and melt completely in a refrigerator at 4°C.

* Poloxamer weight 27%

C-1 to C-5: Weigh poloxamer 407 and poloxamer 188, add 5 g of purified water, and dissolve completely in a refrigerator at 4°C.

* Poloxamer weight 28%

D-1 to D-5: Weigh poloxamer 407 and poloxamer 188, add 5 g of purified water, and dissolve completely in a refrigerator at 4°C.

[Experimental Example 2]

Viscosity measurement according to the total weight of poloxamer and the mixing ratio of poloxamer 407 and poloxamer 188

Viscosity measurement

The viscosity and viscoelastic modulus (Modulus) of the prepared sample were measured using a Reometer MCR 302 (Anton Paar, Austria) according to an increase in temperature from 5°C to 50°C (2.4°C/min), and the measured data conversion was performed by software in the device. This was done by Reo plus (US200).

polymer total weight % Sample Poloxamer Viscosity (Pa) 407 (g) 188 (g) 20℃ 25℃ 30℃ 35℃ 25 A-1 1.5 0.17 448.6 645.3 846.7 935.8 A-2 1.33 0.33 4.279 101.7 484.6 690.5 A-3 1.17 0.5 1.737 2.159 3.15 242.8 A-4 One 0.67 1.057 1.13 1.442 2.718 A-5 0.83 0.83 0.738 0.739 0.886 1.455 26 B-1 1.58 0.18 426.2 591.3 806.3 733 B-2 1.41 0.35 5.65 295.5 537.6 743.5 B-3 1.24 0.53 2.649 3.596 16.93 528.3 B-4 1.05 0.7 1.317 1.469 2.117 5.721 B-5 0.88 0.88 0.889 0.92 1.197 2.255 27 C-1 1.66 0.18 551.9 746.6 982.7 959.3 C-2 1.48 0.37 8.788 434.9 651.2 868.9 C-3 1.29 0.55 2.869 4.008 53.84 593.3 C-4 1.11 0.74 1.547 1.77 2.808 13.2 C-5 0.92 0.92 1.144 1.224 1.716 3.625 28 D-1 1.75 0.19 668.9 889 1,136 1,106 D-2 1.56 0.39 164.8 540.6 787.3 990.8 D-3 1.36 0.58 3.856 5.879 362.5 736 D-4 1.17 0.78 1.945 2.406 4.594 444.5 D-5 0.97 0.97 1.211 1.375 2.175 5.58

As a result, it was confirmed that the mixture of poloxamer 407 and poloxamer 188 had an increase in viscosity as the temperature increased, and the higher the concentration of poloxamer 407, the faster gelation was observed at a low temperature. At a constant temperature (room temperature: 25℃ → body: 35℃), it was possible to confirm the range of 26% of the total weight of the polymer B-3 in which the phase transition change occurred.

[Experimental Example 3]

Polymer solution (hyaluronic acid/carboxymethyl cellulose) manufacturing method

sample preparation

Preparation of hyaluronic acid polymer solution

Dissolve hyaluronic acid (shisheido) and carboxy methyl cellulose (ashland) in 1% Na-OH aqueous solution to prepare a 15% hyaluronic acid solution, compared to the 15% hyaluronic acid solution prepared Molar % of the crosslinking agent BDDE (1,4-Butanediol diglycidyl ether, Sigma-Aldrich) was added.

Sample Hyaluronic acid (HA) carboxymethyl
Cellulose (CMC) Crosslinking agent (BDDE) HC-1 15% - 10 mole % HC-2 10% 5% 10 mole % HC-3 7.5% 7.5% 10 mole % HC-4 5% 10% 10 mole %

After reacting at 37° C. for 24 hours, washing with physiological saline to remove unreacted substances, pulverizing the washed product to adjust the particle size, and adjusting the concentration to be 10 mg/mL, hyaluronic acid/carboxymethyl cellulose polymer solution was prepared.

[Experimental Example 4]

Effects of Poloxamer 407 and Poloxamer 188 alone and when mixed with a polymer solution (hyaluronic acid/carboxymethyl cellulose)

1) Sample preparation

The polymer solution prepared in Example 3 and the B-3 component described in Example 2 were used as raw materials and stirred with a stirrer to uniformly mix, and then sufficiently dissolved at 4° C. to prepare a solution.

Example 1 Example 2 Example 3 Example 4 Example 5 Derivatives (HA/CMC) - HC-1 HC-2 HC-3 HC-4 Poloxamer
(407/188) 26wt% B-3 B-3 B-3 B-3 B-3

2) Viscosity measurement

The viscosity and viscoelastic modulus (Modulus) of the prepared samples (Examples 1, 2, 3, 4, 5) were measured with a Reometer MCR 302 (Anton Paar, Austria) according to an increase in temperature (2.4° C./min) from 5° C. to 50° C. ) was used, and the measured data conversion was measured by in-device software Reo plus (US200).

polymer
total weight % Example Poloxamer Viscosity (Pa) 407 (g) 188 (g) derivative 20℃ 25℃ 30℃ 35℃ 26 One 1.24 0.53 - 2.649 3.596 16.93 528.3 2 1.24 0.53 HC-1 107 675.1 1,012 1,236 3 1.24 0.53 HC-2 106.2 115.8 678.5 977.4 4 1.24 0.53 HC-3 97.89 103.8 463.2 884.7 5 1.24 0.53 HC-4 45.96 49.38 502.5 914.7

Viscosity according to temperature increase was confirmed rheologically using a rheometer. The poloxamer gels (poloxamer 407 and poloxamer 188) and the polymer solution were mixed showed different temperature sensitivities, and the sol was more stable in Examples 2, 3, 4, and 5 in which the derivative was mixed than in Example 1. - Gel transfer was confirmed. Examples 2, 3, 4, and 5 showed higher physical properties than Example 1 due to increased physical crosslinking with the derivative. Example 3 was the most ideal sol-gel transition phenomenon was observed, and the results are shown in FIG. 3 . (25℃: solution, 30℃: gel)

For reference, as shown in FIG. 3 , in Example 2, it was confirmed that the sol-gel transition phenomenon was not ideal due to the absence of carboxymethyl cellulose. The anti-adhesion agent must exist in a liquid state at room temperature to ensure the convenience of the procedure, and after injection into the body, it must be gelled and adhered to the target site with satisfactory adhesion to be effective, but Example 2 is in a liquid state at room temperature Insufficiency appeared. That is, even at 25°C, the viscosity rises to 675.1, which exposes the disadvantage that ease of use is lowered.

3) Stability test (resolution)

Weigh 5 g of a test sample (Examples 1, 2, 3, 4, 5) in a 15 mL tube, mark the height of the sample with a name pen, add 5 mL physiological saline, and store in an incubator at 37 ° C. After removing the physiological saline solution on the upper part of the surface layer, the remaining volume was observed to measure the gel retention time, and the results are shown in FIG. 4 .

Poloxamer (407, 188) single mixture poloxamer gel had a duration of about a week, and if it was present with an excess of water, it would be easily decomposed, so the duration could be shortened to less than one day. In order to compensate for these drawbacks, it was confirmed that the decomposition period was increased by 2 weeks by extending the duration by mixing the poloxamer gel and the polymer solution. This increase was confirmed.

4) Efficacy evaluation (In vivo test)

For inhalation anesthesia in female rats of Sprague Dawley species, Isotroy (Isotroy 100, JSK) was administered by maintaining 2~2.5% oxygen inhalation concentration during anesthesia induction and 1.5~1.8% oxygen inhalation concentration during maintenance of anesthesia. Anesthesia was induced.

Thereafter, the lower abdomen is depilated using a razor, the experimental animal is placed on the operating table, the abdomen is disinfected with an antiseptic solution (povidone), and the laparotomy is performed along the midline by about 4 to 5 cm.

Take out the cecum and use a bone burr with a size of 1 x 2cm to damage the serous to the extent that bleeding occurs, and inflict damage to the opposite abdominal wall with the same size.

After carefully sealing both ends of the peritoneum and the abdominal wall, in the case of the control group, without separate measures, in the case of the experimental group, the prepared sample is injected.

Adhesion grade, adhesion strength, and adhesion area were checked for efficacy evaluation 14 days after surgery.

According to the degree of tissue adhesion, there are 4 levels (0, 1, 2, 3: the larger the number, the more severe the adhesion), the strength of the adhesion is 3 levels (1, 2, 3: the higher the number, the more severe), and the adhesion area is The horizontal and vertical lengths were measured and expressed as area values, and the results for adhesion evaluation are shown in FIG. 5 .

It was confirmed that the longer the residual time of the poloxamer gel, the better the anti-adhesion effect. In addition, since it is in a solution state at room temperature, it is easy to inject into the surgical site with a low viscosity value. have.

Claims (10)

A temperature-sensitive composition obtained by mixing a poloxamer composition and a polymer derivative by crosslinking, wherein the poloxamer composition contains 25 to 28% by weight of a mixture of poloxamer 407 and poloxamer 188, based on the total weight of the temperature-sensitive composition, and the polymer derivative is hyaluronic acid (Hyaluronic acid) and carboxymethyl cellulose (Carboxymethyl cellulose) characterized in that it contains a concentration of 1 to 20% by weight, and becomes a gel at 30-40 ℃, at other temperatures, a temperature-sensitive composition that is a solution state. delete The temperature-sensitive composition according to claim 1, wherein the composition contains poloxamer 407 and poloxamer 188 in a weight ratio of 50-90:10-50. delete delete According to claim 1, wherein the crosslinking agent used for crosslinking hyaluronic acid and carboxymethylcellulose derivative is 1,4-butanediol diglycidyl ether (BDDE), 10 mol% or less on a polymer basis A temperature-sensitive composition comprising: The temperature-sensitive composition according to claim 1, wherein the temperature-sensitive composition in which a poloxamer composition and a polymer derivative by crosslinking are mixed is prepared in the form of a solution, bead, sponge, powder, or membrane. The temperature-sensitive composition according to claim 1, wherein the temperature-sensitive composition is used as a medical device for human insertion, a cell support, a medical dressing, or a pharmaceutical matrix. The temperature-sensitive composition according to claim 8, wherein the temperature-sensitive composition used as a pharmaceutical matrix comprises a hydrophobic drug, a hydrophilic drug, or a protein drug due to the amphiphilic properties of the poloxamer. The temperature-sensitive composition according to claim 8, wherein the temperature-sensitive composition can be used as a drug carrier, a filler for plastic surgery, a dental filler, an orthopedic adjuvant, or an anti-adhesion agent.

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