KR20140037463A - Anti-adhesive composition for forming liquid foam - Google Patents

Abstract

The present invention relates to a tissue adhesion preventing composition for forming a liquid bubble containing hydroxypropyl methylcellulose (HPMC) and water as a polymer, a foam stabilizer; And a container for containing the anti-tissue adhesion composition and a device for preparing a liquid foam having a means for forming a bubble. The present invention also relates to a method for preventing tissue adhesion, which comprises applying the tissue adhesion preventing composition to a surface of a local organ of a human or an animal except a human.
The liquid foam formed by the anti-adhesion composition according to the present invention has the advantage that it can be applied to all surgical sites, which is an advantage of the liquid anti-adhesion agent, and is fixed to the surgical site without the flow of the matrix and film-type advantages, so that the anti-adhesion effect is achieved. Big has all the advantages.

Description

Anti-adhesive composition for forming liquid foam

The present invention relates to a tissue foam preventing composition for forming a liquid foam containing hydroxypropyl methylcellulose (HPMC) and water as a polymer, a foam stabilizer, and a container and foam forming containing the tissue adhesion preventing composition. It relates to a device for producing a liquid foam provided with a means for. The present invention also relates to a method for preventing tissue adhesion, which comprises applying the tissue adhesion preventing composition to a surface of a local organ of a human or an animal except a human.

The adhesion of organs and tissues after surgery is a physiological phenomenon that occurs during proliferation and regeneration of injured tissue cells. However, adhesion of excessive tissue, or unintended adhesion to other tissues or organs, And in some cases it may be a life-threatening factor, such as a need for reattachment of the adhesiolysis.

Generally, adhesion occurs at a frequency of about 60% to 95% after laparotomy, and can cause pain, intestinal obstruction, and infertility. In particular, tissue adhesion is a major cause of intestinal obstruction (80% to 90%), and long-term sequelae after gynecology is a cause of pelvic pain. Tissue adhesions that occur after this surgery can occur in almost every part of the body.

As a method of preventing such adhesions, minimizing wounds during surgery, using anti-inflammatory agents, enhancing fibrin degradation, and peeling surfaces where adhesions have been formed have recently been used. A method using a phosphorus barrier has been developed and used. Among them, a material suitable as a physical barrier, that is, an anti-adhesion agent, acts as a barrier only during the healing period of the wound in the body, and after that, it must be decomposed, and there is no toxicity of the material itself. It should be harmless to. The anti-adhesion agents used for these barriers can be classified into two types. First is a membrane barrier including a film, a nonwoven fabric, and a sponge. A second is a solution barrier including a gel.

Film forms include precluded non-degradable polymer Teflon and interceed manufactured using degradable polymer oxidized cellulose, and seprafilm made by crosslinking hyaluronic acid and carboxymethylcellulose. However, the biggest disadvantage of these film type anti-adhesion agents is that the sutures should be closed with the surrounding tissue to prevent the movement of the anti-adhesion film at the application site. It is difficult to introduce into the minute part, the conduit-shaped part.

In order to overcome this problem, gel-type anti-adhesion agents include carboxymethyl cellulose, dextran 70, and flowgel made of polyethylene oxide-polypropylene oxide copolymer (Pluronic F127) and polylock. Adcon-L based on tic acid, Intergel based on hyaluronic acid, AdbA based on natural polymers, and Spraygel based on polyethylene oxide in the form of a spray are being studied or marketed. However, the disadvantage of the gel form is that it is easily disintegrated and absorbed before the wound is healed due to its ability to be absorbed very quickly in vivo, and thus has low efficacy as an anti-adhesion agent. In addition, an anti-adhesion agent in the form of a solution based on hyaluronic acid and carboxymethyl cellulose has been developed, but it is difficult to distinguish with the naked eye, so it is difficult to apply it correctly to the surgical site and has a problem in that it is easy to flow down due to the characteristics of the liquid and the efficacy is low.

As such, many researches have been conducted on the prevention of tissue adhesion after surgery and many products are on the market, but require expensive materials and high technology, and even though the drugs are expensive, the problems described above have not been improved. The effect of anti-adhesion is not shown.

Therefore, the present inventors can develop a tissue adhesion prevention composition for liquid foam formation with a new formulation that has not existed previously in the field of anti-adhesion, thereby improving adhesion prevention effect and lowering convenience of use and production cost through physical properties of foam, and coating. It is easy to invent a formulation without restrictions on the application site.

SUMMARY OF THE INVENTION An object of the present invention is to provide a tissue adhesion preventing composition for liquid foam formation containing hydroxypropyl methylcellulose (HPMC) and water as a polymer, a foam stabilizer.

It is another object of the present invention to provide an apparatus for preparing a liquid foam having a container containing the anti-tissue adhesion composition and a means for forming a foam.

Another object of the present invention is to provide a method for preventing tissue adhesion, which comprises applying the tissue adhesion preventing composition to a surface of a local organ of a human or an animal except a human in the form of a liquid foam.

In order to solve the above problems, the present invention provides a liquid adhesion preventing composition for forming a liquid foam containing a hydroxypropyl methyl cellulose (HPMC, hydroxypropyl methylcellulose) and water as a polymer, a foam stabilizer (foam stabilizer).

The present invention uses a liquid foam form as a physical barrier for preventing tissue adhesion, and the tissue adhesion preventing composition for forming such liquid foam is a polymer, hydroxypropyl methylcellulose (HPMC) as a foam stabilizer (foam stabilizer) and It is characterized by containing water. Liquid bubbles are those in which bubbles of various sizes are isolated by a thin film of liquid (see FIG. 1).

The liquid foam formed by the anti-adhesion composition according to the present invention is a liquid thin film is formed by the polymer dissolved or dispersed in water, the liquid foam can be maintained for a certain time by hydroxypropyl methylcellulose (HPMC, hydroxypropyl methylcellulose) have.

Bubbles interfere with heat and mass transfer. In addition, the liquid foam formed by the anti-adhesion composition according to the present invention can form a good physical barrier between the tissues by the fact that it does not flow well, can be adhered well to the surgical site can further increase the anti-adhesion effect. In addition, since the foam can be formed with a small amount of polymer to increase the volume, the production cost is also low. In addition, it is not necessary to use a high viscosity liquid polymer to increase the production cost and ease of production.

The amount of foam and the strength of the foam is most important to prevent the foam from flowing well. In this case, the viscosity of the foam retaining agent such as HPMC and the composition ratio of water is an important factor, the lower the viscosity of the HPMC, the higher the water ratio, the higher the amount of foam, while the retention time of the foam is reduced. In order to increase the adhesion prevention effect, it is important to adjust the optimal composition ratio in consideration of both the amount of foam and the retention time of the foam because the foam must be applied to the surgical site to be maintained for a certain time.

In addition, making the size of the bubbles forming the bubbles as small, rich and uniform as possible increases the holding time of the bubbles. To this end, it is preferable to use a nozzle to densify a sieve network that makes the liquid anti-adhesion agent into foam when foaming.

The anti-tissue adhesion composition according to the present invention has a viscosity of 0.5 to 6 cP (centiPoise) at room temperature (25 ° C.) in a liquid state, and preferably has a viscosity of 10 to 70 cP at room temperature (25 ° C.) in a liquid state. .

The lower the viscosity in the liquid phase, the lower the physical resistance, etc., when the foam is generated is easy, and the higher the viscosity in the liquid phase requires a lot of force to make it into a foam. Basically, in order to manufacture foam, water and foaming agent enters to lower the surface tension of water, and foam is generated. At this time, if the ratio of water is high, the interfacial free energy increases and the retention time of foam decreases and foam Increasing the proportion of oil and fat requires a lot of energy to create a foam, it is also undesirable to enter a large amount of foaming agent into the body. Therefore, in order to minimize the foam retaining agent (HPMC) while maintaining the foam for a suitable time, according to a specific embodiment of the present invention, it was confirmed that having the above viscosity (Table 2).

Thermodynamically, when bubbles are formed, the interfacial free energy increases as the area of gas and liquid interface increases. Therefore, it is necessary to apply to the liquid a work equivalent to the change in the interfacial free energy, γΔA (γ; surface tension of the liquid, ΔA; increase in the interface area) from the outside.

Non-limiting examples of the method of making the liquid foam include a method by ventilation, a method by stirring, a method by shaking, and the like. The method by ventilation is a method of venting in liquid through the pores, such as a porous plate, and an individual bubble is formed. In the stirring operation, the foam is put into the liquid by a foaming bowl, a homogenizer, a stirring blade, or the like. Shaking operation is a method of forming a bubble by shaking the liquid in a sealed container.

Therefore, the anti-adhesion composition according to the present invention may form liquid bubbles through means for forming bubbles such as stirring and nozzles.

In the present invention, hydroxypropyl methyl cellulose (HPMC) is used as a foam stabilizer.

Hydroxypropylmethylcellulose (HPMC) is used to stabilize the foam formed, that is, to reduce the interfacial free energy by lowering the surface tension of the liquid, and to increase the stability, mechanical strength of the resulting membrane or to improve the liquid inside the membrane. It can lower the speed at which it flows down and increase the time for which the bubbles once formed are maintained.

In one embodiment of the present invention, by adding HPMC as a foam retaining agent to a commercially available liquid adhesion agent containing hyaluronic acid and carboxymethyl cellulose as a polymer, to prepare a tissue adhesion prevention composition for forming a liquid foam, the liquid adhesion agent ( Control) and anti-adhesion effect was compared. Intestinal adhesion and length were measured in rats induced wounds of the intestines (P <0.05) and significantly inhibited intestinal adhesion (Table 5 and Table 6). When the liquid type was changed to foam type, the anti-intestinal adhesion effect increased by about 22.7% of the control liquid adhesion agent and about 43.3% of the negative control group (treated with the same amount of physiological saline as the control group) in the adhesion severity. It can be seen that (Table 5 and Figure 2). In addition, in terms of length, the anti-intestinal adhesion was increased by about 28% of the control liquid adhesion inhibitor and about 46.5% of the negative control group (Table 6 and FIG. 3). In terms of the standard deviation, as the bubble type has a smaller standard deviation than the liquid phase, it is suggested that the anti-adhesion effect expected at each procedure may be good without individual variation.

Foam retaining agent used in the tissue adhesion prevention composition of the present invention is hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene glycol (PEG), polyethylene oxide (PEO) and the like as the equivalent thereof In combination with these, it is also within the scope of the present invention.

Hydroxypropylmethylcellulose (HPMC) is a type of cellulose that is a dietary fiber with water-soluble properties. Structurally, the cellulose is connected, and the physicochemical characteristics are different depending on the substitution ratio of the methoxy group and the hydroxypropyl group in the residue.

In the present invention, the HPMC preferably has a ratio of methoxy group and hydroxypropyl group of 0.5: 1 to 7.5: 1.

On the other hand, in terms of viscosity, the hydroxypropyl methyl cellulose may be preferably 2 cP to 15 cP, more preferably 3 cP to 6 cP in 20 ℃ 2wt% aqueous solution state. HPMC is available in a variety of viscosities ranging from 3 cP to 100,000 cP depending on the viscosity. As the viscosity increases, the physical force is required to generate the foam. Therefore, the foam formulation of the present invention requires sufficient foam to be used when using 15 cP or less, which can generate the foam in a general manner without any special power source. It was confirmed that it can be formed. In particular, experiments with viscosity of 15 cP or less, it was confirmed that the HPMC of 3 to 6 cP is the most suitable viscosity for foaming (Table 2).

In one embodiment of the present invention, in order to prepare a tissue foam prevention composition for forming a liquid foam having a suitable viscosity, foam volume and foam retention time, the resulting liquid foam, varying the viscosity and concentration of the foam retaining agent HPMC Viscosity, foam volume and foam holding time were measured (Examples 1-1 and Table 2). As a result of the experiment, it was confirmed that the optimum composition ratio of 3wt% of HPMC having a viscosity of 4.5 cp in consideration of the viscosity of the foam, foam volume, foam retention time characteristics.

The anti-adhesion composition according to the present invention may be preferably contained in a concentration of 0.1 to 10wt% HPMC, more preferably 1 to 5wt% concentration.

In general, when the HPMC is included in more than 5wt%, the viscosity of the liquid phase is so high that the physical force is required to require a device with a separate power source to generate bubbles. In addition, when the HPMC is included 10wt% or more, the solution itself becomes difficult to prepare uniformly. Accordingly, the concentration range as described above is preferable.

The polymer used in the anti-adhesion composition according to the present invention is not limited as long as it can dissolve or disperse in water to form a liquid thin film to form a liquid bubble. However, it is preferable that it is a biodegradable polymer.

Biodegradable polymer refers to a polymer that is decomposed and destroyed by simple hydrolysis (chemical decomposition caused by the action of water molecules) or an enzyme. When injected into a living body, the biodegradable polymer is naturally decomposed and absorbed in a low molecular state through in vivo metabolism. It means a polymer. Medical products made using this product do not need to be removed because they disappear after their role in the body, and there is no foreign matter reaction, which is a chronic problem with undecomposed polymer. However, it is necessary to overcome the fact that tissue rejection by the immune system may occur, mechanical properties may not be constant, and control of degradation rate may be difficult.

The biodegradable polymer may be a bio-derived polymer or a non-bio-derived biocompatible polymer.

Bio-derived polymer is a generic term for a polymer including all nucleic acids, proteins, polysaccharides, and complexes thereof synthesized in vivo, and is biocompatible because it is bio-derived.

Non-limiting examples of the bio-derived polymer, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, hyaluronic acid and proteoglycans comprising the same; Collagen and its degradation products gelatin; Elastin, laminin, fibronectin, vitronectin, thrombospontin, tininicin, entaxin; Heparin, hirudin, fibrin; Phospholipids; keratin; Or mixtures thereof. Preferably it may be hyaluronic acid, more preferably sodium hyaluronate.

The hyaluronic acid includes hyaluronic acid and salts thereof, but the salts include, but are not limited to, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronic acid or tetrabutyl hyaluronic acid It may be ammonium.

Non-biologically derived biocompatible polymers refer to all polymers derived from in vitro having biocompatibility. Here, biocompatibility means a property that rejection does not occur when contacted with biological tissue. Non-biologically derived polymers do not irritate biological tissues, do not cause inflammation, allergies, and do not cause cancer. In addition, it is preferable that there is no cytotoxicity and there is no phenomenon of destroying blood components or causing blood clots.

Non-limiting examples of the non-biologically derived biocompatible polymer include polylactic acid (PLA), polyglycolic acid (PGA) and copolymers thereof (PLGA), poly-ε-caprolactone, poly-N-isopropylacrylamide Cellulose derivatives such as (PNIPAM) and copolymers thereof, polypeptides, regenerated cellulose, carboxyethyl cellulose (CEC), carboxymethyl cellulose (CMC), chitosan, chitin and derivatives thereof, glucans, sodium alginate, Poloxamers, polyanhydrides, polyacetals, polyketals, poly-ortho-esters, polyylphosphazenes, or mixtures thereof, consisting of PEG, PEG-PPG-PEG block copolymers. Preferably carboxymethyl cellulose.

The carboxymethyl cellulose is a semi-synthetic hydrophilic cellulose derivative having a high viscosity and a molecular weight of 21,000 to 500,000 by introducing a glycolic acid ether group into a unit of cellulose molecules, and is a granular or fibrous powder, and has a white, yellowish or grayish color, and is slightly Hygroscopic, odorless and tasteless. The carboxymethyl cellulose may be in the form of sodium salt, calcium salt or zinc salt, but is not limited thereto.

The tissue adhesion preventing composition of the present invention may be preferably contained in a concentration of 0.1 to 10wt% of the biodegradable polymer.

In order to stabilize the foam formed by the above method, the surface tension of the liquid must be lowered to reduce the interfacial free energy. For this purpose, stabilizers, for example, so-called surfactants or foam retaining agents which have hydrophilic and hydrophobic groups in the molecule and which can be adsorbed on the surface of the liquid and liquid can be added.

The anti-adhesion composition of the present invention may further include a surfactant.

Surfactant refers to a substance that adheres well to an interface and greatly reduces surface tension when two materials with different properties contact each other. A surfactant is a compound having a hydrophilic portion that is easily soluble in water and a hydrophobic portion that is easily soluble in oil. In general, surfactants can be classified as anionic, cationic, amphoteric, nonionic, or special surfactants depending on the charge of the hydrophilic moiety when dissociated in water.

Non-limiting examples of such surfactants include sodium lauryl sulfate, sorbitan esters and polyoxyethylene sorbitan fatty acid esters (such as polysorbate 80 ^TM ), polyethylene glycol-15-hydroxystearate (such as solutol HS 15 ^TM ), Polyoxyethylene glycolated natural or hydrogenated perm oil (such as Cremophor RH 40 ^TM ), polyoxyethylene-polyoxypropylene copolymer (such as poloxamer 188 ^TM , poloxamer 407 ^TM ), d-α-tocopheryl Polyethylene glycol 1000 succinate (such as vitamin E TPGS ^™ ) and fatty acid macrogol glycerides (such as Gelucire 44/14 ^™ ).

The tissue adhesion preventing composition may be preferably contained in a concentration of 0.01 to 10wt% surfactant.

The anti-tissue adhesion composition according to the present invention can be appropriately adjusted in consideration of the content of the polymer and HPMC used in vivo decomposition properties, site-use properties (tissue, organ, area, etc.).

Preferably, the anti-tissue adhesion composition of the present invention comprises from 0.1 to 10% by weight each of hyaluronic acid, carboxymethyl cellulose and hydroxypropyl methyl cellulose in the total composition, using water or physiological saline as a solvent, the remaining amount of the substance And other materials necessary for the manufacture of the anti-adhesion agent (eg, buffers, tonicity agents, excipients, preservatives, etc.).

The anti-adhesion composition of the present invention can produce a liquid foam and can be maintained for a certain period of time, can have an appropriate viscosity to adhere to the tissue surface without flowing from the organ tissue, the formed liquid foam is preferably 10 at room temperature To viscosities of from 70 cp.

In another aspect, the present invention provides a liquid foam manufacturing apparatus having a container containing the anti-tissue adhesion composition and a means for forming a foam.

The foam forming means may preferably be a specific device such as a pump, spray or the like with a sieve attached to the end of the nozzle capable of generating bubbles.

As another aspect, the present invention provides a method for preventing tissue adhesion, which comprises applying a liquid antifoam composition for forming a liquid bubble according to the present invention to a surface of a local organ of a human or an animal except a human.

In the present invention, "apply" refers to the act of applying an anti-adhesion agent to a surface of a local organ for the purpose of preventing adhesion of the surface of a local organ to create a physical barrier between that surface and the surface of another organ.

In the present invention, the term "local organ surface" refers to all or a part of the surface of an organ or tissue in which surgery is required, such as surgical operation, or the like, in which inflammation has occurred for some reason and adhesion has to be prevented. There are no particular limitations on the site or type of the organ, but it is preferable that the organ is an animal other than the animal (mouse), rat, hamster, rabbit, and other mammals including the human. Examples thereof include gastrointestinal organs such as stomach, small intestine, large intestine, reproductive organs such as uterus and ovary, respiratory organs such as heart and lungs, organs such as muscles, May be a reproductive organs such as uterus, ovary, etc. The state of the surface of the local organs is also not particularly limited.

The operation contents of the organ are not particularly limited. In addition, the surface of the local organs may be a direct object of surgery, and may not be a direct object of surgery, but may be a scarred area as a result of surgery.

When applying the anti-adhesion composition according to the invention in the form of a liquid foam on the surface of the local organ, the ratio of the active ingredient in the anti-adhesion composition may be appropriately selected according to the type of organ, tissue, state of the trauma portion, area, etc. The amount of contact of the surface of the local organ with may be at or above the surface.

According to the present invention, the liquid foam formed by the anti-adhesion composition can be applied to all surgical sites, which is an advantage of the liquid anti-adhesion agent. It has all the advantages.

Figure 1 is a photograph showing the actual foam form of the tissue adhesion prevention composition for foam formation of the present invention.
Figure 2 is a graph showing the degree of adhesion according to the control (liquid phase) or tissue adhesion prevention composition (bubble phase) for foam formation of the present invention.
Figure 3 is a graph showing the length of adhesion according to the control (liquid phase) or the tissue adhesion prevention composition (bubble phase) for foam formation of the present invention.
Figure 4 is a photograph representing the results of the animal experiment according to the negative control of the present invention.
5 is a photograph representing the results of the animal experiment according to the control anti-adhesion agent (liquid phase) of the present invention.
Figure 6 is a photograph representing the results of the animal experiment according to the anti-tissue adhesion composition (foam phase) treatment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for describing the present invention more specifically, and the scope of the present invention is not limited by these examples.

Example  1: Preparation of Tissue Adhesion Prevention Composition for Liquid Foam Formation and Properties thereof

HPMC 2910 is used in various concentrations as a foam stabilizer in Gadix-SOL (Guardix-sol, Hanmi Medicare), a liquid form adhesion agent that is commercially available based on hyaluronic acid and CMC-Na. It was added to prepare a tissue adhesion prevention composition for liquid foam formation (see Table 1). At this time, the absolute amount of the main ingredient of the Giggs was equal, but the liquid amount was increased to prepare a form that is easy to prepare a foam. Specifically, the test drug contains 3.75 mg of 1.5 g of hyaluronic acid (HA) of Gaddix and 7.5 mg of sodium carboxymethyl cellulose (sodium CMC). Sugar HA was 3.75 mg sodium CMC was equally adjusted to 7.5 mg.

Composition for preventing tissue adhesion for foam formation No. Ingredient Composition 1 Composition 2 Composition 3 mg % mg % mg % One Sodium Hyaluronate 3.75 0.1 3.75 0.1 3.75 0.1 2 Sodium CMC 7.5 0.2 7.5 0.2 7.5 0.2 3 Purified water 3631.5 96.84 3594 95.84 3556.5 94.84 4 NaCl 58.5 1.56 58.5 1.56 58.5 1.56 5 KCl 1.5 0.04 1.5 0.04 1.5 0.04 6 KH ₂ PO ₄ 1.5 0.04 1.5 0.04 1.5 0.04 7 Na ₂ HPO ₄ 8.25 0.22 8.25 0.22 8.25 0.22 8 HPMC 37.5 One 75 2 112.5 3 Total amount 3750 100 3750 100 3750 100

By varying the concentration (weight basis) or viscosity of the HPMC, the resulting liquid foam viscosity, foam volume and foam holding time were measured and the results are shown in Table 2.

Using a pump attached to the end of the nozzle, a liquid tissue adhesion preventing composition was passed through the high pressure to produce a liquid foam. The viscosity of the liquid bubbles formed from the tissue adhesion preventing composition (liquid phase) and the tissue adhesion preventing composition for liquid foam formation was measured by a general rotational viscometer method. The rotational viscometer method is a method of measuring the viscosity of a medium from the torque and the angular velocity by rotating a cylinder, a cone, a disk, etc. in the medium to measure a viscosity. Specifically, the measurement was performed under conditions of spindle 4, 60 rpm and 25 ° C. using a BROOKFIELD digital viscometer.

In addition, the volume of the foam was measured in the cylinder by using the pump of the liquid foam produced, the foam holding time was measured by placing the same amount of foam on a flat plate maintained at 37 ℃ and the time the foam disappears.

Changes in Foam Properties with HPMC Concentration or Viscosity HPMC concentration (wt) Viscosity of HPMC
(20 ℃) 3cp 4.5cp 15cp One% Comparison of Viscosity of Liquid / Foam 1.8cp-> 60cp 1cp-> 50cp 1cp-> 41cp Bubble volume of 6ml liquid 37ml 37ml 35 ml Foam retention time at 37 ℃ 21 minutes 21 minutes 38 minutes 3% Comparison of Viscosity of Liquid / Foam 1cp-> 43cp 1.5cp-> 50cp 2cp-> 20cp Bubble volume of 6ml liquid 30ml 30ml 15 ml Foam retention time at 37 ℃ 19 minutes 90 minutes 110 minutes 5% Comparison of Viscosity of Liquid / Foam 1.5cp-> 40cp 1.5cp-> 30cp 5cp-> 15cp Bubble volume of 6ml liquid 27ml 22.5ml 10 ml

Through the experiment, it was confirmed that the viscosity, foam volume, foam retention time were all excellent when 3wt% of HPMC having a viscosity of 4.5cp was added.

Therefore, subsequent experiments were performed by adding 3 wt% of HPMC having a viscosity of 4.5 cp to prepare a tissue adhesion preventing composition for forming foam (composition of Table 1).

Example  2: measurement of anti-adhesion effect of anti-tissue adhesion composition for foam formation

In order to confirm the efficacy of the anti-adhesion composition for foam formation (using 3 wt% of HPMC having a viscosity of 4.5 cps) prepared in Example 1, Guardix-SOL (Guardix-sol, Hanmi Medicare) was used as a control.

2-1. Adhesion Induction and Anti-Adhesion Treatment in Animal Models

The anti-adhesion effect was evaluated using a rat caecum / abdominal scratch model as shown in Table 3 below. Experimental animals used 10 rats of 6-week-old male Sprague-Dawley strains per group. To induce adhesion, Zoletil (40mg / kg) and xylazine (5mg / kg) were intraperitoneally administered under general anesthesia, followed by ablation with a hair remover, sterilized with 70% alcohol and 3-4 along the left 1 cm of the midline. cm opened. After that, the caecum is carefully taken out and the sterilized dry gauze is injured to the extent of bleeding, so that the damaged surface of the cecum comes into contact with the right abdominal wall. Thereby promoting adhesion formation. Then, each of the tissue adhesion preventing composition for forming a liquid bubble and the Giggs-SOL of the control group were injected between the damaged area and the abdominal wall where the damaged surface abuts, and the peritoneum and the skin were continuously sealed and sterilized with povidone.

group gender Population Object number Dosage (ml / head) Negative control group (physiological saline) ♂ 10 Co 1-Co 10 1.5 Anti-adhesion agents ♂ 10 Pc 1 to Pc 10 1.5 (3.75 mg based on HA) Anti-Tissue Adhesion Composition for Foam Formation ♂ 10 Tr 1 to Tr 10 3.75 (3.75 mg based on HA)

In Table 3, HA means hyaluronic acid.

After 14 days of adhesion, Zoletil (40mg / kg) and xylazine (5mg / kg) were intraperitoneally administered and then opened after general anesthesia.Lo HY , Kuo HT , Huang YY . Application of polycaprolactone as moment anti - adhesion biomaterial film . Artif Organs . 2010; 34 (8): 648-653.)Scored according to the record. In addition, the size of adhesion was measured using a ruler. Measurements of degree of adhesion and size of adhesion are expressed as mean and standard deviation.

The degree of adhesion was evaluated according to the criteria in Table 4.

Rating Adhesion severity 0
One
2
3
4 No adhesions
Filmy, fibrin adhesion, easily removed by blunt dissectin (mild)
Fibrous adhesions, easily dissected (moderate)
Thick fibrous adhesions, dissectable (severe)
Thick fibrous adhesions, not dissectable without damage (very severe)

2-2. Result of measurement of adhesion degree and adhesion prevention effect

As a result of measuring the degree and length of intestinal adhesion according to the evaluation criteria, it was confirmed that when injecting the anti-adhesion composition for foam formation, significantly inhibited intestinal adhesion (P <0.05) (Table 5 and Table 6). When the liquid type was changed to the foam type, the intestinal adhesion prevention effect was increased by about 22.7% of the control agent and about 43.3% of the negative control group in terms of adhesion severity (Table 5 and FIG. 2). ).

Degree of adhesion Negative control group GARDIX-SOL Tissue adhesion preventing composition for liquid foam formation Av
(Average) 3.0 2.2 1.7 Std
(Standard Deviation) 1.1 0.9 0.5

In addition, in terms of length, the anti-intestinal adhesion was increased by about 28% of the control agent and about 46.5% of the negative control group (Table 6 and Figure 3). In terms of standard deviation, as the standard deviation decreases, it is suggested that the effect of anti-adhesion can be maintained at a relatively constant level without variation of individual subjects.

Length of adhesion Negative control group GARDIX-SOL Tissue adhesion preventing composition for liquid foam formation Av
(Average) 10.1 7.5 5.4 Std
(Standard Deviation) 4.6 4.5 1.5

Summarizing the above results, it can be confirmed that the liquid foam formed by the tissue adhesion prevention composition for liquid foam formation has a remarkably excellent anti-adhesion effect compared to the liquid type adhesion agent. In other words, the above results increase the anti-adhesion effect only by changing the formulation of the anti-adhesion agent into the liquid foam form, and when the formulation of various conventional anti-adhesion agents or the new anti-adhesion formulation in the foam form, the anti-adhesion effect is excellent. It supports the increase.

From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.

Claims (16)

A composition for preventing tissue adhesion for liquid foam containing hydroxypropyl methylcellulose (HPMC) and water as a polymer and a foam stabilizer.
2. The anti-adhesion composition of claim 1, wherein the bubbles of gas can form liquid bubbles that are separated by a thin liquid film.
The tissue adhesion preventing composition of claim 1, wherein the composition has a viscosity of 0.5 to 6 cP (centiPoise) at 25 ° C., and has a viscosity of 10 to 70 cP at 25 ° C. when the composition is liquid.
The tissue adhesion preventing composition of claim 1, wherein the polymer is a biodegradable polymer.
The method of claim 1, wherein the polymer is chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, hyaluronic acid and proteoglycan comprising the same; Collagen and its degradation products gelatin; Elastin, laminin, fibronectin, vitronectin, thrombospontin, tininicin, entaxin; Heparin, hirudin, fibrin; Phospholipids; keratin; Polylactic acid (PLA), polyglycolic acid (PGA) and copolymers thereof (PLGA); Poly-ε-caprolactone, poly-N-isopropylacrylamide (PNIPAM) and copolymers thereof; Cellulose derivatives such as polypeptides, regenerated cellulose, carboxyethyl cellulose (CEC) and carboxymethyl cellulose (CMC); Chitosan, chitin and derivatives thereof; Glucan, sodium alginate; Poloxamers consisting of PEG, PEG-PPG-PEG block copolymers; And polyanhydrides, polyacetals, polyketals, poly-ortho-esters, polyylphosphazenes.
The composition of claim 1, wherein the polymer is present in a concentration of 0.1 to 10 wt%.
The composition of claim 1, wherein the HPMC has a ratio of methoxy and hydroxypropyl groups of 0.5: 1 to 7.5: 1.
The composition of claim 1, wherein the HPMC has a viscosity of 2 cP (centi-Poise) to 15 cP in a 2 wt% aqueous solution at 20 ° C. 7.
The anti-tissue adhesion composition of claim 1, wherein the HPMC is included in a concentration of 0.1 to 10 wt%.
10. The anti-tissue adhesion composition of claim 9, wherein the HPMC is included in a concentration of 1 to 5 wt%.
The anti-adhesion composition of claim 1, further comprising a surfactant.
The method of claim 11 wherein the surfactant is sodium lauryl sulfate, sorbitan esters and polyoxyethylene sorbitan fatty acid esters, polyethylene glycol-15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenated perm oil, polyoxy An ethylene-polyoxypropylene copolymer, d-α-tocopheryl polyethylene glycol 1000 succinate and fatty acid macrogol glycerides.
13. The tissue adhesion preventing composition of claim 12, wherein the surfactant is included in a concentration of 0.01 to 10 wt%.
An apparatus for producing a liquid foam, comprising a container containing the tissue adhesion preventing composition according to any one of claims 1 to 13, and a means for forming a foam.
15. The apparatus for producing liquid foam according to claim 14, wherein the foam forming means is a nozzle which is a pump or a spray.
A method for preventing adhesion to tissues, comprising applying the tissue adhesion preventing composition according to any one of claims 1 to 13 to the surface of local organs of animals other than humans.

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