KR20120092081A - Patch for curing and/or alleviating the skin diseases accompanying the exudation of plasma proteins - Google Patents

Abstract

PURPOSE: A patch for treating and relieving dermatitis is provided to treat atopic dermatitis without addition of other ingredients into epidermis with safety. CONSTITUTION: A patch for treating or relieving dermatitis accompanying plasma protein effusion contains a polymer matrix(2) of a net structure and polar resin(3) which binds to proteins contained in the matrix and/or resin which binds to the proteins by hydrophobic binding. The polymer matrix is a micro net structure of complex carbohydrate of agar or a micro net structure using polyacrylamide, latex, polystyrene, polyvinyl, silicone polyurethane, or cellulose fiber. The patch further contains triacylglycerol, ceramide, ceramide derivative, complex lipid extracted from animal, or synthetic lipid.

Description

Patch for curing and / or alleviating the skin diseases accompanying the exudation of plasma proteins}

The present invention relates to a patch for the treatment and symptom relief of skin diseases with blood protein exudation or adsorbing blood proteins exuded into the skin.

New understanding of the causes of atopic diseases

Genetic factors, pollen, house dust mite, formaldehyde and other chemicals, and westernized foods are the main causes of atopic dermatitis, but the exact cause of the disease is not clear. Immunological findings in atopic diseases include the activity of Th1 cells in epidermal infections, as a mechanism for regulating immunity, or in the presence of large or persistent or persistent antigenic exposures, such as parasitic infections. One of the phenomena that occurs is the unique activity of Th2 cells active. Rather than focusing on the unique immunological phenomena present in atopic diseases, this patent suggests that blood proteins exuded from blood vessels may stain skin tissues due to metabolic abnormalities or metabolic imbalances. This is a fundamental cause-the immune response seen in atopic dermatitis is thought to be a result of the exudation of blood proteins-to solve the problem. Similarly, psoriasis symptoms are a cause of psoriasis triggered by the exudation of blood proteins to suggest a new treatment method.

Atopic dermatitis was less prevalent in the pre-1980s (in the United States and the United Kingdom before the 1970s) and was not a social problem. Since the late 1980s, the incidence of sudden cases has been high, and now, one in five elementary schools has become a serious social problem with atopic symptoms. Comparing the 1970's and 2000's, bans on the use of leaded gasoline, strong government regulations on the emission of soot from automobiles, the introduction of public transport using natural gas, dust regulation of factories and pollutant emission factories policies As a result, air pollution is much better than 20 to 30 years ago. Air pollution is becoming an environment and condition that is hardly seen as increasing atopic incidence.

Today's dwellings have much larger windows than homes of the 1970s and have been transformed into a structure that allows more sunlight to enter the interior. Vacuum cleaners equipped with microfilters have become commonplace, washing machines with sterilization functions are also used, and detergents have become more powerful and diverse. Compared to the past, house dust mites have become more difficult to live. That is, it is difficult to explain the incidence of house dust mites and atopic diseases. Compared to the city, there are many grasses in the countryside. The concentration of pollen is much higher than in the city. However, the frequency of atopic outbreaks is more common in cities than in rural areas. The concentration of pollen does not match the incidence of atopic diseases. Pollen is also not a cause of atopic diseases.

Significant changes in urban culture compared to the 1970s are delivery restaurants, various fast food restaurants, convenient public transport systems and private cars. In addition, the most notable change since the mid-1980s was the change in food, with common cooking oils (soybean oil, corn oil, olive oil, grapeseed oil, cottonseed oil, etc.) supplied in large quantities at a low price, and the use of them (fried chicken, pork cutlet) , Sweet and sour foods) were suddenly popularized. Margarine, which contains large amounts of trans oil and linoleic acid, has also become popular. Margarine once had a sharp increase in consumption, with the advertisement that it lowers cholesterol and is good for health. In fact, most commercial vegetable oil products are manufactured using extraction with solvents (eg n-hexane). As a result, pure triglycerides are very clear and transparent with almost no polar fat and contain large amounts of unsaturated fatty acids. Given the evolution of humanity, it is easy to infer that they have never consumed as much vegetable triglycerides as they contain. In other words, the physiological changes that can greatly affect the lipid metabolism of humans occurred. Throughout evolution, humans have consumed fats containing natural cis-type fatty acids, and have never consumed trans- fatty acids as much as they do now. As a result of evolution, our bodies do not have enzymes to convert the tran- form of fatty acids into cis- form. Ingestion of trans fatty acids results in slower total lipid metabolism. Due to the development of public transportation and convenience, the amount of activity is drastically reduced, creating a condition in which the ingested fat is not converted into energy in the body. In addition, due to the development of the heating system and the development of clothing materials, the living temperature that the body accepts can be said to have risen sharply.

In conclusion, excessive intake of triglycerides containing unsaturated fatty acids, intake of trans oil, and reduction of the conversion of lipids into energy due to decreased activity result in imbalance of lipid metabolism, and capillaries expand due to rising living temperature. Or a condition in which capillaries function incompletely, an environment in which skin diseases such as atopic disease and psoriasis are developed is prepared.

psoriasis  And commonalities between acute and atopic diseases

Loss of lung (lung) function due to excessive intake of vegetable unsaturated fatty acids is reported by Wolfe et al. (. Wolfe RR, Martini WZ, Irtun O., Hawkins HK, Barrow RE (2002) Dietary fat composition alters pulmonary function in pigs . Nutrition. 18: 647-653). The ingestion of vegetable oils also results in loss of lung tissue complicability and the release of plasma proteins into tissues, thereby affecting their function. Skin can also be affected by excessive intake of unsaturated fatty acids. Patients suffering from atopic disease are high in HDL-cholesterol (Schafer T., et al. (2003) Intake of unsaturated fatty acids and HDL cholesterol levels are associated with manifestations of atopy in adults. Clin. Exp. Allergy. 33: 1360-1367). This can be interpreted as active lipids are delivered to each organ after lipid intake. Skin delivery of lipids containing unsaturated fatty acids can affect the membrane components of blood vessels and epidermal cells, and unsaturated fatty acids with high fluidity degrade blood vessel function, leading to plasma proteins, especially Albumin and immunoglobulin G (immunoglobulin G, IgG). This exudation occurs through gaps between blood vessel cells, and the evidence is that the size of the exuded proteins is limited. 150 KDa IgG is easily exudated, but larger proteins are not easily exudated. This exudation mechanism can be seen in psoriasis as well as atopic diseases. Except for infection or strong physical irritation, psoriasis and atopic dermatitis, erythroderma or edema may be inferred that symptoms occur due to changes in the function or structure of blood vessels. It is interesting to note that atopic dermatitis and psoriasis are significantly different metabolically. Patients with atopic disease have high levels of HDL-cholesterol, while patients with psoriasis have very high levels of blood cholesterol and triacylglycerol. Interestingly, the size of the sebaceous gland secreting triglyceride-based sebum in psoriasis patients is weekly smaller. Simply interpreted, there may be a problem in getting the lipids needed to synthesize sebum from blood vessels. A similar case in atopic dermatitis is that the ceramide lipids required for the protection of the skin are low in the epidermis. In psoriasis and atopic diseases, the profile of lipids contained in the blood is different, but lipid metabolism is actively occurring in the body. Of particular note in atopic dermatitis and psoriasis is that both diseases are associated with blood protein exudation, and despite lipid metabolism in the body, is there a problem with the delivery of lipids to the epidermis, or is it necessary for certain lipids? It can be inferred that this is not being delivered to the epidermis.

Blood protein  New understanding of exudates and inflammatory reactions

What psoriasis and atopic disease have in common is that blood proteins leak out of blood vessels (microvascular leakage) and bleed into skin tissue. Exuded proteins are limited in molecular weight, with immunoglobulin G (IgG, 150KDa) and plasma albumin (serum albumin, 66KDa) being the most common. Unlike those inside the blood vessels, the proteins exuded into the skin slowly dry and increase their salt concentration, resulting in low-affinity, random binding, or non-specific binding. binding or exuded proteins are expected to aggregate. It is inferred that a vicious cycle of more exudation will continue as proteins dry out, causing skin pruritus and scratching triggers histamine release by physical stimulation. Even in the absence of allergens or infections from outside, nonspecific or random clustering of exuded antibodies can be recognized as a signal similar to that of infection, so that neutrophils are primarily directed to the tissue. It is inferred that as they migrate they will recruit several immune cells. In particular, macrophage recruitment into tissues in chronic atopic diseases has been described as an immunological mechanism of Th2 cells due to continuous antigen exposure. However, it can be explained simply by the mechanism by which exuded blood proteins are collected to clean up the aggregates. For example, macrophages clear up aggregated clumps of lipids and surfactant proteins in these small, autologous pneumoconiosis. The movement and activation of eosinophils observed in atopy can also be explained in association with the symptoms of protein exudation. Eosinophils are well known to secrete cationic proteins, which can be seen simply as a cytological simple mechanism by which exuded proteins can be aggregated and then removed. In addition, after neutrophils have been recruited from the pleural cavity for infection or allergen sensitization, eosinophils can be used to reduce ongoing blood protein exudation from atopic dermatitis, as eosinophils are recruited to control or reduce blood protein exudation. It can be interpreted simply as being recruited to an exudation site.

psoriasis  New solutions to skin and atopic skin diseases

Based on the evidence presented above, the common causes of psoriasis and atopic diseases are triggered by an imbalance in lipid metabolism or abnormalities in lipid metabolism, resulting in blood proteins leaking from blood vessels into tissues. If aggregating or degeneration after smin causing various inflammatory reactions, a new approach can be suggested.

The most important and up-to-date treatment is dietary control, refraining from the intake of vegetable oils, especially vegetable triglycerides, and eating cooked foods that avoid trans fats or foods containing trans fats. do. This dietary control method is a method that takes considerable effort and time because it must be performed until the lipid component in the body is changed to a certain level. Patients suffering from atopic disease suffer from extreme pruritus and therefore have a long treatment period. However, dietary control is an essential method.

The second method is to locally inhibit blood protein exudation to relieve inflammation and restore the epidermis. This method was previously proposed by the author and is currently registered in Korea, Australia, Singapore and Russia (Korean Patent 0891595, Australian Patent 2006217261, PCT Application; PCT / KR2006 / 000638). By applying a composition containing a large amount of saturated phospholipids present in the lungs of an animal to the affected area, the lipid metabolism of the affected and surrounding cells and blood vessel cells is altered to inhibit the exudation of blood proteins. This method requires an average of 8 to 12 weeks of treatment and longer treatment for severely ill patients.

 The third method is the method proposed in this patent, in which exuded proteins in the affected area are removed using a protein adsorption patch. You can expect the fastest treatment period of 10 days on average, and it's very safe because it doesn't deliver any substance or active ingredient to your skin, and it's a quick way to reduce the pain caused by pruritus. However, if this method is used without reducing or inhibiting blood protein exudation, then the protein exudation may occur again, possibly causing symptoms to return. In addition to treatments that inhibit protein exudation in a variety of ways, the application of patches to remove blood protein exudates proposed by the present patent may be applied simultaneously to expect complete treatment without recurrence in a short period of time.

The present invention solves the above problems and the object of the present invention is to provide a patch for the treatment of skin diseases and symptom relief accompanied by blood protein exudation.

In order to achieve the above object, the present invention comprises a) a polymer matrix of a net structure: and b) blood protein effluent comprising a polar resin and / or a resin hydrophobic binding to the protein contained in the matrix It provides a patch for the treatment or symptom relief of skin diseases.

In one embodiment of the present invention, the polymer matrix of the net structure is a fine net structure of a complex carbohydrate selected from the group consisting of agar and agarose, polyacrylamide, latex (latex), polystyrene (polystylene), poly It is preferable that the fine net structure using vinyl (polyvynyl chloride), silicone (silicone) polyurethane, or cellulose fibers, but is not limited thereto.

In one embodiment of the invention, the polar resin comprises an organic or inorganic matrix containing functional groups that are ionic or capable of being ionized under suitable pH conditions. The organic matrix may be a synthetic (eg acrylic acid, methacrylic acid, sulfonate styrene, sulfonate divinylbenzene), or partial synthetic (eg modified cellulose and dextran) material. Preferably, the inorganic matrix comprises silica gel modified by the addition of ionic groups. Covalently bound ionic groups are strongly acidic (eg, sulfonic acid, phosphoric acid), weakly acidic (eg, carboxylic acid), strongly basic (eg, primary amine), weakly basic (eg, quaternary ammonium ), Or a combination of acidic and basic groups. In general, ion exchangers of the type suitable for use in ion exchange chromatography and suitable for applications such as deionization of water are suitable for use in controlled release of drug formulations. These ion exchangers are described by HF Walton in "Principles of Ion Exchange" (pp: 312-343) and "Techniques and Applications of Ion-Exchange Chromatography" (pp: 344-361), Chromatography (E. Heftmann, ed.), van Nostrand Reinhold Company, New York (1975).

Examples of such polar resins of the present invention include agarose, Sephadex, or Sepharose having a DEAE (Diethylaminoethyl) -group; Agarose, Sephadex or Sepharose with CM (Carboxymethyl) -group; Agarose, Sephadex or Sepharose with trimethylammonium-; Sulfonyl- or Sulfur as S-cation exchange resin Resins having functional groups of sulfonic acid derivatives; It is preferably, but not limited to, hydroxyapatate particles (granules) or a polystyrene (charged resin) of a polystylene structure.

In one embodiment of the present invention, the hydrophobic interaction (hydrophobic interaction) is a resin that binds to the protein is preferably a resin containing 4 to 10 hydrocarbons (hydrocarbon chain), but is not limited thereto.

In one embodiment of the present invention, it is preferable that the patch is arranged in a plurality of resins having different polarities, the multi-array patch is a positively charged polar resin to first contact the affected area, a negatively charged polar resin Is more preferably arranged on the rear side, but is not limited thereto.

In one application of the invention, the skin disease is atopic dermatitis (atopic dermatitis), eczema (eczema), psoriasis, contact dermatitis, erythema, erythema, lichen, chronic Or contact urticaria (urticaria), benign (crystalline yang prurigo nodlaris), light burn (scald) without damage to the stratum corneum (but not limited to this).

In a preferred embodiment of the present invention, the patch of the present invention preferably further comprises a bisaturated phospholipid, an organic acid and a divalent cation, the bisaturated phospholipid is a bisaturated phospholipid derived from the animal lung is representative of DPPC, DPPI, etc. For example, the organic acid is a representative example of the organic acid constituting the TCA cycle including citric acid, the divalent cation is a typical example of calcium and magnesium ions.

The present invention also provides a topical patch for adsorbing blood proteins exuded into the skin comprising a) a polymer matrix of net structure: and b) a polar resin contained in the matrix.

In another aspect, the present invention provides a patch for the treatment or symptom relief of skin diseases accompanied by blood protein exudation prepared by directly fixing a functional group that binds a protein to a cloth, pad or gauze.

In one embodiment of the present invention, the polar functional group that can be directly fixed to the cloth, pad or gauze is DEAE-, CM-, trimethylammonium-, or sulfonic acid or the length of saturated hydrocarbon chain Is preferably a functional group of 4 to 10 carbons, but is not limited thereto.

The present invention also provides an external patch for adsorbing blood proteins exuded into the skin prepared by directly fixing a functional group that binds to a protein to a cloth, pad or gauze.

Or the present invention provides a polymer matrix of a net structure: and

b) provides a patch for removing protein waste secreted into the skin comprising a polar resin and / or a resin hydrophobic binding to the protein contained in the matrix.

Or the present invention provides a polymer matrix of a net structure: and

b) provides a patch for diagnosing skin diseases accompanied by blood protein exudation comprising a polar resin and / or a hydrophobic bond with a protein contained in the matrix.

As can be seen in Experimental Example 5 and FIG. 6E of the present invention, there is a significant difference between the protein profile seen in psoriasis patients and the profile of proteins seen in atopic patients. Ig or albumin protein is one example. The profiles of these proteins alone can clearly distinguish the differences between the two diseases, and by using these adsorption methods to identify the labeled proteins of various skin diseases or standardize the protein exudation pattern, various skin diseases can be diagnosed.

Hereinafter, the present invention will be described.

The present invention is directed to the affected surface of skin diseases (eg, atopic dermatitis, eczema, psoriasis, contact dermatitis, etc.) with symptoms of blood protein effusion. The present invention relates to a patch that is applied to absorb and remove exuded blood proteins in skin tissue. Patches reduce inflammation by removing proteins exuded from epidermal tissue, while at the same time preserving moisture in the skin to treat or alleviate skin diseases quickly and safely. Polymers of micro-mesh structure, such as agar or agarose, through which extra-vesicular exudated proteins and peptides can be sufficiently passed Polyacrylamide, latex, or polyurethane foam sponge is used to form a matrix to contain water, and various charges with a large surface area with small particles in the matrix structure. Resins--DEAE (Diethylaminoethyl) -cellulose, Carboxymethyl (CM) -cellulose, other polarized carbohydrate compounds (derivatized-complex carbohydrate compounds), hydroxylapatite particles (granules), commonly used in protein chromatography Polystyrene (charged resin), such as a polystyrene structure, is fixed to bind to proteins and peptides that permeate the skin. A patch. According to the present invention, skin diseases such as atopic dermatitis and psoriasis are exuded from blood vessels due to disorder of lipid metabolism or imbalance of lipid intake, and various inflammatory reactions and skin rashes due to exudate. And epithelial cell proliferation. This patent suggests that acute dermatitis, eczema, eczema, and atopic dermatitis can be treated within 10 days using a patch that absorbs and removes blood exuding proteins and peptides from skin tissues on a fixed resin. Psoriasis and similar symptoms suggest the safest and fastest treatment. In addition, it gives a new understanding of these diseases and presents various applications using the developed patches.

The causes of similar diseases such as atopic dermatitis, eczema, and psoriasis are thought to be due to imbalance of lipid metabolism or abnormal lipid metabolism, resulting in the exudation of blood proteins and various inflammations due to blood proteins penetrating into tissues. Reactions or abnormal growth of epidermal cells are thought to occur. To the affected part of this patent is to secure the various resin (resin) used for protein separation and purification, for example, DEAE-cellulose (or agarose), having a number of feeders and CM- hydroxylapatite, ^Dowex? Resin or the like in the agar gel It can be applied as a patch or by attaching a polar group capable of binding protein to a cotton cloth and applying wet-dressing to remove the exuded protein and to treat skin diseases very quickly and effectively. gave.

As can be seen from the present invention, the protein adsorption cloth for patch and wet-dressing of the present invention is the safest treatment method by treating atopic diseases without putting any drugs or specific ingredients into the epidermis other than distilled water. I think this. The treatment method of the present patent, which can treat severe atopic diseases within 10 days, is expected to lead to a new understanding of the causes of atopic diseases and various new treatments.

Figure 1a is a diagram showing the configuration of the patch of the present invention. The external patch was designed to adhere to the affected area and adsorb blood proteins exuded from blood vessels. ① Dressing of material that keeps moisture appropriately with adhesion film such as porous vinyl (polyvinylchloride) or 3M company's Tegaderm ^TM for oxygen supply to skin. ② Microscopic material that can contain moisture such as agar. Matrix of micro-mesh ③ Strongly polar resin (resin), carbohydrate complex (derivatised complex carbohydrate) having polar group such as DEAE-cellulose or bipolar resin such as hydroxylapatite④ Cotton gauze or polyester fibers attached to the gel to prevent them from breaking easily in cotton or folds. ⑤ It shows adhesive tape.
Figure 1b is a diagram showing an example of the arrangement of the patch of the present invention. When using different resins or resins having different polarities, such as DEAE-agarose and CM-agarose, when the resins are mixed in the same gel, it is very likely that the resins will bind together and reduce the protein adsorption efficiency. If the polarities are different in this way, it is desirable to apply the two gels to the epidermis. In particular, since most proteins are negatively charged, positively charged resins such as DEAE- are first brought into contact with affected areas, and positively charged proteins generally have a low molecular weight (e.g., eosinophil cationic protein, 18-22KDa). Because of its relatively high molecular motion and rapid diffusion, CM-like resins can be arranged on the back to adsorb small, positively charged proteins. ⑥ Resin having different polarity.
Figure 1c is a diagram showing the mechanism of action of the patch of the present invention. After applying the patch, the blood proteins exuded from the blood vessels and permeated to the epidermal tissue are diffused into the patch to show the mechanism of binding. By adhering the protein adsorption patch to the epidermis, the exuded blood protein is removed by adsorbing the patch to relieve the inflammatory reaction, and to replenish the moisture as well as to restore the epidermis, thereby restoring the wounds damaged by atopic or psoriasis diseases. Can give
Figure 2 is a diagram showing an example of applying the patch of the present invention to atopic eczema, Figure 2a is a photograph applied to atopic eczema, an example of applying the patch to the instep of a 36-year-old male with severe atopic eczema. 2.5% (w / v) agar gel (2 mm thick) containing 10% (w / v) DEAE-cellulose was applied. The patching time was from 8-9 pm to 8 am every day. Significant improvement was observed from day 1 of patch application, and from day 3, symptoms improved so that the boundary of the affected area was hard to recognize. Figure 2b is a SDS-PAGE analysis of the proteins adsorbed on the patch of the present invention: the patch attached to the atopic eczema patient was cut to a certain size and dissolved in the SDS-PAGE sample buffer was developed by the electrophoresis device. 10% (w / v) polyacrylamide gel was used, and the protein was developed with CBB-R ₂₅₀ . Among the adsorbed proteins, the main proteins are plasma albumin (serum albumin, 66KDa) and immunoglobulin (heavy chain 52KDa and light chain 27KDa). The proteins developed at 7 are the protein profiles of total serum proteins. The major difference from exuded proteins obtained in the affected area is that more than 200 KDa proteins are observed. The condition improved rapidly as the amount of exuded protein permeated into skin tissue (or the amount of exuded protein bound to the patch) rapidly decreased. Protein exudation is closely associated with the severity of atopic diseases.
3 shows an example of applying the patch of the present invention to severe atopic dermatitis in a typical child;
3A is a severe pediatric atopic application example (knee region); A patch consisting of 2.5% agar gel (thickness ~ 2mm) containing 10% (w / v) DEAE-cellulose particles was applied to the knee area of a 7-year-old boy with severe atopic dermatitis. The patient applied during the time of sleeping at night. Severe skin condition improved noticeably every day. Pruritus lasted up to 4 days of patch application, but on day 8 there was little pruritus and the epidermis was normalized.
Figure 3b is an analysis of the exuded protein bound to the patch applied to the knee of severe pediatric atopic dermatitis; After a gel was collected to a certain size from the patches removed from the affected area at a certain time every day, SDS-PAGE was performed to visualize the proteins that diffused from the epidermis and bound to the polar resin. Plasma albumin and immunoglobulin (immunoglobulin) were confirmed to be the main protein. It can be seen that the amount of exuded protein and the recovery of lesions (Fig. 3-1) are closely related.
3C shows an example of application to severe pediatric atopic dermatitis (calf site); We applied the patch applied to atopic dermatitis in the calf of a 7-year-old boy. The patch was formulated with 2.5% agar gel containing 10% (w / v) DEAE-cellulose to 10 mg / ml porcine lung extracted phospholipids, 1.5 mM CaCl ₂ and 5 mM citrate / citric acid (pH 5.8) in water of the gel. This component is the 'composition for inhibiting blood protein effusion' used in the patent (Korean Patent 0891595, Australian Patent 2006217261, PCT Application; PCT / KR2006 / 000638). It is easy to see that the patch containing the above-mentioned phospholipids shows a more stable therapeutic effect than the patch containing only resin (Fig. 3a).
Figure 3d shows the analysis of exuded proteins adsorbed on the patch applied to the calf of severe pediatric atopic dermatitis; compared to Figure 3b, the patch containing phospholipids adsorbed the exuded proteins consistently for a long time. It is highly likely that the phospholipids acted like a mild detergent, allowing the aggregated exuded proteins to diffuse smoothly. It is also possible that citric acid disrupted the binding of the bound proteins and promoted the removal of exudate proteins. SDS-PAGE results show that the presence of large amounts of lipids in the patch does not interfere with the absorption of exuding proteins into the patch. Therefore, the long-term wet-wrapping method may affect the skin barrier. Therefore, even if the patch contains a lipid component that protects the skin barrier, the patch may have a stable therapeutic effect. In particular, for the more stable treatment, it is also desirable to use a method of mixing the patch with a composition that inhibits blood protein exudation, which is mainly composed of phospholipids extracted from pig lungs, in the patch.
4 is an example of application of atopic dermatitis of a severe face with the patch of the present invention; Figure 4a was applied to the patch on the girls with severe atopic dermatitis on both faces to observe the effect of the patch. After applying the patch, it was easy to see a quick recovery from day to day. After 4 days of patch application, the boundary of the affected area was hardly distinguishable, and after 8 days, the skin condition was normal.
Figure 4b was developed by SDS-PAGE proteins adsorbed from the gel of the patch applied to the face. It was found that the extent to which the amount of protein adsorbed decreased and the level of epidermal recovery matched.
FIG. 5 shows an example application of a double patch with a different polar resin, 10% (w / v) on 2.5% (w / v) agar gel (thickness ˜2 mm) containing 10% (w / v) DEAE-cellulose. Patches were prepared to align 2.5% (w / v) agar gel (˜2 mm) containing CM-cellulose in v) (see FIG. 1B). The patch was applied to the atopic eczema affected area of a 45 year old male to observe the effect of the patch and the degree of protein adsorption using SDS-PAGE.
5A; Skin condition after patch application with two different polarities
5B; After applying the affected area, proteins extracted from the gel of the patch and developed by SDS-PAGE
Figure 6 is an example of applying a patch containing various resin to the psoriasis affected area, respectively;
Patches containing resins with different polarities were prepared and applied to psoriasis sites of 28-year-old women. The application was performed for 6 hours, and the effect of each patch was observed based on the extent of skin color and skin thickness. (FIG. 6A). Gel formed from 2.5% (w / v) agar only (~ 2 mm thick), (Figure 6b) 2.5% agar gel (~ 2 mm thick) containing 10% (w / v) DEAE-cellulose, (Figure 6c) 10% ( w / v) 2.5% (w / v) agar gel (~ 2mm thickness) containing CM-cellulose, (Fig. 6d) 2.5% (w / v) agar containing 10% (w / v) hydroxylapatite (bipolar resin) Gels (˜2 mm thick) were applied to the psoriasis affected areas, respectively. Patches containing DEAE-cellulose showed the best effect, while patches containing CM-cellulose did not show any obvious effect.
Figure 6e) shows the protein pattern obtained in the affected area of psoriasis patients and the affected area of atopic dermatitis patients. The two diseases may be the same reason that protein exudation occurs but the types of exuded proteins are different.
7 is an example applied to the wound (negative effect), by applying a patch consisting of 2.5% agar gel (~ 2mm thickness) containing 10% (w / v) DEAE-cellulose to the wound caused by external physical impact Observed. The proteins needed for wound healing are thought to be adsorbed by patches, which slows down the healing of wounds. The patches removed after 6 hours of application showed liquefied adsorbed blood and yellow protein. After detaching the patch, it was observed that the epidermis caused slight bleeding in the affected area even under slight tension. In addition, even when the wound healed, it was observed to leave a large trace of the wound. The patch of this patent needs to be restricted to apply to skin diseases showing blood protein exudation such as atopic dermatitis or psoriasis without a trauma.
Figure 8 is a schematic diagram showing the DEAE-cotton fabrics (DEAE-cotton fabrics) manufacturing process, by coupling the DEAE (Diethylaminoethyl) group to the cotton cloth (coupling) to be used for the treatment of atopic dermatitis or psoriasis disease, DEAE- We optimized the method of binding groups to cellulose and simplified the manufacturing process to enable mass production. This is a schematic of the process using the method created in the laboratory. By moving DEAE-groups while continuously moving fabrics with various thicknesses and mesh sizes, it is judged that it is possible to manufacture various applications according to skin symptoms.
Figure 9 is a photograph showing the exudation protein adsorption using DEAE-cotton fabric, the DEAE-cotton fabric was prepared by coupling the DEAE-group (group) to the normal cotton fabric (cotton fabrics). The left side of Figure 9a is in a dried form, the right side is soaked in distilled water before application to the affected part. Application to the atopic eczema affected area for 5 hours confirmed the exudation protein adsorption. Although a small amount of protein was detected in a normal cotton cloth, DEAE-cotton cloth is easily recognized that a large amount of various blood effusion proteins are adsorbed. [FIG. 9B] Such a polar group or a protein-binding cloth can be applied to a severely curved area. And, if you have systemic dermatitis, it is expected to be able to treat more efficiently by making in the form of clothes. In addition, since it is possible to mix and use a variety of drugs, it is determined that the personalized treatment is possible by adding a drug in the form of a specialist according to the condition of the patient.

The present invention will now be described in more detail by way of non-limiting examples. However, the following examples are intended to illustrate the present invention and the scope of the present invention is not to be construed as limited by the following examples.

Example  1: Preparation and composition of patch for blood protein exudate removal

Agar (agar, agarose) is an experimental material commonly used in molecular biology, and can form a very good gel that is not biodegradable by enzymes of the living body and is edible and irritating to the skin. Such a gel has excellent elasticity, can contain a large amount of moisture, and has many advantages. In addition, large molecular weight particles can easily diffuse and migrate between the micro-meshes formed in the gel. In general, when using agar for electrophoresis, proteins below 200 KDa diffuse too quickly in the gel, making it difficult to identify the band of proteins. This means that the microstructure of the agar is very large. Blood proteins exuded by the epidermis have the highest immunoglobulin G (IgG, 150KDa) and plasma albumin (serum albumin, 66kDa) below 200KDa, so there is no problem for these proteins to diffuse freely in the gel.

Polar resins, such as DEAE-cellulose or DEAE-agarose, CM-cellulose (or agrose) hydroyxylapatite, which bind proteins to fix molecules in gels, irritate the lungs and mucous membranes in a powdered state. There may be, but there is little irritation when fully hydrated or swelled. In the present patent, these particles may be clouded and fixed in a gel such as agar so that they do not come into direct contact with the affected area, thereby minimizing unnecessary irritation.

The resins to be fixed in the gel, such as agar, were soaked in distilled water overnight for a sufficient swelling procedure, in order to remove contaminants that would be attached to the polar group, in order of 0.1M NaOH-0.1M HCl-0.1M NaOH, Or each resin was washed in the order of 0.1M HCl-0.1M NaOH-0.1M HCl. The contaminant-removed resins were washed several times with distilled water, and each of the prepared resins was prepared by autoclave (15 min, 15 lb / cm ² ) at high temperature and high pressure.

The agar gel (agarose gel) and the resin mixture is fixed as follows. Agar gel (2.5% mass / volume ratio) was heated to a liquid state and then maintained at 60 degrees Celsius. The prepared resin was made in the form of a filter cake to remove moisture and then weighed (wet-weight) to 10% of the patch (mass / volume ratio). The agar gel and the resin were mixed homogeneously at 60 degrees Celsius, and then poured into a forming mold and cooled to make the thickness of the gel 1.5 mm to 2 mm. Gel such as agar may be broken if it is excessively folded or bent at the curved part of the body, so attach one layer of cotton gauze (80 ~ 120 water, 80-120mesh) to the gel surface when the gel is in liquid state. The strength of the was reinforced. The structure and principle of operation of the gel is illustrated by figure (Fig. 1).

Experimental Example  1: severe atopic eczema ( atopic eczema Application to affected areas

Patients with very severe atopic eczema (36 years old, male) received a patch of 10% (w / v) DEAE-cellulose fixed on 2.5% (w / v) agar gel in the affected area. This patient suffered from atopic eczema for a long period of more than 10 years due to the involvement of the instep. The patch was applied to avoid the busy day, overnight at around 8-9 pm, and to be removed around 8 am. The affected area was observed daily, and a predetermined amount of gel sample was taken from the patch removed from the affected area, and the protein adsorbed using 10% (w / v) sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Developed. After electrophoresis, the protein bands were developed by Coomassie brilliant blue-R ₂₅₀ staining.

Analysis of the proteins bound to the patches removed from the affected area revealed that the most protein is plasma albumin, followed by the immune antibody protein (heavy chain ~ 52KDa, light chain 27KDa). This is consistent with the fact that in atopic diseases, effusion occurs depending on the molecular weight of blood proteins bleeding out of blood vessels. As the amount of protein adsorbed by the patch (i.e., the amount of blood protein exuded) decreased, it was found that the affected area rapidly improved. This result is indirect evidence that tissue exudates of blood proteins trigger atopic dermatitis. Surprising fact that it is possible to treat atopic dermatitis without the application of any medicinal agents or therapeutic ingredients such as steroids and steroid derivatives, immunomodulatory agents (e.g., Edelel or Taclolimus), moisturizing ointments, etc. Is showing. The treatment period is also very short, because there is no ingredient absorbed into the skin other than distilled water can be called a very safe method [Fig. 2].

Experimental Example 2 Application to Severe Atopic Dermatitis in a Typical Child (Example of Implementing Specific Phospholipids in a Patch )

Patches were applied to some affected 7-year-old boys with severe atopic dermatitis. Two types of patches were applied.

Of 2.5% (w / v) agar gel (thickness ~ 2 mm) containing 10% (w / v) DEAE-cellulose and 10% (w / v) of DEAE-cellulose and 10% (w / v) pig Lung phospholipids, 1.5 mM CaCl ₂ and 5 mM citrate / citric acid (pH 5.8) containing 2.5% (w / v) agar gel (thickness ~ 2 mm) were applied to different affected areas to compare their effects. Phospholipids, 1.5 mM CaCl ₂ and 5 mM citrate / citric acid (pH 5.8), extracted from pig lungs, were described as' a composition for inhibiting blood protein exudation for the treatment of atopic dermatitis [Korean Patent 0891595, Australian Patent 2006217261, PCT Application PCT / KR2006 / 000638] is a composition that has completed the phase 3 clinical trial for the current drug approval. Two types of patches were applied to the affected area to observe the rate of treatment and the profile of the exuded protein. And it was examined whether the added phospholipids prevented the protein from spreading into the patch.

As a result of the application of both types of patch, both types of patches showed very remarkable treatment speed and effectiveness in the treatment of typical severe atopic dermatitis in children. Patches containing phospholipids, calcium ions, and citric acid / citric acid salts more efficiently adsorb exudate proteins. Therapeutic effect was also observed that patches containing phospholipids extracted from porcine lungs were much more stable and normalized. Phospholipids extracted from pig lungs acted as mild detergents, dissociating the exuded proteins accumulated in the skin and dissociating them. It is also possible that the citric acid contained in the composition interfered with possible ionic bonds between the proteins, allowing for more effective removal of the exudate. Saturated phospholipids contained in the patch may have prevented blood protein exudation, which may have resulted in faster recovery of the affected area. The effect of the two types of patches (patches containing only DEAE-cellulose and those containing DEAE-cellulose and porcine lung extracted phospholipids + 1.5 mM CaCl ₂ + 5 mM citrate / citric acid (pH5.8)) can be seen. Importantly, it was concluded that phospholipids did not prevent the exuding proteins from binding to polar resin particles immobilized in the patch.

In order to anticipate a faster and more stable therapeutic effect, it is also desirable to use it with drugs or components having blood protein exudation function.

Wet-wrapping method is used to treat atopic dermatitis. In order to continuously apply the moisture-rich patches proposed by this patent, a method of applying a patch containing ingredients that complement various lipids and skin barriers is also a good way to relieve the pain of atopic patients. Judging. In addition, ointments such as steroids and tacrolimus in the affected areas are known to be effective in inhibiting blood protein exudation in addition to the original antistress and immune reduction functions. Applying the patch while suppressing blood protein exudation before and after applying the patch may be expected to increase the therapeutic effect.

Experimental Example  3: Application to adolescents with severe atopic dermatitis on face

Patches were applied to adolescents (16 years old, female) suffering from severe atopic dermatitis on both cheeks of the face and observed the results. He was suffering from severe atopic dermatitis due to severe pruritus and burning sensation. The face was a site of high secretion of triglycerides through sebum, which could be hampered by the protein's ability to adsorb the patch. The patch was applied with 2.5% (w / v) agar gel (thickness-2 mm) containing 10% (w / v) of DEAE-cellulose. Patches were put to sleep after dinner and released before school in the morning. Symptoms improved one day after patch application and facial skin returned to normal after 8 days patch application. The skin condition of the patient remained normal for about 20 days, after which the cheeks reddened again and minor atopic symptoms appeared again.

From the results of SDS-PAGE, removal of the exudate protein using the patch takes about 5 days on average, and the treatment period takes 8 to 10 days in severe patients. In particular, it is thought that the amount of antibody protein decreases first and is accompanied by improvement of symptoms. In conclusion, it is judged that the amount of blood protein exuded is directly related to the severity of symptoms, and treatment of atopic disease will be very easy if various active treatments that can suppress blood protein exudation are accompanied.

Experimental Example  4: Example of application of a double gel type patch containing a resin having a different polarity

2.5% (w / v) containing 10% (w / v) CM-cellulose on 2.5% (w / v) agar gel (thickness ~ 2 mm) containing 10% (w / v) DEAE-cellulose Double patches with different polarities were made to have agar gel (˜2 mm) (see FIG. 1B). The patch was applied to atopic eczema affected in the leg of a 45 year old male and observed the effect of the patch and protein adsorption. On the first day, the patch was applied to the affected area for 3 hours and 30 minutes, and then the patch was applied every day during sleep. After 3 hours and 30 minutes of applying the patch, it was remarkably recovered, and the symptoms improved rapidly every day.

The amount and type of exuded proteins adsorbed on the gel was determined to be more diverse and clear than when only DEAE-cellulose was used. Therapeutic effect is also observed to be faster.

Experimental Example  5: psoriasis  Application to the patient

Various combinations of patches were applied to the skin of a 28-year-old woman with psoriasis throughout the body (especially with more severe symptoms at the extremity of the extremities) to observe the efficacy of the patch.

 a. Gel formed from only 2.5% (w / v) agar (~ 2 mm thick),

b. 2.5% agar gel containing 10% (w / v) DEAE-cellulose

c. 2.5 (w / v) agar gel, containing 10% (w / v) CM-cellulose,

d. 2.5% (w / v) agar gel containing 10% (w / v) hydroxylapatite (bipolar resin) was attached to the psoriasis lesions for about 5 hours, and then removed. The best effect for psoriasis patients was determined by a 2.5% agar gel patch containing 10% (w / v) DEAE-cellulose, and the least effective patch was 2.5 containing 10% (w / v) CM-cellulose. It was determined by% (w / v) agar gel patch [FIGS. 6, 6A through 6D].

An interesting finding is that the different types of proteins exuded from the affected areas of patients with psoriasis and atopic diseases. Albumin was found in psoriasis patients, but only a few immunoglobulins were found. This may be because the selective exudation according to the molecular weight occurs when proteins are exuded from blood vessels. Antibody proteins with higher molecular weight than albumin can be expected to be not easily exuded. These results may explain why the inflammatory response is more active in atopic dermatitis, and may explain why psoriasis disease causes abnormal division of epidermal cells rather than inflammatory reactions or skin lesions. Through these findings, the diagnosis of psoriasis and atopy can be easily visualized using the patch of the present patent. In other words, if atopic dermatitis and psoriasis are confused using the patch of the present patent, it can be used as a diagnostic standard. In addition, the use of immunological research methods allows the study of various proteins that are exuded. In the future, the patch of this patent shows that various applications, such as research purposes, are possible.

Experimental Example  6: Application to trauma or wound of a patch (Example of the negative effect of a patch)

Patches were applied to wounds or cuts to observe their effects. As a result, it was judged unsuitable to apply protein adsorption patches to wounds. The proteins needed for blood coagulation and tissue restoration were judged to be adsorbed by the patch, and microscopic bleeding was observed in the wound after 8 hours of application. In addition, the rate at which the wound healed was considerably slowed down, leaving the wound open and making it vulnerable to infection. In addition, it was later found that scars could be left even if the wound healed [FIG. 7].

Experimental Example 7: Application using the nature of the patch ( method of combining the polar group to the carbohydrate of the cotton cloth )

Resin such as agarose combined with polar group such as DEAE-cellulose is difficult to reuse when manufactured in patch form. Derivatised complex carbohydrate resins with substituents have a large surface area and high protein binding ability, so that they can achieve the desired effect when used in a gel patch. To solve this problem, DEAE- group and various polar groups can be used in combination with 100% cotton fabric. Chemically modified cloth with protein binding capacity has the advantage of being able to be used in close contact with the flexion part of the body because of its good elasticity, and can be reused several times if the adsorbed protein is efficiently removed. Although the protein binding ability is somewhat lower than using a protein purification resin, there are also advantages that can be applied to various applications. In particular, various drugs (e.g., disinfectants, antibiotics, antihistamines, steroids, etc.) and various lipids (e.g., ceramides, phospholipids, and liposomes in the form of lipid mixtures) can be further added at the physician's discretion. If it is made in the form of clothes, it is expected to be easily used for the treatment of patients suffering from systemic atopy.

This patent proposes a method of easily fabricating a cloth capable of protein adsorption by binding a DEAE-group to a cotton cloth.

The process for producing the DEAE-cotton fabric of the present invention is as follows.

1) wash the cotton cloth with distilled water and dry it;

2) soak in 3M NaOH for 30 seconds;

3) soak for 40 minutes in a solution of 3M NaOH and 3M DEAE-Cl (diethylaminoethyl chloride);

4) soak in 3M DEAE-Cl for 30 seconds;

5) wash with distilled water;

6) Dry.

In the case of mass production by the method of manufacturing the above-described DEAE-cotton fabric, the method can be performed by the method illustrated in FIG. Efficient patching at the lowest possible cost has been made, simplifying the manufacturing process with the wishes of developers who wish to benefit many patients.

After DEAE-cotton fabric made by the method described above was adhered to the affected area for about 4 hours, the adsorption of the exudate protein was confirmed.

9A is a piece of DEAE-cotton fabric, the left side of the fabric being dried and the right side soaked with distilled water prior to application to the affected area.

FIG. 9B is a photograph showing the adsorption of proteins using SDS-PAGE after cutting a regular amount of cloth and a DEAE-cotton cloth in close contact with the affected area for 5 hours. Pure cotton cloth with DEAE- group was found to adsorb and remove blood protein exudates from affected areas, not significantly different from agar gel patches containing DEAE-cellulose.

Cotton cloths with DEAE-groups or other polar groups can be used for the treatment of atopic diseases, psoriasis and similar diseases, but they may also be applied to structurally remove waste products from the skin. It is expected. In some cases, specific lipids or poorly soluble proteins may be removed from the epidermis by combining octyl or butyl-groups. Therefore, in addition to therapeutic purposes, it can also be used for cosmetic purposes (for example, mask packs), and the advantage is that it is economical and environmentally friendly, as it can be used several times.

Claims (15)

a) polymer matrix of net structure: and
b) a patch for treating or alleviating skin diseases accompanied by blood protein exudation comprising a polar resin and / or a resin hydrophobicly binding to a protein included in the matrix. The method of claim 1, wherein the polymer matrix of the net structure is a fine net structure of a complex carbohydrate selected from the group consisting of agar and agarose, polyacrylamide, latex, polystylene, polyvinyl (polyvynyl) A patch for treating or alleviating skin diseases with blood protein exudation, which is a fine mesh structure using chloride, silicone polyurethane, or cellulose fiber. The method of claim 1, wherein the polar resin is agarose, Sephadex, or Sepharose having a DEAE (Diethylaminoethyl)-group; Agarose, Sephadex or Sepharose with CM (Carboxymethyl) -group; Agarose, Sephadex or Sepharose with trimethylammonium-; Sulfonyl- or Sulfur as S-cation exchange resin Resins having functional groups of sulfonic acid derivatives; A patch for treating or alleviating skin diseases accompanied by effusion of hydroxyapatate particles (granules) or blood protein exfoliation, a polystyrene (charged resin) of polystylene structure. According to claim 1, wherein the hydrophobic interaction (hydrophobic interaction) is a resin that binds to the protein is a resin containing 4 to 10 hydrocarbons (hydrocarbon chain), a skin disease treatment or symptomatic patch with blood protein exudation . According to claim 1, wherein the patch is a patch for the treatment or symptomatic relief of skin diseases accompanied by blood protein exudation, characterized in that the multiple arrangement of resins of different polarity. The method of claim 1, wherein the skin disease is atopic dermatitis, eczema, psoriasis, contact dermatitis, erythema, lichen, chronic or contact A patch for the treatment or alleviation of skin diseases accompanied by urticaria, benign (crystalline bilateral prurigo nodlaris), and blood protein effusion that is a mild burn or scalp with no significant damage to the stratum corneum. The patch for treating or alleviating skin disease according to any one of claims 1 to 6, wherein the patch further includes blood protein effusion further comprising a bisaturated phospholipid, an organic acid and a divalent cation. The method of any one of claims 1 to 6, wherein the patch is a treatment or symptom of skin disease accompanied by blood protein exudation further comprising triacylglycerol, ceramide, ceramide derivatives, complex lipids extracted from animals, or synthetic lipids. Mitigating patch. a) polymer matrix of net structure: and
b) an external patch for adsorbing blood proteins exuded into the skin, comprising a polar resin binding to the protein contained in the matrix and / or a resin hydrophobicly binding to the protein. A patch for treating or alleviating skin diseases accompanied by blood protein exudation prepared by directly fixing a functional group that binds a protein to a cloth, pad or gauze. The method of claim 10, wherein the functional group is DEAE-, CM-, trimethylammonium (trimethylammonium), or sulfonic acid (sulfonic acid)-group for the treatment or symptom relief with blood protein exudation. The patch for treating or alleviating skin disease according to claim 10, wherein the functional group is accompanied by blood protein effusion having a saturated hydrocarbon chain having 4 to 10 carbons in length. a) polymer matrix of net structure: and
b) a patch for removing protein waste secreted into the skin comprising a polar resin and / or a resin hydrophobicly binding to a protein included in the matrix. a) polymer matrix of net structure: and
b) a patch for diagnosing skin diseases accompanied by blood protein exudation comprising a polar resin and / or a resin hydrophobicly binding to a protein included in the matrix. a) polymer matrix of net structure: and
b) A patch for the purpose of removing protein or peptide waste accumulated in the epidermis, including a polar resin and / or a resin hydrophobic binding to the protein contained in the matrix.

Images