Patch for treating and alleviating symptoms of skin diseases accompanied by effusion of blood proteins
09662247 ยท 2017-05-30
Assignee
Inventors
Cpc classification
A61P17/02
HUMAN NECESSITIES
A61K9/703
HUMAN NECESSITIES
A61K31/545
HUMAN NECESSITIES
A61F13/00063
HUMAN NECESSITIES
A61L15/42
HUMAN NECESSITIES
International classification
A61L15/16
HUMAN NECESSITIES
A61K9/70
HUMAN NECESSITIES
A61M35/00
HUMAN NECESSITIES
A61L15/42
HUMAN NECESSITIES
A61B5/00
HUMAN NECESSITIES
A61K31/545
HUMAN NECESSITIES
Abstract
Provided is a patch for treating skin diseases or alleviating symptoms of the skin diseases involving an exudation of blood proteins, or for absorbing blood proteins exuded to the skin.
Claims
1. A method of treating skin diseases involving an exudation of blood proteins, the method comprising: applying a patch to a skin-diseased area of a subject in need thereof, wherein the patch comprises: a) a polymer matrix with a mesh structure capable of absorbing the blood proteins; and b) a plurality of polar resins including a first polar resin and a second polar resin capable of binding with the blood proteins contained in the matrix through hydrophobic interaction, wherein the first polar resin has a polarity different from the second polar resin, and wherein the first resin located on a skin-contacting side of the patch has a positive charge, and the second resin located on the opposite side of the patch has a negative charge.
2. The method of treating the skin diseases according to claim 1, wherein the polymer matrix with the mesh structure is a micro-mesh structure of a complex carbohydrate selected from the group consisting of agar and agarose, or a micro-mesh structure produced by using polyacrylamide, latex, polystyrene, polyvinyl chloride, silicone polyurethane, or cellulose fiber.
3. The method of treating the skin diseases according to claim 1, wherein at least one of the plurality of polar resins is agarose, cross-linked dextran, or cross-linked agarose having DEAE (Diethylaminoethyl)-group; agarose, cross-linked dextran, or cross-linked agarose having CM (Carboxymethyl)-group; agarose, cross-linked dextran, or cross-linked agarose having trimethylammonium-group; a resin having a functional group selected from sulfonyl- or sulfonic acid derivatives; or a polar resin (charged resin) of hydroxylapatite granules or polystyrene structure.
4. The method of treating the skin diseases according to claim 1, wherein the at least one of the plurality of polar resins contains a C4 to C10 hydrocarbon chain.
5. The method of treating the skin diseases according to claim 1, wherein the skin disease includes an atopic dermatitis, eczema, psoriasis, a contact dermatitis, erythema, Lichen, chronic or contact urticaria, nodlaris (prurigo nodlaris), and a slight burn or scald that does not damage the stratum corneum.
6. The method of treating the skin diseases according to claim 1, wherein the patch further includes disaturated phospholipids, organic acids, and divalent cations.
7. The method of treating the skin diseases according to claim 1, wherein the patch further includes triacylglycerol, seramide, seramide derivatives, complex lipids extracted from animals, or synthetic lipids.
Description
DESCRIPTION OF DRAWINGS
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11) In
(12)
(13)
(14)
(15)
(16) The patches were prepared to have resins with different polarities, and then applied to the psoriasis area of 28 years old female. The patches were applied for 6 hours, and each effect of the patches was observed based on the thinned degree of the epidermis thickness and epidermis color. (
(17)
(18)
(19)
(20)
BEST MODE
(21) Hereinafter, the present invention will be described in more detail with reference to non-limited Examples. However, the following Examples are intended only to illustrate the present invention, and the range of the present invention is not understood to be limited to the following Examples.
Example 1: Preparation and Constitution of Patch for Removing Exudation of Blood Proteins
(22) Agar (or agarose) is an experimental material that is often used in a molecular biology, is not subjected to a biodegradation by a vivo enzyme, is edible, and can form in a type of very good gel that does not irritate the skin. Such a type of gel has excellent elasticity, can have a great quantity of water, and also has many merits. In addition, particles with large molecular weight can be easily diffused between micro-meshes formed in the gel, and can be easily moved. Generally, when using agar for an electrophoresis, the diffusion of the proteins with 200 kDa or less are too quick in the gel, so that it is difficult to confirm the bands of the proteins. It means that the micro-mesh structure of agar is very large. Since there are a lot of immunoglobulin (IgG, 150 KDa) and serum albumin (66 KDa) with 200 KDa or less as blood proteins exuded to epidermis, there is no problem regarding a freely diffusion of the proteins in the gel.
(23) Polar resins (for example, resins, such as DEAE-cellulose or DEAE-agarose, CM-cellulose (or agarose) and hydroxylapatite) that bond with the proteins in the gel and fix the proteins in the gel can irritate lung and mucous membrane in a state of powder, but in the case of completely hydrating or swelling, there are no irritation. According to the present invention, unnecessary irritation can be minimized by distributing the particles in the gel, such as agar, fixing, and directly contacting to a diseased area.
(24) The resins to be fixed in the gel, such as agar were immersed in distilled water overnight to sufficiently swell. Each of the resins was washed in the order of 0.1 M NaOH-0.1 M HCl-0.1 M NaOH or 0.1 M HCl-0.1 M NaOH-0.1 M HCl in order to remove contaminant attached to the polar group. The resins without the contaminant were repeatedly washed many times with distilled water, and then the washed resins were autoclaved at high temperature and high pressure (15 minutes, 15 lb/cm.sup.2).
(25) A process of mixing an agar gel (or agarose gel) with a resin and then fixing was as follows: After the agar gel (2.5% mass/volume ratio) was heated to prepare it in a liquid phase, the temperature was maintained to 60 C. The prepared resin was prepared in a type of filter cake, the water in the resin was removed, and then the mass of the resin was measured to be 10% (mass/volume ratio) of the patch. The agar gel and the resin was homogenously mixed at 60 C., poured to a mold, and then cooled to have a gel thickness of 1.5 mm to 2 mm. Since when the gel, such as agar was applied to the bend part of the body to be excessively folded or bent, the gel may be broken, one-layered cotton gauze (80 to 120 mesh) was applied to the surface of gel to compensate the strength of gel in the state of a liquid gel. A structure and operation principle of the gel is illustrated in the diagram (
Experimental Example 1: Example of Applying to Diseased Area of Atopic Eczema
(26) A patch prepared by fixing 10% (w/v) DEAE-cellulose to 2.5% (w/v) agar gel was applied to a diseased area of the patient (36 years old male) having very severe atopic eczema. The patient was suffered from an atopic eczema for a long period of time, i.e., 10 years or more due to a diseased are of the top of the foot. The patch was not applied during the daytime having many activities, and applied at about 8 to 9 o'clock overnight, and then released at about 8 a.m. The diseased area was observed every day. A gel sample was collected in a certain amount using a cylinder with a diameter of 2 mm from the patch released from the diseased area, and the absorbed proteins were subjected to a 10% (w/v) SDS-PAGE (Sodium dodecyl sulfate-polyacrylamide gel electrophoresis). After performing the electrophoresis, the protein bands were stained with Coomasse brilliant blue-R.sub.250 staining method.
(27) As a result of analyzing the proteins bonded to the patch released from the diseased area, it was found that the largest number of the proteins was serum albumin and the second largest number of the proteins was immune antibody protein (heavy chain 52 KDa, light chain 27 KDa). The result corresponded to the fact that the exudation of the blood proteins was carried out according to the molecular weight. It was found that when the amount of the protein absorbed to the patch (i.e., the amount of exuded blood protein) was decreased, the condition of the diseased area was dramatically improved. Such a result is an indirect result of verifying that the tissue exudation of the blood proteins promotes an atopic dermatitis. It shows the surprising fact that an atopic skin disease can be treated without any kinds of drugs or treatment drugs showing effectiveness, such as any kinds of steroids, steroid derivatives, drugs of immune control mechanism (for example, Elidel or Tacrolimus), and moistener ointment. The method of the present invention is a very stable method since the treatment time is very short and there are no components to be absorbed to the skin, other than distilled water (
Experimental Example 2: Example of Applying to Severe Atopic Dermatitis of Typical Child (Example Carried Out by Containing Specific Phospholipids in the Patch)
(28) A patch was applied to a partial diseased area of 7 years old boy having severe atopic dermatitis symmetrically on the whole body. Two kinds of the patches were applied.
(29) 2.5% (w/v) agar gel (thickness of 2 mm) containing 10% (w/v) DEAE-cellulose and 2.5% (w/v) agar gel (thickness of 2 mm) containing 10% (w/v) DEAE-cellulose, 10% (w/v) phospholipids extracted from pig lung, 1.5 mM CaCl.sub.2, and 5 mM citrate/citric acid (pH 5.8) were applied to different diseased areas, respectively, and then the effects were compared. The phospholipids extracted from pig lung, 1.5 mM CaCl.sub.2, and 5 mM citrate/citric acid (pH 5.8) component is a composition for suppressing an exudation of blood proteins for treating an atopic dermatitis [Korean Patent No. 0891595, Australia Patent No. 2006217261, PCT Patent No. PCT/KR2006/000638], and now Phase III clinical trials have been completed for premising as a new drug. The speed of treatment was observed by applying two kinds of the patches to the diseased area, and the profile of proteins exuded was observed. In addition, it was investigated that the added phospholipids interrupted the diffusion of the protein to the patch.
(30) As a result of applying two kinds of the patches, it was found that all the two kinds of the patches exhibited very significant treatment speed and effectiveness on the child having a typical severe atopic dermatitis. It was found that the patch containing phospholipids, calcium ion, citrate/citric acid salt absorbed the exuded proteins more effectively. It was observed that for the treatment effect, the patch containing the phospholipids extracted pig lung more stably treated the skin and then normalized the skin. It was believed that the phospholipids extracted from pig lung functions as a mild detergent to dissociate the agglomerated proteins exuded and then stimulated to the skin, so that it exhibits more excellent effect of removing an exudation. In addition, there is a possibility that citric acid contained in the composition interrupts the ion bonding that may be between the proteins, so that the exudation can be more effectively removed. It is believed that since the saturated phospholipids contained in the patch has an effect of suppressing an exudation of blood proteins, the phospholipids allow the recovery of the diseased area to be more quickly. By comparing effects of two kinds of the patches (the patch only containing DEAE-cellulose and the patch containing DEAE-cellulose, and phospholipids extracted from pig lung+1.5 mM CaCl.sub.2+5 mM citrate/citric acid (pH 5.8)), it was confirmed as an important fact that as a conclusion, the phospholipids do not interrupt exuded proteins to bond to the polar resin particles fixed in the patch.
(31) In order to obtain more quick and stable treatment effect, it is believed that drugs or components having a function of suppressing an exudation of blood proteins are preferably used together.
(32) A wet-wrapping method was used for treating an atopic dermatitis. In order to continuously apply the patch having a great quantity of water according to the present invention, it is believed that a method of applying the patch containing various lipids and components capable of compensating skin barrier may be a good method of relieving the pain of patient suffered from an atopic disease. In addition, it is believed that since it is known that ointments such as steroid or Tacrolimus have an effect of suppressing an exudation of blood proteins in addition to original anti-stress activity and immune decrease function, the increase of treatment effect can be expected when using the patch prepared by mixing a proper amount of drug capable of suppressing an exudation of blood proteins in the matrix of the patch, or when applying the patch while suppressing an exudation of blood proteins by applying the drugs capable of suppressing an exudation of blood proteins before and after applying the patch.
Experimental Example 3 : Example of Applying to Teenager Having Face Suffered from Severe Atopic Dermatitis
(33) The result was observed after applying the patch on both of the cheeks of the teenager (16 years old girl) suffered from a severe atopic dermatitis. The patient was suffered from a severe atopic dermatitis, so that the normal life could not be maintained due to a severe itching and burning sensation. An effect of the patch should be tested on the face since neutral fats are secreted in a great quantity through sebum, thereby inhibiting an effect of the patch on absorption of protein. As the patch, 2.5% (w/v) agar gel (thickness of 2 mm) containing 10% (w/v) DEAE-cellulose was applied. The patch was applied during the sleeping time after dinner, and then released before going to the school a.m. After applying the patch, the symptom were getting better every day, and at 8 days after applying the patch, the skin of face was recovered in a normal state. It was observed that the skin condition of the patient was maintained for about 20 days, and subsequently, both the cheeks were again turned red, and a slight symptom of the atopic disease was caused.
(34) From a result of SDS-PAGE, it was confirmed that a removal of exuded proteins using the patch required about 5 days averagely, and the treatment period required for 8 to 10 days in the case of the severe patient. Especially, it is thought that the amount of antibody protein was decreased and then the symptom was getting better. In conclusion, it is believed that the exuded amount of the blood proteins is directly involved in a serious and slight symptom, and also an atopic disease can be easily treated as long as various and active treatment capable of suppressing an exudation of blood proteins is carried out at the same time.
Experimental Example 4 : Example of Applying Double Gel-Type Patch Containing Resins with Different Polarities
(35) A double patch was prepared to have different polarities by applying 2.5% (w/v) agar gel (2 mm) containing 10% (w/v) CM-cellulose on 2.5% (w/v) agar gel (thickness of 2 mm) containing 10% (w/v) DEAE-cellulose (see
(36) It was believed that an amount and the type of the exuded proteins absorbed to the gel were more varied, and also clear, as compared with the case of using only DEAE-cellulose. It was also observed that an effect of treating was much faster.
Experimental Example 5 : Example of Applying to Psoriasis Patient
(37) The effectiveness of patch was observed after applying the patches with various combinations to the skin of 28 years old female having psoriasis caused on the whole body (Especially, the symptom on the limbs, legs and arms regions was worse).
(38) The following gels were applied to the patients with psoriasis, respectively for about 5 hours, and then released. Since then, the diseased areas were observed. The best effect exhibited on the psoriasis patient was 2.5% agar gel patch containing 10% (w/v) DEAE-cellulose and the patch having the worst effect was 2.5% (w/v) agar gel patch containing 10% (w/v) CM-cellulose (see
(39) a. Gel formed by only 2.5% (w/v) (thickness of 2 mm)
(40) b. 2.5% Agar gel containing 10% (w/v) DEAE-cellulose
(41) c. 2.5% (w/v) Agar gel containing 10% (w/v) CM-cellulose
(42) d. 2.5% (w/v) Agar gel containing 10% (w/v) hydroxylapatite (bipolar resin).
(43) The most interesting finding was that types of proteins exuded from the diseased areas of the psoriasis patient and atopic disease patient were different. In the case of the patient suffered from psoriasis, albumin was observed, but immunoglobulin was observed in a very small amount. It is believed that when the proteins are exuded from blood vessel, a selective exudation is carried out according to molecular weight. It can be expected that antibody proteins with larger molecular weight than that of albumin are easily not exuded. As a result, it is believed that a reason why the inflammation response is more active in the case of an atopic dermatitis can be described, and a reason why a pathologic mitosis of epidermis cell is caused rather than an inflammation response of psoriasis disease or skin lesion. According to the observations described above, it is possible to easily diagnosis psoriasis and atopic diseases using the patch of the present invention with eyes. That is, when the distinction between the atopic dermatitis and psoriasis are in confusion, the patch of the present invention can be used as diagnostic criteria. Furthermore, by using an immunological research method, researches on various proteins can be possible. From now on, the patch according to the present invention may be used for various applications, such as a research object, in addition to a treatment object.
Experimental Example 6: Example of Applying Patch on External Injury or Wound (Example of Negative Effect of Patch)
(44) The patch was applied to a cut or wound, and then effect thereof was observed. As a result, it was believed that an application of the protein absorption patch to a wound was not preferable. This is because even proteins required for blood coagulation and tissue recovery are absorbed, and after applying for 8 hours, a slight breeding is again caused. Furthermore, the speed of healing the wound was considerably slow, and also it was weak to an inflection since the wound was open. IN addition, even though the wound is close later, the scar may be marked (
Experimental Example 7 : Application of Patch Using Patch Property (Method of Using by Bonding Polar Group to Carbohydrate of Cotton Fabric)
(45) In the case of preparing and using a resin as a type of patch, it is difficult to reuse the resin such as agarose with a polar group such as DEAE-cellulose. Since a complex carbohydrate resin with a substituent (Derivatised complex carbohydrate) has a wide surface area and a high protein bonding ability, the effect can be obtained when the resin is used by fixing it in a patch in a type of gel. However, it has a disadvantage that it is a little expensive. In order to compensate such a problem, it is possible to use it by bonding various polar groups and DEAE-group to 100% cotton fabric. Since a chemically modified fabric capable of bonding protein has a good elasticity, the fabric can be used by contacting to the bend part of body, and if the absorbed proteins are effectively removed, it can be re-used repeatedly. The protein bonding ability of the fabric is a little reduced as compared with the resin for purifying proteins, but the fabric can be variously applied. Especially, the tailored treatment can be possible by further adding various drugs (for example, disinfectant, antibiotic, an antihistaminic agent, steroid, and the like) and various lipids (for example, ceramide, phospholipids, lipid mixture in a type of liposome, and the like) on a doctor's advice. When it is prepared as a type of cloth, it can be expected that the fabric can be easily used for treating a patient suffered from a whole body atopic disease.
(46) The present invention provides a method for easily preparing a fabric capable of absorbing proteins through bonding DEAE-group to a cotton fabric.
(47) The process of preparing DEAE-cotton fabric according to the present invention is as follows: 1) Drying a cotton fabric after washing it with distilled water; 2) Immersing the cotton fabric thus dried in 3M NaOH for 30 seconds; 3) Immersing the cotton fabric thus obtained in a mixed solution of 3M NaOH and 3M DEAE-Cl (diethylaminoethyl chloride) for 40 minutes; 4) Immersing the cotton fabric thus obtained in 3M DEAE-Cl; 5) Washing the cotton fabric thus obtained with distilled water; and 6) Drying the cotton fabric thus obtained.
(48) When the DEAE-cotton fabric is prepared in a bulk production as described above, the method can be possible by using the mimetic method as disclosed in
(49) The DEAE-cotton fabric prepared by using the process as disclosed above was contacted to a diseased area of a patient with an atopic disease for about 4 hours, and then absorption of exuded proteins was confirmed.
(50)
(51) As illustrated in
(52) A cotton fabric having DEAE-group or other polar groups can be used for treating an atopic disease, psoriasis, and other similar diseases. In addition, it is expected that the above cotton fabric can be used for structurally removing waste products from the skin. In some cases, it can remove specific lipids or poorly water-soluble proteins by bonding with an octyl group, a butyl group, and the like. Accordingly, in addition to an object of treatment, it can be used for an object of beauty treatment (for example, materials for beauty masks), and especially, it is economical and also eco-friendly since it can be used repeatedly.