WO2018143685A1 - Patch composition for reducing blood pressure - Google Patents

Abstract

The present invention relates to a patch composition for reducing blood pressure and, more particularly, to a patch composition comprising an agonist selected from the group consisting of an agonist of transient receptor potential cation channel subfamily V member 1 (TRPV1) and an agonist of transient receptor potential cation channel subfamily A member 1 (TRPA1) as an effective ingredient for reducing blood pressure, a patch coated with the patch composition, and a method of using the patch. Containing an agonist selected from the group consisting of an agonist of TRPV1 and an agonist of TRPA1, the patch composition of the present invention can stimulate C-fibers in the median nerve inside the wrist to effectively reduce blood pressure caused by hypertension. Because the above-mentioned effect can be elicited by contacting a patch composition with the skin, the use of the patch composition or patch of the present invention has the advantage of reducing a blood pressure very conveniently and safely, compared to preexisting oral drugs. In addition, capsaicin or mustard oil rather than expensive compounds can be used as the agonist, which enjoys the advantage of providing the patch at very inexpensive cost.

Description

Blood pressure drop patch composition

The present invention relates to a patch composition for lowering blood pressure, and specifically, among a group consisting of an agonist of TRPV1 (agonist) and agonists of transient receptor potential cation channel subfamily A member 1 (TRPA1). The present invention relates to a patch composition for lowering blood pressure, which contains a selected agonist as an active ingredient, a patch to which the patch composition is applied, and a method of using the patch.

Hypertension is one of the most common diseases in the world, and in Korea, it is a very common disease found in more than 30% of adults. Hypertension causes a variety of complications throughout the body, including coronary artery disease, stroke, and kidney failure, many of which cause serious and life-threatening problems.

About 95% of patients with hypertension correspond to essential hypertension, which has not yet been identified with exact cause. Risk factors associated with hypertension include environmental and psychological factors such as family history, drinking, smoking, aging, lack of exercise, obesity, salty eating and stress.

Until now, in order to solve such hypertension, it has been reliant on oral medications that dilate blood vessels and lower blood pressure, and drugs that inhibit blood pressure increase caused by the action of angiotensin converting enzyme by inhibiting ACE (Angiotensin converting enzyme) are mainly used. have. Such a drug administration method has a burden that the drug must be administered directly through the oral cavity and there is a problem that the risk of side effects cannot be excluded. Therefore, it is necessary to develop a method for lowering blood pressure, which is simpler and has fewer side effects than conventional oral administration drugs.

On the other hand, TRPV (transient receptor potential cation channel subfamily V) is a protein that acts as a receptor for nerve cells to receive heat stimulation. When heat stimulation occurs, the protein is activated to stimulate nerve cells, and the signals generated by the stimulus are nerves. The fibers are transferred to the brain in the head and feel hot. There are six known TRPV proteins, four of which are known to be present in skin cells. The types of TRPV are distinguished according to the temperature at which they are reacted. For example, TRPV1 reacts to a temperature of 43 ° C or higher, TRPV3 reacts to a temperature of 35 ° C or higher, and TRPV4 reacts to a temperature of 33 ° C or higher. In other words, when the temperature of the skin is above a certain temperature, the corresponding TRPV receptor is activated to feel the temperature.

Transient receptor potential cation channel subfamily A member 1 (TRPA1) is a non-selective cation channel expressed in nociceptive neurons containing TRPV1, substance P (SP), and calcitonin gene related peptide (CGRP). )to be. Many recent studies have shown that TRPA1 plays an important role in the conduction of pain caused by various stimuli. For example, TRPA1 is activated by mustards such as allyl isothiocyanate, cinnamaldehyde, allicin, cinnamon and garlic, and environmental hazards such as acrolein. TRPA1 is known to contribute to the pain induced by high threshold mechanical stimulation (Kwan et al., 2006) and cold stimulation below 17 ° C. Recently, cold hypersensitivity and mechanical damage caused by inflammation and nerve damage It is also reported to be involved in hypersensitivity. TRPA1 is reported to be expressed in sensory neurons containing TRPV1 and neuropeptides, suggesting that TRPA1 will most likely be expressed in C-fibers.

The present inventors, unlike the existing techniques related to hypertension, can be more easily used in real life, and studied a method of reducing the blood pressure effectively in the state of Korean medicine in a hypertension state. In particular, it was intended to develop a method of contacting the skin more easily without ingesting it in the form of food or injecting the drug in the form of an injection, etc., and aimed at the development of a suitable patch formulation.

As a result of attempting various studies, it was newly discovered that the blood pressure can be effectively lowered by stimulating C-fiber of medial nerve of medial cuff using agonists of TRPV1 or TRPA1. Using the patch composition containing the agonist of or TRPA1 and the patch coated with the patch composition, it was confirmed that the blood pressure can be effectively lowered through a simple and safe method of attaching the patch to the skin, thereby completing the present invention.

Therefore, the main object of the present invention is to provide a patch composition that can effectively lower blood pressure in a high blood pressure state more simply and safely in real life.

Another object of the present invention to provide a patch for lowering blood pressure to which the patch composition is applied.

Another object of the present invention is to provide a method of effectively using the patch.

According to an aspect of the present invention, the present invention provides an agonist selected from the group consisting of agonists of TRPV1 (agonist) and agonists of transient receptor potential cation channel subfamily A member 1 (TRPA1). Provided is a blood pressure lowering patch composition containing the active ingredient.

In the patch composition of the present invention, the agonist of TRPV1 is capsaicin, and the agonist of TRPA1 is a mustard oil.

In the patch composition of the present invention, it is preferable to contain the agonist of TRPV1 at 0.001 to 20% by weight.

In the patch composition of the present invention, the agonist of TRPA1 is preferably contained in an amount of 0.001 to 20% by weight.

According to another aspect of the present invention, the present invention provides a patch for lowering blood pressure, wherein the patch composition is applied to a support.

According to another aspect of the present invention, the present invention is a method for effectively using the patch, characterized in that by attaching the patch to the skin of the inner bleeding site so that the agonist included in the patch stimulates the internal vascular blood Provides a way to use the patch.

The patch composition of the present invention contains an agonist selected from the group consisting of agonists of TRPV1 and agonists of TRPA1, thereby stimulating C-fiber nerves (C-fiber) of the medial median nerve of the cuff to effectively lower the blood pressure in the hypertensive state. Since the patch composition may have the same effect as the method of contacting the skin, the patch composition or the patch of the present invention has an advantage of lowering blood pressure very easily and safely compared to conventional oral drugs. In addition, it is possible to use capsaicin or mustard oil, rather than an expensive compound, as an agonist.

1 is a graph showing the results of experiments on the blood pressure lowering effect of agonists of TRPV1 (capsaicin) or agonists of TRPA1 (mustard oil) using an animal model.

Figure 2 shows the internal vascular site located inside the wrist of a person.

Figure 3 is a graph showing the results of experiments on the blood pressure lowering effect of the agonist (capsaicin) of TRPV1 through clinical trials.

The present invention uses C-fiber of medial nerve of medial cuff using agonists of TRPV1 (transient receptor potential cation channel subfamily V member 1) or TRPA1 (transient receptor potential cation channel subfamily A member 1) of neurons. Stimulation was based on a new discovery that blood pressure drops.

TRPV1 is a protein that acts as a receptor for neurons to receive thermal stimuli. It is registered in Genbank as Accession number NP_061197, and consists of the amino acid sequence shown in SEQ ID NO: 1.

TRPA1 is a non-selective cation pathway protein expressed in pain sensory nerves and is registered in Genbank as Accession number NP_015628 and consists of an amino acid sequence as shown in SEQ ID NO: 2.

Stimulating the C-fiber nerves of the medial median nerve of the cuff using such agonists of TRPV1 or TRPA1 can be achieved by contacting these agonists to the skin.

Capsaicin or resiniferatoxin may be used as an agonist of TRPV1, and a compound known as an agonist of TRPV1 may be used, and a mustard oil or 4-oxo may be used as an agonist of TRPA1. 2-nonoral (4-oxo-2-nonenal), icilin, polygodial, hepoxilin can be used, and other compounds known as agonists of TRPA-1 can be used. Can be. Among the above agonists, in particular, capsaicin is used as the agonist of TRPV1, and mustard oil is used as the agonist of TRPA1, which is preferable in view of blood pressure lowering effect, side effects, easy availability of materials, and economical efficiency.

In order to stimulate the C fiber nerve (C-fiber) of the medial inner medial nerve of the cuff by contacting the skin with the agonist of TRPV1 or the agonist of TRPA1, a patch may be used.

Therefore, the present invention provides a patch composition for applying to such a patch.

The patch composition of the present invention is characterized by containing an agonist selected from the group consisting of agonists of TRPV1 and agonists of TRPA1 as an active ingredient.

The patch composition of the present invention may be made of only one agonist selected from agonists of TRPV1 and agonists of TRPA1 as an active ingredient, may comprise both agonists of TRPV1 and agonists of TRPA1. Since two types of agonists stimulate different receptor proteins, it may be desirable to include all of them for a more effective blood pressure drop.

The agonist of TRPV1 in the patch composition of the present invention may be contained in 0.001 to 20% by weight of the total weight of the composition. This is a content that can expect a blood pressure lowering effect through sufficient stimulation of the patch composition during skin contact, more preferably 0.01 to 10% by weight in terms of sufficient stimulation of the receptor protein, reduced discomfort due to skin contact, economics, etc. It is good that it is good, More preferably, it is 0.1-2 weight%.

The agonist of TRPA1 may also be contained in 0.001 to 20% by weight of the total weight of the composition for the same reason, more preferably 0.01 to 10% by weight, more preferably 0.1 to 2% by weight.

Since the two types of agonists stimulate different receptor proteins, it is preferable to apply the same content even when both agonists of TRPV1 and agonists of TRPA1 are contained.

The patch composition of the present invention may comprise a diluent or excipient for formulation in addition to the agonist. The diluent may be a solvent capable of dissolving or dispersing the agonist, and water, a buffer, oil, and the like may be used. As an excipient, a polymer capable of increasing the skin adhesion of the patch composition may be used. As the polymer, a polymer forming a hydrophilic gel, a tape, or a film may be used. Such polymers include polyalkylvinylether-maleic acid copolymers, poloxamers, polyvinylpyrrolidones, vinylpyrrolidone-vinylacetate copolymers, polyethylene glycols, polypropylene glycols, polyacrylic acids, sodium polyacrylates or copolymers thereof, poly Synthetic polymers such as vinyl alcohol, polyacrylate, polymethacrylate, polyquaternium, and carboxypolymethylene series; Collagen, galactomannan; Starch, starch derivatives and hydrolysates; Cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose; Colloidal silicic acid; And sugars such as natural compounds such as lactose, saccharose, fructose and glucose or derivatives thereof. As a solvent of these polymers, water or ethanol alone or a mixture thereof is mainly used, and other solvents, for example, ethyl acetate, methylene chloride, isopropyl alcohol, acetonitrile alone, or a mixture thereof may be controlled. It may be.

The patch composition of the present invention may further include a filler, an anticoagulant, a lubricant, a humectant, a fragrance, an emulsifier, a preservative, and the like in addition to the agonist, diluent, and excipient as described above, to provide rapid, sustained or delayed release of the active ingredient.

The patch composition of the present invention can be used as a patch itself in the form of a film, a tape or a gel (gel), but preferably applied to a support to be used in the form of a patch. Such a support may be a nonwoven fabric made of polyester, polyvinylchloride, polyethylene, polypropylene, rayon or cotton, or a water-insoluble polymer, or a polymer partially soluble in water. Polymers that can be used include cellulose acetate phthalate, cellac, polyvinylacetate, ethyl cellulose, polymethyl methacrylate, methacryloylethyl betaine / methacrylate copolymer, methacrylic acid copolymer, aminoalkyl methacrylate airborne Coalescence alone or mixtures thereof.

The patch may be prepared by applying the patch composition of the present invention to the upper surface of the support to form a formulation layer, and it is preferable to further form a release layer on the upper surface of the formulation layer so that the formulation layer is protected before use. Do. As such a peeling layer, the film by which silicone mold release processes, such as polyester and a polypropylene, were used can be used.

When the patch of the present invention is attached to the skin close to the median nerve, that is, the inner skin of the arm, the agonist of TRPV1 or the agonist of TRPA1 contained in the patch stimulates the C fiber nerve (C-fiber) of the median nerve to effectively increase blood pressure. You can descend. More preferably, it is preferable to use the method of contacting each agonist to the skin of the inner vascular site located in the median nerve for more effective blood pressure drop. Internal bleeding is anatomically 5-6 cm away from the wrist in the median nerve of the arm, and according to Bone Medicine, it corresponds to 2/12 villages from the wrist when the total length between the wrist and elbow joint is 1 Say where you are.

Hereinafter, the present invention will be described in more detail with reference to Examples. Since these examples are only for illustrating the present invention, the scope of the present invention is not to be construed as being limited by these examples.

Example 1 Animal Experiment

Mice were used as animal models and their effects on blood pressure were investigated when capsaicin or TRPA1 agonist was used as a TRPV1 agonist and mustard oil was stimulated.

Capsaicin and mustard oil were dissolved in separate physiological saline solution to prepare 0.5% (w / v) solution.

Sprague-Dawley rats weighing about 300 g were divided into three groups and physiological saline (control), capsaicin 0.5% (w / v) solution (experimental group 1) or mustard oil 0.5% (w / v) 50 μl of solution (Experimental Group 2) was injected into a stress bag to induce stress hypertension, and blood pressure was measured every 10 minutes for 120 minutes.

As a result, as shown in the graph of Figure 1, the control group significantly increased the blood pressure to 160mmHg over 120 minutes, whereas the experimental group 1 (Capsaicin into NP) and the experimental group 2 (Mustard oil into NP) is significantly suppressed the increase in blood pressure Appeared. These results indicate that stimulating TRPV1 or TRPA1 with capsaicin or mustard oil, respectively, is very effective for hypertension.

Example 2. Clinical Trials

Clinical trials were performed on four patients with hypertension who had blood pressures of 140 to 160 mmHg.

Intravascular percutaneous nerve stimulation (TENS) was performed for 30 minutes to observe the change of blood pressure in hypertensive patients (control group), and 1% capsaicin was applied to the median nerve area including intravascular blood (experimental group). As a result of observing the blood pressure change for 2 hours in the patient, as shown in the graph of FIG. 3, the experimental group to which capsaicin was applied showed a similar pattern to that of the control group subjected to endothelial percutaneous neural stimulation (TENS) and showed a superior blood pressure lowering effect. .

This indicates that the method of stimulating TRPV1, as shown in animal experiments, is very effective in hypertension.

Since the patch composition of the present invention can effectively lower the blood pressure in the hypertensive state by skin contact of the internal acupuncture points, the patch composition can be used for the manufacture of a patch product for use in lowering blood pressure by attaching to the skin of the internal acupoints. In particular, it is possible to produce a low-cost product because it can exert an excellent effect without using expensive compounds as an active ingredient, it is also easy to mass production.

Claims (6)

An antihypertensive patch composition comprising an agonist selected from the group consisting of agonists of TRPV1 (transient receptor potential cation channel subfamily V member 1) and agonists of transient receptor potential cation channel subfamily A member 1 (TRPA1) as an active ingredient. The method of claim 1, The agonist of TRPV1 is capsaicin, The agonist of TRPA1 is a blood pressure lowering patch composition, characterized in that the mustard (mustard oil). The method of claim 1, A patch composition for lowering blood pressure, comprising an agonist of TRPV1 at 0.001 to 20% by weight. The method of claim 1, A patch composition for lowering blood pressure, comprising an agonist of TRPA1 at 0.001 to 20% by weight. A blood pressure lowering patch, wherein the composition of any one of claims 1 to 4 is applied to a support. As a method for using the patch of claim 5, The patch is attached to the skin of the inner vascular site, the patch using the agonist included in the patch to stimulate the internal vascular.

Images