HYDROGEL PATCH COMPOSITION USING ARNICA FERMENTED EXTRACT

The present invention relates a novel formulation of a hydrogel or cataplasma patch containing an Arnica extract, wherein a composition for a hydrogel or cataplasma patch containing an Arnica extract, includes 30% to 70% by weight of water as a solvent based on the total composition, 20% to 60% by weight of a polyhydric alcohol based on the total composition, and a partially neutralized polyacrylic acid product as a polymer for forming a polyhydric alcohol gel, the composition being effective for suppressing inflammation, alleviating pain or alleviating hot plate pain.

BACKGROUND OF THE INVENTION

The present invention relates to an anti-inflammatory analgesic composition in the form of a transdermal absorption preparation capable of exhibiting therapeutic efficacy on sprains, bruises, muscle pain, joint pain, fracture pain, back pain, stiff shoulders, neuralgia, rheumatic pain, skin itchiness, insect bites, or chilblains, using an Arnica fermented extract (hereinafter also referred to as an Arnica extract).

Patches are classified into cataplasma, which is a moisture-containing poultice, and plaster, which is a solid preparation. Due to the nature of the preparation, cataplasmas include a separate adhesive layer with low elasticity in addition to an adhesive layer containing the drug. Plasters, which contain an acrylic resin or the like, are products that do not contain moisture, so they have the disadvantage of being more skin-irritating than cataplasmas.

Hydrogel patches are being studied as a transdermal absorption preparation to overcome the disadvantages of conventional cataplasmas, plasters, or cream-type formulations.

The history of homeopathic therapy began with Samuel Hahnemann, an 18th-century German physicist who assumed that “like cures like.” In the 19th century, Hugo Paul Friedrich Schultz postulated that taking a small amount of toxin would have opposite effects compared to taking a large amount of toxin. He demonstrated in 1888 that mild concentrations of yeast toxin increased yeast growth a hundredfold. Thus, these different observations were formulated by Arndt in 1988 as an early pharmacological law of homeopathic effectiveness.

Arnica montana refers to a flower of Arnica montana, a plant of Asteraceae family of Asterales order, and the plant grows in grasslands of highlands and is 20 to 30 cm tall. The leaves emerge from the roots, spread in all directions, and are foliated oppositely each other on the stem. The branches split at the end and have 1 to 3 heads. The flowers bloom in yellow from June to July, are 6 to 8 cm in diameter, and are densely covered with pili and hairs. The flowers and rhizomes have a bitter taste and contain an essential oil and a resin. The flowers and rhizomes were used as an all-purpose folk medicine in Europe since ancient times. In oriental medicine, it is also used for stimulating in angina, dilating blood vessels, relieving vascular spasm, and a hemostatic agent treating bruises and hemorrhoids. Among various organs or parts (e.g. leaves, bark, branches, flowers, roots, fruits, stems, etc.) of the Arnica montana, the whole plants are used in the present invention.

An Arnica extract, which is a purely vegetable homeopathy therapeutic agent containing an Arnica extract, is topically used for pain treatment and not orally administered in generally due to the potential toxicity. Gels and ointments for topical use are available. The active ingredients include sesquiterpene lactones, flavonoids, and volatile oils.

For example, Korean Patent Publication No. 10-1321031 discloses a homeopathic preparation including an Arnica extract, which is a tincture preparation blended with ethanol. There is no mention of a patch. On the other hand, Korean Patent Publication No. 10-2021-0135034 relates to a cosmetic composition for reinforcing the skin barrier, but there is no mention of a patch here either, and a lotion or oil blended with alcohol is disclosed.

CHARACTERISTICS OF THE PRESENT INVENTION

Among patches, the primary functions of hydrogel patches are mostly the cooling and soothing effects referred to cryotherapy (general use of low temperature in treatment). The primary effect of cold in pain management is to lower the temperature of damaged tissues, which reduces the metabolic rate of the tissues and helps the tissues survive after damage. In addition, the cooling effect may prevent internal bleeding caused by the constriction of peripheral blood vessels.

The Arnica hydrogel cataplasma patch formulation provided by the present invention provides a unique dual action (cool and hot sensations). Just like the heating effect by the stable ether vanillyl butyl ether (VBE), the patch formulation of the present invention directly stimulates the receptors of the nerve endings to create a feeling of heat. There is no actual change in the skin temperature, but instead, the neurotransmitter of the nerve acts to produce a perceived heating effect.

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SUMMARY OF THE INVENTION

The object of the present invention is to provide an anti-inflammatory analgesic composition exhibiting therapeutic efficacy on sprains, bruises, muscle pain, joint pain, fracture pain, back pain, stiff shoulders, neuralgia, rheumatic pain, skin itchiness, insect bites, or chilblains, using an Arnica montana fermented extract.

The present invention develops a hydrogel cataplasma formulation with water as the main component, so that it has excellent adhesiveness, allows a large amount of drug to be penetrated for a long time, and does not affect activities after the patch is attached to the skin.

After gel cream formulations are applied to the skin, clothing or other things are attached to the skin, hindering long-term drug penetration and limiting the patient's activities. Dry patches, the adhesiveness is low because the surface is oily, and especially when the patient's skin pores sweat or water, the adhesiveness completely disappears. This also limits the patient's activities.

However, the present invention achieves the above and other objects by the description below.

In order to achieve the above object, the present invention has the following structural features.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Definition

The term “Arnica extract” herein does not have a particular specifications, and includes, for example, Arnica montana extracts that are commercially available for ISO-certified supplements, foods, beverages, cosmetics, or pharmaceuticals.

The present invention relates to a hydrogel or cataplasma patch formulation. However, it is to be noted that in the following, the hydrogel or cataplasma patch formulation is also sometimes expressed as a gel, hydrogel, hydrogel patch, or patch. For reference, a hydrogel refers to a gel state, and a cataplasma patch refers to a patch in which a hydrogel is applied to a nonwoven fabric, or the like.

The total amount of the base herein refers to the total weight of the composition.

The present invention provides a pharmaceutical composition in the form of a hydrogel or cataplasma patch including: a pharmaceutically active ingredient; a partially neutralized polyacrylic acid product as a gel-forming agent; a combination of one or more crosslinking agents selected from the group consisting of aluminum salts, magnesium salts, and calcium salts and an acid; and 30% to 70% by weight of water.

a) Active Ingredient

In the pharmaceutical composition of the present invention, the active pharmaceutical ingredient (API) includes an Arnica extract, and other ingredients that may be combined are not particularly limited. Preferred APIs include anti-inflammatory analgesics, and for example, loxoprofen, flurbiprofen, ketoprofen, lidocaine, diclofenac, or pharmaceutically acceptable salts thereof may be combined with the Arnica extract.

The APIs may be used in their therapeutically effective amounts, including the Arnica extract, and are not particularly limited. For example, the Arnica extract may be included in an amount of 0.1% to 5.0% by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention includes a partially neutralized polyacrylic acid product as a gel-forming agent. When a partially neutralized polyacrylic acid product is used as a gel-forming agent, the API is not precipitated from the hydrogel and may provide excellent stability even when stored for a long period of time. Examples of the partially neutralized polyacrylic acid product may include a commercially available powdered partially neutralized polyacrylic acid product manufactured by Nippon Pure Chemical Industries, Ltd. (trade name “ARONVIS AH-105”), a powdered sodium polyacrylate manufactured by Nippon Pure Chemical Industries, Ltd. (trade name “ARONVIS S”), a polyacrylic acid aqueous solution manufactured by Nippon Pure Chemical Industries, Ltd. (concentration 20% by weight, trade name “JURYMER AC-10H”), and a powdered cross-linked polyacrylic acid manufactured by Nippon Pure Chemical Industries, Ltd. (trade name “JUNLON PW-110”). These may be used alone or in combination of two or more. The amount to be used is preferably 1% to 30% by weight based on the total amount of the base (total composition), and more preferably 3% to 15% by weight.

When the use amount of water-soluble polyacrylic acid and/or a salt thereof is less than 1% by weight, it rarely contributes to improving the skin adhesiveness of the obtained base or the gel strength of the solid. In addition, when it exceeds 30% by weight, there are cases where the hardness and adhesiveness of the obtained base are unbalanced.

The base for the patch of the present invention contains a polyhydric alcohol as an essential component as a dispersing agent, and the polyhydric alcohol also serves as a moisturizing agent or a water-retaining agent. Specific examples of polyhydric alcohols that are suitably used include, for example, glycerin, sorbitol, mannitol, xylitol, ethylene glycol, diethylene glycol, 1,3-propanediol, 1,4-butanediol, polyethylene glycol, dipropylene glycol, propylene glycol, butylene glycol, polypropylene glycol, hexylene glycol, and 1,2-hexanediol. The use amount thereof is usually 1% to 60% by weight, preferably 5% to 60% by weight, more preferably 20% to 60% by weight, and even more preferably 20% to 40% by weight, based on the total amount of the base. When the use amount is less than 1% by weight, the moisture evaporates from the obtained base so that the base is dried, and the drug may precipitate into the base. In addition, when it exceeds 60% by weight, there are cases where the hardness and adhesiveness of the obtained base are unbalanced.

d) Organic Acid Having a Hydroxyl Group or a Salt Thereof

In the pharmaceutical composition of the present invention, an organic acid having a hydroxyl group or a salt thereof may be used in combination according to the required properties. Examples of the organic acid having a hydroxyl group or a salt thereof, from the viewpoint of skin irritation or safety, may include tartaric acid, acetic acid, propionic acid, isobutyric acid, caproic acid, caprylic acid, lactic acid, maleic acid, succinic acid, tartaric acid, methanesulfonic acid, citric acid, glycolic acid, gluconic acid, pyruvic acid, oxalic acid, phthalic acid, salicylic acid, benzoic acid, acetylsalicylic acid, ethanesulfonic acid, propylsulfonic acid, butanesulfonic acid, and alkali metal salts thereof. Particularly preferred are tartaric acid, citric acid, malic acid, and alkali metal salts thereof. For example, tartaric acid is preferred also in the sense the gel-hardening speed is accelerated by combined use with aluminum hydroxide or aluminum glycinate.

The base for patch of the present invention is characterized in that it is used in an aqueous system. As water, water such as purified water is usually used. The specific amount of water used is determined according to the characteristics required for the patch base, and is usually 10% to 85% by weight. According to an example, water may be included in an amount of 30% to 70% by weight based on the total amount of the composition, preferably 35% to 60t % by weight, and more preferably 35% to 50% by weight.

In particular, when water and a polyhydric alcohol are mixed at a certain content ratio, patch formation is excellent, and an example of this may be a combination of 30% to 70% by weight of water and 20% to 60% by weight of a polyhydric alcohol.

The base for patch of the present invention may further be mixed with a long-chain fatty acid and/or an ester thereof depending on the purpose. This is used as a hydrophobic additive mixed in the base, as a dissolution aid for drugs, or to improve the percutaneous absorbability of an API. As the long-chain fatty acid and/or ester thereof, oleic acid, linoleic acid, linolenic acid, myristic acid, and esters thereof are preferably used in terms of safety and effectiveness.

The use amount thereof is preferably 0.1% to 20% by weight, more preferably 1% to 10% by weight based on the total amount of the base. When the use amount is less than 0.1% by weight, it rarely contributes to improving the solubility of the hydrophobic additive or drug, and in some cases, the additive or drug may be precipitated into the base, or the percutaneous absorbability of the drug may decrease.

The chelating agent may be edetic acid or a salt thereof, and may be present in an amount of 0.2% to 3% by weight based on the total weight of the composition.

h) Other Ingredients

In addition to the above ingredients, the base for patch of the present invention may be mixed with one or more types of additives commonly used in patches, i.e., other ingredients such as a fragrance, an antioxidant, an antiseptic, an emulsifier, an inorganic powder, a penetration enhancer and the like, in order to improve the quality at the time of use.

As these other ingredients, one or more may be selected from the group consisting of fragrances such as of L-menthol, DL-camphor, eucalyptol, peppermint oil, thymol, peppermint oil, castor oil, eucalyptus oil, and lavender oil; warming sensation agents such as a red pepper extract and a prickly ash extract; antioxidants such as butylated hydroxytoluene and butylated hydroxyanisole; preservatives such as methyl parahydroxybenzoate and propyl parahydroxybenzoate; emulsifiers; and inorganic powders such as kaolin, titanium oxide, and anhydrous silicic acid. As the penetration enhancer, one or more may be selected from the group consisting of isopropyl myristate, lauryl alcohol, propylene glycol monolaurate, oleic acid, polyoxyethylene lauryl ether, diethylene glycol monoethyl ether, and isostearyl glyceryl ether.

Specific examples of the mixing ratio of these fragrances to inorganic additives, and the like, are typically 1% to 20% by weight each based on the total amount of the base for patch.

The present invention is characterized by the composition, and the method of preparing the base for patch of the present invention is not particularly limited.

Generally, the active ingredient Arnica extract and water are weighed in percentage by weight of the example and stirred (solution A). After dissolving water-soluble polyacrylic acid in water (solution B), sodium edetate and an acid are added to solution B, and the resulting mixture is stirred (solution C) Solution A is added to solution C and mixed (solution D). A separate mixture prepared by dissolving glycerin, a dissolution aid, a penetration enhancer, a colorant, and a viscosity modifier (solution E) is added to solution D, and then dispersed for about 30 minutes. The obtained mixture is deposited between a polyethylene terephthalate film and a nonwoven fabric by adjusting the thickness to achieve a target weight. After maturation, the pharmaceutical composition in the form of a hydrogel patch was prepared by cutting (70 cm2/sheet).

Purpose of mixing
Ingredient
Example 1 (wt %)

ingredient

linking

agent

modifier
cellulose

Organic acid
Tartaric acid
0.30

agent

Water
Purified water
50.105

Test Example 1. Study of Anti-Inflammatory Therapeutic Effects

A test for verifying the inflammation inhibitory therapeutic effect and the inflammatory disease marker inhibitory effect of Arnicare Gel® (Boiron Inc., France) and patches was performed using a carrageenan-induced inflammation mouse animal model. Arnicare Gel® is a commercially available product and serves as the control group in the present test.

Experimental Method

Experimental Results

In a mouse model in which edema was induced, a decrease in edema was confirmed in terms of the changes in the thickness in the two formulations, Arnicare Gel® (Boiron Inc., France) and the patch formulation. In addition, the results of the analysis of the tissue photographs collected after the experiment also confirmed the efficacy that the inflammatory cell infiltration was decreased more in the mouse tissues of the group treated with the patch formulation compared to the other group.

Test Example 2. Study of Analgesic Therapeutic Effects

A hot plate pain alleviation validation test was conducted to analyze the analgesic effects of the gel formulation and hydrogel patch formulation containing the Arnica montana extract.

Experimental method

Experimental Results

FIG. 6 shows the pain alleviating effect of the Arnica patch according to the pain score. When the pain score ratio of the treatment group to the control group is compared, it can be confirmed that there was a significant pain alleviating effect in the 1-hour and 2-hour patch formulation application groups.

Patch

Control
Patch 1 h
2 h
Gel 1 h
Gel 2 h

score

ratio

of mean (SEM)

Test Example 3. Formulation Stability

Other compositions were the same as Example 1, and only the contents of purified water and glycerin were adjusted to test the stability of the formulation.

Example 2: 30% by weight of water, 60% by weight of glycerin

Example 3: 40% by weight of water, 50% by weight of glycerin

Example 4: 60% by weight of water, 30% by weight of glycerin

Example 5: 70% by weight of water, 20% by weight of glycerin

As a result of the experiment, no patch was formed in Example 2, and the formulation stability failed to meet the standard. Examples 1, 3, and 4 exhibited excellent patch formation and adhesiveness, and were evaluated as Excellent in terms of skin irritation according to the Dermatest results. Example 5 formed a gel but had no adhesiveness, so it was not suitable as a patch.

The composition of the hydrogel or cataplasma patch formulation of the present invention can enable to fundamentally avoid the disadvantages of conventional cataplasmas and plasters, such as the problem of skin irritation, the toxicity problem due to residual solvents and/or unreacted monomers, and the problem of long-term crosslinking.

In addition, the composition of the hydrogel or cataplasma patch formulation of the present invention can evenly distribute a high concentration of drug while exhibiting excellent transdermal permeability without problems such as crystal precipitation during manufacturing and storage.

In addition, the present invention can provide an anti-inflammatory and analgesic composition containing a powder or extract of a fermented extract of Arnica as an active ingredient, which can alleviate pain through anti-inflammatory and analgesic properties in areas of sprains, bruises, muscle pain, joint pain, fracture pain, back pain, stiff shoulders, neuralgia, rheumatic pain, skin itchiness, insect bites, or chilblains.