KR102512267B1 - Oral film containing a composition including low molecular weight collagen, elastin, hyaluronic acid and boswellia extract as active ingredients - Google Patents

Abstract

In the present invention, disclosed are an oral film and stick jelly containing a composition including low-molecular collagen, elastin, hyaluronic acid and a Boswellia extract as active ingredients. More specifically, the present invention relates to an oral dissolving film, oral mucosal adhesive film and stick-type jelly containing a composition containing Boswellia extract having excellent antioxidant and anti-inflammatory effects as an active ingredient while using a mixture of collagen, elastin, and hyaluronic acid forming the dermal layer of skin as a film forming agent.

Description

An oral film containing a composition containing a composition including low molecular weight collagen, elastin, hyaluronic acid and boswellia extract as active ingredient ingredients}

The present invention relates to an oral film and stick jelly containing a composition including low-molecular collagen, elastin, hyaluronic acid, and a Boswellia extract as an active ingredient, and more specifically, a mixture of collagen, elastin, and hyaluronic acid constituting the dermal layer of the skin as a film forming agent. It relates to an oral dissolving film, an oral mucosal adhesive film, and a stick-type jelly containing a composition including a boswellia extract, which is effective in preventing and improving symptoms of osteoarthritis, as an active ingredient.

The main causes of skin aging are aging and external factors such as ultraviolet rays, fine dust, and stress. As age increases, the function of fibroblasts and the number of cells decrease. In addition, loss of moisture in skin cells causes changes in the structure of the stratum corneum, which causes aging.

Skin aging is largely divided into endogenous aging caused by internal factors such as age increase and stress, and extrinsic aging induced by external environments such as ultraviolet rays and environmental pollution. Among them, the most prominent cause of extrinsic aging is photoaging caused by ultraviolet rays. Sunlight reaching the earth is largely divided into UV (Ultrabiolet), visible light, and infrared regions, and among these, UV acts as the biggest factor in photoaging, although the amount reaching the surface is small. Ultraviolet rays generate active oxygen and give strong oxidative stress to skin cells, which depletes the cellular antioxidant defense mechanism. In cells whose antioxidant defense system is damaged by ROS (Reactive Oxygen Species), the lipids in the cell membrane are oxidized, preventing the cell from functioning normally.

Reactive oxygen species (ROS) generated by UV randomly attack skin cells, and fibroblasts that synthesize collagen are also attacked. Fibroblasts synthesize collagen under the control of various growth factors and cytokines. Collagen is a protein that occupies the largest amount in the dermal tissue of the skin, and together with elastin and hyaluronic acid, is responsible for the skeleton of the skin to maintain elasticity. However, in skin damaged by UV, skin elasticity is reduced because fibroblasts are oxidized by ROS and cannot properly synthesize collagen. UV exposure degrades collagen in the skin and inhibits collagen synthesis, reducing skin elasticity, creating wrinkles, and reducing skin resilience. This is an ingredient that must be ingested to maintain the elasticity of the skin of the middle-aged because the amount of UV irradiation is increasing every year due to the collapse of the stratospheric ozone layer due to environmental pollution and the increase in leisure activities.

Therefore, due to factors such as ultraviolet rays, fine dust, stress, and aging, the three components constituting the skin's dermis are insufficient, resulting in a decrease in skin elasticity. When the three components constituting the dermis are transported through the oral mucosa, the difference in absorption is higher than that of oral administration, and the absorption rate is much higher because digestive juice, first pass of the liver and liver metabolism can be avoided.

However, since the oral dissolving film must be small in size for easy intake and thin in order to rapidly disintegrate in the oral cavity, there is a limitation that it cannot be manufactured with a certain weight or more, and it is well mixed with effective drugs. In order to maintain the strength and solubility suitable for handling the film, a certain amount or more of the polymer must be included in the film, so the content of the active ingredient is inevitably lowered.

Therefore, water-soluble film formers (pullulan, gelatin, pectin, low-viscosity pectin, hydroxypropylmethylcellulose, low-viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, Propyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low-viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soybean The need to develop substances that can replace protein isolates, zein, lebanon, elcinan, gluten, gum acacia, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, and agar) is emerging It became.

Boswellia is a tree sap collected from the bark of a Boswellia tree, and only less than 500g of Boswellia can be collected from one tree per year, so it is highly scarce. In Korea, frankincense has been called frankincense since ancient times, and it is a precious substance in India as well as in the Orient. Recently, boswellia has been attracting attention in relation to joint health. Boswellic acid in boswellia inhibits the production of inflammatory substances in the body, helps maintain cartilage function, and manages pain in the early stages of arthritis as well as degenerative arthritis. It is known to help Boswellia is recorded in Indian traditional Ayurveda medicine as being used for chronic inflammation and arthritis, anti-inflammatory, bruises, respiratory diseases and diarrhea, and is known to have been continuously used for pain relief and inflammation treatment due to its high anti-inflammatory analgesic effect.

Boswellic acid (β-Boswellic acid, Aceryl-β-Boswellic acid, 11-keto-β-Boswellic acid, Acetyl-11-keto-β-Boswellic acid) Four ingredients have been studied as main anti-inflammatory ingredients, and antioxidants in the form of terpenoids are effective. Of these, boswellic acid has recently been studied as a functional substance that exhibits anti-inflammatory and analgesic effects of boswellia.

Boswellic acid inhibits the activity of 5-lipoxygenase (5-LO), thereby suppressing the production of inflammatory response substances and cytokines such as TNF-α and IL-6, which are inflammation-inducing substances in the body, and promoting the production of proteins constituting cartilage tissue It has been studied to show the activity of inhibiting cell death of chondrocytes and chondrocytes.

Inflammatory response is one of the immune system responses of living tissues to immunological stimuli such as mechanical injury, external physical factors such as temperature and radiation, chemical factors such as poisons including strong acids, pathogenic microorganisms and allergies, and repairs damaged tissues. It is a mechanism that wants to play or play. In the mechanism of tissue regeneration in vivo, macrophages play a very important role in regulating inflammatory responses and immune functions. Macrophages activated by external antigens and stimuli secrete large amounts of growth factors, cytokines, prostaglandin E2 (PGE2), lipid mediators, and nitric oxide. It not only causes immune cells to gather, but also promotes the secretion of inflammatory cytokines such as interleukin-6. In addition, when microorganisms invade, macrophages release or produce reactive oxygen intermediates, hypochlorite, nitric oxide, myeloperoxidase, neutral protease, and lysosomal hydroxylase, which cause toxic reactions to the invaded microorganisms, toward the microorganisms. It also directly damages tissues.

These inflammatory reactions are divided into acute and chronic over time and can lead to boils, carbuncles, stomatitis, scrofula, inflammatory bowel disease, gastric ulcer, cystitis, tonsillitis, conjunctivitis, arthritis, etc. has a risk

Therefore, the present inventors can absorb boswellic acid, which can coexist in the digestive system of the human body and exhibit excellent anti-inflammatory effects in the oral cavity, intestines, and joints, through the oral mucosa while using the material constituting the skin dermal layer as an oral film forming agent. development of oral film and stick jelly for food.

Patent Registration No. 101843750 (Patent registration date 2018.03.26.) Patent Registration No. 102291180 (Patent registration date 2021.08.12.) Korean Patent Registration No. 10-1843750 relates to an oral disintegrating film for removing bad breath containing wild ginseng concentrate and a method for manufacturing the same. For removing bad breath, including wild ginseng concentrate, which can easily ingest active ingredients of wild ginseng, is easy to carry and is convenient to use, and can maintain oral cleanliness by effectively removing odors in the mouth that occur after eating or on an empty stomach. An orally disintegrating film and a manufacturing method thereof are described. Korean Patent Registration No. 1022911800000 relates to a film-type preparation that disintegrates quickly in the oral cavity, and can provide safe intake, stress relief, and convenience to companion animals who have difficulty taking tablets or emergencies due to pulmonary edema at home. The effect of increasing the efficiency of animal management by ingesting furosemide without this reluctance is described.

An object of the present invention is to provide an oral dissolving film containing a composition including low-molecular-weight collagen, elastin, hyaluronic acid and Boswellia extract as an active ingredient.

Another object of the present invention is to provide an oral mucosal adhesive film containing a composition including low-molecular-weight collagen, elastin, hyaluronic acid and Boswellia extract as an active ingredient.

Another object of the present invention is to provide a stick-type jelly for food containing a composition including low-molecular-weight collagen, elastin, hyaluronic acid and Boswellia extract as an active ingredient.

The above and other objects of the present invention can all be achieved by the present invention described in detail below.

oral dissolving film

The mouth-dissolving film according to the present invention is characterized in that it contains, as an active ingredient, a composition containing a water-soluble film-forming agent composed of low-molecular-weight collagen, elastin, and hyaluronic acid, and a Boswellia extract.

The weight composition ratio of low molecular weight collagen:elastin:hyaluronic acid constituting the water-soluble film forming agent is preferably 10:0.5:3 parts by weight based on 100 parts by weight of the total composition for effective oral mucosal permeability.

In addition, the low-molecular-weight collagen can be both animal and vegetable collagen in its kind, and in the case of molecular weight, hydrolyzed collagen with a molecular weight of 1 to 2 KDa or less is preferable for effective oral mucosal penetration.

Oral mucosa adhesive film

The oral mucosal adhesive film according to the present invention is composed of a dual structure of an oral adhesive layer (adhesive layer) directly attached to the oral mucosa and a protective layer (support layer) to prevent dissolution and dissolution into other parts of the oral cavity or intestinal tract. It is characterized by having

On the other hand, in the oral mucosal adhesive film according to the present invention, the oral adhesive layer is made of a film forming agent composition including low molecular weight collagen, elastin, and hyaluronic acid, and the support layer is made of a composition containing Boswellia extract. Characterized in that do.

stick jelly

The stick jelly according to the present invention is characterized in that it contains a composition containing a water-soluble film forming agent composed of low-molecular collagen, elastin, and hyaluronic acid and a Boswellia extract as an active ingredient.

The oral dissolving film, oral mucosal adhesive film, and stick jelly containing low-molecular-weight collagen, elastin, hyaluronic acid, and Boswellia extract according to the present invention contain a water-soluble polymer, a film forming agent, a plasticizer, a thickener, an emulsifier, a sweetener, and a sweetening agent for each formulation. The most desirable components may be further added or subtracted in each composition by varying the presence or absence and content of fragrances, preservatives, pH regulators, lubricants, and the like.

The present invention has the effect of providing an oral film containing, as an active ingredient, a composition including low-molecular-weight collagen, elastin, hyaluronic acid, and Boswellia extract having excellent oral mucosal permeability.

In addition, the present invention has the effect of the present invention to provide an oral film and stick jelly containing a composition including low-molecular collagen, elastin, hyaluronic acid and boswellia extract having excellent antioxidant and anti-inflammatory effects as an active ingredient.

1 is a result of preparing an oral dissolving film containing Boswellia extract according to the present invention.
Figure 2 is a result of manufacturing an oral mucosal adhesive film containing Boswellia extract according to the present invention,
Figure 3 shows the dual structure of the oral mucosa adhesive film and its attachment position in the oral mucosa.
Figure 4 shows the stick jelly process according to the present invention.
Figure 5 sequentially shows the stick jelly process chart according to the present invention.
6 is an anti-inflammatory mitigation test result of the Boswellia extract according to the present invention.

The skin is composed of three layers: epidermis, dermis, and subcutaneous tissue. Among the three layers, the dermis is closely related to skin beauty effects such as skin elasticity and moisturizing. Most of the dermis is occupied by collagen, and hyaluronic acid or elastin exists in between. Collagen creates a network structure throughout the skin to give elasticity to the skin, and hyaluronic acid plays a role in retaining moisture in the skin. In fact, according to many papers, collagen is found to be effective for skin health. Therefore, supplementing collagen in the dermis can help improve skin elasticity, and for this purpose, there have been attempts to eat or apply collagen in the past.

Collagen used in the present invention is not particularly limited. However, in the case of high-molecular collagen, absorption may not be easy, and low-molecular collagen may be preferably used. For example, collagen with a molecular weight of 500 to 10,000 may be used.

In the case of a polymer, the absorption rate is not good, and more preferably, in the present invention, hydrolyzed collagen having a molecular weight of about 1 to 2 KDa or less so as to be effective in permeating the oral mucosa may be preferable. It is okay to use vegetable or animal collagen as the collagen, but fish collagen was generally adopted because it is known that fish collagen can be produced with inexpensive and low molecular weight collagen.

[Manufacturing process-oral dissolving film]

Film formulations are basically manufactured through five steps: preparation of crude liquid, coating and drying, aging, slipping, and pouching.

In the present invention, the crude liquid in which raw materials are dissolved and added refers to a liquid prepared to produce a film preparation, and the crude liquid preparation is a slime having a specific viscosity by injecting all raw materials, including the main component, and removing bubbles generated in the process it's work

Coating/drying is the process of applying the crude liquid from which air bubbles have been removed to the required thickness on a PET base liner and passing through a long drying channel to obtain a dried semi-finished product.

The maturation process is a process to achieve water equilibrium and smooth PET separation by storing the semi-finished product obtained in the coating/drying process for a required period.

The slitting process is a process of unwinding semi-finished products that have been matured, cutting them to a certain required width and rewinding them to form a specific number of rolls that are narrower than the existing semi-finished products.

The pouching process is a process of cutting a semi-finished roll obtained by slitting into a required film size and packaging it in the primary wrapping paper.

In the oral dissolving film, raw materials acceptable to the Food Codex (including the Food Additives Codex), the Korean Pharmacopoeia (KP), and the standards and test methods (KQC) for quasi-drugs were used, and a small amount was used to form a water-soluble film forming agent for the support layer. It should be possible to secure the strength and plasticity of the film.

In general, polymers with high molecular weight and high viscosity in aqueous solution exhibit these properties. Polymers such as high molecular weight hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC) also have this property, but the film swells and corrodes slowly when in contact with moisture, making it difficult to disintegrate in the oral cavity. The downside is that it takes a long time. Thus, the present inventors used collagen, elastin, and hyaluronic acid constituting the skin dermal layer as a water-soluble film forming agent support layer.

In the present oral dissolving film invention, the presence or absence of low-molecular collagen, elastin, hyaluronic acid and water-soluble polymers (film forming agents) including boswellia extract, plasticizers, thickeners, emulsifiers, sweeteners, flavoring agents, preservatives, pH adjusting agents, lubricants, etc. Experiments related to the composition were conducted by varying the addition and content, and the most suitable component ratio was tested by conducting sensory evaluation of the taste and odor of the product.

Water-soluble polymer (film former)

The oral dissolving film according to the present invention contains the following water-soluble polymer as a film forming agent:

Pullulan, gelatin, pectin, low-viscosity pectin, hydroxypropylmethylcellulose, low-viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, methyl methacrylate Copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low-viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, zein, levan, elcinan, gluten, acacia gum, carrageenan, It may be at least one water-soluble polymer selected from the group consisting of gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, and agar.

Preferably, at least one water-soluble polymer selected from the group consisting of pullulan, gelatin, pectin, low-viscosity pectin, low-viscosity alginic acid, hydroxypropylmethylcellulose, and modified starch is usually used, but in the present invention, collagen constituting the skin dermis layer , elastin, and hyaluronic acid were used as a water-soluble film forming agent support layer.

The water-soluble polymer is preferably contained in an amount of 30 to 85% based on the total weight of the solution.

active ingredient

The oral dissolving film of the present invention used Boswellia extract as an active ingredient, a raw material that can be purchased as a food raw material. However, it is important to dissolve Boswellia powder or solid ingredients using a solvent.

Solvents that can be used at this time include water, alcohol, alkyl acetate, dimethylformamide, dimethylsulfoxide, acetone, anisole, acetic acid, butylmethyl ether, ethyl ether, ethyl formate, formic acid, pentane, heptane, methylethyl ketone and It may be one or more selected from the group consisting of methyl isobutyl ketone, but since it should be used as a food raw material, water and alcohol are preferably used.

These solvents may be contained in the solution in an amount between 20% and 80% by weight based on the total weight of the solution.

filler

The film formulation of the present invention may include a filler. The filler serves to increase the density and maintain the shape of the film. In addition, it reduces the adhesion between the films, and can control the stickiness, the decomposition rate of the film in the oral cavity, and the dissolution rate of the drug. The filler may be added in an amount of 0.01 to 40% by weight (w/w) based on the total weight of the oral film formulation.

The filler may be one or more components selected from the group consisting of microcrystalline cellulose, cellulose polymer, microcrystalline cellulose carboxymethylcellulose sodium, magnesium carbonate, calcium carbonate, limestone powder, silicate, clay, talc, titanium dioxide and calcium phosphate. The filler is not limited thereto. At this time, the filler is preferably contained in an amount of 0.01 to 40% based on the total weight of the solution.

plasticizer

The film formulation of the present invention may contain a plasticizer. The plasticizer serves to impart flexibility and flexibility to the film made of polymer so that it is not easily broken.

The plasticizers include glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, hydrogenated starch syrup, starch syrup, glycerin, and triacetin. At least one selected from the group consisting of glycerol oleate, sucrose fatty acid ester, and medium chain fatty acid may be used, but the plasticizer is not limited thereto. At this time, the plasticizer is preferably contained in an amount of 0.01% to 30% based on the total weight of the solution.

emulsifier

The film formulation of the present invention may include an emulsifier (surfactant). Surfactant is used to ensure stability and uniformity of the compositions forming the oral disintegrating film, and the surfactant is any one selected from the group consisting of cationic, anionic, nonionic or amphoteric surfactants. You can use more than

For example, as the surfactant, any one selected from the group consisting of poloxamer, sodium lauryl sulfate, glycerin fatty acid ester, polyoxyethylene fatty acid ester, sucrose fatty acid ester, lecithin, polysorbate, sorbitan fatty acid ester, and sucrose fatty acid ester One or more materials may be used, but the technical spirit of the present invention is not necessarily limited thereto, and various surfactants may be used.

sweetener

The film formulation of the present invention may contain a sweetener. A sweetener is included to add a taste suitable for the taste of the orally disintegrating film or to further improve the taste masking effect.

The sweetening agent is, for example, sugar, glucose, maltose, oligosaccharide, galactose, starch syrup, sorbitol, maltitol, invert sugar, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose, aspartame, acesulfame salt, sucralose, saccharin At least one selected from the group consisting of salt, Neotime, Taomartin, Thomasin mixture, cyclamate salt, Thomasin, Luohan fruit extract, licorice extract, stevioside, enzyme-treated stevioside, neohesperidin, and monellin. It may, but is not limited thereto. At this time, the sweetener is preferably contained in an amount of 0.1 to 40% based on the total weight of the solution.

flavoring agent

The film formulation of the present invention may contain a flavoring agent.

As the flavoring agent, natural flavoring agents, artificial flavoring agents, or mixtures thereof may be used without limitation, and may preferably be extracts from plant leaves, flowers, fruits, and the like, and plant oils. In addition, as artificial fragrances, artificial synthetic fruit fragrances having fragrances such as lemon, orange, grape, lime, and strawberry, artificial synthetic fragrances having fragrances such as vanilla, chocolate, coffee, cocoa, pine needles, ginseng, red ginseng, and citrus may be used. there is. Safflower essential oil, castor essential oil, coconut essential oil, cottonseed essential oil, canola essential oil, herring essential oil, palm fruit essential oil, palm essential oil, peanut essential oil, soybean essential oil, rapeseed essential oil, flaxseed Essential oil, rice bran essential oil, pine essential oil, sesame oil, sunflower seed essential oil, hydrogenated safflower essential oil, red ginseng essential oil and the like can be used. Methods for producing natural essential oils are known in the art, and may be obtained by, for example, steam distillation, compression, extraction, and the like. The flavoring agent may be included in the food composition of the present invention in the range of 0.1% to 5% by weight based on the total weight of the solid content.

antiseptic

The film formulation of the present invention may contain a preservative.

Preservatives include hydrogen peroxide, sodium hypochlorite, calcium hypochlorite, bleaching powder, benzoic acid or its sodium salt, sorbic acid or its sodium or potassium salt, sodium dehydroacetate, Propionic acid or its calcium salt or sodium salt can be used. These preservatives may be included in the range of 0.1% to 5% by weight based on the total weight of the solid content in the food composition of the present invention.

pH modifier

The film formulation of the present invention may contain a pH adjusting agent. In the present invention, using a pH adjusting agent affects the viscosity of the oral film support layer, and affects the taste and stability of the formulation.

Suitable pH adjusting agents for increasing the pH of the crude liquid include, for example, citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipic acid ( adipic acid, succinic acid, sodium dihydrogen phospate (monosodium phospate), disodium dihydrogen pyrophospate (sodium acid pyrophospate), acid citrate salts, amino acid hydrochloride acid hydrochlorides, sodium acid sulphite, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, glycine The group consisting of sodium glycine carbonate, l-lysine carbonate, arginine carbonate, amorphous calcium carbonate, and calcium carbonate may be mentioned, but here is not limited to The amount of the alkalizing agent may be appropriately adjusted within a range capable of matching the pH range, but is preferably included in an amount of 0.1 to 10.0% by weight.

Among the above alkalizing agents, an optimal range that does not adversely affect film formation was derived due to a specific alkalizing agent and a specific alkalizing agent combination. According to the study of the present inventors, when adjusting the pH range using the alkalinizing agent and using a combination of sweeteners, etc., a combination that does not affect the flavor of the taste was found, but an unexpected problem was found that film formation did not work well. did That is, the use of an alkalizing agent affects the ability to form a film, and as a result, film formation does not occur at all or problems arise in viscosity formation. In order to solve this problem, the present inventors have achieved excellent film forming ability when adjusting the pH range to the range of 4.8 to 5.8 using magnesium oxide, sodium hydroxide and potassium carbonate as an alkalizing agent.

In addition, it is preferable to use magnesium oxide, sodium hydroxide, and potassium carbonate in a ratio of 1:5:1 to 5:1:1, and the combined amount of magnesium oxide, sodium hydroxide, and potassium carbonate is 0.1 to 10.0% of the total weight of the formulation. It is preferable to

[Manufacturing process - Oral mucosa adhesive film]

Compared to conventional oral dissolving films, the oral mucosal adhesive film according to the present invention includes an adhesive (adhesive) layer in direct contact with the oral mucosa and a protective (support) layer to prevent dissolution and dissolution into other parts of the oral cavity or intestinal tract, that is, It consists of two parts, the adhesive layer and the protective layer.

The adhesive layer is water-soluble but adhereable and should not rapidly disintegrate. The protective layer is water-insoluble and cannot be easily penetrated by saliva and must be decomposed in the digestive system when ingested.

The adhesive layer and the protective layer are separately prepared and developed, respectively. The adhesive layer may be developed first and the protective layer may be developed after drying, or the protective layer may be developed and the adhesive layer may be developed after drying. The present inventors experimented with the conditions of developing the adhesive layer first and then developing the protective layer after drying.

In the present invention, the oral mucosal adhesive film is composed of an adhesive (adhesion) layer composed of low-molecular collagen, elastin, and hyaluronic acid, and a support (protection) layer containing a surfactant for dissolving Boswellia extract. For the oral mucosal adhesive film, experiments related to the composition were conducted by varying the presence or absence and content of water-soluble polymers (film formers), plasticizers, thickeners, emulsifiers, sweeteners, flavoring agents, preservatives, pH regulators, lubricants, etc. The most suitable component ratio was tested by conducting a sensory evaluation of taste and odor.

Wrinkle improvement, skin aging prevention, skin elasticity strengthening, whitening, etc. Low-molecular collagen, elastin, and hyaluronic acid that maintain skin elasticity form a mucous membrane (adhesive) layer, and support containing surfactants that dissolve boswellia extract components ( Oral containing low-molecular collagen, elastin, hyaluronic acid, and boswellia extract that are manufactured in a film form attached to the oral mucosa formed as a protective) layer to increase the absorption rate of skin dermal components and to be easily absorbed in the oral cavity The present invention relates to a mucoadhesive film composition.

Most of the oral mucosa, unlike the skin, absorbs the active ingredient easily and quickly, and relatively large molecular weight substances are also absorbed, so its utilization value is very high as a main route of active ingredient administration. In particular, drugs absorbed through the oral mucosa or gums are not affected by gastrointestinal disorders and hepatic first pass effects, and studies are being actively conducted to expand their use to the drug field for the purpose of local drug delivery effects and minute systemic actions.

Oral mucosal adhesive films are basically manufactured through 5 steps: liquid preparation, coating and drying, aging, sleeping, and pouching.

In the present invention, the crude liquid in which raw materials are dissolved and added refers to a liquid prepared to produce a film preparation, and the crude liquid preparation is a slime having a specific viscosity by injecting all raw materials, including the main component, and removing bubbles generated in the process it's work

Coating/drying is the process of applying the crude liquid from which air bubbles have been removed to the required thickness on a PET base liner and passing through a long drying channel to obtain a dried semi-finished product.

The maturation process is a process to achieve water equilibrium and smooth PET separation by storing the semi-finished product obtained in the coating/drying process for a required period.

The slitting process is a process of unwinding semi-finished products that have been matured, cutting them into a certain width and rewinding them to form a specific number of rolls that are narrower than the existing semi-finished products.

The pouching process is a process of cutting a semi-finished roll obtained by slitting into a required film size and packaging it in the primary wrapping paper. The present invention is characterized by taking a dual structure externally by applying a support (protection) layer on the adhesive (adhesion) layer during the coating and drying process.

(1) Liquefaction process of support layer:

The active ingredient and the surfactant of the supporting (protective) layer are first stirred. The supporting (protective) layer is additionally used in a small amount for a plasticizer such as polyethylene glycol or glycerin and an adhesive agent such as carbomer, polyacrylic acid or carrageenan to stabilize the film surface properties so that it can adhere well to the mucosal (adhesion) layer and to improve oral mucosal adhesiveness. can improve

(2) Liquefaction process of the mucosal layer:

The mucosal (adhesive) layer is pullulan, gelatin, pectin, low-viscosity pectin, hydroxypropylmethylcellulose, low-viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinyl alcohol, poly Acrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low-viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, zein, levan, elcinan, gluten , acacia gum, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, and at least one water-soluble polymer selected from the group consisting of agar.

Preferably, at least one water-soluble polymer selected from the group consisting of pullulan, gelatin, pectin, low-viscosity pectin, low-viscosity alginic acid, hydroxypropylmethylcellulose, and modified starch is usually used, but in the present invention, collagen constituting the skin dermal layer , elastin and hyaluronic acid were used as a water-soluble film forming agent support layer. The water-soluble polymer is preferably contained in an amount of 30 to 85% based on the total weight of the solution.

After adding an active ingredient, an alkalizing agent, a surfactant, a plasticizer, etc., and stirring uniformly, a sweetener, a flavoring agent, a water-soluble polymer, and a coloring agent are added and stirred homogeneously to prepare a crude liquid for oral film preparation. At this time, the range of final pH of the crude liquid is 4.38 to 5.25, and magnesium oxide and/or sodium hydroxide can be preferably used as an alkalizing agent. Further, as the solvent (solvent), propylene glycol, polyogyl 35 castor oil, polyethylene glycol 400, polyethylene glycol 300, trichloromonofluoromethane, sodium hydrogencarbonate, ethyl acetate, water for injection, refined soybean oil, purified water, isopropanol, One selected from the group of liquid paraffin, sodium chloride, ethanol, acetone, physiological saline injection, benzyl alcohol, isopropyl myristate, anhydrous ethanol, sterile purified water, N-methylpyrrolidone, agricultural glycerin, glycerin, methylen chloride, and toluene The above solvent, more preferably one or more solvents selected from the group of sterile purified water, purified water, ethanol, methylene chloride, and toluene may be selected, but is not limited thereto. In addition, the pH of the crude solution is obtained by dissolving the pharmaceutical composition of the present invention in a solvent and measuring the pH of the prepared crude solution.

(3) Molding process:

The coating liquid is introduced into a molding machine to form a film. At this time, the temperature of the forming machine is 15 to 150 ° C, preferably 25 to 120 ° C, more preferably 40 to 100 ° C, and the film is formed in the form of a roll.

(4) Aging process:

The molded film goes through an aging process of about 1 to 30 days at a relative humidity of 30 to 90% to contain moisture suitable for slitting or cutting. At this time, the moisture content is appropriately 30% or less.

(5) Cutting process:

The aged roll is slit into small rolls, cut into suitable sizes, and filled into small containers or aluminum wrappers.

(6) Packaging process:

Filled small containers or products in aluminum wrapping paper are repackaged in small boxes or commercialized through blisters.

In the present oral mucosal adhesive film invention, water-soluble polymers (film forming agents) including low-molecular collagen, elastin, hyaluronic acid and boswellia extract, plasticizers, thickeners, emulsifiers, sweeteners, flavoring agents, preservatives, pH adjusting agents, lubricants, etc. Experiments related to the composition were conducted by varying the presence or absence of addition and content, and the most suitable component ratio was tested by conducting a sensory evaluation of the taste and smell of the product.

Water-soluble polymer (film former)

The oral dissolving film of the present invention considered the following water-soluble polymer as a film forming agent. Pullulan, gelatin, pectin, low-viscosity pectin, hydroxypropylmethylcellulose, low-viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, methyl methacrylate Copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low-viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, zein, levan, elcinan, gluten, acacia gum, carrageenan, It may be at least one water-soluble polymer selected from the group consisting of gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, and agar. Preferably, at least one water-soluble polymer selected from the group consisting of pullulan, gelatin, pectin, low-viscosity pectin, low-viscosity alginic acid, hydroxypropylmethylcellulose, and modified starch is usually used, but in the present invention, collagen constituting the skin dermal layer , elastin, and hyaluronic acid were used as a water-soluble film forming agent support layer. The water-soluble polymer is preferably contained in an amount of 30 to 85% based on the total weight of the solution.

active ingredient

The oral dissolving film of the present invention used Boswellia extract as an active ingredient, a raw material that can be purchased as a food raw material.

However, it is important to dissolve Boswellia powder or solid ingredients using a solvent. Solvents that can be used at this time include water, alcohol, alkyl acetate, dimethylformamide, dimethylsulfoxide, acetone, anisole, acetic acid, butylmethyl ether, ethyl ether, ethyl formate, formic acid, pentane, heptane, methylethyl ketone and It may be one or more selected from the group consisting of methyl isobutyl ketone, but since it should be used as a food raw material, water and alcohol are preferably used.

These solvents may be contained in the solution in an amount between 20% and 80% by weight based on the total weight of the solution.

filler

The film formulation of the present invention may include a filler. The filler serves to increase the density and maintain the shape of the film. In addition, it reduces the adhesion between the films, and can control the stickiness, the decomposition rate of the film in the oral cavity, and the dissolution rate of the drug.

The filler may be added in an amount of 0.01 to 40% by weight (w/w) based on the total weight of the oral film formulation. The filler may be at least one component selected from the group consisting of microcrystalline cellulose, cellulose polymer, microcrystalline cellulose carboxymethylcellulose sodium, magnesium carbonate, calcium carbonate, limestone powder, silicate, clay, talc, titanium dioxide and calcium phosphate. The filler is not limited thereto.

At this time, the filler is preferably contained in an amount of 0.01 to 40% based on the total weight of the solution.

plasticizer

The film formulation of the present invention may contain a plasticizer. The plasticizer serves to impart flexibility and flexibility to the film made of polymer so that it is not easily broken.

The plasticizers include glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, hydrogenated starch syrup, starch syrup, glycerin, and triacetin. At least one selected from the group consisting of glycerol oleate, sucrose fatty acid ester, and medium chain fatty acid may be used, but the plasticizer is not limited thereto.

At this time, the plasticizer is preferably contained in an amount of 0.01% to 30% based on the total weight of the solution.

emulsifier

The film formulation of the present invention may include an emulsifier (surfactant). Surfactant is used to ensure stability and uniformity of the compositions forming the oral disintegrating film, and the surfactant is any one selected from the group consisting of cationic, anionic, nonionic or amphoteric surfactants. The above may be used, for example, as the surfactant, poloxamer, sodium lauryl sulfate, glycerin fatty acid ester, polyoxyethylene fatty acid ester, sucrose fatty acid ester, lecithin, polysorbate, sorbitan fatty acid ester, and sucrose fatty acid ester Any one or more materials selected from the group consisting of may be used, but the technical spirit of the present invention is not necessarily limited thereto, and various surfactants may be used.

sweetener

The film formulation of the present invention may contain a sweetener. A sweetener is included to add a taste suitable for the taste of the orally disintegrating film or to further improve the taste masking effect.

The sweetening agent is, for example, sugar, glucose, maltose, oligosaccharide, galactose, starch syrup, sorbitol, maltitol, invert sugar, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose, aspartame, acesulfame salt, sucralose, saccharin At least one selected from the group consisting of salt, Neotime, Taomartin, Thomasin mixture, cyclamate salt, Thomasin, Luohan fruit extract, licorice extract, stevioside, enzyme-treated stevioside, neohesperidin, and monellin. It may, but is not limited thereto.

At this time, the sweetener is preferably contained in an amount of 0.1 to 40% based on the total weight of the solution.

flavoring agent

The film formulation of the present invention may contain a flavoring agent.

The flavoring agent may be a natural flavoring agent, an artificial flavoring agent, or a mixture thereof without limitation, and may preferably be an extract from plant leaves, flowers, fruits, etc., or plant oil. In addition, as artificial fragrances, artificial synthetic fruit fragrances having fragrances such as lemon, orange, grape, lime, and strawberry, artificial synthetic fragrances having fragrances such as vanilla, chocolate, coffee, cocoa, pine needles, ginseng, red ginseng, and citrus may be used. there is.

Safflower essential oil, castor essential oil, coconut essential oil, cottonseed essential oil, canola essential oil, herring essential oil, palm fruit essential oil, palm essential oil, peanut essential oil, soybean essential oil, rapeseed essential oil, flaxseed Essential oil, rice bran essential oil, pine essential oil, sesame oil, sunflower seed essential oil, hydrogenated safflower essential oil, red ginseng essential oil and the like can be used. Methods for producing natural essential oils are known in the art, and may be obtained by, for example, steam distillation, compression, extraction, and the like.

The flavoring agent may be included in the food composition of the present invention in the range of 0.1% to 5% by weight based on the total weight of the solid content.

antiseptic

The film formulation of the present invention may contain a preservative.

The preservative is hydrogen peroxide, sodium hypochlorite, calcium hypochlorite, bleaching powder, benzoic acid or its sodium salt, sorbic acid or its sodium or potassium salt, sodium dehydroacetate , propionic acid or its calcium salt or sodium salt can be used.

These preservatives may be included in the range of 0.1% to 5% by weight based on the total weight of the solid content in the food composition of the present invention.

pH modifier

The film formulation of the present invention may contain a pH adjusting agent.

In the present invention, using a pH adjusting agent affects the viscosity of the oral film support layer, and affects the taste and stability of the formulation.

Suitable pH adjusting agents for increasing the pH of the crude liquid include, for example, citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipic acid ( adipic acid, succinic acid, sodium dihydrogen phospate (monosodium phospate), disodium dihydrogen pyrophospate (sodium acid pyrophospate), acid citrate salts, amino acid hydrochloride acid hydrochlorides, sodium acid sulphite, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, glycine The group consisting of sodium glycine carbonate, l-lysine carbonate, arginine carbonate, amorphous calcium carbonate, and calcium carbonate may be mentioned, but here is not limited to

The amount of the alkalizing agent may be appropriately adjusted within a range capable of matching the pH range, but is preferably included in an amount of 0.1 to 10.0% by weight.

Among the alkalizing agents, an optimal range that does not adversely affect film formation was derived due to a specific alkalizing agent and a specific alkalizing agent combination.

According to the study of the present inventors, when adjusting the pH range using the alkalinizing agent and using a combination of sweeteners, etc., a combination that does not affect the flavor of the taste was found, but an unexpected problem was found that film formation did not work well. did

That is, the use of an alkalizing agent affects the ability to form a film, and as a result, film formation does not occur at all or problems arise in viscosity formation.

In order to solve this problem, the present inventors have achieved excellent film forming ability when adjusting the pH range to the range of 4.8 to 5.8 using magnesium oxide, sodium hydroxide and potassium carbonate as an alkalizing agent.

In addition, it is preferable to use magnesium oxide, sodium hydroxide, and potassium carbonate in a ratio of 1:5:1 to 5:1:1, and the combined amount of magnesium oxide, sodium hydroxide, and potassium carbonate is 0.1 to 10.0% of the total weight of the formulation. It was preferable to

[Manufacturing Process - Stick Jelly]

Jelly is a mixture of semi-solidifying agents (saponifying agents) such as pectin, gelatin, agar, starch, and alginic acid, sugars, acidulants, and fruit juice, and coagulated to have enough hardness to maintain a soft shape.

Jelly is mainly used as a snack or after-meal dessert because it has a sweet taste due to sugars, and is preferred across all ages because of its soft texture, chewable and easy-to-swallow characteristics. Recently, the development of jellies with increased functionality and / or sensuality by adding various materials is increasing, considering jelly itself as one finished food.

Jelly is a sugar favorite food containing around 20% water content, and is made by adding sugar and a gelling agent at an appropriate concentration to fruit juice. The manufacturing process generally includes a process of concentrating, molding, and drying by mixing sugars and a gelling agent.

Types of gelling agents include pectin, agar, gelatin, and starch, and accordingly, types of jellies may be classified into pectin jelly, agar jelly, gelatin jelly, and starch jelly. Depending on the type of gelling agent, chewability such as formation of hard tissue and toughness appears differently. Pectin jelly is easily broken and has a slight chewiness, agar jelly is more easily broken, gelatin jelly is tough and has excellent chewability, and starch Jelly hardens tissues.

When combining a plurality of gelling agents, in the case of a specific gelling agent, gelation may be weakened depending on the pH during the manufacturing process, and the strength of the jelly may change depending on the external temperature. Optimization is an important consideration. The research team developed a nutritious and highly palatable jelly that can consume the functional ingredients of Boswellia and the three major ingredients of the dermal layer of the skin.

Hereinafter, the present invention will be described in more detail in examples, and the scope of the present invention is not limited only to the following examples, and includes all modifications of equivalent technical ideas.

[Experimental Example 1: Comparative evaluation of oral dissolving film composition]

The oral dissolution film was evaluated for comparison of the film under the conditions of six types (A-1 to A-6) as shown in Table 1 below.

A film was formed through four processes of solvent development: mixing/development/drying/cutting.

(1) Mixing process:

The A+B phase was completely dissolved after slowly adding the film forming agent in a water bath condition (90° C.). After stirring separately, the active ingredients of phase C are dissolved in a water bath at 90 ° C, and phases D to G are introduced in order. Inject phases C to G into A+B phases in order. At this time, when the G phase is added, the viscosity increases.

(2) Development process:

In order to develop the mixed solution (1), it was applied on polyethylene release paper while maintaining a constant speed and constant thickness. Film unfolding was conducted using a film unfolding machine (model KP-3000V), and the thickness was 0.70 ~ 0.80 mm and the unfolding speed was 9.0 mm/sec.

(3) Drying process:

Drying should be carried out according to the type of solvent used, the volume of the solvent, the viscosity, and the film thickness, and in some cases, the melting point or stability of the drug should be considered. Boswellic acid has a high melting point of 195 ~ 274 ℃, and an emulsifier was used to dissolve it, but only a small concentration can be used because it hardens into a solid. The film paper was placed in a drying oven set at 80° C. and dried for about 1 to 2 hours.

(4) Cutting process:

According to the thickness and weight of the film, it was cut using a cutting machine. In the case of cracking or deformation of the film during the cutting process, it was determined that the film was not formed, and the experimental conditions were continuously changed. A film was selected and cut under conditions in which no problem occurred during the cutting process and deformation did not occur.

As a result of manufacturing 6 kinds of oral dissolving films (A-1 ~ A-6) by the solvent development method, films were not formed for PVA and PVP, and films were formed for HPMC, but they were strongly attached to the release paper and were not separated. However, the CMC-Ca film was formed, but the surface of the film was non-uniform. In the case of Pullulan, the strength of the film itself was low and the adhesion property was high, so the film form was not maintained for a long time.

On the other hand, in the case of sodium alginate (Sodium Alginate), the film strength is high and the surface is homogeneous, so the present inventors most desired formulation was selected, and the most suitable oral dissolving film was formed in formulation A-1 of the experimental example.

Comparison of composition of oral dissolving film

[Experimental Example 2: Comparative evaluation of solubilization of Boswellia extract of oral dissolving film]

Boswellia extract ((Boswellia serrata R.) powder contains terpenoids, glycosaminoglycans and boswellic acid, so it has strong viscosity and is difficult to dissolve.

Therefore, for each condition of each experiment B-1 to B-6 in Table 2 below, first dissolve phase C in glycerin, add a solubilizing agent, etc., warm to 70 ~ 80 ° C, and then add ethanol of phase G for each condition to achieve complete dissolution Check.

At this time, for complete dissolution, Sonication was used. In the same manner as in Experimental Example 1, it was uniformly applied to a release paper or a Petri dish according to the experimental prescription. Put the release paper or Petri dish in a dry oven set at about 70 ~ 80 ℃, and completely dry the mixture until a film is formed for about 20 ~ 50 minutes, then peel the formed film and cut it into 2cm × 3cm standard to evaluate characteristics and A quality evaluation was conducted. Table 2 below lists the solubilization condition comparison experiment prescription.

In one embodiment according to the present invention according to Table 2, the oral dissolving film according to the present invention is characterized in that it contains, as an active ingredient, a composition containing a water-soluble film-forming agent composed of low-molecular collagen, elastin, and hyaluronic acid and a Boswellia extract. .

In addition, the composition ratio of hyaluronic acid:collagen:elastin constituting the water-soluble film forming agent was preferably 3:10:0.5 parts by weight based on 100 parts by weight of the total composition for effective oral mucosal permeability.

On the other hand, as a result of preparing by dissolving the Boswellia extract by adding ethanol, it was confirmed that the higher the content of the Boswellia extract, the more particles agglomerated, resulting in a solubility problem. Therefore, an effective concentration was selected rather than increasing the content of Boswellia cold water. In this experimental example, the content of boswellia included in the oral dissolving film according to the present invention was preferably 0.1 to 3 parts by weight based on 100 parts by weight of the total composition.

In addition, the oral dissolution film according to the present invention may further include sodium alginate as a film forming agent component. It was possible to prepare an orally dissolving film within minutes.

Comparison of Solubilization of Boswellia Extract in Oral Dissolving Films

[Experimental Example 3: Oral Mucoadhesive Film-Comparative Evaluation of Formation of Double Layer Polymer Film]

(1) Manufacture of adhesive (adhesive) layer film

The structures of the mucosal (adhesive) layer and the supporting (protective) layer are shown in detail in FIG. 3 . The mucosal (adhesive) layer is an adhesive layer in direct contact with the oral mucosa, and is usually composed of ingredients that increase adhesion to the tongue or oral cells.

As the component constituting the oral mucosal layer, a component comprising at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hypromellose phthalate, titanium dioxide and methacrylic acid is usually used, but the present inventors use The tongue, oral cells, and collagen, elastin, and hyaluronic acid adhere immediately to facilitate absorption. Preferably, the mucosal (adhesion) layer is prepared by changing the composition ratio of collagen, elastin, and hyaluronic acid based on the total weight and setting the concentration that achieves the best adhesion, thereby making a commonly used double-structured oral mucosal adhesive film.

In this experimental example, the composition ratio of hyaluronic acid:collagen:elastin constituting the water-soluble film forming agent included in the oral mucosa adhesive film according to the present invention was preferably 3:10:0.8 parts by weight based on 100 parts by weight of the total composition.

(2) Manufacture of supporting (protective) layer film

A double oral mucosal film comprising at least one polymer selected from the group consisting of hydroxypropylmethylcellulose, lambda carrageenan, and polyacrylic acid is commonly used, but the present invention includes sodium alginate, modified starch and The invention relates to a double oral mucosal membrane adhesive film composed of a support (protective layer) made of a combination of Boswellia and a surfactant. The composition ratio and components are described in detail in Table 3 below.

As shown in Table 3 below, the oral mucosal membrane adhesive film was subjected to comparative evaluation through the process of making and drying the film of the support (protection) layer and the mucosal (adhesive) layer under six types (C-1 to C-6) conditions. did Films were formed through six processes of solvent development: mixing/development/drying/redevelopment/redrying/cutting.

(1) Mixing process:

Phase A was completely dissolved after slowly adding the film forming agent in a water bath condition (80° C.). The solubility of Boswellic acid is high at 195 ~ 274 ℃, and an emulsifier was used to dissolve it, and only a small amount can be administered because it hardens into a solid. After stirring separately, the active ingredients were dissolved in the B-phase emulsifier and dissolved in a water bath at 90° C. (supporting layer preparation). Phase C was completely dissolved after slowly adding the film forming agent in a water bath condition (90° C.). D to G phases are introduced in order. Injecting phase G increases the viscosity (preparation of the mucosal layer).

(2) Development process:

The support layer mixture solution was first applied on polyethylene release paper while maintaining a constant speed and constant thickness. The film unfolding was tested using a film unfolding machine (model KP-3000V), and the thickness was 0.35 ~ 0.40 mm and the unfolding speed was 9.0 mm/sec.

(3) Drying process:

Drying should be carried out according to the type of solvent used, the volume of the solvent, the viscosity, and the film thickness, and in some cases, the melting point or stability of the drug should be considered. The film was semi-dried for 20 to 40 minutes in a drying oven set at 80°C.

(4) Redeployment process:

On the support layer in a semi-dry state, the mixed solution for the mucosal layer was applied again while maintaining a constant speed and constant thickness. Film unfolding was conducted using a film unfolding machine (model KP-3000V), and the thickness was 0.7 to 0.80 mm and the unfolding speed was 5.0 mm/sec.

(5) Redrying process:

Reconstitution should be performed according to the type of solvent used in the support layer and the mucosal layer, the volume of the solvent, the viscosity, and the film thickness, and in some cases, the melting point or stability of the drug should be considered. The film paper was placed in a drying oven set at 80° C. and dried for about 1 to 2 hours.

(6) Cutting process:

According to the thickness and weight of the film, it was cut using a cutting machine. In the case of cracking or deformation of the film during the cutting process, it was determined that the film was not formed, and the experimental conditions were continuously changed. The film was cut under conditions in which no problem occurred during the cutting process and deformation did not occur.

As a result of manufacturing 6 kinds of oral dissolving films (C-1 ~ C-6) by the solvent development method, films were not formed for PVA and PVP, and films were formed for HPMC, but they were strongly attached to the release paper and were not separated. The same phenomenon was observed, and a film was formed in CMC-Ca, but the film surface became non-uniform. In the case of Pullulan, the strength of the film itself was low and the adhesion property was high, so the film form was not maintained for a long time.

On the other hand, in the case of sodium alginate (Sodium Alginate), the film strength is high and the surface is homogeneous, so the present inventors selected the desired formulation, and the C-1 formulation was formed as the most suitable oral dissolving film.

Comparison of formation of oral mucoadhesive film-double-layer polymer film

[Experimental Example 4: Manufacturing Process of Boswellia Extract-Containing Stick Jelly]

Edible jelly is a gelling agent (gelatin, agar, pectin, etc.) such as thickened polysaccharide or high-molecular protein hydrated in water, acidulant, concentrated liquid, flavoring, etc. that made it come out Depending on the type of gelling agent, the texture of the jelly is affected, and the mixing ratio of sugars is directly related to the appearance, molding ability and productivity of the jelly.

When manufacturing a jelly formulation, after dissolving at a temperature higher than the temperature at which the gelling agent is dissolved, other ingredients are blended and dissolved while maintaining the temperature continuously, and the sugar content is adjusted through a concentration process, which is a measure of tissue strength and stability of the formulation. . For this reason, special attention must be paid to raw materials whose components are altered by being affected by high temperatures.

In the present invention, the blending ratio of xanthan gum, locust bean gum, agar, and carrageenan was optimally adjusted, and spit jelly containing low-molecular collagen, elastin, hyaluronic acid, and boswellia extract was made, and the experiment was conducted with the most optimal mixing ratio. The most suitable component ratio was tested by conducting a sensory evaluation of product stability and taste and smell.

1) Preparation of ingredients for making stick jelly

Prepare materials for preparing stick jelly as shown in [Table 4] below. The weight percentages listed below may vary slightly. Table 4 below is an example of preparing a stick jelly containing low-molecular-weight collagen, elastin, hyaluronic acid, and Boswellia extract.

In this experimental example, the gelling agent was used as a food gel NS-K raw material composed of a combination of locust bean gum and xanthan gum or a combination of locust bean gum and agar. Here, the weight % of the purified water, sugar-gelling agent composition, functional ingredients, sweeteners, and natural concentrates were prepared and tested as shown in Table 4 above, but are not limited thereto, and some ranges may be changed to the extent that the object of the invention is met. Of course there is.

2) Heating purified water to 70 ~ 80 ℃

In the present invention, sugars are not dissolved in purified water in advance, and only purified water is measured and then heated. Preferably, the mixture was heated to 80° C. to form conditions under which the sugar-gelling agent composition could be added thereafter.

3) Preparing a sugar-gelling agent composition

If the gelling agent is not first mixed with the oligosaccharide, it is difficult to disperse the gelling agent. This is because the gelling agent increases in strength when the sugar content is high, but is weak against acid. If gelatin is used, it is sensitive to external temperature to the extent that the product must be stored in the refrigerator, and it is also animal-free.

Locust bean gum, xanthan gum, and agar, which are vegetable natural gelling agents, were selected for consumers who are sensitive to ingredients. Since agar is hydrolyzed by the organic acid of fruit juice and does not form gel well, jelly was formed using food gel NS-K, whose stability was secured through locust bean gum and xanthan gum, which are not sensitive to pH.

4) Mixing the sugar-gelling agent composition with purified water at 80 ° C and heating it

A concentrate is prepared by mixing the sugar-gelling agent composition with purified water heated to 80°C and heating it at 85 to 95°C until it becomes slightly thick. Preferably, after heating to 85 ° C., it is concentrated for about 5 to 10 minutes.

5) Mixing Water-soluble Polymer (Film Forming Agent) Components

While maintaining the temperature of the concentrate at 85 ° C., the water-soluble polymer (film forming agent) is dissolved and selectively introduced and mixed.

6) Additional Mixing of Active Ingredients, Plasticizer, and Sweetener

Hydrous citric acid, vitamin C, trisodium citrate, calcium lactate, and enzyme-treated stevia are weighed and selectively added. After adding functional ingredients and sweeteners, heat to 95-98℃ while heating and concentrating for 5-10 minutes. Preferably, when the temperature reaches 98 ° C., natural fragrance is added. After that, mix while maintaining the temperature for 15 to 20 minutes.

7) Packing step

The heated concentrate is dispensed into a mold, cooled, and packed to complete stick jelly.

Comparison of Composition of Stick Jelly Containing Boswellia Extract

[Experimental Example 5: Anti-inflammatory evaluation of Boswellia extract]

An inflammatory response, which is a kind of immune response, is a defense mechanism of the human body after harmful stimuli are applied by microorganisms or compounds, and refers to all processes from elimination of stimuli to restoration of damaged tissues. It has been reported that when an inflammatory reaction occurs chronically, it is involved in various pathological mechanisms, such as excessive secretion of inflammatory mediators to promote the growth of cancer cells or aggravation of arteriosclerosis by increasing insulin resistance.

In the immune system, macrophages regulate inflammatory responses and immune functions, and play an important role in maintaining homeostasis. The activity is increased by stimulation of LPS (Lipopolysaccharide), which is a complex of lipids and polysaccharides covalently bound to external antigens, and is an endotoxin that exists mainly as a component of the outer membrane of Gram-negative bacteria. )am.

Macrophages activated by stimulation promote the secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. When these inflammatory mediators are formed, they play a major role in inflammatory mediation by being involved in the process of converting arachidonic acid into leukotrienes, thromboxanes, prostaglandins, etc. through the action of COX (Cyclooxygenase) and the mass production of NO (Nitric Oxide). It is known to cause damage.

ERK1/2 (extracellular signal-regulated kinase 1/2), p38 (p38 kinases), JNK (c-Jun NH2-terminal kinase) and It is known that the same MARKs (mitogen-activated protein kinases) and NF-κ (nuclear factor kappa B) are involved. When macrophages are stimulated by LPS, MAPKs and NF-κ are activated and induce the production of various inflammatory factors.

First, Raw 264.7 cells were dispensed in a 96-well plate at a final concentration of 2×10 ⁵ cells/well. The cells were cultured for 24 hours in a 37° C., 5% CO ₂ incubator, and then each Boswellia extract was treated with 50 μg/mL. Then, 2 hours later, inflammation was stimulated by treatment with 1 μg/ml of LPS, and cultured for 18 hours. Each test method was performed according to the test method recommended by the manufacturer. The experimental results are shown in FIG. 6 . 6, it was confirmed that the Boswellia extract lowered the levels of inflammatory cytokines, IL-1β, IL-8, TLR4 and IL-6.

[Experimental Example 6: Antioxidant ability and anti-inflammatory evaluation of oral dissolving film containing Boswellia extract, oral mucosal adhesive film, and stick jelly]

(1) Antioxidant activity verification (DPPH free radical scavenging)

Based on the final experimental prescription selected above, after uniformly dissolving the oral dissolving film (B-1), oral mucosal film (C-1), and stick jelly (A-1) at 1%, 10,000 rpm, 5 min, Cell free extract (CFE) was prepared by centrifugation at 4°C.

3.0mL of 2,2-DiPhenyl-2-Picryl hydrazyl hydrate (DPPH) solution (5mg/100mL ethanol) was mixed with 500μL of prepared CFE, and the same amount of ethanol, MRS solution, and ascrobic acid (100 μg/mL) were mixed. It was used as a control, blank, and comparison group.

Then, after mixing with the DPPH solution, incubated in the dark for 30 minutes, the absorbance at 517 nm was measured, and the antioxidant activity was converted to % using the following formula, and the calculation formula is as follows.

Acid tolerance
(relative to 0h %) oral dissolving film oral mucosa
adhesive film stick jelly DPPH free radical scavenging (%) 88 105 107 102 81

As a result of the above, it could be seen that the oral dissolving film, the oral mucosal adhesive film, and the stick jelly containing the Boswellia extract according to the present invention have an antioxidant ability.

(2) Anti-inflammatory verification

Inflammatory derivatives such as NO, iNOS, COX-2, IL-1β and IL-6 are excessively produced by the NF-κB signaling pathway. NF-κB is one of the most important transcription factors involved in inflammatory mechanisms in immune cells.

Abnormal activation of NF-κB by various causes has been known as a mechanism of various autoimmune diseases such as atopy, allergy, and arthritis. Therefore, in order to evaluate the effect of the present invention on NF-κB signaling activation, LPS was induced in HT-29 cells to investigate IκB-α degradation, phosphorylation, and changes in the content of various cytokines. The specific experimental method is as follows. proceeded.

After artificially treating LPS, an inflammation-inducing substance, whether there was an anti-inflammatory effect was evaluated.

Based on the final experimental prescription selected above, the oral dissolving film, the oral mucosal adhesive film, and the stick jelly were uniformly dissolved at 1 g / 1 ml each, and then centrifuged at 10,000 rpm, 5 min, 4 ° C to obtain cell free extract (CFE). ) was prepared. After dispensing to 2 x 10 ⁵ cells per well in a 96-well plate, they were cultured in a 37°C, 5% CO ₂ incubator for 24 hours. After overnight, it was replaced with a new medium, and LPS (1ug/ml) and extract were administered by concentration and cultured for 24 hours. After incubation, the supernatant was reacted with Griess' reagent at a ratio of 1:1, and absorbance was measured at 570 nm.

The HT-29 cell line used in this experiment was purchased from Korea Culture Type Collection (KCTC, Korea) and contained 10% heat-inactivated fetal bovine serum (FBS, Gibco), penicillin G (100 IU/ml), and streptomycin (100 IU/ml). mg/ml) was added using RPMI 1640 medium (Gibco BRL, USA) and cultured in an atmospheric environment of 37° C. and 5% CO ₂ .

HT-29 cells were seeded in a 96 well plate under conditions of 1 x 10 ⁵ cells/well, cultured for 24 hours, and then the heat-treated strain was pre-treated for 24 hours. After removing the media, the reaction was performed for 24 hours by treatment with Lipopolysaccharide (LPS) (1 μg/mL) to induce an inflammatory response. At this time, the groups were largely set to Positive, Negative, and strain treatment groups. The positive group was blank, the negative group was treated with LPS only, and the strain treatment group was treated with LPS.

For RNA Extraction and cDNA synthesis, after suctioning the media in the LPS-treated plate well, 1 mL of Trizol reagent (Invitrogen) was treated. Thereafter, the cells were completely removed with a cell scraper, 200 μL of chloroform was added and stirred, and after incubation for 5 minutes, centrifugation was performed at 12000 rpm for 15 minutes at 4 ° C. Then, the resulting supernatant was dispensed into an ep tube, and 200 μL of isopropanol was added to the tube and incubated for 10 minutes. After incubation, centrifugation was performed at 12000 rpm for 15 minutes at 4°C, and the supernatant was removed. At this time, the pellet in the tube was washed with 75% EtOH, and centrifugation was performed at 7500 rpm for 5 minutes at 4°C to remove the supernatant. did Then, air drying was performed for 5 minutes, and RNA concentration was measured by taking nanodrops after dispensing 20 μL of DEPC. Based on the concentration value, RNA was diluted to 100 ng/μL, and cDNA was obtained by PCR using a cDNA kit (Applied Biosystems). was synthesized. PCR was performed at 25°C for 10 minutes, 37°C for 2 hours, and 85°C for 5 minutes.

After diluting the synthesized cDNA to 100 ng/μL, the genetic expression of inflammatory cytokines was measured using qRT-PCR, and IL-1β, IL-8, TLR4, and IL-6 were measured as markers of the inflammatory response. Primer sequences used are shown in Table 6 below.

Gene - Gene Sequence Tm (℃) GAPDH f 5'-CCT GCT TCA CCA CCT TCT-3' 59.8 r 5’-ATG ACC ACA GTC CAT GCC-3’ IL-1β f 5'-CCA GCT ACG AAT CTC GGA CCA CC-3' 63.0 r 5'-TTA GGA AGA CAC AAA TTG CAT GGT GAA GTC AGT-3' IL-8 f 5'-GTT GTG AGG ACA TGT GGA AGC ACT-3' 56.5 r 5'-CAC AGC TGG CAA TGA CAA GAC TGG-3' TLR4 f 5'-CAG AAC TGC AGG TGC TGG-3' 53.2 r 5'-GTT CTC TAG AGA TGC TAG-3' IL-6 f 5'-CCG GAG AGG AGA CTT CAC AG-3' 64.2 r 5'-GGA AAT TGG GGT AGG AAG GA-3'

The result of measuring the expression level of each inflammatory cytokine was collected and calculated by substituting into the following conversion formula to obtain an average (%). The difference in expression level for each concentration and for each Cytokine type was converted into percent concentration and shown in Table 7 below.

Cytokine oral dissolving film Oral mucosal adhesive film stick jelly Boswellia added no additives Boswellia added no additives Boswellia added no additives BLANK 2 2 3 3 4 3 LPS (1ug/ml) 100 100 100 100 100 100 IL-1β 10 30 7 40 15 35 IL-8 18 45 10 42 24 45 TLR4 20 50 10 45 27 59 IL-6 15 32 12 35 26 50

As a result of the above, it was confirmed that the oral dissolving film, the oral mucosal adhesive film, and the stick jelly containing the Boswellia extract according to the present invention have excellent anti-inflammatory relieving effects.

Claims (7)

delete It contains a film forming agent consisting of low molecular weight collagen, elastin, and hyaluronic acid having a molecular weight of 1 to 2 KDa and Boswellia extract,
Further comprising an alkalizing agent using magnesium oxide, sodium hydroxide and potassium carbonate,
The oral dissolving film, characterized in that the magnesium oxide, sodium hydroxide and potassium carbonate are mixed in a weight ratio of 1 to 5: 1 to 5: 1 (magnesium oxide; sodium hydroxide; potassium carbonate). According to claim 2,
Oral dissolution film, characterized in that the blending weight ratio of the low molecular weight collagen, elastin, hyaluronic acid constituting the composition is 10: 0.5: 3 relative to 100 parts by weight of the total composition. According to claim 2,
Oral dissolution film, characterized in that the content of Boswellia extract constituting the composition is 0.1 to 3 parts by weight relative to the total 100 parts by weight. According to claim 2,
Oral dissolution film, characterized in that it further comprises sodium alginate (Sodium Alginate) as a film forming agent in the composition. It contains a film forming agent consisting of low molecular weight collagen, elastin, and hyaluronic acid having a molecular weight of 1 to 2 KDa and Boswellia extract,
The film forming agent forms an oral mucosal adhesive layer, and the Boswellia extract forms a support layer,
Further comprising an alkalizing agent using magnesium oxide, sodium hydroxide and potassium carbonate,
An oral mucosal adhesive film having a dual structure, characterized in that the magnesium oxide, sodium hydroxide and potassium carbonate are mixed in a weight ratio of 1 to 5:1 to 5:1 (magnesium oxide; sodium hydroxide; potassium carbonate). delete

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