KR102044515B1 - Sustained release type orally disintegrating film with excellant oral mucoadhesion and the manufacturing method thereof - Google Patents

Abstract

The present invention relates to a sustained-release oral disintegrating film having excellent oral mucosa adhesion, which contains a component with improved oral mucosa adhesion to allow efficient introduction of effective ingredients contained in an oral mucosa film through a capillary inside a mucosal layer since long-term attachment can be performed when being attached to the oral mucosa for use, and a disintegration time can be delayed by oral saliva by increasing adhesion for oral mucosa through a combination of chitosan or a compound thereof and glutathione with respect to components of an oral mucosa attachable sustained-release oral disintegrating film, and being formed by coating ethyl cellulose exhibiting hydrophobic characteristics on one side of the film, and to a manufacturing method thereof. In addition, the sustained-release oral disintegrating film is purposed for a health functional food or medicine and medical supplies by appropriately mixing and combining effective ingredients having various functional effects on the basis of film base ingredients secured in the present invention.

Description

Sustained release oral disintegrating film with excellant oral mucoadhesion and the manufacturing method

The present invention relates to a sustained-release oral disintegrating film having excellent oral mucoadhesive force and a method for manufacturing the same, and more particularly, comprising chitosan or chitosan-modified derivative as a constituent of the oral mucosa-adhesive oral disintegrating film. It relates to a sustained release oral disintegrating film having excellent oral mucoadhesive force comprising an active active ingredient contained in and a preparation method thereof.

Many food companies and pharmaceutical researchers around the world, including Korea, are bringing new products to market through a variety of rapid technological changes that are inevitable in the rapidly aging society.

As of 2017, the size of the health functional food market in Korea was 27,474.7 billion won, with domestic production of 22,374 billion won and imported products of 575 billion won. (Source: Ministry of Food and Drug Safety 2018.08)

As of 2016, the global health supplement market is approximately $ 121.2 billion, with annual growth rate of 5.7%, with growth expected to exceed $ 160 billion by 2020. (Source: 2017 Global supplement business report, New Hope Network, USA)

As such, the domestic and international health functional food market is steadily growing every year, but the formulation of the product does not deviate from the shape range of liquid, concentrated liquid, powder, jelly, pills, the dosage method depends on simple oral intake.

On the other hand, the pharmaceutical market, which is not a dietary supplement, has been applied to various surgical therapies such as intravenous injection, patch, inhalation, insertion, mucosal absorption, and absorption of the skin layer as a method of intrabody delivery. Recently, attempts have been made to increase absorption in the body by applying such medical treatments in the beauty market and the health functional market.

For example, in the beauty market or some therapeutic supplement products, products for improving skin beauty using patches, ointments, creams, etc. are being produced, and anti-smoking supplements have been used for a long time.

Reflecting this trend, some health functional foods are made in the form of film formulations and commercialized, but most of them are inclined to rapid disintegration, which is dissolved in saliva and quickly passes to the oral cavity.

Regarding the oral intake metabolism, the metabolism of our body when food is ingested is neutralized by various enzymatic reactions in the process that food absorbed through the oral cavity is decomposed by gastric acid and absorbed through the small and large intestine. The basic metabolites absorbed in this way are detoxified and neutralized by the liver through the portal vein, and the blood flows to the whole body. In this process, most of the nutrients undergo physical and physicochemical reactions. Most of the form is lost, and as is well known, carbohydrates are broken down into glucose and fructose, fats are broken down into fatty acids and glycerol, and proteins are broken down into amino acids for absorption in the body.

In the oral intake as described above, the food broken down in the mouth down the esophagus is mostly broken down by gastric acid of the stomach is changed into porridge, carbohydrates are about 1 to 2 hours, protein is 5 to 6 hours, It takes about 7 to 8 hours for fat and less than 3 to 4 hours for fiber, 30 to 1 hour for fruits and nuts, and 10 to 30 minutes for water.

Foods containing many nutrients and functional ingredients to maintain a healthy body, as described above, are also degraded and denatured during metabolic processes, resulting in extremely low absorption.

To solve this problem, manufacturers can either formulate a functional ingredient, take a precursor material, design a state containing a large amount of the active ingredient in consideration of the body's absorption rate, or encapsulate it to withstand the secretions of the intestine. The solution is proposed by using drug delivery techniques.

As a way to increase the absorption rate of products using these functional ingredients, foods using the oral mucosa absorption method, which is one of the drug delivery systems (DDS) that are used in medicine, goes beyond simple oral administration. Doing. (Japanese Patent Laid-Open No. 10-2017-0131542)

The drug delivery technique (DDS) uses the nutrients or ingredients that are useful for the human body, which are often lacking in daily meals, and the benefits of high body absorption through the oral mucosa, ease of taking, and portability. Although it has the possibility of being applied to the functional food market, there is a problem that the field where it can be applied is extremely limited.

The reason for this is, firstly, since disintegration must be continued without dissociation for a long time in the state of being attached to oral cavity, the volume must eventually be small, which is limited to a component that can contain a desired content of an active ingredient and achieve a desired effect. .

Second, if disintegration occurs at a rapid rate by saliva in the oral cavity, the formulation is slowly disintegrated because it does not differ from ordinary oral intake, which goes directly through the oral cavity with the saliva, and undergoes decomposition by gastric acid. It should be possible.

Third, because the contact area between the product and the oral mucosa is large enough to be sufficiently absorbed through the capillaries in the mucosa, it should have a rectangular sheet shape including a rectangular structure, and in order to minimize the heterogeneity in the mouth described above, It should be small and thin, so that the formulation should be possible in the form of a thin film.

Fourth, if the side mucous membrane of the oral cavity, oral ceiling, and sublingual tongue have the adhesive strength of appropriate strength, no gap or lifting between the product and the oral mucosa will occur so that the mucosal capillaries can be efficiently absorbed. Because it becomes.

Fifth, if the active ingredient is adhered to the oral mucosa for a long time in the form of a highly concentrated film, water is released from the mucosal layer of the body by osmotic pressure, and the thin mucosa loses its elasticity. This is because if the material with a mucous membrane may cause damage.

Sixth, because the liver does not undergo the first-pass effect through the portal vein, it should be used only with ingredients that have proven safe for absorption in the body.

As such, despite the fact that the absorption method through the oral mucosa is an efficient delivery method for efficiently absorbing the active ingredient into the body, it is extremely limited for various reasons as described above.

Currently, oral disintegrating film formulations containing sexual improvement agents (viagra, cialis, etc.), red ginseng films, vitamins, mouthwashes, propolis, hangover relievers, lactic acid bacteria, collagen and other nutritional supplements Most of them are sold as rapid oral disintegrating formulations that disintegrate immediately by saliva in the oral cavity and pass into the esophagus, rather than by the mechanism of being slowly absorbed into capillaries through the oral mucosa.

Meanwhile, while the consumption of collagen products is rapidly increasing as a product of the beauty industry group, the company manufactures and sells oral mucosa-absorbing collagen film products, and it is a product with sustained-release technology that maintains oral disintegration time of about 30 to 50 minutes. Although they did not adhere well to the mucous membrane, they were inconvenient to get stuck in the teeth or detachment from the mucosa.

The reason for this is that the technique for enhancing adhesion with the oral mucosa has not been completed, and various prior art and thesis data have been searched.

In addition, in the case of a lot of saliva produced in the oral cavity or due to frequent movement of the tongue and contact there is a problem that a lot of difference in the dissolution rate through the back of the adhesion surface occurs.

Looking at the conventional patent technology related to the orally disintegrating film developed in the prior art, Korea Patent Registration 10-0855566 (Registration date August 26, 2008) film forming agent, antimicrobial agent, fragrance, filler, softener, stabilizer, Oral consumption film comprising saliva stimulant and sweetener and sorbitol fatty acid ester and polysorbet, wherein the film former is composed of a mixture of starch: alginate having a weight ratio of 1: 2.4 to 1: 3 Although consuming films are known, these films improve the physicochemical stability of the functional ingredients and / or pharmaceuticals contained in the film, and improve the storage safety of the film and the capacity to accommodate the functional ingredients and / or pharmaceuticals. It is intended to provide sustained release of the active ingredient.

In addition, Korean Patent Publication No. 10-2009-0128402 (published December 15, 2009) is more than 40% by weight, preferably 40% to 90% by weight of the film, more preferably 50% to 80% by weight Active agents constituting most preferably 50% to 70% by weight, wherein the active agent is a poorly soluble solid at room temperature; And at least one water-soluble polymer, preferably pullulan, which comprises from 10% to 40%, preferably from 10% to 30%, more preferably from 12% to 18% by weight of the film. Fast-dissolving or fast disintegrating films are known, but are intended for fast solubility as opposed to providing sustained release of the active ingredient.

In addition, Korean Patent No. 10-1074271 (Registration date October 11, 2011) discloses rebaudio with a content of rebaudioside A of at least 97% as one or more water-soluble polymers, one or more medically active ingredients, and a tail enhancer. Side A, and oral use comprising at least one first sweetener selected from the group consisting of aspartame, acesulfame salt, neotime, sucralose, taumartin, saccharin, licorice extract, neohesperidine and monelin as taste blockers Although the inner film is known, it is only for shielding the bitter and unpleasant taste of the oral disintegrating film, and does not relate to the sustained release film.

In addition, Korean Patent Registration No. 10-1809174 (Dec. 08, 2017) includes (a) ginseng processed products, and (b) selected from the group consisting of blueberry extracts and thorny ooga extracts for masking bitter taste of the ginseng processed products. And (c) a film forming base, wherein the processed ginseng is a lactic acid bacteria fermented red ginseng concentrate of 60 to 70 Brix, and the blueberry extract is a concentrate of a water extract of 50 to 70 Brix blueberries and Prickly Pear Extract is a concentrate of the Prickly Pear Extract from 50 to 70 Brix, and the Blueberry Concentrate is contained in an amount of 40 to 60 parts by weight based on 100 parts by weight of Fermented Red Ginseng Concentrate. Although the ginseng processed material-containing composition of the orally disintegrating film formulation, which is contained as a part, is known, Film dosage forms are intended for absorption into the body into soluble, removing the bitter and unpleasant taste of oral boron film to also be different at all is the sustained-release film.

In addition, Korean Laid-Open Patent Publication No. 10-2017-0131542 (published November 29, 2017) discloses a base material that can be applied or adhered to the oral cavity, and transdermally contained in the base material. (Iii) An intraoral application containing a polymer active ingredient is known which has a polymer active ingredient having a high molecular weight to an extent that absorption is difficult, and which enables efficient absorption of the polymer active ingredient by application in the oral cavity. As a preparation by transdermal absorption superior to that by injection or oral administration, it is also intended for rapid solubility.

In addition, Korean Patent Laid-Open Publication No. 10-2019-0032384 (published March 27, 2019) discloses an oral mucoadhesive material having a freeze-dried body containing a polymer on an adhesive surface with an oral mucosa, wherein the polymer in the freeze-dried body is The oral mucoadhesive material is known to have a content of 20% by mass or more and a content of hyaluronic acid in the polymer of 50% by mass or more.However, due to the property of having high adhesion as a therapeutic agent for oral mucosal disease, the hyaluronic polymer is an oral mucoadhesive agent. The content of lonic acid is more than 10% of the total mass as a component, and also no sustained-release film is presented.

As described above, most of the oral disintegrating film formulations are sold as rapid oral disintegrating formulations which disintegrate immediately by saliva in the oral cavity and pass to the esophagus, rather than a mechanism of being slowly absorbed into capillaries through the oral mucosa. .

Meanwhile, mucin, a mucus secreted from the oral mucosa, is mainly an oligosaccharide chain based on 5 to 15 monomers such as N-acetylgalactosamine, N-acetylglucosamine, fucose, galactose, and sialic acid. a highly glycosylated protein per consisting of less than 80% carbohydrate as, it contains many anions of an acetyl group and a large amount of sulfonic acid sodium divalent ions (Na ^2+), calcium divalent cation, such as ion (Ca ²⁺⁾ It is well known that it can be combined with cations.

In addition, in the previous paper (Guanyu Chen et al., JPP 2014), polymers for enhancing the absorption of mucous membranes of the sublingual agent have characteristics such as excellent spreadability, biodegradable or bioerodable, viscoelastic ( It has been reported that there should be no loss of compatibility or efficacy with viscoelastic, biocompatible, and active ingredients, and it should be able to help secondary infection improvement such as solubility, economy, shelf life, and dental erosion.

Another paper (Adriana Trapani et al., Bio Macromolecules, 2014) reported that the mucous properties are mainly due to acidic amino acids such as aspartic acid and glutamic acid, and thus the physical properties vary depending on the surrounding pH.

If in acidic environment, hydrogen ions are combined, they are electrically neutral, and the expansion is minimized to prevent the movement of internal materials. However, if the pH is high enough, they have negative properties to attract positive ions and then water to osmosis. It can be expected that the volume is adjusted according to the pH and the permeability of the material is adjusted due to the expansion.

Accordingly, the present inventors have a sustained release of the oral mucosa layer and the disintegrating film in the oral disintegration film produced in a sustained release without being easily separated from the mucosa through the selection, blending, etc. of the film base component and its manufacturing method And research and development of the present invention.

[Patent Document 001] Korea Patent Registration 10-0855566 (Registration Date August 26, 2008) [Patent Document 002] Korea Patent Publication 10-2009-0128402 (published date: December 15, 2009) [Patent Document 003] Korea Patent Registration 10-1074271 (Registration Date October 11, 2011) [Patent Document 004] Korea Patent Registration 10-1809174 (Registration Date December 08, 2017) [Patent Document 005] Korea Patent Publication 10-2017-0131542 (published November 29, 2017) [Patent Document 006] Korea Patent Publication 10-2019-0032384 (Publication date March 27, 2019)

[Paper 001] Evaluation of Absorbability of Macromolecular Substances in the Oral Mucosa and Skin using Three-Dimensional Tissue Culture Model; Takenokuchi et al., Biol Med 2018.10. 5. [Paper 002] Mucoadhesive polymers-based film as a carrier system for sublingual delivery of glutathione; Guanyu Chen et al., Journal of Pharmacy and Pharmacology, 2014 [Paper 003] Mucoadhesive Property and Interaction with P-Glycoprotein (P-gp) of Thiolated-Chitosans and -Glycol Chitosans and Corresponding Parent Polymers: A Comparative Study; Adriana Trapani et al., Bio Micromolecules, 2014 [Paper 004] Effect of N-acetylcycteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study; Bernard Schmitt et al., Redox Biology 2015.

The present invention improves the adhesion to the oral mucosa through the combination of chitosan or chitosan-modified derivatives and glutathione in the components of the oral mucosa-adhesive sustained-release disintegration film, while also showing hydrophobic characteristics on the other side of the film. By coating the formulation, it is possible to adhere to the mucous membrane for a long time when using oral mucosa, and to delay the disintegration time by saliva in the oral cavity so that efficient inflow is possible through the capillaries inside the mucosal layer of useful components contained in the oral mucosa film. An object of the present invention is to provide a sustained-release oral disintegrating film having excellent oral mucoadhesive force containing a component having improved oral mucoadhesive properties.

In addition, the present invention is to solve the problem of providing an oral mucosa absorption type film of the sustained release type for the purpose of health functional food or medicament by properly blending or combining the active ingredients having various functional effects based on the film base component. It is a task.

The present invention solves the problem of a slow-release oral disintegrating film comprising chitosan or chitosan-modified derivative as a constituent of the oral mucoadhesive oral disintegrating film, and having excellent oral mucoadhesive strength including an active active ingredient contained in the film. By means.

The chitosan-modified derivative is to solve the problem that the chitosan is glycol chitosan combined with ethylene glycol.

The active active ingredient is collagen and / or glutathione as a solution to the problem.

The collagen is a fish collagen having a low-volume structure having an average molecular weight of 4,000 Daltons (Da) or less.

The chitosan or chitosan-denatured derivative is combined with an acetyl group contained in mucin, which is a mucus secreted from the oral mucosa, to bind chitosan-N-acetyl-cysteine (CS-NAC) or glutathione as the active ingredient. In combination with the chitosan-glutathione (chitosan-glutathione) to form a chitosan derivative thiomer to solve the problem.

The sustained release oral disintegrating film has a pH of 6.5 or more as a solution for the problem.

The sustained release oral disintegrating film is coated with hydrophobic ethyl cellulose (Ethyl cellulose) on the opposite side attached to the oral mucosa as a solution to the problem.

The sustained release oral disintegrating film is a water-impermeable material is attached to the opposite side that is attached to the oral mucosa as a solution to the problem.

The sustained release oral disintegrating film comprises at least one component selected from flulan, dextrin, glycerin, carrageenan, ascorbic acid, hyaluronic acid, elastin, xylitol, lemon oil, peppermint leaf oil. It is done.

The sustained release oral disintegrating film is used as a food, health functional food, cosmetics, pharmaceuticals as a means of solving the problem.

According to the present invention, the chitosan or chitosan compound and glutathione are formulated in a disintegrating film component for oral mucosa adhesion, and contact with saliva in the oral cavity by thinly coating acetyl cellulose which lowers the water penetration ability to the other side of the film. Sustained-release type mucoadhesive oral disintegrating film that prevents the maximal blockage of the membrane can be maintained for long time adhesion with the oral mucosa, thereby increasing disintegration time, so that useful functional components in the film can stably flow into the capillaries under the mucosal layer. As it does not go through the normal metabolic processes in the body, there is an effect that can maximize the influx effect through the blood circulation system quickly.

1 is an oral disintegration condition test apparatus having INFOGEST saliva mimic conditions

The present invention comprises a chitosan or chitosan-modified derivative as a constituent of an oral mucosa-adhesive oral disintegrating film, and has an excellent oral mucoadhesive film including an active active ingredient contained in the film. It features.

The chitosan-modified derivative is characterized in that the chitosan is a glycol chitosan combined with ethylene glycol.

The active ingredient is collagen and / or glutathione is characterized by a technical configuration.

The collagen is a fish collagen having a low-volume structure having an average molecular weight of 4,000 Daltons (Da) or less.

The chitosan or chitosan denatured derivative is combined with an acetyl group contained in mucin, which is a mucus secreted from the oral mucosa, and then chitosan-N-acetyl-cysteine (CS-NAC) or glutathione as the active ingredient. In combination with the chitosan-glutathione (chitosan-glutathione) to form a chitosan derivative is characterized by the technical configuration.

The sustained release oral disintegrating film is characterized by a technical configuration that the pH is 6.5 or more.

The sustained release oral disintegrating film is characterized by being coated with ethyl cellulose (Ethyl cellulose) having hydrophobicity on the opposite side that is attached to the oral mucosa.

The sustained release oral disintegrating film is characterized in that the water-impermeable material is attached to the opposite side that is attached to the oral mucosa.

The sustained release oral disintegrating film comprises at least one component selected from pullulan, dextrin, glycerin, carrageenan, ascorbic acid, hyaluronic acid, elastin, xylitol, lemon oil, and peppermint leaf oil. It is done.

The sustained release oral disintegrating film is characterized by the technical configuration that is used as food, health functional food, cosmetics, pharmaceuticals.

Hereinafter, the present invention will be described in detail with reference to embodiments and / or drawings so that those skilled in the art may easily implement the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.

First, a polymer plasticizer having cationic properties whose food safety has been verified and capable of forming a film can be found. First, candidates that can be dissolved in saliva mimic conditions shown in Table 1 were selected.

The reason for this process in advance is that even a polymeric plasticizer with good cationic properties, if it is insoluble by oral saliva, is left as a foreign substance in the oral cavity.

Pullulan was selected as a viscosity enhancer and the dextrin, a modified starch, was selected as the viscosity stabilizer.

Carrageenan (alkaline), moisturizing glycerin and hyaluronic acid, elastin (Elastin), vitamin C (ascorbic acid), which acts as a thickener, gelling agent and stabilizer, Xylitol was selected as a sweetener, lemon oil and peppermint leaf oil were selected as flavoring agents.

Table 1 used standardized protocols based on international consensus developed by the INFOFEST network established by more than 35 countries around the world to mimic gastric juice.

Constituent Saliva Mimic Conditions ml / 400L ml / 1L KCl 15.1 37.75 KH2PO4 3.7 9.25 NaHCO3 6.8 17.00 NaCl - - MgCl 2 (H 2 O) 6 0.5 1.25 (NH4) 2CO3 0.06 0.15 NaOH - - HCl 0.09 0.23 CaCl2 (H2O) 2 0.025 0.06 water Up to 400 934.31

Soluble in the saliva mimic condition solution, there is no dispersibility, biodegradability or biocorrosion, viscoelasticity, biocompatibility, or compatibility with the active ingredient in the polymer plasticizer having solubility and cationic properties, solubility, economy, storage, Chitosan was chosen as the final material that could help improve secondary infections such as dental erosion.

Chitosan is made from chitin, a polymer that forms shells of crabs and shrimps, and is already widely known as a health food. It is also proven to be edible and hydrolyzed in the body to produce a substance called glucosamine.

Furthermore, chitosan has a multi-amino group of constituent cations, which makes it possible to form a firm bond with the anionic group of mucus, thereby increasing mucoadhesiveness, as reported in the research paper (Adriana Trapani et al., Bio Macromolecules, 2014). Pharaoh reported that it increases mucoadhesion of hydrophilic drugs.

Nevertheless, at pH 6.5 and above, it has a disadvantage of low solubility. Usually, the pH of the oral saliva varies from about 5.75 to 7.05, so in some cases, the chitosan in the film may be insolubilized. Further investigation is needed.

After much investigation and trial and error, Glycol chitosan (GCS) combined with ethylene glycol was found to be water-soluble under neutral conditions, especially thiol on the polymer bond structure. It was found that covalent bonds with groups were possible.

Chitosan derivatives bound to thiol groups are called thiomers, and can covalently bind to glycoproteins of mucin in mucus, and are replaced with the disulfides of thiol groups to form chitosan-en-acetyl-cysteine. Multiple chitosan binding based thiomers, such as Chitosan-N-acetyl-cysteine (CS-NAC) or Chitosan-glutathione, will be produced.

Therefore, it was convinced that the addition of chitosan and glutathione, which are well-known as a functional raw material for film composition, could be very useful for enhancing the performance of oral mucosal absorption type film products. Especially, glutathione has a skin whitening effect and antioxidant activity. Due to its efficacy, the parallel use with collagen has doubled its effectiveness, and we know that this type of product has not yet appeared on the market.

In some cases, the secretion of saliva in the oral cavity may increase the rate of film disintegration, and in this case, the saliva and other functional components must go directly to the stomach, so on the other side of the film that is not attached to the mucosa For the purpose of the present invention, a thin coating of ethyl cellulose (Ethyl cellulose), which can serve to block water permeability, is proposed.

Comparative Example 1

[Step 1: Material Preparation]

Collagen purchased granular products extracted from Weishardt's fish, which has an average molecular weight of 4,000 Daltons or less, and even though absorption through oral mucosa is obvious, the absorption rate decreases as the molecular weight increases. The selection of products below Dalton is considered cost-effective.

Ethyl cellulose was purchased as an EP grade liquid Duksan chemical product, and flulan, which is used as a thickener, was purchased through Sinwon Trading Co., Ltd. as a product for food in the pH range of 5-7.

Dextrin, a thickener and viscosity stabilizer, is a food grade product with a pH range of 4.5 to 7, purchased through Shinwon Trading Co., Ltd., carrageenan acting as a thickener, gelling agent, stabilizer, vegetable glycerin, edible hyaluronic acid, It was purchased from Now Food Co., Ltd.

Ascorbic acid and xylitol were purchased from Sigma Aldrich Co., Ltd., with a purity of 99% or higher, while lemon oil and peppermint leaf oil were purchased through Shinwon Trading.

[Step 2: Adjusting Mixing Ratio]

Based on the pure collagen content 100mg using the prepared material, the basic component ratio for the main component affecting the physical properties of the film having a weight of the final 300mg, a sample product containing no chitosan was investigated as shown in [Table 2].

[Unit: mg ] Sample Number Collagen Pluran dextrin glycerin Carrageenan One 100 100 50 50 0 2 100 100 50 30 20 3 100 100 50 10 40 4 100 80 70 50 0 5 100 80 70 30 20 6 100 80 70 10 40 7 100 50 100 50 0 8 100 50 100 30 20 9 100 50 100 10 40 10 100 30 120 50 0 11 100 30 120 30 20 12 100 30 120 10 40

It is noted that this blending condition is an empirical criterion for finding the basic formulations which the inventors have learned by long experience.

[Step 3: Sample Preparation]

Twelve Petri dishes (150 × 25 mm) were prepared, and a 100 μm thick PET film was cut to the same bottom size of 150 × 25 mm to prepare a dry container attached to the Petri dish bottom.

When the formulation is formulated with a ratio of 1 to 1 with purified water to prepare a total of 600mg liquid to be dissolved by mixing for 30 minutes using a magnetic stirrer, and should not be left in the bottom of the beaker should be clear and transparent.

Each sample was poured into Petri dishes at a height of 1 mm, dried for 1 hour in a convection oven at 100 ° C., and then a total of 12 completed samples were prepared after 30 minutes of aging at 50 ° C.

In order to match the height of 1mm, 1mm metal piece should be prepared and put into Petri dish first, and then poured slowly until the metal piece is locked.

The reason for annealing at 50 ° C after drying at 100 ° C is to easily generate cracks during quenching so that stepwise cooling is necessary and to relieve internal stress in the film layer generated during the high temperature drying process.

The finished sample is first visually observed for defects such as microscopic cracks and bubbles, and the crack is generated by hardening during cutting to 30x20mm (width x length).

Each cut specimen is bent 180 degrees in the longitudinal direction and re-observed for flexibility and cracking.

Based on 100 mg of pure collagen content, the results of drying the film having a weight of 300 mg, which is a sample product containing no chitosan, are summarized in [Table 3].

Sample Number Sample surface in Petri dish Sample change during the cutting process Sample change when bending 180 degrees Perfection One Microbubbles Good Good △ 2 Good Good Good △ 3 Microbubbles Good Good △ 4 Good Good Good ○ 5 Good Good Good ◎ 6 Good Good Good ◎ 7 Good Good Good ○ 8 Warping Weak crumbs Crumbs × 9 Warping Good Crumbs × 10 crack offshoot Crumbs × 11 crack offshoot Crumbs × 12 crack offshoot Crumbs ×

As can be seen from Table 3, when the amount of pullulan is increased, microbubbles are generated in the drying process, and as the amount of dextrin increases, the internal hardness increases to show cracking, cracking, and chipping.

In the above results, the sample No. 5, 6 was determined to be the best, and the content of the main component of the sample product containing 100 mg of collagen and not containing chitosan was 80 mg of flulan, 70 mg of dextrin, 30 mg of carrageenan, as shown in [Table 4]. 20 mg of glycerin was used as the base formulation.

[Unit: 300mg ] Main ingredient content Collagen Ffuran dextrin Carrageenan glycerin 100 80 70 30 20

The content of collagen is 100 mg, with a total content of 200 mg of pullulan, dextrin, carrageenan, and glycerin, based on the total content of 200 mg of pullulan 40%, dextrin 35%, carrageenan 15%, and glycerin 10%. In this drying process, it was judged that it had the least influence on the appearance change of the film.

In other words, when the collagen content is fixed at 100, the blending ratio of pullulan: dextrin: carrageenan: glycerin is 4: 3.5: 1.5: 1 means that the weight ratio of the mixture.

Here, since high content of flulan, dextrin, carrageenan, and glycerin have a great influence on product properties during the drying process, the difference in component ratio is primarily examined, and other excipients have a large effect on properties due to the addition of a small amount. It was determined that it does not affect the general composition of the oral disintegrating type film is generally used.

Therefore, the final formulation ratio of the sample product containing 100 mg of collagen and no chitosan in the composition shown in Table 5 was determined.

[Unit: 300mg ] Final compounding ratio Collagen Pluran dextrin glycerin Carrageenan Ascorbic acid Hyaluronic acid Elastin Xylitol Lemon Oil Peppermint Leaf Oil 100 69 60 26 17 10 6 2 5 3 2

It is noted that the compounding ratio of pullulan: dextrin: carrageenan: glycerin in the remaining amount excluding the addition amount of other excipients is reconstituted as 4: 3.5: 1.5: 1 in the compounding ratio.

With the composition as shown in Table 5, 10 sample products including 100 mg of collagen and a total weight of 300 mg without chitosan were prepared through the same process as the sample preparation method described above.

[Step 1: Material Preparation]

In addition to the material used in Comparative Example 1, chitosan is a product having an electrically positive charge by deacetylation with sodium hydroxide in a commercially available product, and more specifically, by Glycol chitosan (GCS), VITATRA (US) The product was purchased.

[Step 2: Adjusting Mixing Ratio]

Based on the pure collagen content 100mg using the prepared material, the basic component ratio for the main component affecting the physical properties of the film weighing the final 300mg, a sample product containing chitosan was investigated.

In Example 1 was used in the same manner as the material composition of Comparative Example 1, but the physical properties change in the drying process was first confirmed under the conditions of [Table 6] to find the optimal mixing ratio according to the content of chitosan.

[Unit: 300mg ] sample Glycol
Chitosan Collagen Pluran dextrin glycerin Carrageenan Ascorbic acid Hyaluronic acid Elastin Xylitol Lemon Oil Peppermint Leaf Oil One 10 100 65 57 24 16 10 6 2 5 3 2 2 20 100 61 53 23 15 10 6 2 5 3 2 3 30 100 57 50 21 14 10 6 2 5 3 2 4 40 100 53 47 19 13 10 6 2 5 3 2 5 50 100 49 44 18 12 10 6 2 5 3 2

The ratio of flulan: dextrin: carrageenan: glycerin with respect to the remaining amount in the state in which both the collagen 100 mg and the small amount of excipients added to 10 mg or less were fixed while varying the amount of glycol chitosan added up to 10 to 50 mg. 4: 3.5: 1.5: 1

[Step 3: Sample Preparation]

Five Petri dishes (150x25mm) were prepared, and a 100 μm-thick PET film was cut and attached to the Petri dish bottom surface with the same bottom size of 150x25mm. The same procedure was followed.

[Table 7] summarizes the results of changing the appearance of a film having a weight of 300 mg, which is a sample product containing chitosan, based on 100 mg of pure collagen content.

Sample Number Sample surface in Petri dish Sample change during the cutting process Sample change when bending 180 degrees Perfection One Good Good Good ◎ 2 Good Good Good ◎ 3 Good Good Good ◎ 4 Microbubbles crack Good x 5 Micropore Good Crumbs x

As can be seen from the above table, when the amount of glycol chitosan was increased, the internal hardness increased during the drying process, and it was found that cracking, cracking, and chipping phenomena occurred.

Therefore, based on the results, the pure collagen content based on 100mg, the formulation ratio of the composition of the film having a weight of the final 300mg of the sample product containing chitosan was determined as shown in Table 8.

GCS Collagen Pluran dextrin glycerin Carrageenan Ascorbic acid Hyaluronic acid Elastin Xylitol Lemon Oil Peppermint Leaf Oil 30 100 57 50 21 14 10 6 2 5 3 2

In the results of Table 8, GCS can be used in the range of all 10 ~ 30mg, the essential purpose of the present invention mucus through the glycol chitosan (Glycol chitosan, GCS) combined with ethylene glycol (Ethylene glycol) It is necessary to maximize the amount of addition, if possible, to make thiomers based on the acetyl group and chitosan bond of anion of mucin.

 Experimental Example

Sustained release (disintegration) measurement

6 Comparative Samples and 6 Example Samples were prepared based on the compositions determined in Comparative Examples 1 and 1, respectively, and then 3 samples of the samples of Comparative Examples 1 and 1 were prepared in ethyl cellulose ( Ethyl cellulose) was thinly coated to compare the disintegration rate.

It is a matter of course that all samples were prepared in the same process sequence as in the previous method, and only the presence or absence of ethyl cellulose spray coating is different.

Ethyl cellulose was dissolved in purified water at a ratio of 10 and put into a small mist sprayer. Sprayed three times at a distance of about 30 cm from Petri dishes, and completely dried in a 50 ° C convection oven for 30 minutes to prepare a final disintegrated sample. It was produced.

The device for disintegrating was configured as shown in [Figure 1], wherein the solution used is the INFOGEST saliva mimic condition protocol as specified in [Table 1].

[Table 9] is based on 100mg of pure collagen content, three film samples having a final weight of 300mg, a sample product containing no chitosan, and coated with ethyl cellulose, which can serve to block water permeability. 3 film samples, 3 film samples containing chitosan and weighing final 300 mg based on 100 mg of pure collagen content, and a film sample coated with ethyl cellulose, which serves to block water permeability. The total disintegration time for each sample in the saliva mimic condition apparatus was measured for a total of 12 samples including the medium.

Sample Number Chitosan
Contains Ethyl cellulose coating Disintegration time (minutes) Ethyl cellulose presence average (min) Chitosan presence average (minutes) One (X) (X) 12.3 12.9 14.5 2 13.7 3 12,6 4 3 coating 14.6 16.1 5 17.5 6 16.3 7 30 mg (X) 29.4 32.6 37.0 8 35.6 9 32.9 10 3 coating 41.1 41.5 11 39.5 12 43.8

As seen from the above results, the disintegration time is increased by 155% when the chitonic acid is contained, and the average disintegration delay time is increased by about 26% when ethyl cellulose is coated.

[Oral Mucoadhesion Measurement]

[Table 10] shows a film sample containing chitosan and weighing 300 mg of pure collagen, and a film sample coated with ethyl cellulose, which can serve to block water permeability. It is the result of testing the adhesion force in the oral mucosa of each of three samples including the oral mucosa-adhesive collagen film (product name CH.V, our product) on sale.

Since this experiment is for investigating the effect of adhesion with saliva secreted from the oral mucosa, it is impossible to implement an experimental simulation device. Therefore, the result was directly attached to the oral mucosa of the subjects.

The test subjects consisted of age groups of 20 ~ 40 years old and were limited to 5 volunteers who did not have inconvenience due to sufficient saliva secretion when chewing biscuits or chewing gum.The test was repeated for 3 days (n = 15) for each sample. Result was obtained.

phenomenon Contains 100 mg of collagen,
Chitosan-containing Contains 100 mg of collagen,
Chitosan,
Ethylcellulose coating Our product
(Product Name: CH.V) Mucosa adhesion 14/15 13/15 4/15 Attachment to teeth 0/15 1/15 6/15 Complete tally 0/15 0/15 3/15 Folding light guitar 1/15 1/15 2/15

As can be seen from the above results, the inclusion of chitosan, regardless of the presence or absence of ethyl cellulose coating, it can be seen that the discomfort is greatly reduced by improving the adhesion to the oral mucosa.

[Mixed evaluation of glutathione]

Table 11 shows chitosan as a constituent of the oral mucosa absorption film, but a film having a final weight of 300 mg obtained by adding glutathione instead of collagen or mixing collagen and glutathione in a 1: 1 ratio appears in the drying process. The change results are summarized.

sample Glycol
Chitosan Collagen Glutathione Pluran dextrin glycerin Carrageenan Ascorbic acid Properties after drying (n = 3) One 30 100 0 57 50 21 14 10 normal 2 30 50 50 57 50 21 14 10 normal 3 30 0 100 57 50 21 14 10 normal

The glutathione used herein was purchased from L-glutathione powder (NSF, USA) and used, and the experimental conditions and test methods were performed in the same manner as in [Table 3].

        The property after drying was examined as a result of inspection of microbubbles, macro cracks, warpage, cracks (hair shapes), and chipping, which are the inspection items in [Table 3].

        This experiment is only a preliminary experiment in place of collagen or in the case of using a mixture of collagen and glutathione, but concerns about the change in properties during the drying process, the addition of glutathione is a chitosan prepared in a sustained release in the present invention as in the case of collagen It was confirmed that it is in harmony with the containing composition.

Through several previous tests, it contains chitosan or more preferably Glycol chitosan (GCS) as a component of sustained release film formulations for rapidly absorbing functional foods or medicines through oral mucosa. It can be confirmed that doing so can increase the disintegration time caused by oral saliva.

Even if it is defined as a comprehensive feature of chitosan having an anionic acetyl group and a sulfonic acid group and a cationic group capable of bonding structure in the mucosa secreted by the oral mucosa as a core component of the film component, those skilled in the art Of course, there will be no objection.

In addition, it was confirmed that the disintegration time by saliva in the oral cavity can be increased by coating the other side of the film with ethyl cellulose (Ethyl cellulose) capable of blocking the moisture permeability.

It is to be clarified that the method of applying any hydrophobic coating or an extreme thin vinyl film to the opposite coating surface attached to the oral mucosa does not deviate significantly from the scope claimed in the present invention.

The above description is merely illustrative of the technical spirit of the present invention, and those skilled in the art to which the present invention pertains may make various modifications and changes without departing from the essential characteristics of the present invention.

Therefore, the embodiments and / or drawings disclosed in the present invention are not intended to limit the technical spirit of the present invention, but to explain, and the scope of the technical spirit of the present invention is not limited by these embodiments and / or drawings. .

The protection scope of the present invention should be interpreted by the following claims, and all technical ideas within the equivalent scope should be interpreted as being included in the scope of the present invention.

1: sample holding support
2: INFOGEST saliva mimic condition
3: collagen film sample
4: Magnetic stirrer for temperature maintenance and oral condition
5: timer for disintegration time measurement
6: pH meter with thermometer function

Claims (10)

The oral mucoadhesive type oral disintegrating film comprises chitosan-modified derivatives comprising glycol chitosan in which chitosan is combined with ethylene glycol, and the active ingredient contained in the film is collagen or collagen and glutathione. Sustained release oral disintegrating film excellent in oral mucoadhesive, characterized in that it comprises a mixture
delete delete The method of claim 1,
The collagen is a slow release oral mucoadhesive film having excellent adhesion to oral mucosa, characterized in that the fish collagen having a low molecular weight structure of less than 4,000 Daltons (Da) in average molecular weight.
The method of claim 1,
The chitosan-modified derivatives bind to acetyl groups contained in mucin, a mucus secreted from the oral mucosa, and bind to chitosan-N-acetyl-cysteine (CS-NAC) or glutathione, the active ingredient. Sustained release oral disintegration film excellent in oral mucosa, characterized in that to form a chitosan derivative of chitosan-glutathione (chitosan-glutathione)
The method of claim 1,
The sustained release oral disintegrating film is excellent in oral mucoadhesive strength, characterized in that the pH is 6.5 or more sustained release oral disintegrating film
The method of claim 1,
The sustained release oral disintegrating film is a slow release oral mucoadhesive film having excellent adhesion to oral mucosa, characterized in that coated with hydrophobic ethyl cellulose (Ethyl cellulose) on the opposite side attached to the oral mucosa.
The method of claim 1,
The sustained release oral disintegrating film is a slow release oral disintegrating film having excellent oral mucoadhesive properties, characterized in that the water impermeable material is attached to the opposite side attached to the oral mucosa
The method of claim 1,
The sustained release oral disintegrating film is oral cavity characterized in that it comprises at least one component selected from flulan, dextrin, glycerin, carrageenan, ascorbic acid, hyaluronic acid, elastin, xylitol, lemon oil, peppermint leaf oil. Sustained release oral disintegration film with excellent mucoadhesion
The method of claim 1,
The sustained release oral disintegrating film is a slow release oral disintegrating film having excellent oral mucoadhesive characteristics, which are used as foods, health functional foods, cosmetics, and medicines.

Images