TWI277419B - Oral gel composition for releasing the pains caused by mucositis - Google Patents

Abstract

The present invention discloses an oral gel composition for releasing the pains caused by mucositis, which includes water and the following components dissolved in water: polyvinylpyrrolidone having a K value of 30-100 and protonated chitosan. The weight ratio of protonated chitosan to polyvinylpyrrolidone ranges from 0.1:100 to 10:100. The oral gel composition has a viscosity of 50-1500 centipoise.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intraoral adhesive composition for alleviating the pain caused by mucosal or gum ulcers in the oral cavity. Prior Art Oral mucositis is characterized by recurrent, erythema and painful ulcers, and is a common complication of standard and high-dose chemotherapy or radiation therapy for head and neck cancer. This situation is estimated to affect approximately 40% of patients receiving standard dose chemotherapy and 75 percent of patients receiving the same dose of chemotherapy or bone grafting, while almost all patients with head and neck cancer are receiving radiation therapy. Oral mucositis will occur afterwards. In addition, this symptom is common in patients with weakened immune systems, such as AIDS patients. Oral ulcers are extremely painful and often cause the patient to be unable to eat properly, so the necessary food intake and water supplementation may result in the use of intravenous water and/or nasogastric tube feeding. Studies have shown that 70% of patients with bone marrow transplants need to use an intravenous opiate to relieve pain. In many patients, the severity of H pain affects the slowing of cancer treatment time: even completely stopped, it is reported in the literature that when the patient has one to two oral mucositis, the average cost is 913 dollars. Handle it.曰 Currently, the most common treatments are local anesthesia, sebum steroids, general analgesic, systemic or topical anti-inflammatory drugs, but there is no “golden” standard treatment for pain reduction. Up to now, 3 V people are satisfied 5 1277419 - The treatment is available. Therefore, there is a great need to develop a drug that can effectively alleviate or protect patients from oral ulcers. U.S. Patent Publication No. US 2002/0173485 A1 discloses a pharmaceutical composition for alleviating pain caused by ulcers of mucous membranes (e.g., oral cavity, stomach, etc.) and for treating or preventing inflammation of the mucosa, including 〇〇5 wt% hyaluronic acid 〇 The crucible has a viscosity of from 50 to 5 centipoise (cps), from 4 to 15 by weight of 1% of polyethylene π, and between 86 and 98% by weight of water. However, φ hyaluronic acid is a raw material which is expensive and must be stored at a low temperature, so the use of hyaluronic acid is not conducive to the manufacturing cost. The content of this patent is incorporated herein by reference. Chitin and chitin (chit〇san) are naturally non-toxic southern molecules and are biodegradable. Their structure is similar to cellulose, with 1000-3000 N-acetylglucosamine ( N-acetyl-2 amin〇_2 DEOXYHGLUCOSE or n-ACETYL-d-GLUCOSAMINE) A linear polymer saccharide consisting of cold-1,4 bonds (the structural formula is shown below). In nature, chitin is the most abundant amino sugar type polysaccharide on earth, second only to cellulose. It is mainly found in the shells of invertebrates such as insects and aquatic crustaceans, as well as the cell wall of fungi. Its role in the organism is mainly used as a body skeleton and protection. Chitosan is a chitin-deacetylated product. Usually, the chitosan-deacetylated group is more than 70%, and it becomes an acid-soluble chitosan product. 6 .1277419 CH3

¥ Chitosan is insoluble in water and organic solvents, but soluble in some organic acids. The chitosan acidic solution can be used as a bacteriostatic agent because the amino group of chitosan (-NH2) is positively charged (·νΗ3+) in an acidic solution, and the cell wall of the microorganism is negatively charged, so it can be combined with the cell wall. It destroys cell production and achieves bacteriostatic effects. The salt after protonation (or neutralization) of chitosan can be directly dissolved in water, for example, Kytamer PCA, which is a chitosan product neutralized by pyrrolidone carboxylic acid. A chitosan product, Seacure + 2 10, which is commercially available from Amerchol Corporation and neutralized with giutaniic acid, is commercially available from Protan Corporation. In addition to being an adsorbent for adsorbing heavy metals and odor molecules, solids of chitosan are also used as oral agents for adsorbing fats and lowering cholesterol. In addition, an aqueous solution of neutralized chitosan and an aqueous solution of polyvinylpyrrolidone are mixed to prepare a film for wound dressing, for example, 1; 8 5, 420, 197 and 6, 379, 702, 7. 127.7419. The contents of these two U.S. patents are hereby incorporated by reference in its entirety for all of the utility of the present disclosure in the present disclosure. &Essentially preserved and manufactured at a cost compared to the present invention, the intraoral gel composition comprises water and the following active ingredients dissolved in water. Polyvinylpyrrolidone having a kappa value of 3〇_1〇〇; and protonation Chitosan; wherein the protonated chitosan to polyvinylpyrrolidone has a weight ratio of 0.1:100 to 10:1, preferably a protonated chitin of the present invention. The weight ratio of bile to polyvinylpyrrolidone ranges from 〇5:100 to 6:100. Preferably, the intraoral gel composition of the present invention has a viscosity of from 5 〇 to 1 5 〇〇. Embodiment 1 A method suitable for preparing the intraoral gel composition of the present invention comprises the steps of: a) mixing chitosan, water and acid to form an acidic aqueous solution in which chitosan is dissolved; b) slowing polyvinylpyrrolidone or The chitosan aqueous solution of step a) is added in portions and stirred to form an intra-oral gel group 8.1277419 _ of the desired viscosity. Another suitable method for preparing the intraoral gel composition of the present invention comprises dissolving the neutralized chitosan in water, adding the polyvinylpyrrolidone slowly or batchwise to the aqueous solution, and stirring to form a mouth having a desired viscosity. Gum composition. It is apparent that the polyvinylpyrrolidone can also be added to the aqueous solution in which chitosan is dissolved in the form of an aqueous solution. Chitosan suitable for use in the present invention has a degree of deacetylation of from 60 to 99% and a molecular weight of from 1 to 10 Torr to 1 Torr. Suitable for use in the present invention. The chitosan is a salt of the aforementioned polybutanization which is suitable for use in the present invention, such as pyrrolidone hydroxy acid salt and glutamic acid as described in the aforementioned prior art section. Salt and so on. Polyvinylpyrrolidone suitable for use in the present invention is a polyethyl hydrazine having a K value of from 3 Å to 1 〇 0. The κ value represents a function of the molecular weight of the polyethylene oxime. The enthalpy is calculated from the viscosity measurement and is calculated according to the Eikentscher's formula described by Kline, α Μ., Lu uPolyvinylpyrrolidone, 5, Modern Plastics, P. 157 (Nov. 1945). The ratio of the chitosan to the polyvinylpyrrolone in the adhesive composition of the present invention is in a weight ratio of 0.1 to 10:100. If the amount of chitosan is too small, for example, less than 1 part by weight of chitosan per 100 parts by weight of polyhexene oxime ketone, there is not enough interaction between the two, if The use of more than 10 parts by weight of polybutanose may result in a film having a low adhesion to the film formed by applying the adhesive composition to the mucosa. In the foregoing process for preparing the present personal gel composition, the amount of water 9 1277419 is related to the viscosity of the final composition. When the intraoral gel composition has a viscosity of from 50 to 1500 centipoise, the water content may be from 2 to 20 times the weight of the polyvinylpyrrolidone and the polybutanose. The total amount of water used can be used in batches or once in the preparation of the oral gel composition. However, it is also possible that the intraoral gel composition is stored in a concentrated manner (i.e., only a portion of the water is used during preparation) and is diluted with water to a desired viscosity during use. Preferably, the acid used in the step a) of the method for preparing the intraoral gel composition of the present invention is selected from the group consisting of formic acid, acetic acid, lactic acid, citric acid, Tartaric acid, suceinic acid, malic acid, oxalic acid, glycolic acid, dichloroacetic acid, trifluoroacetic acid, single a group of tannic acids. The acid is used in an amount sufficient to dissolve all of the chitosan enough to theoretically suffice the amount of all amines of chitosan. Excessive acid is not conducive to the preservation of the intraoral adhesive composition p of the present invention. use. The intraoral glue composition of the present invention can be improved to include a Viscosity-increasing agent, a Surfactant, a Stabilizing agent/Preservatives, a flavoring agent, a flavoring agent, a sweetener (flavor). , fragrance, sweetening agent), bioadhesive and co-solubilizer. For example, cellulose derivatives, (mercapto) propionate polymers and copolymers, ethylene glycol or propylene glycol, polyethoxylated hydrogenated castor oil, EDTA, sodium benzoate, potassium hexadienoate (potassium) Sorb ate), 1277419 . Dextrin, s〇dium saccharin, aspartame, and other ingredients that can be used in mouthwash formulations. The intraoral gel composition of the present invention may further comprise a pharmaceutically active ingredient such as a bactericide, a disinfectant, an antifungal agent, an antiallergic agent, an anti-inflammatory agent and the like. Suitable antimicrobial agents include, but are not limited to, a fourth ammonium salt such as benzalkonium chloride. When the intraoral glue composition of the present invention contains the above components other than polybutanose and polyethylidene φpyrrolidinone, the components may be directly added to an aqueous solution in which polybutanose and polyvinylpyrrolidone are dissolved, or as an aqueous solution. Or the dispersion form is mixed with the aqueous solution in which polybutanose and polyvinylpyrrolidone are dissolved. The invention is further understood by the following examples, which are intended to be illustrative only and not to limit the scope of the invention. Example 1

This example was carried out to evaluate the intraoral adhesive composition as a topical treatment for oral mucositis caused by chemotherapy. " 1277419 Test medication First group ~V ^ 〇U7〇 J Polyvinylpyrrole (K90) Ligand diol Potassium dienonate Sodium benzoate

Ethylene diamine tetraacetic acid steel smoke-based gas card ammonium saccharin sodium pure water preparation method: 尺胶1 · 0.1 grams of chitosan (to the acetaminophen and one minute 畺 '| in 10,000 to 350,000, Kay Desheng Technology Co., Ltd., Taiwan) Suspended to 42.5 g of pure water and added 13 g of lactic acid solution to a clear clarification. Polyethylene ruthenium (a total of 9.59 g) was added in portions (K value of 90 'Huimin Pharmaceutical Co., Ltd. Taiwan) and stirring was continued to form a gelatin gel. / Mixing liquid 2. Add 4 g of hexadiene I potassium 〇 · 01 g of sodium ethylene diamine tetraacetate, 〇. 〇 4 g of sodium benzoate, 〇 12 g of hydrocarbyl carbamide, and continuously stir in 42.5 g of an aqueous solution. To clear and transparent, finally add the sucrose syrup 'continuous mixing' at this time the solution is a white non-clarified suspension. The first component: the solution 2 is slowly added to the water gel 1, and the solution is changed from heterogeneous to homogeneous clarification, and finally 3.2 g of propylene glycol and 12 127.7419 - 丨 76 g of pure water are added, and the mixture is stirred. Uniformly available ο. 1% light yellow chitosan water gel. The second group of weight percentage (%) oTio 0. 26 9. 59 3· 20 0. 04 0. 04 0. 01 0. 12 0.01 86· 43 Group composition chitin poly ^ ' lactic acid (> 80%) polyethylene Pyrrolidone (K60) propylene diacetate potassium benzoate ethylene diamine tetraacetic acid naphthenic gas card ammonium saccharin sodium pure water preparation method: water gel 3: 〇 · 3 grams of chitosan (deacetylation degree of 97%) And a molecular weight of between 350,000 and 1 million, Kaidesheng Technology Co., Ltd., Taiwan) suspended in 42.5 grams of pure water, and added 〇 13 grams of lactic acid solution to stir transparent clarification. Polyvinylpyrrolidone (9.59 g in total) (K value of 60, Huimin Pharmaceutical Co., Ltd., Taiwan) was added in portions and continuously stirred into a clarified thick gel. Solution 4: sequentially add 〇·04 g of potassium dibutate, ο·οιg of sodium ethylenediaminetetraacetate, 004 g of sodium benzoate, and 12 g of hydrocarbyl chlorocarbamide in a 42.5 g aqueous solution, stirring continuously until clarification Transparent, finally added 〇. 〇 1 g of sodium saccharin, stirring continuously, at this time the solution was a white non-clarified suspension. 13 1277419 Second component: Slowly add solution 4 to the water gel 3, at which time the solution changes from heterogeneous to homogeneous, and finally adds 2-3 g of propylene glycol and 1 · 43 g of pure water, stirring continuously. A light yellow chitosan water gel of (10) is available. The third group Weight percentage (%) 0:50 0. 39 9· 59 3. 20 0. 04 0. 04 0. 01 0. 12 0. 01 86. 10

Chitosan lactic acid (> 80%) polyvinylpyrrolidone (K30) propylene glycol hexadienoate potassium benzoic acid sodium methoxide monoamine tetraacetic acid naphthyl gas catalyzed sodium saccharin sodium pure water preparation method: / 5 · will 〇 · 5 grams Butanose (to the degree of deacetylation and one point 1 '10,000 to 330,000, Kaidesheng Technology Co., Ltd., Taiwan) Suspended to 42 5 ancient Μ, 1 · see 砘 water, and add 0 · U grams of lactic acid solution Stir until clear and clear. Male 4 ^ 3〇 · - People added polyvinylpyrrolidone (9. 59 grams) (depreciation is a limited company 'Taiwan) and continued to stir the water gel.

Solution 6 : 9 c , potassium L acid was added sequentially to 4 · 5 g of 〇 · 〇 4 g of hexadiene, 〇 01 swallowed ethylene diamine tetraacetate, 〇 · 〇 4 g of sodium benzoate, 〇 12, 127.7419 g The hydrocarbon-based chlorinated saddle was stirred until clear and transparent, and finally the strontium sulphate sodium was continuously stirred. At this point the solution was a white non-clarified suspension. The third component······························································································· Available in 5% of light yellow chitosan water gel. The fourth component weight percentage (%) polyvinylpyrrolidone (K100) 9. 59 propylene glycol 3. 20 hexadieno acid unloading 0. 04 sodium benzoate 0. 04 sodium ethylene diamine tetraacetate 0. 01 hydrocarbyl chlorocarbamide 0. 12 Sodium saccharin 0. 01 Pure water 86· 99 φ Preparation method: Water gel 7: Add polyvinylpyrrolidone (9.59 g total) in 42.5 g of pure water (kappa value is 1 〇〇, Huimin) Pharmaceutical Co., Ltd., Taiwan), and continued to stir into a condensed concentrated water gel. Solution 8: 〇·04 g of potassium hexadienoate, 0.01 g of sodium ethylenediaminetetraacetate, sodium gram benzoate, 0.12 g of hydrocarbyl chlorocarbamide were sequentially added to a 42.5 g aqueous solution, and stirring was continued until clear and transparent, and finally 0· 01 g of sodium saccharin was continuously stirred, at which time the solution was a white non-clarified suspension. The second component: the solution 8 is slowly added to the water gel 7, the solution is dissolved in 15, 127, 7419. The liquid is changed from a heterogeneous phase to a homogeneous phase, and finally added 3. 2 g of propylene glycol and 1.99 g of pure Water, continuous stirring to obtain a transparent colorless water gel. Group 5 Composition Weight percent (%) Pure water 100.00

The sixth component weight percentage (%) hyaluronic acid 0. 10 glycyrrhizic acid 0. 06 polyvinylpyrrolidone (K60~K100) 9. 00 malt 6.00 propylene glycol 2. 94 potassium hexadienoate 0. 30 sodium benzoate 0. 30 Ethyl cellulose 1. 50 PEG-40 hydrogenated castor oil 0. 27 Ethylene diamine tetraacetate 0. 10 Hydrocarbyl chlorocarbamide 0. 50 Saccharin sodium 0.16 Fragrance 0. 10 Pure water 78. 44 The sixth component is Commercially available intraoral gel composition Gelclair® (Sinclair Pharma Ltd.) 〇16 J27.7419 Group 7 weight percent (Q/o) Group composition 100

Ax^m±^___ * The yield of the B is 97% and the molecular weight is between 10,000 and 330,000. Kaide Biotech Co., Ltd., Taiwan Group 8 The eighth group is the same as the second group.

The following is a list of the first to eighth groups of medications and whether hamsters are induced to have cancer: ---------- Whether the hamsters induce ulceration changes mainly in the first group, the second group is 0. 1% chitosan is 0.3% chitosan, the third group is 0.5% chitosan, the fourth group is free of chitosan, the f group is pure water sixth, and is commercially available. Gelclair8 (Sinclair pharma Ltd.) The seventh group is the eighth group of chitosan solids - no 0. 3 % chitosan anticancer drug induced oral mucositis to gold hamsters (8 weeks, 90-100 grams) For the experimental subjects, a total of 64 animals were required for the experiment, and the food was a standard standard experimental diet with no water. Among them, 56 animals 'induced inflammation of the oral mucosa 17 1277419 by 5_Fu (60mg/Kg, IP), one dose on the 0th day and the 2nd day respectively, and on the 4th day, the cheeks on the left side of the hamster were turned outwards. Use an 18 gauge needle to stimulate the oral mucosa but do not break it. On the 6th day, the oral mucositis in the left cheek of the hamster was evaluated daily and photographed to the wth day (six different degrees) at the end of the treatment. The evaluation criteria were 〇 to 5, six different degrees of score, as follows Column: 〇 = healthy without erosion or vasodilation.

1 = erythema but no mucosal erosion. 2 = severe erythema, vasodilation and surface erosion. 3 = ulcers formed in one or more places, but did not exceed 25% of the oral mucosal surface area. Severe erosion and vasodilation. 4 = cumulative ulcers exceed 5% of the oral mucosal surface area. 5 The oral mucosa completely collapses and loses its softness. Each hamster was assigned to the sturdy group according to different severity (the disease was evenly distributed, 8 t per group, and each animal was numbered, and the other 8 hamsters that did not induce oral mucositis were grouped (the eighth group). On the 7th day, the hamster was anesthetized with a mystery gas, and then the cheeks on the left side were turned out. 'Start with a cotton swab dipped in the adhesive gel. 'Each treatment dose is Likou: The capsule is treated three times a day (early, Middle and late), for a total of seven days, during treatment, mother: animal wound photography 'removal of food, water after treatment. Hours. Daily measurement of the weight of hamsters and the shape of the observed diet and drinking water. Finally, change data, use A statistical method was used to analyze the body weight of the hamster and the amount of food consumed to determine whether the intraoral glue composition of the present invention is similar in effect to the effect of 18 1277419 stomatitis. The results are shown in Fig. 1 and Fig. 2. The therapeutic drug is soothing for oral mucositis. The effect can be evaluated by the test animal's feed intake and body weight change analysis during the experiment, and the data of Figure 2 shows that the composition of the present invention is evaluated on the efficacy of stomatitis. There is no significant difference in Gelclair® (p < 〇〇 5 ). Brief description of the figure ^ Figure 1 shows the change in body weight of the oral mucosa k during the local treatment of the hamster caused by chemotherapy in Example 1. 2 shows the change in the weight of the feed intake of the oral mucosa in the hamster of Example 1 due to chemotherapy treatment during the local treatment.

Claims (1)

1277419 Mi Naben (amended in December 2006) X. Patent application scope: 1. An intraoral gel composition for relieving pain caused by oral ulcers, comprising water and the following active ingredients dissolved in water: polyvinylpyrrolidone, It has a K value between 30 and 100; and protonated chitosan; wherein the weight ratio of protonated chitosan to polyvinylpyrrolidone is between 0.5:100 and 6:100. 2. The intraoral gel composition of claim 1, which has a viscosity of 50 to 500 centipoise. 3. The intraoral gel composition of claim 1, wherein the protonated chitosan has a deacetylation degree of 60-99% and a molecular weight of 10,000 to 1,000,000 ° 20