WO2018010594A1 - 羟丙基甲基纤维素及含有其的组合物在上消化道黏膜护理药物的制备中的应用 - Google Patents

羟丙基甲基纤维素及含有其的组合物在上消化道黏膜护理药物的制备中的应用 Download PDF

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WO2018010594A1
WO2018010594A1 PCT/CN2017/092090 CN2017092090W WO2018010594A1 WO 2018010594 A1 WO2018010594 A1 WO 2018010594A1 CN 2017092090 W CN2017092090 W CN 2017092090W WO 2018010594 A1 WO2018010594 A1 WO 2018010594A1
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weight
parts
purified water
added
hydroxypropylmethylcellulose
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PCT/CN2017/092090
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French (fr)
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高宇
卜允利
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合肥九研医药科技开发有限公司
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Priority to US16/247,540 priority Critical patent/US10835553B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the invention relates to the application of a substance with special effects, in particular to the application of hydroxypropyl methylcellulose in the care of upper gastrointestinal mucosal damage.
  • the upper digestive tract consists of the mouth, pharynx, esophagus, stomach, and duodenum.
  • Oral Composed of the lips, cheeks, palate, teeth, tongue and oral glands. After the mouth is stimulated by food, the glands in the mouth secrete saliva, and the chewed food is mixed with saliva. The salivary action of the saliva passes through the esophagus, and the amylase in the saliva partially decomposes the carbohydrate.
  • Pharynx It is a common channel between the respiratory tract and the digestive tract.
  • the pharynx can be divided into three parts: the nasopharynx (part), the oropharynx (part), and the hypopharynx (part).
  • the main function of the pharynx is to complete the complex reflex action of swallowing.
  • the esophagus (dao) has three stenosis parts, which are easy to retain foreign bodies and are also a good site for esophageal cancer.
  • the main function of the esophagus is to transport food into the stomach, followed by preventing air from entering the esophagus during breathing, and preventing the stomach contents from flowing back into the esophagus (channel).
  • Stomach divided into four parts: the cardia, the fundus, the stomach and the antrum.
  • the total volume of the stomach is about 1000-3000 ml.
  • the gastric mucosa contains a large number of glands, which can secrete gastric juice.
  • the gastric juice is acidic.
  • the pH value (pH) usually fluctuates between pH 2.0 and pH 3.0, and sometimes it may reach pH 1.0.
  • the main components of gastric acid are hydrochloric acid, sodium, potassium chloride, digestive enzymes, mucin, and the like.
  • the role of gastric juice is many. Its main function is to digest food, kill bacteria in food, protect gastric mucosa and lubricate food, and make food easy to pass in the stomach.
  • the main function of the stomach is to contain and digest food.
  • the food group that enters the stomach from the esophagus forms a chyme after mechanical digestion and chemical digestion in the stomach.
  • the chyme is successively discharged into the duodenum by the movement of the stomach.
  • Duodenum the beginning of the small intestine. The length is equivalent to the fingertips of my twelve fingers (about 25 to 30 cm), hence the name.
  • the duodenum is C-shaped and wraps around the head of the pancreas.
  • the purpose of the present invention is to propose the application of hydroxypropyl methylcellulose in the treatment of upper digestive tract mucosal damage, and hydroxypropyl methylcellulose has continuous shielding, moisturizing, bacteriostatic, town on the upper gastrointestinal mucosal injury care. The role of pain.
  • a second object of the invention is to propose a composition comprising hydroxypropyl methylcellulose.
  • a third object of the invention is to propose a process for the preparation of the composition.
  • a fourth object of the invention is to propose the use of the composition.
  • hydroxypropyl methylcellulose in the treatment of upper gastrointestinal mucosal injury has the effects of continuous shielding, moisturizing, bacteriostatic and analgesic effects.
  • hydroxypropylmethylcellulose may also be a composition containing hydroxypropylmethylcellulose, the composition comprising the following components in parts by weight: hydroxypropylmethylcellulose 1 to 28 parts by weight And purified water 1000 parts by weight.
  • composition containing hydroxypropylmethylcellulose further comprises the following components in parts by weight: 1 to 10 parts by weight of sodium carboxymethylcellulose, 30 to 150 parts by weight of glycerin, and 0.3 to 20 parts by weight of a stabilizer.
  • the essence is 0.001 to 0.1 parts by weight.
  • sodium carboxymethylcellulose can be replaced by maltodextrin.
  • composition containing hydroxypropylmethylcellulose further comprises the following components in parts by weight: 1 to 90 parts by weight of sodium hydrogencarbonate, 10 to 40 parts by weight of xylitol, 0.1 to 6 parts by weight of citric acid, 2 to 9 parts by weight of potassium hydroxide, 2 to 10 parts by weight of phosphoric acid, and benzene Sodium formate is 0.1 to 2 parts by weight.
  • the above hydroxypropylmethylcellulose-containing composition may further comprise 10 to 40 parts by weight of polydextrose.
  • the stabilizer used in the present invention is a mixture of polysorbate, sorbitan fatty acid ester, monoglycerin fatty acid ester, gum arabic, gelatin, egg yolk or a mixture of several substances.
  • a method of preparing a composition comprising hydroxypropyl methylcellulose comprising the steps of:
  • Step 1 Add hydroxypropyl methylcellulose to the purified water with a total water consumption of 40% under stirring, and continue stirring until the swelling is completely transparent;
  • Step 2 Add the remaining purified water and stir for 0.5 h.
  • a method of preparing a composition comprising hydroxypropyl methylcellulose comprises the steps of:
  • Step 1 Add hydroxypropyl methylcellulose to the purified water with a total water consumption of 40% under stirring, and continue stirring until the swelling is completely transparent;
  • Step 2 sodium carboxymethylcellulose is dissolved in purified water with a total water consumption of 20%, glycerin is added, and the mixture is stirred at 37 ° C for 0.5 h;
  • Step 3 The two solutions prepared in the steps 1 and 2 are stirred and mixed, and the remaining 40% purified water and the stabilizer are added and stirred for 0.5 h;
  • Step 4 Add the essence to the solution prepared in step 3 and stir until completely dissolved.
  • step 3 is: stirring and mixing the two solutions prepared in the steps 1 and 2, and adding the remaining 40% to the mixed solution. Purify the water, and then add stabilizer, xylitol, sodium bicarbonate, potassium hydroxide, stir at 37 ° C for 0.5 h, add citric acid for 0.5 h, add phosphoric acid to adjust the pH value of 6.5-8.5 and then add benzene. Sodium formate is stirred evenly.
  • the combination of sodium carboxymethyl cellulose and hydroxypropyl methylcellulose has good adhesion and adhesion to the esophageal mucosa. Its dynamic viscosity ranges from 300 to 20,000 cP, which can ensure the esophagus in the case of oral administration. The mucosa performs a good adhesion.
  • composition of the invention in the preparation of an upper gastrointestinal mucosal injury care drug.
  • hydroxypropylmethylcellulose has the effect of producing a film in the esophagus, and can effectively shield harmful bacteria and harmful environment from the mucosa, and the resulting film has mucoadhesiveness and acts as a film.
  • hydroxypropylmethylcellulose-containing composition of the present invention hydroxypropylmethylcellulose and sodium carboxymethylcellulose are combined to form a film in the esophagus, and the resulting film has a mucosa. It has stronger adhesion and long duration of film action, which can effectively improve the breeding environment of bacteria.
  • glycerin has a moisturizing effect and is advantageous for repairing a damaged ulcerated surface, and the effect is the same as that of the film formed as described above.
  • Xylitol can specifically bind to intestinal mucosa, competitively eliminate pathogens, form a biological barrier, protect mucous membranes; at the same time, polydextrose can also adsorb pathogenic bacteria and have strong binding ability to plant lectins on the surface of bacteria, causing disease The bacteria combine with polydextrose and do not adhere to the upper digestive tract wall. At the same time, the pathogenic bacteria cannot use polydextrose to obtain nutrients, which lacks energy and eventually dies and is excreted.
  • the hydroxypropylmethylcellulose-containing composition of the present invention is particularly suitable for functioning in a complex environment of the upper digestive tract, is suitable for functioning in a complex environment of the esophagus and stomach, and can adjust the pH of the mucosal environment. Values make the disease develop in a beneficial direction.
  • composition containing hydroxypropylmethylcellulose provided by the present invention, wherein the composition containing hydroxypropylmethylcellulose has a stable viscosity, good properties, and good storage stability. Sex.
  • SD rats weighing 200-240 g; experimentally set the 1-3 medication group, blank control group and model control group, 20 SD rats in each group, 4 rats in the group and model control group for esophageal mucosal injury
  • the blank control group was a healthy rat
  • the model of the esophageal mucosal injury model was made by bending the syringe needle into a curvature of about 0.5 mm, which was used to extend the esophageal mucosa of the rat esophagus, and the length of the scratch was Rats 1-4 mm, which did not continue bleeding after 24 hours, were successful rats.
  • the drug-administered group took the composition containing hydroxypropylmethylcellulose prepared in Examples 1-3, Three times a day, 3 grams each time.
  • the blank control group took pure water three times a day, 3 grams each time.
  • the model control group took pure water three times a day, 3 grams each time.
  • the blank group took pure water three times a day, 3 grams each time.
  • Incidence rate (%) number of rats with esophageal mucosal damage in a group / number of rats in the group ⁇ 100%;
  • Damage integral index sum of group injury scores / number of animals in the group
  • hydroxypropyl methylcellulose is soluble in water and has a film-forming effect in the digestive tract of the animal, which causes the mucosal damage to heal.
  • the basic rule is that the more the dosage, the better the effect, the highest inhibition rate of damage in the ratio of hydroxypropyl methylcellulose: purified water is 15-28:1000.
  • the effect of the amount of hydroxypropyl methylcellulose reached the plateau at about 20g, and the amount of cellulose was increased, and the damage healing effect was not significantly improved. Subsequent experiments were conducted to study and optimize the composition.
  • the hydroxypropyl methylcellulose was added to the purified water with a total water consumption of 40% under stirring, and stirring was continued until the swelling was completely transparent; sodium carboxymethylcellulose was dissolved in purified water having a total water consumption of 20%, and glycerin was added. Stir at 37 ° C for 0.5 h. Add the remaining purified water and stabilizer to stir for 0.5 h, then add the essence and stir until completely dissolved.
  • Step 1 the hydroxypropyl methylcellulose was added to the purified water with a total water consumption of 40% under stirring, stirring was continued until the swelling was completely transparent, and the mixture was stirred at 37 ° C for 1 h;
  • Step 2 sodium carboxymethyl cellulose is dissolved in purified water with a total water consumption of 20%, glycerin is added, and the mixture is stirred at 37 ° C for 0.5 h;
  • Step 3 mixing and mixing the two solutions prepared in steps 1 and 2, mixing The remaining 40% purified water was added to the solution, and then stabilizer, xylitol, sodium hydrogencarbonate and potassium hydroxide were added successively, and stirred at 37 ° C for 0.5 h, then citric acid was added and stirred for 0.5 h, and then phosphoric acid was added to adjust the pH. After the value is 6.5-8.5, add sodium benzoate and stir evenly;
  • Step 1 the hydroxypropyl methylcellulose was added to the purified water with a total water consumption of 40% under stirring, stirring was continued until the swelling was completely transparent, and the mixture was stirred at 37 ° C for 1 h;
  • Step 2 sodium carboxymethyl cellulose is dissolved in purified water with a total water consumption of 20%, glycerin is added, and the mixture is stirred at 37 ° C for 0.5 h;
  • Step 3 the two solutions prepared in the step 1 and the step 2 are stirred and mixed, and the remaining 40% purified water is added to the mixed solution, and then the stabilizer, xylitol, sodium hydrogencarbonate and potassium hydroxide are sequentially added, at 37 After stirring at ° C for 0.5 h, citric acid was added and stirred for 0.5 h, and then phosphoric acid was added to adjust the pH value to 6.5-8.5, and then sodium benzoate was added and stirred uniformly;
  • Step 1 the hydroxypropyl methylcellulose was added to the purified water with a total water consumption of 40% under stirring, stirring was continued until the swelling was completely transparent, and the mixture was stirred at 37 ° C for 1 h;
  • Step 2 sodium carboxymethyl cellulose is dissolved in purified water with a total water consumption of 20%, glycerin is added, and the mixture is stirred at 37 ° C for 0.5 h;
  • Step 3 the two solutions prepared in the step 1 and the step 2 are stirred and mixed, and the remaining 40% purified water is added to the mixed solution, and then the stabilizer, xylitol, sodium hydrogencarbonate and potassium hydroxide are sequentially added, at 37 After stirring at ° C for 0.5 h, citric acid was added and stirred for 0.5 h, and then phosphoric acid was added to adjust the pH value to 6.5-8.5, and then sodium benzoate was added and stirred uniformly;
  • maltodextrin 15g of hydroxypropylmethylcellulose, 100g of glycerin, 90g of sodium bicarbonate, 40g of xylitol, 6g of citric acid, 9g of potassium hydroxide, 10g of phosphoric acid, benzene 2 g of sodium formate, 0.3 g of stabilizer, 0.001 g of flavor, and 1000 g of purified water.
  • Step 1 the hydroxypropyl methylcellulose was added to the purified water with a total water consumption of 40% under stirring, stirring was continued until the swelling was completely transparent, and the mixture was stirred at 37 ° C for 1 h;
  • Step 2 maltodextrin is dissolved in purified water with a total water consumption of 20%, adding glycerin, and stirring at 37 ° C for 0.5 h;
  • Step 3 the two solutions prepared in the step 1 and the step 2 are stirred and mixed, and the remaining 40% purified water is added to the mixed solution, and then the stabilizer, xylitol, sodium hydrogencarbonate and potassium hydroxide are sequentially added, at 37 After stirring at ° C for 0.5 h, citric acid was added and stirred for 0.5 h, and then phosphoric acid was added to adjust the pH value to 6.5-8.5, and then sodium benzoate was added and stirred uniformly;
  • Step 1 Add hydroxypropyl methylcellulose to the total water consumption of 40% under stirring. Purify the water, continue to stir until the swelling is completely transparent solution, continue to add polydextrose, and stir at 37 ° C for 1 h;
  • Step 2 sodium carboxymethyl cellulose is dissolved in purified water with a total water consumption of 20%, glycerin is added, and the mixture is stirred at 37 ° C for 0.5 h;
  • Step 3 the two solutions prepared in the step 1 and the step 2 are stirred and mixed, and the remaining 40% purified water is added to the mixed solution, and then the stabilizer, xylitol, sodium hydrogencarbonate and potassium hydroxide are sequentially added, at 37 After stirring at ° C for 0.5 h, citric acid was added and stirred for 0.5 h, and then phosphoric acid was added to adjust the pH value to 6.5-8.5, and then sodium benzoate was added and stirred uniformly;
  • Step 1 the hydroxypropyl methylcellulose was added to the purified water with a total water consumption of 40% under stirring, stirring was continued until the swelling was completely transparent, and the polydextrose was continuously added, and the mixture was stirred at 37 ° C for 1 hour;
  • Step 2 sodium carboxymethyl cellulose is dissolved in purified water with a total water consumption of 20%, glycerin is added, and the mixture is stirred at 37 ° C for 0.5 h;
  • Step 3 the two solutions prepared in the step 1 and the step 2 are stirred and mixed, and the remaining 40% purified water is added to the mixed solution, and then the stabilizer, xylitol, sodium hydrogencarbonate and potassium hydroxide are sequentially added, at 37 After stirring at ° C for 0.5 h, citric acid was added and stirred for 0.5 h, and then phosphoric acid was added to adjust the pH value to 6.5-8.5, and then sodium benzoate was added and stirred uniformly; the solution prepared in the step 3 was stirred and dissolved until completely dissolved.
  • Polydextrose has a pharmaceutically auxiliary effect and can improve film forming properties.
  • the results of this example show that the film-forming performance of sodium carboxymethyl cellulose is not significantly improved, and the stability of the preparation is lowered, and the trait of the accelerated test is slightly changed at 6 months.
  • Step 1 the hydroxypropyl methylcellulose was added to the purified water with a total water consumption of 40% under stirring, stirring was continued until the swelling was completely transparent, and the polydextrose was continuously added, and the mixture was stirred at 37 ° C for 1 hour;
  • Step 2 sodium carboxymethyl cellulose is dissolved in purified water with a total water consumption of 20%, glycerin is added, and the mixture is stirred at 37 ° C for 0.5 h;
  • Step 3 the two solutions prepared in the step 1 and the step 2 are stirred and mixed, and the remaining 40% purified water is added to the mixed solution, and then the stabilizer, xylitol, sodium hydrogencarbonate and potassium hydroxide are sequentially added, at 37 After stirring at ° C for 0.5 h, citric acid was added and stirred for 0.5 h, and then phosphoric acid was added to adjust the pH value to 6.5-8.5, and then sodium benzoate was added and stirred uniformly;
  • the first drug-administered group took the hydroxypropylmethylcellulose-containing composition prepared in Example 2 three times a day, 3 grams each time.
  • the second administration group took the hydroxypropylmethylcellulose-containing composition prepared in Example 5 three times a day, 3 grams each time.
  • the third medication group was administered the composition containing hydroxypropylmethylcellulose prepared in Example 8, three times a day, 3 grams each time.
  • the fourth administration group took the hydroxypropylmethylcellulose-containing composition prepared in Example 12 three times a day, 3 grams each time.
  • the blank control group took pure water three times a day, 3 grams each time.
  • the model control group took pure water three times a day, 3 grams each time.
  • Example 8 As can be seen from Table 3, the compositions containing hydroxypropylmethylcellulose prepared in Example 2, Example 5, Example 8 and Example 12 have a good effect in the treatment and treatment of damage to the esophageal mucosa.
  • the composition of Example 8 has better stability, film insulation and adhesion.
  • Example 2 The hydroxypropylmethylcellulose-containing compositions prepared in Example 2, Example 5, Example 8 and Example 12 were administered to patients with radiation esophagitis, and 10 patients with radioactive esophagitis were selected for each composition. Oral administration 3 times, 10 ml each time, using randomized control method, the control group was treated with the same amount of normal saline (10 cases were selected), and used continuously for 3 weeks. The results showed that Example 2, Example 5, Example 8 and implementation The composition containing hydroxypropylmethylcellulose prepared in Example 11 had a significant difference in the degree of relief of radiation esophagitis symptoms (pain, mucosal damage degree) and the degree of relief in the saline control group, and the symptoms were significantly alleviated.
  • the invention discloses the application of hydroxypropyl methylcellulose in the preparation of upper digestive tract mucosal care drugs.
  • the invention also provides a composition containing hydroxypropyl methylcellulose, which comprises The invention comprises the following components: 1 to 28 parts by weight of hydroxypropylmethylcellulose and 1000 parts by weight of purified water; and the preparation method comprises the following steps: adding hydroxypropylmethylcellulose to the purified water having a total water consumption of 40% under stirring; Stirring is continued until the swelling is completely clear; the remaining purified water is added and stirred until completely dissolved.
  • hydroxypropylmethylcellulose of the present invention and the composition containing hydroxypropylmethylcellulose have the effect of producing a film in the upper digestive tract, and the resulting film has mucoadhesiveness, so that the film action is sustainable. Therefore, it has broad application prospects.

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Abstract

一种含有羟丙基甲基纤维素的组合物，包括：羟丙基甲基纤维素1～28重量份、纯化水1000重量份；进一步还包括：羧甲基纤维素钠或麦芽糊精1～10重量份、甘油30～150重量份、稳定剂0.3～20重量份、香精0.001～0.1重量份；进一步还包括：碳酸氢钠1～90重量份、木糖醇10～40重量份、柠檬酸0.1～6重量份、氢氧化钾2～9重量份、磷酸2～10重量份、苯甲酸钠0.1～2重量份；进一步还包括：聚葡萄糖10～40重量份。羟丙基甲基纤维素及含有其的组合物在上消化道产生薄膜，并具有粘膜粘附性。

Description

[根据细则37.2由ISA制定的发明名称]　羟丙基甲基纤维素及含有其的组合物在上消化道黏膜护理药物的制备中的应用 技术领域
本发明涉及一种具有特殊功效的物质的应用，尤其涉及羟丙基甲基纤维素在上消化道黏膜损伤护理上的应用。
背景技术
上消化道由口腔、咽、食管、胃、十二指肠组成。口腔：由口唇、颊、腭、牙、舌和口腔腺组成。口腔受到食物的刺激后，口腔内腺体即分泌唾液，嚼碎后的食物与唾液搅和，借唾液的滑润作用通过食管,唾液中的淀粉酶能部分分解碳水化合物。咽：是呼吸道和消化道的共同通道。咽依据与鼻腔、口腔和喉等的通路，可分为鼻咽(部)、口咽(部)、喉咽(部)三部。咽的主要功能是完成吞咽这一复杂的反射动作。食管(食道)：食管(道)是一长条形的肌性管道，全长约25～30厘米。食管(道)有三个狭窄部，这三个狭窄部易滞留异物,也是食管癌的好发部位。食管(道)的主要功能是运送食物入胃，其次有防止呼吸时空气进入食管，以及阻止胃内容物逆流入食管(道)的作用。胃：分为贲门、胃底、胃体和胃窦四部分，胃的总容量约1000～3000毫升。胃壁粘膜中含大量腺体，可以分泌胃液，胃液呈酸性，pH值(酸碱度)通常在pH2.0到pH3.0之间波动，有的时候可能会达到pH1.0。胃酸的主要成分有盐酸、钠、钾的氯化物、消化酶、粘蛋白等。胃液的作用很多，其主要作用是消化食物、杀灭食物中的细菌、保护胃粘膜以及润滑食物，使食物在胃内易于通过等。胃的主要功能是容纳和消化食物。由食管进入胃内的食团,经胃内的机械性消化和化学性消化后形成食糜，食糜借助胃的运动逐次被排入十二指肠。十二指肠:为小肠的起始段。长度相当于本人十二个手指的指幅(约25～30厘米)，因此而得名。十二指肠呈C型弯曲，包绕胰头，可分为 上部、降部、下部和升部四部分。其主要功能是分泌粘液、刺激胰消化酶与胆汁的分泌，为蛋白质的重要消化场所等。
上消化道的所有生理功能的实现均离不开黏膜的作用，而黏膜又是容易受到损伤的部位，黏膜损伤就容易诱发感染并可以形成黏膜下脓肿，影响上消化道的正常生理功能。目前治疗食管黏膜损伤多使用消炎药，通过胃肠道给药、注射或者静脉滴注，基本都是全身给药，用药量大，且不能直接对局部受损的黏膜部位进行用药，起效慢。
发明内容
本发明的目的在于提出羟丙基甲基纤维素在上消化道黏膜损伤护理上的应用，羟丙基甲基纤维素在上消化道黏膜损伤护理上具有持续的屏蔽、保湿、抑菌、镇痛的作用。
本发明的第二个目的是提出含有羟丙基甲基纤维素的组合物。
本发明的第三个目的是提出所述组合物的制备方法。
本发明的第四个目的是提出所述组合物的应用。
本发明是通过以下技术方案来达到目的：
羟丙基甲基纤维素在上消化道黏膜损伤护理上的应用，具有持续的屏蔽、保湿、抑菌、镇痛的作用。
进一步的，羟丙基甲基纤维素还可以是含有羟丙基甲基纤维素的组合物，所述的组合物包括以下成分按重量份组成：羟丙基甲基纤维素1～28重量份、纯化水1000重量份。
进一步的，含有羟丙基甲基纤维素的组合物还包括以下成分按重量份组成：羧甲基纤维素钠1～10重量份、甘油30～150重量份、稳定剂0.3～20重量份、香精0.001～0.1重量份。
其中，羧甲基纤维素钠可以用麦芽糊精替代。
更进一步的，含有羟丙基甲基纤维素的组合物还包括以下成分按重量份组成：碳酸氢钠1～90重量份、木糖醇10～40重量份、柠檬酸0.1～6重量份、氢氧化钾2～9重量份、磷酸2～10重量份、苯 甲酸钠0.1～2重量份。
上述的含有羟丙基甲基纤维素的组合物中还可以包括聚葡萄糖10～40重量份。
本发明使用的稳定剂为聚山梨酯、山梨醇脂肪酸酯、单甘油脂肪酸酯、阿拉伯胶、明胶、卵黄中的一种或几种物质的混合物
一种制备含有羟丙基甲基纤维素的组合物的方法，包括如下步骤：
步骤1：将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；
步骤2：加入剩余的纯化水搅拌0.5h，即得。
进一步的，制备含有羟丙基甲基纤维素的组合物的方法，包括如下步骤：
步骤1：将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；
步骤2：羧甲基纤维素钠溶于总用水量20％的的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3：将步骤1和步骤2中制备的两种溶液搅拌混合，加入剩余的40％纯化水、稳定剂搅拌0.5h；
步骤4：在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
进一步的，上述制备含有羟丙基甲基纤维素的组合物的方法，其中所述步骤3为：将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀。
羧甲基纤维素钠、羟丙基甲基纤维素组合使用，对食管黏膜具有很好的粘附性和粘结性，其动力粘度范围为300～20000cP，可以确保在通过口服的情况对食管黏膜进行很好的粘附效果。
本发明所述的组合物在上消化道黏膜损伤护理药物制备中的应用。
本发明的优点是：
(1)本发明中，羟丙基甲基纤维素，在食道中产生薄膜的效果，能有效屏蔽有害细菌及有害环境对粘膜的影响，且所产生的薄膜具粘膜粘附性，使薄膜作用具有可持续性。
(2)羟丙基甲基纤维素的上述特征在不同上消化道的不同环境中依然具有相同的有益功效。
(3)本发明的含有羟丙基甲基纤维素的组合物中，羟丙基甲基纤维素和羧甲基纤维素钠组合，在食道中成膜效果更好，所产生的薄膜具粘膜粘附性更强，薄膜作用持续时间长，可有效改善细菌的繁殖环境。
(4)本发明的含有羟丙基甲基纤维素的组合物中，甘油具有保湿效果，有利于已发生破损的溃疡面的修复，且该效果同上述形成的薄膜具有同样的可持续性。木糖醇可以和肠黏膜特异性结合，竞争性排除病原体，形成生物屏障，保护黏膜；同时聚葡萄糖还可以吸附致病菌，并与细菌表面的植物凝集素有很强的结合能力，致病菌与聚葡萄糖结合，不会附着于上消化道壁上，同时致病菌不能利用聚葡萄糖获得养分，从而缺乏能源，最终死亡并被排出体外。
(5)本发明的含有羟丙基甲基纤维素的组合物，特别适合于在上消化道复杂环境下发挥作用，适合于在食道和胃部复杂环境下发挥作用，并可调节黏膜环境pH值使疾病向有益方向发展。
(6)本发明提供的含有羟丙基甲基纤维素的组合物的制备方法，可制备出的含有羟丙基甲基纤维素的组合物具有稳定的粘度，性状良好，具有较好储藏稳定性。
具体实施方式
以下结合具体实施例对本发明作进一步说明：
实施例1
称取羟丙基甲基纤维素1克、纯化水1000克。将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；加入剩余的纯化水搅拌0.5h，即得。
实施例2
称取羟丙基甲基纤维素15克、纯化水1000克。将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；加入剩余的纯化水搅拌0.5h，即得。
实施例3
称取羟丙基甲基纤维素28克、纯化水1000克。将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；加入剩余的纯化水搅拌0.5h，即得。
动物实验1：
SD大鼠，体重200～240g；实验设实施例1-3服药组、空白对照组和模型对照组，每组SD大鼠20只，4个服用组和模型对照组的大鼠为食道黏膜损伤模型大鼠，空白对照组为健康大鼠；食道黏膜损伤模型大鼠具体造模为：将注射器针头做成约0.5mm的弯曲，用来伸入大鼠食道划伤食道黏膜，划伤长度在1-4mm，24小时后不继续出血的大鼠为造模成功的大鼠。食道黏膜损伤的肉眼观察及评分在体视解剖显微镜下或肉眼下用游标卡尺测量出血带的长度和宽度。因宽度所代表损伤的严重性远较长度大，故双倍积分。其评分标准见表1。
表1大鼠食道利器损伤肉眼观察评分标准
损伤程度 1分 2分 3分 4分
出血带长度(mm) 1 2 3 4
出血带宽度(mm) 1 1.5 —— ——
总积分＝长度分值+(宽度分值×2)
服药组服用实施例1-3制备的含有羟丙基甲基纤维素的组合物， 一日三次，每次3克。空白对照组服用纯净水，一日三次，每次3克。
模型对照组服用纯净水，一日三次，每次3克。
空白组服用纯净水，一日三次，每次3克。
正常喂养一周，处死，解剖，观察指标：各实验组食道粘膜损伤程度以损伤发生率(％)、损伤积分指数和损伤抑制率表示。
损伤发生率(％)＝某组出现食道黏膜损伤的大鼠数量/该组大鼠数量×100％；
损伤积分指数＝组损伤评分总和/组动物数量；
损伤抑制率(％)＝(A-B)/A×100％(A、B分别为模型组与服药组的损伤积分)。具体指标见表2。
表2各指标记录结果表
Figure PCTCN2017092090-appb-000001
本发明的申请人惊奇地发现，羟丙基甲基纤维素溶于水，在动物上消化道中具有产生薄膜的效果，使黏膜损伤愈合。进一步地，比较不同羟丙基甲基纤维素用量，基本规律是用量越多、效果越好，在羟丙基甲基纤维素：纯化水为15-28：1000的比例下，损伤抑制率最高，但羟丙基甲基纤维素用量带来的效果在20g左右达到平台期，再增加纤维素用量，损伤愈合效果没有显著提高。后续试验据此进行了组合物的研究和优化。
实施例4
称取羟丙基甲基纤维素1克、羧甲基纤维素钠1克、甘油30克、稳定剂20克、香精0.1克、纯化水1000克。将羟丙基甲基纤维素 在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；羧甲基纤维素钠溶于总用水量20％的纯化水中，加入甘油，在37℃下恒温搅拌0.5h。加入剩余的纯化水、稳定剂搅拌0.5h后加入香精搅拌至完全溶解，即得。
实施例5
称取羟丙基甲基纤维素15克、羧甲基纤维素钠5克、甘油100克、稳定剂10克、香精0.05克、纯化水1000克；将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；羧甲基纤维素钠溶于总用水量20％的纯化水中，加入甘油，在37℃下恒温搅拌0.5h。加入剩余的纯化水、稳定剂搅拌0.5h后加入香精搅拌至完全溶解，即得。
实施例6
称取羟丙基甲基纤维素28克、羧甲基纤维素钠10克、甘油150克、稳定剂0.3克、香精0.001克、纯化水1000克。
将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；羧甲基纤维素钠溶于总用水量20％的纯化水中，加入甘油，在37℃下恒温搅拌0.5h。加入剩余的纯化水、稳定剂搅拌0.5h后加入香精搅拌至完全溶解，即得。
实施例7
称取羧甲基纤维素钠1克、羟丙基甲基纤维素1克、甘油30克、碳酸氢钠50克、木糖醇25克、柠檬酸3克、氢氧化钾6克、磷酸6克、苯甲酸钠1克、稳定剂10克、香精0.05克、纯化水1000克；
步骤1，将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液，在37℃下恒温搅拌1h；
步骤2，羧甲基纤维素钠溶于总用水量20％的的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3，将步骤1和步骤2中制备的两种溶液搅拌混合，向混 合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀；
在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
实施例8
称取羧甲基纤维素钠5克、羟丙基甲基纤维素15克、甘油100克、碳酸氢钠90克、木糖醇40克、柠檬酸6克、氢氧化钾9克、磷酸10克、苯甲酸钠2克、稳定剂0.3克、香精0.001克、纯化水1000克。
步骤1，将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液，在37℃下恒温搅拌1h；
步骤2，羧甲基纤维素钠溶于总用水量20％的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3，将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀；
在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
本实施例加入辅料羧甲基纤维素钠5克，观察到成膜的隔绝性能、粘附性能有显著提升。
实施例9
称取羧甲基纤维素钠10克、羟丙基甲基纤维素28克、甘油150克、碳酸氢钠1克、木糖醇10克、柠檬酸0.1克、氢氧化钾2克、磷酸2克、苯甲酸钠0.1克、稳定剂0.3克、香精0.001克、纯化水1000克。
步骤1，将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液，在37℃下恒温搅拌1h；
步骤2，羧甲基纤维素钠溶于总用水量20％的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3，将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀；
在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
实施例10
称取麦芽糊精5克、羟丙基甲基纤维素15克、甘油100克、碳酸氢钠90克、木糖醇40克、柠檬酸6克、氢氧化钾9克、磷酸10克、苯甲酸钠2克、稳定剂0.3克、香精0.001克、纯化水1000克。
步骤1，将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液，在37℃下恒温搅拌1h；
步骤2，麦芽糊精溶于总用水量20％的的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3，将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀；
在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
实施例11
称取聚葡萄糖10克、羧甲基纤维素钠1克、羟丙基甲基纤维素1克、甘油30克、碳酸氢钠1克、木糖醇10克、柠檬酸0.1克、氢氧化钾2克、磷酸2克、苯甲酸钠0.1克、稳定剂20克、香精0.1克、纯化水1000克。
步骤1，将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的 纯化水中，继续搅拌至溶胀完全呈透明溶液，继续加入聚葡萄糖，在37℃下恒温搅拌1h；
步骤2，羧甲基纤维素钠溶于总用水量20％的的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3，将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀；
在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
实施例12
称取聚葡萄糖25克、羧甲基纤维素钠5克、羟丙基甲基纤维素15克、甘油100克、碳酸氢钠50克、木糖醇25克、柠檬酸3克、氢氧化钾6克、磷酸6克、苯甲酸钠1克、稳定剂10克、香精0.05克、纯化水1000克；
步骤1，将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液，继续加入聚葡萄糖，在37℃下恒温搅拌1h；
步骤2，羧甲基纤维素钠溶于总用水量20％的的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3，将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀；在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
聚葡萄糖具有药学辅助作用，可提高成膜性能。但本实施例结果表明，相对于羧甲基纤维素钠成膜性能的提高不太明显，而制剂稳定性有所降低，加速试验6个月性状稍有变化。
实施例13
称取聚葡萄糖30克、羧甲基纤维素钠10克、羟丙基甲基纤维素28克、甘油150克、碳酸氢钠90克、木糖醇40克、柠檬酸6克、氢氧化钾9克、磷酸10克、苯甲酸钠2克、稳定剂0.3克、香精0.001克、纯化水1000克。
步骤1，将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液，继续加入聚葡萄糖，在37℃下恒温搅拌1h；
步骤2，羧甲基纤维素钠溶于总用水量20％的的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
步骤3，将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀；
在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
动物实验2：
试验操作和评分标准同动物实验1。
第一服药组服用实施例2制备的含有羟丙基甲基纤维素的组合物，一日三次，每次3克。第二服药组服用实施例5制备的含有羟丙基甲基纤维素的组合物，一日三次，每次3克。第三服药组服用实施例8制备的含有羟丙基甲基纤维素的组合物，一日三次，每次3克。第四服药组服用实施例12制备的含有羟丙基甲基纤维素的组合物，一日三次，每次3克。
空白对照组服用纯净水，一日三次，每次3克。
模型对照组服用纯净水，一日三次，每次3克。
正常喂养一周，处死，解剖，观察指标。具体指标见表3。
表3各指标记录结果表
Figure PCTCN2017092090-appb-000002
由表3可知，实施例2、实施例5、实施例8和实施例12制备的含有羟丙基甲基纤维素的组合物在对食道黏膜损伤的治疗护理上具有很好的效果。实施例8的组合物具有更好的稳定性、成膜的隔绝性和粘附性。
将实施例2、实施例5、实施例8和实施例12制备的含有羟丙基甲基纤维素的组合物给放射性食管炎病人服用，每种组合物选10例放射性食管炎患者服用，每日口服3次，每次10ml，采用随机对照方法，对照组以生理盐水同量同法使用(选10例)，连续使用3周，结果显示实施例2、实施例5、实施例8和实施例11制备的含有羟丙基甲基纤维素的组合物对放射性食管炎症状(疼痛，粘膜损伤度)的缓解程度与生理盐水对照组缓解程度有显著性差异，症状明显减轻。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
工业实用性
本发明公开了羟丙基甲基纤维素在上消化道黏膜护理药物的制备中的应用。本发明还提出一种含有羟丙基甲基纤维素的组合物，包 括以下成分：羟丙基甲基纤维素1～28重量份、纯化水1000重量份；其制备方法包括：将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；加入剩余的纯化水搅拌至完全溶解，即得。本发明的羟丙基甲基纤维素及含有羟丙基甲基纤维素的组合物，在上消化道中产生薄膜的效果，所产生的薄膜具粘膜粘附性，使薄膜作用具有可持续性，因而具有广泛的应用前景。

Claims (9)

  1. 羟丙基甲基纤维素在上消化道黏膜护理药物的制备中的应用，其特征在于，是在上消化道黏膜损伤护理的药物制备中的应用。
  2. 一种含有羟丙基甲基纤维素的组合物，其特征在于：所述的组合物包括以下重量份的成分：羟丙基甲基纤维素1～28重量份、纯化水1000重量份。
  3. 如权利要求2所述的含有羟丙基甲基纤维素的组合物，其特征在于：所述的组合物还包括以下重量份的成分：羧甲基纤维素钠或麦芽糊精1～10重量份、甘油30～150重量份、稳定剂0.3～20重量份、香精0.001～0.1重量份。
  4. 如权利要求3所述的含有羟丙基甲基纤维素的组合物，其特征在于，所述稳定剂为聚山梨酯、山梨醇脂肪酸酯、单甘油脂肪酸酯、阿拉伯胶、明胶、卵黄中的一种或几种物质的混合物。
  5. 如权利要求3所述的含有羟丙基甲基纤维素的组合物，其特征在于：所述的组合物还包括以下重量份成分：碳酸氢钠1～90重量份、木糖醇10～40重量份、柠檬酸0.1～6重量份、氢氧化钾2～9重量份、磷酸2～10重量份、苯甲酸钠0.1～2重量份。6.如权利要求5所述的含有羟丙基甲基纤维素的组合物，其特征在于：所述的组合物还包括聚葡萄糖10～40重量份。
  6. 一种制备如权利要求2所述的含有羟丙基甲基纤维素的组合
    物的方法，其特征在于：包括如下步骤：
    步骤1：将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；
    步骤2：加入剩余的纯化水搅拌0.5h，即得。
  7. 如权利要求7所述的方法，其特征在于：包括如下步骤：
    步骤1：将羟丙基甲基纤维素在搅拌状态下加入总用水量40％的纯化水中，继续搅拌至溶胀完全呈透明溶液；
    步骤2：羧甲基纤维素钠溶于总用水量20％的纯化水中，加入甘油，在37℃下恒温搅拌0.5h；
    步骤3：将步骤1和步骤2中制备的两种溶液搅拌混合，加入剩余的40％纯化水、稳定剂搅拌0.5h；
    步骤4：在步骤3制得的溶液中加入香精搅拌至完全溶解，即得。
  8. 如权利要求8所述的方法，其特征在于：所述步骤3为：将步骤1和步骤2中制备的两种溶液搅拌混合，向混合溶液中加入剩余的40％纯化水，再依次加入稳定剂、木糖醇、碳酸氢钠、氢氧化钾，在37℃下搅拌0.5h后，加入柠檬酸搅拌0.5h，再加入磷酸调整pH值为6.5-8.5后加入苯甲酸钠搅拌均匀。
  9. 权利要求2～6任一所述的组合物在上消化道黏膜损伤护理药物制备中的应用。
PCT/CN2017/092090 2016-07-12 2017-07-06 羟丙基甲基纤维素及含有其的组合物在上消化道黏膜护理药物的制备中的应用 WO2018010594A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103347901A (zh) * 2010-11-29 2013-10-09 生物科技药物学会 葡聚糖组合物
CN105342897A (zh) * 2015-10-22 2016-02-24 合肥九研医药科技开发有限公司 一种口腔护理组合物及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0808629A4 (en) * 1995-02-02 1998-03-04 Chugai Pharmaceutical Co Ltd PREPARATION OF SUCRALFATE
US20020103219A1 (en) * 2000-10-05 2002-08-01 Jeremy Jacob Stable viscous liquid formulations of amlexanox for the prevention and treatment of mucosal diseases and disorders
US20050244509A1 (en) * 2004-03-17 2005-11-03 Fu-Pao Tsao Ophthalmic solutions
GB2423711B (en) * 2005-10-24 2007-02-14 Fortune Apex Dev Ltd Method for preparing a pharmaceutical composition with enhanced mucoadhesion
JP2011507665A (ja) * 2007-12-31 2011-03-10 アクラレント インコーポレイテッド 粘膜組織包帯剤及び使用方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103347901A (zh) * 2010-11-29 2013-10-09 生物科技药物学会 葡聚糖组合物
CN105342897A (zh) * 2015-10-22 2016-02-24 合肥九研医药科技开发有限公司 一种口腔护理组合物及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PAN, XIHAI, ET AL.: "Progress of Bioadhesive Preparations", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 28, no. 10, 31 October 1997 (1997-10-31), pages 473 - 476, ISSN: 1001-8255 *

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