WO2023044700A1 - Procédé et gel aqueux pour le traitement de la mucosite orale - Google Patents

Procédé et gel aqueux pour le traitement de la mucosite orale Download PDF

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Publication number
WO2023044700A1
WO2023044700A1 PCT/CN2021/120097 CN2021120097W WO2023044700A1 WO 2023044700 A1 WO2023044700 A1 WO 2023044700A1 CN 2021120097 W CN2021120097 W CN 2021120097W WO 2023044700 A1 WO2023044700 A1 WO 2023044700A1
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WO
WIPO (PCT)
Prior art keywords
water
organic silver
silver ion
ion compound
oral mucositis
Prior art date
Application number
PCT/CN2021/120097
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English (en)
Chinese (zh)
Inventor
王式禹
Original Assignee
世福莱德生技股份有限公司
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Publication date
Application filed by 世福莱德生技股份有限公司 filed Critical 世福莱德生技股份有限公司
Priority to PCT/CN2021/120097 priority Critical patent/WO2023044700A1/fr
Publication of WO2023044700A1 publication Critical patent/WO2023044700A1/fr

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Classifications

    • 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
    • A61K31/28—Compounds containing heavy metals
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics

Definitions

  • the present invention relates to a method for treating oral mucositis, which includes providing a water-based gel containing a water-soluble organic silver ion compound, and applying it to damaged oral mucosa with an appropriate application method, and is mainly used in the treatment of oral mucosa Inflammation (Oral Mucositis).
  • the method of the present invention is mainly applied to patients with oral mucositis caused by cancer radiotherapy and chemotherapy, but it can also be applied to patients with oral mucosa inflammation or ulcers caused by other factors.
  • the present invention is also related to a treatment for oral mucositis
  • the water-based gel is characterized in that the composition of the water-based gel contains a water-soluble organic silver ion compound and a polymer thickener.
  • the water-based gel When used, the water-based gel will be used due to the viscosity and shear thinning characteristics of the water-based gel.
  • the damaged oral mucosa can stay for a long time, so that the water-soluble organic silver ion compound in the water-based gel can fully exert its effect, and promote the recovery of the damaged oral mucosa during radiotherapy and chemotherapy.
  • Oral mucositis is one of the lesions that occur in the oral mucosa. Oral mucositis especially refers to the oral mucosal lesions, ulcers and inflammation caused by the treatment of cancer patients during chemotherapy and radiation therapy. It is a kind of It is a very common complication after chemical drug treatment and radiation therapy. Severe oral mucositis can cause cancer patients to have difficulty eating and swallowing. In severe cases, they will die due to inability to eat and cause insufficient nutrition to fight cancer.
  • hematopoietic stem cell transplantation hematopoietic stem cell transplantation
  • the main treatment method is usually local medication in the oral cavity, including the application of local analgesics, such as the use of narcotic preparations (Lidocaine, Benzocaine or benzydamine) Sprays, gels or mouthwashes, use topical anti-inflammatory agents such as steroid preparations (apply Nincort intraoral gel, Salcoat oral spray capsules), use topical antiseptics such as mouthwashes containing chlorohexidine.
  • local analgesics such as the use of narcotic preparations (Lidocaine, Benzocaine or benzydamine) Sprays, gels or mouthwashes
  • topical anti-inflammatory agents such as steroid preparations (apply Nincort intraoral gel, Salcoat oral spray capsules)
  • use topical antiseptics such as mouthwashes containing chlorohexidine.
  • a water-based gel used to reduce the discomfort or pain of oral mucositis such as Gelclair, which is a thick liquid that is used like a mouthwash and can be used directly or diluted Use, the main function is to form a protective layer on the damaged oral mucosa to reduce the discomfort and pain of patients with oral mucositis, but this type of aqueous gel can only relieve the discomfort of oral mucositis, and cannot improve the oral mucosa Symptoms of inflammation.
  • the inventors of the present invention have found that water-soluble organic silver ion compounds are very effective for treating oral mucositis, and have developed a method of using water-soluble organic silver ion compounds to treat oral mucositis and water-based solutions containing water-soluble organic silver ion compounds. gel.
  • the present invention mainly relates to a method for treating oral mucositis, which includes providing a water-based gel containing a water-soluble organic silver ion compound, and applying it to the damaged oral mucosa with an appropriate application method, mainly for the treatment of radiotherapy and chemotherapy
  • the cancer patients treated of course, in addition to the oral mucositis patients generally obtained during the chemotherapy and radiation therapy of cancer, there are also patients with recurrent aphthous ulcer (Recurrent aphthous Ulcer) and those caused by wearing braces.
  • Oral ulcer patients or patients with oral ulcers caused by other diseases can use the method of the present invention.
  • Oral mucositis is one of the common side effects after receiving chemotherapy and radiotherapy, and it often occurs in 4-7 days and 7-14 days after chemotherapy and reaches the peak.
  • the stomatitis caused by radiation therapy may start around 2-3 weeks and reach its peak in the late stage of treatment.
  • Symptoms of oral mucositis include dry mouth, bad breath, inflammation and pain, etc. In severe cases, mucosal damage or ulcers in the oral cavity or oropharynx, bleeding, changes in taste, difficulty in swallowing and speaking, etc. may occur.
  • the World Health Organization grading standard for oral mucositis divides the condition of the oral mucosa into 5 grades, grade 0 is no change in the oral mucosa, grade 1 is oral mucosa pain and erythema, and grade 2 is oral mucosa pain and erythema combined Ulcers, can eat solid food, grade 3 is oral mucosa pain and erythema combined with ulcers, can only eat liquid food, grade 4 is oral mucosa pain and erythema combined with ulcers, unable to eat.
  • the methods of the present invention may be used with damaged oral mucosa at any of the grades described above.
  • the water-based gel in the present invention is a viscous water-based gel containing a water-soluble organic silver ion compound. Its use method is very diverse. It can be similar to mouthwash, and an appropriate amount of the water-based gel of the present invention can be poured into the mouth. In the mouth, use the oral movement to evenly distribute the water-based gel to the damaged mucosa of the mouth, then hold the water-based gel in the mouth for a period of time, and then spit it out. Or it can be sprayed on the damaged oral mucosa in the mouth, or it can be sprayed deeper into the throat. It can also be smeared on damaged oral mucosa.
  • this aqueous gel Due to the viscous and shear-thinning characteristics of this aqueous gel, it can stay on the damaged oral mucosa for a long time, so that the water-soluble organic silver ion compound in the aqueous gel can play its role more effectively .
  • the aqueous gel of the present invention contains a water-soluble organic silver ion compound and also contains a polymer thickener, and its effect is to improve the viscosity of the aqueous gel of the present invention.
  • a suitable polymer thickener includes Cellulose, Acrylic (polyacrylate), natural gum, polyvinylpyrrolidone (polyvinylpyrrolidone) and other water-based organic thickeners, cellulose thickeners include sodium carboxylmethyl cellulose, methyl cellulose ( Methyl Cellulose), Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxyethyl cellulose, Microcrystalline cellulose or other water-soluble thickeners Efficient cellulose derivatives, acrylics include polyacrylic acid, sodium polyacrylate, copolymers of acrylic acid and other acrylic monomers, copolymers of sodium acrylate and other acrylic monomers, or other water-soluble thickeners Water-soluble acrylic polymer with agent performance, natural gum contains guar gum (Guar gum),
  • the above polymer thickener will also give the water-based gel of the present invention the characteristics of shear thinning (Shear thinning), which makes the water-based gel of the present invention During use, it can stay in the oral mucosa for a long time, so that the water-soluble organic silver ion compound in the water-based gel can play its role more effectively.
  • Shear thinning shear thinning
  • the property of shear thinning is a characteristic of a non-Newtonian fluid, that is, the viscosity of the fluid decreases with the increase of the shear force, which is different from the viscosity of the Newtonian body that does not change with the change of the shear force.
  • the specific advantage of the property of shear thinning in the use of the hydrogel of the present invention is to make the application method more acceptable to the user, and to allow the water-soluble organic silver polymer to contact the damaged oral mucosa for a longer period of time. to fully utilize its effectiveness,
  • the water-based gel When the water-based gel is used in the form of mouthwash, when it is poured into the mouth, the movement of the oral cavity exerts a shear force on the water-based gel. The faster the frequency of oral movement, the greater the shear force, because The water-based gel of the present invention has the property of shear thinning, so its viscosity will be much lower. A low-viscosity mouthwash will be more acceptable to users than a high-viscosity mouthwash, and it will also make the water-based gel easier to process. And more completely cover every mucous membrane in the oral cavity, whether it is damaged or undamaged mucous membranes can be covered.
  • the shear force is zero, and the water-based gel of the present invention has increased viscosity and is not easy to flow when remaining on the oral mucosa, so it can stay on the damaged mucosa, and because of its high viscosity, it is not easy to be washed away by saliva in the oral cavity, making the water-based gel It can stay on the damaged mucosa for a long time, and the water-soluble organic silver ion compound in the water-based gel can also play its role more effectively.
  • the same water-based gel of the present invention When used in the form of a spray, the same water-based gel of the present invention is subjected to the power given by the spray bottle when spraying out, and is sprayed at a high speed. At this time, the water-based gel is thinned by shearing characteristics and the viscosity is reduced, so that the water-based gel can be sprayed out smoothly. When it is sprayed on the damaged oral mucosa, the force of the nozzle has disappeared and the viscosity of the water-based gel has increased, so it can stay on the damaged oral mucosa for a long time. On the mucous membrane, the water-soluble organic silver ion compound in the aqueous gel can also play its role more effectively.
  • the same water-based gel of the present invention When used in the way of smearing, the same water-based gel of the present invention is subjected to the force applied when smearing and the viscosity is reduced, so that the water-based gel can be smoothly applied to the damaged oral mucosa.
  • the viscosity of the water-based gel of the present invention increases because the force of smearing has disappeared, so it can stay on the damaged mucosa for a long time, and the water-soluble organic silver ion compound in the water-based gel also to play its role more effectively.
  • the nature of shear thinning is usually represented by Thixotropic Index, which refers to the viscosity ratio measured under low and high shear forces. If the Thixotropic Index is equal to 1, it represents the The fluid is a Newtonian fluid, and if the thixotropy index is greater than 1, it means that the fluid is non-Newtonian and has the property of shear thinning.
  • the rotation of the fluid is used to measure the viscosity of the fluid, and the magnitude of the shear force is represented by the rotational speed of the cone and the spindle.
  • the thixotropic index defined in the present invention refers to the viscosity ratio measured when the rotating speed of the cone or spindle is 1 revolution per second and 10 revolutions per second.
  • the thixotropy index of the aqueous gel of the present invention must be greater than 1.1, more preferably greater than 1.5, and more preferably greater than 2.
  • the effective substance contained in the aqueous gel for treating oral mucositis is a water-soluble organic silver ion compound
  • the water-soluble organic silver ion compound can be a small molecule organic silver ion compound or a macromolecular organic silver ion compound .
  • the small-molecule organic silver ion compound of the present invention refers to organic silver salts with a molecular weight less than 1000, including but not limited to organic silver salts of carboxylates, organic silver sulfonates, and complexes of organic heterocyclic compounds and silver ions.
  • the solubility of the ionic compound in water at normal temperature (25°C) must be greater than 0.01%, preferably greater than 0.1%, more preferably greater than 1%.
  • the organic silver carboxylate salt of the present invention can be the alkyl organic carboxylate silver salt that generally contains 1 to 10 carbon number, such as silver formate, silver acetate, silver propionate, silver butyrate etc., or it may contain other water-soluble functional groups
  • Alkyl organic carboxylic acid silver salts such as the organic carboxylic acid silver salts with the chemical formula CH 3 -O-(CH 2 CH 2 O) n -CH-COOAg mentioned in European Patent EP2159270A1, or other structures silver salts of organic carboxylic acids.
  • the organic sulfonate silver salt of the present invention can be silver toluenesulfonate or other organic sulfonate silver salts.
  • the complex compound of organic heterocyclic compound and silver ion of the present invention can be the complex compound of imidazole compound (imidazole compound) or triazole compound (triazole compound) and silver, for example in document (Dalton Trans.,2009,6985-6990 ) The water-soluble imidazole/silver complexes and water-soluble triazole/silver complexes studied in ), or the complexes of other heterocyclic compounds and silver.
  • the macromolecular organic silver ion compound of the present invention can be the water-soluble acrylic polymer silver salt disclosed in US Pat.
  • the silver content in the aqueous gel of the present invention must be at least greater than 10ppm, preferably greater than 50ppm, and more preferably greater than 150ppm. The higher the silver ion content, the better the effect of treating oral mucositis.
  • the aqueous gel of the present invention can also add appropriate flavoring agents to increase user acceptance, such as sweeteners or cooling agents.
  • the raw material of the aqueous gel contains polyvinylpyrrolidone (Polyvinylpyrrolidone, BASF) and hydroxypropylmethylcellulose (Hydroxypropylmethylcellulose, Metolose 90SH-100000SR, Shin-Etsu), the water-soluble organic silver ion compound used is macromolecular sodium acrylate-silver acrylate copolymer (Poly(sodium acrylate-co -silver acrylate), provided by Cunshengtai International Co., Ltd., which provides sodium acrylate-silver acrylate copolymer solution (Poly(sodium acrylate-co-silver acrylate) solution), sodium acrylate-silver acrylate copolymer solution
  • the sodium acrylate-silver acrylate copolymer content is 2.5%, and the silver ion content is 1%, that is, each sodium acrylate-silver acrylate copolymer molecule contains an average
  • composition of the aqueous gel is shown in the table below, as shown in the table, the silver content in the prepared aqueous gel is 150ppm (0.015%), and the viscosity measured at 1 revolution per second with the Brookfield DV1 rheometer is 367cps, and the viscosity at 10 revolutions per second is 298cps, the thixotropic index of this aqueous gel is 1.23.
  • CCRT concurrent chemoradiotherapy
  • the intervention of hydrogel was given on the 23rd day (T0) after the start of the treatment, and he was asked to take it after meals every day.
  • gargling before going to bed gargle for at least one minute each time, spit out the water-based gel after rinsing, and have a weekly oral examination by an oral surgeon according to the Oral Assessment Guildline (OAG, Oral Assessment Guildline).
  • CCRT concurrent chemoradiotherapy
  • the intervention of hydrogel was given on the 16th day (T0) after the start of the treatment, and he was asked to eat after meals and Rinse your mouth before going to bed, gargle for at least one minute each time, spit out the water-based gel after rinsing, and have a weekly oral examination by an oral surgeon according to the Oral Assessment Guildline (OAG, Oral Assessment Guildline). 4 weeks (T1 to T4) until the end of the course of treatment, the results are shown in the table below:
  • the intervention of hydrogel was given on the 27th day (T0) after the start of treatment. She was asked to rinse her mouth after meals and before going to bed every day. Gargle for at least one minute at a time, and spit out the water-based gel after rinsing.
  • the oral cavity is checked by an oral surgeon according to the Oral Assessment Guildline (OAG, Oral Assessment Guildline) every week for a total of 4 weeks (T1 to T4) So until the end of its course of treatment, the results are shown in the table below:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un gel aqueux pour le traitement de la mucosite orale, qui est caractérisé en ce qu'il contient un composé d'ion argent organique soluble dans l'eau et un épaississant polymère. Le gel aqueux est utilisé dans la préparation d'un médicament pour le traitement de la mucosite orale, en particulier la mucosite orale provoquée par la chimioradiothérapie du cancer. Lorsqu'il est utilisé, en raison de la viscosité et de la caractéristique de rhéofluidification du gel aqueux, le gel aqueux peut rester sur la muqueuse buccale endommagée pendant une longue période, de telle sorte que l'efficacité du composé d'ion argent organique soluble dans l'eau dans le gel aqueux peut être complètement réalisée, et la restauration de la muqueuse buccale endommagée dans le processus de chimioradiothérapie est favorisée.
PCT/CN2021/120097 2021-09-24 2021-09-24 Procédé et gel aqueux pour le traitement de la mucosite orale WO2023044700A1 (fr)

Priority Applications (1)

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PCT/CN2021/120097 WO2023044700A1 (fr) 2021-09-24 2021-09-24 Procédé et gel aqueux pour le traitement de la mucosite orale

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PCT/CN2021/120097 WO2023044700A1 (fr) 2021-09-24 2021-09-24 Procédé et gel aqueux pour le traitement de la mucosite orale

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105209049A (zh) * 2013-05-02 2015-12-30 医学科技研究公司 抗微生物组合物及其制造方法
US20160243164A1 (en) * 2011-05-05 2016-08-25 Celacare Technologies, Llc Antimicrobial silver hydrogel composition for the treatment of burns and wounds
TWI566783B (zh) * 2015-08-21 2017-01-21 王式禹 銀高分子漱口水
CN106397640A (zh) * 2015-04-21 2017-02-15 王式禹 水溶性抗菌压克力高分子银盐
US20190388392A1 (en) * 2018-06-11 2019-12-26 Abon Pharmaceuticals Llc. Oral eliglustat transmucosal delivery system

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160243164A1 (en) * 2011-05-05 2016-08-25 Celacare Technologies, Llc Antimicrobial silver hydrogel composition for the treatment of burns and wounds
CN105209049A (zh) * 2013-05-02 2015-12-30 医学科技研究公司 抗微生物组合物及其制造方法
CN106397640A (zh) * 2015-04-21 2017-02-15 王式禹 水溶性抗菌压克力高分子银盐
TWI566783B (zh) * 2015-08-21 2017-01-21 王式禹 銀高分子漱口水
US20190388392A1 (en) * 2018-06-11 2019-12-26 Abon Pharmaceuticals Llc. Oral eliglustat transmucosal delivery system

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TANG, YUXIN: "Analysis of the Effect of Active Silver Ion Antibacterial Liquid Nursing on Oral Ulcers Caused by Chemotherapy", ELECTRONIC JOURNAL OF GENERAL STOMATOLOGY, vol. 6, no. 12, 1 April 2019 (2019-04-01), pages 77 - 77, XP093053583, DOI: 10.16269/j.cnki.cn11-9337/r.2019.12.057 *

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