WO2023044700A1 - Method and aqueous gel for treating oral mucositis - Google Patents

Abstract

Disclosed is an aqueous gel for treating oral mucositis, which is characterized in that same contains a water-soluble organic silver ion compound and a polymer thickener. The aqueous gel is used in the preparation of a drug for treating oral mucositis, in particular oral mucositis caused by cancer chemoradiotherapy. When in use, due to the viscosity and the shear thinning characteristic of the aqueous gel, the aqueous gel can stay on the damaged oral mucosa for a long time, so that the effectiveness of the water-soluble organic silver ion compound in the aqueous gel can be fully realized, and the restoration of damaged oral mucosa in the chemoradiotherapy process is promoted.

Description

Method and aqueous gel for treating oral mucositis technical field

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. 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.

Background technique

Oral mucositis (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.

Cancer patients receiving high-dose chemotherapy and hematopoietic stem cell transplantation (hemato poietic stem cell transplantation) have almost 100% chance of getting oral mucositis, and 80% of patients with head and neck malignancies receiving radiation therapy will get oral mucositis Oral mucositis occurs in up to 40-70% of cancer patients receiving chemotherapy.

When oral mucositis occurs, in addition to the need to strengthen the cleaning and care of the oral cavity, 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.

The above local treatment effects are not very significant. Studies have shown that mouthwash containing chlorohexidine antibacterial agent has no great effect on oral mucositis (European Journal of Cancer Care, 2006, 15, 431–439). When oral mucositis is severe, Topical application of the drug becomes very cumbersome, so that the therapeutic effect will be reduced.

There is also 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.

Contents of the invention

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 (such as diabetes, hand-mouth-foot disease) 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.

Generally, there are three evaluation standards to choose from for the evaluation of damaged oral mucosa, which are the World Health Organization Oral Toxicity scale, the Oral Assessment Guildline (OAG, Oral Assessment Guildline) and the National Cancer Institute of the United States. The Institute's Common Toxicity Criteria for Adverse Events (National Cancer Institute Common Toxicity Criteria for Adverse Events, NCI-CTCAE V5.0, 2017), these evaluation standards grade the degree of damage to the oral mucosa to facilitate the evaluation of oral mucosa in cancer patients Damage analysis and care.

For example, 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. 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), agar (agar), xanthan gum (Xanthan gum), sodium alginate (sodium alginate), starch (starch) , chitosan (chitosan), collagen (collagen), locust bean gum (Locust bean gum) or gum Arabic (gum Arabic), etc., polyvinylpyrrolidone contains a copolymer of polyvinylpyrrolidone and vinylpyrrolidone and other monomers. The aqueous gel of the present invention may use only one kind of thickener, or two or more kinds of thickeners may be used in combination.

In addition to improving the viscosity of the water-based gel of the present invention, 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.

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. There are two kinds of fluids with this characteristic, one is pseudoplastic fluid (Pseudoplastic fluid), the other is thixotropic fluid (Thixotropic fluid), the difference is that the viscosity of pseudoplastic fluid does not vary with time, The viscosity of the thixotropic viscosity-breaking fluid decreases with the increase of the shear force, and the viscosity change is different from that of the increase of the shear force during the recovery process of the decrease of the shear force, that is, there is a time factor in it, and the aqueous gel of the present invention It can be a pseudoplastic fluid or a thixotropic viscous fluid, because both have the property of shear thinning.

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,

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.

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.

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. When the smearing action stops, 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.

There are many methods for fluid measurement. The two most convenient methods are Cone and Plate and Spindle. Representative instrument manufacturers are Texas Instruments and AMETEK Brookfield. These two instruments are based on Cone and Spindle. 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.

In the present invention, the effective substance contained in the aqueous gel for treating oral mucositis is a water-soluble organic silver ion compound, and 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.

In addition to the above ingredients, the aqueous gel of the present invention can also add appropriate flavoring agents to increase user acceptance, such as sweeteners or cooling agents.

Detailed ways

Preparation of water-based gel:

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 of about 40% silver, while The molecular weight is greater than 5,000,000.

The 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.

Case 1:

A 59-year-old male patient, suffering from hypopharyngeal cancer, received concurrent chemoradiotherapy (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. As well as 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). Carry out 4 weeks (T1 to T4) so until the end of its course of treatment, the results are shown in the table below:

It can be seen from the results in the table that the patient's condition was very poor at T0, and his condition improved a lot in the first week of intervention (T1), and his condition improved after the second week of intervention (T2). becoming steady.

Case 2:

A 51-year-old male patient, suffering from throat cancer, received concurrent chemoradiotherapy (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:

From the results in the table, it can be seen that the condition of the patient was very poor at T0, and in the first week of intervention (T1), his condition improved a lot, and after the second week of intervention (T2), his condition became more and more stable. more stable.

Case 3:

A 40-year-old female patient, suffering from oropharyngeal cancer, received radiation therapy. 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:

From the results in the table, it can be seen that the condition of the patient has not developed to a very bad condition at T0, and in the first and second weeks of intervention (T1&T2), the condition has not deteriorated or even improved somewhat. After the third week (T3), the condition has improved and progressed until the end of the course of treatment (T4).

Claims (14)

1. A method for treating oral mucositis, characterized in that it includes providing a water-based gel containing a water-soluble organic silver ion compound, and applying the water-based gel to damaged oral mucosa with an appropriate application method, wherein the water-based gel The silver content of the glue is greater than 10 ppm.
2. The method for treating oral mucositis according to claim 1, wherein the water-soluble organic silver ion compound is a small molecular weight organic silver ion compound with a molecular weight less than 1000 or a large molecular weight organic silver ion compound with a molecular weight greater than 1000.
3. The method for treating oral mucositis according to claim 2, wherein the low-molecular-weight organic silver ion compound is an organic silver carboxylate, an organic silver sulfonate, or a complex compound of an organic heterocyclic compound and silver ions.
4. The method for treating oral mucositis according to claim 2, wherein the large molecular weight organic silver ion compound is a water-soluble acrylic polymer silver salt.
5. The method for treating oral mucositis according to claim 1, wherein the appropriate application method is mouthwash, spray or smear.
6. The method for treating oral mucositis according to claim 1, wherein the damaged oral mucosa is any one of the five levels of mucosa in the World Health Organization's oral mucositis grading standard.
7. The method for treating oral mucositis according to claim 1, wherein the thixotropic index of the aqueous gel is greater than 1.1.
8. A water-based gel for treating oral mucositis is characterized in that its components contain a water-soluble organic silver ion compound and a polymer thickener, and the silver content of the water-based gel is greater than 10 ppm.
9. The aqueous gel according to claim 8, wherein the solubility of the water-soluble organic silver ion compound in water is greater than 0.01%.
10. The aqueous gel according to claim 8, wherein the water-soluble organic silver ion compound is a small molecular weight organic silver ion compound with a molecular weight of less than 1000 or a large molecular weight organic silver ion compound with a molecular weight greater than 1000.
11. The aqueous gel according to claim 10, wherein the low molecular weight organic silver ion compound is an organic silver carboxylate, an organic silver sulfonate or a complex compound of an organic heterocyclic compound and silver ions.
12. The aqueous gel according to claim 10, wherein the large molecular weight organic silver ion compound is a water-soluble acrylic polymer silver salt.
13. The aqueous gel according to claim 8, wherein the macromolecule thickener is cellulose, acrylic, natural gum, polyvinylpyrrolidone or polyoxyethylene, and can be used singly or in combination of two or more.
14. The aqueous gel according to claim 8, wherein its thixotropic index is greater than 1.1.