CN111700887A

CN111700887A - Benzenesulfonic acid preparation for treating mucosal rupture

Info

Publication number: CN111700887A
Application number: CN202010675065.1A
Authority: CN
Inventors: 陈明丰
Original assignee: Sante Healthcare Alliance International Ltd
Current assignee: Sante Healthcare Alliance International Ltd
Priority date: 2020-07-14
Filing date: 2020-07-14
Publication date: 2020-09-25

Abstract

The invention discloses a benzenesulfonic acid preparation for treating mucosal rupture, which is prepared by uniformly mixing 70-90% of benzenesulfonic acid, 8-20% of water and 2-10% of colloidal silicon dioxide by weight. The invention mainly adopts the monoaromatic sulfonic acid which has strong water absorbability and can remove the biofilm from the surface to effectively kill bacteria. The present formulation provides real-time pain relief and accelerated ulcer healing for the user, kills infectious microorganisms, i.e., they seek and attack necrotic or damaged tissue, quickly draws water away from the affected area, forms a protective layer, relieves pain, prevents contamination and aids healing, achieves the effect of drawing water away from the affected area through physical action, removes damaged tissue, and is therefore very effective in a single application with an ulcer or other mucosal end. Only contains one aromatic sulfonic acid, has simpler formula, is safer and has lower risk factors.

Description

Benzenesulfonic acid preparation for treating mucosal rupture

Technical Field

The invention relates to the technical field of medicines, in particular to a medicine for treating oral ulcer mucosa rupture.

Background

Canker sores are ulcerative lesions commonly found in the mucous membranes of the mouth, most often in the inner labial area, tongue, abdomen, buccal mucosa, vestibular sulcus, soft palate, etc., where the mucous membranes lack a cornified layer or are poorly keratinized. For long-term or repeated-onset oral ulcer, a treatment mode of local inflammation diminishing, oral pain relieving and ulcer healing promoting is generally adopted at present, some treatments adopt traditional Chinese medicines, and some treatments adopt western medicines. However, the currently used drugs mainly have the following disadvantages that firstly, the effect is slow, even if the pain is relieved, the drugs are repeatedly used for a plurality of days regularly to relieve the pain, not to mention the wound healing, especially traditional Chinese medicines; second, formulations for the treatment of chronic wounds and bacterial infections usually contain sulphuric acid, for example, topical ointments containing steroids for anti-inflammatory use, whereas sulphuric acid and two sulphonic acid formulations cause various colouring, perfuming and flavouring agents to be unstable and to degrade over time, creating risk factors that not only reduce the efficacy of the drug itself, but also present safety hazards, which is particularly common with western medicines.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides the benzenesulfonic acid preparation for treating mucosal rupture, which has the advantages of simple formula, only contains one aromatic sulfonic acid, no sulfuric acid, higher safety and quicker effect.

In order to solve the technical problems, the invention adopts the following technical scheme: an benzenesulfonic acid preparation for treating mucosal rupture, characterized by: 70-90% of benzenesulfonic acid, 8-20% of water and 2-10% of colloidal silicon dioxide by weight, and uniformly mixing the three raw materials to prepare a preparation; the preparation process comprises the following steps: weighing benzenesulfonic acid, water and colloidal silicon dioxide in a clean indoor environment at normal temperature (such as about 25 ℃) and at relative humidity of 55-65%, adding the weighed materials into a container, heating the materials to 90 ℃, stirring the materials for 1 hour until the materials are completely dissolved and uniformly mixed, and naturally cooling the solution to room temperature for use.

Heating the prepared preparation to 30 ℃, and then directly injecting a quantitative preparation into a polypropylene container; finally, heating to 120-150 ℃ by using a pure aluminum foil film to seal the preparation in the polypropylene container.

Preferably, the benzene sulfonic acid is 80%, the water is 10%, and the colloidal silica is 10%.

A cotton swab is arranged in the polypropylene container for disposable use.

The using method comprises the following steps: 1. firstly, the affected part is wiped clean by using a common clean cotton stick or a common paper towel, so that the preparation can exert the best effect;

2. opening the packaging tinfoil, and sticking a proper amount of preparation on a cotton swab in the packaging;

3. the cotton bud with the preparation is applied to the affected part for 3-5 s. The preparation medicine is completely covered on the affected part in a rolling mode, the preparation is not applied to the affected part in the using process, and is also not applied to the non-affected part so as to avoid possible red swelling of the oral mucosa;

4. after 3-5 seconds, the mouth is rinsed thoroughly with clear water, and pain can disappear completely.

The invention mainly adopts the monoaromatic sulfonic acid which has strong water absorbability and can remove the biofilm from the surface to effectively kill bacteria. The present formulation provides real-time pain relief and accelerated ulcer healing for the user, kills infectious microorganisms, i.e., they seek and attack necrotic or damaged tissue, quickly draws water away from the affected area, forms a protective layer, relieves pain, prevents contamination and aids healing, achieves the effect of drawing water away from the affected area through physical action, removes damaged tissue, and is therefore very effective in a single application with an ulcer or other mucosal end.

At the same time, the formulation of the invention contains only one aromatic sulfonic acid, no sulfuric acid, and the formulation with mono-sulfonic acid has the same benefits as the formulation with two sulfonic acids, but the formulation is simpler. In addition, the preparation of the invention does not contain sulfuric acid, so that the problem that a plurality of coloring agents, fragrances and spices are unstable and degrade over time due to sulfuric acid and two sulfonic acid preparations is avoided, and the coloring agents, the fragrances and the spices have wider application range, are safer and have lower risk factors.

Drawings

FIG. 1 is a chart of no apparent pain scores for patients receiving HybenX (invention) and Salicept (existing drug oral patch) treatments;

figure 2 shows the drug forming a protective layer of coagulated tissue fragments on the surface of the ulcer by placing the tip of a cotton swab over the ulcer for 10 seconds.

Detailed Description

The following is further described in conjunction with the detailed description:

example 1, the benzenesulfonic acid preparation for treating mucosal rupture comprises 70% by weight of benzenesulfonic acid, 20% by weight of water and 10% by weight of colloidal silicon dioxide, and the three raw materials are uniformly mixed to prepare the preparation.

Weighing benzenesulfonic acid, water and colloidal silicon dioxide at normal temperature (such as about 25 ℃) and relative humidity of 60% in a clean indoor environment, adding the weighed materials into a container, heating the materials to 90 ℃, stirring the materials for 1 hour till the materials are completely dissolved and uniformly mixed, and naturally cooling the solution to room temperature for use.

Heating the prepared preparation to 30 ℃, and then directly injecting a quantitative preparation into a polypropylene container with a specific shape; finally, heating to 120-150 ℃ by using a pure aluminum foil film to seal the preparation in the polypropylene container.

A cotton swab is arranged in the polypropylene container for disposable use.

Example 2, except that 80% by weight of benzenesulfonic acid, 10% by weight of water and 10% by weight of colloidal silica were mixed uniformly to prepare a preparation.

Example 3, except that 90% by weight of benzenesulfonic acid, 8% by weight of water and 2% by weight of colloidal silica were mixed uniformly to prepare a preparation.

4. after 3-5 seconds, the mouth is rinsed thoroughly with clear water, and pain can disappear completely. Preferably, the benzene sulfonic acid is 80%, the water is 10%, and the colloidal silica is 10%.

A cotton swab is arranged in the polypropylene container for disposable use.

Randomized control trials for treatment of recurrent aphthous stomatitis with the present invention (HybenX):

test unit: research in oral medicine and health services, eastman dental institute, university of london, uk.

Background: treatment of Recurrent Aphthous Stomatitis (RAS) is primarily aimed at reducing pain and duration of each ulcer attack, however, there are still few drugs with clear evidence to suggest benefit.

The purpose is as follows: the purpose of this study was to determine the efficacy of the present invention (HybenX) with another commonly used drug for treating RAS (Salicept oral patch, carlington laboratories, europe, texas, usa) to reduce the symptoms and duration of RAS and to determine the safety of clinical application of HybenX.

Materials and methods: 63 persons (36 men, 27 women, mean age 25 years, range 17.8-57.9 years) were included in a randomized controlled trial comparing HybenX to Salicept oral patches.

As a result: at 5 days post-treatment, the pain symptoms decreased in two phases, with few side effects of these two drugs-9 adverse events were recorded for 8 patients in total, but neither of these was likely to be associated with a therapeutic device. HybenX only applies to the HybenX group, and individuals in the Salicept group are able to request medications. The average number of Salicept patches used per subject per day was 3(s.d.3.3) on day 1, 3.4(s.d.3.1) on days 2 and 2.7, and 2 and 2.7 (s.d.1.9) on days 2 and 2.7 after treatment. Thereafter, the number of days 7 dropped to an average of 0.8.

And (4) conclusion: HybenX safely and effectively reduced the pain symptoms in RAS patients.

The cause of recurrent oral ulceration is not clear and most patients do not have a clear cause. Some patients develop ulceration after oral trauma (e.g., vigorous cleaning of teeth or dental treatment). Others may suffer from an increase in RAS events caused by smoking cessation (maculo et al, 2007) or psychological stress (stacury, 2006). Suggested etiological factors include RAS family history, idiopathic hemoglobin deficiency and more rarely food sensitivity, immunodeficiency, menstrual cycle variation and possible infant feeding practices (McCullough et al, 2007).

Thalidomide is currently the only drug that successfully blocks RAS recurrence (Jurge et al, 2006; Scully and Porter, 2008). However, ulcers usually recur when treatment is stopped, and the well-known side effects of thalidomide, particularly the teratogenic and peripheral neuropathy liability, limit its clinical application to specialist practice (baud and haerhh, 2002). Thus, treatment is primarily intended to reduce the duration of ulcers and pain. Typical treatment regimens include chlorhexidine gluconate (0.2%) mouthwash, topical corticosteroids (such as 1% carboxy cellulose paste or betamethasone or prednisolone mouthwash) and topical minocycline (golsby, 2007).

Random control comparisons were used to treat this ulcer with another drug (Salicept). In addition, the study also attempted to determine the performance and safety of HybenX in treating RAS.

Materials and methods

Ethical approval

Consisting of 53 healthy adults over 18 years of age with a history of RAS (baud and stacurie, 2005). In particular, all subjects had a history of recurrent ulceration episodes of the non-keratinized oral mucosa, including two episodes in the past 12 months. None of the subjects had any ulcer of local origin and any infectious, hematologic, gastrointestinal or dermatological disease history could cause ulceration of the oral mucosa. All subjects received drug treatment that may lead to oral mucosal ulceration (Scully et al, 2003). During the course of the study, all subjects agreed to avoid the use of other canker sore treatments (i.e. topical or systemic anti-inflammatory or analgesic drugs (such as aspirin, paracetamol or ibuprofen), corticosteroids, analgesics, mouthwashes with alcohol or narcotics) and tooth bleaching agents. All female patients were examined for pregnancy prior to study entry, and the females found that they were pregnant and did not enter the study.

Study protocol

At study entry, all subjects had at least one oral mucosal ulcer for less than 48 hours. At baseline, the size, location, color and depth of each ulcer were assessed clinically and the intensity of pain assessed by photograph and subject were asked to be on a 100 mm visual analog scale (VAS; baseline non-controversial pain assessment). The subject then holds 20 ml of natural orange juice in the ulcerated region for more than 5 seconds and then swallows or expectorates the juice. Further VAS (baseline challenge pain assessment) was then recorded, and each subject was then randomly assigned to either HybenX or Salicept groups, followed by a single application of HybenX or Salicept to the ulcer by the clinician. This was followed by a record of the non-challenged VAS (non-challenged pain assessment immediately after treatment) and challenged pain assessment. After 20 minutes of application of the drug (20 minutes post-treatment non-challenged and challenged pain assessment), further estimates of non-challenged and challenged VAS were made.

The subject was then discharged. Subjects of the Salicept group received guidance regarding appropriate home self-administration of Salicept-these can be used as often as the subjects wish. The theme in the HybenX group did not receive any additional equipment. All in the next 8 days, subjects were asked to complete one of the highest estimated score VAS per day-this was done before they were sleeping. The Salicept group also records the number of Salicept uses accepted per day. The researcher reminded him/her of these tasks by phone contact and all subjects also noted any potential side effects of HybenX or Salicept.

After day 8 treatment, all subjects were examined by clinician, patient masked for treatment to determine size, oral mucosal ulcer by degree of healing compared to baseline clinical notes and photographs. After day 8 treatment, a challenge-free and challenge-free pain assessment was performed. In addition, patients completed a self-administered questionnaire regarding their satisfaction with the treatment provided by the device they received.

Based on statistical analysis of pain assessments in patients with HybenX-combined drugs, mean changes in VAS baseline were observed for both arms, at least 22 sample size per treatment group, to detect a 15 mm difference in pre-treatment and post-treatment pain scores for both groups. This assumption is a bilateral test at 80% power at a significance level of 5%. Baseline changes in the VAS pain scores at all designated time points were compared for HybenX and Salicept and compared to HybenX and Salicept, and the challenged pain score and challenged pain score were analyzed, respectively. Pain scores recorded on a 100 mm scale were considered a sustained result. Differences in pain scores at each time point of the treatment groups were compared by student t-test.

To assess the overall effect of non-disputed pain scoring treatment (including all time points), a repeated measures regression model was fitted to each patient's pain score at each time. Covariates included an intercept, an indicator for the HybenX treatment group, time of assessment (values 0-8), time of assessment interaction for the treatment group and baseline pretreatment pain score. The Fisher's exact test was used to compare the rate at which all ulcers in the treatment group patients completely healed on day 8 and was evaluated by the questioned evaluators. The number of days of ulcer healing (subjects compared perception between treatment groups using the Cox proportional hazards model. this model includes HybenX treatment as an index variable. risk ratio estimates >1 indicate that HybenX patients feel faster for healing.

The number of Salicept drugs reapplied after challenge the pain assessment was summarized by the treatment groups. Similarly, information about the number of uses per day in a daily diary.

The general health changes were calculated for each patient as follows: for each body system evaluated in the screening and the physical examination on day 8, a score of 0 (no change), 1 (new reported on day 8) or-1 (unreported screening on day 8) was assigned. The sum of the scores is used to measure the change in overall health. Treatment groups between total health score calculations for each patient used (non-parametric) two-sample wilcoxon rank test, compared as off-normal score distributions. Given the small number of adverse events, no statistical analysis was performed to compare their incidence between treatment groups. Instead, a complete list of adverse events and a complete description thereof are provided.

Results

63 patients participated in the study. 32 cases (19 males, median age 23.1 years, age 18.3-57.9 years) were randomly divided into HybenX group, and 31 cases (17 males, median age 27 years, age 17.8-53.4 years) were in Salicept group. The 8 subjects in the HybenX group were eventually excluded when new ulcers appeared during the study, so the final HybenX group included 24 patients (14 men, mean age 23.1 years, age 20-47.6 years). In the Salicept group, two patients were also excluded because they developed new ulcers, so the final Salicept group included 29 subjects (17 men, age average 27 years, age between 17.8 and 53.4 years). The baseline characteristics (e.g., gender, age, medical history, concurrent medication, pulse, blood pressure, and respiratory rate) and the number, size, color, or estimated depth of the ulcers (no difference in data) were statistically insignificant in both groups.

Pain scores before, immediately after treatment and 20 min treatment

There was no controversial pain scoring before treatment, and there were no statistical differences between the two groups at 20 minutes and 8 days post-treatment as in table 1, although patients in the HybenX group had a greater tendency to pain than the Salicept group. HybenX-like Salicept observations after application of one mode of increasing scores are as in table 2, although it is noted that the HybenX group has a larger pre-treatment challenge score (P ═ 0.025).

Undisputed treatment pain score on days 1-8

The decrease in pain scores recorded by the patients is detailed in table 3 and figure 1. The decrease in mean pain scores in the HybenX group was statistically greater on day 1 (P ═ 0.016) and day 2 (P ═ 0.007) than in the salicept group (P ═ 0.007), as detailed in fig. 1. HybenX caused an initial increase in pain (as indicated by negative values), which probably reflected the initial tingling sensation after application. However, in the next two days HybenX was the more effective pain-relieving of these two drugs.

Subjective evaluation of ulcer healing

By day 8, all ulcers were completely healed in 50% of HybenX subjects and 44.4% of Salicept subjects, and this difference was not statistically significant. The mean occlusion rate for the largest ulcers also did not differ significantly between the two groups. Except on day 4, the cumulative percentage of HybenX patients was higher.

Table 1 summary of pain relief without challenge on day 8 before, immediately after, 20 min after and after treatment in patients receiving HybenX or Salicept treatment

TABLE 2 summary of the pain relief difficulties in patients receiving HybenX or Salicept treatment before, immediately after, 20 minutes after and 8 days after treatment

The ulcers were considered to have healed, but the pain perceived was not statistically different between the two groups, as in table 4.

Security

9 adverse reactions were recorded for 8 patients. All of which are unlikely to be relevant to therapeutic devices. The 5 adverse events in the HYbenX group included a possible common cold (2), sore throat (1), cough (1) and ankle sprain (1). The 4 adverse events in the Salicept group were dyspepsia and diarrhea (two events in one patient), traumatic lower lip lesions (1 case) and hay fever (1 case).

Acceptability of

The reduction in the use of Salicept by subjects was reported to be primarily due to a reduction in their clinical needs, although other reasons include inconvenient application, too busy or forgetting to use the patch.

Discussion of the related Art

Recurrent aphthous stomatitis remains a difficult disease to treat. Since the exact cause is not clear, there is currently no specific, safe and effective means to stop the outbreak of ulcers, and therefore almost all treatments are directed to reducing the painful symptoms and duration of the ulcers. Patients may seek appropriate treatment from a variety of sources and are often self-treated with a range of drugs.

TABLE 3 Subjects receiving Hybenx or Salicept for post-treatment pain relief summary a

TABLE 4 number of cumulative ulcer healed subjects receiving HybenX or Salicept treatment

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

HybenX(n＝24)

3(12.5％)

6(25.0％)

10(41.7％)

14(58.3％)

16(66.7％)

19(79.2％)

SaliCept(n＝29)

2(7.7％)

3(12.0％)

9(34.0％)

10(38.5％)

13(52.0％)

15(62.5％)

The percent response of the patients on each study day for each group was calculated.

There is still no systematic review of the treatment of the RAS, and although a wide range of drugs are considered to be of some benefit, the main methods of treatment are topical corticosteroids and antibiotics. Such as chlorhexidine, however, there is little substantive data that may cause unpleasant bitter taste and externally stained teeth for the former and the latter. Newer drugs include local minocycline and amlexanox. The latter, in some but not all formulations, have been found to alleviate clinical symptoms and symptoms. Symptoms of the RAS, particularly ulcers developing in the prodromal phase, are not widely used in all countries. Therefore, like herpes cheilitis, a topical drug has a therapeutic effect, can be easily applied to a site of pain or facial disease of an affected individual, will safely reduce pain symptoms, and is widely available to the public.

Previous findings suggest that chemical cauterization or coagulation may be clinically beneficial in treating the RAS, but it is currently unclear whether there is any treatment randomization. This study discusses that HybenX can conveniently release a solution from a chemically coagulated ulcer area, with approximately 0.2 ml of cauterizing solution being delivered from the hollow shaft of a cotton swab to the tip and then placed at the ulcer for 10 seconds (see FIG. 2). The HybenX solution comprises a concentrated aqueous solution of free sulfate and sulfonated aromatics, particularly hydroxybenzenesulfonic acid, hydroxymethoxybenzenesulfonic acid and pyruvic acid. The benzaldehydes are gonio-soluble, whereas the sulfonic and sulfuric acids are hygroscopic and denatured. The result of application to the ulcerated region is to denature, precipitate and coagulate tissue fragments at the surface of the ulcer and form a protective layer of coagulated tissue fragments on the surface of the ulcer, thereby reducing local discomfort to the painful stimulus, which protects the surface fragments from being absorbed during the healing process.

The study is a prospective, random trial with the appropriate number of subjects selected to achieve the required statistical intensity. At the beginning of the study, the age, sex, RAS and related pain symptoms were comparable in both groups of subjects. The results show that topical application of HybenX significantly reduced RAS pain after 2 days compared to a patch designed to protect the canker sore area (Salicept). HybenX and Salicept caused a reduction in pain scores between day 1 and day 4 without challenge, but reduction in HybenX was always more. HybenX was confirmed to be a potentially similar Salicept as it created a physical barrier that alleviated discomfort caused by local painful stimuli. The HybenX group, which treated challenged and unprovished pain immediately, was expected to be larger than the Salicept group because the former was acidic, while the latter provided a flat coverage and the presently observed benefits HybenX appeared to increase local pain beyond a brief post-treatment.

Although not the primary goal of this study, the performance of these two drugs in aiding ulcer healing was evaluated. It has been previously reported that debarkon induces early RAS healing much faster than topical glucocorticoid paste or no treatment. In this study, there was no difference in patient perception of ulcer healing during days 1-7 of the study period, and no difference in ulcer healing on day 8, as observed by the clinician's masking of the trial treatments. The results of these comparisons probably reflect the difference in the drugs used, as there is a higher sulphuric acid content than benzenesulphonic acid, but it is doubtful that this is a mechanism to enhance healing, as this acid aids tissue necrosis. The comparative results may reflect the control agent/device used in both studies, but it is equally difficult to understand how these changes explain the different healing results. The effect of this drug on nerve endings is unclear, so it is unclear whether HybenX causes pain relief to some extent due to local nerve activity. The current results reflect the patient's opinion, while earlier studies were based on a more accurate examination by the clinician. As such, current research results may emphasize the effect of HybenX (and/or Salicept) on ulcer healing. There was no correlation between the time of ulcer onset and the start of treatment and either drug. However, early application of HybenX accelerated the pain relief of this type of ulcer.

The present invention has been described in detail, and it should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

Claims

1. An benzenesulfonic acid preparation for treating mucosal rupture, characterized by: 70-90% of benzenesulfonic acid, 8-20% of water and 2-10% of colloidal silicon dioxide by weight, and uniformly mixing the three raw materials to prepare a preparation;

the preparation process comprises the following steps: under the conditions of normal temperature and relative humidity of 55-65%, adding benzenesulfonic acid, water and colloidal silicon dioxide into a container, heating to 90 ℃, stirring until the benzenesulfonic acid, the water and the colloidal silicon dioxide are completely dissolved and uniformly mixed, and naturally cooling the solution to room temperature for use.

2. The benzenesulfonic acid preparation for treating mucosal rupture according to claim 1, wherein: heating the prepared preparation to 30 ℃, and then directly injecting a quantitative preparation into a polypropylene container; finally, heating to 120-150 ℃ by using a pure aluminum foil film to seal the preparation in the polypropylene container.

3. The benzenesulfonic acid preparation for treating mucosal rupture according to claim 1, wherein: 80% of benzenesulfonic acid, 10% of water and 10% of colloidal silicon dioxide.

4. The benzenesulfonic acid preparation for treating mucosal rupture according to claim 2, wherein: a cotton swab is arranged in the polypropylene container for disposable use.