CN111741759A - Use of nocardia rubra cell wall skeleton in preparation of medicine for treating lichen planus - Google Patents
Use of nocardia rubra cell wall skeleton in preparation of medicine for treating lichen planus Download PDFInfo
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Abstract
The present application relates to the use of nocardia rubra cell wall scaffolds in the preparation of a medicament for the treatment of lichen planus. Particularly, the nocardia rubra cell wall skeleton effectively reduces the erosion area of lichen planus, reduces the pain degree, and shows better clinical curative effect after being used. The application reports that the cell wall skeleton of the red nocardia is adopted to treat the erosive oral lichen planus for the first time, and the curative effect and the safety of the red nocardia are preliminarily observed.
Description
The present application claims priority of the chinese patent application nocardia rubra cell wall scaffold for use in the preparation of a medicament for the treatment of lichen planus, filed 2019, 09.01.9 (application No. 201910018064.7), the entire content of which is incorporated herein by reference.
The present application relates to the field of medicine, in particular to the use of nocardia rubra cell wall scaffolds in the treatment of lichen planus.
Nocardia is polymorphic and has a spherical, rod-like or filamentous shape. The thallus has no motility, some strains have weak acid resistance, and are obligately aerobic, and the nutrition requirement is general. After the culture on a common agar plate, a visible bacterial colony is formed, the bacterial colony is raised after 7 to 10 days, and the surface is villous after aerial hyphae are formed. Colonies of different species are yellow, orange, red or mixtures thereof. The G + C molar content in the DNA is between 60% and 72%. Most of the saprophytic bacteria exist in soil.
Nocardia rubra (Nocardia rubra) is one of Nocardia. The red nocardia thallus can be fermented, broken and degraded by protease to obtain the red nocardia cell wall skeleton (hereinafter referred to as Nr-CWS or N-CWS). In the prior art, Nocardia rubra cell wall frameworks include, but are not limited to, those commercially available from, for example, Liaoning Graishite biopharmaceutical GmbH (trade name "Nakejia").
Nocardia rubra cell wall skeleton has been used for the treatment of cervical erosion, precancerous lesions of cervical cancer (CN101073583A), anti-human papilloma virus (CN1935262A), skin lesions (CN101209267A), skin lesions (eczema, neurodermatitis, nonspecific dermatitis, atopic dermatitis and psoriasis) (CN108938674A), acne (CN108295095A), fungal infections, herpes simplex and herpes zoster (CN 1879661A).
Oral Lichen Planus (OLP) is a chronic inflammatory disease of the skin mucosa mediated by cellular immunity (Oral mucosae pathology, beijing university medical press, 2014). Is quite common clinically, with a prevalence of 0.1% to 4%. Long-term erosive Oral lichen planus carries a potential risk of malignant change (Lodi G et al Current controls in Oral Medicine plants: Report of an Oral care meeting, part 2; clinical management and clinical transformation. Oral Surgery Oral Pathology Oral Radiology and Endomostics, 2005, 100(2): 164-78). WHO classified it as a potential malignant lesion in the Oral cavity (OPMD) in 2005, and a recent study in 2019 showed a malignant transformation rate of OLP of 0.8% to 1.5%.
The diagnosis of lichen planus can refer to the diagnosis guide of lichen planus prepared by the professional Committee of oral mucosa disease of the Chinese medical society in combination with the professional Committee of Chinese medical society combining Chinese and Western medicine, or refer to the diagnosis standard of lichen planus of oral cavity in WHO 2003. Lichen planus is classified into reticular, ring, streak, papular, erosive, plaque, blister and collapsed forms in "oromucosal pathology".
The etiology of OLP is unclear, and the course of disease is easy to prolong and repeat. No radical treatment is available, and the treatment mainly comprises symptomatic and immunoregulation treatment. Clinically, topical glucocorticoid is a first-line therapeutic Drug (Garc i a-Pola MJ et al Treatment of organic plant, systemic review and therapeutic guide. medicinal Cli nica, 2017,149(8):351 (362)), serious patients can use glucocorticoid or immunosuppressant and the like systemically for a short period, but topical and Long-term glucocorticoid Treatment has a large side effect, such as causing mucosal atrophy and aggravating infection and other complications, systemic side effect, such as electrolyte disturbance, wound healing retardation and growth inhibition in children and the like, so these drugs are not suitable for Long-term clinical use (Oray M et al Long-term side effects of glucocorticoids.
Therefore, the search for a safe and effective drug without obvious side effects is a problem to be solved urgently in clinic.
Disclosure of Invention
According to some embodiments of the present application, there is provided a nocardia rubra cell wall skeleton for use in the treatment of lichen planus.
According to some embodiments of the present application, there is provided a use of nocardia rubra cell wall scaffold in the treatment of lichen planus.
According to some embodiments of the present application, there is provided a use of nocardia rubra cell wall scaffold in the manufacture of a medicament for the treatment of lichen planus.
In some embodiments, the lichen planus is selected from any one or combination of the following: reticular, ring, stripe, papular, erosive, plaque, vesicular, and collapsed lichen planus. In a specific embodiment, the lichen planus is erosive lichen planus.
According to some embodiments of the present application, there is provided a pharmaceutical composition comprising:
-nocardia rubra cell wall skeleton; and
-a pharmaceutically acceptable carrier.
Any suitable vector known to those skilled in the art may be used in the present application.
In some embodiments, the medicament or pharmaceutical composition is prepared in a dosage form selected from the group consisting of: ointment, cream, gel, lotion, tincture, liniment, oil, cataplasm, aerosol, buccal tablet, patch, lyophilized powder and suspension.
In some embodiments, the dosage form is a buccal tablet. For example, it is prepared by tabletting lyophilized powder.
In some embodiments, the pharmaceutically acceptable carrier is selected from one or more of the following: filler, stabilizer, flavoring agent, disintegrating agent, binder, and lubricant.
According to some embodiments of the present application, there is provided a method of treating lichen planus comprising the steps of: providing a therapeutically effective amount of nocardia rubra cell wall skeleton (or a therapeutically effective amount of the above pharmaceutical composition) to a subject.
In the context of the present application, the only therapeutically active ingredient in the medicament or pharmaceutical composition is the nocardia rubra cell wall skeleton.
According to some embodiments of the present application, there is provided a method of treating lichen planus comprising the steps of: contacting the subject with a therapeutically effective amount of nocardia rubra cell wall skeleton (or a therapeutically effective amount of the above pharmaceutical composition).
In some embodiments, twice a day, or once in two days; the dosage of each administration is different according to the condition of the patient, and is usually 1 mu g to 1000 mu g per unit dose per administration; specifically, for example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 μ g per unit dose per time, and ranges between any two of the foregoing values.
In some embodiments, administration is performed at the following frequency: 1 to 3 applications a day, 1 to 6 applications a day, 1 to 9 applications a three day, 1 to 14 applications a week, 1 to 60 applications a month.
In some embodiments, the treatment lasts from 2 days to 2 months. Specifically, for example, 2, 4, 6, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 days; as another example, 1, 2, 3, 4, 5 weeks may be mentioned. In a specific embodiment, the subject is administered the pharmaceutical composition for 4 weeks, and once every other day.
FIG. 1 shows the comparison of the effect between the test group and the control group before and after administration.
In embodiments of the present application, suitable pharmaceutically acceptable carriers are selected from: dextran, lactose, microcrystalline cellulose, trehalose, glycine, xylitol, sodium carboxymethylcellulose, erythritol, gelatin, magnesium stearate, a propellant, a humectant, a solvent, a solubilizer, an emulsifier, an antioxidant, a pH regulator and a preservative.
Specifically, non-limiting examples of pharmaceutically acceptable carriers include: white petrolatum, carbomer, hypromellose, methylcellulose, sodium carboxymethylcellulose, chitosan, sucralfate chitosan, polyvinylpyrrolidone, polyvinyl alcohol, sodium hyaluronate, dimethyl ether, tetrafluoroethane, hydrofluoroalkane, glycerol, propylene glycol, deionized water, water for injection, distilled water, ethanol, cetyl alcohol, stearyl alcohol, p-aminobenzoic acid, acetamide, isopropyl alcohol, tween, polyoxyethylene hydrogenated castor oil, stearic acid, glyceryl monostearate, triglycerol monostearate, sucrose fatty acid ester, sucrose acetate isobutyrate, sucrose anhydride tristearate, isopropyl myristate, cholesterol, squalene, squalane, n-butanol, ethylene glycol, ethanol, propylene glycol, polyglycerol ester, sulfite, cysteine, di-tert-butyl hydroxytoluene, potassium sorbate, phosphate buffer solution, Triethanolamine, sodium hydroxide, ethylenediamine, laurylamine, sodium bicarbonate, hydrochloric acid, parabens, thimerosal, chlorocresol, chlorobutanol, benzoic acid and its sodium salt.
The formulations of the present disclosure may be prepared in the form of a unit formulation (unit formulation). In some embodiments, a unit dose in the medicament (or formulation, or therapeutic agent, or medical device) contains from 0.001mg to 500mg of the nocardia rubra product; or 0.001mg to 500mg of the nocardia rubra cell wall; or 0.001mg to 500mg of the nocardia rubra cell wall skeleton. Specific examples of unit doses are 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500mg ± 10%, and ranges between any two of the foregoing.
"administering", "providing", "treating" when applied to an animal, human, cell, tissue, organ, or biological sample means that the drug (therapeutic agent, active ingredient, or composition) is in contact with the animal, human, cell, tissue, organ, or biological sample.
By "treating" is meant administering an internal or external drug (therapeutic agent, active ingredient or composition) (e.g., nocardia rubra cell wall or pharmaceutical composition thereof according to the present disclosure) to a subject who has, is suspected of having, or is susceptible to one or more diseases or symptoms thereof, to alleviate (reduce, delay, ameliorate, cure) one or more symptoms of the disease in the subject (or population) being treated so as to reach a clinically measurable degree.
The amount of drug (therapeutic agent, active ingredient or composition) that is effective to alleviate any symptoms of the disease is referred to as a therapeutically effective amount. May vary depending on a number of factors, such as the disease state, age and weight of the subject. It is understood that a drug (therapeutic agent, active ingredient or composition) may not be effective in alleviating a target disease or symptom thereof in an individual subject, but the drug (therapeutic agent, active ingredient or composition) is statistically effective against the target disease or symptom thereof as determined by any statistical test method known in the art, such as Student's T test, chi-square test, U-test by Mann and Whitney.
The terms "a", "an", "the" and "the" include their corresponding plural forms if not expressly stated.
The present disclosure is further described below with reference to examples. These examples are not intended to limit the scope of the present disclosure. When the specific conditions are not specified, the operation is carried out under the conventional conditions, as recommended by the raw material supplier. Reagents of no particular origin are indicated as conventional reagents purchased on the market.
Examples
Example 1 pharmaceutical compositions
Nocardia rubra Cell Wall Skeleton (trade name: Nakejia; Nocardia rubra Cell Wall Skeleton) available from Liaoning Graishite biopharmaceutical Co., Ltd (approved article number national drug Standard S20030009). The medicine composition is 0.5ml per bottle, and comprises the following components in proportion:
-60 μ g of active ingredient;
-dextran 4015 mg.
The skilled artisan will appreciate that the nocardia rubra cell wall skeleton is not limited to a particular supplier, and any product known in the art, produced by any manufacturer, or made by a nocardia rubra strain of the depository may be used in the practice of the present application. Examples which may be mentioned include cell wall skeleton preparations prepared by the method disclosed in CN 1443542A.
Example 2 treatment of oral lichen planus
1. Criteria for case diagnosis and inclusion/exclusion
1.1 diagnostic basis
According to WHO 2003 diagnosis standards for Oral lichen planus (Meij EHVD, Waal IVD. Lock of clinical Pathology correction in the diagnosis of Oral lichen planus of Oral Pathology based on the presentation available diagnosis and regulations for the regulation. journal of Oral Pathology & Medicine,2003,32(9):507 and 512).
1.2 inclusion criteria
Firstly, diagnosing the patients with erosive oral lichen planus according to the medical history, clinical manifestations and pathology;
② the age of the onset is 18-75 years old, and no related treatment medicine is taken 1 month before the onset;
and patients without visual field defects, fundus oculi lesions and systemic diseases (Liu Qing lan et al, observation of curative effect and safety of triamcinolone acetonide oral ointment for treating congestion erosive oral lichen planus, journal of practical oral medicine, 2017, 33 (04): 536-doped 540).
1.3 exclusion criteria
(ii) patients with other established oral mucosal diseases;
② patients with uncontrolled and steady diabetes, tumor and the like;
③ the patient uses antibiotics within 1 month and immune preparation within 3 months;
some medicines or silver mercury alloy fillings can cause moss-like reaction;
people with allergic constitution and allergic history to drugs and food;
sixthly, incomplete records of medication or experimental procedures which cannot follow the medical advice, and influence the judgment of curative effect (Gorouhi F et al random of clinical research laboratory triamcinolone acetate past in the treatment of organic cement plants, Journal of the American Academy of Dermatology, 2007, 57(5):806 + 813).
1.4 subjects
Selecting erosive oral lichen planus patients accepted by the department of oral mucosa 2019.03-2019.09 of the oral hospital of Beijing university, and meeting the diagnosis standard.
The method adopts a random, double-blind and placebo-controlled clinical test method, and is divided into a test group and a control group according to random numbers. The study protocol was approved by the ethics committee and registered for clinical trials (registration No. ChiCTR 1900022245). The subjects signed an informed consent.
1.5 sample size
In the test, 60 effective cases of small samples are collected (30 cases of the test group and the control group respectively, the falling rate is considered to be 20%, and the number of collected cases is 75).
2. Treatment methods and groups
2.1 treatment group
Topically applying lyophilized powder (lot No. 2015R005186) containing Nr-CWS to the erosion face of patient, 1 time every other day, 1 bottle (60 μ g) each time, and rinsing with normal saline for 28 days;
the using method comprises the following steps: before each use, normal saline is used for gargling, then the erosion face is wiped clean by a cotton stick, and the freeze-dried powder is placed on the erosion face of a patient with erosive oral lichen planus for 2 hours.
2.2 control group
Topically applying placebo (lyophilized powder without Nr-CWS) on the erosion face of patient, 1 bottle (60 μ g) every other day for 1 time, and rinsing with normal saline for 28 days; the using method comprises the following steps: as above.
3. Index for evaluating therapeutic effect
3.1 sign scoring
The sign scoring was performed using the REU scale (REU screening system) (Table 1) (Park HK et al, Oral screening system screens with a path, Oral Surgery Oral Medicine Oral Radiology, 2012, 114(1): 75-82).
TABLE 1 oral lichen planus REU Scale
3.2 pain symptom Scoring
Subjective indices were rated on a Visual Analog Scale (VAS) in 10 grades, with pain levels scored as 1 to 10 points, and assessed in a subject diary card by the patient each day, starting in the morning after dosing (table 2).
TABLE 2 VAS Scale in patients with oral lichen planus
3.3 OHIP-14 Scale
The OHIP-14 scale consists of 14 entries for 7 segments, i.e. restriction of oral function, physiological pain, psychological discomfort, physiological disorders, psychological disorders, social disorders and disabilities. Each entry in the scale is divided into 5 levels and has a corresponding score (0 is none, 1 is few, 2 is sometimes, 3 is frequent, 4 is very frequent), with a total score of 0 to 56, with lower scores indicating better oral health.
This trial was filled in at the initial visit and at weeks 1, 2, and 4 after the drug administration (see, Sampgna F et al, company of properties 'and providers' diagnosis evaluation of oral microbiological conditions, journal of the American Academy of Dermatology, 2011, 65(1): 69-76).
3.4 evaluation criteria for therapeutic Effect
After significant treatment, congestion and erosion completely disappeared with no or slight white streaks (score 0 or 1);
complete disappearance of pain (0 score for symptom score);
effective treatment with reduced congestion, erosion (decreased sign score);
pain relief (decreased symptom score);
no change or increase in congestion, erosion (no change or increase in sign score) after ineffective treatment;
no reduction or worsening of pain (no change or increase in symptom score);
total effective rate is (significant + effective) × number of cases/total number of cases × 100%.
Reference can be made to Zhougang et al, evaluation criteria of curative effect of oral lichen planus (collapsed type and erosive type), China journal of oral medicine, 2005, 40(2): 92-93.
3.5 evaluation of safety
Laboratory indexes include blood cell analysis, liver and kidney function and blood sugar detection.
3.6 evaluation period of therapeutic Effect
Symptoms and signs scores after 1, 2, 4 weeks of administration and OHIP-14 scale scores were observed to evaluate "4 weeks after treatment efficacy and whether adverse reactions occurred during the observation period.
3.7 statistical methods
Data processing analysis was performed using SPSS 24.0 statistical software. The counting data is compared by chi-square test, the measurement data groups are compared by rank-sum test or t-test in groups, and the self comparison before and after the treatment in groups is by rank-sum test or t-test in pairs. Differences of < 0.05 were statistically significant (Huang Yue Du, clinical epidemiology, people health Press, 2014).
4. Results
4.1 general data on the subjects
A total of 62 patients were enrolled in this trial, 2 of which were missed and 60 completed the observation.
Test group 31, 8 men, 23 women, mean age 52.9 ± 12.4 years, mean course 9.06 ± 3.46 months.
The control group had 29 persons, 10 persons in men, 19 persons in women, a mean age of 54.07 + -12.40 years and a mean course of disease of 9.90 + -3.12 months.
The general condition and oral hygiene of the two groups of patients were not significantly different (P > 0.05).
TABLE 3 Baseline characteristics of study populations of test and control groups
Data are shown as x ± s (n ═ 2).
4.2 effectiveness analysis
(1) Comparison of two sets of REU sign scores
After patients in the test group and the control group are treated for 1, 2 and 4 weeks, the difference of the physical sign scores before and after treatment in the test group has statistical significance P less than 0.05; the difference in sign scores between the two groups after 4 weeks treatment was statistically significant P < 0.05 (Table 4).
TABLE 4 comparison of the two REU sign scores
*Comparison before and after treatment in groups;
+post-treatment group comparisons;
data are shown as x ± s (n ═ 2).
(2) Comparison of two sets of symptom scores
After treatment of patients in the test group and the control group for 1, 2 and 4 weeks, the difference in symptom scores between the test group and the control group was statistically significant (P < 0.05), and the difference in symptom scores between the two groups after treatment was statistically significant (P < 0.05) (Table 5).
TABLE 5 comparison of two VAS scores
*Comparison before and after treatment in groups;
+post-treatment group comparisons;
data are shown as x ± s (n ═ 2).
(3) Comparison of scores on two OHIP-14 scale
After 1, 2 and 4 weeks of treatment, the OHIPS-14 scores of the patients in the test group and the control group are obviously reduced after treatment and have statistical significance (P is less than 0.05), and the difference of the OHIPS-14 scores of the patients in the two groups after treatment has statistical significance (P is less than 0.05) (Table 6).
TABLE 6 score comparison of OHIP-14 two-group scale
*Comparison before and after treatment in groups;
+post-treatment group comparisons;
data are shown as x ± s (n ═ 2).
(4) Comparison of post-treatment efficacy of two groups
The total effective rate of the test group after 2 weeks of treatment and 4 weeks of treatment is 77.42% and 83.87%, respectively, and the total effective rate of the control group is 24.14% and 24.14%, respectively.
4.3 safety analysis
After 4 weeks of administration, the test group and the control group have no statistical difference (P is more than 0.05) in blood cell analysis, liver and kidney function and blood sugar examination, and no irritation symptom and anaphylactic reaction of patients occur during administration, and no adverse reaction occurs.
4.4 follow-up visit after drug withdrawal
The application also visits 9 patients in the test group 4 weeks after stopping taking the medicine, and finds that only 1 patient has the recurrence of the erosion face. After the medicine is taken by patients, no irritation symptom or anaphylactic reaction occurs, and no adverse reaction occurs.
Researches show that the total effective rate of the test groups after 1, 2 and 4 weeks of administration is obviously higher than that of the control group, the erosion area, pain degree and oral health influence degree of the test groups after 1, 2 and 4 weeks of administration are obviously reduced compared with those before treatment, and the total effective rate is obviously different from that of the control group. The control group in the study results had a slight reduction in pain level and oral health effects compared to the pre-treatment group, considering the predominantly placebo effect.
The cell wall skeleton of the nocardia rubra is used for treating erosive lichen planus, the erosive area of OLP can be effectively reduced, the pain degree is reduced, and the nocardia rubra shows better clinical curative effect after being used. The safety index was not statistically different from the control group.
Claims (10)
- Use of a nocardia rubra cell wall scaffold in the manufacture of a medicament or medical device for the treatment of lichen planus.
- The use according to claim 1 wherein the lichen planus is selected from any one or combination of: reticular, ring, streak, papular, erosive, plaque, vesicular, and collapsed lichen planus; preferably, the lichen planus is erosive lichen planus.
- The use according to claim 1 or 2, wherein the medicament is prepared in a dosage form selected from the group consisting of: ointment, cream, gel, lotion, tincture, liniment, oil, cataplasm, aerosol, buccal tablet, lyophilized powder, and suspension; the medical device is selected from: dressings, patches, bandages, films.
- The use according to any one of claims 1-3, wherein the unit dose of the medicament or medical device is from 1 μ g to 1000 μ g of active ingredient; preferably, 20. mu.g, 30. mu.g, 40. mu.g, 50. mu.g, 60. mu.g, 70. mu.g, 80. mu.g, 90. mu.g, 100. mu.g.
- The use according to any one of claims 1 to 4, wherein the treatment is carried out at a frequency selected from the group consisting of:1 to 3 administrations a day, 1 to 6 administrations a day, 1 to 9 administrations a three day, 1 to 14 administrations a week, 1 to 60 administrations a month; preferably, administration is 1 time on two days.
- The use according to any one of claims 1-5, wherein the treatment lasts for 2 days to 2 months, preferably for 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks.
- A method of treating lichen planus comprising:a step of contacting the subject with a therapeutically effective amount of nocardia rubra cell wall skeleton;wherein the lichen planus is selected from any one or a combination of: reticular, ring, streak, papular, erosive, plaque, vesicular, and collapsed lichen planus; preferably, the lichen planus is erosive lichen planus.
- The method of claim 7, wherein the nocardia rubra cell wall skeleton is prepared in a dosage form selected from the group consisting of: ointment, cream, gel, lotion, tincture, liniment, oil, paste, aerosol, buccal tablet, patch, lyophilized powder, suspension, dressing, bandage, and membrane.
- The method of claim 7, wherein the unit dose of nocardia rubra cell wall skeleton is 1 μ g to 1000 μ g; preferably, 20. mu.g, 30. mu.g, 40. mu.g, 50. mu.g, 60. mu.g, 70. mu.g, 80. mu.g, 90. mu.g, 100. mu.g.
- The method of claim 7, wherein:-said treatment is carried out with the following frequency: 1 to 3 administrations a day, 1 to 6 administrations a day, 1 to 9 administrations a three day, 1 to 14 administrations a week, 1 to 60 administrations a month; preferably, 1 administration is given on two days;-said treatment lasts from 2 days to 2 months, preferably for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks.
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| CN201910018064 | 2019-01-09 | ||
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| PCT/CN2019/125185 WO2020143393A1 (en) | 2019-01-09 | 2019-12-13 | Use of red nocardia cell wall skeleton for preparing pharmaceutical for treating lichen planus |
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2019
- 2019-12-13 WO PCT/CN2019/125185 patent/WO2020143393A1/en active Application Filing
- 2019-12-13 CN CN201980010492.3A patent/CN111741759A/en active Pending
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