CN111658626B - Pharmaceutical composition, preparation method and medical application thereof - Google Patents
Pharmaceutical composition, preparation method and medical application thereof Download PDFInfo
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition which comprises the following components: 0.05-16 parts of chlorhexidine and 1 part of 2, 4-dichlorobenzyl alcohol. The invention also relates to a preparation method and medical application of the pharmaceutical composition. The chlorhexidine and the 2, 4-dichlorobenzyl alcohol in the pharmaceutical composition have synergistic bactericidal or bacteriostatic action, and the pharmaceutical composition has a prevention or treatment effect on oral diseases such as periodontitis and/or gingivitis.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition, and a preparation method and medical application of the pharmaceutical composition.
Background
At present, most of the commercially available disinfectants contain halogen or compounds thereof and peroxide, and the disinfectants are widely used because the materials are easily available, the preparation is simple, the price is low, and the sterilizing effect is reliable. However, these disinfectants also have the following disadvantages: 1) in recent years, epidemiological investigations have indicated that chlorine-disinfected drinking water is susceptible to the induction of cancer of the rectum, colon and bladder; 2) the precipitate generated by iodine disinfection easily causes large-scale damage to equipment, and the iodine disinfectant also easily causes skin allergy; 3) temperature, pH and heavy metals deactivate peroxides, and peroxides tend to attack the skin causing refractory gangrene, and may also cause tumors; 4) the disinfectant sold in the market generally has the defects of pungent smell, irritation and corrosion to skin, poor stability, non-lasting effect and the like. Therefore, there is a need to develop new disinfectants.
The human oral cavity contains over 600 bacteria, most of which are probiotics and few of which are harmful bacteria. In the oral cavity of a healthy person, probiotics and harmful bacteria can reach a balanced state, and the beneficial bacteria dominate the balanced state so as to protect the health of the oral cavity and the gastrointestinal tract. Research shows that the flora balance is closely related to human health, and disorder of the flora balance state easily causes various diseases, such as common periodontitis, gingivitis and the like. The initial symptoms of diseases such as periodontitis, gingivitis and the like are gingival inflammation and swelling, then bacterial plaque is accumulated and aggravated and extends from the upper part of the gum to the lower part of the gum, and a large number of periodontal pathogenic bacteria (such as gingivalis, intermediate bacteroids, spirochetes and the like) with strong toxicity are easily bred from the bacterial plaque under the gum, so that the inflammation of the gum is aggravated and extended, periodontal pockets are formed and alveolar bone is absorbed, and finally periodontitis, local red swelling, pain, surface temperature rise, chewing function reduction and the like are generated in the oral cavity.
Recent studies have demonstrated that oral bacteria are closely associated with many specific diseases. For example, studies published in "Scientific Reports" have demonstrated that 26% of patients with intracerebral hemorrhage have a specific type of bacteria, CNM-positive Streptococcus mutans, in their saliva and that more cerebral microhemorrhage occurs in patients with CNM-positive Streptococcus mutans than in patients without the bacteria, and that analysis by researchers of patients who have MRI tests showing the presence of cerebral microhemorrhage indicates that such patients may develop dementia and cerebral hemorrhage. In addition, many foreign studies have shown that many bacteria in the oral cavity are closely related to serious diseases such as tumor, heart disease, meningitis, and the like. Therefore, the maintenance of oral hygiene and the balance of the flora in the oral cavity are important methods for reducing the occurrence of common diseases such as periodontal disease and gingivitis and are one of the key factors for reducing the occurrence of other secondary diseases.
Therefore, there is a need for a pharmaceutical composition that can maintain oral hygiene, maintain the balance of the oral flora, and prevent or treat periodontitis and gingivitis.
Disclosure of Invention
An object of the present invention is to provide a pharmaceutical composition containing chlorhexidine and 2, 4-dichlorobenzyl alcohol having a synergistic bactericidal (bacteriostatic) effect, and having a prophylactic or therapeutic effect on oral diseases such as periodontitis and gingivitis. On the basis, the invention provides the medical application of the pharmaceutical composition. The invention also aims to provide a preparation method of the pharmaceutical composition.
The invention relates to a pharmaceutical composition, which comprises the following components:
0.05 to 16 parts by weight (e.g., 0.08, 0.1, 0.3, 0.5, 0.7, 0.9, 1, 1.2, 1.4, 1.6, 1.7, 1.9, 2, 2.1, 2.3, 2.5, 2.7, 2.9, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.1, 4.3, 4.5, 4.7, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6, 6.4, 6.6, 6, 6.7, 6.8, 6, 7.8, 7, 8, 7.8, 9, 8, 8.8, 8, 9.8, 8, 8.9, 8, 9.6, 8, 8.7, 8, 8.8, 8, 7, 8, 4.6.2, 4, 8, 4.6, 4, 8, 4, 8, 4, 2, or more parts by weight of chlorhexidine, 10 parts by weight, 10.4 parts by weight, 10.8 parts by weight, 11 parts by weight, 11.3 parts by weight, 11.6 parts by weight, 11.8 parts by weight, 12 parts by weight, 12.5 parts by weight, 13 parts by weight, 13.5 parts by weight, 14 parts by weight, 14.5 parts by weight, 15 parts by weight, 15.5 parts by weight, 16 parts by weight)
1 part by weight of 2, 4-dichlorobenzyl alcohol.
In some embodiments of the first aspect of the present invention, the pharmaceutical composition contains chlorhexidine in an amount of 0.1 to 10 parts by weight, preferably 0.1 to 8 parts by weight.
In some embodiments of the first aspect of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
In some embodiments of the first aspect of the present invention, the pharmaceutically acceptable excipient is selected from at least one of a sweetener, a penetration enhancer, and a solvent.
In some embodiments of the first aspect of the present invention, the pharmaceutically acceptable excipient is 80 to 1000 parts by weight, such as 100 parts by weight, 110 parts by weight, 120 parts by weight, 140 parts by weight, 160 parts by weight, 180 parts by weight, 200 parts by weight, 220 parts by weight, 240 parts by weight, 260 parts by weight, 280 parts by weight, 300 parts by weight, 320 parts by weight, 340 parts by weight, 360 parts by weight, 380 parts by weight, 400 parts by weight, 420 parts by weight, 440 parts by weight, 460 parts by weight, 480 parts by weight, 500 parts by weight, 520 parts by weight, 540 parts by weight, 560 parts by weight, 580 parts by weight, 600 parts by weight, 620 parts by weight, 640 parts by weight, 660 parts by weight, 680 parts by weight, 700 parts by weight, 720 parts by weight, 740 parts by weight, 760 parts by weight, 780 parts by weight, 800 parts by weight, 820 parts by weight, 840 parts by weight, 860 parts by weight, 900 parts by weight, 920 parts by weight, 940 parts by weight, 960 parts by weight, 980 parts by weight.
In some embodiments of the first aspect of the present invention, the solvent is 100 to 800 parts by weight, such as 120 parts by weight, 140 parts by weight, 160 parts by weight, 200 parts by weight, 220 parts by weight, 240 parts by weight, 260 parts by weight, 280 parts by weight, 300 parts by weight, 310 parts by weight, 330 parts by weight, 350 parts by weight, 370 parts by weight, 390 parts by weight, 400 parts by weight, 420 parts by weight, 440 parts by weight, 460 parts by weight, 480 parts by weight, 500 parts by weight, 520 parts by weight, 540 parts by weight, 560 parts by weight, 580 parts by weight, 600 parts by weight, 620 parts by weight, 640 parts by weight, 660 parts by weight, 680 parts by weight, 700 parts by weight, 720 parts by weight, 740 parts by weight, 760 parts by weight, 780 parts by weight, 800 parts by weight.
In some embodiments of the first aspect of the present invention, the solvent is ethanol and/or water.
In some embodiments of the first aspect of the present invention, the weight ratio of ethanol to water in the solvent is 1 (1-10), such as 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1: 10.
In some embodiments of the first aspect of the present invention, the sweetener is 1 to 40 parts by weight, such as 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 14 parts by weight, 16 parts by weight, 20 parts by weight, 21 parts by weight, 23 parts by weight, 25 parts by weight, 27 parts by weight, 29 parts by weight, 30 parts by weight, 32 parts by weight, 34 parts by weight, 36 parts by weight, 38 parts by weight, 39 parts by weight.
In some embodiments of the first aspect of the present invention, the sweetener is xylitol and/or mannitol.
In some embodiments of the first aspect of the present invention, the weight ratio of xylitol to mannitol in the sweetener is 1 (5-20), for example 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1: 19.
In certain embodiments of the first aspect of the present invention, the penetration enhancer is 0.5 to 15 parts by weight, such as 0.8 parts by weight, 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13 parts by weight, 14 parts by weight.
In some embodiments of the first aspect of the present invention, the penetration enhancer is menthol.
In certain embodiments of the first aspect of the present invention, the pharmaceutical composition is as follows:
the pharmaceutical composition comprises the following components:
chlorhexidine 0.1 to 10 parts by weight (e.g., 0.3 part by weight, 0.5 part by weight, 0.7 part by weight, 1 part by weight, 1.2 parts by weight, 1.4 parts by weight, 1.6 parts by weight, 1.7 parts by weight, 1.9 parts by weight, 2 parts by weight, 2.1 parts by weight, 2.3 parts by weight, 2.5 parts by weight, 2.7 parts by weight, 2.9 parts by weight, 3 parts by weight, 3.2 parts by weight, 3.4 parts by weight, 3.6 parts by weight, 3.8 parts by weight, 4.1 parts by weight, 4.3 parts by weight, 4.5 parts by weight, 4.7 parts by weight, 5.2 parts by weight, 5.4 parts by weight, 5.6 parts by weight, 5.8 parts by weight, 6.2 parts by weight, 6.4 parts by weight, 6.6 parts by weight, 6.8 parts by weight, 7.7 parts by weight, 7.6.8 parts by weight, 9.8 parts by weight, 8.8 parts by weight, 9.8 parts by weight, 8.8 parts by weight, 9.8 parts by weight, 8 parts by weight, 9.8.8 parts by weight, 8 parts by weight, 6.8 parts by weight, 8 parts by weight, 6.3.3.3.3.3.3.3.3.3.3.3.3.3.3.3 parts by weight, 4 parts by weight, or more parts by weight, 4 parts by weight, or more preferably 1 parts by weight, 4.3.3.3.3.3.3.3.3.3 parts by weight, 4 parts by
1 part by weight of 2, 4-dichlorobenzyl alcohol
Xylitol 0.1 to 15 parts by weight (e.g., 0.3 parts by weight, 0.5 parts by weight, 0.7 parts by weight, 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 14 parts by weight)
Mannitol 1 to 25 parts by weight (e.g., 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 14 parts by weight, 16 parts by weight, 20 parts by weight, 21 parts by weight, 23 parts by weight, 25 parts by weight)
50 to 300 parts by weight of ethanol (e.g., 60 parts by weight, 70 parts by weight, 80 parts by weight, 90 parts by weight, 100 parts by weight, 110 parts by weight, 120 parts by weight, 130 parts by weight, 140 parts by weight, 150 parts by weight, 160 parts by weight, 180 parts by weight, 200 parts by weight, 210 parts by weight, 220 parts by weight, 240 parts by weight, 260 parts by weight, 270 parts by weight, 280 parts by weight, 290 parts by weight)
80 to 500 parts by weight of water (e.g., 90 parts by weight, 100 parts by weight, 110 parts by weight, 120 parts by weight, 140 parts by weight, 160 parts by weight, 200 parts by weight, 220 parts by weight, 240 parts by weight, 260 parts by weight, 280 parts by weight, 300 parts by weight, 310 parts by weight, 330 parts by weight, 350 parts by weight, 370 parts by weight, 390 parts by weight, 400 parts by weight, 420 parts by weight, 440 parts by weight, 460 parts by weight, 480 parts by weight, 490 parts by weight);
preferably, the pharmaceutical composition further comprises 0.5 to 13 parts by weight (e.g., 0.6 parts by weight, 0.8 parts by weight, 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13 parts by weight) of menthol;
the pharmaceutical composition comprises the following components:
preferably, the pharmaceutical composition further comprises 0.5 to 10 parts by weight (e.g., 0.6 parts by weight, 0.8 parts by weight, 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight) of menthol.
In the present invention, the water is selected from at least one of purified water, mineral water, deionized water, distilled water, tap water, plain boiled water, and medical water.
The second aspect of the present invention relates to a process for preparing the pharmaceutical composition according to the first aspect of the present invention, comprising the following steps (1) to (3) and optionally step (4):
(1) mixing chlorhexidine, water, and optionally xylitol to obtain a first mixture;
(2) mixing 2, 4-dichlorobenzyl alcohol, ethanol, optionally mannitol, and optionally menthol to obtain a second mixture;
(3) mixing the first mixture with the second mixture to obtain a third mixture;
(4) standing the third mixture, filtering and collecting filtrate;
wherein the pharmaceutical composition is a third mixture or filtrate.
In some embodiments of the second aspect of the invention, the method of preparation comprises one or more of the following a to h:
a. in the step (1), mixing is carried out by stirring;
preferably, the stirring speed is 60-200 rpm, such as 80rpm, 100rpm, 120rpm, 140rpm, 160rpm, 180rpm, 190 rpm;
b. in the step (1), the mixing time is 0.5 to 5 hours, such as 0.7 hour, 0.9 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours;
c. in the step (2), mixing is carried out by stirring;
d. in the step (3), the mixing temperature is 10 ℃ to 45 ℃, for example, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃ and 43 ℃;
e. in the step (3), the mixing pressure is 80-120 KPa, such as 90KPa, 95KPa, 100KPa, 105KPa, 110KPa, 115 KPa;
f. in the step (3), mixing is carried out by stirring;
preferably, the stirring speed is 300-700 rpm, such as 320rpm, 350rpm, 370rpm, 400rpm, 420rpm, 440rpm, 460rpm, 480rpm, 500rpm, 520rpm, 550rpm, 570rpm, 590rpm, 600rpm, 620rpm, 640rpm, 650rpm, 670rpm, 680rpm, 690 rpm;
g. in the step (3), the mixing time is 2-10 hours, such as 3, 4, 5, 6, 7, 8 and 9 hours;
h. in the step (4), the standing time is 1-4 days, such as 2, 3 and 4 days.
In a third aspect, the present invention relates to a method of in vitro bactericidal or in vitro bacteriostatic comprising the step of administering to a subject in need thereof a pharmaceutical composition according to the first aspect of the present invention.
In a fourth aspect, the present invention relates to the use of a pharmaceutical composition according to the first aspect of the present invention in the manufacture of a bactericidal or bacteriostatic agent or in the manufacture of a medicament for the prevention or treatment of gingivitis and/or periodontitis disease.
In some embodiments of the fourth aspect of the invention, the bacteriostatic agent is an oral bacteriostatic agent or a skin external bacteriostatic agent.
In some embodiments of the fourth aspect of the present invention, the antiseptic is an oral antiseptic or a skin antiseptic for external use.
In the present invention, unless otherwise specified, wherein:
the term "chlorhexidine" is also known as chlorhexidine and is known by the chemical name chlorhexidine.
The term "menthol" is white crystals extracted from the leaves and stems of peppermint, and has the formula C10H20O, CAS numberIs 89-78-1.
The invention obtains at least one of the following beneficial effects:
1. the chlorhexidine and the 2, 4-dichlorobenzyl alcohol in the pharmaceutical composition have synergistic bactericidal or bacteriostatic effects.
2. The pharmaceutical composition has the effects of preventing and treating oral diseases such as periodontitis and/or gingivitis.
Detailed Description
Embodiments of the present invention will now be described more fully hereinafter with reference to the accompanying examples, in which some, but not all embodiments of the invention are shown. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
EXAMPLE 1 preparation of pharmaceutical composition 1
Mixing chlorhexidine, xylitol and purified water according to the formula shown in Table 1, pouring into a reaction kettle, and stirring at the rotating speed of 120rpm of 100-; uniformly mixing 2, 4-dichlorobenzyl alcohol, mannitol and ethanol to obtain a second mixture; pouring the second mixture into the reaction kettle containing the first mixture, stirring for 4-6h at the rotation speed of 500-550rpm under the conditions of 20-30 ℃ and 100-101 kPa, standing for 48h, filtering, collecting the filtrate, and filling to obtain the pharmaceutical composition 1.
TABLE 1
| Raw materials | In percentage by weight of the total raw materials (%) |
| Chlorhexidine | 0.15 |
| 2, 4-dichlorobenzyl alcohol | 0.15 |
| Xylitol, its preparation method and use | 0.1 |
| Mannitol | 1.0 |
| Ethanol | 40 |
| Purified water | The rest(s) |
EXAMPLE 2 preparation of pharmaceutical composition 2
Mixing chlorhexidine, xylitol and purified water according to the formula shown in Table 2, pouring the mixture into a reaction kettle, and stirring the mixture for 1 to 2 hours at the rotating speed of 100 plus 120rpm to obtain a first mixture; uniformly mixing 2, 4-dichlorobenzyl alcohol, mannitol and ethanol to obtain a second mixture; pouring the second mixture into the reaction kettle containing the first mixture, stirring for 4-6h at the rotation speed of 500-550rpm under the conditions of 20-30 ℃ and 100-101 KPa, standing for 48h, filtering, collecting the filtrate, and filling to obtain the pharmaceutical composition 2.
TABLE 2
| Raw materials | In percentage by weight of the total raw materials (%) |
| Chlorhexidine | 0.1 |
| 2, 4-dichlorobenzyl alcohol | 0.45 |
| Xylitol, its preparation method and use | 0.3 |
| Mannitol | 3.0 |
| Ethanol | 40 |
| Purified water | The rest(s) |
EXAMPLE 3 preparation of pharmaceutical composition 3
Mixing chlorhexidine, xylitol and purified water according to the formula shown in Table 3, pouring the mixture into a reaction kettle, and stirring the mixture for 1 to 2 hours at the rotating speed of 120rpm of 100-; uniformly mixing 2, 4-dichlorobenzyl alcohol, mannitol and ethanol to obtain a second mixture; pouring the second mixture into the reaction kettle containing the first mixture, stirring for 4-6h at the rotation speed of 500-550rpm under the conditions of 20-30 ℃ and 100-101 KPa, standing for 48h, filtering, collecting the filtrate, and filling to obtain the pharmaceutical composition 3.
TABLE 3
EXAMPLE 4 preparation of pharmaceutical composition 4
Mixing chlorhexidine, xylitol and purified water according to a formula shown in Table 4, pouring the mixture into a reaction kettle, and stirring the mixture for 1 to 2 hours at a rotating speed of 120rpm of 100-; uniformly mixing 2, 4-dichlorobenzyl alcohol, mannitol, menthol and ethanol to obtain a second mixture; pouring the second mixture into the reaction kettle containing the first mixture, stirring for 4-6h at the rotation speed of 500-550rpm under the conditions of 20-30 ℃ and 100-101 KPa, standing for 48h, filtering, collecting the filtrate, and filling to obtain the pharmaceutical composition 4.
TABLE 4
| Raw materials | In percentage by weight of the total raw materials (%) |
| Chlorhexidine | 0.3 |
| 2, 4-dichlorobenzyl alcohol | 0.5 |
| Xylitol, its preparation method and use | 0.3 |
| Mannitol | 3.0 |
| Menthol crystal | 1.0 |
| Ethanol | 40 |
| Purified water | The rest(s) |
Comparative example 1 preparation of pharmaceutical composition A
The same procedure as in example 1 was repeated except that 2, 4-dichlorobenzyl alcohol was not used and the percentage by weight of chlorhexidine based on the total raw materials was increased to 0.3%, to obtain a pharmaceutical composition A.
Comparative example 2 preparation of pharmaceutical composition B
Without chlorhexidine, the weight percentage of 2, 4-dichlorobenzyl alcohol to the total raw material was increased to 0.3%, and the rest was the same as example 1, to obtain a pharmaceutical composition B.
Comparative example 3 preparation of pharmaceutical composition C
The same procedure as in example 4 was repeated except that 2, 4-dichlorobenzyl alcohol was not used and the percentage by weight of chlorhexidine based on the total amount of the raw materials was increased to 0.8%, to obtain pharmaceutical composition C.
Comparative example 4 preparation of pharmaceutical composition D
Without chlorhexidine, and the weight percentage of 2, 4-dichlorobenzyl alcohol to the total raw material was increased to 0.8%, the rest was the same as example 4, to obtain a pharmaceutical composition D.
Experimental example 1 Sterilization test
The sterilization experiments were performed on the pharmaceutical compositions 1-4 and pharmaceutical compositions a-D.
The method of the sterilization experiment: the bactericidal effects of the pharmaceutical compositions 1 to 4 and the pharmaceutical compositions A to D were examined according to the regulations of the Ministry of public health of the people's republic of China, Disinfection technical Specification (2002 edition), page 126, 132.
(1) Preparing a bacterial suspension: the test bacteria were staphylococcus aureus (ATCC6538), pseudomonas aeruginosa (ATCC15442), and candida albicans (ATCC10231) (purchased from military medical academy of sciences). Separating and purifying each test bacterium, inoculating the test bacterium on a solid culture medium slant, culturing at 37 ℃ for 24h, taking a fresh slant culture, washing lawn with Phosphate Buffer Solution (PBS) and diluting to a bacterial suspension with a required concentration for later use.
(2) And (3) identification test of a neutralizer: 6 sets of tests were designed, as represented by Staphylococcus aureus (ATCC6538) and Candida albicans (ATCC10231), and a neutralizer (D/E neutralization broth) identification test was performed according to the bacterial suspension quantification test procedure. As a result, the group 1 grows aseptically or only a few microorganisms grow, the group 2 has more bacteria than the group 1, the bacteria of the groups 3, 4 and 5 meet the bacteria requirement of a test design control group, the error rate between the groups is less than or equal to 15 percent, and the group 6 grows aseptically. The test was repeated 3 times, and the results of each test were consistent, indicating that the selected neutralizing agent (D/E neutralized broth) was satisfactory.
(3) Quantitative sterilization test of bacterial suspension: the test was carried out in a water bath at 20 ℃. + -. 1 ℃. Adding 1ml of the bacterial suspension into a sterile test tube, spraying 4ml of the pharmaceutical composition, immediately mixing, acting for a specified time in Table 5, taking out 0.5ml of the bacterial-drug mixed solution, adding into a test tube filled with 4.5ml of a neutralizer (D/E neutralizing broth), uniformly mixing, after 10min of neutralization, performing viable count culture on a sampling solution, and calculating according to the concentration of the bacterial suspension to obtain a bactericidal logarithm value, wherein the result is shown in Table 5.
TABLE 5
As can be seen from Table 5, the pharmaceutical composition of the present invention has a stronger bactericidal effect than the pharmaceutical composition using chlorhexidine or 2, 4-dichlorobenzyl alcohol alone, which indicates that the chlorhexidine and 2, 4-dichlorobenzyl alcohol in the pharmaceutical composition of the present invention have a synergistic bactericidal effect.
Experimental example 2 toxicity and irritation test
Toxicity and irritation tests were performed on pharmaceutical compositions 1-4.
The detection conclusion is as follows: for the pharmaceutical composition 1-4, the acute oral toxicity LD50 of the mouse is more than 5000mg/Kg of body weight, and the toxicity classification is practically nontoxic. The result of the micronucleus test of the bone marrow cells of the mouse by the pharmaceutical composition is negative. The pharmaceutical composition has no irritation to eyes, damaged skin and vaginal mucosa of rabbits.
Experimental example 3 clinical test
Clinical trials were conducted on 65 untreated gingivitis patients and 63 untreated periodontitis patients, who were 18-60 years old, had >18 teeth remaining in the mouth, had no systemic disease, normal bleeding, platelets, bleeding time, and diagnosed as simple gingivitis or simple periodontitis. The patients were observed as parallel controls and divided into a gingivitis test group (33 patients), a gingivitis control group 1(17 patients), a gingivitis control group 2(15 patients), a periodontitis test group (32 patients), a periodontitis control group 1(16 patients) and a periodontitis control group 2(15 patients). Test group was administered pharmaceutical composition 4, and control groups 1-2 were administered pharmaceutical composition C, D, respectively.
Plaque index (PLI) (score standard 0-5), Gingival Index (GI), gingival Sulcus Bleeding Index (SBI), periodontal Pocket Depth (PD) and degree of tooth loosening (MD) were examined by a professional doctor through a probe before, 7 days after, and 14 days after treatment for each group of patients, and the results were averaged and shown in tables 6-7. Lower scores indicate better efficacy.
The pain levels of each group of patients before treatment, 7 days after treatment and 14 days after treatment were evaluated by a medical professional according to a Visual Analogue Scale (VAS) and a verbal graded scale (VRS), and the pain levels were classified into four grades of none, light, medium and heavy, and the results were averaged, as shown in tables 8-9.
Patients in the periodontitis test group and the periodontitis control group were examined by a medical professional for the presence of occlusal disorders before, 7 days after, and 14 days after treatment, and the results are shown in Table 10.
The efficacy of each group was examined by a professional physician 14 days after treatment. The judgment standard of the curative effect is as follows: according to subjective symptoms and various clinical observation indexes, the medicine is divided into healing, obvious effect, improvement and ineffectiveness. (1) And (3) healing: the symptoms completely disappear, and each periodontal inspection index is normal; (2) the effect is shown: the subjective symptom is obviously improved, the reduction of GI, PLI and SBI values is more than or equal to 1, the odontoseisis is reduced, the teeth have no tapping pain, the depth of the periodontal pocket is reduced by 1mm, and (3) the improvement: the symptoms are reduced, the gingival bleeding is improved, the tooth tapping pain is reduced, and at least one of clinical periodontal inspection indexes is reduced; (4) and (4) invalidation: the symptoms and various periodontal indexes are not improved.
TABLE 6 comparison of the indices of the gingivitis test group and the gingivitis control group
". indicates that P <0.05 in the test group compared to the control group.
As can be seen from table 6, compared with the pharmaceutical composition containing chlorhexidine or 2, 4-dichlorobenzyl alcohol alone, the pharmaceutical composition of the present invention can significantly improve the plaque index (PLI) (score standard 0-5), the Gingival Index (GI), the gingival Sulcus Bleeding Index (SBI), the periodontal Pocket Depth (PD), and the degree of tooth loosening (MD) of the gingivitis patient, and has a significant effect of treating gingivitis.
TABLE 7 comparison of indices of periodontitis test group and periodontitis control group
". indicates that P <0.05 in the test group compared to the control group.
As can be seen from table 7, compared with the pharmaceutical composition containing chlorhexidine or 2, 4-dichlorobenzyl alcohol alone, the pharmaceutical composition of the present invention can significantly improve the plaque index (PLI) (score standard 0-5), the Gingival Index (GI), the gingival Sulcus Bleeding Index (SBI), the peri-alveolar Pouch Depth (PD), and the degree of odontoseisis (MD) of the periodontitis patient, and has a significant effect of treating periodontitis.
TABLE 8 comparison of pain levels in the gingivitis test group and the gingivitis control group
As can be seen from table 8, the pharmaceutical composition of the present invention significantly eases the pain symptoms of gingivitis patients and has a therapeutic effect on gingivitis as compared to the use of a pharmaceutical composition containing chlorhexidine or 2, 4-dichlorobenzyl alcohol alone.
TABLE 9 comparison of pain levels in periodontitis test group and periodontitis control group
As can be seen from table 9, compared with the pharmaceutical composition containing chlorhexidine or 2, 4-dichlorobenzyl alcohol alone, the pharmaceutical composition of the present invention can significantly relieve the pain symptoms of the patients with periodontitis after 14 days of treatment, and has a therapeutic effect on periodontitis.
TABLE 10 comparison of occlusal disorders in periodontitis test group and periodontitis control group
As can be seen from table 10, the pharmaceutical composition of the present invention can significantly improve the occlusal disorder of patients with periodontitis and has a therapeutic effect on periodontitis, as compared to the pharmaceutical composition containing chlorhexidine or 2, 4-dichlorobenzyl alcohol alone.
TABLE 11 comparison of therapeutic effects of the groups
As can be seen from Table 11:
the cure rate of the medicinal composition containing chlorhexidine alone or 2, 4-dichlorobenzyl alcohol alone to gingivitis is 12% and 13% respectively, and the ineffective rate of the medicinal composition containing chlorhexidine alone to gingivitis is 6%, and the cure rate of the medicinal composition of the invention to gingivitis is 64% and the ineffective rate is 0. As can be seen, the curative effect of the pharmaceutical composition of the invention on gingivitis is more obvious compared with the pharmaceutical composition containing chlorhexidine alone or 2, 4-dichlorobenzyl alcohol alone.
The cure rate of the pharmaceutical composition containing chlorhexidine alone or 2, 4-dichlorobenzyl alcohol alone to periodontitis is 0, the significant efficiency is 31 percent and 27 percent respectively, and the ineffective efficiency is 13 percent respectively, and the cure rate of the pharmaceutical composition of the invention to periodontitis is 28 percent, the significant efficiency is 53 percent, and the ineffective efficiency is 0. As can be seen, compared with the drug composition containing chlorhexidine alone or 2, 4-dichlorobenzyl alcohol alone, the drug composition of the invention has more obvious curative effect on periodontitis.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (20)
1. A pharmaceutical composition for preventing or treating gingivitis and/or periodontitis diseases comprises the following active components:
0.5 to 10 parts by weight of chlorhexidine
1 part by weight of 2, 4-dichlorobenzyl alcohol.
2. The pharmaceutical composition according to claim 1, wherein the chlorhexidine is 0.5 to 8 parts by weight.
3. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable excipient.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable excipient is selected from at least one of a sweetener, a penetration enhancer, and a solvent.
5. The pharmaceutical composition according to claim 4, wherein the solvent is 100 to 800 parts by weight.
6. The pharmaceutical composition of claim 5, wherein the solvent is ethanol and/or water.
7. The pharmaceutical composition according to claim 6, wherein the weight ratio of the ethanol to the water is 1 (1-10).
8. The pharmaceutical composition according to any one of claims 4 to 7, wherein the sweetener is 1 to 40 parts by weight.
9. The pharmaceutical composition according to claim 6 or 7, wherein the sweetener is xylitol and/or mannitol.
10. The pharmaceutical composition according to claim 9, wherein the weight ratio of the xylitol to the mannitol is 1 (5-20).
11. A pharmaceutical composition according to any one of claims 4 to 7, wherein the penetration enhancer is 0.5 to 15 parts by weight.
12. A pharmaceutical composition according to claim 6 or 7, wherein the penetration enhancer is menthol.
13. The pharmaceutical composition according to any one of claims 1 to 7, which is the following item I or II:
the pharmaceutical composition comprises the following components:
the pharmaceutical composition comprises the following components:
14. the pharmaceutical composition according to claim 13, wherein the pharmaceutical composition further comprises 0.5 to 13 parts by weight of menthol.
15. The pharmaceutical composition according to claim 13, wherein in item II, the pharmaceutical composition further comprises 0.5 to 10 parts by weight of menthol.
16. A process for the preparation of a pharmaceutical composition according to claim 6 or 7 or 9 or 10 or 12 or 13 or 14 or 15, comprising the following steps (1) to (3) and optionally step (4):
(1) mixing chlorhexidine, water, and optionally xylitol to obtain a first mixture;
(2) mixing 2, 4-dichlorobenzyl alcohol, ethanol, optionally mannitol, and optionally menthol to obtain a second mixture;
(3) mixing the first mixture with the second mixture to obtain a third mixture;
(4) standing the third mixture, filtering and collecting filtrate;
wherein the pharmaceutical composition is a third mixture or filtrate.
17. The method according to claim 16, characterized by one or more of the following a to h:
a. in the step (1), mixing is carried out by stirring;
b. in the step (1), the mixing time is 0.5-5 hours;
c. in the step (2), mixing is carried out by stirring;
d. in the step (3), the mixing temperature is 10-45 ℃;
e. in the step (3), the mixing pressure is 80-120 KPa;
f. in the step (3), mixing is carried out by stirring;
g. in the step (3), the mixing time is 2-10 hours;
h. in the step (4), the standing time is 1-4 days.
18. The method according to claim 17, wherein in the step (1) in the item a, the stirring speed is 60 to 200 rpm.
19. The method according to claim 17, wherein in item f, in step (3), the stirring speed is 300 to 700 rpm.
20. Use of a pharmaceutical composition according to any one of claims 1 to 15 in the manufacture of a medicament for the prevention or treatment of gingivitis and/or periodontitis disease.
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| GB1428748A (en) * | 1973-01-24 | 1976-03-17 | Hurka W | Disinfecting towels |
| RU2009148264A (en) * | 2009-12-24 | 2011-06-27 | Закрытое акционерное общество "Научно-производственное объединение "Антивирал" (RU) | PHARMACEUTICAL COMPOSITION FOR LOCAL USE WITH ANTIBACTERIAL, ANTI-INFLAMMATORY AND IMMUNOMODULATING ACTION, AND ITS APPLICATIONS |
| CN106265295A (en) * | 2016-08-30 | 2017-01-04 | 杭州国光旅游用品有限公司 | A kind of wet tissue alleviating hemorrhoid symptom and preparation method thereof |
| CN109010098A (en) * | 2018-10-23 | 2018-12-18 | 郑州吉尔康消毒制品有限公司 | Antimicrobial mouthwash and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1428748A (en) * | 1973-01-24 | 1976-03-17 | Hurka W | Disinfecting towels |
| RU2009148264A (en) * | 2009-12-24 | 2011-06-27 | Закрытое акционерное общество "Научно-производственное объединение "Антивирал" (RU) | PHARMACEUTICAL COMPOSITION FOR LOCAL USE WITH ANTIBACTERIAL, ANTI-INFLAMMATORY AND IMMUNOMODULATING ACTION, AND ITS APPLICATIONS |
| CN106265295A (en) * | 2016-08-30 | 2017-01-04 | 杭州国光旅游用品有限公司 | A kind of wet tissue alleviating hemorrhoid symptom and preparation method thereof |
| CN109010098A (en) * | 2018-10-23 | 2018-12-18 | 郑州吉尔康消毒制品有限公司 | Antimicrobial mouthwash and preparation method thereof |
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