CN101138557A - Chlorhexidine acetate topical film-forming gel composition and application thereof - Google Patents

Abstract

The invention discloses a local film-forming gel composition of chlorhexidine acetate, which comprises the following components in percentage by weight: 0.5% to 7% of hydroxyalkyl cellulose, 1% to 10% of esterifying agent, and crosslinking agent 0.5% to 5%, solvent 75% to 95%, and chlorhexidine acetate 0.01% to 3%. Among them, the crosslinking agent is saturated fatty polyalcohol or alkyd, and its general chemical formula is C _n H _{2n+2- m-l} (OH) _m (COOH) _l , n≥m≥2, l≥0, m+l is 4-8, and n+l is 4-8. The chlorhexidine acetate film-forming gel composition of the present invention is used to treat local infectious diseases of the skin/mucosa, and when it is applied on the surface of the skin or oral mucosa, it will form a smooth, tough, wear-resistant, hydrophobic protective film, The film is not easy to break, dissolve and/or erode, and the film has the characteristics of long maintenance time and sustained drug release. The gel film can be effectively retained on the skin surface for more than 8 hours, and on the oral mucosa surface for about 5 hours.

Description

Chlorhexidine acetate topical film-forming gel composition and application thereof

technical field

The invention relates to a local film-forming gel composition of chlorhexidine acetate and its application in treating local infectious diseases of skin/mucosa.

Background technique

Chlorhexidine Acetate (Chlorhexidine Acetate) is a biguanide compound, also known as chlorhexidine acetate (tai), chlorhexidine acetate, chlorhexidine acetate, etc., belonging to disinfection and antiseptic drugs. It changes the permeability of the bacterial cytoplasmic membrane to make the cell content leak out, thereby playing a bactericidal effect, and has a bactericidal effect on Staphylococcus cutaneous, Streptococcus mutans, Streptococcus salivarius, Escherichia coli, Propionibacterium and Candida albicans, etc. Both have antibacterial activity. Common chlorhexidine acetate topical preparations include solutions, gels, ointments, and sprays. However, when chlorhexidine acetate in the above dosage form is used for local sterilization and disinfection, due to the normal activities of the disinfection site and surrounding tissues, such as friction, secretion and flushing of body fluids or saliva, these agents will be dissolved and/or eroded, displaced, If it falls off, the time between the agent and the disinfection site is relatively short, which significantly reduces the curative effect.

Some topical film-forming gel compositions (film-forming gels) that form an adhesive film on the skin or moist mucosal surfaces, such as the oral mucosa, have been studied and are commonly referred to as such gel compositions. A bioadhesive film-forming gel composition. The drug-loaded local film-forming gel composition forms a film and adheres to the body part, which can provide a mechanism for sustained release of drugs, thereby improving the curative effect. Examples of these film-forming gel compositions are disclosed by Rencher (USP5192802, 5314915), Tinnell (USP4381296 and 4285934), Promerantz (USP5081158), Epstein (USP5906814), Tapolsky (USP6103266).

One type of topical film-forming composition is usually made of water-soluble materials, such as tragacanth, gum arabic, xanthan gum, sodium alginate, sodium carboxymethylcellulose, carbomer, etc., such as the adhesive combination disclosed in USP5192802 The product is composed of sodium carboxymethyl cellulose, xanthan gum, sodium alginate and so on. However, most of the adhesive materials used in this preparation are water-soluble substances, which have a very short residence time in the affected area and are easily eluted from the administration site by saliva or body fluids.

Another type of topical film-forming gel composition (film-forming gel) is usually formed by reacting hydroxyalkylcellulose with an esterifying agent to form a hydroxyalkylcellulose ester, which is then crosslinked by a crosslinking agent to form a bioadhesive gel. film-forming gel. Due to the difference in the structure and properties of the cross-linking agent used, the physical properties of the adhesive film formed by this type of film-forming gel composition, such as flexibility, adhesion, abrasion resistance and the maintenance time of the film on the affected area, vary greatly. The disclosed local film-forming gel composition of USP5081158 is made up of following components: 1) hydroxypropyl cellulose; 2) nontoxic volatile solvent, as ethanol; 3) esterification agent, as salicylic acid and tannic acid (also tannic acid, tannic acid); 4) cross-linking agent, such as boric acid; 5) drugs, such as neomycin, etc. Salicylic acid and tannic acid can be used as esterification agents to react with the hydroxyl group on hydroxypropyl cellulose to form hydroxypropyl cellulose ester. After cross-linking hydroxypropyl cellulose ester with boric acid, the following effects can be produced: ① If no cross-linking agent is added, a two-layer film will be formed, and the two-layer film can be combined after adding a cross-linking agent; ② After cross-linking, a tougher and stronger film can be formed. According to the report of USP5906814 and our research on the examples of USP5081158, it is found that the film formed by using boric acid as a cross-linking agent is relatively thick and fragile. The residence time on the mucous membrane is only 4-5 hours. USP5906814 believes that the reason for this phenomenon may be related to the structural properties of boric acid. The three hydroxyl groups on the boric acid can be cross-linked with the three sites on the hydroxypropyl cellulose ester. Since the distance between the three hydroxyl groups on the boric acid is very close, The three cross-linked sites are separated only by the interstices of the boron atoms, resulting in tightly bound products after cross-linking, forming a rigid, fragile opaque film. Furthermore, boric acid is an irritant to the skin and mucous membranes of many individuals.

USP5906814 discloses another local film-forming gel composition, which differs from USP5081158 in that monoglyceryl laurate is used as a crosslinking agent instead of boric acid, and other components remain basically unchanged. After hydroxypropyl cellulose reacts with an esterifying agent to form hydroxypropyl cellulose ester, a relatively flexible film can be formed after cross-linking with monoglyceride laurate, which can improve the brittleness of USP5081158 film. However, we have found that the local film-forming gel composition made of monoglyceryl laurate as a cross-linking agent, although the flexibility of the film is enhanced, the time of adhesion to body tissues or mucous membranes is relatively short, as in The film formed on the oral mucosa is easily eroded/dissolved by body fluids or saliva, causing the film to rupture and fall off prematurely, so that it disappears quickly.

Therefore, if the technology of the above-mentioned existing film-forming gel composition is used to prepare the local film-forming gel of chlorhexidine acetate, the retention time of the medicament and the affected part will be shorter, which will affect the therapeutic effect.

Contents of the invention

The object of the present invention aims to solve the problems in the above-mentioned prior art, to provide a kind of chlorhexidine acetate topical film-forming gel composition with better flexibility, adhesion, abrasion resistance and longer acting time.

The above-mentioned purpose of the present invention is achieved by the following technical solutions: chlorhexidine acetate local film-forming gel composition of the present invention comprises hydroxyalkyl cellulose, esterifying agent, linking agent, solvent and chlorhexidine acetate; Wherein, The crosslinking agent is saturated fatty polyol or alkyd, the chemical formula of the fatty polyol or alkyd is C _n H _2n+2-ml (OH) _m (COOH) _l , the n≥m≥2,l ≥0, m+l is 4-8, n+l is 4-8.

The content of each component in the local film-forming gel composition of chlorhexidine acetate of the present invention can refer to existing film-forming gel composition technology, as the disclosed component content of above-mentioned U.S. Patent USP5081158 and USP5906814, but the present invention Chlorhexidine acetate local film-forming gel composition can preferably select the content of following percentage by weight: hydroxyalkyl cellulose preferably 0.5%～7%, more preferably 2%～5%; Esterifying agent preferably 1%～10% %, more preferably 3% to 8%; the cross-linking agent is preferably 0.5% to 5%, more preferably 1% to 3%; and chlorhexidine acetate takes a therapeutically effective amount, which should be treated according to the specific condition to be treated The age and physiological condition of the patient, the severity of the disease, the length of the course of treatment and the medicinal site are determined, preferably 0.01% to 3%, more preferably 0.05% to 1%; and the solvent can be 75% to 95%. When the solvent is added to 100%, usually 85% to 90%.

Wherein, the local film-forming gel composition of chlorhexidine acetate of the present invention may also contain less than 5% of enhancer, preferably 0.5%-5%, more preferably 2%-3%.

In the structural formula of a preferred embodiment of the present invention, n+l is preferably no more than 6, and correspondingly m+l is usually no more than 6, that is, it can be a C ₄ -C ₆ saturated fatty polyol, as used in daily Some sugar alcohols; or C ₄ -C 6 saturated fatty alkyd acids containing more than two hydroxyl groups, and the number of hydroxyl and carboxyl groups is _4-6 .

As in the above formula, n=m=1=2, for example: tartaric acid, its structural formula is as follows:

Tartaric acid C ₄ H ₆ O ₆ has a molecular weight of 150.09

In the structural formula of another preferred embodiment of the present invention, n=m is 5～6, as xylitol, mannitol or sorbitol, and its structural formula is as follows:

The molecular weight of mannitol C ₆ H ₁₄ O ₆ is 182.17

The molecular weight of sorbitol C ₆ H ₁₄ O ₆ is 182.17

The molecular weight of xylitol C ₅ H ₁₂ O ₅ is 152.15

The molecular weight of the saturated fatty polyol or alkyd of the present invention is preferably 122-250, more preferably 150-183.

The hydroxyalkyl cellulose in the present invention refers to the cellulose containing at least one hydroxyl group on the branch chain of the cellulose backbone, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, etc., and the preferred hydroxypropyl cellulose in the present invention is base cellulose.

The esterification agent is a substance that can react with the hydroxyl group on the branched chain of hydroxyalkyl cellulose to generate an ester, such as an organic carboxylic acid, preferably salicylic acid, tannic acid or a mixture thereof, and is most preferably A blend of salicylic and tannic acids. Both salicylic acid and tannic acid can undergo esterification reaction with hydroxypropyl cellulose alone, in which salicylic acid can not only undergo esterification reaction with hydroxyalkyl cellulose, but also the hydroxyl group on salicylic acid can also react with cross-linked cellulose. The hydroxyl groups on the linking agent are cross-linked in the form of hydrogen bonds.

The reinforcing agent mentioned in the present invention refers to a substance that can increase the hydrophobicity, abrasion resistance and/or adhesion durability of the film. In the present invention, water-insoluble alkyl celluloses are preferred, such as ethyl cellulose, cellulose acetate, or mixtures thereof.

The solvent refers to a solvent that can dissolve various components in the film-forming gel composition and their esterification products and cross-linking products. The solvent used in the present invention can be a volatile alcohol solvent, such as any one or a mixture thereof in ethanol, isopropanol; or alcohol solvent and water; it can not only dissolve and carry the above-mentioned components but also contribute to the gel combination The substance forms a film at the site of use.

Of course, various additives can also be added to the gel composition as required, such as penetration enhancers: laurocapram (Azone), menthol, borneol, oleic acid, isopropyl myristate, etc.; Agents: vitamin E, vitamin C, sodium bisulfite, sodium thiosulfate, tert-butyl p-hydroxyanisole, etc.; chelating agents: edetate disodium salt, edetate calcium sodium salt, etc.; Bacteria: sorbic acid and its salts, benzoic acid and its salts, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorobutanol, etc.; pigment: β-carrot Sodium, tartrazine, brilliant blue, sunset yellow, beet red, etc., as well as other commonly used additives in pharmaceuticals.

In a word, except that the cross-linking agent is replaced by the saturated fatty polyhydric alcohol or alkyd or its mixture of the present invention, the remaining components in the chlorhexidine acetate topical film-forming gel composition of the present invention: such as hydroxyalkyl cellulose, For the specific components or contents of the esterification agent and solvent, etc., reference may be made to the prior art.

The present invention adopts saturated fatty polyhydric alcohol or alkyd or its mixture in film-forming gel composition as linking agent, has following unique advantage: (1) linking agent molecular weight used in the present invention is less, preferably as : The molecular weight of xylitol, mannitol, sorbitol, tartaric acid is between 150～183, is to contain hydroxyl, or contain the C ₄ ～C ₈ carbon alkane that total number of hydroxyl and carboxyl is 4～8, because cross-linking agent can There is basically no steric hindrance between the cross-linked hydroxyl groups or carboxyl groups, and the hydrogen bond formed after cross-linking with the hydroxyalkyl cellulose ester maintains a suitable distance, so that the formed film has better flexibility. (2) The crosslinking agent used in the present invention is a saturated fatty polyol containing at least 4 hydroxyl groups, or a saturated fatty alkyd acid containing at least 2 hydroxyl groups and a total number of hydroxyl and carboxyl groups of 4, such as tartaric acid containing two hydroxyl groups and Two carboxyl groups, sorbitol, mannitol and xylitol all contain 5 to 6 hydroxyl groups. Since these crosslinking agents have more crosslinkable groups, multiple hydroxyalkyl cellulose ester molecules can be effectively crosslinked. Together, a network complex with stronger internal binding force and larger mass is formed, so that the entire cross-linked product remains stable, thus effectively avoiding the above-mentioned problems caused by using boric acid or monoglyceryl laurate as a cross-linking agent. defect. (3) The present invention selects the saturated fatty polyhydric alcohol or alkyd as cross-linking agent for use, as tartaric acid, sorbitol, mannitol and xylitol etc. are pharmaceutical excipients or food additives, biocompatibility is good, and raw material is easy to get .

The preparation method of the local film-forming gel of the present invention is: stirring and dissolving chlorhexidine acetate and an esterifying agent in an appropriate amount of solvent (which can dissolve the solute therein), slowly adding hydroxyalkyl cellulose under stirring to make it completely Dissolve/swell, continue to stir to form a uniform gel; then add a crosslinking agent (additives and additives can be added if necessary), continue to stir until completely uniform, add the remaining amount of solvent, stir evenly, and degas, that is .

Since the chlorhexidine acetate local film-forming gel composition of the present invention has adopted the _C4 ～ _C8 carbon alkane that contains hydroxyl or hydroxyl and carboxyl total number is 4～8 as crosslinking agent, also can also water-insoluble alkyl Cellulose acts as a reinforcing agent so that the formed film has better toughness, abrasion resistance, durability and hydrophobicity than other known topical film-forming compositions, and its effective residence time in the affected area is longer. After the chlorhexidine acetate local film-forming gel forms a film on the surface of the affected area, chlorhexidine acetate is released from the film to the surface of the affected area, so that the affected area maintains a high concentration for a long time to obtain better disinfection and sterilization effects In addition, at the same time, due to the existence of the membrane, it plays a role of barrier and protection, reduces external stimulation and pollution, can effectively avoid or alleviate the pain caused by external stimulation to the affected area, and also avoids its own secondary infection, thereby Promote lesion healing.

Another object of the present invention is to provide the application of the chlorhexidine acetate film-forming gel composition of the present invention in the preparation of local antibacterial drugs for the treatment of skin and mucous membrane local infectious diseases. Chlorhexidine acetate is a disinfectant, antiseptic and antiseptic drug that has antibacterial activity against Staphylococcus cutaneous, Streptococcus mutans, Streptococcus salivarius, Escherichia coli, Propionibacterium and Candida albicans.

The local film-forming gel composition of chlorhexidine acetate of the present invention can adopt cotton swab or directly use clean finger to apply preparation on the affected part of skin or oral mucosa, after the solvent volatilizes, a smooth, tough and wear-resistant layer can be formed on the affected part , Adhesive and durable hydrophobic film, under normal circumstances, the film can be effectively retained on the surface of the oral mucosa for about 5 hours, and effectively retained on the surface of the skin for more than 8 hours. Moreover, the chlorhexidine acetate film-forming gel composition of the present invention has no irritation to its local application and has good safety.

Detailed ways

The following examples are used to describe the present invention, but are not intended to limit the present invention.

The various component raw materials in the following examples are conventional commercially available products. Wherein the percentages not specified are all percentages by weight.

Embodiment 1～16 and comparative example

The chlorhexidine acetate (do not add chlorhexidine acetate) and the esterifying agent stirring and dissolving in soluble amount respectively in embodiment 1～14 in table 1 and the chlorhexidine acetate of consumption in the comparative example (1 ' represents) In the solvent, slowly add hydroxypropyl cellulose under stirring to completely dissolve/swell, then continue to stir to form a uniform gel; then add a cross-linking agent (if necessary, add a reinforcing agent), continue to stir to make it completely uniform Supplement the solvent of remaining amount, make reach prescription quantity, stir, degassing, respectively make chlorhexidine acetate local film-forming gel composition and 100 grams of contrast film-forming gel composition not containing chlorhexidine acetate.

Table 1

Example Chlorhexidine acetate% Hydroxypropyl Cellulose% Esterifying agent% Cross-linking agent% Enhancer% Solvent% Salicylic acid Tannic acid Ethyl cellulose Cellulose acetate pure water Isopropanol ethanol 1' 2.5 2.5 5.0 Xylitol 2.0 2.0 6.0 80.0 1 0.5 2.5 2.5 5.0 Xylitol 2.0 2.0 6.0 79.5 2 0.75 2.5 2.5 5.0 Xylitol 2.0 2.0 6.0 79.25 3 0.05 2.5 4.0 6.0 Mannitol 1.0 Tartaric Acid 1.0 2.5 3.0 49.95 30.0

4 0.05 2.5 2.5 2.5 Tartrate 0.5 Sorbitol 2.5 2.0 10 77.45 5 0.02 2.5 2.5 5.0 Mannitol 1.0 Sorbitol 1.0 2.0 10 75.98 6 0.1 2.5 6.0 Xylitol 3.0 Tartaric Acid 2.0 2.0 2.0 10 72.4 7 1.0 3.5 5.0 3.0 Xylitol 1.5 Mannitol 1.0 1.0 10 74.0 8 0.025 1.5 6.0 Xylitol 1.0 Sorbitol 0.5 1.5 6.0 83.475 9 0.5 5.0 3.0 5.0 Xylitol 3.0 3.0 10 70.5 10 2.0 2.0 3.0 Mannitol 1.0 2.0 5.0 85 11 0.01 7.0 3.0 7.0 Sorbitol 5.0 0.5 15 62.49 12 3.0 0.5 1.0 Tartaric acid 0.5 5.0 20.0 70.0 13 0.5 2.5 2.5 5.0 Xylitol 2.0 6.0 81.5 14 1.5 2.5 2.5 3.0 Tartaric Acid 1.0 Xylitol 1.0 5.0 83.5

Experimental results show that the chlorhexidine acetate local film-forming gel composition has a translucent yellow-brown appearance, and can form a smooth, tough, wear-resistant and durable hydrophobic film on body tissues.

Effect Example 1

The chlorhexidine acetate local film-forming gel of embodiment 1 is carried out influence factor and stability investigation, the result shows that this product is each 10 days influence factor test, accelerated test under light (4500LUX), high temperature (40 ℃) condition (30°C, RH75%) for 6 months and room temperature reserved samples (25°C, RH60%) for 6 months, the properties, uniformity, drug content, related substances, etc. have no significant changes compared with the original data, The results are shown in Table 2.

Table 2

traits Uniformity content (%) relative substance(%) original Yellow-brown semi-solid gel with ethanol odor Uniform, no suspended matter 99.37 0.36 lighting Yellow-brown semi-solid gel with ethanol odor Uniform, no suspended matter 98.28 0.29 high temperature Yellow-brown semi-solid gel with ethanol odor Uniform, no suspended matter 98.15 0.34 Accelerated test Yellow-brown semi-solid gel with ethanol odor Uniform, no suspended matter 96.78 0.65 Keep samples at room temperature Yellow-brown semi-solid gel with ethanol odor Uniform, no suspended matter 98.54 0.43

Effect Example 2

Get the chlorhexidine acetate local film-forming gel composition of embodiment 2～14, the sample prepared by the embodiment 1 method of U.S. Patent USP5081158, be called for short USP Gel-A, add chlorhexidine acetate (prescription w/w) in the formula : chlorhexidine acetate 0.5%, hydroxypropyl cellulose 2.5%, salicylic acid 2.5%, tannic acid 7%, boric acid 1%, ethanol 86.5%), the sample prepared by the embodiment Gel D method of U.S. Patent USP5906814 , referred to as USP Gel-B, with chlorhexidine acetate instead of benzocaine (formula w/w: chlorhexidine acetate 0.5%, hydroxypropyl cellulose 1.5%, salicylic acid 2.0%, monoglyceryl laurate 5.0 %, EDTA disodium salt 0.05%, vitamin E 0.1%, ethanol 90.85%, etc.) samples were compared for in vitro skin adhesion performance, damage status and residence time, all of the above gels contain chlorhexidine acetate, The latter two serve as controls.

Take 3×4cm fresh back skin of rats, trim off blood vessels and connective tissue inside the skin, soak in saline, wash, and dry; The sample is coated into the mold ring, scraped with a flat plate, and dried naturally at room temperature to form a film, then the mold ring is taken out, and the skin is fixed on a glass slide. Fix the above glass slide at the bottom of the dissolution apparatus container at an angle of 45°, and operate according to the Chinese Pharmacopoeia dissolution method (second method), 900mL distilled water, 200rpm rotation speed, and 32°C temperature. Observe the situation of the film on the glass slide, the results are shown in Table 3.

table 3.

Adhesive properties Corrosion status residence time USP Gel-A Smooth and flat, good adhesion After 4hr, the membrane begins to partially erode; after 5hr, it gradually breaks; at 6hr, the membrane partially falls off, and at 8hr, the membrane falls off in pieces from the mucosa 6～8hr USP Gel-B Smooth and flat, good adhesion After 1hr, the membrane begins to corrode; after 3hr, the membrane becomes thinner and partly damaged; after 4hr, the membrane partially falls off, and after 5 hours, the membrane basically disappears 4～5hrs Example 2 Smooth and flat, good adhesion After 5hr, it became slightly thinner, but remained intact; after 10hr, the membrane remained intact and tightly adhered to the mucosa >10 hours Example 3 Smooth and flat, good adhesion After 5hr, it became slightly thinner, but remained intact; after 10hr, the membrane remained intact and tightly adhered to the mucosa >10 hours Example 4 Smooth and flat, good adhesion After 5hr, it became slightly thinner, but remained intact; after 10hr, the membrane remained intact and tightly adhered to the mucosa >10 hours Example 5 Smooth and flat, good adhesion After 5hr, it became slightly thinner, but remained intact; after 10hr, the membrane remained intact and tightly adhered to the mucosa >10 hours Example 6 Smooth and flat, good adhesion The surface peeled off slightly after 3hr, and became slightly thinner after 5hr. After 10hr, the membrane remained intact and adhered tightly to the mucous membrane >10 hours Example 7 Smooth and flat, good adhesion After 5 hours, it becomes slightly thinner, and after 10 hours, the membrane remains intact and adheres tightly to the mucous membrane >10 hours Example 8 Smooth surface and good adhesion After 1 hr, some solids fell off the surface; 5 hrs, the membrane was partially ruptured and shed incompletely, and there was a small amount of insoluble solids in the solution, which were slightly mixed. After 10 hrs, the membrane was slightly damaged but still adhered to the mucous membrane >10 hours Example 9 Smooth and flat, good adhesion After 5hr, it became slightly thinner, but remained intact; after 10hr, the membrane remained intact and tightly adhered to the mucosa >10 hours

Example 10 Smooth surface and good adhesion After 1 hour, some solids fell off the surface; after 5 hours, the film became thinner, and there was a small amount of insoluble solid in the solution, which was slightly mixed; after 10 hours, the film was still tightly adhered to the mucous membrane >10 hours Example 11 Rough surface, good adhesion After 10 hours, the membrane remains intact and adheres tightly to the mucous membrane >10 hours Example 12 Smooth surface and good adhesion After 1 hour, some solids fell off the surface; after 5 hours, the film became thinner, and there was a small amount of insoluble solid in the solution, which was slightly mixed; after 10 hours, the film was still tightly adhered to the mucous membrane >10 hours Example 13 Smooth and flat, good adhesion After 5hr, it became slightly thinner, but remained intact; after 10hr, the membrane remained intact and tightly adhered to the mucosa >10 hours Example 14 Rough surface, good adhesion After 5hr, it became slightly thinner, but remained intact; after 10hr, the membrane remained intact and tightly adhered to the mucosa >10 hours

The above results show that: USP Gel-A, USP Gel-B and the local film-forming gel composition of chlorhexidine acetate of the present invention can form a layer of adhesive film on the skin surface, but USP Gel-A, USP Gel-B The membrane will be eroded and damaged in water. The film formed by the chlorhexidine acetate local film-forming gel composition of the present invention has extremely strong bioadhesion and hydrophobicity, and even if it is placed in water for more than 10 hours, the film basically remains intact and still tightly adheres to the mucous membrane.

Effect Example 3

Get the chlorhexidine acetate local film-forming gel composition that embodiment 1, 13 prepare, the sample of above-mentioned USPGel-A, USP Gel-B carry out the comparison of human oral mucosa adhesion property, erosion situation and residence time, latter two as control.

Divide 20 healthy volunteers into 4 groups at random, 5 people in each group, dry the moisture on the surface of the buccal fossa mucosa with clean gauze, apply the samples in a thin layer on the treated oral mucosa, and open the mouth After 1 minute of normal breathing, a layer of adhesive film could be formed on all 4 samples. During the investigation period, the volunteers were free to drink water and talk, and those who stayed for more than 4 hours could eat once. Observe the adhesive properties, erosion conditions and residence time on the mucosa (based on the disappearance of more than 1/2 of the film area), and ask volunteers to describe the feeling of the film on the oral mucosa. The results are shown in Table 4.

Table 4.

sample USP Gel-A USP Gel-B Example 1 Example 13 Adhesive properties Smooth, flat, good adhesion Smooth, flat, good adhesion Smooth, flat, good adhesion Smooth, flat, good adhesion Feel No foreign body sensation, slightly tight No foreign body sensation No foreign body sensation No foreign body sensation Corrosion status After 2 hours, the membrane begins to dissolve and rupture; after 3 hours, the membrane falls off in fragments, and the membrane is incomplete; by 4 hours, about 1/2 of the membrane has disappeared After 1 hour, the membrane begins to dissolve; after 2 hours, the membrane ruptures, and the area gradually shrinks; after 3 hours, about 1/2 of it disappears After 4 hours, it began to slowly dissolve and become thinner, but the film was still intact; at 5 hours, the edge of the film was gradually damaged; at 6 hours, more than 1/2 of the film remained After 3 hours, it began to slowly dissolve and become thinner, but the film was still intact; after 4 hours, the edge of the film was gradually damaged; after 5 hours, the remaining 1/2 residence time about 4hr about 3hr ＞6 hours about 5hr

The test results showed that all four samples could form an adhesive film on the oral mucosa, and the film formed by USP Gel-A felt slightly tight, which may be related to the poor flexibility of the film; USP Gel-B and chlorhexidine acetate The film formed by the film-forming gel has no obvious foreign body sensation, but the film of USP Gel-B is easily dissolved, and more than 1/2 of the film has disappeared after 3 hours. The residence time of the film formed by the chlorhexidine acetate local film-forming gel composition of embodiment 1 than the film formed by the chlorhexidine acetate film-forming gel composition of embodiment 13 (do not contain reinforcing agent) It shows that the addition of ethyl cellulose in the prescription of Example 1 can effectively prolong the residence time of the film as a reinforcing agent; the local film-forming gels of Examples 1 and 13 are obviously better than other gels in terms of erosion conditions and residence time. 2 control samples.

Effect Example 4

The chlorhexidine acetate topical film-forming gel of embodiment 1, 13, the sample of above-mentioned USP Gel-A, USPGel-B carry out the comparison of rat skin adhesion performance, damaged condition and residence time.

Divide 16 experimental rats into 4 groups at random, 4 in each group, cut off the hair on the back of the rat and shave the fine hair on the surface with a razor, disinfect with alcohol, and after drying, apply a thin layer to the 4 samples respectively Apply on the treated skin in the same way, the area is 9cm ² , apply about 150mg of samples in each area, all 4 samples can form a layer of solid adhesive film on the skin surface. Use a damp wool brush to gently brush the surface of the film back and forth 5 times every 1 hour, and observe the adhesion performance, damage and residence time of the film on the skin. The results are shown in Table 5.

table 5.

sample Adhesive properties Corrosion status residence time USP Gel-A Smooth, flat, good adhesion After 5 hours, it began to rupture and fall off; after 6 hours, the membrane was irregularly broken and incomplete; after 7 hours, it basically disappeared. about 7hr USP Gel-B Smooth, flat, good adhesion After 3 hours, the membrane ruptured and fell off; after 4 hours, the membrane was irregularly broken and incomplete; at 5 hours, it basically disappeared. about 5hr Example 1 Smooth, flat, good adhesion After 6 hours, it began to gradually become thinner, but the membrane was still intact; after about 10 hours, the membrane was gradually damaged and fell off, and it basically disappeared after 12 hours. about 12hr Example 13 Smooth, flat, good adhesion After 6 hours, it began to thin slowly, but the film was still intact; after about 8 hours, the film gradually damaged and fell off, and it basically disappeared after 10 hours about 10 hours

The test results showed that all four samples could form an adhesive film on the skin. However, the membrane of USP Gel-B is easy to break and fall off, and the membrane basically disappears at 5 hours, and the membrane of USP Gel-A basically disappears at 7 hours. The retention of the film formed by the chlorhexidine acetate topical film-forming gel composition of Example 1 than the film formed by the chlorhexidine acetate topical film-forming gel composition of Example 13 (without enhancer) on the skin surface The time is long, shows that in the prescription of embodiment 1, adding ethyl cellulose can prolong the residence time of film as reinforcing agent; The film that the chlorhexidine acetate local film-forming gel composition of embodiment of the present invention 1,13 forms no matter in erosion The condition and retention time are significantly better than the two control samples USP Gel-A and USP Gel-B. The prolongation of the residence time enables the drug in the membrane to be continuously released to the affected area, improving the therapeutic effect and reducing the frequency of administration.

Effect Example 5

Adopt in vitro antibacterial test method to verify the antibacterial effect of the chlorhexidine acetate local film-forming gel of embodiment 1.

1. Preparation of bacterial suspension: Wash the fresh slant cultures of Staphylococcus aureus (ATCC 6538), Escherichia coli (8099), and Pseudomonas aeruginosa (ATCC 15442) for 18 hours with tryptone diluent and prepare the test bacterial suspension Liquid, for antibacterial test ring test application.

2. Bacteriostasis test method: Dip the test bacteria suspension with a sterile cotton swab and smear it on the surface of the nutrient agar medium plate, and dry it at room temperature for 5 minutes. Get a piece of sterile stainless steel die ring (there are 5 round holes with a diameter of 5 mm and a thickness of 0.5 mm on the die ring, and the center of each round hole is more than 30 mm apart) gently covering the surface of the culture medium, and the sample of Example 1 The gel was applied to the four surrounding holes and scraped off with a flat plate, and the middle hole was smeared with Comparative Example 1'. After the gel dries and forms a film, take out the die ring, place the petri dish in a constant temperature oven at 37°C for 16-18 hours, take it out, measure the diameter of the antibacterial ring with a digital vernier caliper and record the measurement data. The test is repeated 4 times.

3. Antibacterial test results: Table 6 shows the average antibacterial test results of the gel in Example 1 against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.

Table 6.

Test serial number Diameter of inhibition zone for different bacteria (mm) Staphylococcus aureus Escherichia coli Pseudomonas aeruginosa negative control 1234 average 12.1212.5512.4712.4012.77 13.6414.1013.4013.8513.75 12.4012.5612.6512.2412.46 0.000.000.000.000.00

Embodiment 1 gel is respectively 12.77mm, 13.75mm and 12.46mm to the average bacteriostatic ring diameter of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, all greater than 7mm diameter, shows that chlorhexidine acetate local film-forming gel Has a strong antibacterial effect.

Effect Example 6

1, observe the local irritation reaction of the chlorhexidine acetate local film-forming gel (test sample) of embodiment 2 and the film-forming gel (control sample) of contrasting embodiment to guinea pig skin single and multiple administration .

Method: Take 12 guinea pigs and divide them into two groups evenly, single administration group and multiple administration group. The hair on the back of the guinea pig was trimmed in advance, and after being disinfected with alcohol, the test sample and the control sample were respectively applied to the two pre-marked areas of the guinea pig. The single administration group is 0.3g/guinea pig/day; the multiple administration group is 0.3g/guinea pig/day, for 7 consecutive days, observe whether there is redness, swelling, hyperemia, exudation, Local irritation such as degeneration or necrosis.

The test result shows: after applying the local film-forming gel of chlorhexidine acetate of embodiment 2, there is no redness, swelling, hyperemia, exudation, degeneration or necrosis etc. Local irritation response, and there was no significant difference between the test group and the control group.

2, observe the chlorhexidine acetate local film-forming gel (test sample) of embodiment 1 and the film-forming gel (control sample) in the comparative example to rabbit oral mucosa after single and multiple administration local irritation.

Method: Take 12 rabbits and divide them into two groups on average, single administration group and multiple administration group. Apply the test sample and the control sample respectively on both sides of the oral mucosa of rabbits, the single administration group is 1.2mL/rabbit/day, and the multiple administration group is 1.2mL/rabbit/day, continuously for 7 days, respectively The general and pathological changes were observed 24 hours after the last administration.

The results of the test showed that no obvious abnormalities were found in the general condition, oral cavity, oral mucosa, and respiratory tract of the single and multiple administration groups, and there was no significant difference between the experimental group and the control group; the pathological report showed that the oral mucosal epithelium of rabbits All were clear, and no special lesions were visible in the epithelium or subepithelium. The test results show that the chlorhexidine acetate local film-forming gel of Example 1 and its control sample have no obvious irritation reaction to the general and pathological aspects of the oral mucosa of rabbits administered single or multiple times.

The above test shows that the chlorhexidine acetate local film-forming gel of the present invention has good safety during local application.

Claims (10)

1. chlorhexidine acetate partial film forming gel composition, it is characterized in that comprising following components in weight percentage: hydroxy alkyl cellulose 0.5%～7%, esterifying agent 1%～10%, cross-linking agent 0.5%～5%, solvent 75%～95% and chlorhexidine acetate 0.01%～3%; Wherein, this cross-linking agent is saturated fatty polyol or alkyd, and the chemical general formula of this aliph polyols or alkyd is C _nH _2n+2-m-l(OH) _m(COOH) _lThis n 〉=m 〉=2, l 〉=0, m+l is 4～8, n+l is 4～8.

2. compositions according to claim 1 is characterized in that hydroxy alkyl cellulose is 2%～5%, and esterifying agent is 3%～8%, and cross-linking agent is 1%～3%, and solvent is 85%～90%, and chlorhexidine acetate is 0.05%～1%.

3. compositions according to claim 1 and 2 is characterized in that it also comprises 0.5%～5% reinforcing agent.

4. compositions according to claim 3 is characterized in that this reinforcing agent is ethyl cellulose and/or cellulose acetate, and its content is 2%～3%.

5. compositions according to claim 1 and 2 is characterized in that this n+l is no more than 6.

6. compositions according to claim 5 is characterized in that this n=m=l=2.

7. compositions according to claim 6 is characterized in that this saturated fatty polyol or alkyd are tartaric acid.

8. compositions according to claim 5 is characterized in that this n=m is 5～6.

9. compositions according to claim 8 is characterized in that this saturated fatty polyol or alkyd are xylitol, mannitol or sorbitol.

10. the application of chlorhexidine acetate partial film forming gel composition according to claim 1 and 2 in the medicine of preparation treatment skin, mucosa local infection disease.