CN118045066A - A long-acting analgesic oral ulcer one-way release film preparation and preparation method thereof - Google Patents

Abstract

The invention relates to a long-acting analgesic oral ulcer unidirectional release film preparation and a preparation method thereof, belonging to the technical field of medicines. Aiming at the problems that the existing common film agent has short adhesion time and the medicines are easy to be scoured by saliva, the invention provides a one-way release film agent which integrates multiple medicines, can relieve pain for a long time and can prevent the medicines from being scoured, and comprises a medicine adhesion layer and a hydrophobic isolation layer, wherein the active medicines in the medicine adhesion layer comprise local anesthetics for relieving canker sore pain, anti-inflammatory medicines for treating canker sore inflammation and medicines for promoting wound healing, the defect that the multiple medicines for canker sore are used in combination is overcome, the medicine adhesion layer is tightly adhered to oral mucosa to prevent the medicine films from hydration, so that the active medicines are slowly released and are enriched on focus for a long time, the hydrophobic isolation layer can isolate the medicines from being scoured by saliva and swallowed, and simultaneously, the secondary stinging caused by oral movement of the canker sore surface is reduced, thereby relieving the pain of patients and the defect of frequent administration.

Description

A long-acting analgesic oral ulcer one-way release film preparation and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, and in particular to a long-acting analgesic oral ulcer one-way release film preparation and a preparation method thereof.

Background Art

Oral ulcers often occur on the superficial mucosa in the oral cavity. They can range in size from rice grains to soybeans, and are round or oval in shape. The ulcer surface is concave, and the surrounding area is congested, accompanied by a burning sensation, which can lead to limited opening of the mouth. The disease is characterized by periodicity, recurrence, and self-limitation. Generally, there are no systemic symptoms. It often occurs in the patient's cheeks, lips, and tongue edges. Because the mucosal tissue layer of the disease contains blood vessels and nerves, it is very easy to cause pain and bleeding to the patient when ulcers occur. When the patient eats irritating foods, there will be strong burning pain in the ulcer. Therefore, the disease is clinically called recurrent oral ulcers, recurrent aphthous stomatitis, and recurrent oral ulcers. According to statistics, the prevalence of stubborn oral ulcers in the general population is 10% to 25%, and the incidence in specific populations can be as high as 50%.

Commonly used dosage forms for the treatment of oral ulcers in clinical practice include gargles, aerosols, powders, films, tablets, ointments and gels, among which liquid dosage forms such as gargles and aerosols are the most widely used. These preparations are easy to use, but due to the particularity of the oral environment and function, the continuous secretion of saliva and the movement of the tongue, the liquid preparations stay on the oral ulcer wound for a short time, the amount of medicine is easy to lose, the drug utilization is not high, frequent administration is required, and the adverse reactions of the drug will increase after multiple administrations, resulting in poor patient compliance; solid preparations such as powders and tablets have better stability, but due to their poor adhesion , the drug cannot be completely concentrated in the lesion site, resulting in a low local effective drug concentration, and the drug release is easily affected by saliva, the bioavailability is low, and it does not have a good therapeutic effect; the use of ointments, gels, etc. is not affected by the size of the ulcer surface and is easy to apply, but the drug is easily dissolved by saliva and diffused throughout the mouth, which not only has a poor taste, but is also easy to swallow and cause certain adverse reactions; film preparations have good adhesion, can effectively protect the ulcer surface, relieve pain, and are small in size, light in weight, easy to carry and transport, and have good compliance. They are currently the best dosage form accepted by patients with oral ulcers.

Since ordinary films have a short adhesion time, the drug is easily washed away by saliva, making the bitter taste or discomfort of the drug easily diffused throughout the mouth, and swallowing the drug may lead to reduced efficacy or increased adverse reactions. In addition, due to the inflammation of the oral ulcer surface and the frequent strong burning pain during the attack, the pain causes great mental pressure on the patient's life and work, seriously affecting the quality of life. Therefore, in clinical practice, multiple drugs for analgesia, anti-inflammatory and wound healing are often used in combination to relieve various symptoms of oral ulcers, such as the classic drug combination: compound chlorhexidine gargle, compound gentamicin film, vitamin B2 and zinc gluconate; domiphene lozenges, propolis oral film, B vitamins and vitamin C; cediodine lozenges, Bingpengsan and Kunming Shanhaitang tablets; long-term and cumbersome use of multiple drugs makes patients suffer.

Therefore, it is very necessary to develop a multi-drug preparation suitable for oral ulcers, which can provide long-lasting analgesia and prevent the drug from being washed away.

Summary of the invention

In view of the above-mentioned deficiencies, the present invention aims to propose a skeleton-type one-way release membrane preparation made of one or several polymer materials, which can evenly disperse a variety of drugs for treating oral ulcers in a molecular or crystalline state in the skeleton to form a unified whole, and at the same time add a layer of hydrophobic film on the outer layer away from the oral mucosa, so as to achieve the purpose of isolating the drugs contacting the oral ulcer from other parts of the oral cavity, so that the drug film can still accumulate at the lesion site for a long time in harsh environments such as oral movement and saliva flushing, so as to achieve a long-term analgesic effect, thereby solving the problems existing in the background technology.

In order to achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

The first aspect disclosed in the present invention is: a long-acting analgesic drug compound for oral ulcers, comprising a local anesthetic, an anti-inflammatory drug and a healing-promoting drug, wherein:

Local anesthetics are used to relieve the pain of oral ulcers, accounting for 50% to 80%;

Anti-inflammatory drugs are used to eliminate inflammation on the ulcer surface, accounting for 10% to 30%;

Healing-promoting drugs are used to promote the healing of ulcer wounds, accounting for 10% to 30%.

The second aspect disclosed by the present invention is: a long-acting analgesic drug adhesion layer for oral ulcers, comprising a drug compound and a film-forming system, wherein the drug compound is evenly distributed on the skeleton type of the film-forming system.

As a further preferred embodiment of the above technical solution: the proportion of the drug compound is 5% to 30%, and the proportion of the film-forming system is 70% to 95%.

As a further preferred scheme of the above technical scheme: the film-forming system includes a film-forming material 1, a plasticizer, a surfactant, a filler and a colorant, wherein the film-forming material 1 accounts for 10% to 70%, the plasticizer accounts for 30% to 60%, the surfactant accounts for 0% to 2%, the filler accounts for 0% to 20%, and the colorant accounts for 0% to 2%.

As a further preferred embodiment of the above technical solution: the drug compound comprises a local anesthetic, an anti-inflammatory drug and a healing-promoting drug, wherein:

Local anesthetics are used to relieve pain from oral ulcers, accounting for 5% to 20%;

Anti-inflammatory drugs are used to eliminate inflammation on the ulcer surface, accounting for 1% to 10%;

Healing-promoting drugs are used to promote the healing of ulcer wounds, accounting for 1% to 10%.

The third aspect disclosed by the present invention is: a one-way release film preparation for oral ulcers with long-term analgesia, comprising a drug adhesion layer and a hydrophobic isolation layer, the drug adhesion layer adheres to the oral mucosa and slowly releases the drug, and the hydrophobic isolation layer is located on the adhesion layer and away from the side of the ulcer mucosa to isolate the drug from direct contact with the oral environment.

A further preferred embodiment of the above scheme is that the hydrophobic isolation layer includes film-forming material 2, plasticizer, surfactant and colorant, wherein the film-forming material 2 accounts for 20% to 70%, the plasticizer accounts for 10% to 50%, the surfactant accounts for 0% to 5%, and the colorant accounts for 0% to 2%.

The fourth technical solution disclosed in the present invention is: a method for preparing a long-acting analgesic oral ulcer unidirectional release film preparation, comprising the following steps:

S1: Perform swelling treatment on the second film-forming material, and add plasticizer, surfactant and colorant in proportion, stir and dissolve, and fix the volume to obtain the isolation layer glue solution for standby use;

S2: subjecting the film-forming material 1 to swelling treatment, and adding the dissolved active drug, plasticizer, surfactant, filler, and colorant in proportion, stirring and dissolving, and fixing the volume to obtain an adhesive layer glue solution for standby use;

S3: Lay the first layer of film with the isolation layer glue, and after preliminary drying, lay the second layer of film on the first layer of film with the adhesive layer glue, and after the two layers of film are completely dried, cut and package them independently to obtain a one-way release film preparation.

An optimized solution based on the above solution is: in step S1, the ratio of the second film-forming material, plasticizer, surfactant, and colorant is (2-7): (1-5): (0-0.5): (0-0.2).

The optimization scheme based on the above scheme is: in step S2, the ratio of film-forming material 1, active drug, plasticizer, surfactant, filler and colorant is (1-7): (0.5-3): (3-6): (0-0.2): (0-2): (0-0.2).

The present invention has the following advantages through the above technical solution:

1. The one-way release film preparation of the present invention evenly disperses the active drug in a molecular or crystalline state in a skeleton made of a polymer material to form a bioadhesive layer drug film. The biomucosal adhesive material contained in the adhesive layer can ensure that the drug film is tightly adhered to the oral mucosa. The release of the drug is affected by the expansion of the skeleton material and the diffusion of the drug. The polymer material used is highly adhered to the mucosal surface, which can effectively hinder the hydration of the drug film, so that the active drug is slowly released and enriched in the lesion for a long time to achieve a long-term analgesic effect. At the same time, an isolation layer with good hydrophobic effect is added on the back of the adhesive layer to prevent the drug from contacting other parts of the oral cavity, so that the one-way release film preparation can also be accumulated in the lesion site for a long time under harsh environments such as oral movement and saliva flushing, thereby reducing the secondary stimulation pain of the ulcer surface and avoiding the disadvantages of frequent drug administration. It can also ensure that the drug contained in the one-way release film preparation is unidirectionally released to the mucosal site of the ulcer surface, thereby improving the utilization of biological drugs.

2. The active drugs in the one-way release membrane preparation of the present invention include local anesthetics for relieving pain from oral ulcers, anti-inflammatory drugs for treating inflammation of the ulcer surface, and drugs for promoting wound healing, which solves the shortcomings of the combined use of multiple drugs for oral ulcers. The active drug biopolymer materials are jointly prepared into a one-way release membrane preparation, which increases the residence time of the drug in the lesion, thereby prolonging the analgesic time (greater than 3 hours), reducing the number of medications, and greatly improving the patient's compliance with the drug.

3. Compared with the discomfort caused by traditional drugs being dissolved by saliva and diffused throughout the oral cavity, especially when the raw materials are bitter or contain local anesthetics, which will cause the entire oral cavity to be bitter or numb, the one-way release membrane preparation of the present invention plays a good protective role, preventing the drug from directly contacting saliva and causing a sense of ectopic sensation in the oral cavity. It is especially suitable for people who are sensitive to taste.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments.

FIG. 1 is a physical diagram of a one-way release film preparation of the present invention;

Fig. 2 is a test diagram of the unidirectional release property of the unidirectional release film preparation of the present invention;

FIG3 is a device for testing the adhesion time of the one-way release film preparation of the present invention;

FIG4 is a graph showing the adhesion time results of the one-way release film preparation of the present invention;

FIG5 is a test diagram of the in vitro release curve of the one-way release film preparation of the present invention;

FIG6 shows the results of the one-way release film preparation of the present invention on rat mucosal analgesia.

DETAILED DESCRIPTION

In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

1-6, the present invention provides a long-acting analgesic oral ulcer unidirectional release film preparation and a preparation method thereof, wherein:

In order to allow the drug to stay in the lesion site for a long time to achieve the purpose of long-term analgesia, reduce the number of medications, and improve patient compliance, the present invention has developed a one-way release membrane. By adding a hydrophobic isolation layer, it is used to isolate the drug from direct contact with saliva, avoid the drug being washed away by saliva and the influence of swallowing, and also reduce the secondary stimulation pain of the ulcer surface caused by oral movements such as talking and eating, thereby improving the patient's pain and frequent medication problems.

Specifically, the one-way release film preparation includes a drug adhesion layer and a hydrophobic isolation layer, wherein the hydrophobic isolation layer is attached to the drug adhesion layer. In a state of use, the hydrophobic isolation layer is on a side of the drug adhesion layer away from the oral ulcer mucosa.

Preferably, the drug adhesion layer comprises an active drug, a film-forming material 1, a plasticizer, a surfactant, a filler and a colorant, and the active drug accounts for 5% to 30%, the film-forming material 1 accounts for 10% to 70%, the plasticizer accounts for 30% to 60%, the surfactant accounts for 0% to 2%, the filler accounts for 0% to 20%, and the colorant accounts for 0% to 2%; wherein:

The active drug is a compound composed of a local anesthetic that helps relieve the pain of oral ulcers, an anti-inflammatory drug that helps eliminate inflammation, and a healing-promoting drug that helps promote wound healing. From the perspective of the prepared drug adhesion layer as a whole, the local anesthetic accounts for 5% to 20%, which includes any one or more of cocaine hydrochloride, benzocaine, tetracaine hydrochloride, lidocaine hydrochloride, bupivacaine hydrochloride, levobupivacaine hydrochloride, ropivacaine hydrochloride and prilocaine; the anti-inflammatory drug accounts for 1% to 10%, which includes any one or more of dexamethasone, prednisone, triamcinolone acetonide, bisabolol, menthol, D-flavonoids, glycyrrhizic acid, glycyrrhetinic acid, dipotassium glycyrrhizinate and diammonium glycyrrhizinate; the healing-promoting drug accounts for 1% to 10%, which includes any one or more of hyaluronic acid, sodium hyaluronate and allantoin.

The first film-forming material is any one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, sodium hyaluronate, chitosan, xanthan gum, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone, carbomer, polycarbophil, polyacrylic acid, and sodium polyacrylate.

The filler is any one of calcium carbonate, sodium citrate and potassium citrate.

In the present invention, the hydrophobic isolation layer includes film-forming material 2, plasticizer, surfactant and colorant, and the film-forming material 2 accounts for 20% to 70%, the plasticizer accounts for 10% to 50%, the surfactant accounts for 0% to 5%, and the colorant accounts for 0% to 2%.

The components of the plasticizer, surfactant and colorant used in the drug adhesion layer and the hydrophobic isolation layer of the present invention are the same, specifically: the plasticizer is any one or more of glycerol, polyethylene glycol, sorbitol, propylene glycol, and triethyl citrate, the surfactant is any one or more of sodium lauryl sulfate and benzalkonium chloride, and the colorant is a pigment.

The invention discloses a method for preparing a long-acting analgesic oral ulcer unidirectional release film preparation, comprising the following steps:

S1: Perform swelling treatment on the second film-forming material, and add plasticizer, surfactant and colorant in proportion, stir and dissolve, and fix the volume to obtain the isolation layer glue solution for standby use;

Among them: the ratio of film-forming material 2, plasticizer, surfactant and colorant is (2-7): (1-5): (0-0.5): (0-0.2).

S2: subjecting the film-forming material 1 to swelling treatment, and adding the dissolved active drug, plasticizer, surfactant, filler, and colorant in proportion, stirring and dissolving, and fixing the volume to obtain an adhesive layer glue solution for standby use;

Among them: the ratio of film-forming material 1, active drug, plasticizer, surfactant, filler and colorant is (1-7): (0.5-3): (3-6): (0-0.2): (0-2): (0-0.2).

S3: Lay the first layer of film with the isolation layer glue, and when it is dried to a moisture content of 5% to 15%, lay the second layer of film on the first layer with the adhesive layer glue. After the two layers of film are completely dry, cut them into individual films of 1cm×1cm square, φ10mm circle or other shapes as needed, and package each cut film independently to obtain a one-way release film preparation.

The preferred embodiments of the present invention are listed below to further describe the present invention in detail, but are not intended to limit the scope of implementation of the present invention.

The following is a pharmacological analysis of the selected drug components of the present invention:

The most typical symptoms of oral ulcers are inflammation and ulceration of the wound surface and severe burning pain. To address the above problems, the present invention selects local anesthetics to relieve the patient's pain, and also selects a natural anti-inflammatory drug with a hormone-like effect and a drug that promotes wound repair to form a formula to eliminate inflammation, reduce the oral ulcer wound surface, relieve pain and ultimately cure the oral ulcer.

Lidocaine hydrochloride is an amide medium-acting local anesthetic with a strong anesthetic effect, twice that of procaine, strong penetration and rapid onset. It is considered to be an ideal local anesthetic. It can act on local nerve endings or nerve trunks, reversibly block the occurrence and conduction of nerve impulses, and temporarily eliminate local sensation. Compared with procaine of the same concentration, lidocaine hydrochloride has the characteristics of rapid onset, strong and lasting effect, strong penetration and a wide safety range. It does not dilate blood vessels or irritate tissues. Unless used on a large area of skin/mucous membranes, there is generally no obvious systemic poisoning phenomenon. In the oral acute toxicity test, the mouse _LD50 is 220mg/kg, and in the intravenous acute toxicity test, the minimum toxic dose for humans (males) is 14mg/kg. Lidocaine hydrochloride has few adverse reactions at conventional dosages and is a safe topical analgesic.

Licorice has been proven to have significant anti-inflammatory effects. Licorice extracts have been used as mouthwashes and patches to treat oral ulcers, which can significantly reduce the pain of patients, significantly reduce the diameter of the ulcer surface inflammation halo and necrosis, and have a good effect on the healing of oral ulcers. Dipotassium glycyrrhizinate is a derivative of glycyrrhizic acid extracted and separated from licorice as a raw material. It is hydrolyzed into aglycone glycyrrhetinic acid in the body to exert its efficacy. Modern pharmacological studies have shown that glycyrrhetinic acid can inhibit the activity of liver steroid metabolic enzymes and kidney 11β-hydroxysteroid dehydrogenase, hinder the reduction metabolism of corticosteroids by related organs, and thus produce an effect of enhancing the effect of steroid hormones. This effect is mainly a hydrocortisone-like effect, inhibiting the production of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), major histocompatibility complex (MHC) and interstitial adhesion molecule 1 (ICAM-1), and inducing apoptosis of leukocytes (inflammatory cells). Therefore, dipotassium glycyrrhizinate has a strong anti-inflammatory effect. In clinical practice, glycyrrhizic acid (dipotassium) can be used as a weak glucocorticoid-like drug, which can not only enhance the effects of glucocorticoids, but also antagonize the side effects of high-dose glucocorticoids. It can be seen that dipotassium glycyrrhizinate has an inhibitory effect on inflammatory mediators and inflammatory cytokines.

Sodium hyaluronate, also known as sodium hyaluronate, is a natural polymer compound with strong hydrophilicity and lubricity. The main research direction of clinical ophthalmology is to use it to stabilize the lacrimal gland, prevent corneal and conjunctival drying, and reduce friction of eye tissues, so as to relieve the discomfort of dry eyes. The application of sodium hyaluronate to damaged animal epithelial cells can further accelerate the migration speed and mobilize macrophages to accelerate wound healing. At the same time, it can also transport certain proteins and peptides, which has a significant effect on promoting wound healing. In addition, the rapid metabolism of sodium hyaluronate can effectively remove cell fragments. In this process, cell fragments are embedded in the macromolecular network structure of sodium hyaluronate and can eventually be excreted along with sodium hyaluronate.

Therefore, the local anesthetic lidocaine hydrochloride selected by the present invention can be used to relieve the pain of oral ulcers, the anti-inflammatory drug dipotassium glycyrrhizinate can inhibit the development of ulcer surface inflammation, and the sodium hyaluronate that promotes wound healing can accelerate the rapid healing of the ulcer surface. The three together form a new compound preparation that can achieve the purpose of relieving pain and ultimately curing oral ulcers.

Embodiment 1:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 1 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 1 Detailed composition and dosage of raw materials used in Example 1

In this embodiment, the active drug compound is prepared by mixing 0.62g of benzocaine, 0.12g of dexamethasone and 0.32g of hyaluronic acid. The method for preparing the one-way release film preparation is as follows:

(1) Add a proper amount of ethanol or water to the film-forming material 2, stir to disperse, heat or allow to stand to fully swell, add a plasticizer, a surfactant, and a colorant according to the weight in Table 1, stir to dissolve, add ethanol or water to make up the prescribed amount, stir evenly, exhaust, and obtain an isolation layer glue solution for standby use;

(2) Add a proper amount of ethanol or water to the film-forming material 1, stir to disperse, heat or allow to fully swell, add the dissolved active drug, plasticizer, pigment, surfactant, and filler according to the weight in Table 1, stir to dissolve, add ethanol or water to make up the prescribed amount, stir evenly, exhaust, and obtain the adhesive layer glue solution for use;

(3) Using the obtained isolation layer adhesive to lay the first layer of film, and when the film is dried to a moisture content of 5% to 10%, using the adhesive layer adhesive to lay the second layer of film on the first layer of film, and after the two layers of film are completely dried, cut them into individual films of 1 cm × 1 cm square, φ10 mm circle or other shapes as needed, and package each cut film independently to obtain a one-way release film preparation.

Embodiment 2:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 2 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 2 Detailed composition and dosage of raw materials used in Example 2

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 3:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 3 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 3 Detailed composition and dosage of raw materials used in Example 3

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 4:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 4 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 4 Detailed composition and dosage of raw materials used in Example 4

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 5:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 5 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 5 Detailed composition and dosage of raw materials used in Example 5

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 6:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 6 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 6 Detailed composition and dosage of raw materials used in Example 6

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 7:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 7 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 7 Detailed composition and dosage of raw materials used in Example 7

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 8:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 8 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 8 Detailed ingredients and dosage of raw materials used in Example 8

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 9:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 9 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 9 Detailed composition and dosage of raw materials used in Example 9

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 10:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 10 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 10 Detailed composition and dosage of raw materials used in Example 10

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 11:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 11 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 11 Detailed ingredients and dosage of raw materials used in Example 11

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

Embodiment 12:

In this example, the raw materials used for the drug adhesion layer and the hydrophobic isolation layer are shown in Table 12 below, and 1000 pieces of one-way release film preparations are prepared according to the following preparation method.

Table 12 Detailed ingredients and dosage of raw materials used in Example 12

In this example, the method for preparing the one-way release film preparation is the same as that in Example 1.

In order to verify the performance of the one-way release membrane preparation prepared by the method of the present invention, the one-way release membrane preparations prepared in some embodiments were tested and evaluated from five aspects: one-way release, adhesion time, in vitro release, long-acting analgesic effect, and clinical application of analgesic effect.

A1: One-way release

The one-way release film preparation prepared in Examples 1-7 of the present invention was sandwiched between two ground-mouth bottles, and the two ground-mouth bottles were filled with artificial saliva in advance. The docked ground-mouth bottles were placed in an inverted and upright state for 24 hours, respectively. The results were shown in FIG2 . The bottle on the side corresponding to the drug adhesion layer was full of pigment, while the bottle on the side corresponding to the hydrophobic isolation layer was not dyed.

This test result fully demonstrates that the hydrophobic isolation layer can effectively isolate the drug from being washed away by saliva and prevent the drug from being released outward. At the same time, the drug can be released unidirectionally from the drug adhesion layer to the lesion site.

A2: Adhesion time

For ulcers in the oral cavity, in order to allow the drug to accumulate in the lesion for a long time, the adhesive layer of the one-way release film needs to be adhered to the mucosa for a long time.

In order to test the adhesion time of the one-way release film preparations of Examples 1-7 of the present invention, the lifting disintegration tester was modified, the hanging basket was suspended on the bracket through the stainless steel shaft at the upper end, immersed in a 1000mL beaker, the beaker was filled with 550mL of water at a temperature of 37°C, the hanging basket was about 25mm away from the water surface, the hanging basket must not be immersed in the solution, a dry 10mL test tube (tube length 6cm, diameter 1.5cm) bottom was drilled, fresh duck intestines were pasted on the outer wall of the test tube, the adhesion layer of the one-way release film was pasted on the duck intestines, the test tube was inverted in the hanging basket hole, the instrument was started, and the film shedding time was recorded. The test device is shown in Figure 3, and the adhesion time results are shown in Figure 4.

As shown in FIG4 , the results show that the mucosal adhesion time of the one-way release film preparations is greater than 6 hours, which proves that the one-way release film preparations prepared by the present invention can adhere to the mucosa for at least 6 hours in a sports environment of saliva flushing.

A3: In vitro release

This performance test was conducted with reference to the "Expert Consensus on Technical Specifications for In Vitro Release Testing of Semisolid Preparations for Skin and Mucous Membranes", and a Franz diffusion cell was used to evaluate the in vitro release behavior of the unidirectional release membranes of Examples 1-7.

The experiment uses a vertical diffusion cell, which can be immersed in a constant temperature water bath to maintain the temperature. The receiving chamber has a branch pipe for sampling and a magnetic stirring of the mixed solution. An artificial membrane is fixed in the middle to separate the supply chamber and the receiving chamber (the volume of the receiving chamber is 8.0 mL). The artificial membrane is pre-soaked in the receiving solution (i.e., homemade artificial saliva) for 10 minutes.

The artificial membrane of the supply chamber is covered with a one-way release membrane preparation, the adhesive layer is attached to the artificial membrane, artificial saliva is injected into the receiving chamber as the receiving liquid, bubbles are removed, the liquid surface of the receiving liquid is in contact with the inner layer of the artificial membrane, and the electromagnetic stirrer is started to stir at a constant speed and maintain a constant temperature of 37°C;

1.1 mL of sample was taken at 0.25 h, 0.5 h, 1 h, 2 h, and 3 h after administration, and the drug content in the one-way release membrane preparation was determined by high performance liquid chromatography after filtration. After each sampling, the same volume of fresh receiving solution was added, and the bubbles in the receiving chamber were removed;

Calculate the drug content and calculate the cumulative release amount (degree) Q according to the following formula:

Where _Cn is the mass concentration (mg/mL) measured by sampling at the nth time point; V is the volume of the receiving chamber (mL); is the sum of the cumulative amounts of drugs at the time of sampling; _Ci is the drug mass concentration (mg/mL) measured by sampling at the ith time point; _Vi is the sampling volume (mL); M: the mass of drug in the sample (mg).

As shown in Figure 5, the results show that the drug in the one-way release membrane preparation is first released quickly and then slowly. The cumulative release rate in 15 minutes is about 50%, and the cumulative release rate in 3 hours can reach more than 90%, showing a good sustained-release effect, which is a strong evidence that the one-way release membrane preparation can provide long-term analgesia.

A4: Long-lasting analgesic effect

This test uses VonFrey silk to stimulate the oral mucosa of rats to test the analgesic effect of the one-way release membrane preparation of Example 1. The specific test process is as follows:

1) 36 rats were randomly divided into 6 groups, group 1 was the negative control group (normal saline), and groups 2 to 6 were experimental groups;

2) After grouping, normal saline was applied to the mucosa of rats in group 1, and 1 cm × 1 cm one-way release membrane preparations were applied to rats in groups 2 to 6;

3) At 15 min, 30 min, 1 h, 2 h, and 3 h after administration, the one-way release membrane preparations of the experimental rats in groups 2 to 6 were peeled off, and the exposed mucosa was stimulated with Von Frey silk. The rats in the negative control group were stimulated at the same time points, and the corresponding administration site was measured 5 times, with at least 3 to 5 s between each measurement. The behavior of the rats struggling and attempting to escape was defined as a sign of pain, and the number of pain times was recorded (pain ≤ 2 times was considered to be effective in anesthesia, and pain ≥ 3 times was considered to be ineffective).

4) Record the pain conditions of each group and calculate the average value.

As shown in Figure 6, the results showed that the negative control group had ≥3 pain reactions at the same time points, while the pain reactions of the test groups 2 to 6 were ≤2 times at the corresponding time points, indicating that the one-way release membrane preparation prepared by the present invention can achieve the effect of anesthesia and analgesia within 15 minutes, and the analgesic effect can be maintained for at least 3 hours, achieving a significant long-term analgesic effect.

A5: Clinical application of analgesic effect

In order to further verify the analgesic effect of the present invention, the one-way release film prepared in Example 1 was selected for testing, and the specific testing process is as follows:

1) 10 patients with oral ulcers diagnosed by doctors without other diseases were selected and randomly divided into 2 groups by lottery. The first group was the positive control group (propolis oral film) and the second group was the experimental group (one-way release film).

2) After grouping, each group of patients applied a piece of the corresponding group of drugs on the ulcer surface, and recorded the analgesic onset time and maintenance time according to the patients' feelings. The analgesic onset time refers to the complete absence of pain when the patient speaks, and the maintenance time refers to slight pain on the ulcer surface or recovery to the same pain as before medication.

3) Observe, inquire, and record the pain conditions of patients in each group and calculate the average value. The results are shown in Table 1.

Table 1 Comparison of clinical tests on analgesic effects of oral ulcers (n=5)

As shown in Table 1, the results show that both the propolis oral film and the one-way release film of the present invention have analgesic effects, but there are obvious differences in analgesic onset time, analgesic maintenance time and local irritation. From the comparison of the data in Table 1, it can be seen that the analgesic onset time of the propolis oral film is slower, about 12 minutes, and the analgesic effect is not obvious, and the analgesic maintenance time is about 20 minutes; the one-way release film has a faster analgesic onset time, about 2 minutes, and the analgesic maintenance time is about 4 hours, and the analgesic effect is better; in terms of local irritation, both did not show obvious irritation to the ulcer surface, and there were no other adverse reactions.

The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which shall fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims (10)

1. A long-acting analgesic pharmaceutical compound for dental ulcer, which is characterized by comprising a local anesthetic, an anti-inflammatory agent and a healing promoting agent, wherein:

The local anesthetic is used for relieving the canker sore pain, and the local anesthetic accounts for 50-80 percent;

The anti-inflammatory agent is used for eliminating ulcer inflammation, and the proportion of the anti-inflammatory agent is 10% -30%;

The healing promoting medicine is used for promoting the healing of ulcer wound surface, and the ratio of the healing promoting medicine is 10-30%.

2. The drug adhesion layer for the oral ulcer with long-acting pain relieving is characterized by comprising a drug compound and a film forming system, wherein the drug compound is uniformly distributed on a framework type of the film forming system.

3. The long-acting analgesic oral ulcer unidirectional release film preparation as claimed in claim 2, wherein the drug compound accounts for 5% -30% and the film forming system accounts for 70% -95%.

4. A drug-adhesive layer for oral ulcer with a long-acting analgesic effect according to claim 3, wherein the film-forming system comprises a film-forming material 1, a plasticizer, a surfactant, a filler and a colorant, wherein the film-forming material 1 accounts for 10% -70%, the plasticizer accounts for 30% -60%, the surfactant accounts for 0% -2%, the filler accounts for 0% -20%, and the colorant accounts for 0% -2%.

5. The drug-adhesive layer for treating dental ulcer with long-acting pain relieving effect according to claim 4, wherein the drug compound comprises a local anesthetic, an anti-inflammatory agent and a healing promoting agent, wherein the local anesthetic accounts for 5% -20%, the anti-inflammatory agent accounts for 1% -10%, and the healing promoting agent accounts for 1% -10%.

6. The unidirectional release film formulation for the drug-adhered layer for treating canker sores with a long-acting analgesic effect as claimed in any one of claims 2 to 5, comprising a drug-adhered layer adhered to the oral mucosa and releasing the drug slowly, and a hydrophobic isolation layer on the adhered layer at a side far from the ulcer mucosa for isolating the direct contact of the drug with the oral environment.

7. The one-way release film formulation for treating oral ulcer with long-acting analgesic as claimed in claim 6, wherein the hydrophobic isolation layer comprises a second film forming material, a plasticizer, a surfactant and a colorant, wherein the second film forming material accounts for 20% -70%, the plasticizer accounts for 10% -50%, the surfactant accounts for 0% -5%, and the colorant accounts for 0% -2%.

8. A method for preparing a long-acting analgesic oral ulcer unidirectional release film preparation, which is characterized by comprising the following steps:

S1: swelling the film-forming material II, adding a plasticizer, a surfactant and a colorant in proportion, stirring and dissolving, and fixing the volume to obtain an isolation layer glue solution for later use;

s2: swelling the film forming material I, adding the dissolved drug compound, the plasticizer, the surfactant, the filler and the colorant in proportion, stirring and dissolving, and fixing the volume to obtain adhesive layer glue solution for later use;

s3: and (3) paving a first layer of paving films by using the isolating layer glue solution, paving a second layer of paving films on the first layer of paving films by using the adhesive layer glue solution after preliminary drying, cutting and independently packaging after the two layers of paving films are completely dried, thus obtaining the unidirectional release film preparation.

9. The method for preparing the long-acting analgesic oral ulcer unidirectional release film preparation as claimed in claim 8, wherein in step S1, the proportion of the film forming material two, the plasticizer, the surfactant and the colorant is (2-7): (1-5): (0-0.5): (0 to 0.2).

10. The method for preparing the one-way release film preparation for dental ulcer with long-acting pain relieving effect according to claim 8, wherein in the step S2, the proportion of the film forming material I, the active drug, the plasticizer, the surfactant, the filler and the colorant is (1-7): (0.5-3): (3-6): (0-0.2): (0-2): (0 to 0.2).