Low-irritation double-layer gel anesthetic for urethra and preparation method of low-irritation double-layer gel anesthetic

Abstract

The invention provides a urethra low-irritation double-layer gel anesthetic and a preparation method thereof.The anesthetic comprises a first gel layer, a second gel layer and a third gel layer, the first gel layer comprises a local anesthetic and a temperature-sensitive reversible gel matrix, and the temperature-sensitive reversible gel matrix is subjected to sol-gel transition at 25-40 DEG C; the second gel layer comprises aloe polysaccharide and an irreversible gel skeleton, and the irreversible gel skeleton is formed by a polysaccharide gel agent; wherein the first gel layer and the second gel layer are physically compounded at an interface to form a double-layer whole. According to the double-layer gel anesthetic, the local anesthetic and the temperature-sensitive reversible gel matrix are compounded, gel can be rapidly formed under the body temperature condition, it is guaranteed that the drug fully stays and slowly releases in the local part of the urethra, and the anesthetic effect is remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a urethral low-irritation double-layer gel anesthetic and a preparation method thereof. BACKGROUND

[0002] Lidocaine hydrochloride belongs to amide class of local anesthetics, which can reversibly block voltage-gated sodium ion channels, inhibit the depolarization of nerve cell membranes, and prevent the formation and conduction of action potentials, thereby blocking the transmission of pain signals. The blocking effect on high-frequency discharging nerve fibers is stronger, and the anesthetic effect is more significant. Lidocaine hydrochloride can quickly penetrate the nerve cell membrane, has a short anesthetic onset time, and has strong penetration on the mucosa, and is suitable for surface anesthesia, such as urethral anesthesia for examination.

[0003] After the gel is administered locally, it can stay at the administration site for a long time, has a large contact area with the administration site, and has a rapid onset. At the same time, it has good biocompatibility, fast absorption, and high bioavailability. Local administration can increase the local concentration of the drug, improve the therapeutic effect, and reduce the risk of systemic side effects. However, it may cause local irritation, especially the urethral mucosa is sensitive and fragile, which may cause burning, stinging or redness, and is more obvious when the mucosa is damaged. Improper use may cause secondary injury to the patient.

[0004] At present, the anesthetic gel used for urethral examination generally has lubricating and anesthetic effects, which may cause local irritation to the urethral mucosa, causing stinging or redness, and has no soothing and anti-inflammatory effect on mucosal damage. SUMMARY

[0005] In order to solve the above technical problems, the present application provides a urethral low-irritation double-layer gel anesthetic and a preparation method thereof.

[0006] The first aspect of the present application provides a urethral low-irritation double-layer gel anesthetic, comprising: A first gel layer, the first gel layer comprises a local anesthetic and a temperature-sensitive reversible gel matrix, the temperature-sensitive reversible gel matrix undergoes sol-gel transition at 25-40℃; a second gel layer, the second gel layer comprises aloe polysaccharide and an irreversible gel skeleton, the irreversible gel skeleton is formed by a polysaccharide gel agent; wherein the first gel layer and the second gel layer are physically compounded at the interface to form a double-layer whole.

[0007] The double-layer gel anesthetic of the present invention is able to rapidly form a gel under body temperature conditions by compounding a local anesthetic with a thermosensitive reversible gel matrix, ensuring sufficient retention and sustained release of the drug in the local urethra, and significantly improving the anesthetic effect. The introduction of aloe polysaccharide in the second gel layer, combined with the irreversible polysaccharide gel skeleton, not only gives the gel good structural stability, but also provides moisturizing, repairing, anti-inflammatory and soothing effects for the urethral mucosa, effectively reducing local irritation and pain. The design of the double-layer structure enables the anesthetic and repair functions to work together, significantly reducing the patient's discomfort during urethral examination, and improving the safety and clinical applicability of the preparation. Compared with traditional single-layer anesthetic gels, the double-layer gel of the present invention shows obvious advantages in stability, local irritation and comfort.

[0008] Furthermore, the local anesthetic is lidocaine hydrochloride or a pharmaceutically acceptable salt thereof. This limitation ensures the reliability and safety of the anesthetic effect. Lidocaine hydrochloride, as a commonly used local anesthetic in clinical practice, has the advantages of rapid onset and strong penetrating power. Specifically, it can be lidocaine hydrochloride, lidocaine base, lidocaine monohydrate, lidocaine hydrochloride, lidocaine citrate, lidocaine lactate, procaine, tetracaine, mepivacaine, articaine, bupivacaine, ropivacaine, mepivacaine hydrochloride, tetracaine hydrochloride, procaine hydrochloride, etc.

[0009] Furthermore, the thermosensitive reversible gel matrix is ​​poloxamer 407. Poloxamer 407 can undergo a sol-gel transition within the range of 25-40°C, facilitating the molding of the formulation at body temperature and improving local retention. In other embodiments, poloxamer 188, poloxamer 338, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycol-polypropylene glycol copolymers, polycaprolactone-polyethylene glycol copolymers, polylactic acid-polyethylene glycol copolymers, and the like may also be used.

[0010] Furthermore, the polysaccharide gelling agent is gellan gum. Gellan gum, as an irreversible gel skeleton, can give the second gel layer good structural stability and biocompatibility. In other embodiments, it can be sodium alginate, carrageenan, xanthan gum, agar, chitosan, gelatin, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, gum arabic, pectin, etc.

[0011] Furthermore, the second gel layer also contains sodium hyaluronate. Sodium hyaluronate has excellent moisturizing and repairing properties, which can further enhance the gel's protective effect on the urethral mucosa. In other embodiments, it can be potassium hyaluronate or zinc hyaluronate.

[0012] Further, the first gel layer further comprises hydroxypropyl-β-cyclodextrin. Hydroxypropyl-β-cyclodextrin can include local anesthetics to improve their solubility and sustained-release performance, and enhance the anesthetic effect. In other embodiments, it can be hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, ethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, etc.

[0013] Further, the first gel layer and / or the second gel layer comprise a pH regulator to make the gel pH 6.0-7.0. This pH range is suitable for the human urethral environment, improves biocompatibility, and reduces irritation. Specifically, the pH regulator can be sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium acetate, sodium lactate, etc.

[0014] Further, the first gel layer and / or the second gel layer comprise a preservative selected from hydroxybenzoic acid ester, hydroxybenzyl propyl ester or a combination thereof. The introduction of preservatives helps to improve the storage stability and safety of the preparation. In other embodiments, it can be hydroxybenzoic acid ester, hydroxybenzyl propyl ester, hydroxybenzyl ethyl ester, hydroxybenzyl butyl ester, benzalkonium chloride, sodium benzoate, potassium sorbate, propyl gallate, propylene glycol, etc.

[0015] The second aspect of the present application provides a preparation method of the urethral low-irritation double-layer gel anesthetic as described above, comprising: a) preparing the second gel layer: dissolving the polysaccharide gel agent and aloe polysaccharide in water at 60-80°C, cooling to 45-55°C, then adding optional sodium hyaluronate, pouring into a mold and cooling to form an irreversible gel; b) preparing the first gel layer: dissolving the local anesthetic and the temperature-sensitive reversible gel matrix in water at 0-10°C to maintain low-temperature fluidity; c) pouring the low-temperature solution obtained in step b onto the surface of the irreversible gel obtained in step a, and forming a double-layer whole after standing, followed by moist heat sterilization.

[0016] This method ensures the integrity of the double-layer structure and the functional synergy through step-by-step preparation and physical compounding, and the process is simple and easy to industrialize.

[0017] Further, in step b, the local anesthetic is first formed into an inclusion compound with hydroxypropyl-β-cyclodextrin in water, and then mixed with the temperature-sensitive reversible gel matrix. This step helps to improve the solubility and sustained-release effect of the anesthetic, and further optimizes the performance of the preparation. DETAILED DESCRIPTION

[0018] For ease of understanding of the present application, the present application will be described more fully below. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0019] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of such features. In the description of the application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of this application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0021] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0022] In this application, when referring to numerical ranges, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0023] Unless otherwise specified, the percentage contents mentioned in this application refer to mass percentage for solid-liquid mixture and solid-solid mixture, and refer to volume percentage for liquid-liquid mixture.

[0024] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0025] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows for temperature fluctuations within the precision range of instrument control.

[0026] The "particles" mentioned in this application, or materials with a defined particle size distribution, are not necessarily spherical in shape but may be irregular, primary or secondary. The particle size of irregular particles is the average of their maximum and minimum diameters.

[0027] Example 1 Preparation of aloe polysaccharide layer (second gel layer): Add 0.015 parts of sodium hydroxide to a vacuum stirred kettle, add 94.0 parts of purified water, and stir until dissolved. Add 0.03 parts of 20-mesh propylparaben, heat in a water bath to 70-80°C, and stir until completely dissolved (130-180 rpm). Add 1.0 parts of aloe polysaccharide and 0.8 parts of gellan gum, and stir until transparent. Vacuum and cool to 0.07±0.01 MPa. Cool to 50°C, add 0.2 parts of sodium hyaluronate, and stir until completely dissolved. While hot, inject into a 4°C pre-cooled mold to form an irreversible gel. Remove any uneven surface areas to obtain Component A for later use.

[0028] Preparation of lidocaine hydrochloride layer (first gel layer): Add 0.012 parts of sodium hydroxide and 0.07 parts of methylparaben to 68.0 parts of purified water, stir until dissolved, cool to 4°C, add 3.0 parts of poloxamer 407, and gently stir until transparent to obtain Solution 1. Dissolve 1.0 parts of hydroxypropyl-β-cyclodextrin in 30.0 parts of 4°C purified water, add 2.0 parts of lidocaine hydrochloride, and stir until clear to obtain Solution 2. Slowly add Solution 2 to Solution 1 and stir evenly to obtain Component B.

[0029] Assembly: Pour component B at 4°C onto the surface of component A to a liquid layer thickness of about 2 mm, let it stand at room temperature for 10 minutes, and terminally sterilize to obtain a double-layer gel anesthetic.

[0030] Example 2 Preparation of aloe polysaccharide layer (second gel layer): Add 0.015 parts of sodium hydroxide to a vacuum stirred kettle, add 94.0 parts of purified water, and stir until dissolved. Add 0.03 parts of 20-mesh propylparaben, heat in a water bath to 70-80°C, and stir until completely dissolved (130-180 rpm). Add 2.0 parts of aloe polysaccharide and 0.8 parts of gellan gum, and stir until transparent. Vacuum and cool to 0.07±0.01 MPa. Cool to 50°C, add 0.2 parts of sodium hyaluronate, and stir until completely dissolved. While hot, inject into a 4°C pre-cooled mold to form an irreversible gel. Remove any uneven surface areas to obtain Component A for later use.

[0031] Preparation of lidocaine hydrochloride layer (first gel layer): Add 0.012 parts of sodium hydroxide and 0.07 parts of methylparaben to 68.0 parts of purified water, stir until dissolved, cool to 4°C, add 3.0 parts of poloxamer 407, and gently stir until transparent to obtain Solution 1. Dissolve 1.0 parts of hydroxypropyl-β-cyclodextrin in 30.0 parts of 4°C purified water, add 2.0 parts of lidocaine hydrochloride, and stir until clear to obtain Solution 2. Slowly add Solution 2 to Solution 1 and stir evenly to obtain Component B.

[0032] Assembly: Pour component B at 4°C onto the surface of component A to a liquid layer thickness of about 2 mm, let it stand at room temperature for 10 minutes, and terminally sterilize to obtain a double-layer gel anesthetic.

[0033] Example 3 Preparation of aloe polysaccharide layer (second gel layer): Add 0.015 parts of sodium hydroxide to a vacuum stirred kettle, add 94.0 parts of purified water, and stir until dissolved. Add 0.03 parts of 20-mesh propylparaben, heat in a water bath to 70-80°C, and stir until completely dissolved (130-180 rpm). Add 1.5 parts of aloe polysaccharide and 0.8 parts of gellan gum and stir until transparent. Turn on the vacuum and cool to 0.07±0.01MPa. Cool to 50°C, add 0.2 parts of sodium hyaluronate, and stir until completely dissolved. While hot, inject into a 4°C pre-cooled mold to form an irreversible gel. Remove any uneven surface areas to obtain component A for later use.

[0034] Preparation of lidocaine hydrochloride layer (first gel layer): Add 0.012 parts of sodium hydroxide and 0.07 parts of methylparaben to 68.0 parts of purified water, stir until dissolved, cool to 4°C, add 3.0 parts of poloxamer 407, and gently stir until transparent to obtain Solution 1. Dissolve 1.0 parts of hydroxypropyl-β-cyclodextrin in 30.0 parts of 4°C purified water, add 2.0 parts of lidocaine hydrochloride, and stir until clear to obtain Solution 2. Slowly add Solution 2 to Solution 1 and stir evenly to obtain Component B.

[0035] Assembly: Pour component B at 4°C onto the surface of component A to a liquid layer thickness of about 2 mm, let it stand at room temperature for 10 minutes, and terminally sterilize to obtain a double-layer gel anesthetic.

[0036] Comparative Example 1 Preparation of lidocaine hydrochloride monolayer gel: Add 0.012 parts of sodium hydroxide and 0.07 parts of methylparaben to 68.0 parts of purified water, stir until dissolved, cool to 4°C, add 3.0 parts of poloxamer 407, and gently stir until transparent to obtain Solution 1. Dissolve 1.0 parts of hydroxypropyl-β-cyclodextrin in 30.0 parts of 4°C purified water, add 2.0 parts of lidocaine hydrochloride, and stir until clear to obtain Solution 2. Slowly add Solution 2 to Solution 1, stir thoroughly, and let stand at room temperature to form a lidocaine hydrochloride gel, which is then terminally sterilized.

[0037] Test Example 1: The double-layer gel containing lidocaine hydrochloride and aloe polysaccharide prepared in the comparative example and Examples 1-3 was stored under accelerated stability conditions. The changes in the active ingredient content, viscosity, pH, sterility, and stratification of the preparations under accelerated conditions were tested. The results are shown in the table below.

[0038] Table 1 Test results of Experimental Example 1.

[0039] Note: ND means not tested, NA means not applicable.

[0040] Experimental Example 2: 120 patients undergoing urethral examinations in this study were randomly divided into three groups: a control group (n=40), a comparative example group (n=40), and Example 3 group (n=40). The control group used conventional paraffin oil, and the patients' pain after administration was assessed using a visual analog scale. The total score ranges from 0 to 10, with pain being categorized as no pain (0), mild pain (1-3), moderate pain (4-6), and severe pain (7-10). Pain incidence = (number of cases with moderate pain + number of cases with severe pain) / total number of cases × 100%.

[0041] Table 2 Test results of Experimental Example 2.

[0042] The incidence of stimulation pain in patients in Example 3 was lower than that in the control group, and the difference was statistically significant (P < 0.05).

[0043] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0044] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A low-irritation double-layer gel anesthetic for the urethra, characterized in that: include: The invention relates to a first gel layer, wherein the first gel layer comprises a local anesthetic and a thermosensitive reversible gel matrix, and the thermosensitive reversible gel matrix undergoes a sol-gel transition at 25-40°C; a second gel layer, wherein the second gel layer comprises aloe polysaccharide and an irreversible gel skeleton, and the irreversible gel skeleton is formed by a polysaccharide gelling agent; wherein the first gel layer and the second gel layer are physically compounded at the interface to form a double-layer entity.

2. The low-irritation double-layer urethral gel anesthetic according to claim 1, characterized in that: The local anesthetic is lidocaine hydrochloride or a pharmaceutically acceptable salt thereof.

3. The low-irritation double-layer urethral gel anesthetic according to claim 1, characterized in that: The thermosensitive reversible gel matrix is ​​poloxamer 407.

4. The low-irritation double-layer urethral gel anesthetic according to claim 1, characterized in that: The polysaccharide gelling agent is gellan gum.

5. The low-irritation double-layer urethral gel anesthetic according to claim 1, characterized in that: The second gel layer further comprises sodium hyaluronate.

6. The low-irritation double-layer urethral gel anesthetic according to claim 1, characterized in that: The first gel layer further comprises hydroxypropyl-β-cyclodextrin.

7. The low-irritation double-layer urethral gel anesthetic according to claim 1, characterized in that: The first gel layer and / or the second gel layer comprises a pH adjuster to adjust the gel pH to 6.0-7.

0.

8. The low-irritation double-layer urethral gel anesthetic according to claim 1, characterized in that: The first gel layer and / or the second gel layer comprises a preservative, and the preservative is selected from methylparaben, propylparaben or a combination thereof.

9. A method for preparing the low-irritation double-layer gel anesthetic for urethra according to any one of claims 1 to 8, characterized in that: include: a) Preparing the second gel layer: dissolving a polysaccharide gel and aloe polysaccharide in water at 60-80°C, cooling to 45-55°C, adding optional sodium hyaluronate, and injecting into a mold and cooling to form an irreversible gel; b) Preparing the first gel layer: dissolving a local anesthetic and a thermosensitive reversible gel matrix in water at 0-10°C, maintaining low-temperature fluidity; c) pouring the low-temperature solution obtained in step b onto the surface of the irreversible gel obtained in step a, allowing it to stand to form a double-layer structure, which is then sterilized with moist heat.

10. The method according to claim 9, characterized in that In step b, the local anesthetic and hydroxypropyl-β-cyclodextrin are firstly formed into an inclusion complex in water, and then mixed with the thermosensitive reversible gel matrix.

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