Metal ion complexing agent, metronidazole gel preparation thereof and preparation method of metronidazole gel preparation

Abstract

The invention relates to the technical field of medicine, in particular to a metal ion complexing agent, a metronidazole gel preparation thereof and a preparation method of the metronidazole gel preparation. The first component is selected from at least one of disodium edetate, sodium calcium edetate and tetrasodium edetate; the second component is selected from at least one of sodium tartrate and sodium citrate; wherein the mass ratio of the first component to the second component is (8: 1)-(1: 6). The metronidazole gel preparation has the advantages that the preparation process is simple, the stability is better, and the safety and the effectiveness can be guaranteed.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a metal ion complexing agent, its metronidazole gel formulation, and its preparation method. Background Technology

[0002] Metronidazole is mainly used to treat and prevent systemic or local infections caused by anaerobic bacteria. It is available in gel, cream, and lotion forms. Topical metronidazole is effective for moderate to severe erythema and inflammatory lesions, and is suitable for the local treatment of inflammatory papules, impetigo, and rosacea. Metronidazole gel is also suitable for the treatment of acne vulgaris.

[0003] Metronidazole gels typically contain metal ion complexing agents to ensure their stability. The metal ions in the gel may originate from production equipment or packaging materials, and they have a significant catalytic effect on oxidation reactions. The metal ion complexing agents can form stable, water-soluble complexes with the metal ions, inhibiting the growth of impurities. Therefore, metal ion complexing agents play an important role in metronidazole gels.

[0004] Metronidazole gel is a topical preparation, typically packaged in an aluminum ointment tube. It is packaged in multiple-dose containers; after opening, the screw cap is tightened, allowing for multiple uses. However, after a period of time, the remaining gel inside the packaging, especially near the tube opening, will turn yellow, exhibit rapid increase in related substances, and decrease in viscosity. Simultaneously, the remaining gel may show precipitation of the active pharmaceutical ingredient, affecting the safety and efficacy of the preparation. Patients often squeeze out and discard the gel near the tube opening, resulting in waste.

[0005] Metronidazole gel typically contains a metal ion complexing agent. However, once opened, the rapid changes in ambient temperature, pH, and oxygen levels render a single metal ion complexing agent ineffective in providing adequate protection. Different metal ion complexing agents exhibit varying complexing effects against metal ions with different properties under different environments. Therefore, this invention addresses the formulation characteristics of metronidazole gel by providing a combination of two metal ion complexing agents to better leverage their synergistic effect.

[0006] The preparation process of metronidazole gel usually involves two steps: preparing the gel matrix and performing the first pH adjustment, and preparing the drug-containing solution. Finally, after the two are mixed evenly, the pH is adjusted again. The whole process requires two pH adjustments, making the preparation process complex.

[0007] This patent relates to a metronidazole gel pharmaceutical composition and its preparation method. The prepared gel product can maintain its original quality after opening and can be used multiple times over a long period of time. Moreover, the preparation method is simple and has high production efficiency.

[0008] Patent CN120420270A discloses a benzene-free metronidazole gel. After the composition is opened for a period of time, the gel near the tube opening turns into a yellow gel, related substances increase significantly, viscosity decreases, and the active pharmaceutical ingredient precipitates out. The safety and efficacy of the remaining gel cannot be guaranteed.

[0009] Patent CN116650403B discloses a metronidazole gel with high freeze-thaw resistance. The preparation method of this composition requires two pH adjustments and a long ultrasonic treatment time, making the preparation process complex and time-consuming. Summary of the Invention

[0010] The purpose of this invention is to overcome the shortcomings of the prior art and provide a metal ion complexing agent, a metronidazole gel formulation, and a preparation method thereof. This invention can improve the phenomena of yellowing, decreased viscosity, growth of related substances, and precipitation of raw materials in the remaining gel after opening and use of metronidazole gel, ensuring the safety and effectiveness of the remaining gel after opening and avoiding waste of metronidazole gel during use.

[0011] The present invention is achieved through the following technical solution: a metal ion complexing agent for metronidazole gel formulation is provided, which is composed of a first component and a second component; The first component is selected from at least one of disodium edetate, calcium sodium edetate, and tetrasodium edetate; The second component is selected from at least one of sodium tartrate and sodium citrate; The mass ratio of the first component to the second component is 8:1 to 1:6.

[0012] Furthermore, the complexing agent is composed of disodium edetate and sodium tartrate.

[0013] A metronidazole gel formulation is also provided, comprising, by weight percentage, 0.75% metronidazole, 0.5-3 wt% gel matrix, 0.5-5.5 wt% humectant, 0.01-0.15 wt% metal ion chelating agent, 0.01-0.18 wt% antibacterial agent, 0.04-0.16 wt% pH adjuster, and the balance being solvent; wherein the total weight percentage of the above raw materials is 100%.

[0014] Furthermore, the metal ion complexing agent is the metal ion complexing agent described above for metronidazole gel formulation.

[0015] Preferably, the gel matrix is ​​selected from at least one of carbomer, sodium alginate, tragacanth gum, and gelatin.

[0016] Preferably, the moisturizer is selected from at least one of propylene glycol, glycerin, butylene glycol, and sorbitol.

[0017] Preferably, the pH adjuster is selected from at least one of sodium hydroxide, sodium carbonate, and sodium bicarbonate.

[0018] Finally, a method for preparing the above-mentioned metronidazole gel formulation is provided, the method comprising the following steps: Step 1) Weigh the gel matrix according to the above mass percentage, disperse the gel matrix in a portion of the solvent under stirring, and allow it to swell fully to form a uniform viscous dispersion. Step 2) Under heating and stirring conditions, metronidazole, humectant, metal ion complexing agent and antibacterial agent are dissolved in the remaining solvent in sequence to obtain a mixture. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to make it fully contact the swollen gel matrix particles; then add an aqueous solution of pH adjuster, which neutralizes the acidic groups on the gel matrix molecular chains by hydroxide ions, induces them to dissociate and extend, and cross-link with each other in the aqueous phase to form a three-dimensional network structure, which finally encapsulates all liquid phase components. Continue stirring until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

[0019] Further, in step 2), the heating temperature is 50°C.

[0020] Further, in step 3), the aqueous solution of the pH adjuster is added at a linear rate for 5 to 15 minutes; and after the addition is complete, the mixture is stirred continuously for 20 to 40 minutes.

[0021] Beneficial effects This invention, by determining the combination of metal ion complexing agents and the proportion of each component, can improve the phenomena of yellowing, decreased viscosity, growth of related substances, and precipitation of raw materials in the remaining gel after opening and use of metronidazole gel, thus ensuring the safety and effectiveness of the remaining gel after opening and avoiding waste of metronidazole gel during use.

[0022] The gel preparation process of this invention is simple, requires no secondary pH adjustment, and has high production efficiency. Attached Figure Description

[0023] Figure 1 The samples prepared in Examples 1 to 6 are observed under 50x microscope polarized light conditions; Figure 2 The sample prepared in Comparative Example 1 was observed under 50x microscope polarized light conditions. Figure 3 The sample prepared in Comparative Example 2 was observed under 50x microscope polarized light conditions. Figure 4 The sample prepared in Comparative Example 3 was observed under 50x microscope polarized light conditions. Figure 5 The sample prepared in Comparative Example 4 was observed under 50x microscope polarized light conditions. Figure 6 The sample prepared in Comparative Example 5 was observed under 50x microscope polarized light conditions. Figure 7 The sample prepared in Comparative Example 6 was observed under 50x microscope polarized light conditions. Figure 8 The sample prepared in Comparative Example 7 was observed under 50x microscope polarized light conditions. Figure 9 The sample prepared in Comparative Example 8 was observed under 50x microscope polarized light conditions. Figure 10 The image shows the state of the sample prepared in Comparative Example 9 under 50x microscope polarized light conditions. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0025] Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of this invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0026] Unless otherwise specified, the reagents and raw materials used in the embodiments and comparative examples of this invention are commercially available.

[0027] Example 1 A metal ion complexing agent for metronidazole gel formulations, comprising disodium edetate and sodium tartrate, wherein the mass ratio of disodium edetate to sodium tartrate is 4:1.

[0028] A method for preparing a metronidazole gel formulation, the method comprising the following steps: Step 1) Weigh 0.65% carbomer and disperse it in 42% purified water with stirring to allow it to fully hydrate and swell, forming a uniform viscous dispersion. Step 2) Under heating and stirring conditions at 50°C, 0.75% metronidazole, 3.0% propylene glycol, 0.04% disodium edetate, 0.01% sodium tartrate, 0.08% methylparaben, and 0.02% propylparaben are dissolved in the remaining water in sequence to prepare a mixed solution. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to ensure full contact with the swollen gel matrix particles; then add a 1.0% sodium hydroxide aqueous solution at a linear rate over 5 min. The hydroxide ions neutralize the acidic groups on the gel matrix molecular chains, inducing their dissociation and extension, and cross-linking in the aqueous phase to form a three-dimensional network structure, ultimately encapsulating all liquid phase components. After the sodium hydroxide aqueous solution is completely added, continue stirring for 30 min until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

[0029] Example 2 A metal ion complexing agent for metronidazole gel formulation, which is composed of disodium edetate and sodium tartrate; the mass ratio of disodium edetate to sodium tartrate is 6.5:1.

[0030] A method for preparing a metronidazole gel formulation, the method comprising the following steps: Step 1) Weigh 1.3% carbomer and disperse it in 42% purified water with stirring to allow it to fully hydrate and swell, forming a uniform viscous dispersion. Step 2) Under heating and stirring conditions at 50°C, 0.75% metronidazole, 3.5% propylene glycol, 0.026% disodium edetate, 0.004% sodium tartrate, 0.15% methylparaben, and 0.005% propylparaben are dissolved in the remaining water in sequence to prepare a mixed solution. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to ensure full contact with the swollen gel matrix particles; then add a 1.5% sodium hydroxide aqueous solution at a linear rate over 5 minutes. The hydroxide ions neutralize the acidic groups on the gel matrix molecular chains, inducing their dissociation and extension, and cross-linking in the aqueous phase to form a three-dimensional network structure, ultimately encapsulating all liquid phase components. After the sodium hydroxide aqueous solution is completely added, continue stirring for 30 minutes until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

[0031] Example 3 A metal ion complexing agent for metronidazole gel formulation, which is composed of disodium edetate and sodium tartrate; the mass ratio of disodium edetate to sodium tartrate is 0.15:1.

[0032] A method for preparing a metronidazole gel formulation, the method comprising the following steps: Step 1) Weigh 1.0% carbomer and disperse it in 42% purified water with stirring to allow it to fully hydrate and swell, forming a uniform viscous dispersion. Step 2) Under heating and stirring conditions at 50°C, 0.75% metronidazole, 1.2% propylene glycol, 0.004% disodium edetate, 0.026% sodium tartrate, 0.14% methylparaben, and 0.04% propylparaben are dissolved in the remaining water in sequence to prepare a mixed solution. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to ensure full contact with the swollen gel matrix particles; then add an aqueous solution of 1.5% sodium bicarbonate at a linear rate for 5 minutes. The hydroxide ions neutralize the acidic groups on the molecular chains of the gel matrix, inducing their dissociation and extension, and cross-linking in the aqueous phase to form a three-dimensional network structure, ultimately encapsulating all liquid phase components. After the aqueous solution of sodium hydroxide is added, continue stirring for 30 minutes until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

[0033] Example 4 A metal ion complexing agent for metronidazole gel formulation, which is composed of disodium edetate and sodium tartrate; the mass ratio of disodium edetate to sodium tartrate is 0.15:1.

[0034] A method for preparing a metronidazole gel formulation, the method comprising the following steps: Step 1) Weigh 0.65% tragacanth gum and disperse it in 42% purified water under stirring to allow it to fully hydrate and swell, forming a uniform viscous dispersion. Step 2) Under heating and stirring conditions at 50°C, 0.75% metronidazole, 3.0% glycerol, 0.016% disodium edetate, 0.104% sodium tartrate, 0.08% methylparaben, and 0.02% butylparaben are dissolved in the remaining water in sequence to prepare a mixture. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to ensure full contact with the swollen gel matrix particles; then add 1.2% sodium carbonate aqueous solution at a linear rate over 5 min. The hydroxide ions neutralize the acidic groups on the gel matrix molecular chains, inducing their dissociation and extension, and cross-linking in the aqueous phase to form a three-dimensional network structure, ultimately encapsulating all liquid phase components. After the sodium hydroxide aqueous solution is added, continue stirring for 30 min until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

[0035] Example 5 A metal ion complexing agent for metronidazole gel formulation, which is composed of disodium edetate and sodium tartrate; the mass ratio of disodium edetate to sodium tartrate is 6.5:1.

[0036] A method for preparing a metronidazole gel formulation, the method comprising the following steps: Step 1) Weigh 0.55% gelatin and disperse it in 42% purified water under stirring to allow it to fully hydrate and swell, forming a uniform viscous dispersion. Step 2) Under heating and stirring conditions at 50°C, 0.75% metronidazole, 3.0% sorbitol, 0.104% disodium edetate, 0.016% sodium tartrate, and 0.14% phenoxyethanol are dissolved in the remaining water in sequence to prepare a mixed solution. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to ensure full contact with the swollen gel matrix particles; then add a 1.0% sodium hydroxide aqueous solution at a linear rate over 5 min. The hydroxide ions neutralize the acidic groups on the gel matrix molecular chains, inducing their dissociation and extension, and cross-linking in the aqueous phase to form a three-dimensional network structure, ultimately encapsulating all liquid phase components. After the sodium hydroxide aqueous solution is completely added, continue stirring for 30 min until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

[0037] Example 6 A metal ion complexing agent for metronidazole gel formulations, comprising sodium calcium edetate and sodium citrate, wherein the mass ratio of sodium calcium edetate to sodium citrate is 4:1.

[0038] A method for preparing a metronidazole gel formulation, the method comprising the following steps: Step 1) Weigh 0.85% sodium alginate and disperse the sodium alginate in 42% purified water under stirring to allow it to fully hydrate and swell, forming a uniform viscous dispersion. Step 2) Under heating and stirring conditions at 50°C, 0.75% metronidazole, 4.5% butanediol, 0.04% calcium sodium edetate, 0.01% sodium citrate, and 0.14% benzyl alcohol are dissolved in the remaining water in sequence to prepare a mixed solution. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to ensure full contact with the swollen gel matrix particles; then add a 1.0% sodium hydroxide aqueous solution at a linear rate over 5 min. The hydroxide ions neutralize the acidic groups on the gel matrix molecular chains, inducing their dissociation and extension, and cross-linking in the aqueous phase to form a three-dimensional network structure, ultimately encapsulating all liquid phase components. After the sodium hydroxide aqueous solution is completely added, continue stirring for 30 min until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

[0039] Comparative group The raw material formulation of the comparative example, which differs from the above embodiments, is as follows:

[0040] Compared with Example 1, the preparation method of Comparative Example 10 is as follows: the viscous dispersion obtained in step 1) is first mixed with a portion of pH adjusting agent solution, then the mixture obtained in step 2) is added to the viscous dispersion obtained in step 1) and mixed evenly, and then another portion of pH adjusting agent solution is added to finally form a gel.

[0041] Effect Example Gel properties results Method of evaluation: The samples of the examples and comparative examples were opened once a day. After five days, about 1g of sample was squeezed out onto white paper and the gel properties were observed.

[0042] The results of the gel properties examination are shown in the table below. The gel should be colorless to pale yellow.

[0043]

[0044] in conclusion: In Examples 1-6, when the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01-0.15 wt%, and the proportion of disodium edetate and sodium tartrate is in the range of 8-1:1-6, the gel near the tube opening is still a colorless gel after five days of opening, which meets the requirements.

[0045] Comparative Example 1: When the metal ion complexing agent of the gel is disodium edetate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, the gel near the tube opening turns into a yellow gel five days after opening, which does not meet the requirements.

[0046] Comparative Example 2: When the metal ion complexing agent of the gel is sodium tartrate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, the gel near the tube opening turns into a yellow gel five days after opening, which does not meet the requirements.

[0047] Comparative Example 3: When the metal ion complexing agent of the gel is a combination of calcium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, and the proportion of calcium edetate and sodium tartrate is in the range of 8~1:1~6, the gel near the tube opening turns into a yellow gel after five days of opening, which does not meet the requirements.

[0048] Comparative Example 4: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is less than 0.01~0.15wt%, the gel near the tube opening turns into a yellow gel five days after opening, which does not meet the requirements.

[0049] Comparative Example 5: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel near the tube opening turns into a yellow gel after five days of opening, which does not meet the requirements.

[0050] Comparative Example 6: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel near the tube opening turns into a yellow gel after five days of opening, which does not meet the requirements.

[0051] Comparative Example 7: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel near the tube opening turns into a yellow gel after five days of opening, which does not meet the requirements.

[0052] Comparative Example 8: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel near the tube opening turns into a yellow gel after five days of opening, which does not meet the requirements.

[0053] Comparative Example 9: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent exceeds the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is within the range of 8~1:1~6, the gel near the tube opening is still a colorless gel after five days of opening, which meets the requirements. However, the amount of metal ion complexing agent exceeds the maximum daily dosage of topical preparations specified by the FDA, increasing the risk of adverse reactions.

[0054] Gel viscosity results Method of evaluation: The samples of the examples and comparative examples were opened once a day. After five days, about 1g of sample was squeezed out and the gel viscosity was measured using a cone-plate viscometer.

[0055] The results of the gel viscosity study are shown in the table below:

[0056] in conclusion: 1. In Examples 1-6, when the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01-0.15wt%, and the proportion of disodium edetate and sodium tartrate is in the range of 8-1:1-6, the gel viscosity near the tube opening is in the range of 600-700mPa·s five days after opening.

[0057] 2. Comparative Example 1: When the metal ion complexing agent of the gel is disodium edetate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0058] 3. Comparative Example 2: When the metal ion complexing agent of the gel is sodium tartrate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0059] 4. Comparative Example 3: When the metal ion complexing agent of the gel is a combination of calcium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, and the proportion of calcium edetate and sodium tartrate is in the range of 8~1:1~6, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0060] 5. Comparative Example 4: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is less than 0.01%~0.15wt%, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0061] 6. Comparative Example 5: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0062] 7. Comparative Example 6: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0063] 8. Comparative Example 7: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0064] 9. Comparative Example 8: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the viscosity of the gel near the tube opening decreases significantly after five days of opening, resulting in a poor application experience.

[0065] 10. Comparative Example 9: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent exceeds the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is in the range of 8~1:1~6, the gel viscosity near the tube opening is in the range of 600~700mPa·s five days after opening. However, the amount of metal ion complexing agent exceeds the maximum daily dosage of topical preparations stipulated by the FDA, and the risk of adverse reactions increases.

[0066] Results of gel-related substances Methods of Investigation: Samples from the examples and comparative examples were opened daily. After five days, approximately 1g of sample was extruded and used to detect relevant substances. The detection methods are as follows: Method: High performance liquid chromatography (ChP 2025 edition, Part IV, General Rule 0512).

[0067] Chromatographic conditions: Column: Octadecylsilane-bonded silica gel as the packing material (Agilent ZORBAX Eclipse Plus C18, 4.6 mm × 250 mm, 5 μm or equivalent column). Detection wavelength: 319nm; Flow rate: 1.0 ml / min Column temperature: 30℃; Injection volume: 30µl; Mobile phase A: methanol-water (20:80); Mobile phase B: Methanol; The results of the relevant substance test are as follows:

[0068] in conclusion: 1. In Examples 1-6, when the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, and the proportion of disodium edetate and sodium tartrate is in the range of 8~1:1~6, there is no significant increase in gel-related substances near the tube opening five days after opening.

[0069] 2. Comparative Example 1: When the metal ion complexing agent of the gel is disodium edetate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, the gel-related substances near the tube opening increase rapidly five days after opening.

[0070] 3. Comparative Example 2: When the metal ion complexing agent of the gel is sodium tartrate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, the gel-related substances near the tube opening increase rapidly five days after opening.

[0071] 4. Comparative Example 3: When the metal ion complexing agent of the gel is a combination of calcium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, and the proportion of calcium edetate and sodium tartrate is in the range of 8~1:1~6, the gel-related substances near the tube opening increase rapidly five days after opening.

[0072] 5. Comparative Example 4: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is less than 0.01~0.15wt%, the gel-related substances near the tube opening increase rapidly five days after opening.

[0073] 6. Comparative Example 5: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel-related substances near the tube opening increase rapidly five days after opening.

[0074] 7. Comparative Example 6: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel-related substances near the tube opening increase rapidly after five days of opening.

[0075] 8. Comparative Example 7: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel-related substances near the tube opening increase rapidly five days after opening.

[0076] 9. Comparative Example 8: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, the gel-related substances near the tube opening increase rapidly after five days of opening.

[0077] 10. Comparative Example 9: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent exceeds the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is in the range of 8~1:1~6, there is no significant increase in gel-related substances near the tube opening five days after opening. However, the amount of metal ion complexing agent exceeds the maximum daily dosage of topical preparations stipulated by the FDA, and the risk of adverse reactions increases.

[0078] Results of gel microstructure Methods of evaluation: Samples from the examples and comparative examples were opened once daily. After five days, approximately 1g of sample was squeezed out and observed under a polarizing microscope. The active pharmaceutical ingredient (API) exhibited a luminescent structure under the polarizing microscope, indicating whether API precipitation had occurred. Gels without API precipitation showed no luminescent structure under polarized light; however, if API precipitation occurred, a luminescent structure could be observed under polarized light.

[0079] For detailed measurement results, please refer to the attached diagram in the instruction manual.

[0080] in conclusion: 1. In Examples 1-6, when the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, and the proportion of disodium edetate and sodium tartrate is in the range of 8~1:1~6, no raw material drug precipitation is observed in the gel near the tube opening five days after opening.

[0081] 2. Comparative Example 1: When the metal ion complexing agent of the gel is disodium edetate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, a small amount of raw material precipitates out of the gel near the tube opening five days after opening.

[0082] 3. Comparative Example 2: When the metal ion complexing agent of the gel is sodium tartrate alone, and the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, a small amount of raw material precipitates out of the gel near the tube opening five days after opening.

[0083] 4. Comparative Example 3: When the metal ion complexing agent of the gel is a combination of calcium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, and the proportion of calcium edetate and sodium tartrate is in the range of 8~1:1~6, a small amount of raw material precipitates out of the gel near the tube opening five days after opening.

[0084] 5. Comparative Example 4: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent is less than 0.01~0.15wt%, a certain amount of raw material precipitates out of the gel near the tube opening five days after opening.

[0085] 6. Comparative Example 5: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, a small amount of raw material precipitates out of the gel near the tube opening five days after opening.

[0086] 7. Comparative Example 6: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, a small amount of raw material precipitates out near the tube opening after five days of opening.

[0087] 8. Comparative Example 7: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, a small amount of raw material precipitates out of the gel near the tube opening five days after opening.

[0088] 9. Comparative Example 8: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, the proportion of the metal ion complexing agent is in the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is not in the range of 8~1:1~6, a small amount of raw material precipitates out near the tube opening after five days of opening.

[0089] 10. Comparative Example 9: When the metal ion complexing agent of the gel is a combination of disodium edetate and sodium tartrate, and the proportion of the metal ion complexing agent exceeds the range of 0.01~0.15wt%, but the proportion of disodium edetate and sodium tartrate is in the range of 8~1:1~6, no raw material drug precipitation is observed near the tube opening of the gel five days after opening. However, the amount of metal ion complexing agent exceeds the maximum daily dosage of topical preparations stipulated by the FDA, and the risk of adverse reactions increases.

[0090] Gel preparation process time Method of investigation: The time taken during the gel preparation process of Examples 1-6 and Comparative Example 10 was recorded.

[0091] The results are as follows:

[0092] in conclusion: Example 1 uses the preparation method of the present invention, and the sample preparation time is about 2.5 hours. Comparative Example 10 uses the conventional preparation method, and the sample preparation time is about 3.2 hours. The preparation time for one batch of samples can be shortened by about 0.7 hours, and the production efficiency is greatly improved.

[0093] In summary, the metal ion complexing agent in the metronidazole gel of this invention effectively leverages the synergistic effect of its two components, maintaining the stability of the remaining metronidazole gel within the package after opening and protecting the safety and efficacy of the formulation. Typically, the lone pair electrons of the complexing agent coordinate with the empty orbitals of the metal ion to form a stable chelate ring, making it difficult for the metal ion to exert its catalytic effect and thus inhibiting the growth of impurities. The ligand cavity of the metal ion complexing agent is specific, exhibiting high selectivity for specific metal ions, and the chelating effect of the surrounding environment, such as temperature, pH, and oxygen levels, significantly affects the complexing effect, making it difficult for a single metal ion complexing agent to exert a good stabilizing effect. However, the two-component metal ion complexing agent proposed in this invention can compensate for the shortcomings of a single complexing agent, better leveraging its synergistic effect.

[0094] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A metal ion complexing agent for metronidazole gel formulations, characterized in that, It is composed of a first component and a second component; The first component is selected from at least one of disodium edetate, calcium sodium edetate, and tetrasodium edetate; The second component is selected from at least one of sodium tartrate and sodium citrate; The mass ratio of the first component to the second component is 8:1 to 1:

6.

2. The metal ion complexing agent for metronidazole gel formulation according to claim 1, characterized in that, The complexing agent is composed of disodium edetate and sodium tartrate.

3. A metronidazole gel formulation, characterized in that, By weight percentage, the raw materials include 0.75% metronidazole, 0.5~1.5wt% gel matrix, 0.5%~5.5wt% humectant, 0.01~0.15wt% metal ion complexing agent, 0.01~0.18wt% antibacterial agent, 0.04~0.16wt% pH adjuster, and the balance being solvent; wherein, the total weight percentage of the above raw materials is 100%.

4. The metronidazole gel formulation according to claim 3, characterized in that, The metal ion complexing agent is the metal ion complexing agent for metronidazole gel formulation as described in claim 1 or 2.

5. The metronidazole gel formulation according to claim 3, characterized in that, The gel matrix is ​​selected from at least one of carbomer, sodium alginate, tragacanth gum, and gelatin.

6. The metronidazole gel formulation according to claim 3, characterized in that, The moisturizer is selected from at least one of propylene glycol, glycerin, butylene glycol, and sorbitol; And / or, the antibacterial agent is selected from at least one of methylparaben, ethylparaben, propylparaben, butylparaben, phenoxyethanol, or benzyl alcohol.

7. The metronidazole gel formulation according to claim 3, characterized in that, The pH adjuster is selected from at least one of sodium hydroxide, sodium carbonate, and sodium bicarbonate.

8. A method for preparing the metronidazole gel formulation according to claim 4, characterized in that, The method includes the following steps: Step 1) Weigh the gel matrix according to the above mass percentage, disperse the gel matrix in a portion of the solvent under stirring, and allow it to swell fully to form a uniform viscous dispersion. Step 2) Under heating and stirring conditions, metronidazole, humectant, metal ion complexing agent and antibacterial agent are dissolved in the remaining solvent in sequence to obtain a mixture. Step 3) While stirring, add the mixture obtained in Step 2) to the viscous dispersion obtained in Step 1) to make it fully contact the swollen gel matrix particles; then add an aqueous solution of pH adjuster, which neutralizes the acidic groups on the gel matrix molecular chains by hydroxide ions, induces them to dissociate and extend, and cross-link with each other in the aqueous phase to form a three-dimensional network structure, which finally encapsulates all liquid phase components. Continue stirring until a stable gel structure is formed. Step 4) Fill the gel obtained in Step 3) into an aluminum medicinal ointment tube, seal the end, and you have the product.

9. The method for preparing the metronidazole gel formulation according to claim 7, characterized in that, In step 2), the heating temperature is 50°C.

10. The method for preparing the metronidazole gel formulation according to claim 7, characterized in that, In step 3), the aqueous solution of the pH adjuster is added at a linear rate over a period of 5 to 15 minutes; and after the addition is complete, the mixture is stirred continuously for 20 to 40 minutes.

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