Lidocaine gel plaster and method for improving stability of lidocaine gel plaster

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly provides a lidocaine gel plaster and a method for improving the stability of the lidocaine gel plaster, only an antioxidant needs to be added into a medicine package, so that the medicine stability in the lidocaine gel plaster is high, the generation of impurities is effectively avoided or reduced, the impurity content can reach 0.09, and the lidocaine gel plaster has the advantages that the stability of the lidocaine gel plaster is improved; the medicine stability, the storage stability and the safety are higher.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a lidocaine gel patch and a method for improving the stability of the lidocaine gel patch. Background Art

[0002] Lidocaine gel patch was first approved for marketing in the United States in 1999 for the treatment of postherpetic neuralgia. It is currently the only topical skin patch for the treatment of postherpetic neuralgia. It can act directly on the painful area, is easy to use, leaves no residue, and has a cooling effect, which patients feel good about. Currently, lidocaine gel patch has been marketed in many countries around the world.

[0003] However, since the formulation of gel patches is relatively complex, mostly composed of ingredients such as matrix materials, pH regulators, cross-linking regulators, cross-linking agents, moisturizers and water, there are many materials in the preparation, and there are interactions between different materials. In addition, reactions are more likely to occur in the presence of water, resulting in gel patch preparations being prone to produce more impurities.

[0004] Research has found that many lidocaine gel patches currently on the market still produce a lot of impurities at high temperatures of 60°C or 40°C, and some impurities have exceeded the identification limit (0.20%), and safety in use cannot be guaranteed. Therefore, developing a lidocaine gel patch with high stability and low impurity levels is an urgent problem to be solved in this field. Summary of the invention

[0005] In view of the deficiencies in the prior art, the object of the present invention is to provide a lidocaine gel patch and a method for improving the stability of the lidocaine gel patch, by adding an antioxidant to the drug packaging, the drug stability in the lidocaine gel patch is high, the generation of impurities is effectively avoided or reduced, and the corresponding drug stability, storage stability and safety are increased.

[0006] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0007] In a first aspect, the present invention provides a lidocaine gel patch, characterized in that an antioxidant is added into the packaging of the lidocaine gel patch.

[0008] The present invention has found in research that sources of impurities generated during the preparation and storage of the gel patch include oxidation reactions of the drug, interactions between different excipients, etc. Therefore, the lidocaine gel patch provided by the present invention introduces an antioxidant in the packaging, which can inhibit the oxidation reaction of the drug, interactions between different excipients, etc., thereby avoiding or reducing the generation of impurities and improving the stability of the drug.

[0009] In some embodiments, the antioxidant is mainly a substance having a competitive oxidizing effect, including reducing iron powder.

[0010] Preferably, the antioxidant comprises reducing iron powder.

[0011] In some embodiments, the antioxidant capacity of the antioxidant, that is, the amount of oxygen that can be absorbed per bag, is 10 mL-100 mL. Within this range, the impurities in the lidocaine gel patch are significantly reduced.

[0012] Preferably, the antioxidant capacity of the antioxidant is 30 mL.

[0013] In some embodiments, the antioxidant is provided in any form.

[0014] In some embodiments, the antioxidant is provided in the form of an antioxidant packet and / or an antioxidant sheet and / or an antioxidant bar.

[0015] In some embodiments, because the gel patch contains a large amount of water (about 30%-45%), the antioxidant does not include a hygroscopic desiccant, such as anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, etc.

[0016] In some embodiments, the lidocaine gel patch includes the following components in parts by mass: 0.01 to 20.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.001 to 3.0 parts of a cross-linking agent, 0.001 to 3.0 parts of a cross-linking regulator, 0.01 to 10.0 parts of a pH regulator, 0.1 to 30.0 parts of an aqueous polymer compound, 5.0 to 45.0 parts of a moisturizer, 10 to 80 parts of water, and 1.0 to 30.0 parts of a solvent.

[0017] Preferably, the lidocaine gel patch comprises the following components in parts by mass:

[0018] 2-10.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.01-1.0 parts of a cross-linking agent, 0.01-1.0 parts of a cross-linking regulator, 0.5-5.0 parts of a pH regulator, 3.0-20.0 parts of an aqueous polymer compound, 10.0-30.0 parts of a humectant, 20-60 parts of water, and 2.0-20.0 parts of a solvent.

[0019] In some embodiments, the cross-linking agent includes any one or a combination of at least two of aluminum glycolate, aluminum hydroxide, aluminum chloride, aluminum citrate, synthetic aluminum silicate, aluminum glutamate, potassium aluminum sulfate, calcium hydroxide, and calcium chloride; and / or the cross-linking regulator includes any one or a combination of at least two of tartrate, citrate, phosphate, malate, edetate, metaphosphate, and gluconic acid, and the salt is any one or a combination of at least two of potassium salt, sodium salt, and calcium salt; and / or the pH regulator is an organic acid and / or an inorganic acid, and the organic acid includes formic acid, acetic acid, citric acid, The inorganic acid includes phosphoric acid and / or hydrochloric acid; and / or the aqueous polymer compound includes any one or a combination of at least two of polyacrylic acid partially neutralized product, polyacrylic acid and its salt, polyvinyl alcohol, gum arabic, gelatin, carbomer, polyvinyl pyrrolidone, acrylic acid grafted starch, cellulose derivatives; the humectant includes any one or a combination of at least two of glycerol, propylene glycol, polyethylene glycol, fructose, sorbitol, xylitol, urea; and / or the solvent includes any one or a combination of at least two of propylene glycol and butylene glycol.

[0020] In a second aspect, the present invention provides a method for improving the stability of a lidocaine gel patch, comprising adding an antioxidant into the lidocaine gel patch packaging.

[0021] In some embodiments, the antioxidant is mainly a substance having a competitive oxidizing effect, including reducing iron powder.

[0022] Preferably, the antioxidant comprises reducing iron powder.

[0023] In some embodiments, the antioxidant capacity of the antioxidant is 10 mL-100 mL, within which range the impurities in the lidocaine gel patch are significantly reduced.

[0024] Preferably, the antioxidant capacity of the antioxidant is 30 mL.

[0025] In some embodiments, the antioxidant is provided in any form.

[0026] In some embodiments, the antioxidant is provided in the form of an antioxidant packet and / or an antioxidant sheet and / or an antioxidant bar.

[0027] In some embodiments, because the gel patch contains a large amount of water (about 30%-45%), the antioxidant does not include a hygroscopic desiccant, such as anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, etc.

[0028] In some embodiments, the lidocaine gel patch includes the following components in parts by mass: 0.01 to 20.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.001 to 3.0 parts of a cross-linking agent, 0.001 to 3.0 parts of a cross-linking regulator, 0.01 to 10.0 parts of a pH regulator, 0.1 to 30.0 parts of an aqueous polymer compound, 5.0 to 45.0 parts of a moisturizer, 10 to 80 parts of water, and 1.0 to 30.0 parts of a solvent.

[0029] Preferably, the lidocaine gel patch comprises the following components in parts by mass:

[0030] 2-10.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.01-1.0 parts of a cross-linking agent, 0.01-1.0 parts of a cross-linking regulator, 0.5-5.0 parts of a pH regulator, 3.0-20.0 parts of an aqueous polymer compound, 10.0-30.0 parts of a humectant, 20-60 parts of water, and 2.0-20.0 parts of a solvent.

[0031] In some embodiments, the cross-linking agent includes any one or a combination of at least two of aluminum glycolate, aluminum hydroxide, aluminum chloride, aluminum citrate, synthetic aluminum silicate, aluminum glutamate, potassium aluminum sulfate, calcium hydroxide, and calcium chloride; and / or the cross-linking regulator includes any one or a combination of at least two of tartrate, citrate, phosphate, malate, edetate, metaphosphate, and gluconic acid, and the salt is any one or a combination of at least two of potassium salt, sodium salt, and calcium salt; and / or the pH regulator is an organic acid and / or an inorganic acid, and the organic acid includes formic acid, acetic acid, citric acid, Acid, tartaric acid, lactic acid, any one or a combination of at least two, the inorganic acid includes phosphoric acid and / or hydrochloric acid; and / or the aqueous polymer compound includes partially neutralized polyacrylic acid, polyacrylic acid and its salt, polyvinyl alcohol, gum arabic, gelatin, carbomer, polyvinyl pyrrolidone, acrylic acid grafted starch, cellulose derivatives, any one or a combination of at least two; the moisturizer includes glycerol, propylene glycol, polyethylene glycol, fructose, sorbitol, xylitol, urea, any one or a combination of at least two; and / or the solvent includes propylene glycol, butylene glycol, any one or a combination of at least two. Compared with the prior art, the present invention has the following beneficial effects:

[0032] The method of the present invention does not require the addition of antioxidants or nitrogen filling, vacuuming and other operations in the lidocaine gel patch prescription. It only requires the addition of antioxidants in the drug packaging, so that the lidocaine gel patch has high drug stability, effectively avoids or reduces the generation of impurities, and the impurity content can reach 0.09, with higher drug stability, storage stability and safety. DETAILED DESCRIPTION

[0033] The technical scheme of the present invention is further described below by specific embodiments. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention. The terms "comprise", "include", "have", "contain" or any other variations thereof as used herein are intended to cover non-exclusive inclusions. For example, a composition, step, method, product or device comprising the listed elements need not be limited to those elements, but may also include other elements not explicitly listed or elements inherent to such a composition, step, method, product or device.

[0034] "Optionally" or "either" means that the subsequently described matter or event can or cannot occur, and that the description includes instances where the event occurs and instances where it does not.

[0035] The indefinite articles "a" and "an" before the elements or components of the present invention have no limitation on the quantity requirements (i.e. the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the elements or components in the singular form also include the plural form, unless the quantity obviously refers to the singular form only.

[0036] In the present invention, the features defined as "first" or "second" may include one or more of the features explicitly or implicitly, and are used to distinguish and describe the features, without distinction of order or importance. In the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0037] HPLC conditions:

[0038] Mobile phase A: pH 7.4 potassium dihydrogen phosphate solution, mobile phase B: acetonitrile, mobile phase A: mobile phase B = 60:40;

[0039] Detection wavelength: 230nm;

[0040] Flow rate: 1ml / min;

[0041] Chromatographic column: Waters Xbridge C18 (3.5 μm 4.6*150 mm);

[0042] Injection volume: 20ul;

[0043] Column temperature: 40°C;

[0044] Elution mode: isocratic elution.

[0045] Preparation Example

[0046] Preparation Examples 1-5

[0047] Table 1 Lidocaine Gel Patch Preparation Examples 1-5 Prescription Table

[0048]

[0049] Weigh the API and add it to the API solvent (propylene glycol), heat and dissolve it, then add the water-based polymer compound, aluminum glycolate, disodium edetate, and moisturizer and stir and mix them evenly as the suspension phase; add the pH adjuster into purified water and dissolve it as the aqueous solution phase, then add the aqueous solution phase to the prepared suspension phase and stir and mix them evenly to form a paste, and finally spread the paste on a polyester non-woven fabric and cover it with a layer of polypropylene film to form a sample. The prepared gel patch and the reduced iron powder package are placed in a paper / aluminum / polyethylene medicinal composite film and bag.

[0050] Stability Study Example

[0051] Stability Study Example 1 Stability Study of Commercially Available Lidocaine Gel Patch

[0052] The commercially available lidocaine gel patch was placed in the original packaging at a high temperature of 60°C for 30 days and the impurity changes were detected by high performance liquid chromatography. The results are shown in Table 2:

[0053] Table 2 Changes in impurity content of commercially available lidocaine gel patches

[0054]

[0055] Stability Study Example 2 Stability Study of Lidocaine Gel Patch

[0056] No antioxidant was placed in the lidocaine gel patch package prepared in Preparation Example 1, and the packaged product was placed at a high temperature of 60° C. for 30 days and the change of impurities was detected by high performance liquid chromatography.

[0057] Stability Study Example 3 Stability Study of Lidocaine Gel Patch

[0058] An antioxidant (10 ml) was placed in the lidocaine gel patch package prepared in Preparation Example 2, and the packaged product was placed at a high temperature of 60° C. for 30 days, and the change of impurities was detected by high performance liquid chromatography.

[0059] Stability Study Example 4 Stability Study of Lidocaine Gel Patch

[0060] An antioxidant (20 ml) was placed in the lidocaine gel patch package prepared in Preparation Example 3, and the packaged product was placed at a high temperature of 60° C. for 30 days, and the change of impurities was detected by high performance liquid chromatography.

[0061] Stability Study Example 5 Stability Study of Lidocaine Gel Patch

[0062] An antioxidant (30 ml) was placed in the lidocaine gel patch package prepared in Preparation Example 4, and the packaged product was placed at a high temperature of 60° C. for 30 days, and the change of impurities was detected by high performance liquid chromatography.

[0063] Stability Study Example 6 Stability Study of Lidocaine Gel Patch

[0064] An antioxidant (100 ml) was placed in the lidocaine gel patch package prepared in Preparation Example 5, and the packaged product was placed at a high temperature of 60° C. for 30 days, and the change of impurities was detected by high performance liquid chromatography.

[0065] Table 3 Stability Study Example 2 - Stability Study Example 6 Lidocaine Gel Patch Impurity Content Changes

[0066]

[0067] From the results in Table 2 and Table 3, it can be seen that the total impurities of the commercially available lidocaine gel patch after being placed at a high temperature of 60°C for 30 days are between 0.39 and 0.55; in the stability study Example 2, the total impurities of the lidocaine gel patch without an antioxidant placed at a high temperature of 60°C for 30 days are 0.49; in the stability study Examples 3 to 6, the total impurities of the lidocaine gel patch with an antioxidant placed at a high temperature of 60°C for 30 days are significantly reduced.

[0068] Comparative Example

[0069] Table 4 Lidocaine Gel Patch Comparative Examples 1-3 Prescription Table

[0070]

[0071]

[0072] Weigh the API and add it to the API solvent (propylene glycol), heat to dissolve, then add the aqueous polymer compound, aluminum glyoxylate, disodium edetate, moisturizer, and antioxidant and stir and mix evenly to form a suspension phase; add the pH adjuster into purified water and dissolve it as an aqueous solution phase, then add the aqueous solution phase to the above-prepared suspension phase and stir and mix evenly to form a paste, finally spread the paste on a polyester non-woven fabric and cover it with a layer of polypropylene film to form a sample.

[0073] The lidocaine gel patch prepared in Comparative Examples 1-3 was placed at a high temperature of 60° C. for 30 days and the changes in impurities were detected using a high performance liquid chromatograph.

[0074] Table 5 Changes in impurity content in comparative examples 1-3

[0075]

[0076] From the results in Table 5, it can be seen that the total impurities of the lidocaine gel patch with added antioxidants after being placed at a high temperature of 60°C for 30 days are between 0.30% and 0.38%; in the stability study Example 2, the total impurities of the lidocaine gel patch without antioxidants after being placed at a high temperature of 60°C for 30 days are 0.49%; in the stability study Examples 3 to 6, the total impurities of the lidocaine gel patch with antioxidants after being placed at a high temperature of 60°C for 30 days are significantly lower.

Claims

1. A lidocaine gel patch, characterized in that: Antioxidants are added to the lidocaine gel patch packaging.

2. The lidocaine gel patch according to claim 1, characterized in that: The antioxidant includes reducing iron powder.

3. The lidocaine gel patch according to claim 1, characterized in that: The antioxidant capacity of the antioxidant is 10mL-100mL.

4. The lidocaine gel patch according to claim 1, characterized in that: The antioxidant is provided in the form of an antioxidant bag and / or an antioxidant sheet and / or an antioxidant bar.

5. The lidocaine gel patch according to claim 1, characterized in that: The antioxidant does not include a hygroscopic desiccant.

6. The lidocaine gel patch according to any one of claims 1 to 5, characterized in that: The lidocaine gel patch comprises the following components in parts by mass: 0.01-20.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.001-3.0 parts of a cross-linking agent, 0.001-3.0 parts of a cross-linking regulator, 0.01-10.0 parts of a pH regulator, 0.1-30.0 parts of an aqueous polymer compound, 5.0-45.0 parts of a humectant, 10-80 parts of water, and 1.0-30.0 parts of a solvent.

7. The lidocaine gel patch according to claim 6, characterized in that: The cross-linking agent includes any one or a combination of at least two of aluminum glycolate, aluminum hydroxide, aluminum chloride, aluminum citrate, synthetic aluminum silicate, aluminum glutamate, potassium aluminum sulfate, calcium hydroxide, and calcium chloride; and / or the cross-linking regulator includes any one or a combination of at least two of tartrate, citrate, phosphate, malate, edetate, metaphosphate, and gluconic acid, and the salt is any one or a combination of at least two of potassium salt, sodium salt, and calcium salt; and / or the pH regulator is an organic acid and / or an inorganic acid, and the organic acid includes formic acid, acetic acid, citric acid, tartaric acid , lactic acid, any one or a combination of at least two of them, the inorganic acid includes phosphoric acid and / or hydrochloric acid; and / or the aqueous polymer compound includes any one or a combination of at least two of partially neutralized polyacrylic acid, polyacrylic acid and its salts, polyvinyl alcohol, gum arabic, gelatin, carbomer, polyvinyl pyrrolidone, acrylic acid grafted starch, and cellulose derivatives; the humectant includes any one or a combination of at least two of glycerol, propylene glycol, polyethylene glycol, fructose, sorbitol, xylitol, and urea; and / or the solvent includes any one or a combination of at least two of propylene glycol and butylene glycol.

8. The lidocaine gel patch according to claim 7, characterized in that: The lidocaine gel patch comprises the following components in parts by mass: 2-10.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.01-1.0 parts of a cross-linking agent, 0.01-1.0 parts of a cross-linking regulator, 0.5-5.0 parts of a pH regulator, 3.0-20.0 parts of an aqueous polymer compound, 10.0-30.0 parts of a humectant, 20-60 parts of water, and 2.0-20.0 parts of a solvent.

9. A method for improving the stability of lidocaine gel patch, characterized in that: Antioxidants are added to the lidocaine gel patch packaging.

10. The method according to claim 9, characterized in that The antioxidant includes reducing iron powder.

11. The method according to claim 6, characterized in that The antioxidant capacity of the antioxidant is 10mL-100mL.

12. The method according to claim 9, characterized in that The antioxidant does not include a hygroscopic desiccant.

13. The method according to claim 9, characterized in that The antioxidant is provided in the form of an antioxidant bag and / or an antioxidant sheet and / or an antioxidant bar.

14. The method according to any one of claims 9 to 13, characterized in that: The lidocaine gel patch comprises the following components in parts by mass: 0.01-20.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.001-3.0 parts of a cross-linking agent, 0.001-3.0 parts of a cross-linking regulator, 0.01-10.0 parts of a pH regulator, 0.1-30.0 parts of an aqueous polymer compound, 5.0-45.0 parts of a humectant, 10-80 parts of water, and 1.0-30.0 parts of a solvent.

15. The method according to claim 14, characterized in that The cross-linking agent includes any one or a combination of at least two of aluminum glycolate, aluminum hydroxide, aluminum chloride, aluminum citrate, synthetic aluminum silicate, aluminum glutamate, potassium aluminum sulfate, calcium hydroxide, and calcium chloride; and / or the cross-linking regulator includes any one or a combination of at least two of tartrate, citrate, phosphate, malate, edetate, metaphosphate, and gluconic acid salts, and the salt is any one or a combination of at least two of potassium salt, sodium salt, and calcium salt; and / or The pH regulator is an organic acid and / or an inorganic acid, wherein the organic acid includes any one of formic acid, acetic acid, citric acid, tartaric acid, and lactic acid, or a combination of at least two thereof; the inorganic acid includes phosphoric acid and / or hydrochloric acid; and / or the aqueous polymer compound includes any one of partially neutralized polyacrylic acid, polyacrylic acid and its salt, polyvinyl alcohol, gum arabic, gelatin, carbomer, polyvinyl pyrrolidone, acrylic acid grafted starch, and cellulose derivatives, or a combination of at least two thereof; the moisturizer includes any one of glycerol, propylene glycol, polyethylene glycol, fructose, sorbitol, xylitol, and urea, or a combination of at least two thereof; and / or the solvent includes any one of propylene glycol and butylene glycol, or a combination of at least two thereof.

16. The method according to claim 15, characterized in that The lidocaine gel patch comprises the following components in parts by mass: 2-10.0 parts of lidocaine or a pharmaceutically acceptable salt thereof, 0.01-1.0 parts of a cross-linking agent, 0.01-1.0 parts of a cross-linking regulator, 0.5-5.0 parts of a pH regulator, 3.0-20.0 parts of an aqueous polymer compound, 10.0-30.0 parts of a humectant, 20-60 parts of water, and 2.0-20.0 parts of a solvent.

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