KR102132590B1 - A composition comprising local anesthetics and sodium polyacrylate - Google Patents

Abstract

The present invention relates to a percutaneous absorbent formulation comprising lidocaine or a pharmaceutically acceptable salt thereof, and sodium polyacrylate having a sodium substitution degree of 55 mole percent or more, and not an aqueous sorbitol solution and an aqueous polyacrylic acid solution.
The transdermal absorbent formulation of the present invention has excellent transdermal permeability and dissolution rate of lidocaine, and the property stability of the formulation is improved, and as it is capable of aging at room temperature in a packaged state, a large-scale facility for aging the formulation at a high temperature is unnecessary, thereby mass production of the formulation. There is an advantage that can significantly reduce the time and cost consumed.

Description

A composition comprising local anesthetics and sodium polyacrylate

The present invention relates to a transdermal absorbent preparation comprising lidocaine. Specifically, the present invention relates to a transdermal absorbent containing lidocaine and sodium polyacrylate, and having excellent transdermal permeability, dissolution rate and property stability, but capable of aging at room temperature in a packaged state.

Ideal local anesthesia/analgesics have no systemic toxicity at effective concentrations, rapid onset of action, and pharmacological action to persist for a period of time. In addition, topical anesthesia/analgesics are water soluble, stable in solution, sterile and sterilizable, and should be effective and reversible when applied by injection or mucosa. However, the synthesis of a compound having all of the properties of an ideal local anesthetic/analgesic is very difficult, and thus has a disadvantage in at least one part. Therefore, an appropriate and effective application of the local anesthetic/analgesic required in a specific situation is required.

As an pharmaceutical preparation for clinically applying local anesthesia/analgesics, injections and creams are commercially available. However, in the case of an injection, the injection needle must penetrate the skin in order to deliver the drug to the target site, which has the potential to cause another patient's pain, which can reduce patient compliance and must be administered with the help of a medical practitioner. There is an inconvenience that you should receive. On the other hand, in the case of a cream, it is not easy to control the precise dosage, and even if the correct dosage is administered at the beginning of administration, it is not easy to maintain the correct dosage because it is easily removed by clothes or sweat.

On the other hand, external preparations containing lidocaine, which is a local anesthetic/painkiller for amides having the structure of the formula (I), are sold in the market.

[Formula I]

Conventional transdermal absorbers containing lidocaine are produced through the process of application, cutting, aging and packaging of the drug. In the maturation process, a high temperature must be applied to the preparation for a long time, and thus there is a disadvantage in that large-scale equipment and cost are required.

In order to overcome this, the present inventors show a sufficient elution and transdermal permeability of lidocaine, and have excellent property stability when stored for a long time, and are capable of aging at a high temperature as they can be aged at room temperature (1 to 30°C) in a packaged state. The present invention was developed by developing a formulation capable of significantly reducing the time and cost required for mass production of the formulation because no equipment is required.

Percutaneous absorbents containing lidocaine should exhibit the designed percutaneous permeability and dissolution rate, and stability of properties should be maintained even during long-term storage.

An object of the present invention is to provide a lidocaine transdermal absorbent that can be aged at room temperature in a packaged state without a large-scale facility for aging the formulation at a high temperature for a long time in a manufacturing process, while ensuring excellent transdermal permeability, dissolution rate and storage stability.

An object of the present invention is to provide a lidocaine transdermal absorbent that can be aged at room temperature (1 to 30°C) in a packaged state while securing excellent transdermal permeability, dissolution rate and storage stability.

Accordingly, the present invention provides a percutaneous absorbent agent comprising lidocaine as an active ingredient and sodium polyacrylate as an adhesive, and the sodium substitution degree of the sodium polyacrylate is 55 mole percent or more.

Preferably, the degree of sodium substitution of sodium polyacrylate in the transdermal absorber of the present invention may be 70 mole percent or more.

At this time, the transdermal absorbent formulation of the present invention can secure excellent dissolution rate and permeability of lidocaine.

In addition, the transdermal absorbent formulation of the present invention can be prepared as a formulation that does not contain an aqueous solution of sorbitol and polyacrylic acid.

At this time, the transdermal absorbent preparation does not discolor the color of the drug layer for a long period of time, specifically, for 3 months at a temperature of 40° C. and a humidity of 75%. It is possible to mass production without aging process and large-scale equipment.

In addition, the transdermal absorbent formulation of the present invention may be prepared by further including at least one additive selected from the group consisting of sodium edetate and glycerin.

The transdermal absorbent formulation of the present invention has excellent transdermal permeability and dissolution rate of lidocaine, and the property stability of the formulation is improved, and as it can be aged at room temperature in a packaged state, a large-scale facility for aging the formulation at a high temperature is unnecessary, thereby mass production of the formulation. It has the advantage of significantly reducing the time and cost.

1 is a result of testing the permeability of the formulations of Examples 1 to 4 and the control drug (Lidoderm patch, Endo Pharmaceuticals and Lidotop patch, SK Chemicals).
2 is a comparative dissolution test results of the formulation of Example 1 and a control drug (Lidoderm patch).
Figure 3 is a result showing the change in properties during long-term storage of the formulation of Example 1 in harsh conditions.
Figure 4 is a result showing the change in properties during long-term storage of the formulation of Comparative Example 1 in harsh conditions.
Figure 5 confirms the degree of aging of the formulation of Example 1 stored at room temperature.
Figure 6 confirms the aging degree of Comparative Examples 1 and 2 formulations stored at a temperature of 40 ℃.
Figure 7 confirms the aging degree of the preparations of Comparative Examples 1 and 2 stored at a temperature of 50 ℃.

The present invention relates to a percutaneous absorber comprising Lidocaine or a pharmaceutically acceptable salt thereof as an active ingredient, and sodium polyacrylate as an adhesive.

The term "lidocaine" as used herein is used interchangeably with xylocaine and lignocaine, and may include pharmaceutically acceptable salts of lidocaine. Lidocaine can be represented as 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide according to the IUPAC nomenclature.

The sodium polyacrylate used in the present invention constitutes a matrix of transdermal absorbents and serves as an adhesive. In the embodiment of the present invention, sodium polyacrylate used NP-600, NP-700, NP-800 and F480SS manufactured by Viscomate ^® (manufactured by Showa Denko, Japan).

NP-600 corresponds to a sodium substitution degree in sodium polyacrylate of 70 mol percent as follows.

NP-700 corresponds to a sodium substitution degree of 50 mol percent in sodium polyacrylate as follows.

NP-800 corresponds to a sodium substitution degree of 35 mol percent in sodium polyacrylate as follows.

F480SS corresponds to a sodium substitution degree of 100 mol percent in sodium polyacrylate as follows.

The sodium polyacrylate preferably has a sodium substitution degree of 55 mole percent or more, and more preferably 70 mole percent or more.

The present invention comprises a lidocaine (Lidocaine) or a pharmaceutically acceptable salt thereof as an active ingredient, and sodium polyacrylate (sodium polyacrylate) as an adhesive, a transdermal absorbent characterized in that it does not contain an aqueous solution of sorbitol and an aqueous solution of polyacrylic acid It is about.

In addition, the transdermal absorbent formulation of the present invention may further include at least one additive selected from the group consisting of gelatin, sodium edetate and glycerin.

The transdermal absorbent formulation of the present invention does not discolor the drug when stored for 3 months at a temperature of 40° C. and a humidity of 75%, and more preferably, the drug does not discolor when stored for 6 months.

In addition, the transdermal absorbent formulation of the present invention is capable of aging at room temperature in a packaged state, and in particular, aging is completed within 14 days at room temperature.

The present invention comprises the steps of preparing a mixed solution by mixing gelatin, sodium edetate and glycerin; And mixing the mixed solution and lidocaine or a pharmaceutically acceptable salt thereof to prepare a final mixed solution.

In addition, the present invention may further include the step of aging at room temperature after applying, cutting, and packaging the final mixed solution in the above-described manufacturing method.

Hereinafter, the present invention will be described in more detail through examples. These examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited by these examples.

[Examples 1 to 4]

Preparation of transdermal absorbers containing lidocaine

Percutaneous absorbent preparations of Examples 1 to 4 were prepared comprising lidocaine and sodium polyacrylate of Table 1 below.

ingredient Example 1 Example 2 Example 3 Example 4 Polyacrylic acid
salt NP-600 NP-700 NP-800 F480SS

Sodium polyacrylate in Table 1 was used by purchasing a product of the product name Viscomate ^® (manufacturer SHOWA DENKO), which is divided into NP-600, NP-700, NP-800, and F480SS according to the degree of substitution of sodium.

The formulations of Examples 1 to 4 were prepared by the following method without using sorbitol aqueous solution and polyacrylic acid aqueous solution.

Purified water was added to the preparation container, gelatin, polyvinyl alcohol, urea, and tartaric acid were sequentially added and dissolved to prepare a gelatin solution (primary solution). Thereafter, some purified water was put separately, and sodium edetate was added and dissolved to prepare a sodium edetate solution (secondary solution). Lidocaine, propylene glycol, methylparaben, propylparaben, and Tween 80 were added and dissolved to prepare a main component solution (tertiary solution).

Concentrated glycerin is added to a separate preparation container. A dispersant, sodium polyacrylate, a thickener, and a crosslinking agent were added and mixed to prepare a concentrated glycerin mixed solution.

The gelatin solution (primary solution) and sodium edetate solution (secondary solution) were added to the final stirring tank and stirred. Subsequently, the mixture was concentrated by adding the concentrated glycerin mixed solution and the main component solution (tertiary solution) to the final stirring tank.

After applying the mixed solution to a certain thickness (100 ~ 1100um), cut into a certain size (50 ~ 140 cm ² ), and then packaged one by one. After packaging, it was stored at room temperature and aged.

[Comparative Examples 1 to 4]

Preparation of transdermal absorbers containing lidocaine

Percutaneous absorbents of Comparative Examples 1 to 4 were prepared containing lidocaine, D-sorbitol, aqueous polyacrylic acid solution, and sodium polyacrylate of Table 2 below.

ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Polyacrylic acid
salt NP-600 NP-700 NP-800 F480SS

After adding purified water to the preparation container, gelatin, polyvinyl alcohol, D-sorbitol solution, urea, and tartaric acid were added and dissolved at 50°C to prepare a gelatin solution (primary solution). Lidocaine and propylene glycol were dissolved in a separate preparation container at 50°C to prepare a main component solution (secondary solution). In addition, an aqueous polyacrylic acid solution was dissolved in purified water to prepare an aqueous polyacrylic acid solution (tertiary solution).

Add concentrated glycerin to the other dispensing container. A dispersant, sodium polyacrylate, a thickener, and a crosslinking agent were added and mixed to prepare a concentrated glycerin mixed solution.

In the stirring tank, the gelatin solution (primary solution) and sodium edetate were added and stirred until dissolved, and then the main component solution (secondary solution) was added and stirred. Thereafter, the aqueous polyacrylic acid solution (third solution) was added and stirred, and then the concentrated glycerin mixture was added and finally stirred.

After applying the mixed solution to a certain thickness (100 ~ 1100um), cut into a certain size (50 ~ 140 cm ² ), and then packaged one by one. After packaging, it was stored at room temperature and aged.

[Test Example 1]

Percutaneous permeability comparison test

For the formulations of Examples 1 to 4, and the control drugs (Lidoderm patch, Endo Pharmaceuticals and Lidotop patch, SK Chemicals), percutaneous permeability was tested.

After removing the skin of a 6-week-old female hairless mouse to a size of 3 cm Х 3 cm, skin with subcutaneous fat removed was purchased. To the epidermal layer of the extracted skin, samples of Examples 1 to 4, which were cut into a circle having a size of 1.767 cm 2, and a control drug were attached. The endothelial layer of the skin was attached facing the Franz diffusion cell. The receptor layer of the Franz diffusion cell was carefully filled with a pH 7.4 pH (Phosphate buffered saline) buffer solution so that no bubbles were generated and stirred at 600 rpm while maintaining the temperature of the Franz diffusion device at 32±0.5°C. After taking 200 µl for 2, 4, 6, 8, and 12 hours, the sample was filled with the same amount of fresh buffer solution. After diluting with 200 μl of pH 7.4 PBS buffer, the content of lidocaine was analyzed using HPLC analysis and the same amount of buffer was filled in the receptor layer. The effective skin area of the hairless mice attached to the Franz diffusion cell was 1.767 cm 2, the receptor volume was 12.5 ml, and a skin permeation test was performed under sink conditions.

HPLC analysis conditions are as follows. As a mobile phase, a solution in which pH 8.0 buffer (4.85 g of KH ₂ PO ₄ was dissolved in 1 L and dissolved and then adjusted pH 8.0 with 10 N NaOH solution) and acetonitrile at 50:50 (v/v) was used. Μl, flow rate of 1 ml/min, detection wavelength of 230 nm, column of Agilent Zorbox XDB C18 was used, and the column temperature was maintained at 40° C. during analysis.

The results of transdermal permeability are shown in Table 3 and FIG. 1 below.

Hour (hr) ㎍/㎠ Example 1 Example 2 Example 3 Example 4 Lidodom Lithotop 2 39.3 0.0 7.6 55 46.0 10.4 4 107.7 19.4 16.9 173.6 105.0 56.0 6 171.2 36.5 35.1 249.6 168.0 106.8 8 233.6 50.4 50.7 333.0 226.9 131.9 12 342.7 122.1 106.0 488.7 347.7 277.5

As can be seen from Table 3 and Figure 1, it can be seen that the formulations of Examples 1 and 4 exhibit superior transdermal permeability equal to or higher than that of the control drug. In particular, the formulations of Examples 1 and 4 showed better transdermal permeability compared to other formulations.

[Test Example 2]

Comparative dissolution test

For the formulations of Examples 1 and 3 and the control drug (Lidoderm patch, Endo Pharmaceuticals), a comparative dissolution test was performed in the following manner.

The formulations of Examples 1 and 3 and the control drug (Lidoderm patch, Endo Pharmaceuticals) were each taken 6 sheets (13.33 cm 2 /1 sheet) and attached to the disk assembly with the double-sided adhesive tape facing up. 500 ml of water was placed in an elution container, and 1 ml of eluate was added at 10, 20, 30, 60, 120, 180, and 240 minutes at the conditions of elution temperature 32±0.5°C and paddle rotation speed 50 rpm. Was collected. The same amount of new buffer solution was filled. Lidocaine contained in the collected eluate was analyzed by HPLC. HPLC analysis conditions are as follows.

As a mobile phase, a solution in which pH 8.0 buffer (4.85 g of KH ₂ PO ₄ was dissolved in 1 L and dissolved and then adjusted pH 8.0 with 10 N NaOH solution) and acetonitrile at 50:50 (v/v) was used. Μl, flow rate of 1 ml/min, detection wavelength of 230 nm, column of Agilent Zorbox XDB C18 was used, and the column temperature was maintained at 40° C. during analysis.

Similarity was determined according to the paddle over disk method of the United States Pharmacopia (USP) transdermal absorber.

The comparative dissolution test results are shown in Table 4 and FIG. 2 below.

Hours (minutes) %, Dissolution Example 1 Example 3 Lidodom Lithotop 10 17.5 17.0 13.7 13.1 20 28.5 28.0 23.3 21.0 30 37.9 36.9 31.0 27.4 60 59.3 56.9 61.3 44.3 120 81.6 78.6 84.5 70.2 180 91.4 89.0 90.5 85.9 240 96.2 95.4 96.5 92.6

As shown in Table 4, the formulations of Examples 1 and 3 exhibited superior dissolution patterns equal to or higher than those of the control drugs.

[Test Example 3]

Property change test for long-term storage

For the formulations of Examples 1 to 4 and Comparative Example 1, changes in properties during long-term storage were observed.

In order to observe the change in properties of each agent, storage was performed for 6 months at 40°C and 75% humidity, and the change in properties of the drug layer of the agent was measured every 3 months.

The results are shown in Table 5, Figures 3 and 4 below.

time Example 1 Example 2 Example 3 Example 4 Comparative Example 1 0 White White White White White 3 months White White White White Dark yellow
(deep yellow) 6 months Slight discoloration
(yellowish) Slight discoloration
(yellowish) Slight discoloration
(yellowish) Slight discoloration
(yellowish) Brown
(brown)

As can be seen from Table 5, Figures 3 and 4, both the formulations of Examples and Comparative Examples were initially observed in white. After 3 months, the color of the drug layer of Comparative Example 1 was changed to deep yellow, but the drug layer of the example was not discolored and remained white. After 6 months, the drug layer of Comparative Example 1 was completely discolored to brown, but the drug layer of the example preparations maintained a white color only as a slight yellowish was observed.

That is, it can be seen that the formulations of the examples not containing the aqueous D-sorbitol solution and the aqueous polyacrylic acid solution hardly discolor the drug layer even when stored for a long period of time in harsh conditions, and thus have excellent property stability.

[Test Example 4]

Confirmation of the aging of the formulation

In order to confirm the aging of the formulations for the formulations of Example 1 and Comparative Examples 1 and 2, a swelling test was performed.

The formulations of Example 1 and Comparative Example 1 were aged for 2 weeks at room temperature in a packaged state. During aging, some of the preparations were cut into 4-5 cm x 4-5 cm sizes and swelled in deionized water for 1 hour to observe properties over time.

As shown in FIG. 5, it was confirmed that the preparation of Example 1 not containing an aqueous sorbitol solution and an aqueous polyacrylic acid solution was completed in 14 days at room temperature in a packaged state. However, it was confirmed that the preparation of Comparative Example 1 did not proceed at all at room temperature.

Additionally, formulations having the compositions of Comparative Examples 1 and 2 were aged at room temperature, 40°C or 50°C. During aging, some of the preparations were cut into 4-5 cm × 4-5 cm sizes and swelled in a buffer solution of pH 4 for 2 hours to observe properties over time.

6 and 7, it was confirmed that the preparations of the comparative examples were completed after at least 36 hours at a temperature of 40° C., and the aging was completed after 24 hours at a temperature of 50° C.

After all, in the actual manufacturing process, the formulation of Example 1 can be aged at room temperature in a packaged state immediately after application and cutting, so a large-scale facility for aging the formulation at high temperature is unnecessary, and the time spent for mass production of the formulation It has the advantage of significantly reducing the cost.

Claims (10)

In the transdermal sorbent comprising a lidocaine (Lidocaine) or a pharmaceutically acceptable salt thereof as an active ingredient, and sodium polyacrylate having a sodium substitution degree of 70 mol% or more as an adhesive,
It does not contain an aqueous solution of sorbitol and an aqueous solution of polyacrylic acid,
The color of the drug does not discolor when stored for 3 months at a temperature of 40 ℃ and humidity of 75%,
A percutaneous absorbent formulation characterized in that it is aged at room temperature in a packaged state.
delete delete delete The method of claim 1, wherein the transdermal absorbent, characterized in that it further comprises at least one additive selected from the group consisting of gelatin, sodium edetate and glycerin.
delete delete According to claim 1, wherein the transdermal absorbent preparation is characterized in that aging is completed within 14 days at room temperature.
delete delete

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