WO2020032616A1 - Composition comprising local anesthetic and sodium polyacrylate - Google Patents

Abstract

The present invention relates to a transdermal absorption preparation which comprises lidocaine or a pharmaceutically acceptable salt thereof, and sodium polyacrylate having a substitution degree of sodium of 55 mol% or more, and does not comprise an aqueous sorbitol solution and an aqueous polyacrylic acid solution. The transdermal absorption preparation according to the present invention exhibits excellent transdermal permeability and high elution rate of lidocaine, and enhanced appearance stability, and can be aged at room temperature in a packing state, and thus does not require large-scale equipment for aging the preparation at a high temperature. Therefore, the time and cost for mass-production of the preparation can be remarkably reduced.

Description

Compositions Including Local Anesthetics and Sodium Polyacrylate

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

Ideal local anesthesia / analgesics should have no systemic toxicity at effective concentrations, fast onset of action, and sustain pharmacological action for some time. Local anesthesia / analgesics should also be water soluble, stable in solution, sterile, sterilized and effective and reversible in injection or mucosal applications. However, the synthesis of a compound having all the characteristics of an ideal local anesthetic / analgesic agent is very difficult and has disadvantages in at least one part. Therefore, an appropriate local anesthetic / analgesic agent required in a specific situation should be properly selected and applied safely and safely.

As pharmaceutical preparations for the application of local anesthetic / analgesic in clinical practice, injections and creams are commercially available. In the case of injections, however, the needle must penetrate the skin to deliver the drug to the target site, which can cause pain in another patient, which can reduce patient compliance and must be administered with the help of a healthcare professional. There is an inconvenience to receive. Meanwhile, in the case of cream, it is not easy to control the exact dose, and even if the correct dose is initially administered, it is not easy to maintain the exact dose because it is easily removed by clothes or sweat.

On the other hand, an external preparation including lidocaine, which is a local anesthetic / analgesic agent of amides having the structure of formula (I) shown below, is sold on the market.

[Formula I]

Conventional transdermal absorbents, including lidocaine, are produced by the process of application, cleavage, maturation and packaging of the drug. In the aging process, it is necessary to apply a high temperature to the preparation for a long time, there is a disadvantage that requires a large amount of equipment and costs.

In order to overcome this problem, the present inventors exhibit sufficient dissolution and transdermal permeability of lidocaine, and have excellent stellar stability when stored for a long time, and can be aged at room temperature (1 to 30 ° C.) in a packaged state at large scale to mature the preparation at high temperature. The present invention has been developed by developing a formulation which can significantly reduce the time and cost required for mass production of the formulation because no equipment is required.

Percutaneous absorption preparations containing lidocaine should exhibit a designed transdermal permeability and dissolution rate, and maintain stability during long-term storage.

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

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

Accordingly, the present invention provides lidocaine as an active ingredient and sodium polyacrylate as a pressure-sensitive adhesive, and the sodium substitution degree of sodium polyacrylate is 55 mol percent or more.

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

At this time, the percutaneous absorption preparation of the present invention can ensure excellent dissolution rate and transdermal permeability of lidocaine.

In addition, the transdermal absorption preparation of the present invention may be prepared as a formulation containing no sorbitol and polyacrylic acid aqueous solution.

At this time, the transdermal absorption agent does not discolor the color of the drug layer even if stored for a long period of time, specifically at a temperature of 40 ℃ and 75% humidity conditions for three months, and aged in 14 days at room temperature even in the packaging state is completed separately It is possible to mass-produce without the aging process and large scale equipment.

In addition, the transdermal absorption preparation of the present invention may be prepared further comprising one or more additives selected from the group consisting of sodium edetate and glycerin.

The transdermal absorption preparation of the present invention has excellent transdermal permeability and dissolution rate of lidocaine, improves the stability of the formulation, and can be matured at room temperature in a packaged state, thus eliminating the need for a large-scale facility for aging the formulation at high temperature. It has the advantage of significantly reducing the time and cost consumed.

1 is a result of testing the transdermal permeability of the formulations and the control agents of Examples 1 to 4 (Lidoderm patch, Endo Pharmaceuticals and Lidotop patch, SK Chemicals).

Figure 2 is a comparative dissolution test results of the formulation of Example 1 and the Lidoderm patch.

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

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

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

NP-600 corresponds to 70 mole percent sodium substitution in sodium polyacrylate as follows.

NP-700 corresponds to 50 mole percent sodium substitution in sodium polyacrylate as follows.

NP-800 corresponds to 35 mole percent sodium substitution in sodium polyacrylate as follows.

F480SS corresponds to 100 mole percent sodium substitution in sodium polyacrylate as follows.

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

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

In addition, the transdermal absorption preparation of the present invention may further include one or more additives selected from the group consisting of gelatin, sodium edetate and glycerin.

The transdermal absorbent preparation of the present invention does not discolor the color of the drug when stored for three months at a temperature of 40 ℃ and 75% humidity conditions, more preferably the color of the drug hardly discolored when stored for six months.

In addition, the transdermal absorption preparation 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 it relates to a method for producing a transdermal absorption preparation comprising the step of mixing the mixed solution, and Lidocaine (Lidocaine) or a pharmaceutically acceptable salt thereof to prepare a final mixed solution.

In addition, the present invention may further comprise the step of applying, cutting and packaging the final mixed solution in the above production method, and then aging at room temperature.

Hereinafter, the present invention will be described in more detail with reference to 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 Percutaneous Absorbents Containing Lidocaine

The transdermal absorbent preparations of Examples 1 to 4 including lidocaine and sodium polyacrylate of Table 1 were prepared.

ingredient	Example 1	Example 2	Example 3	Example 4
Sodium polyacrylate	NP-600	NP-700	NP-800	F480SS

Sodium polyacrylate of Table 1 is divided into NP-600, NP-700, NP-800, F480SS according to the degree of substitution of sodium, product name Viscomate  The product of (Manufacturer SHOWA DENKO) was purchased and used.

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

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

Add concentrated glycerin to a separate container. A dispersant, sodium polyacrylate, a thickener, and a crosslinking agent were added and mixed, and then a concentrated glycerin mixture was prepared.

The gelatin solution (primary solution) and sodium edetate solution (secondary solution) were added to the final stirring tank and stirred. Thereafter, the concentrated glycerin mixed solution and the main component solution (tertiary solution) were added to the final stirring tank for final stirring.

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

[Comparative Examples 1 to 4]

Preparation of Percutaneous Absorbents Containing Lidocaine

The transdermal absorbent preparations of Comparative Examples 1 to 4 containing lidocaine, D-sorbitol, polyacrylic acid aqueous solution, and sodium polyacrylate of Table 2 were prepared.

ingredient	Comparative Example 1	Comparative Example 2	Comparative Example 3	Comparative Example 4
Sodium polyacrylate	NP-600	NP-700	NP-800	F480SS

Purified water was added to the preparation container, gelatin, polyvinyl alcohol, D-sorbitol solution, urea and tartaric acid were added, followed by dissolution at 50 ° C. to prepare a gelatin solution (primary solution). Lidocaine and propylene glycol were dissolved at 50 ° C. in a separate preparation container 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).

Put concentrated glycerin in another preparation container. Dispersant, sodium polyacrylate, thickener, crosslinking agent was added and mixed to prepare a concentrated glycerin mixture.

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

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

[Test Example 1]

Transdermal Permeability Comparison Test

Percutaneous permeability was tested for the formulations of Examples 1-4, and control agents (Lidoderm patch, Endo Pharmaceuticals and Lidotop patch, SK Chemicals).

The skin of 6-week-old female hairless rats was extracted to a size of 3 cm Х 3 cm, and then skin was removed. The specimens of Examples 1 to 4 and the reference drug cut into a 1.767 cm 2 sized circle were attached to the epidermal layer of the extracted skin. The endothelial layer of skin was attached facing the Franz diffusion cell. The receptor layer of the Franz diffusion cell was carefully filled with PBS (Phosphate buffered saline) buffer solution of pH 7.4 so as not to generate bubbles, and stirred at 600 rpm while maintaining the temperature of the Franz diffusion device at 32 ± 0.5 ° C. Samples were taken in 200 μl at 2, 4, 6, 8, and 12 hours, and then filled with the same amount of fresh buffer solution. After dilution 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 into the receptor layer. The effective skin area of the hairless rat attached to the Franz diffusion cell was 1.767 cm 2, the receptor volume was 12.5 ml, and the skin permeation test was conducted under sink conditions.

HPLC analysis conditions are as follows. As a mobile phase, a solution containing pH 8.0 buffer (1.85 g of KH ₂ PO ₄ dissolved in 1L, dissolved, and then adjusted to pH 8.0 with 10N NaOH) and acetonitrile at 50:50 (v / v) was used. The flow rate was 1 ml / min, the detection wavelength was 230 nm, and the column was Agilent Zorbox XDB C18. The column temperature was maintained at 40 ° C. during the analysis.

Transdermal permeability test results are shown in Table 3 and FIG. 1.

Hour (hr)	㎍ / ㎠
	Example 1	Example 2	Example 3	Example 4	Lidoderm		Lito Top
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 confirmed in Table 3 and FIG. 1, it can be seen that the formulations of Examples 1 and 4 exhibited superior percutaneous permeability, equivalent to or higher than that of the reference drug. In particular, the formulations of Examples 1 and 4 showed better transdermal permeability compared to other formulations.

[Test Example 2]

Comparative Dissolution Test

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

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

As a mobile phase, a solution containing pH 8.0 buffer (1.85 g of KH ₂ PO ₄ dissolved in 1L, dissolved, and then adjusted to pH 8.0 with 10N NaOH) and acetonitrile at 50:50 (v / v) was used. The flow rate was 1 ml / min, the detection wavelength was 230 nm, the column was Agilent Zorbox XDB C18, 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 absorbent.

Comparative dissolution test results are shown in Table 4 and FIG. 2.

Time (min)	%, Dissolution
	Example 1	Example 3	Lidoderm		Lito Top
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 showed an excellent dissolution pattern equal to or higher than that of the reference drugs.

[Test Example 3]

Property change test for long term storage

The change in appearance during long-term storage was observed for the formulations of Examples 1 to 4 and Comparative Example 1.

In order to observe the change in the properties of each formulation, it was stored for 6 months at 40 ℃, 75% humidity conditions, and the change in the properties of the drug layer of the formulation every three months.

The results are shown in Table 5 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	Deep yellow
6 months	Slight yellowish	Slight yellowish	Slight yellowish	Slight yellowish	Brown

As confirmed in Table 5 above, both the formulations of the Examples and Comparative Examples were initially observed to be white. After 3 months, the color of the drug layer of Comparative Example 1 was changed to deep yellow, but the drug layer of 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 formulations remained white overall with slight yellowish observed.

That is, the formulations of the examples that do not include the aqueous solution of D-sorbitol and polyacrylic acid are hardly discolored even after long-term storage under severe conditions, and thus it can be seen that the property stability is excellent.

[Test Example 4]

Confirmation of Aging of the Formulation

In order to confirm the maturation of the formulation with respect to the formulations of Example 1, Comparative Examples 1 and 2, a swelling test was conducted.

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

As a result, it was confirmed that the preparation of Example 1 containing no aqueous sorbitol solution and polyacrylic acid solution was completed in 14 days even 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.

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

As a result, the formulations of Comparative Examples were aged after at least 36 hours at a temperature of 40 ℃, it was confirmed that aging is completed after 24 hours at a temperature of 50 ℃.

As a result, the formulation of Example 1 can be aged at room temperature in the actual manufacturing process, immediately packaged after application and cutting, thus eliminating the need for a large-scale facility for aging the formulation at high temperatures and time required for mass production of the formulation. And it has the advantage that can significantly reduce the cost.

Claims (10)

1. A transdermal absorption preparation comprising lidocaine or a pharmaceutically acceptable salt thereof as an active ingredient and sodium polyacrylate as an adhesive.
2. The transdermal absorption preparation according to claim 1, wherein the sodium substitution degree of sodium polyacrylate is 55 mol percent or more.
3. The transdermal absorption preparation according to claim 1, wherein the sodium substitution degree of sodium polyacrylate is 70 mole percent or more.
4. The transdermal absorption preparation according to claim 1, further comprising an aqueous sorbitol solution and an aqueous polyacrylic acid solution.
5. The transdermal absorption preparation according to claim 1, further comprising one or more additives selected from the group consisting of gelatin, sodium edetate and glycerin.
6. The percutaneous absorption preparation of claim 1, wherein the color of the drug does not discolor when stored for 3 months at a temperature of 40 ° C. and a humidity of 75%.
7. The percutaneous absorption preparation of claim 1, wherein the percutaneous absorption preparation is capable of room temperature aging in a packaged state.
8. The transdermal absorption preparation according to claim 1, wherein the transdermal absorption preparation is completed within 14 days at room temperature.
9. Preparing a mixed solution by mixing gelatin, sodium edetate and glycerin; And

   Method for producing a transdermal absorbent preparation comprising the step of mixing the mixture, and Lidocaine (Lidocaine) or a pharmaceutically acceptable salt thereof to prepare a final mixture.
10. 10. The method of claim 9, further comprising the step of aging at room temperature after applying, cutting and packaging the final mixture.

Images