JP5888706B2 - Loxoprofen sodium containing topical patch - Google Patents

Description

  The present invention relates to a patch containing loxoprofen sodium, and in particular, to an oily external patch containing loxoprofen sodium which exhibits excellent drug release properties and has high stability of the preparation.

  Loxoprofen sodium is a drug that exhibits excellent anti-inflammatory and analgesic effects as a non-steroidal anti-inflammatory analgesic based on phenylpropionic acid, and has traditionally been studied for formulation as an external preparation, regardless of whether it is aqueous or oily. Already, poultices (brand name: Loxonin Papp) and plaster drugs (brand name: Loxonin Tape) are already on the market.

  In patches containing non-steroidal anti-inflammatory analgesics such as loxoprofen, solubilizing agents such as crotamiton, pyrrolidones, higher fatty acids and fatty acid esters, or cooling agents such as L-menthol, mint oil, and DL-camphor Attempts have been made to improve transdermal absorbability by adding. In particular, when loxoprofen sodium is blended in an oily base, loxoprofen sodium is water-soluble, so for the purpose of improving solubility in an oily base, the above ingredients are blended together with loxoprofen sodium. It is often seen. However, some of these solubilizers or refreshing agents cause skin irritation, and there are many components that promote the decomposition of loxoprofen sodium in products, which are problematic.

  For example, Patent Document 1 discloses a plaster agent in which a rosin ester derivative is used as a solubilizing agent and a patch together with L-menthol for nonsteroidal anti-inflammatory analgesics such as loxoprofen. Patent Document 2 describes a loxoprofen-containing patch containing styrene-isoprene-styrene block copolymer as a base base and blended with crotamiton. The former is characterized by using a rosin ester derivative, which was often used as a tackifying resin, as a solubilizer for loxoprofen sodium, and the latter is characterized by using crotamiton as a main agent solubilizer. However, rosin ester has a skin sensitizing action and may give an undesirable side effect to the skin when the preparation is applied. In addition, since one crotamiton destroys the physical properties of the patch and adversely affects the patch, such as a decrease in adhesive strength, the combination of these additives is preferable for the patch preparation. I couldn't say that.

Patent Document 3 describes a loxoprofen-containing patch containing a pyrrolidone compound, but the pyrrolidone compound, like crotamiton, easily deteriorates the physical properties of the preparation, and the pyrrolidone compound has a highly volatile component. In addition, when blended into a patch, it volatilizes during storage and the transdermal absorbability may be reduced.
Furthermore, Patent Document 4 describes a loxoprofen-containing patch containing a terpene resin or a rosin resin, and the rosin resin in this patch is a skin sensation preparation as described above, which is preferable for the skin. There is no influence.

  Patent Document 5 discloses a loxoprofen-containing external patch containing 0.1 to 3% by weight of an aliphatic hydroxy acid and 0.1 to 5% by weight of a higher fatty acid. The patch for external use is characterized by containing a combination of an aliphatic hydroxy acid and a higher fatty acid as a solubilizing agent for the active ingredient, but substantially malic acid or citric acid is selected as the aliphatic hydroxy acid. . When these aliphatic hydroxy acids are used, the solubility of loxoprofen is insufficient and the patch remains problematic in terms of transdermal absorbability.

  Thus, when blending loxoprofen sodium into an oily base, it is very difficult to select a solubilizing agent for the main drug, so it still contains loxoprofen, which achieves both the percutaneous absorption of the main drug and the stability of the main drug. The present condition is that the plaster agent is not developed.

International publication WO93 / 04677 JP 2004-43512 A JP 2008-163017 A JP 2008-214337 A JP 2011-20997 A

  Therefore, the present invention solves the above-mentioned problem, and in a loxoprofen sodium-containing external patch, it exhibits a high percutaneous absorption of the active ingredient and is stable enough to suppress the formation of degradation products for a preparation during storage. It is an object to provide an external patch having high properties.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that in an external patch in which a pressure-sensitive adhesive layer containing loxoprofen sodium is provided on a support, the pressure-sensitive adhesive layer is a main base. As styrene-isoprene-styrene block copolymer, highly safe tackifier for skin, alicyclic saturated hydrocarbon resin, and lactic acid and higher fatty acid as specific agents for topical use By using the patch, it was found that loxoprofen sodium was stably dissolved in the adhesive base, and the percutaneous absorbability was improved while maintaining high stability of loxoprofen sodium, and the present invention was completed. It was.

  Therefore, the basic aspect of the present invention is an external patch in which a support is provided with a pressure-sensitive adhesive layer containing 0.1 to 10% by weight of loxoprofen sodium, and the pressure-sensitive adhesive layer comprises styrene-isoprene-styrene. Containing 5 to 30% by weight of block copolymer, 10 to 50% by weight of alicyclic saturated hydrocarbon resin, 0.1 to 1% by weight of lactic acid, and 5 to 15% by weight of higher fatty acid, The external patch, wherein the blending ratio is lactic acid / higher fatty acid = 1/50 to 1/5.

  Specifically, in the present invention, the higher fatty acid is one or two selected from isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, capric acid, lauric acid, and caproic acid. This is an external patch as described above.

  More specifically, the present invention is an external patch wherein the higher fatty acid is isostearic acid alone, a combination of isostearic acid and myristic acid, or a combination of isostearic acid, myristic acid and palmitic acid.

  The external patch provided by the present invention is an external patch in which an adhesive layer containing loxoprofen sodium is provided on one side of a support, and the adhesive layer is a styrene-isoprene-styrene block copolymer as a main base. A polymer and an alicyclic saturated hydrocarbon resin, which is a highly safe tackifier for the skin, and a topical formulation containing lactic acid and higher fatty acid as a solubilizer for loxoprofen sodium, the main agent. By using the patch, loxoprofen sodium can be stably dissolved in the adhesive base, and has high transdermal absorbability and stability of the active ingredient, which could not be achieved with conventional patches. It has become possible to provide an external patch containing loxoprofen sodium.

  In particular, lactic acid and higher fatty acid isostearic acid alone, a combination of isostearic acid and myristic acid, or a combination of isostearic acid, myristic acid and palmitic acid are in the range of lactic acid / higher fatty acid = 1/50 to 1/5. Therefore, very good solubility and transdermal absorbability are exhibited.

It is the figure which showed the fixed_quantity | quantitative_assay result of the decomposition product 1 of Test Example 4 in this invention. It is the figure which showed the fixed_quantity | quantitative_assay result of the decomposition product 2 of Test Example 4 in this invention.

In the external preparation provided by the present invention, the amount of loxoprofen sodium as the main drug in the external patch is not particularly limited as long as it can be formulated, but preferably 0.1 to 0.1% based on the total weight of the preparation. It can be blended in an amount of 10% by weight, more preferably 0.5 to 6% by weight.
When the loxoprofen sodium content in the preparation is less than 0.1% by weight, the transdermal absorbability is insufficient, and when it exceeds 10% by weight, not only the physical properties of the patch are impaired, but also economically. Is also disadvantageous and not preferred.

In the external patch of the present invention, a styrene-isoprene-styrene block copolymer (hereinafter referred to as “SIS”) as a base component imparts adhesiveness to the pressure-sensitive adhesive layer, and each component is contained in the pressure-sensitive adhesive. It has a role to hold.
The amount of SIS is blended in consideration of the blending amount of other components, but is usually 5 to 30% by weight, preferably 10 to 25% by weight. When the blending amount is less than 5% by weight, the cohesive strength and shape retention of the base are lowered. On the other hand, if the blending amount exceeds 30% by weight, it is not preferable because it causes a decrease in adhesive strength, unevenness of the plaster, and a decrease in workability in the manufacturing process.

The alicyclic saturated hydrocarbon resin blended in the base in the external patch of the present invention is used as a tackifier.
In addition to high safety to the skin, alicyclic saturated hydrocarbon resins have low polarity, so they are less reactive with loxoprofen sodium and other ingredients, improving the stability of loxoprofen sodium in the formulation From this point of view, it is a preferable tackifier.

Specific examples of such alicyclic saturated hydrocarbon resins include Alcon P100, Alcon P90, and Alcon P115 (all trade names: manufactured by Arakawa Chemical Industries).
The blending amount of the alicyclic saturated hydrocarbon resin in the external patch of the present invention is not particularly limited as long as it can be formulated, but it is preferably blended in the range of 10 to 50% by weight based on the total weight of the formulation. It is good to do. More preferably, it is 15 to 40% by weight.
If the blending amount of the alicyclic saturated hydrocarbon resin in the preparation is less than 10% by weight, the adhesive strength is weak, causing problems such as peeling during sticking. On the contrary, the force becomes too strong and the skin irritation becomes high, which is not preferable.

In the present invention, lactic acid is a very excellent solubilizing agent for loxoprofen sodium, and by mixing it, loxoprofen sodium is stably dissolved in the adhesive base and exhibits an excellent transdermal absorption promoting effect. It is a component that can.
However, lactic acid is an additive with one aspect that it reacts with loxoprofen sodium to produce a decomposition product and reduce the stability of the preparation. Therefore, the blending amount of lactic acid in the external patch of the present invention is 0.1 to 1.0% by weight, preferably 0.1 to 0.8% by weight, more preferably 0.8%, based on the total weight of the preparation. It is good to mix | blend in the range of 2-0.6 weight%. If the amount of lactic acid is less than 0.1% by weight, it is impossible to sufficiently dissolve loxoprofen sodium in the adhesive base, and the percutaneous absorbability of the preparation is reduced, or the crystal of the main ingredient in the preparation during storage Precipitation or the like occurs, and conversely, when the blending amount of lactic acid exceeds 1.0% by weight, the decomposition product derived from lactic acid increases and the stability of the preparation decreases.

In the external patch of the present invention, a higher fatty acid is blended together with the above lactic acid to ensure the function as a solubilizer for loxoprofen sodium. In the present invention, it is possible to suppress an increase in decomposition products derived from lactic acid without lowering the transdermal absorbability of the preparation by blending a higher amount of higher fatty acid into the preparation.
Examples of such higher fatty acids include isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, capric acid, lauric acid, caproic acid, and the like, or a combination of one or more of them In the present invention, isostearic acid, myristic acid, and palmitic acid are particularly preferably used in the present invention.

  The compounding quantity of the higher fatty acid in a formulation is 5 to 15 weight%, Preferably it is 6 to 10 weight%, More preferably, it is 6 to 8 weight%. When the blending amount of the higher fatty acid is less than 5% by weight, dissolution of loxoprofen sodium in the preparation is insufficient, and degradation products derived from lactic acid increase. On the other hand, when the amount of the higher fatty acid exceeds 15% by weight, not only the physical properties of the preparation deteriorate, but also problems such as skin irritation occur, which is not preferable.

In the external patch provided by the present invention, a combination of a relatively small amount of lactic acid and a relatively large amount of a higher fatty acid is added to the preparation in order to achieve both the percutaneous absorption of the active ingredient and the stability of the active ingredient. It is characterized by that.
The blending amount of lactic acid or higher fatty acid is as described above, but in addition, it has been found preferable to adjust the blending ratio of lactic acid and higher fatty acid within a certain range.
In the external patch of the present invention, the blending ratio of lactic acid and higher fatty acid is lactic acid / higher fatty acid = 1/50 to 1/5, preferably 1/30 to 1/5, more preferably 1 /. 30 to 1/15. When the blending ratio of lactic acid is less than 1/50, the transdermal absorbability is lowered, and when the blending ratio of lactic acid is more than 1/5, the production of degradation products derived from lactic acid increases in the preparation during storage, and the drug The stability of is reduced.

  Preferred lactic acid and higher fatty acid combinations are lactic acid and isostearic acid, or lactic acid and isostearic acid and myristic acid. More preferred is a combination of lactic acid and isostearic acid, myristic acid and palmitic acid.

The softener blended in the external patch of the present invention has good compatibility with other base components and gives flexibility to the base. Specifically, polyisobutylene, liquid polyisoprene, polybutene, Lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, liquid paraffin, and the like can be mentioned. Among them, polybutene and liquid paraffin are preferable.
These softeners can be used alone or in combination of two or more. The blending amount of the softener is usually 10 to 75% by weight, preferably 15 to 50% by weight, although the blending amount of other liquid components blended in the preparation is also considered.

  In the external patch provided by the present invention, L-menthol is preferably blended as a cooling agent. However, L-menthol itself may react with loxoprofen sodium, which is a non-steroidal anti-inflammatory analgesic having a carboxylic acid group in the molecule, to produce a decomposition product (L-menthol ester). Therefore, when it mix | blends abundantly, it exists in the tendency for the production amount of a decomposition product (L-menthol ester body) to increase with the quantity. Moreover, when too much L-menthol is blended, the cooling sensation felt on the skin is too strong, and some people feel uncomfortable. Therefore, the compounding quantity of L-menthol in the external patch of this invention is 0.1 to 10 weight%, Preferably it is 0.5 to 5 weight%.

  In addition, you may mix | blend a polyvalent metal salt with the external patch of this invention in order to suppress the increase in this decomposition product. In particular, the incorporation of aluminum glycinate is effective for degradation products derived from lactic acid. The said polyvalent metal salt is mix | blended in 0.001 to 5 weight%, Preferably it is 0.005 to 3 weight%.

  In the pressure-sensitive adhesive layer of the external patch of the present invention, a solubilizer and other absorption promoters can be blended as necessary. These solubilizers or absorption promoters include fatty acid esters such as isopropyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, isopropyl palmitate, and other polyvalent compounds such as propylene glycol, polyethylene glycol, butylene glycol, and glycerin. Examples include pyrrolidone compounds such as alcohol, N-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, N-octyl-2-pyrrolidone, crotamiton, and other various surfactants.

  In the external patch of the present invention, various base components used in usual external preparations can be used as long as they do not affect others. The base component is not particularly limited, and examples thereof include rubber-based elastomers such as butyl rubber, polyisobutylene, natural rubber, and polyisoprene rubber; water-soluble polymers such as polyvinyl pyrrolidone, polyvinyl alcohol, and polyacrylic acid; ethyl cellulose, hydroxy Cellulose derivatives such as propylcellulose and hydroxypropylmethylcellulose, silicon compounds such as silicic anhydride and light anhydrous silicic acid, dibutylhydroxytoluene, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxy Phenyl) propionate], tocopherol acetate, ascorbic acid and the like; inorganic fillers such as zinc oxide, aluminum oxide, titanium dioxide, silicas, magnesium oxide, iron oxide and zinc stearate. Furthermore, antiseptics, refreshing agents, bactericides, flavoring agents, coloring agents and the like can be added as necessary.

  Examples of the support for the external patch include films, nonwoven fabrics, knitted fabrics, and laminate composites of nonwoven fabrics and films. Examples of materials for these supports include polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate.

  Polyethylene terephthalate, polypropylene, paper or the like can be used as the release liner used for the external patch, and polyethylene terephthalate is particularly preferable. The release liner may be subjected to silicon treatment as necessary in order to optimize the peeling force.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited to a following example.

Example 1:
SIS (Quintac 3570C; manufactured by Zeon Corporation), alicyclic saturated hydrocarbon resin (Arcon P-100; manufactured by Arakawa Chemical Industries), polybutene (HV-300F; manufactured by Nippon Oil Corporation), liquid paraffin (High Coal M-352; Kaneda) And BHT (butylhydroxytoluene) were dissolved by stirring under heating in a nitrogen atmosphere. Subsequently, loxoprofen sodium, L-menthol, lactic acid, isostearic acid, palmitic acid, and myristic acid, which are main agents, were added to the adhesive, and further stirred and mixed to prepare an adhesive.
The prepared pressure-sensitive adhesive was coated on a silicon-treated polyethylene terephthalate film to form a pressure-sensitive adhesive layer of about 150 μm. The obtained pressure-sensitive adhesive layer was laminated to a polyester woven fabric as a support to obtain an external patch of the present invention.
Table 1 shows the amount of each component.

Examples 2-6:
With the composition shown in Table 1 below, each external patch of Examples 2 to 6 was obtained according to the production method of Example 1.

Comparative Examples 1-9:
With the compositions shown in Tables 2 and 3 below, each external patch of Comparative Examples 1 to 9 was obtained according to the production method of Example 1.
In addition, in the test example described later, as Comparative Example 10, a commercially available loxoprofen-containing plaster agent was used.

Unit:% by weight

*: Reference value unit:% by weight

Test Example 1: Remaining human sticking test Under informed consent, each of the preparations of Examples 2 to 4 and Comparative Examples 1 to 3 was punched into a size of 3 × 4 cm, and each preparation was applied to the subject's back for 24 hours. After the preparations were peeled and collected, loxoprofen sodium remaining in each preparation was extracted, and the amount of the drug was measured by HPLC. The amount of drug disappearance of each preparation was calculated by subtracting the amount of each remaining drug from the amount of loxoprofen drug measured from the preparation applied for 0 hours (not attached). The results are shown in Tables 4 and 5.

  From the results shown in each table, it was confirmed that the preparations of each example, which is an external patch of the present invention, had a higher drug disappearance amount than each comparative example, that is, a preparation having high transdermal absorbability.

Test Example 2: Human keratin drug amount measurement test <Test method>
Under informed consent, each co-trial preparation (2.5 × 2.5 cm) of Example 1 and Comparative Example 10 (commercially available product) was attached to the back of the subject. After pasting for 24 hours, the preparation was peeled off, and the keratin at the peeling site (hereinafter referred to as the peeling site) of each test preparation was peeled off with a keratin peeling tape, and the keratin was collected. Loxoprofen sodium in the obtained stratum corneum was extracted with methanol, and the amount was measured by HPLC measurement. The results are shown in Table 6.

  From the above results, it was confirmed that the external patch of Example 1 of the present invention showed transdermal absorbability equivalent to or higher than that of a commercially available loxoprofen-containing plaster (Comparative Example 10).

Test Example 3: Mouse Skin Permeability Test In vitro mouse skin permeability test using hairless mice was performed to examine the main drug release properties of the external patches of Examples 1-6 and Comparative Examples 2-10. .
The dorsal skin of 8-10 week old hairless mice was peeled off and attached to a Franz-type cell (opening area: 1.77 cm ² ) in which 37 ° C. warm water was circulated around the outer periphery with the dermis side as the receptor layer side. Next, each patch was applied to the stratum corneum side of the skin, and the receptor liquid was sampled at a rate of 2.25 mL / hr for 90 minutes using a PBS (pH 7.4) solution as the receptor liquid, and a high performance liquid chromatography method was performed. Thus, the drug concentration in the collected liquid was measured.
From the results, the skin permeation rate (Flux: μg / cm ² / hr) in a steady state (18-24 hours after the start of the test) was calculated.
The results are shown in Table 7. The flux value is shown as a flux ratio with respect to Comparative Example 10.

      Flux ratio = (flux value in steady state of each example and comparative example) / (flux value in steady state of comparative example 10)

From the above results, it was confirmed that the external patch of each Example exhibited transdermal absorbability equivalent to or higher than that of a commercially available loxoprofen-containing plaster (Comparative Example 10).
On the other hand, the external patches of Comparative Examples 2, 3, and 5-9 were significantly inferior in percutaneous absorbability than Comparative Example 10.

Test Example 4: Stability test (quantitative test of decomposition products)
For each of the preparations of Examples 1 to 4, Example 6, Comparative Example 4 and Comparative Example 5, the degradation products in the stored samples in the storage period of 1 month were measured under the storage conditions at 60 ° C. Further, for each of the preparations of Example 1 and Example 4, the amount of degradation products in the storage sample during the storage period of 3 months was also measured. The sample preparation method and HPLC measurement conditions are shown below.
In this stability test, degradation products derived from lactic acid were particularly measured. Under the HPLC measurement conditions shown below, a decomposition product (hereinafter referred to as decomposition product 1) detected at a relative retention time of 1.55 to 1.60 when the retention time of loxoprofen sodium is 1, and relative A decomposition product (hereinafter referred to as decomposition product 2) detected at a retention time of 1.65 to 1.70 is a main decomposition product derived from lactic acid. Table 8 shows the quantification results of the degradation products in each preparation subjected to the test. Particularly, regarding the quantification results of Example 1 and Comparative Example 4, the quantification results of the degradation product 1 are shown in FIG. The quantitative results are shown in FIG.

<Sample preparation method>
Each preparation was punched into a size of 5 × 7 cm, tetrahydrofuran (hereinafter referred to as THF) was added, and ultrasonic extraction and extraction with a shaker were performed. The obtained extract was made up to 100 mL with THF to obtain an extract. 3 mL of this extract was taken, made up to 50 mL with 40% acetonitrile, filtered using a membrane filter (0.45 μm), and the resulting solution was used as a test sample.

<HPLC measurement conditions>
Column: Unison UK-C18 (3 x 150 mm)
Mobile phase: acetonitrile: water: phosphoric acid = 400: 600: 1
Flow rate: 0.5 mL / min Wavelength: 223 nm
Injection volume: 10 μL

Unit:% generated

  As is apparent from the results shown in Table 8, FIG. 1 and FIG. 2, in the preparation of Comparative Example 4, the amount of degradation products derived from lactic acid increased dramatically over time, whereas the present invention In the preparation of Example 1, the production of decomposition products is greatly suppressed.

INDUSTRIAL APPLICABILITY According to the present invention, an oily external patch containing loxoprofen sodium, having excellent drug release properties and having high stability is provided.
The patch provided by the present invention is an anti-inflammatory analgesic external preparation containing loxoprofen sodium, for example, osteoarthritis, rheumatoid arthritis, low back pain, periarthritis, tendonitis, tendonitis, suprahumeral It is useful for the prevention and treatment of condyleitis (tennis elbow, etc.), muscle pain, swelling and pain after trauma.

Claims (3)

  In an external patch provided with a pressure-sensitive adhesive layer containing 0.1 to 10% by weight of loxoprofen sodium on a support, the pressure-sensitive adhesive layer comprises 5 to 30% by weight of a styrene-isoprene-styrene block copolymer, an alicyclic ring Group saturated hydrocarbon resin 10 to 50% by weight, lactic acid 0.1 to 1% by weight, and higher fatty acid 5 to 15% by weight, and the blending ratio of lactic acid and higher fatty acid is lactic acid / higher fatty acid = 1/50. A patch for external use, which is ˜1 / 5.   The higher fatty acid is one or more selected from isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, capric acid, lauric acid, and caproic acid. The external patch as described.   The external patch according to claim 1 or 2, wherein the higher fatty acid is isostearic acid alone, a combination of isostearic acid and myristic acid, or a combination of isostearic acid, myristic acid and palmitic acid.

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