阅读说明：本技术 消炎镇痛外用剂 (External-use anti-inflammatory analgesic ) 是由 石桥贤树 滨本英利 于 2018-06-15 设计创作，主要内容包括：本发明提供一种外用剂,其是包含利多卡因乳酸盐和双氯芬酸或其盐的外用剂,其中作为有效成分的利多卡因和双氯芬酸显示出优异的透皮吸收性且实现了适合于临床应用的经皮渗透性,该外用剂中,利多卡因乳酸盐的含量为双氯芬酸或其盐的2～5摩尔倍。(The present invention provides an external preparation comprising a lidocaine lactate and diclofenac or a salt thereof, wherein lidocaine and diclofenac as active ingredients exhibit excellent transdermal absorbability and achieve transdermal permeability suitable for clinical use, and the content of the lidocaine lactate in the external preparation is 2 to 5 molar times that of diclofenac or a salt thereof.)

1. An external preparation comprising a lidocaine lactate and diclofenac or a salt thereof, wherein the content of the lidocaine lactate is 2 to 5 mol times that of the diclofenac or the salt thereof.

2. The external preparation according to claim 1, wherein the content of the lactic acid salt of lidocaine is 5 to 40% by weight.

3. The external preparation according to claim 1 or 2, wherein diclofenac or a salt thereof is contained in an amount of 1 to 20% by weight.

4. The external preparation according to claim 1 ~ 3, further comprising an ester.

5. The external preparation according to claim 4, wherein the ester is diethyl sebacate, methyl laurate, diisopropyl adipate, isopropyl myristate, propylene carbonate or a mixture thereof.

6. The external preparation according to any one of claims 1 ~ 5, which is a matrix-type patch preparation (patch).

7. The external preparation according to claim 6, wherein the adhesive layer comprises: a polymer dispersed with a solution comprising lidocaine lactate and diclofenac or its salt.

8. A method for producing the external preparation according to claim 1, which comprises:

mixing lidocaine with lactic acid to obtain a lidocaine lactate which is liquid at normal temperature; and

and a step of dissolving diclofenac or a salt thereof in a lactic acid salt of lidocaine.

Technical Field

The present application claims priority to japanese patent application No. 2017-119144, which is hereby incorporated by reference in its entirety into this specification.

The present invention (disclosure) relates to an external preparation containing an equimolar salt of lidocaine-lactic acid (lidocaine lactate) and diclofenac or a salt thereof.

Background

Various proposals have been made for external preparations containing a non-steroidal anti-inflammatory analgesic and a local anesthetic (for example, patent documents 1 to 5). Diclofenac sodium, one of the widely used non-steroidal anti-inflammatory analgesics, has low solubility in a solvent, and is difficult to produce into an external preparation such as a patch preparation. In order to improve the transdermal permeability of diclofenac, attempts have been made to combine diclofenac with a local anesthetic and ionically liquefy the diclofenac (patent documents 2 to 5). It has been reported that formation of ion pairs can achieve certain results such as lowering of melting point, improvement of solubility in organic solvents, and reduction of skin irritation. However, the solubility of diclofenac-lidocaine salts in solvents is still insufficient, and further improvement in formulation is desired. Therefore, there has been no report of clinically usable external preparations containing diclofenac and lidocaine.

As a technique for improving the transdermal absorbability by easily dissolving lidocaine in an organic solvent, a lidocaine lactate in which lidocaine is ionically liquefied by reacting lidocaine with an equimolar amount of lactic acid is known (patent document 6).

Disclosure of Invention

Technical problem to be solved by the invention

The purpose of the present invention is to provide an external preparation which comprises lidocaine and diclofenac or a salt thereof as active ingredients, wherein both the drugs have excellent percutaneous absorbability and can achieve percutaneous permeability suitable for clinical use.

Technical scheme for solving technical problem

Then, the present inventors have conducted extensive studies to solve the above problems, and as a result, have found that when diclofenac sodium is dissolved in an appropriate ratio in an equimolar salt (ionic liquid) of lidocaine-lactic acid, crystals of lidocaine and diclofenac are not precipitated, and the solution state is maintained, whereby percutaneous permeability suitable for clinical use is obtained for both drugs. Further, it has been found that even in the case of preparing an external preparation containing lidocaine and diclofenac or a salt thereof as active ingredients at a high concentration, crystals thereof are not precipitated and exist in a state of being uniformly compatible or dispersed in an adhesive layer, thereby exhibiting excellent transdermal permeability, and the present invention has been completed.

That is, the present invention provides the following embodiments;

[1] an external preparation comprising a lidocaine lactate and diclofenac or a salt thereof, wherein the content of the lidocaine lactate is 2 to 5 molar times that of the diclofenac or the salt thereof;

[2] the external preparation according to [1], wherein the content of the lactic acid salt of lidocaine is 5 to 40 wt%;

[3] the external preparation according to [2], wherein the content of diclofenac or a salt thereof is 1 to 20% by weight;

[4] the external preparation according to any one of [1] to [3], further comprising an ester;

[5] the external preparation according to [4], wherein the ester is diethyl sebacate, methyl laurate, diisopropyl adipate, isopropyl myristate, propylene carbonate or a mixture thereof;

[6] the external preparation according to any one of [1] to [5], which is a matrix type patch preparation (テープ agent);

[7] the external preparation according to [6], wherein the adhesive layer comprises: a polymer dispersed with a solution comprising a lactic acid salt of lidocaine and diclofenac or a salt thereof;

[8] a process for producing the external preparation according to [1], which comprises:

mixing lidocaine with lactic acid to obtain a lidocaine lactate which is liquid at normal temperature; and

and a step of dissolving diclofenac or a salt thereof in a lactic acid salt of lidocaine.

ADVANTAGEOUS EFFECTS OF INVENTION

By combining two analgesics (lidocaine and diclofenac) having different mechanisms of action, both have sufficient transdermal permeability, and an extremely excellent analgesic for reducing both inflammatory pain and neuropathic pain can be provided. In addition, the two drugs lidocaine and diclofenac exist in a solution state, and thus the decrease in adhesion to the skin is suppressed in the case of making a patch.

Drawings

FIG. 1 is a three-component phase diagram (three-component mixed state diagram) showing a state in which lidocaine, lactic acid and diclofenac sodium are mixed at relative ratios, ● shows a transparent solution state in which no crystal precipitation of lidocaine and diclofenac occurs, ■ shows a turbid white solution state in which no crystal precipitation of lidocaine and diclofenac occurs, and a solid state in which a part or all of lidocaine and/or diclofenac sodium is not dissolved is left;

FIG. 2 is a graph showing the transition of the concentration of diclofenac in plasma (change with time) in a pharmacokinetic test using a minipig;

fig. 3 is a graph showing the transition (change with time) of the plasma concentration of lidocaine in a pharmacokinetic test using a mini-pig.

Detailed Description

[ Lidocaine lactate (ionic liquid) ]

The lidocaine lactate is an ionic liquid (ambient temperature molten salt) obtained by combining lidocaine with an equimolar amount of lactic acid. The lactic acid salt of lidocaine was obtained by: lidocaine and an equimolar amount of lactic acid are mixed in the presence or absence of a solvent, and heated (for example, 80 ℃). Alternatively, the lactate salt of lidocaine can be obtained by mixing at room temperature. It may be that lidocaine reacts with a portion of the lactic acid to form an equimolar salt, with unreacted lidocaine and/or lactic acid present. Lidocaine is a solid at ordinary temperature, but lidocaine lactate is a viscous liquid at ordinary temperature.

The content of the lactic acid salt of lidocaine is, for example, 5 to 40% by weight, preferably 10 to 35% by weight, more preferably 20 to 30% by weight, most preferably 25 to 30% by weight. The concentration of lidocaine lactate may be about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, or about 40 wt%.

[ diclofenac acid or salt thereof ]

Diclofenac or its salt is usually used in the form of a metal salt such as a sodium salt, a potassium salt or the like, but is not limited thereto. The diclofenac salt includes pharmaceutically acceptable salts such as salts with a free acid or an organic base. In one embodiment, diclofenac or its salts are selected from diclofenac sodium or diclofenac potassium.

The external preparation of the present invention contains 2 to 5 moles, 2 to 4 moles, or 2.5 to 3.5 moles of a lactic acid salt of lidocaine per 1 mole of diclofenac. If the ratio of the lactate salt of lidocaine to diclofenac is within the above range, the transdermal absorbability of lidocaine and diclofenac is improved together.

The content of diclofenac or its salt is, for example, 1 to 20% by weight, preferably 2 to 20% by weight, more preferably 5 to 10% by weight. For example, the concentration of diclofenac sodium may be about 1 weight percent, about 2 weight percent, about 5 weight percent, about 10 weight percent, about 15 weight percent, or about 20 weight percent.

The external preparation of the present invention may contain unreacted lidocaine and/or lactic acid.

In one embodiment, diclofenac is dissolved in lidocaine lactate. In this case, the external preparation of the present invention is not only a mixture of lidocaine, lactic acid and diclofenac, but also a mixture of lidocaine-diclofenac salt and lactic acid.

The external preparation of the present invention can be prepared, for example, by mixing lidocaine, lactic acid, and diclofenac, and mixing them with heating (for example, about 80 ℃) as necessary. In one embodiment, the external preparation of the present invention can be prepared by mixing lidocaine and lactic acid, heating and mixing them as necessary to prepare a lidocaine lactate, and mixing diclofenac with the lidocaine lactate.

The external preparation of the present invention may further contain an organic solvent having a transdermal absorption promoting effect such as alcohols, esters, fatty acids, amines, and the like. Two or more kinds of organic solvents may be used in combination. The content of the organic solvent is, for example, 1 to 30% by weight, preferably 1 to 20% by weight, more preferably 1 to 10% by weight. In addition, the organic solvent may contain less than 1.0 wt% of water. When the external preparation of the present invention is a matrix-type adhesive preparation (patch), if the content of the organic solvent is too large, the pressure-sensitive adhesive layer of the adhesive preparation is softened, and the preparation may be difficult.

In one embodiment, the alcohol may be a monohydric alcohol such as lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, or cetyl alcohol; dihydric alcohols such as propylene glycol, butylene glycol, dipropylene glycol, diisobutylene glycol, polyethylene glycol, hexylene glycol and the like; trihydric alcohols such as glycerol and hexanetriol. One kind of alcohols may be used or two or more kinds may be used in combination.

In one embodiment, the ester may be diethyl sebacate, methyl laurate, diisopropyl adipate, isopropyl myristate, or propylene carbonate. In addition, one kind of ester may be used or two or more kinds may be used in combination.

In one embodiment, the external preparation of the present invention comprises lidocaine lactate, diclofenac or a salt thereof, and isopropyl myristate. Isopropyl myristate has the effect of promoting transdermal penetration of both lidocaine and diclofenac.

In one embodiment, the fatty acid may be a saturated or unsaturated fatty acid such as levulinic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, or oleic acid. In addition, one kind of fatty acid may be used or two or more kinds may be used in combination.

In one embodiment, the amine may be monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine, ethylenediamine, or tris (hydroxymethyl) aminomethane. Further, one kind of the amine may be used or two or more kinds may be used in combination.

The external preparation of the present invention may further comprise a surfactant. The surfactant can be nonionic surfactant such as glyceryl monostearate and polyoxyethylene hydrogenated castor oil; anionic surfactants such as sodium lauryl sulfate and potassium lauryl sulfate; cationic surfactants such as benzalkonium chloride and octadecyl trimethyl ammonium chloride. Two or more kinds of surfactants may be used in combination.

The content of the surfactant is, for example, 0.01 to 2% by weight, preferably 0.01 to 1% by weight.

In one embodiment, the external preparation of the present invention may further comprise lidocaine or a salt thereof which does not form a lactate salt of lidocaine, and/or lactic acid.

[ base type adhesive preparation ]

The external preparation of the present invention may have a structure in which an adhesive layer containing an active ingredient is provided on at least one surface of a support. In the external preparation of the present invention, a solution containing a lactic acid salt of lidocaine and diclofenac or a salt thereof is dispersed in a pressure-sensitive adhesive layer made of a suitable polymer (elastomer) to prepare a matrix-type patch preparation. Useful polymers may include acrylic polymers, rubber-based polymers, silicone-based polymers, vinyl ether-based polymers. In one embodiment, a rubber-based polymer such as a styrene-isoprene-styrene block copolymer, a styrene-butadiene-styrene block copolymer, polyisoprene, polyisobutylene, or polybutadiene can be preferably used. The rubber-like polymer may be present in an amount of about 5 to 40 wt%, or about 5 to 20 wt%, relative to the total dry weight of the adhesive layer. The acrylic polymer and the silicone polymer may be contained in an amount of about 45 to 90 wt%, or about 50 to 80 wt%, relative to the total dry weight of the adhesive layer. Further, two or more kinds of the polymers may be used in combination.

In one embodiment, the adhesive layer may further contain a filler such as hydrated silica, fumed silica, talc, crystalline cellulose, starch, carboxymethyl cellulose, or a carboxymethyl cellulose metal salt. The filler can improve the adhesion characteristics of the adhesive layer and increase the release rate of the active ingredient. The content of the filler is, for example, in the range of 0.5 to 15% by weight, preferably about 1 to 10% by weight, more preferably about 2 to 5% by weight, based on the total dry weight of the adhesive layer.

The adhesive layer may further contain other additives such as a tackifier, a softener, an antioxidant, and the like. Examples of the tackifier include rosin esters, hydrogenated rosin esters, maleated rosin, alicyclic saturated hydrocarbon resins, terpene resins, and polyolefin resins. Examples of the softener include vegetable oils such as naphthenic process oils, camellia oils, and castor oils; liquid rubbers such as liquid polybutene and liquid isoprene rubber, and liquid paraffin. Examples of the antioxidant include dibutylhydroxytoluene, ascorbic acid, propyl gallate, sodium sulfite, and sodium metabisulfite.

When the external preparation of the present invention is prepared into a matrix type adhesive preparation, the content of the lactic acid salt of lidocaine may be in the range of about 5 to 40%, about 10 to 35%, about 20 to 30%, or about 25 to 30% of the total dry weight of the adhesive layer.

In the present specification, the term "about" when a numerical value is included means a range including ± 2% of the value. The range of values includes all values between the two endpoints and both endpoints. For example, "about 5%" means "5% ± 2%". However, it is not 0% or less.

The external preparation of the present invention can also be used as cream, ointment, lotion, cataplasm, etc.

The dosage of the external preparation of the present invention varies depending on the symptoms, age and the like of the patient, and it is generally preferred to apply the external preparation 1 time to several times in a day for an adult. More preferably, the administration is performed 1 to 2 times per day, but the number of administrations may be increased depending on the symptoms.

The external preparation of the present invention shows the following characteristics in a pharmacokinetic test using a mini-pig. That is, the AUC of diclofenac obtained in the case of 12 hours after application of the external preparation of the present invention_0-12About 6 to about 7 times of the case where a commercially available diclofenac paste preparation (Flector (registered trademark)) containing the same amount of diclofenac was used, C_maxFrom about 8 to about 9.5 times. AUC of lidocaine at 12 hours after application of the external preparation of the present invention_0-12About 3.5 to about 4.5 times that of a commercially available lidocaine patch preparation (Lioderm (registered trademark)) containing the same amount of lidocaine, C_maxFrom about 4 to about 5 times.