Patent Application
20240245635
The present invention relates to a patch comprising loxoprofen or a salt thereof, or a hydrate thereof, a C2-C6 hydroxy acid, and a metal oxide, and a method for producing the same.
Loxoprofen is one of the nonsteroidal anti-inflammatory analgesics that exhibits an excellent anti-inflammatory analgesic effect, and has been used as an external agent for a long time, and various studies have been conducted so far to improve the stability and skin permeability of the drug. For example, a technique that suppresses the esterification reaction of a non-steroidal anti-inflammatory analgesic having a carboxy group in the molecule with L-menthol by adding a metal oxide (Patent Document 1), and a technique for suppressing the generation of related substances and improving the drug release rate into the skin by adding an anti-inflammatory drug component having a carboxy group, a C12 to C18 fatty acid, a metal oxide, and liquid paraffin in a pasty preparation, and using a monohydric lower alcohol at the time of production (Patent Document 2), are disclosed. However, these documents do not specifically disclose a loxoprofen-containing patch. Also, regarding a patch containing loxoprofen sodium, a technique for suppressing the generation of degradation products and improving permeability by adding lactic acid and a higher fatty acid at a specific ratio is disclosed (Patent Document 3). However, the patch and the method for producing the same of the present invention are not disclosed nor suggested.
An object of the present invention is to provide a patch that suppresses the degradation products of loxoprofen and shows excellent skin permeability, and a method for producing the same.
The present inventor has earnestly studied in order to solve the above problems. As a result, he has surprisingly found that a patch comprising loxoprofen or a salt thereof, or a hydrate thereof (hereinafter also referred to as “loxoprofen component”), a C2-C6 hydroxy acid, and a metal oxide in a pasty preparation not only suppresses the generation of the menthol ester form in case L-menthol is added, but also suppresses the generation of the ring-opened form in which the 5 membered ring (cyclopentyl ring) of loxoprofen is opened (hereinafter referred to as “ring-opened form of loxoprofen”) which is an oxidative degradation product, and finally completed the present invention. Further, the present inventor has also found that the stability and skin permeability of the drug of said patch are improved by adding additives at the production of a drug liquid in a specific order. More specifically, the present inventor has found that when a drug liquid comprising a loxoprofen component, a C2-C6 hydroxy acid, and a metal oxide is prepared, if the C2-C6 hydroxy acid and the loxoprofen component is mixed at first and then the metal oxide is added thereto, the workability of the preparation of the drug liquid can be improved, and further a patch that suppresses the generation of related substances as well as shows excellent skin permeability can be obtained.
The present invention provides a patch characterized by comprising a loxoprofen component, a C2-C6 hydroxy acid, and a metal oxide in a pasty preparation, and a method for producing the same.
Namely, the present invention relates to the followings.
[1] A patch comprising loxoprofen or a salt thereof, or a hydrate thereof; a C2-C6 hydroxy acid; and a metal oxide in a pasty preparation (hereinafter also referred to as “Present patch”).
[2] The patch according to [1], wherein
The patch according to [10] or [11], wherein the contained amount of the L-menthol is 0.1 to 10% by weight, the contained amount of the higher fatty acid is 0.1 to 20% by weight, the contained amount of the fatty acid ester is 0.1 to 20% by weight, and the contained amount of the antioxidant is 0.05 to 5% by weight, relative to the pasty preparation weight.
[13] The patch according to any one of [1] to [10] comprising loxoprofen sodium dihydrate, lactic acid, zinc oxide, a styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, polybutene, liquid paraffin, L-menthol, isostearic acid, and dibutylhydroxytoluene in a pasty preparation.
[14] A method for producing the patch according to any one of [1] to [13], comprising
The method according to [14], wherein the C2-C6 hydroxy acid-containing solution comprises a C2-C6 hydroxy acid and one or more ingredient(s) selected from the group consisting of L-menthol, a higher fatty acid, and a fatty acid ester.
According to the present invention, a patch that suppresses the generation of degradation products of loxoprofen and shows excellent skin permeability, and a method for producing the same in which the workability at the production is improved, can be provided.
In the present description, “contain” or “comprise” may be used interchangeably with “blend”. Also, in the present description, “contained amount” may be used interchangeably with “amount”.
The Present patch comprises a loxoprofen component, a C2-C6 hydroxy acid, and a metal oxide in a pasty preparation. The pasty preparation is a pasty composition usually comprising an adhesive base comprising an adhesive as a main ingredient, and a drug, and may also be referred to as “adhesive composition”.
Examples of the loxoprofen component contained in the Present patch as an active ingredient include a free form of loxoprofen, a base addition salt of loxoprofen (for example, loxoprofen sodium), and a hydrate of a free form of loxoprofen or a base addition salt of loxoprofen (for example, loxoprofen sodium dihydrate). As the loxoprofen component, loxoprofen sodium or a hydrate thereof is preferable, and loxoprofen sodium dihydrate is more preferable.
The contained amount of the loxoprofen component is not specifically limited as long as formulating can be carried out, but is usually within a range of 0.1 to 10% by weight, preferably 0.5 to 8% by weight, and more preferably 1 to 6% by weight, relative to the pasty preparation weight. When the contained amount of the loxoprofen component in the pasty preparation is less than 0.1% by weight, the transdermal absorbability becomes insufficient. Meanwhile, when said amount is more than 10% by weight, the physical properties of the patch are impaired and said amount is also economically disadvantageous.
The C2-C6 hydroxy acid contained in the Present patch is a very excellent solubilizer of the loxoprofen component, and the loxoprofen component can be stably dissolved in the adhesive base and an excellent transdermal absorption promoting effect can be achieved by containing it.
The C2-C6 hydroxy acid contained in the Present patch is not specifically limited as long as it is an acid with 2 to 6 carbon atoms having hydroxy group(s) and carboxy group(s) in the molecule. Examples of the C2-C6 hydroxy acid include one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitric acid, mevalonic acid, and pantoic acid, one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, and tartaric acid are preferable, and lactic acid is more preferable.
The C2-C6 hydroxy acid is an additive which may react with the loxoprofen component, produce degradation products thereof, and decrease the stability of the formulation. Thus, the contained amount of the C2-C6 hydroxy acid in the Present patch is usually within a range of 0.1 to 2.0% by weight, preferably 0.1 to 1.7% by weight, and more preferably 0.1 to 1.5% by weight, relative to the pasty preparation weight. When the contained amount of the C2-C6 hydroxy acid is less than 0.1% by weight, it is impossible to sufficiently dissolve the loxoprofen component in the adhesive base, and decrease in the transdermal absorbability of the formulation, crystal precipitation of the drug in the formulation during the storage, or the like may occur. Meanwhile, when the contained amount of the C2-C6 hydroxy acid is more than 4.0% by weight, degradation product(s) derived from the C2-C6 hydroxy acid increases, and the stability of the formulation decreases.
Also, the weight ratio of the contained amount of the loxoprofen component and the contained amount of the C2-C6 hydroxy acid is preferably 1:0.01 to 1:0.4, more preferably 1:0.05 to 1:0.35, and further preferably 1:0.07 to 1:0.3.
The metal oxide contained in the Present patch has a function that suppresses the generation of degradation products of loxoprofen.
Examples of the metal oxide contained in the Present patch include one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, calcium oxide, titanium oxide, and iron oxide, one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, and calcium oxide are preferable, and zinc oxide is more preferable.
The amount of the metal oxide contained in the Present patch is usually within a range of 0.03 to 1.5% by weight, preferably 0.06 to 1.2% by weight, and more preferably 0.1 to 1.0% by weight, relative to the pasty preparation weight.
The amount of the metal oxide contained in the Present patch is preferably adjusted depending on the contained amount of the loxoprofen component in order to suppress the generation of degradation products of the loxoprofen component. The weight ratio of the contained amount of the loxoprofen component and the contained amount of the metal oxide is preferably within a range of 1:0.03 to 1:0.3, more preferably 1:0.04 to 1:0.3, and further preferably 1:0.05 to 1:0.3. When the weight ratio of the contained amount of the metal oxide relative to the loxoprofen component is less than 0.03, the effect for suppressing the generation of degradation products becomes insufficient. Meanwhile, when the ratio is more than 0.3, the skin permeability of the drug is suppressed.
Also, the metal oxide is not dissolved, but dispersed in the formulation. The metal oxide contained in the Present patch preferably has a particle size of 1 to 100 nm in view of the dispersibility at the time of manufacture.
In one embodiment, the pasty preparation of the Present patch may further comprise one or more ingredient(s) selected from the group consisting of a base polymer, a tackifier resin, and a softener, and may further optionally comprise other ingredient(s).
Examples of the base polymer which can be used in the Present patch include acrylic adhesives, rubber adhesives, and silicone adhesives, and a rubber adhesive is preferably used. Examples of the rubber adhesive include a natural rubber, polyisobutylene, polyisoprene, polybutadiene, a styrene-isoprene-styrene block copolymer (hereinafter also referred to as “SIS”), a styrene-butadiene rubber, and a styrene-isoprene rubber. One of them or a combination of two or more of them may be used, and a styrene-isoprene-styrene block copolymer (SIS) is preferably used.
The amount of the base polymer contained in the Present patch is determined in view of the contained amounts of other ingredients, and usually within a range of 5 to 50% by weight, preferably 10 to 40% by weight, and more preferably 10 to 30% by weight, relative to the pasty preparation weight. When the contained amount of the base polymer in the pasty preparation is less than 5% by weight, the cohesive force and/or shape retention property of the pasty preparation decrease(s). Meanwhile, when the amount is more than 50% by weight, the adhesive force decreases, the pasty preparation becomes heterogeneous, and the workability during the manufacture decreases.
The tackifier resin used in the Present patch is not specifically limited as long as it is generally contained in a patch, and examples thereof include a rosin resin such as a rosin ester and a hydrogenated rosin glycerol ester; a petroleum resin such as an alicyclic saturated hydrocarbon resin; and a terpene resin, and one of them or a combination of two or more of them may be used. One or more selected from the group consisting of a rosin resin and a petroleum resin are preferable, one or more selected from the group consisting of a hydrogenated rosin glycerol ester and an alicyclic saturated hydrocarbon resin are more preferable, and an alicyclic saturated hydrocarbon resin is further preferable.
The amount of the tackifier resin contained in the Present patch is not specifically limited as long as formulating can be carried out, but is usually within a range of 10 to 60% by weight, preferably 15 to 50% by weight, and more preferably 20 to 40% by weight, relative to the pasty preparation weight. When the contained amount of the tackifier resin in the pasty preparation is less than 10% by weight, the physical properties of the formulation are deteriorated and undesirable phenomena such as pasty preparation residues at the peeling occur. Meanwhile, when said amount is more than 60% by weight, skin irritation occurs.
The softener used in the Present patch is not specifically limited as long as it is compatible with the other base ingredients and provides the pasty preparation with plasticity. Examples of the softener which can be used in the Present patch include polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin, and one of them or a combination of two or more of them may be used. One or more selected from the group consisting of polybutene and liquid paraffin are preferable.
The amount of the softener contained in the Present patch is determined also in view of the contained amounts of the other liquid ingredients contained in the pasty preparation, and usually within a range of 10 to 60% by weight, preferably 20 to 50% by weight, and more preferably 30 to 45% by weight, relative to the pasty preparation weight.
In one embodiment, the pasty preparation of the Present patch may further comprise L-menthol.
L-menthol contained in the Present patch functions as a transdermal absorption enhancer and a refreshing agent. The amount of the L-menthol contained in the Present patch is not specifically limited as long as formulating can be carried out, but is usually within a range of 0.1 to 10% by weight, preferably 0.5 to 8% by weight, and more preferably 1 to 5% by weight, relative to the pasty preparation weight. When the contained amount of the L-menthol in the pasty preparation is less than 0.1% by weight, the transdermal absorbability becomes insufficient. Meanwhile, when said amount is more than 10% by weight, the physical properties of the patch are impaired.
In one embodiment, the pasty preparation of the Present patch may further comprise liquid ingredient(s). In this regard, the liquid ingredient is not necessarily liquid at the normal temperature, and those which are converted to liquids by heating at the time of manufacture are also encompassed.
The liquid ingredient contained in the Present patch has a function that improves the manufacturability by adjusting the viscosity of the drug liquid. Examples of such liquid ingredient include higher fatty acids and fatty acid esters.
Examples of the higher fatty acid include isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, capric acid, lauric acid, and caproic acid, and one of them or a combination of two or more of them may be used. One or more selected from the group consisting of isostearic acid and oleic acid are preferable, and isostearic acid is more preferable.
The amount of the higher fatty acid contained in the Present patch is usually within a range of 0.1 to 20% by weight, preferably 0.5 to 15% by weight, and more preferably 1 to 10% by weight, relative to the pasty preparation weight.
Examples of the fatty acid ester include hexyl laurate, isopropyl myristate, methyl myristate, myristyl myristate, cetyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isopropyl isostearate, diisobutyl adipate, diisopropyl adipate, dioctyl adipate, diisopropyl sebacate, diethyl sebacate, ethyl oleate, decyl oleate, oleyl oleate, ethyl linoleate, isopropyl linoleate, cetyl lactate, and ethyl lactate, and one of them or a combination of two or more of them may be used. One or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate are preferable, and diethyl sebacate is more preferable.
The amount of the fatty acid ester contained in the Present patch is appropriately adjusted by the viscosity of the drug liquid within a range which does not affect the formulation properties, and usually within a range of 0.1 to 20% by weight, preferably 0.5 to 15% by weight, and more preferably 1 to 10% by weight, relative to the pasty preparation weight.
Also, the Present patch may comprise various base ingredients used in normal patches as long as they do not affect the other ingredients. Examples of such base ingredients include, but are not specifically limited to, cellulose derivatives such as polyvinylpyrrolidone, polyvinyl alcohol, and hydroxypropyl methylcellulose; silicon compounds such as anhydrous silicic acid and light anhydrous silicic acid; antioxidants such as dibutylhydroxytoluene (also referred to as “BHT”), pentaerythrityl-tetrakis-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], tocopherol acetate, and ascorbic acid; and inorganic fillers such as silica and zinc stearate. The Present patch may further comprise preservatives such as p-hydroxybenzoates (for example, methyl p-hydroxybenzoate); fungicides such as ethanol and isopropyl alcohol; flavoring agents such as mentha oil; colorants such as yellow ferric oxide, and the like, if necessary, and they may be optionally contained in the Present patch at appropriate amounts.
In one embodiment, the pasty preparation of the Present patch may further comprise an antioxidant. As the antioxidant, dibutylhydroxytoluene is preferable.
The amount of the antioxidant contained in the Present patch is usually within a range of 0.05 to 5% by weight, preferably 0.1 to 1% by weight, and more preferably 0.2 to 0.5% by weight, relative to the pasty preparation weight.
The Present patch usually consists of a backing, a pasty preparation, and a release liner, and the pasty preparation is spread or applied between a backing and a release liner.
Examples of the backing used in the Present patch include films, non-woven fabrics, woven fabrics, knitted fabrics, and laminate composites of non-woven fabrics and films. Examples of the material of these backings include polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate.
Examples of the release liner used in the Present patch include polyethylene terephthalate, polypropylene, and paper, and especially polyethylene terephthalate is preferable. The release liner may be siliconized if necessary in order to optimize the release force.
Examples of the production method of the Present patch include, but are not limited to, a solvent method characterized in that the drug and each base ingredient are dissolved in an organic solvent such as toluene and hexane, and the organic solvent is removed by coating and drying steps; and a hot melt method characterized in that an adhesive composition is melted at a high temperature of 100° C. or higher, and then a coating step is carried out. In one embodiment, the Present patch is produced by a hot melt method.
In the present description, the term of “C2-C6 hydroxy acid-containing solution” may be a solution comprising a C2-C6 hydroxy acid only, or a solution comprising a C2-C6 hydroxy acid and other ingredient(s) (for example, one or more ingredient(s) selected from the group consisting of L-menthol, a higher fatty acid, and a fatty acid ester). Examples of the C2-C6 hydroxy acid-containing solution include a lactic acid solution, and a solution consisting of lactic acid and one or more ingredient(s) selected from the group consisting of L-menthol, a higher fatty acid, and a fatty acid ester.
In the present description, the term of “loxoprofen-containing solution” means a solution obtained by dissolving a loxoprofen component in a C2-C6 hydroxy acid-containing solution.
In the present description, the term of “drug liquid” means a liquid obtained by mixing a loxoprofen-containing solution and a metal oxide.
In the present description, the term of “adhesive solution” means a solution obtained by mixing ingredients comprising an adhesive other than a drug liquid.
The method for producing the Present patch comprises
In one embodiment of the Present production method, the C2-C6 hydroxy acid-containing solution comprises a C2-C6 hydroxy acid and one or more ingredient(s) selected from the group consisting of L-menthol, a higher fatty acid, and a fatty acid ester.
Another embodiment of the Present production method further comprises
Because the Present patch comprises loxoprofen as an active ingredient, it is useful in the prevention or treatment of disease(s) or symptom(s) whose clinical condition(s) is/are expected to be improved by administering loxoprofen. Examples of such disease (s) or symptom(s) include inflammation and pain. Also, examples of the inflammation or pain include muscle pain, osteoarthritis, and posttraumatic swelling and pain.
In the present invention, the term of “prevention” means administering the Present patch to an individual who has not developed disease (s) or symptom(s). Also, the term of “treatment” means administering the Present patch to an individual who has already developed disease(s) or symptom(s). Thus, administering the Present patch to an individual who has already developed disease(s) or symptom(s) for the prevention of deterioration, attack, or recurrence of symptom(s) and the like is an aspect of “treatment”.
The Present patch is usually applied to a patient, for example a human or an animal, and preferably a human who suffers from or is at risk of suffering from the above disease (s) or symptom(s). The frequency of application may appropriately vary depending on conditions such as severity of the disease(s) or symptom(s), age, weight, and sex of the patient, and the amount of loxoprofen in patch. When applied to a human, the Present patch is usually exchanged one or more time(s) per day such as 1 to 3 time(s), 1 to 2 time(s), and once per day, or every several days such as every 2 to 3 days.
Hereinafter, aspects of the present invention are described. Aspects produced by optionally combining the following aspects and aspects produced by optionally combining the following aspect(s) with any of aspect(s) or embodiment(s) etc. disclosed in the present description are also encompassed by the present invention.
The Present patch comprising a loxoprofen component, a C2-C6 hydroxy acid, and a metal oxide in a pasty preparation.
The Present patch according to the Aspect 1, wherein the loxoprofen component is loxoprofen sodium or a hydrate thereof.
The Present patch according to the Aspect 1, wherein the loxoprofen component is loxoprofen sodium dihydrate.
The Present patch according to any one of the Aspects 1 to 3, wherein the C2-C6 hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitric acid, mevalonic acid, and pantoic acid.
The Present patch according to any one of the Aspects 1 to 3, wherein the C2-C6 hydroxy acid is one or more selected from the group consisting of glycolic acid, lactic acid, glyceric acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, γ-hydroxybutyric acid, malic acid, and tartaric acid.
The Present patch according to any one of the Aspects 1 to 3, wherein the C2-C6 hydroxy acid is lactic acid.
The Present patch according to any one of the Aspects 1 to 6, wherein the metal oxide is one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, calcium oxide, titanium oxide, and iron oxide.
The Present patch according to any one of the Aspects 1 to 6, wherein the metal oxide is one or more selected from the group consisting of zinc oxide, magnesium oxide, aluminum oxide, and calcium oxide.
The Present patch according to any one of the Aspects 1 to 6, wherein the metal oxide is zinc oxide.
The Present patch according to the Aspect 1, wherein
The Present patch according to the Aspect 1, wherein
The Present patch according to any one of the Aspects 1 to 11, wherein the contained amount of the loxoprofen component is 0.1 to 10% by weight, the contained amount of the C2-C6 hydroxy acid is 0.1 to 2.0% by weight, and the contained amount of the metal oxide is 0.03 to 1.5% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspects 1 to 11, wherein the contained amount of the loxoprofen component is 0.5 to 8% by weight, the contained amount of the C2-C6 hydroxy acid is 0.1 to 1.7% by weight, and the contained amount of the metal oxide is 0.06 to 1.2% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspects 1 to 11, wherein the contained amount of the loxoprofen component is 1 to 6% by weight, the contained amount of the C2-C6 hydroxy acid is 0.1 to 1.5% by weight, and the contained amount of the metal oxide is 0.1 to 1.0% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspects 1 to 14, wherein the weight ratio of the contained amount of the loxoprofen component and the contained amount of the C2-C6 hydroxy acid is 1:0.01 to 1:0.4.
The Present patch according to any one of the Aspects 1 to 14, wherein the weight ratio of the contained amount of the loxoprofen component and the contained amount of the C2-C6 hydroxy acid is 1:0.05 to 1:0.35.
The Present patch according to any one of the Aspects 1 to 14, wherein the weight ratio of the contained amount of the loxoprofen component and the contained amount of the C2-C6 hydroxy acid is 1:0.07 to 1:0.3.
The Present patch according to any one of the Aspects 1 to 17, wherein the weight ratio of the contained amount of the loxoprofen component and the contained amount of the metal oxide is 1:0.03 to 1:0.3.
The Present patch according to any one of the Aspects 1 to 17, wherein the weight ratio of the contained amount of the loxoprofen component and the contained amount of the metal oxide is 1:0.04 to 1:0.3.
The Present patch according to any one of the Aspects 1 to 17, wherein the weight ratio of the contained amount of the loxoprofen component and the contained amount of the metal oxide is 1:0.05 to 1:0.3.
The Present patch according to any one of the Aspects 1 to 20, wherein the particle size of the metal oxide is 1 to 100 nm.
The Present patch according to any one of the Aspects 1 to 21 further comprising one or more ingredient(s) selected from the group consisting of a base polymer, a tackifier resin, and a softener in the pasty preparation.
The Present patch according to the Aspect 22, wherein the base polymer is a rubber adhesive.
The Present patch according to the Aspect 23, wherein the rubber adhesive is one or more selected from the group consisting of a natural rubber, polyisobutylene, polyisoprene, polybutadiene, a styrene-isoprene-styrene block copolymer, a styrene-butadiene rubber, and a styrene-isoprene rubber.
The Present patch according to the Aspect 23, wherein the rubber adhesive is a styrene-isoprene-styrene block copolymer.
The Present patch according to any one of the Aspects 22 to 25, wherein the tackifier resin is one or more selected from the group consisting of a rosin resin and a petroleum resin.
The Present patch according to any one of the Aspects 22 to 25, wherein the tackifier resin is one or more selected from the group consisting of a hydrogenated rosin glycerol ester and an alicyclic saturated hydrocarbon resin.
The Present patch according to any one of the Aspects 22 to 25, wherein the tackifier resin is an alicyclic saturated hydrocarbon resin.
The Present patch according to any one of the Aspects 22 to 28, wherein the softener is one or more selected from the group consisting of polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin.
The Present patch according to any one of the Aspects 22 to 28, wherein the softener is one or more selected from the group consisting of polybutene and liquid paraffin.
The Present patch according to the Aspect 22, wherein
The Present patch according to any one of the Aspects 22 to 31, wherein the contained amount of the base polymer is 5 to 50% by weight, the contained amount of the tackifier resin is 10 to 60% by weight, and the contained amount of the softener is 10 to 60% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspects 22 to 31, wherein the contained amount of the base polymer is 10 to 40% by weight, the contained amount of the tackifier resin is 15 to 50% by weight, and the contained amount of the softener is 20 to 50% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspects 22 to 31, wherein the contained amount of the base polymer is 10 to 30% by weight, the contained amount of the tackifier resin is 20 to 40% by weight, and the contained amount of the softener is 30 to 45% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspects 1 to 34 further comprising one or more ingredient(s) selected from the group consisting of L-menthol, a higher fatty acid, a fatty acid ester, and an antioxidant in the pasty preparation.
The Present patch according to the Aspect 35, wherein the higher fatty acid is one or more selected from the group consisting of isostearic acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, capric acid, lauric acid, and caproic acid.
The Present patch according to the Aspect 35, wherein the higher fatty acid is one or more selected from the group consisting of isostearic acid and oleic acid.
The Present patch according to the Aspect 35, wherein the higher fatty acid is isostearic acid.
The Present patch according to any one of the Aspect 35 to 38, wherein the fatty acid ester is one or more selected from the group consisting of hexyl laurate, isopropyl myristate, methyl myristate, myristyl myristate, cetyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isopropyl isostearate, diisobutyl adipate, diisopropyl adipate, dioctyl adipate, diisopropyl sebacate, diethyl sebacate, ethyl oleate, decyl oleate, oleyl oleate, ethyl linoleate, isopropyl linoleate, cetyl lactate, and ethyl lactate.
The Present patch according to any one of the Aspect 35 to 38, wherein the fatty acid ester is one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, and diethyl sebacate.
The Present patch according to any one of the Aspect 35 to 38, wherein the fatty acid ester is diethyl sebacate.
The Present patch according to any one of the Aspect 35 to 41, wherein the antioxidant is one or more selected from the group consisting of dibutylhydroxytoluene, pentaerythrityl-tetrakis-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], tocopherol acetate, and ascorbic acid.
The Present patch according to any one of the Aspect 35 to 41, wherein the antioxidant is dibutylhydroxytoluene.
The Present patch according to the Aspect 35, wherein
The Present patch according to any one of the Aspect 35 to 44, wherein the contained amount of the L-menthol is 0.1 to 10% by weight, the contained amount of the higher fatty acid is 0.1 to 20% by weight, the contained amount of the fatty acid ester is 0.1 to 20% by weight, and the contained amount of the antioxidant is 0.05 to 5% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspect 35 to 44, wherein the contained amount of the L-menthol is 0.5 to 8% by weight, the contained amount of the higher fatty acid is 0.5 to 15% by weight, the contained amount of the fatty acid ester is 0.5 to 15% by weight, and the contained amount of the antioxidant is 0.1 to 1% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspect 35 to 44, wherein the contained amount of the L-menthol is 1 to 5% by weight, the contained amount of the higher fatty acid is 1 to 10% by weight, the contained amount of the fatty acid ester is 1 to 10% by weight, and the contained amount of the antioxidant is 0.2 to 0.5% by weight, relative to the pasty preparation weight.
The Present patch according to any one of the Aspects 1 to 47 further comprising one or more ingredient(s) selected from the group consisting of a cellulose derivative, a silicon compound, an inorganic filler, a preservative, a fungicide, a flavoring agent, and a colorant in the pasty preparation.
The Present patch according to the Aspect 48, wherein
The Present patch comprising loxoprofen sodium dihydrate, lactic acid, zinc oxide, a styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, polybutene, liquid paraffin, L-menthol, isostearic acid, and dibutylhydroxytoluene in the pasty preparation.
The Present patch, wherein the pasty preparation consists of loxoprofen sodium dihydrate, lactic acid, zinc oxide, a styrene-isoprene-styrene block copolymer, an alicyclic saturated hydrocarbon resin, polybutene, liquid paraffin, L-menthol, isostearic acid, and dibutylhydroxytoluene.
The Present patch according to the Aspect 50 or 51, comprising
The Present patch according to the Aspect 50 or 51, comprising
The Present patch according to the Aspect 50 or 51, comprising
The Present patch according to any one of the Aspects 52 to 54, wherein the weight ratio of the contained amount of the loxoprofen sodium dihydrate and the contained amount of the lactic acid is 1:0.01 to 1:0.4.
The Present patch according to any one of the Aspects 52 to 54, wherein the weight ratio of the contained amount of the loxoprofen sodium dihydrate and the contained amount of the lactic acid is 1:0.05 to 1:0.35.
The Present patch according to any one of the Aspects 52 to 54, wherein the weight ratio of the contained amount of the loxoprofen sodium dihydrate and the contained amount of the lactic acid is 1:0.07 to 1:0.3.
The Present patch according to any one of the Aspects 52 to 57, wherein the weight ratio of the contained amount of the loxoprofen sodium dihydrate and the contained amount of the zinc oxide is 1:0.03 to 1:0.3.
The Present patch according to any one of the Aspects 52 to 57, wherein the weight ratio of the contained amount of the loxoprofen sodium dihydrate and the contained amount of the zinc oxide is 1:0.04 to 1:0.3.
The Present patch according to any one of the Aspects 52 to 57, wherein the weight ratio of the contained amount of the loxoprofen sodium dihydrate and the contained amount of the zinc oxide is 1:0.05 to 1:0.3.
A method for producing the patch according to any one of the Aspects 1 to 60, comprising
The method according to the Aspect 61, wherein the C2-C6 hydroxy acid-containing solution comprises a C2-C6 hydroxy acid and one or more ingredient(s) selected from the group consisting of L-menthol, a higher fatty acid, and a fatty acid ester.
The method according to the Aspect 61 or 62 further comprising
The method according to any one of the Aspects 61 to 63, comprising
A Present patch produced by the method according to any one of the Aspects 61 to 64.
The Present patch according to any one of the Aspects 1 to 60 or 65 for preventing or treating inflammation or pain.
Use of the Present patch according to any one of the Aspects 1 to 60 or 65 in the manufacture of a medicament for preventing or treating inflammation or pain.
A method for preventing or treating inflammation or pain, which comprises administering the Present patch according to any one of the Aspects 1 to 60 or 65 to a patient.
Use of the Present patch according to any one of the Aspects 1 to 60 or 65 in the prevention or treatment of inflammation or pain.
Hereinafter, the present invention is more specifically illustrated by means of Examples, but the present invention is not limited to the following Examples. In the Examples (Ex.) and Comparative Examples (Com.), numerical values are expressed in “% by weight”, unless otherwise specified.
Loxoprofen sodium dihydrate (hereinafter also referred to as “loxoprofen Na·2H2O”), lactic acid, and isostearic acid were mixed, dissolution of loxoprofen sodium was visually confirmed, and then zinc oxide was added thereto to prepare a drug liquid.
The contained amount of each ingredient is shown in Table 1.
According to each amount shown in Table 1 and Table 2, loxoprofen sodium dihydrate, lactic acid, isostearic acid, and L-menthol were mixed, dissolution of loxoprofen sodium was visually confirmed, and then zinc oxide was added thereto to prepare each drug liquid of Examples 2S to 7S.
Loxoprofen sodium dihydrate and lactic acid were mixed, dissolution of loxoprofen sodium was visually confirmed, and then zinc oxide was added thereto to prepare a drug liquid.
The contained amount of each ingredient is shown in Table 2.
Lactic acid, isostearic acid, and zinc oxide were mixed, and then loxoprofen sodium dihydrate was added thereto to prepare a drug liquid.
The contained amount of each ingredient is shown in Table 3.
According to each amount shown in Table 3 and Table 4, lactic acid, isostearic acid, zinc oxide, and L-menthol were mixed, and then loxoprofen sodium dihydrate was added thereto to prepare each drug liquid of Comparative Examples 2S to 7S.
Loxoprofen sodium dihydrate, lactic acid, and isostearic acid were mixed, dissolution of loxoprofen sodium was visually confirmed, and then zinc oxide was added thereto to prepare each drug liquid of Comparative Examples 8S to 10S in the same manner as Example 1S except that Comparative Example 8S did not comprise lactic acid and Comparative Example 10S did not comprise isostearic acid.
The contained amount of each ingredient is shown in Table 4.
Loxoprofen sodium dihydrate, lactic acid, and isostearic acid were mixed, dissolution of loxoprofen sodium was visually confirmed, and then zinc oxide was added thereto to prepare a drug liquid.
The ingredients other than the drug liquid, i.e., a SIS (SIS5002; manufactured by JSR Corporation), an alicyclic saturated hydrocarbon resin (ARKON P100; manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (HICALL M-352; manufactured by KANEDA Co., Ltd.), and BHT were stirred and dissolved under heating under nitrogen atmosphere to obtain an adhesive solution. To the adhesive solution was added the drug liquid, and the resulting mixture was further stirred and mixed to prepare an adhesive composition. A siliconized polyethylene terephthalate film was coated with the resulting adhesive composition to form an adhesive layer having a thickness of about 150 μm. The resulting adhesive layer was applied on a polyester woven fabric as a backing to obtain a laminate and prepare a patch of Example 9.
The contained amount of each ingredient is shown in Table 5.
Lactic acid, isostearic acid, and zinc oxide were mixed, and then loxoprofen sodium dihydrate was added thereto to prepare a drug liquid.
The ingredients of a SIS (SIS5002; manufactured by JSR Corporation), an alicyclic saturated hydrocarbon resin (ARKON P100; manufactured by Arakawa Chemical Industries, Ltd.), liquid paraffin (HICALL M-352; manufactured by KANEDA Co., Ltd.), and BHT were stirred and dissolved under heating under nitrogen atmosphere to obtain an adhesive solution. To the adhesive solution was added the drug liquid, and the resulting mixture was further stirred and mixed to prepare an adhesive composition. A siliconized polyethylene terephthalate film was coated with the resulting adhesive composition to form an adhesive layer having a thickness of about 150 μm. The resulting adhesive layer was applied on a polyester woven fabric as a backing to obtain a laminate and prepare a patch of Comparative Example 11.
The contained amount of each ingredient is shown in Table 5.
Each patch of Examples 10 and 11 was obtained according to the same method as Example 9 using the contained amounts shown in Table 6, except that to the adhesive solution was added polybutene and to the drug liquid was added L-menthol.
The patch of Example 12 was obtained according to the same method as Example 9 using the contained amounts shown in Table 6, except that diethyl sebacate was used instead of isostearic acid.
The patch of Comparative Example 12 was obtained according to the same method as Example 9 using the contained amounts shown in Table 6, except that to the adhesive solution was added polybutene, to the drug liquid was added L-menthol, and zinc oxide was not contained.
The dissolution state of each drug liquid of Examples 1S to 8S and Examples 9 to 12, and Comparative Examples 1S to 10S and Comparative Examples 11 to 12 was visually confirmed. A drug liquid showing a dissolved state (clear state) was indicated as “o”, while a drug liquid showing an undissolved matter (white cloudy state) was indicated as “x”.
The test results are shown in Tables 1 to 6.
Each patch of Example 9 and Comparative Example 11 stored under a storage condition of 60° C. for 2 weeks, and Examples 10 to 12 and Comparative Example 12 stored under a storage condition of 40° C. for 6 months was cut into a size of 5×7 cm2, put into a 50 mL centrifuge tube, an internal standard substance and tetrahydrofuran (hereinafter referred to as “THF”) were added thereto, and the patch was subjected to ultrasonic extraction and extraction with a shaker. A 0.5 mL of said extract was taken, and a 40% acetonitrile aqueous solution was added thereto such that the volume became 5 mL. Then, the resulting solution was filtered through a membrane filter (0.45 μm), and the produced amount of ring-opened form of loxoprofen was measured by HPLC method using the following measurement conditions.
The test results are shown in Tables 5 and 6. In this regard, the produced amount of ring-opened form of loxoprofen is shown as the ratio of peak area of ring-opened form of loxoprofen (%) relative to peak area of the drug ingredient (loxoprofen sodium).
Each patch of Example 9 and Comparative Example 11 was subjected to an in vitro hairless rat skin permeability test. An excised abdominal skin of a male hairless rat (HWY strain, 7 weeks old) was put in a Franz diffusion cell. The dermis side was set to be the receptor side, the inside of the receptor side was filled with phosphate buffered saline, and hot water of 37° C. was circulated in the water jacket. Each patch was cut into a round shape (1.54 cm2), and applied to the excised skin. The receptor solution was sampled after the test start until 12 hours, and the amount of the drug permeated the skin was measured by HPLC method using the following measurement conditions.
The test results are shown in Table 5.
As can be understood from the results of Examples 1S to 8S and Example 9, and Comparative Examples 1S to 7S and Comparative Example 11, when loxoprofen sodium dihydrate and lactic acid were mixed at first and then zinc oxide was added thereto, the resulting drug liquid showed a dissolution state. Meanwhile, when lactic acid and zinc oxide were mixed at first and then loxoprofen sodium dihydrate was added thereto, undissolved matters were observed and a homogeneous drug liquid could not be prepared.
Also, as can be understood from the comparison of Example 9 with Comparative Example 11, the patch prepared by mixing loxoprofen sodium dihydrate and lactic acid at first and then adding zinc oxide thereto reduced the produced amount of ring-opened form of loxoprofen, which is a degradation product specific to loxoprofen, to about 90%, and yet showed a high cumulative permeation amount of the drug of about 146% at 12 hours, as compared to the patch prepared by mixing lactic acid and zinc oxide at first and then adding loxoprofen sodium dihydrate thereto. Thus, the Present patch was illustrated to be a formulation which can suppress the degradation of the drug and show excellent skin permeability.
Also, as can be understood from the results of Comparative Examples 8S to 10S, even when loxoprofen sodium dihydrate and lactic acid were mixed at first and then zinc oxide was added thereto, if the contained amount of lactic acid was insufficient or the contained amount of lactic acid was too much, undissolved matters were observed in the drug liquid and a homogeneous drug liquid could not be prepared.
Further, as can be understood from the results of Examples 10 to 12 and Comparative Example 12, Examples 10 to 12 comprising zinc oxide significantly suppressed the produced amount of ring-opened form of loxoprofen, as compared to Comparative Example 12 comprising no zinc oxide.
The present invention can provide a patch which shows excellent drug releasability and suppresses the generation of ring-opened form of loxoprofen which is a degradation product specific to loxoprofen and produced in a formulation during storage or manufacturing process. Also, because an undissolved matter of a drug liquid is not generated at the time of manufacture according to the present invention, the present invention can provide a method for producing the patch having excellent manufacturing properties such as improvement in the workability during the preparation of a drug liquid and ease in homogeneously containing the drug in a pasty preparation.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2021-034394 | Mar 2021 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2022/009210 | 3/3/2022 | WO |
