JP6495723B2 - Celecoxib transdermal absorption preparation - Google Patents

Description

  The present invention relates to a celecoxib transdermal absorption preparation.

  To harm cyclooxygenase (COX), nonsteroidal anti-inflammatory drugs (NSAIDs) exert their characteristic anti-inflammatory, antipyretic and analgesic effects by inhibiting the production of prostaglandins. It is considered a mechanism. Conventional NSAIDs, such as ketorolac, diclofenac, naproxen and their salts, are the therapeutically used doses of COX-1, a constitutive (resident) enzyme, and induction related to pathologies such as inflammation and tumorigenesis It inhibits two isozymes of COX-2, which is a type enzyme. Inhibition of COX-1 which produces prostaglandins required for normal cell function appears to be a major cause of certain side effects associated with the use of conventional NSAIDs. On the other hand, selective inhibition of COX-2, which does not substantially inhibit COX-1, provides anti-inflammatory, antipyretic, analgesic and other useful therapeutic effects, but minimizes or eliminates such side effects. Do not wake up. This has led to selective COX-2 inhibitors representing a major advance in the art.

  Many compounds have been reported to have selective COX-2 inhibitory effects that are therapeutically and / or prophylactically useful and treat or prevent specific COX-2 mediated disorders or general such disorders. Are disclosed as having utility in

  Selective COX-2 inhibitors are formulated in various ways, primarily for oral delivery. Among them, celecoxib is widely used as an oral preparation as one of selective COX-2 inhibitors having an excellent anti-inflammatory action.

  Such selective COX-2 inhibitors are expected to be applied to transdermally absorbable preparations for the purpose of achieving not only systemic effects but also local therapeutic effects.

  For example, Patent Document 1 and Patent Document 2 disclose the topical administration of those subject compounds including celecoxib and valdecoxib.

  Thus, the percutaneous absorption preparation of a selective COX-2 inhibitor is expected to be developed because it can be an effective local therapeutic agent with low side effects. However, a percutaneous absorption preparation of selective COX-2 inhibitors including celecoxib has not been commercialized yet. Under such technical circumstances, there is still a need for a transdermally absorbable preparation that enables efficient local administration while stably holding selective COX-2 inhibitors such as celecoxib.

US Pat. No. 5,466,823 US Pat. No. 5,633,272

  In order to apply celecoxib to a percutaneous absorption preparation with good skin permeation, it is necessary to dissolve celecoxib stably in a base or absorption enhancer for the percutaneous absorption preparation. Accordingly, the present inventors tried to dissolve celecoxib in various bases or absorption enhancers for transdermal absorption preparations. As a result, celecoxib was dissolved in the bases or absorption enhancers for transdermal absorption preparations. It was clarified that crystals were precipitated with low solubility. Accordingly, the present invention provides a transdermal absorption preparation capable of stably dissolving and retaining celecoxib, and particularly a transdermal absorption preparation capable of stably dissolving and retaining celecoxib and capable of being locally administered efficiently. For the purpose.

  As a result of intensive studies, the present inventors have recently been able to stably dissolve and retain celecoxib in a transdermal absorption preparation by combining celecoxib with a specific component and crosslinking, and in particular, celecoxib has been administered. It has been found that it can be stably dissolved and retained in a skin-absorbing preparation and can be efficiently administered locally. The present invention is based on such knowledge.

According to the present invention, the following can be provided.
(1) A transdermally absorbable preparation comprising celecoxib, alkyl myristate, an acrylic polymer compound containing a carboxyl group, and a polyvalent metal-based crosslinking agent in an amount of 0.01% by weight or more and less than 0.1% by weight.
(2) The transdermally absorbable preparation according to (1), wherein the content of the celecoxib is 1% by weight or more and 30% by weight or less.
(3) The percutaneously absorbable preparation according to (1) or (2), wherein the alkyl myristate is C1-C25 alkyl myristate.
(4) The transdermally absorbable preparation according to any one of (1) to (3), wherein the acrylic polymer compound containing a carboxyl group is a copolymer comprising (meth) acrylic acid as a monomer unit. .
(5) The transdermal system according to any one of (1) to (4), wherein the acrylic polymer compound containing a carboxyl group is a copolymer comprising (meth) acrylic acid ester as a monomer unit. Absorption formulation.
(6) The warp according to any one of (1) to (5), wherein the polyvalent metal-based crosslinking agent is at least one selected from the group consisting of magnesium oxide, zinc oxide, and aluminum acetylacetonate. Skin absorption preparation.
(7) The percutaneous absorption preparation according to any one of (1) to (6), further comprising a pharmaceutically acceptable additive.
(8) The pharmaceutically acceptable additive is at least one selected from the group consisting of lauromacrogol, sodium cocoylmethyl taurate, hydrogenated soybean phospholipid, polyvinylpyrrolidone, zinc stearate, and menthol. The transdermally absorbable preparation according to any one of 1) to (7).

  According to the transdermal absorption preparation of the present invention, celecoxib can be stably dissolved and retained in the transdermal absorption preparation. In addition, the transdermally absorbable preparation of the present invention can be advantageously used in that celecoxib can be stably dissolved and retained in the transdermally absorbable preparation and efficiently administered locally.

It is a graph which shows the result of an in vitro hairless mouse skin permeation test using the percutaneous absorption preparation by this invention.

Detailed description of the invention

Definitions In this specification, “alkyl” means linear, branched or cyclic alkyl.

Transdermally absorbable preparation The transdermally absorbable preparation of the present invention comprises celecoxib, alkyl myristate, an acrylic polymer compound containing a carboxyl group, and a polyvalent metal-based crosslinking agent of 0.01 wt% or more and less than 0.1 wt%. A drug-containing layer.

  The content of celecoxib is not particularly limited as long as the effect of the present invention is not hindered, but is preferably 1% by weight to 30% by weight of the drug-containing layer, more preferably 1% by weight to 20% by weight, Preferably they are 1 weight% or more and 10 weight% or less.

  The alkyl myristate in the present invention is preferably C1-C25 alkyl myristate, more preferably C2-C20 alkyl myristate, still more preferably isopropyl myristate or octyldodecyl myristate, and more preferably Isopropyl myristate.

  The content of alkyl myristate is not particularly limited as long as the effect of the present invention is not hindered, but is preferably 1% by weight to 50% by weight, more preferably 10% by weight to 40% by weight of the drug-containing layer. More preferably, it is 15 wt% or more and 35 wt% or less, and more preferably 20 wt% or more and 30 wt% or less.

  Further, the acrylic polymer compound containing a carboxyl group in the transdermally absorbable preparation of the present invention is a copolymer comprising (meth) acrylic acid as a monomer unit capable of stably dissolving and retaining celecoxib in a large amount. Is preferably used. Examples of the acrylic polymer compound include (meth) acrylic acid alkyl esters (preferably (meth) acrylic acid) represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate, and the like. A copolymer obtained by further copolymerizing at least one C1-C10 alkyl ester) can be preferably used. Examples of such (meth) acrylic polymers include acrylic acid-2-ethylhexyl / vinyl acetate / acrylic acid copolymer, acrylic acid-2-ethylhexyl / butyl acrylate / acrylic acid copolymer, and acrylic acid. 2-ethylhexyl / methyl acrylate / glycidyl methacrylate / acrylic acid copolymer, Duro-Tak (registered trademark) 87-2100, Duro-Tak (registered trademark) 87-2852, Duro-Tak (registered trademark) 87- 2174, Duro-Tak® 87-2196, Duro-Tak® 87-2353, Duro-Tak® 87-2051, Duro-Tak® 87-2052, Duro-Tak ( Registered trademark) 87-2054, Duro-Tak (registered trademark) 87-2825, Duro-Tak (registered trademark) 87-2677 (manufactured by Henkel Japan), and the like. Therefore, according to one aspect of the present invention, the acrylic polymer compound comprises a copolymer comprising at least one monomer unit selected from the group consisting of alkyl (meth) acrylate, vinyl acetate, and vinyl alcohol. More preferably, it is a copolymer comprising monomer units selected from the group consisting of (meth) acrylic acid, 2-ethylhexyl acrylate, vinyl acetate and vinyl alcohol.

  In the acrylic polymer compound, the molar ratio of the monomer units, the molecular weight, and the like can be appropriately adjusted by those skilled in the art.

  The content of the acrylic polymer compound containing a carboxyl group is not particularly limited as long as the effect of the present invention is not hindered, but is preferably 10% by weight to 50% by weight, more preferably 20% by weight or more of the drug-containing layer. It is 40% by weight or less, more preferably 30% by weight or more and 40% by weight or less, and further preferably 30% by weight or more and 35% by weight or less.

  The polyvalent metal-based crosslinking agent in the present invention is preferably magnesium oxide, zinc oxide or aluminum acetylacetonate, more preferably magnesium oxide or zinc oxide, and further preferably magnesium oxide.

  The content of the polyvalent metal-based crosslinking agent is not particularly limited as long as the effect of the present invention is not hindered, but is preferably 0.01% by weight or more and less than 0.1% by weight of the drug-containing layer, more preferably 0.02%. It is not less than 0.08% by weight and more preferably not less than 0.03% by weight and not more than 0.05% by weight.

Moreover, the percutaneously absorbable preparation of the present invention may contain other pharmaceutically acceptable additives as desired in addition to the above components, as long as the effects of the present invention are not hindered.
Examples of other pharmaceutically acceptable additives include surfactants, plasticizers, excipients, lubricants, solubilizers, and the like. More specifically, for example, polyvinylpyrrolidone, lauromacrogol, cocoyl methyl taurine sodium, L-menthol, hydrogenated soybean phospholipid, zinc stearate and the like can be mentioned.

Production method A preferred production method of the transdermally absorbable preparation according to the present invention is as follows.
First, a necessary amount of the above-described constituents of the present invention is prepared, and stirred and mixed for 60 to 240 minutes under a temperature condition of room temperature to 40 ° C. to obtain a paste solution. The obtained plaster solution is applied onto a polyethylene terephthalate film and dried at a drying temperature of 80 ° C. to obtain a drug-containing layer. If desired, a support layer can be laminated on the drug-containing layer and cut to a desired size to obtain a transdermally absorbable preparation.

  The transdermally absorbable preparation of the present invention is preferably applied about once a day in consideration of suppression of skin irritation and stable and efficient administration of the drug. Therefore, according to another aspect of the present invention, there is provided a method for treating an inflammatory disease comprising applying the transdermally absorbable preparation to the skin of a living body once a day.

  Examples of the living body include rabbits, dogs, and humans, with human beings being preferred.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.

Test Example 1: Selection of Base and Absorption Accelerator In order to make celecoxib into a transdermal absorption preparation, it is necessary to add an absorption accelerator and control celecoxib in the base in order to control the flux. Therefore, as shown below, a base and an absorption accelerator for a celecoxib percutaneous absorption preparation were selected.

1-1: Examination of absorption enhancer Various absorption enhancers (isopropyl myristate, octyl dodecyl myristate, etc.) were added to celecoxib and tested for solubility in each absorption enhancer. It was confirmed not to. From this, in order to stably dissolve celecoxib in the drug-containing layer, not only the absorption promoter, but also an adhesive base (in the drug-containing layer, components excluding celecoxib which is the main ingredient component are shown. ) It was necessary to dissolve it as a whole, and the following examination was conducted. That is, the solubility of celecoxib in the adhesive base was examined.

1-2: Examination of combination of celecoxib, base and absorption enhancer
1-2-1: Styrene / Isoprene / Styrene Block Copolymer Styrene / Isoprene / Styrene Block Copolymer (SIS) is selected as a base, and celecoxib (0.1 to 20% by weight) and four absorption accelerators ( 0.1 to 40% by weight: Isopropyl myristate, polyethylene glycol 400, propylene glycol monocaprylate or diethyl sebacate) was added to each adhesive base, and celecoxib (0.1 to 20% by weight) was blended. All drug-containing layers did not aggregate and could not be formulated.

1-2-2: Polymer compound without carboxyl group Polymer compound without carboxyl group (DURO-TAK (registered trademark) 87-4287 (Henkel Japan), MAS683 (registered trademark) (Cosmedy Pharmaceutical Co., Ltd.) Company), MAS811B (registered trademark) (Cosmedy Pharmaceutical Co., Ltd.), Hi-Tac S-1000 (Toyo Chemical Co., Ltd.) or Hi-Tac S-2000 (Toyo Chemical Co., Ltd.) are selected as the bases, and three types of absorption promotion Adhesive bases containing 0.1 to 40% by weight (isopropyl myristate, cocoyl methyl taurine sodium or hydrogenated soybean phospholipid (Resinol (registered trademark), Nikko Chemicals Co., Ltd.)) were prepared. When celecoxib (0.1 to 20% by weight) was added, good physical properties could not be obtained for all drug adhesive layers, and formulation could not be achieved.

1-2-3: Acrylic polymer compound having a carboxyl group Acrylic polymer compound having a carboxyl group (DURO-TAK (registered trademark) 87-2194: 2-ethylhexyl acrylate / vinyl acetate / acrylic acid copolymer , Henkel Japan) as a base, and three absorption promoters (propylene glycol monocaprylate, isopropyl myristate, octyldodecyl myristate, propylene carbonate or propylene glycol dicaprylate: 0.1 to 40% by weight) Each prepared adhesive base was prepared, and celecoxib (0.1-20% by weight) was added to them. Celecoxib dissolved in the adhesive base only in preparations containing isopropyl myristate or octyldodecyl myristate And the composition obtained is agglomerated and confirmed that it can be formulated. It was.

  From this result, an acrylic polymer compound having a carboxyl group was selected as a base for a celecoxib transdermal absorption preparation, and an myristic acid alkyl ester was selected as an absorption accelerator.

Test Example 2: Examination of prevention of crystal precipitation / Selection of type and concentration of crosslinking agent
2-1: Examination of types of crosslinking agent As the crosslinking agent, a polyvalent metal-based crosslinking agent (aluminum acetylacetonate, magnesium oxide or zinc oxide) was selected as a crosslinking agent for the acrylic polymer compound. A preparation in which such a cross-linking agent was added to a concentration of about 0.01 to 0.4% by weight with respect to the total amount of the composition and a preparation that was not added were stored at room temperature, and their physical properties were compared.

  As a result, for the preparations to which no polyvalent metal-based crosslinking agent was added, crystals were precipitated in the preparations, but for the preparations to which the polyvalent metal-based crosslinking agent was added, precipitation of crystals was observed. I couldn't. That is, it has been found that the addition of a polyvalent metal-based crosslinking agent has effects such as prevention of crystal precipitation.

2-2: Examination of the concentration of the polyvalent metal-based cross-linking agent In addition, the same procedure as in 2-1, except that the concentration of the polyvalent metal-based cross-linking agent (magnesium oxide) is 0.01 to 0.15% by weight. The components of the skin-absorbing preparation were mixed, stirred under a temperature condition of room temperature to 40 ° C. for 60 to 240 minutes, and dried for 15 to 60 minutes to obtain a transdermal absorption preparation. Next, a 12-day accelerated test was performed using the obtained transdermally absorbable preparation under a temperature and humidity condition of 40 ° C. and 75% RH.

  As a result, no precipitation of crystals was observed when the polyvalent metal crosslinking agent was in the range of 0.01 to 0.1% by weight. In particular, when the polyvalent metal crosslinking agent was within a range of 0.01 to less than 0.05% by weight, no change was observed in the preparation, and the adhesiveness was maintained. On the other hand, when the content of the polyvalent metal-based cross-linking agent exceeded 0.1% by weight, crystals did not precipitate immediately but became rubbery and adhesiveness was lowered.

  Further, when the polyvalent metal crosslinking agent was in the range of 0.01 to 0.1% by weight, no change in the content of celecoxib was observed before and after the acceleration test.

Test Example 3: In vitro hairless mouse skin permeation test using percutaneous absorption preparation I) Preparation of test preparation Each component shown in Table 1 was prepared and stirred at room temperature to 40 ° C for 60 to 240 minutes. Thus, a plaster solution was obtained.

The plaster solution was applied onto a polyethylene terephthalate liner and dried at 80 ° C. for 30 minutes to obtain a drug-containing layer. The amount of the drug-containing layer after drying was adjusted to be 143 g / m ² .
Next, a support layer (woven fabric RA001, manufactured by Montel) was laminated on one side of the drug-containing layer opposite to the liner to obtain a desired transdermally absorbable preparation.

II) In vitro hairless mouse skin permeability test The percutaneous absorption preparation (application area: 4.52 cm ² ) was applied to the stratum corneum side of hairless mouse skin, and warm water was circulated so that the skin surface was about 32 ° C. A flow-through cell (5 cm ² ) was set. A 40% (v / v) PEG400 aqueous solution was used as a receiver solution, and the receiver solution was sampled at a rate of 10 mL / hr every 24 hours for up to 24 hours. For the sampling solution, the amount of drug was measured by HPLC, the permeation amount every 2 hours was calculated, and the flux (mcg / cm ² / hr) was calculated.

The result was as shown in FIG. Example 1 and Example 2 show a good flux compared with the comparative example which does not contain a polyvalent metal-based crosslinking agent (magnesium oxide), and target flux 3.6 expected to have a medicinal effect from the results of medicinal effect tests. It was more than (mcg / cm ² / hr).

Test Example 4: Drug efficacy test using carrageenan paw edema model A preparation similar to that in Example 1 and Example 2 was prepared separately, and "Meloxicam's analgesic / anti-inflammatory action. Applied pharmacology. 53 (4/5), 351- 366, 1997 "etc., and then a drug efficacy test using a carrageenan paw edema model was performed (rat, n = 5).
As a result, the edema rate was significantly lower than that of the control group at 2 hours after induction (p <0.01).

Claims (8)

  A transdermally absorbable preparation comprising celecoxib, alkyl myristate, an acrylic polymer compound containing a carboxyl group, and a polyvalent metal-based cross-linking agent in an amount of 0.01% by weight to less than 0.1% by weight.   The transdermally absorbable preparation according to claim 1, wherein the content of celecoxib is 1% by weight or more and 30% by weight or less.   The percutaneous absorption preparation according to claim 1 or 2, wherein the alkyl myristate is C1-C25 alkyl myristate.   The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the acrylic polymer compound containing a carboxyl group is a copolymer containing (meth) acrylic acid as a monomer unit.   The transdermally absorbable preparation according to any one of claims 1 to 4, wherein the acrylic polymer compound containing a carboxyl group is a copolymer comprising (meth) acrylic acid ester as a monomer unit.   The transdermally absorbable preparation according to any one of claims 1 to 5, wherein the polyvalent metal-based cross-linking agent is at least one selected from the group consisting of magnesium oxide, zinc oxide and aluminum acetylacetonate. .   The percutaneous absorption preparation according to any one of claims 1 to 6, further comprising a pharmaceutically acceptable additive. The pharmaceutically acceptable additives, lauroyl macrogol, cocoyl methyl taurine sodium, hydrogenated soybean phospholipid, polyvinylpyrrolidone, at least one of which is selected from the group consisting of zinc stearate and menthol, in claim 7 The transdermally absorbable preparation described.

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