JP5410071B2 - Esterification inhibitor and method for inhibiting esterification - Google Patents

Description

  The present invention relates to an esterification inhibitor and an esterification inhibition method for improving the storage stability of a nonsteroidal anti-inflammatory drug in an external preparation.

  For example, as an anti-inflammatory analgesic agent, it contains an anti-inflammatory drug having a carboxyl group such as ibuprofen, indomethacin, flurbiprofen, ketoprofen, loxoprofen, diclofenac, felbinac, etc. A patch containing a compound having a hydroxyl group is provided.

In such a patch, the compound having a carboxyl group and a hydroxyl group of the drug produces an ester compound during the storage of the preparation, and the content of the drug in a non-aqueous patch decreases with time. It has been known.
Therefore, in order to prevent a decrease in the content of the drug over time, it has been studied to suppress the formation of the ester compound by blending a specific compound as follows.

  For example, Patent Document 1 discloses an external patch containing an anti-inflammatory drug having a carboxylic acid group in its molecule (for example, ketoprofen), l-menthol, and a fatty acid metal salt, and the external patch contains a fatty acid metal salt. Thus, an external patch is disclosed in which the formation of an ester compound between a drug and l-menthol is suppressed, the stability is excellent, and the drug absorbability is also excellent.

  Patent Document 2 discloses indomethacin and a patch containing polyethylene glycol as a solubilizer thereof, and describes a stable patch in which the esterification reaction is suppressed by using a specific polyethylene glycol. .

  However, the techniques for preventing esterification using fatty acid metals, polyethylene glycol, and the like disclosed so far have not been sufficient, and a technique for further suppressing the esterification reaction between a drug and l-menthol has been demanded.

On the other hand, antioxidants (antioxidants) having sulfur atoms in their molecules are widely used in pharmaceutical preparations and food fields to prevent the oxidation of drugs and the like and improve storage stability.
For example, Patent Document 3 discloses an anti-inflammatory analgesic composition for external use, which discloses a non-steroidal anti-inflammatory analgesic (for example, ketoprofen), sodium bisulfite, 2-mercaptobenzimidazole and the like as an antioxidant, and a dosage form Describes liquids, creams, ointments, gels, patches, aerosols and the like, and describes 1-menthol as a component added as necessary. However, there is no disclosure or suggestion on the point of suppressing esterification of a non-steroidal anti-inflammatory analgesic agent, which is a drug, and l-menthol and stabilizing the drug.

  Also, Patent Document 4 discloses an emulsified external preparation containing diclofenac sodium, and discloses an example of an emulsified external preparation containing l-menthol and sodium bisulfite. Similarly, diclofenac sodium which is a drug is disclosed. There is no disclosure or suggestion on the point of inhibition of esterification between 1 and menthol.

  Patent Document 5 discloses an indomethacin-containing external preparation composition containing sodium thiosulfate as an indomethacin stabilizer and an anti-coloring agent, and by adding sodium thiosulfate, indomethacin excellent in stability and anti-coloring effect A containing external preparation composition is provided. However, there is no description that sodium thiosulfate suppresses the formation of ester compounds.

Republished patent WO96 / 08245 (A1) JP 2001-302502 A JP 2002-128701 A JP-A-9-012452 JP 2000-072672 A

  An object of the present invention is to provide an esterification inhibitor and a method for inhibiting esterification that effectively suppress the formation of an ester compound in a composition in which a nonsteroidal anti-inflammatory drug having a carboxyl group in the molecule coexists with l-menthol. The point is to provide.

  When a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule coexists with l-menthol in the composition, an equilibrium reaction proceeds and an ester compound is generated. This reaction proceeds during storage of the composition, and is accelerated and generated particularly by heat load during manufacture of the composition. As a result of intensive studies to suppress the formation of the ester compound as described above, the present inventors have surprisingly been able to produce an ester compound by blending sodium bisulfite, 2-mercaptobenzimidazole and the like. It was found to be suppressed.

That is, the present invention, during external preparation of the non-aqueous, a non-steroidal anti-inflammatory drugs and l- menthol to suppress the esterification of Rue esterification inhibitor having a carboxyl group in the molecule, bisulfite The mass ratio of the non-steroidal anti-inflammatory drug consisting of sodium and / or 2-mercaptobenzimidazole having a carboxyl group in the molecule, the l-menthol and the esterification inhibitor is 1: 1 to 2: 0. An esterification inhibitor characterized by being used in a range of from 0.5 to 0.5 is provided.
The present invention also provides that the non-steroidal anti-inflammatory drug having a carboxyl group in the molecule is diclofenac, ampenac, indomethacin, acemetacin, etodolac, sulindac, nabumetone, mofezolac, felbinac, aluminoprofen, ibuprofen, ketoprofen, flurbi There is provided an esterification inhibitor characterized by being one selected from the group consisting of profen, loxoprofen, oxaprozin, zaltoprofen, thiaprofenic acid, naproxen, and pranoprofen.
The present invention is a non-steroidal anti-inflammatory drugs having a carboxyl group in the molecule to provide an esterification inhibitor, which is a ketoprofen.
The present invention, when stored for 10 days at 70 ° C., non-steroidal anti-ratio of generating the number of moles of the esterified compound for inflammatory drug, characterized in that 0.007 or less esterification inhibitor to provide.
Furthermore, this invention uses the esterification inhibitor of the said invention, and suppresses esterification with the non-steroidal anti-inflammatory drug which has a carboxyl group in the said molecule | numerator, and the said 1-menthol in a non-aqueous external preparation. It is an esterification suppression method, Comprising: Mass ratio of the non-steroidal anti-inflammatory drug which has a carboxyl group in the said molecule | numerator, the said 1-menthol, and the said esterification inhibitor is 1: 1-2: 0.05-0. In the range which becomes 5, the esterification inhibitor is used.

  Hereinafter, the esterification inhibitor and the esterification inhibition method of the present invention will be described in detail.

As the esterification inhibitor referred to in the present invention, sodium bisulfite and / or 2-mercaptobenzimidazole are used.
Sodium bisulfite is sodium bisulfite, a compound represented by the chemical formula NaHSO ₃ , and is also called sodium bisulfite. Sodium bisulfite is generally blended in foods and pharmaceuticals as an antioxidant.
2-Mercaptobenzimidazole is also generally blended with external preparations as an antioxidant and is sometimes called an anti-aging agent in the rubber industry.
By blending sodium bisulfite and 2-mercaptobenzimidazole, esterification of a nonsteroidal anti-inflammatory drug having a carboxyl group in the molecule with l-menthol can be excellently suppressed.

The non-steroidal anti-inflammatory drug having a carboxyl group in the molecule according to the present invention includes, for example, diclofenac, ampenac, indomethacin, acemetacin, etodolac, sulindac, nabumetone, mofezolac, felbinac, aluminoprofen, ibuprofen, ketoprofen, Flurbiprofen, loxoprofen, oxaprozin, zaltoprofen, thiaprofenic acid, naproxen, pranoprofen and the like are preferable. These drugs can also be pharmaceutically acceptable salts. Pharmaceutically acceptable salts are, for example, salts with alkali metals such as potassium, sodium, calcium and magnesium, alkaline earth metals and ammonium.
In the present invention, a drug that is unstable to heat load or light such as ketoprofen is particularly preferably used.

The mass ratio of non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, and esterification inhibitor should be used in the range of 1: 0.2 to 5: 0.01 to 1, respectively. It is more preferable that it is used at 1: 1 to 2: 0.05 to 0.5. By using each component in this predetermined range, the production amount of the ester compound can be suppressed extremely low.
When a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, and an esterification inhibitor are mixed and stored at 70 ° C. for 10 days, the ratio of the ester compound produced is the original non-steroidal mixed The ratio of the number of moles to the number of moles of anti-inflammatory drug is 0.007 or less (0.7% or less when expressed as a percentage).

  The reason why the formation of the ester compound is suppressed by sodium bisulfite and / or 2-mercaptobenzimidazole is not clear, but any radical species generated by a thermal load in the production process or chemical species generated via the radical species are drugs. The possibility of being involved in the production of the ester compound is considered, and it is speculated that the esterification inhibitor effectively inhibits the production reaction.

  Sodium bisulfite and / or 2-mercaptobenzimidazole as the esterification inhibitor of the present invention can be used by blending in the composition. That is, sodium bisulfite and / or 2-mercaptobenzimidazole as an esterification inhibitor has a situation where an ester bond occurs, in other words, a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule and l-menthol. The present invention is effective in a non-aqueous composition, for example, a non-aqueous pharmaceutical composition, although it can be used regardless of whether it is an aqueous composition or a non-aqueous composition. Can be used in products or formulations. Although it does not specifically limit as a non-aqueous pharmaceutical formulation, For example, a patch, an ointment, and an aerosol agent are mentioned, For example, it is especially effective in a patch as an external preparation.

  In addition, the non-aqueous composition as used in the field of this invention is a composition which does not contain a water | moisture content substantially, and means the composition whose water | moisture content in a composition is 5 mass% or less, Preferably it is 3 mass% or less.

As an external preparation to which the present invention is applied, for example, a patch is a preparation as follows.
The patch can be used in either a reservoir type or a matrix type, but in the case of a matrix type, usually a support, an adhesive layer containing a drug on at least one side thereof, and the adhesive layer until immediately before use. A protective film for protecting
The pressure-sensitive adhesive layer contains at least a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, and an esterification inhibitor, and further contains a pressure-sensitive adhesive to impart pressure-sensitive adhesiveness.

The non-steroidal anti-inflammatory drug having a carboxyl group in the molecule is blended in the adhesive layer without any particular limitation as long as it has a concentration exhibiting its effect, but is usually 0.1 to 10% by mass with respect to the entire adhesive layer, If it is preferably 0.2 to 8% by mass, more preferably 0.3 to 5% by mass, a therapeutic effect due to anti-inflammatory action can be obtained.
When the concentration of the drug is less than 0.1% by mass, a sufficient therapeutic effect cannot be obtained, and when the concentration is increased, the effect is increased. May reduce the adhesion of the skin to the skin.

  l-Menthol is blended according to the refreshing sensation to be obtained, or blended for the purpose of drug dissolution, absorption promotion, etc., and blended at 0.5 to 10% by mass with respect to the entire adhesive layer.

  Sodium bisulfite and / or 2-mercaptobenzimidazole as an esterification inhibitor is preferably blended at 0.01 to 2% by mass with respect to the entire adhesive layer. If the amount is less than 0.01% by mass, the inhibitory effect on the formation of the ester compound is insufficient, and if the concentration is increased, the inhibitory effect is enhanced. However, even if the amount exceeds 2% by mass, the effect is not significantly increased.

  The pressure-sensitive adhesive to be blended in the pressure-sensitive adhesive layer is not particularly limited as long as it is a pressure-sensitive adhesive that can be usually used in patches, and acrylic pressure-sensitive adhesives and rubber-based pressure-sensitive adhesives mainly composed of natural or synthetic rubber can be used. In particular, a polymer having no reactive functional group such as a carboxyl group or a hydroxyl group does not cause esterification with l-menthol or a non-steroidal anti-inflammatory agent, so that a more stable preparation can be obtained. In view of this, a non-functional rubber-based pressure-sensitive adhesive having no reactive functional group is more preferably used.

  The natural or synthetic rubber is not particularly limited as long as it is generally used for a patch. For example, natural rubber, polyisoprene, polyisobutylene, polybutadiene, styrene-isoprene-styrene block copolymer ( S-I-S block copolymer), styrene-butadiene rubber, or styrene-isoprene rubber may be used alone or in combination, and a styrene-isoprene-styrene block copolymer is preferred. Natural or synthetic rubber is blended in an amount of 10 to 40% by mass with respect to the entire pressure-sensitive adhesive layer. If it is less than 10% by mass, the pressure-sensitive adhesiveness is insufficient, and this effect increases with increasing concentration, but exceeds 40% by mass. And there is a tendency that pressure-sensitive adhesiveness suitable as a patch cannot be obtained.

  In addition to the pressure-sensitive adhesive, the pressure-sensitive adhesive layer can contain a tackifier resin, a softener, and other additives as necessary.

  The tackifying resin is not particularly limited as long as it is generally used for a patch. For example, polyterpene resin, rosin ester resin, hydrogenated rosin ester resin, alicyclic saturated hydrocarbon resin, terpene Phenol resins and petroleum resins are preferred. The tackifier resin is blended in an amount of 10 to 40% by mass with respect to the entire adhesive layer, and if it is less than 10% by mass, the effect of imparting tackiness is insufficient. If it exceeds, pressure-sensitive adhesiveness suitable as a patch will not be obtained.

  The softening agent is not particularly limited as long as it is generally used for patches, but for example, liquid paraffin, liquid polybutene, liquid polyisoprene, animal and vegetable oils and the like are preferable. The softening agent is blended in an amount of 30 to 70% by mass with respect to the entire pressure-sensitive adhesive layer, and appropriate pressure-sensitive adhesiveness can be imparted within this range.

  The above-mentioned other additives are not particularly limited as long as they are generally used for patches, but if exemplified, drugs other than the above-mentioned drugs, absorption promoters, fillers, oxidation Examples thereof include an inhibitor, a solubilizer, a solubilizer, an ultraviolet absorber, a fragrance, and a pigment.

  In addition to non-steroidal anti-inflammatory analgesics, drugs to be blended in addition to the above-mentioned drugs include hot pepper ingredients such as capsaicin, warm sensation ingredients such as nonylic acid vanillylamide, essential oil ingredients, and other ingredients (for example, plant extracts, acetic acid) Tocopherol etc.) can be blended.

  The thickness of the adhesive layer of the patch is preferably 20 to 300 μm, and is effective in maintaining pressure-sensitive adhesiveness suitable as a patch within this range.

  The patch support is a layer provided by laminating the above-mentioned adhesive layer, and is not particularly limited as long as it is generally used for a patch. For example, polyethylene, polypropylene, polybutadiene, ethylene- Synthetic resins such as vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride, polyamide, polyester, nylon, cellulose derivatives, polyurethane can be used, film, sheet, sheet-like porous body, Sheet-like foams, fabrics such as woven fabrics, knitted fabrics, and nonwoven fabrics, or laminates thereof can be used. As the support, a material having elasticity such as a knitted fabric is preferable for making a patch excellent in adhesion to the skin. In addition, a support having a self-supporting property is preferable for handling the patch.

  The protective film of the patch is a liner that is temporarily attached to the adhesive layer and is removed when the patch is used, and is not particularly limited as long as it is generally used for the patch. For example, polyester, polypropylene, A sheet-like material made of polyethylene, paper, or a laminate of these materials can be used, and those having a surface subjected to a release treatment such as silicone coating are preferably used.

Melt coating method:
In the melt coating method, first, an esterification inhibitor and components of an adhesive layer such as an adhesive, a tackifier resin, and a plasticizer are mixed at a predetermined ratio in an inert atmosphere and melted. Thereafter, l-menthol, a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, is added to the melt and mixed to obtain a uniform melt. The mixing temperature is, for example, 100 to 220 ° C., and the mixing time is, for example, 30 to 120 minutes.
Next, this melt is applied to the protective film with a predetermined thickness, a support is laminated thereon, and then cut into a predetermined size to obtain a patch.

Solution application method:
In the solution coating method, first, a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, an esterification inhibitor, and components of the adhesive layer such as an adhesive, a tackifying resin, and a plasticizer are mixed in a predetermined ratio. On the other hand, an appropriate solvent such as toluene, ethyl acetate, hexane or cyclohexane is added and mixed to dissolve uniformly.
Next, this solution is applied to a protective film with a predetermined thickness, and heated in a dryer to evaporate and remove the solvent contained in the applied liquid, thereby forming an adhesive layer and supporting it. After laminating the body, it is cut into a predetermined size to obtain a patch.

As an external preparation to which the present invention is applied, for example, an ointment is a preparation as follows.
The ointment contains at least a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, and an esterification inhibitor in an oily ointment base.
The ointment is preferably a non-aqueous composition or pharmaceutical preparation which substantially does not contain water, and is a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, an esterification inhibitor and an ointment Add base.

The ointment base is composed of, for example, liquid paraffin, solid paraffin, microcrystalline wax, plastibase, purified lanolin, white petrolatum, fatty acid triglyceride, silicone oil, silicone wax, beeswax, candelilla wax, carnauba wax, ceresin and the like. Absorption promoters, solubilizers, stabilizers such as antioxidants and ultraviolet absorbers, surfactants, and other additives can be blended with the oily base.
Examples of the solubilizer include plant oils such as olive oil, soybean oil, corn oil, camellia oil, almond oil, sesame oil, terpene oil, and palm oil, animal oils such as mink oil, squalene, and squalane, and fatty acid esters. It is done.
Examples of the antioxidant include dibutylhydroxytoluene and butylhydroxyanisole.

As an external preparation to which the present invention is applied, for example, an aerosol is a preparation as follows.
The aerosol contains at least a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, and an esterification inhibitor.
Also in the aerosol, it is preferably a non-aqueous composition or pharmaceutical preparation that substantially does not contain water, and for non-steroidal anti-inflammatory drugs having a carboxyl group in the molecule, l-menthol, and esterification inhibitors, Aerosol bases and propellants such as solubilizers, surfactants and fillers can be blended.

  Hereinafter, regarding the patch as one of the external preparations, sodium bisulfite and / or 2-mercaptobenzimidazole as an esterification inhibitor of the present invention and an esterification suppression method using them will be described more specifically by way of examples. The present invention is not limited by these examples.

The patches of Examples 1 to 6 and Comparative Examples 1 to 2 were prepared as follows.
After mixing each component of Table 1 and Table 3 by a predetermined quantity and fuse | melting uniformly (120-220 degreeC), the adhesive layer per 70 cm < ² > is 1g with the polyester film which performed the mold release process by silicone coating. The knitted fabric was applied uniformly as a support, and a knitted knitted fabric was bonded thereon as a support and cut into a 70 cm ² rectangle to obtain a patch.

The patches of Examples 7 to 12 and Comparative Examples 3 to 4 were prepared as follows.
Thickness where 1 g of adhesive layer per 70 cm ² is applied to a polyester film which has been subjected to a release treatment by silicone coating after uniformly mixing each component described in Table 2 and Table 3 in a predetermined amount (120 to 160 ° C.). Then, a knitted fabric as a support was pasted thereon, cut into a 70 cm ² rectangle, and used as a patch.

Test example:
As a method for confirming the quality of preparation stability in long-term storage, the patches obtained in Examples and Comparative Examples were hermetically packaged in aluminum laminate bags and kept in a constant temperature oven at 70 ° C. for 10 days, which is severer than normal storage conditions. Then, the amount of the drug and l-menthol ester compound produced in the adhesive layer was measured by the HPLC method. The ester compound production rate is calculated by using the number of moles of a compound such as ketoprofen or indomethacin, which is a nonsteroidal anti-inflammatory drug having a carboxyl group in the molecule, and the number of moles of the ester compound produced. The results are shown in Tables 1 to 3.

  The esterification inhibitor and the esterification inhibition method of the present invention can be widely used particularly in the medical field.

Claims (5)

In a non-aqueous external preparation, a Rue esterification inhibitor to suppress the esterification of a non-steroidal anti-inflammatory drugs and l- menthol having a carboxyl group in the molecule, sodium hydrogen sulfite and / or 2 The mass ratio of the non-steroidal anti-inflammatory drug comprising the mercaptobenzimidazole having a carboxyl group in the molecule, the l-menthol, and the esterification inhibitor is 1: 1 to 2: 0.05 to 0.5. The esterification inhibitor characterized by being used in the range which becomes . Non-steroidal anti-inflammatory drugs having a carboxyl group in the molecule are diclofenac, ampenac, indomethacin, acemetacin, etodolac, sulindac, nabumetone, mofezolac, felbinac, aluminoprofen, ibuprofen, ketoprofen, flurbiprofen, loxoprofen, oxaprozin The esterification inhibitor according to claim 1, wherein the esterification inhibitor is one selected from the group consisting of: zaltoprofen, thiaprofenic acid, naproxen, and pranoprofen . The esterification inhibitor according to claim 2, wherein the non-steroidal anti-inflammatory drug having a carboxyl group in the molecule is ketoprofen . The ratio of the number of moles of the esterified compound produced relative to the nonsteroidal anti-inflammatory drug when stored at 70 ° C for 10 days is 0.007 or less. The esterification inhibitor according to Item . The ester of the non-steroidal anti-inflammatory drug which has a carboxyl group in the molecule | numerator in the non-aqueous external preparation using the esterification inhibitor of any one of Claims 1-4, and the said 1-menthol. A method for inhibiting esterification, wherein a mass ratio of the nonsteroidal anti-inflammatory drug having a carboxyl group in the molecule, the l-menthol, and the esterification inhibitor is 1: 1 to 2: 0. An esterification inhibiting method comprising using the esterification inhibitor in a range of 05 to 0.5.