JP5410070B2 - Metal carbonate as esterification inhibitor and method for inhibiting esterification with metal carbonate - 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.

  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 a non-steroidal anti-inflammatory analgesic having a carboxylic acid group in the molecule, l-menthol, and an external patch containing a metal oxide, and the external patch contains a metal oxide. Describes that the formation of an ester compound of a drug and l-menthol is suppressed.

  Patent Document 3 discloses an anti-inflammatory drug having a carboxyl group (or a salt thereof) in the molecule, an additive having a hydroxyl group in the molecule, and an external preparation containing a metal hydroxide. There is described a topical preparation with excellent stability, which contains a hydroxide and effectively suppresses the esterification product formation reaction of a drug and an additive having a hydroxyl group in the molecule.

  Patent Document 4 discloses an adhesive patch containing indomethacin, and discloses a stable adhesive patch that produces less ester form of indomethacin because indomethacin has a specific particle size.

  However, the techniques for preventing esterification using fatty acid metals, metal oxides, metal hydroxides and the like disclosed so far are not sufficient, and techniques for further suppressing the esterification reaction between a drug and l-menthol. Was demanded.

On the other hand, metal carbonates are generally used as excipients and fillers in pharmaceutical preparations.
For example, Patent Document 5 discloses a transdermal patch including a pressure-sensitive adhesive, a terpene (for example, l-menthol), a nonsteroidal anti-inflammatory analgesic, and the like, and magnesium carbonate is exemplified as a filler. However, in Patent Document 5, aluminum hydroxide, silicate, calcium carbonate and the like are listed as the filler, but only magnesium carbonate is described, and a non-steroidal anti-inflammatory analgesic that is a drug and There is no disclosure or suggestion of suppressing the formation of an ester compound with 1-menthol.
In Patent Document 6, non-steroidal anti-inflammatory analgesic, 1-menthol, and magnesium carbonate are described as components of the patch. Similarly, non-steroidal anti-inflammatory analgesic and l-menthol, in which magnesium carbonate is a drug, are described. There is no disclosure or suggestion on the point of suppressing the esterification of.

Republished patent WO96 / 08245 (A1) JP 2002-226366 A JP 2005-314328 A JP 2007-176880 A JP 2008-013494 A Republished patent WO2004 / 082672 (A1)

  The subject of this invention exists in the point which provides the esterification inhibitor and the esterification suppression method which produce | generate effectively the ester compound produced by the non-steroidal anti-inflammatory drug which has a carboxyl group in a molecule | numerator, and l-menthol.

When a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule and l-menthol coexist, an equilibrium reaction proceeds and an ester compound may be generated.
As a result of intensive studies to suppress the formation of such ester compounds, the present inventors have surprisingly found that the formation of ester compounds is extremely suppressed by incorporating a carbonate metal salt such as magnesium carbonate. I found.

That is, the present invention, during external preparation of the non-aqueous, a non-steroidal anti-inflammatory drugs and l- Rue esterification inhibitor to suppress the esterification of the menthol having a carboxyl group in the molecule, magnesium carbonate It provides an esterification inhibitor, characterized in that it consists of.
Moreover, this invention is used in the range from which the 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 magnesium carbonate will be 1: 1-2: 0.05-2. An esterification inhibitor is provided.
Further, the present invention provides a nonsteroidal anti-inflammatory drug having a carboxyl group in the molecule, diclofenac, ampenac, indomethacin, acemetacin, etodolac, sulindac, nabumetone, mofezolac, felbinac, aluminoprofen, ibuprofen, ketoprofen, flurbipro Fen, provided loxoprofen, oxaprozin, zaltoprofen, tiaprofenic acid, naproxen, esterification inhibitor which is characterized in that one selected from the group consisting of pranoprofen.
Further, 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 0.005 or less esterification inhibitor to provide.
Further, the present invention uses the esterification inhibitor of the present invention, and suppresses esterification of the non-steroidal anti-inflammatory drug having a carboxyl group in the molecule and the l-menthol in a non-aqueous external preparation. The present invention provides a method for inhibiting esterification.

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

The metal carbonate as an esterification inhibitor in the present invention is not particularly limited as long as it functions as an esterification inhibitor, but potassium carbonate, sodium hydrogen carbonate, sodium carbonate, and magnesium carbonate are preferably used, and among these, magnesium carbonate Is particularly preferable in terms of suppressing the formation of ester compounds.
As the above-mentioned magnesium carbonate, light magnesium carbonate, heavy magnesium carbonate and the like are used in addition to anhydrides and hydrates. Among these, heavy magnesium carbonate is preferably used.

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 the non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, and the metal carbonate that suppresses the formation of the ester compound is 1: 0.2 to 5: 0.01 to 5, respectively. It is preferable to use in the range of 1: 1-2: 0.05-2 more preferably. 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 the anti-inflammatory drug is 0.005 or less (in terms of percentage, 0.5% or less).

  The reason why the formation of ester compounds is suppressed by compounding metal carbonate is not clear, but the carboxyl group of the drug becomes a salt of the metal, which can be chemically stabilized and less susceptible to esterification. Sex is conceivable.

  The metal carbonate as the esterification inhibitor of the present invention can be used by blending it in the composition. That is, a metal carbonate as an esterification inhibitor can coexist in a situation where an ester bond occurs, in other words, a system in which a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule and l-menthol are present, Although it can be used regardless of an aqueous composition or a non-aqueous composition, the present invention is particularly effective in a non-aqueous composition. For example, it can be used for a non-aqueous pharmaceutical composition or formulation. it can. Although it does not specifically limit as a non-aqueous formulation, For example, a patch, an ointment, an aerosol agent is 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 a metal carbonate, 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 depending on the refreshing sensation to be obtained, or blended for the purpose of solubilizing the drug, promoting absorption, etc., preferably 0.5 to 10% by weight based on the entire adhesive layer.

  It is preferable that the metal carbonate as an esterification inhibitor is blended at 0.01 to 3% by mass with respect to the entire adhesive layer. When the amount is less than 0.01% by mass, the effect of suppressing the ester compound generation is insufficient, and when the concentration is increased, the effect of suppression is increased. There may be a need for a pre-fabrication process for uniform mixing.

  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, a metal carbonate salt and an adhesive layer such as an adhesive, a tackifier resin, and a plasticizer are mixed and melted at a predetermined ratio in an inert atmosphere. 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:
First, the solution coating method uses toluene for a predetermined ratio of non-steroidal anti-inflammatory drug having a carboxyl group in its molecule, l-menthol, metal carbonate, and adhesive layer components such as an adhesive, a tackifying resin, and a plasticizer. Then, an appropriate solvent such as 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 its molecule, l-menthol, and a metal carbonate in an oily ointment base.
Such an ointment is also preferably a non-aqueous composition or pharmaceutical preparation substantially free of water, a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, metal carbonate and ointment base Is blended.

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 is a preparation containing at least a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, l-menthol, and a metal carbonate.
Aerosols are also preferably non-aqueous compositions and pharmaceutical preparations that do not substantially contain water, and are soluble in non-steroidal anti-inflammatory drugs having a carboxyl group in the molecule, l-menthol, and metal carbonates. Aerosol bases such as agents, surfactants, fillers, and propellants can be blended.

  Hereinafter, regarding the patch as one of the external preparations, the examples of the esterification inhibitor of the present invention will be described in more detail with reference to the examples of the present invention. It is not limited at all.

The patches of Examples 1 to 6 and Comparative Examples 1 to 3 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 9 and Comparative Examples 4 to 6 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, indomethacin and felbinac, which are non-steroidal anti-inflammatory drugs having a carboxyl group in the molecule, and the number of moles of the ester compound produced. Conversion is performed according to the following formula, and 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 (6)

During external preparation of the non-aqueous, a non-steroidal anti-inflammatory drugs and l- Rue esterification inhibitor to suppress the esterification of the menthol having a carboxyl group in the molecule, and characterized by comprising the magnesium carbonate An esterification inhibitor . The non-steroidal anti-inflammatory drug having a carboxyl group in the molecule, the l-menthol, and the magnesium carbonate are used in a range of 1: 1 to 2: 0.05 to 2. The esterification inhibitor according to claim 1 . 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 , zaltoprofen, esterification inhibitor according to claim 1 or 2, characterized in that tiaprofenic acid, naproxen, is one selected from the group consisting of pranoprofen. The esterification inhibitor according to claim 3 , wherein the non-steroidal anti-inflammatory drug having a carboxyl group in the molecule is ketoprofen . When stored at 70 ° C. 10 days, claim 1, wherein 4 of the ratio of the generation number of moles of the esterified compound to the non-steroidal anti-inflammatory drug is 0.005 or less 1 The esterification inhibitor according to Item . An ester of a non-steroidal anti-inflammatory drug having a carboxyl group in the molecule and the l-menthol in a non-aqueous external preparation using the esterification inhibitor according to any one of claims 1 to 5. A method for inhibiting esterification, characterized by inhibiting crystallization.