JP2009114094A - Percutaneous absorption promoter containing polyglycerol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a percutaneous absorption promoter promoting the percutaneous absorption of a nonsteroidal anti-inflammatory agent formulated in a percutaneous absorption preparation, and a percutaneous absorption preparation exhibiting sufficient drug efficacy by the efficient absorption of a nonsteroidal anti-inflammatory agent through the skin. <P>SOLUTION: The percutaneous absorption promoter for nonsteroidal anti-inflammatory agents contains a polyglycerol or its ester. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a transdermal absorption enhancer and a transdermal absorption preparation for transdermal administration of a nonsteroidal anti-inflammatory drug.

  Conventionally, dosage forms containing a wide variety of drugs (active ingredients) have been proposed as transdermally absorbable preparations, and typical examples thereof include patches for locally administering anti-inflammatory drugs and bronchodilators systemic. Tapes for transdermal administration are used. For example, non-steroidal anti-inflammatory drugs such as indomethacin are widely used in various dosage forms as treatments for bruises, sprains, myalgia, arthritis, etc., but severe oral diseases such as gastrointestinal disorders and cardiac dysfunction In order to prevent such side effects, external preparations such as liquids, ointments and patches are used.

  However, since the skin inherently has a barrier function to prevent the invasion of foreign substances from outside the body, even if an active ingredient is blended in the percutaneous absorption preparation, sufficient percutaneous absorption cannot be obtained. In many cases, sufficient medicinal effects cannot be obtained. Non-steroidal anti-inflammatory drugs also have a problem that the absorption rate from the skin is low, and the percutaneous absorption preparation cannot provide a therapeutic effect equivalent to or higher than that of internal use. Therefore, various studies have been made to promote percutaneous absorption of active ingredients.

  As a transdermal absorption enhancer, many compounds such as Azone, which are highly toxic while promoting transdermal absorption, organic solvents such as DMSO and ethanol, fatty acids, terpene compounds, urea and phospholipid compounds have been studied. (For example, refer nonpatent literature 1). However, since the percutaneous absorption preparation is used directly on the skin, safety and good usability are also required. Therefore, it is desired to develop a transdermal absorption enhancer that has an excellent transdermal absorption promoting action and that is safe and good in use feeling. Patent Document 1 discloses a transdermal absorption enhancer containing glycerol or polyglycerol fatty acid ester as an active ingredient. However, there has been room for improvement to make it particularly effective for transdermal absorption of nonsteroidal anti-inflammatory drugs.

Polyglycerol dendrimer (PGD) is a dendrimer synthesized for the first time by Hagg et al., And has a feature that it has a very small molecular weight distribution and a uniform structure. A method for synthesizing 3 to 5 generations of PGD has already been established (for example, see Non-Patent Document 2), and it is known that paclitaxel (trade name Taxol), which is a poorly water-soluble drug, is dissolved by its nano-sized PG structure. It has been. For example, in the case of PGD, it has been revealed that the solubility of paclitaxel is significantly improved compared to polyethylene glycol 400 (PEG 400) used in the pharmaceutical industry (see, for example, Non-Patent Documents 3 and 4). ).
Japanese Examined Patent Publication No. 7-64754 AC Williams, BW Barry, Adv.Drug Delivery Rev., 2004 56, 603-618 R. Haag et al., J. Am. Chem. Soc., 122, 2954-2955 (2000) T. Ooya et al., Bioconjugate Chem., 15, 1221-1229 (2004) T. Ooya et al., J. Controlled Release, 93, 121-127 (2003)

  The present invention relates to a transdermal absorption enhancer capable of promoting the transdermal absorbability of a nonsteroidal anti-inflammatory drug incorporated in a transdermal absorption preparation, and the nonsteroidal anti-inflammatory drug is efficiently absorbed into the skin. Therefore, an object of the present invention is to provide a percutaneous absorption-type preparation that can sufficiently obtain a medicinal effect.

As a result of intensive studies in view of the above situation, the present inventors have found that linear or cyclic polyglycerols in which a plurality of glycerols (glycerin) are bonded, dendrimers composed of glycerol, and esters thereof are non-steroids. It has been found that it has a transdermal absorption promoting action of an anti-inflammatory drug. In addition, these polyglycerols and their esters are less irritating to the skin and do not have a strong odor. Therefore, when blended into a transdermal absorption preparation, the transdermal absorption is safe, excellent in use, and highly effective. It discovered that it could be set as a formulation. These linear or cyclic polyglycerols, dendrimers composed of glycerol, and esters thereof are known compounds, and some compounds have been conventionally incorporated into cosmetics or widely used as oil solidifying agents. However, it has not been known that this compound has a significant transdermal absorption promoting action on non-steroidal anti-inflammatory drugs. Furthermore, a transdermal absorption preparation containing polyglycerol or an ester thereof and a non-steroidal anti-inflammatory drug can efficiently absorb the non-steroidal anti-inflammatory drug transdermally, thereby improving its therapeutic effect. As a result, the present invention has been completed.
The percutaneous absorption preparation is a preparation that is used in close contact with the skin, and refers to a preparation that acts on the skin, nearby tissue, or the whole body when an active ingredient is taken into the subcutaneous tissue or blood.

That is, the present invention
(1) a transdermal absorption enhancer of a non-steroidal anti-inflammatory drug containing polyglycerol or an ester thereof,
(2) The transdermal absorption according to the above (1), wherein the polyglycerol or ester thereof is at least one selected from the group consisting of linear polyglycerol, cyclic polyglycerol and polyglycerol dendrimer, and esters thereof. Accelerator,
(3) The non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, diclofenac, ibuprofen, piroxicam, aspirin, acetaminophen, felbinac, pranoprofen, meloxicam and ketoprofen, and pharmaceutically acceptable salts thereof At least one percutaneous absorption enhancer according to (1) or (2),
(4) a transdermal absorption preparation containing polyglycerol or an ester thereof and a nonsteroidal anti-inflammatory drug,
(5) The percutaneous absorption according to the above (4), wherein the polyglycerol or its ester is at least one selected from the group consisting of linear polyglycerol, cyclic polyglycerol and polyglycerol dendrimer, and these esters. Formulation, and
(6) The nonsteroidal anti-inflammatory drug is selected from the group consisting of indomethacin, diclofenac, ibuprofen, piroxicam, aspirin, acetaminophen, felbinac, pranoprofen, meloxicam and ketoprofen, and pharmaceutically acceptable salts thereof. At least one transdermally absorbable preparation according to (4) or (5),
About.

The present invention also provides
(7) Use of a composition containing polyglycerol or an ester thereof as a transdermal absorption enhancer for non-steroidal anti-inflammatory drugs,
(8) Use of a composition containing polyglycerol or an ester thereof for producing a transdermal absorption enhancer for nonsteroidal anti-inflammatory drugs,
(9) Use of a composition containing polyglycerol or an ester thereof and a nonsteroidal anti-inflammatory drug as a transdermally absorbable preparation, and
(10) Use of a composition containing polyglycerol or an ester thereof and a nonsteroidal anti-inflammatory drug for producing a transdermally absorbable preparation,
About.

The present invention also provides
(11) A method of applying a composition containing polyglycerol or an ester thereof and a nonsteroidal anti-inflammatory drug to the skin to promote transdermal absorption of the nonsteroidal anti-inflammatory drug, and
(12) A method of treating pain, fever or inflammation by applying a composition containing polyglycerol or an ester thereof and a non-steroidal anti-inflammatory drug to the skin,
About.

  With the transdermal absorption enhancer of the present invention, non-steroidal anti-inflammatory drugs and the like, which are active ingredients of transdermal absorption preparations, can be efficiently absorbed into the skin. Since the percutaneous absorption type preparation of the present invention can efficiently absorb non-steroidal anti-inflammatory drugs, which are active ingredients, into the skin, the high therapeutic effect of non-steroidal anti-inflammatory drugs can be obtained. It can be done.

The present invention is described in detail below.
The polyglycerol used in the percutaneous absorption enhancer of the present invention is a compound in which a plurality of glycerols (glycerin) are bound. As polyglycerol, linear polyglycerol, cyclic polyglycerol, and polyglycerol dendrimer are preferable. Among these, at least one selected from the group consisting of cyclic polyglycerol, polyglycerol dendrimers, and esters thereof is more preferable because it is excellent in the transdermal absorption promoting action of nonsteroidal anti-inflammatory drugs. Particularly preferred is at least one selected from the group consisting of glycerol dendrimers. The ester of polyglycerol is preferably an ester of the polyglycerol and a fatty acid represented by the general formula RCOOH (wherein R represents a hydrocarbon group having 6 to 20 carbon atoms). These may be used alone or in combination of two or more.

  As the linear polyglycerol or ester thereof, a linear compound formed by combining 3 to 6 molecules of glycerol is preferable. Preferred is polyglycerol represented by the following general formula (1) (hereinafter also simply referred to as “PG”) (trimer of glycerol) or an ester thereof.

In the general formula (1), R represents H (hydrogen atom) or COC _n H _{2n + 1} , and n is usually 6 to 20, preferably 10 to 18, more preferably 13 to 17.
Examples of the ester of glycerol trimer include, for example, myristic acid (C14: R in formula (1) R is COC ₁₃ H ₂₇ ) ester of glycerol trimer, palmitic acid (C16: formula (1) R is a COC ₁₅ H ₃₁ ) ester, stearic acid (C18: R in the general formula (1) is COC ₁₇ H ₃₅ ) ester, and arachidic acid ester (C20: R in the general formula (1) is COC ₁₉ H ₃₉ ) Preferably, stearic acid ester and arachidic acid ester are more preferable.

  As the cyclic polyglycerol, a cyclic compound formed by combining 3 to 6 molecules of glycerol is preferable. Further, cyclic polyglycerol (glycerol trimer) represented by the following formula (2) (hereinafter also referred to as “cyclic PG (glycerol trimer)”) is more preferable.

  As the polyglycerol dendrimer or an ester thereof, a polyglycerol dendrimer having 2,2-bis (hydroxymethyl) -1-butanol as a core (hereinafter also simply referred to as “PGD”) is preferable. The number of generations (number of repeating structures) of such dendrimers is not particularly limited, and those of the first generation to the eighth generation can be used. The first generation to the fifth generation are preferable, and the first generation to the fourth generation are more preferable.

  Polyglycerol dendrimer first generation (hereinafter also referred to as “PGD-G1”) having 2,2-bis (hydroxymethyl) -1-butanol as a core is a compound represented by the following formula (3): The third generation of dendrimer (hereinafter also referred to as “PGD-G3”) is a compound represented by the following formula (4), and the fourth generation of polyglycerol dendrimer (PGD) (hereinafter also referred to as “PGD-G4”) is A compound represented by the following formula (5).

  The said polyglycerol or its ester can use what was manufactured by the well-known method (For example, the method described in the nonpatent literature 3 and 4).

  The above-mentioned polyglycerol or its ester can be used by appropriately selecting one or two or more kinds depending on the kind of nonsteroidal anti-inflammatory agent described later.

  The transdermal absorption enhancer of the present invention may contain components other than polyglycerol or its ester as long as the effects of the present invention are exhibited. Other components include, for example, hydrocarbons such as petrolatum; lower alcohols such as methanol and ethanol; higher alcohols such as cetanol and oleyl alcohol; fatty acids such as stearic acid and oleic acid; terpenes such as menthol and camphor Compounds; polyhydric alcohols such as glycerin and 1,3-butanediol; and surfactants such as nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Such components are preferably contained in a mass ratio of 0.01 to 100, with the mass of polyglycerol or its ester being 1.

  The polyglycerol or ester thereof contained in the non-steroidal anti-inflammatory drug percutaneous absorption enhancer of the present invention can be incorporated into the transdermal absorption preparation to increase the solubility of the active ingredient incorporated in the transdermal absorption preparation. While improving, it can promote the percutaneous absorption. The transdermal absorption preparation containing the transdermal absorption enhancer and active ingredient of the present invention is one of the preferred embodiments of the present invention.

The drug for which the percutaneous absorption enhancer of the present invention improves the absorption from the skin is a non-steroidal anti-inflammatory drug.
Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs that have anti-inflammatory, analgesic and antipyretic effects and are used to treat pain, fever and inflammation, not steroids Say things. The nonsteroidal anti-inflammatory drug in the present invention is selected from the group consisting of indomethacin, diclofenac, ibuprofen, piroxicam, aspirin, acetaminophen, felbinac, pranoprofen, meloxicam, and ketoprofen, and pharmaceutically acceptable salts thereof. One type or two or more types are preferable. Among these, one or more selected from the group consisting of indomethacin, diclofenac, piroxicam, meloxicam, ketoprofen, and pharmaceutically acceptable salts thereof are more preferable.

  A transdermally absorbable preparation containing polyglycerol or an ester thereof and a nonsteroidal anti-inflammatory drug is also one aspect of the present invention. The non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, diclofenac, ibuprofen, piroxicam, aspirin, acetaminophen, felbinac, pranoprofen, meloxicam and ketoprofen, and pharmaceutically acceptable salts thereof as described above At least one is preferred.

  What is necessary is just to set suitably the compounding quantity of polyglycerol or its ester in the transdermal absorption preparation of this invention according to the kind of polyglycerol or its ester, the kind of non-steroidal anti-inflammatory drug, dosage form, etc. For example, when linear polyglycerol or an ester thereof is used, the polyglycerol or an ester thereof is preferably 0.001 to 5% by mass in 100% by mass of the transdermally absorbable preparation. More preferably, the content is 01 to 2% by mass. When cyclic polyglycerol or ester thereof is used, it is preferable that the polyglycerol or ester thereof is 0.001 to 5% by mass in 100% by mass of the transdermally absorbable preparation, and 0.01 to 2% by mass. % Is more preferable. When using a polyglycerol dendrimer, it is preferable that the polyglycerol or an ester thereof is 0.001 to 5% by mass, and 0.01 to 2% by mass in 100% by mass of the percutaneous absorption preparation. It is more preferable to do so. In particular, in combination with indomethacin, the blending amount of polyglycerol dendrimer is preferably 0.3 to 4% by mass, and preferably 0.5 to 2% by mass in 100% by mass of the transdermally absorbable preparation. It is more preferable. By setting it as such a compounding quantity, a non-steroidal anti-inflammatory drug can be absorbed into skin effectively.

  The amount of the nonsteroidal anti-inflammatory drug in the transdermally absorbable preparation of the present invention may be appropriately set according to the type of nonsteroidal anti-inflammatory drug, target disease, symptom, patient sex, age, dosage form, etc. . For example, in 100% by mass of the transdermally absorbable preparation, the non-steroidal anti-inflammatory drug is preferably 0.01 to 5% by mass, more preferably 0.1 to 3% by mass. .

Examples of the dosage form of the transdermally absorbable preparation of the present invention include a tape, a poultice, an ointment, a cream, an aerosol, a liniment, a liquid, a lotion, a plaster, and a solid preparation.
The percutaneously absorbable preparation of the present invention can be prepared by a known method by blending necessary pharmacologically acceptable components according to the dosage form within a range not impairing the effects of the present invention.
Examples of pharmacologically acceptable components to be blended as needed include, for example, bases, surfactants, thickeners, preservatives, pH adjusters, stabilizers, antioxidants, irritation reducers, fillers , Antiseptics, colorants, dispersants, fragrances and the like. These components may be used alone or in combination of two or more.

  The percutaneous absorption preparation of the present invention is effective in treating pain, fever and inflammation because non-steroidal anti-inflammatory drugs are effectively absorbed into the skin when applied to the skin. In particular, low back pain (muscular / fascial low back pain, osteoarthritis, intervertebral disc disease, lumbar sprain), osteoarthritis, shoulder periarthritis, tendon / tendon sheathitis, peritonitis, humerus condyle (tennis) It is effective for the treatment of elbows etc.

  As a method for applying the transdermally absorbable preparation of the present invention to the skin, an appropriate amount is applied to the affected area in one day in consideration of the type of nonsteroidal anti-inflammatory drug to be contained, target disease, patient sex, age, symptoms, etc. It may be applied, sprayed or applied once to several times depending on the dosage form.

(1) Use of a composition containing polyglycerol or an ester thereof as a transdermal absorption enhancer for nonsteroidal anti-inflammatory drugs, (2) Nonsteroidal anti-inflammatory of a composition containing polyglycerol or an ester thereof Use for producing a medicinal transdermal absorption enhancer, (3) Use of a composition containing polyglycerol or an ester thereof, and a nonsteroidal anti-inflammatory drug as a transdermal absorption preparation, and (4) Poly The use of a composition containing glycerol or an ester thereof and a nonsteroidal anti-inflammatory drug for the manufacture of a transdermally absorbable preparation is also one aspect of the present invention. The transdermal absorption enhancer and transdermal absorption preparation for non-steroidal anti-inflammatory drugs, and preferred embodiments thereof are the same as those described above.

(5) a method of applying to the skin a composition containing polyglycerol or an ester thereof and a non-steroidal anti-inflammatory drug to promote transdermal absorption of the non-steroidal anti-inflammatory drug, and (6) polyglycerol or A method of treating pain, fever or inflammation by applying a composition containing the ester and a non-steroidal anti-inflammatory drug to the skin is also one aspect of the present invention. As the composition containing polyglycerol or an ester thereof and a non-steroidal anti-inflammatory drug, the above-mentioned transdermal absorption preparation of the non-steroidal anti-inflammatory drug is suitable. As a method of applying the composition (percutaneous absorption preparation) to the skin, the composition may be applied, sprayed or pasted according to the dosage form.

  Below, based on an Example and a test example, this invention is demonstrated more concretely, This invention is not limited to these. In the examples, unless otherwise specified, “%” means “% by mass”.

(1) Materials and Reagents (1-1) Substrates The polyglycerol dendrimer (PGD) first generation (PGD-G1), the third generation (PGD-G3), and the first represented by the above formulas (3) to (5) Four generations (PGD-G4) were synthesized by the following production method. In the above general formula (1), R is a hydrogen atom, a linear polyglycerol (PG), a cyclic polyglycerol represented by the above formula (2) (Cyclic PG), and a straight chain represented by the above general formula (1). Polyglycerol (PG3mer) saturated fatty acid ester (fatty acid alkyl chains: C14, C16, C18 and C20; also referred to as C14-PG, C16-PG, C18-PG and C20-PG, respectively) was synthesized by the following production method did.

(1-2) Keratin sheet Artificial cultured skin (TESTSKIN ^™ LSE-high) was purchased from Toyobo Life Science Division.

(2) Synthetic method of transdermal absorption enhancer (2-1) Synthesis of polyglycerol dendrimer (PGD) The above-mentioned method of Ooya et al. (Non-patent document 3: T. Ooya et al., Bioconjugate Chem., 15, 1221-1229 (2004) and non-patent document 4: T. Ooya et al., J. Controlled Release, 93, 121-127 (2003)), polyglycerol dendrimer (PGD) was synthesized.

(2-2) Synthesis of linear polyglycerol (PG) (trimer of glycerol) 1,3-O-bis (2,3-O-isopropylideneglyceryl) glycerol (1,3-O manufactured by Riken Vitamin) -Bis (2,3-O-isopropyleneglycyl) glycerol) was treated with 80% aqueous acetic acid to obtain linear polyglycerol (glycerol trimer).

(2-3) Synthesis of cyclic polyglycerol (PG) (glycerol trimer) 1,3-O-bis (2,3-O-isopropylideneglyceryl) glycerol (3.0 g, 9.36 mmol) manufactured by Riken Vitamin ) Was treated with 2 equivalents of NaH to give an alkoxide and then reacted with 1.5 equivalents of benzyl bromide to give benzyl ether in a yield of 3.74 g, 97% as a colorless oil.

  The resulting benzyl ether (3.74 g, 9.12 mmol) was quantitatively converted to tetraol (3.01 g) by treatment with 80% aqueous acetic acid, and then immediately with 5 equivalents of triethylamine in dichloromethane. By reacting with 3 equivalents of tert-butylchlorodiphenylsilane in the presence of a catalytic amount of 4- (dimethylamino) pyridine, a compound in which only the primary hydroxyl group is selectively silylated is obtained in a yield of 5.96 g. Obtained as a colorless oil at a rate of 81%.

  Disilyl ether (64.1 g, 79.3 mmol) was treated with 4 equivalents of NaH at room temperature and then reacted with 3 equivalents of benzyl bromide to yield tri6.4 ether in a yield of 76.4 g, 98%. Obtained as a colorless oil.

The resulting tribenzyl ether (12.2 g, 12.3 mmol) was treated with 3 equivalents of tetrabutylammonium fluoride (TBAF) in THF for desilylation, yielding a diol yield of 6.17 g, 98%. Obtained as a colorless oil in yield. The resulting diol (1.0 g, 1.96 mmol) was reacted with 1.1 equivalents of p-toluenesulfonyl chloride in dichloromethane in the presence of 3 equivalents of triethylamine and a catalytic amount of 4- (dimethylamino) pyridine. The cyclized precursor monotosylate was obtained as a colorless oil in a yield of 724 mg and a yield of 56%.
This THF solution of monotosylate was dropped into a refluxing THF suspension of NaH over 3 hours, and then refluxed for 19 hours to obtain a cyclized product (glycerol trimer) with a yield of 60%. It was.

(2-4) Synthesis of linear glycerol (PG) (glycerol trimer) stearate ester NaH (449 mg) was well dispersed in THF (60 mL) cooled to 0 ° C., and then 1, 2, 10 , 11-O-isopropylidene-4,8-dioxaundecan-6-ol (3.00 g) was dissolved and stirred well for 20 minutes. Thereafter, benzyl bromide (1.67 mL) was added and stirred for about 20 minutes, then returned to room temperature and stirred for 20 hours. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate (volume ratio) = 4: 1) to obtain a colorless oily substance (3.74 g, yield 97%).

The obtained colorless oily substance (3.74 g) was dissolved in 80% acetic acid (60 mL) and stirred for 8 hours. The solvent was distilled off under reduced pressure, and acetic acid was removed overnight under reduced pressure to obtain a colorless oil (3.01 g, 100%).
The obtained compound (10.4 g) was dissolved in DMF (300 mL), and triethylamine (18.4 mL) and DMAP (1.93 g) were added and stirred. TBDPSCl (17.2 mL) was added thereto and stirred overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium acetate and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate (volume ratio) = 3: 1) to obtain a colorless oil (20.5 g, yield 81%).

  The obtained colorless oil (5.84 g) was dissolved in THF (20 mL), and added to a mixed solvent of THF (160 mL) and DMF (60 mL) cooled to 0 ° C. in which NaH (782 mg) was dispersed. Stir vigorously for 20 minutes, add benzyl bromide (2.58 mL) and continue stirring for 1 hour, then at room temperature for 16 hours. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium acetate and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate (volume ratio) = 10: 1) to obtain a colorless oil (6.06 g, yield 85%).

  The obtained compound (1.00 g) was dissolved in THF (20 mL), 1.0 M TBAF / THF solution (3.04 mL) was added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium acetate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate (volume ratio) = 2: 3) to obtain a colorless oil (377 mg, yield 73%).

  The obtained oil (692 mg) was dissolved in pyridine (40 mL), DMAP (82.8 mg) stearoyl chloride (961 μl) was added, and the mixture was stirred at room temperature for 10 hr. The reaction was stopped by adding MeOH, extracted with dichloromethane, and washed with saturated brine. The organic layer was dried over anhydrous sodium acetate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate (volume ratio) = 7: 1), and further purified by silica gel thin layer chromatography (hexane: ethyl acetate (volume ratio) = 5: 1). Purification gave white crystals (740 mg, 52% yield).

The obtained crystals (709 mg) were dissolved in THF (7 mL) and EtOH (7 mL), Pd / C (75.0 mg) was added, and the mixture was stirred overnight at room temperature under H ₂ atmosphere. The catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting compound was recrystallized from ethyl acetate to obtain white crystals (428 mg, yield 78%).
Further, substances other than stearic acid esters were produced in the same manner.

Example 1
1. Procedure (1) One bag of powder (manufactured by SIGMA) for preparing a phosphate buffer solution (PBS) was dissolved in 1000 mL of pure water to prepare a 0.1M phosphate buffer solution (PBS, pH 7.4).
(2) Each substrate was added to PBS. At this time, PGD-G1, G3, G4, linear PG trimer, and cyclic PG trimer were made into 1% by mass or 5% by mass solution (completely dissolved), and C14-PG, C16-PG, C18-PG and C20-PG were each used as a 1% by mass suspension. Next, an amount of a predetermined drug powder to a concentration of 1 mg / mL was added to each solution and stirred overnight. Further, for each component, a control to which the percutaneous absorption enhancer was not added was used as a control.

(3) The stratum corneum sheet (cultured skin) was taken out with a cutter and sandwiched between Franz-type cells (effective diffusion area: 0.79 cm ² ). Work was done quickly so that the sheet did not dry.
(4) After setting the stratum corneum, about 5.5 mL (one is about 9 mL) of PBS was put in the lower part (receiver side).
(5) 1 ml of the solution prepared in (2) was poured into the cell with a micropipette, and a stirrer bar was installed and stirred to start the experiment.

(6) For sampling, 0.5 mL was taken over time from the receiver side, and the same amount of PBS was added. The sampled solution was put into a HPLC bottle through a microfilter (0.45 μm), and the lid was sealed. Sampling times are 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours after the start of the experiment. Of these, the data at 4 hours and 8 hours (cumulative drug penetration determined by (7) below) are shown in Table 1.

(7) HPLC (Agilent 1100 series LC-MSD (Hewlett Packard), column: Cosmosil AR-II (Nacalai tesque), developing solvent: methanol: 3% acetonitrile aqueous solution (volume ratio) = 4: 1, flow rate: 0.5 mL / min, injection volume (Injection volume: 5 μL). Indomethacin was detected from UV absorption at 262 nm and mass, and quantified from a calibration curve. Diclofenac sodium was detected using methanol: 0.18% phosphoric acid aqueous solution (volume ratio) = 7: 3 as the mobile phase at an absorption wavelength λ = 266 nm. Piroxicam was detected using an acetonitrile: 0.18% phosphoric acid aqueous solution (volume ratio) (55:45) as a mobile phase at an absorption wavelength λ = 238 nm. Meloxicam was detected using an acetonitrile: 2% aqueous phosphoric acid solution (volume ratio) (60:40) as the mobile phase at an absorption wavelength λ = 254 nm. Ketoprofen was detected using acetonitrile: 0.18% phosphoric acid aqueous solution (volume ratio) (55:45) as a mobile phase at an absorption wavelength λ = 248 nm.

  From the above data, it was found that polyglycerol or its esters, especially linear polyglycerols, cyclic polyglycerols and polyglycerol dendrimers, and these esters promote the transdermal absorption of non-steroidal anti-inflammatory drugs.

  The transdermal absorption enhancer of the present invention improves the solubility of non-steroidal anti-inflammatory drugs and can be efficiently absorbed into the skin. The effect of the inflammatory drug can be fully exerted. In addition, since the transdermal absorption preparation of the present invention can efficiently absorb non-steroidal anti-inflammatory drugs into the skin, the high therapeutic effect of non-steroidal anti-inflammatory drugs can be obtained.

Claims (6)

  A transdermal absorption enhancer of a non-steroidal anti-inflammatory drug containing polyglycerol or an ester thereof.   The transdermal absorption enhancer according to claim 1, wherein the polyglycerol or an ester thereof is at least one selected from the group consisting of linear polyglycerol, cyclic polyglycerol and polyglycerol dendrimer, and esters thereof.   The non-steroidal anti-inflammatory drug is at least one selected from the group consisting of indomethacin, diclofenac, ibuprofen, piroxicam, aspirin, acetaminophen, felbinac, pranoprofen, meloxicam and ketoprofen, and pharmaceutically acceptable salts thereof The transdermal absorption enhancer according to claim 1 or 2.   A transdermal absorption preparation containing polyglycerol or an ester thereof and a nonsteroidal anti-inflammatory drug.   The transdermally absorbable preparation according to claim 4, wherein the polyglycerol or an ester thereof is at least one selected from the group consisting of linear polyglycerol, cyclic polyglycerol and polyglycerol dendrimer, and esters thereof.   The non-steroidal anti-inflammatory drug is at least one selected from the group consisting of indomethacin, diclofenac, ibuprofen, piroxicam, aspirin, acetaminophen, felbinac, pranoprofen, meloxicam and ketoprofen, and pharmaceutically acceptable salts thereof The percutaneous absorption preparation according to claim 4 or 5.