WO2014024896A1 - Adhesive patch agent containing agomelatine - Google Patents

Description

Patch composition containing agomelatine

The present invention relates to a patch composition containing agomelatine. In particular, the present invention relates to a patch composition having improved transdermal absorbability of agomelatine.

Agomelatine is a compound of the following structural formula (1), which is a selective agonist of melatonin action receptor and an antagonist of 5-HT _2C receptor.

Agomelatine has a strong central nervous system effect and is currently marketed in Europe as a treatment for depression.
However, it has been reported that agomelatine is susceptible to metabolism by the liver, the utilization rate by oral administration is much lower than parenteral administration, and the influence of individual differences is great (Patent Document 1).
Then, in order to improve the low utilization rate of agomelatine, the trial which makes it difficult to receive metabolism in a liver by the rapid absorption from the mucous membrane in an oral cavity is reported (patent document 2). However, Agomelatine is highly irritating, and it is considered difficult to examine intraoral quick disintegrating tablets or sublingual tablets. Recently, pharmaceutical formulation has been studied to improve it (Patent Document 1).
In order to improve the utilization rate of agomelatin, it is essential to avoid the first pass effect of the liver (FIRST PASS EFFECT), and for that purpose, transdermal administration by transdermal formulation is considered to be most effective. However, there has been no such study so far.

JP 2012-92132 A EP1427724

An object of the present invention is to provide a patch composition with improved transdermal absorbability of agomelatine.

The present inventors have made a patch with improved transdermal absorbability of a drug by using a fatty acid-based ionic liquid (WO2009 / 066457). As drugs, there are many drugs that easily form a salt, such as acidic drugs or basic drugs, and there are few neutral drugs such as agomelatin. Accordingly, the present inventors examined a new combination of fatty acid-based ionic liquids when studying the preparation of agomelatin as a transdermal formulation. Since Agomelatine is a poorly soluble substance, first, it was dissolved in an ionic liquid, and another additive such as an organic solvent was added to examine the patch composition. As a result, a combination of easily meltable decanoic acid-based ionic liquid, salicylic acid-based ionic liquid, and oleic acid-based ionic liquid, agomelatin-insoluble isostearic acid-based ionic liquid, levulinic acid-based ionic liquid, and lactic acid-based ionic liquid Thus, it was found that the transdermal absorbability of agomelatine can be greatly improved.
The present inventors further studied improvement of a pressure-sensitive adhesive layer suitable for agomelatine, in which agomelatine is easily released from the pressure-sensitive adhesive layer in order to improve transdermal absorbability. As a result, by adding a filler to the pressure-sensitive adhesive layer, a mixed solution of an ionic liquid containing agomelatin and an organic solvent is stored in the gap formed between the filler and the pressure-sensitive adhesive layer, and is transmitted through the gap. Thus, it was found that the agomelatin solution inside the pressure-sensitive adhesive layer can exude. Since the agomelatin solution contained inside the adhesive layer passes through the voids and exudes to the surface of the adhesive layer, the remaining rate of agomelatin in the adhesive layer is the same as the remaining rate of the tape agent so far. In comparison, it was found to be very little. Based on the above findings, the present inventors have completed the present invention.

The gist of the present invention is as follows.
(1) Agomelatin-containing patch composition comprising at least one ionic liquid selected from decanoic acid-based ionic liquid, salicylic acid-based ionic liquid, and oleic acid-based ionic liquid together with agomelatine.
(2) The agomelatin-containing patch composition according to (1) above, wherein a filler is further added.
(3) The agomelatin-containing patch composition according to (1) or (2) above, wherein the filler is added in an amount of 3 to 10% by weight.
(4) The agomelatin-containing patch composition according to any one of (1) to (3) above, wherein the filler is crystalline cellulose and / or silicic anhydride.
(5) By selecting one or more base compounds of the decanoic acid ionic liquid, salicylic acid ionic liquid, and oleic acid ionic liquid from diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. Agomelatin-containing patch composition according to any one of (1) to (4) above.
(6) The agomelatin-containing patch composition according to any one of (1) to (5), wherein the oleic acid-based ionic liquid is an oleic acid triisopropanolamine salt.
(7) The above (1) to (6), wherein one or more ionic liquids are selected and added from isostearic acid ionic liquid, levulinic acid ionic liquid, and lactic acid ionic liquid. The patch composition containing agomelatin according to any one of the above.
(8) By selecting one or more base compounds of the above-mentioned isostearic acid-based ionic liquid, levulinic acid-based ionic liquid, and lactic acid-based ionic liquid from diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. The agomelatin-containing patch composition according to (7) above.
(9) Agomelatin, decanoic acid triisopropanolamine salt, decanoic acid triethanolamine salt, oleic acid triisopropanolamine salt, isostearic acid diisopropanolamine salt, isostearic acid triethanolamine salt, lactate triethanolamine salt, lactate diisopropanol The patch composition containing agomelatin according to (8) above, wherein one or more amine salts are selected.
(10) The organic solvent according to any one of (1) to (9), wherein at least one selected from N-methylpyrrolidone, diethyl sebacate, isopropyl myristate, propylene carbonate, and polyethylene glycol is added as an organic solvent. A patch composition containing agomelatine.
(11) The adhesive composition containing agomelatine as described in (9) above, containing 1 to 10 parts by weight of the above ionic liquid with 1 part by weight of agomelatin.
(12) The agomelatin-containing patch composition according to (9) above, containing 1 to 10 parts by weight of agomelatine and 5 to 10 parts by weight of the ionic liquid.
(13) The agomelatin-containing patch composition according to any one of (1) to (12) above, wherein the elastomer of the patch is SIS.
(14) The adhesive composition containing agomelatine as described in (1) to (13) above, wherein the adhesive composition is non-aqueous.

The agomelatin-containing patch composition of the present invention is a preparation in which agomelatin, which is hardly soluble in an organic solvent, is dissolved in a fatty acid-based ionic liquid and uniformly dispersed in a plaster. As a feature of the present invention, it was shown that transdermal absorbability was remarkably improved by using a mixed ionic liquid obtained by combining a readily soluble ionic liquid of agomelatin and a hardly soluble ionic liquid.
Furthermore, by adding a filler to the pressure-sensitive adhesive layer, the agomelatin-containing solution inside the pressure-sensitive adhesive layer is easily exuded, the transdermal absorbability of agomelatine is further improved, and the content of agomelatine remaining in the patch is also increased. The effective utilization rate of agomelatin can be increased.
Due to the two effects of the fatty acid-based ionic liquid that dissolves agomelatine, which is a feature of the present invention, and the filler that facilitates the release of the agomelatine-containing solution from the adhesive layer, the patch composition of the present invention allows the in vivo treatment of agomelatin. It has been shown that a high blood concentration can be achieved while maintaining blood concentration and achieving sustained release of agomelatine.

It is a figure showing that the difference of an ionic liquid influences the transdermal absorbability of agomelatin. It shows that the percutaneous absorbability is further improved by combining a plurality of ionic liquids. 1 represents the addition of triisopropanolamine decanoate, 2 represents the addition of triethanolamine decanoate, 3 represents the addition of triisopropanolamine oleate, and 4 represents the addition of triisopropanolamine salicylate. 1 + 3 represents the addition of triisopropanolamine decanoate and triisopropanolamine oleate. Other combinations of numbers also have the same meaning. It is a figure showing the result of the in vivo test (blood concentration change of a mouse | mouth) using the patch composition (test No. A068) of this invention produced combining the some ionic liquid. The concentration of agomelatine in plasma peaked at 2 hours after application, and a tendency toward sustained release was observed. It is a figure showing the result of the in vivo test (blood concentration change of a mouse | mouth) using the patch composition (test No. A244) of this invention. It has been shown that by using a filler, a sustained release effect of agomelatine can be achieved and bioavailability is improved. It is a figure showing the result of the in vivo test (blood concentration change of a mouse | mouth) using the patch composition (test No. A248) of this invention. The peak concentration of agomelatine in plasma was 4 hours after application, and the sustained release of agomelatine was promoted overall, and the blood concentration tended to be kept constant.

The “agomelatin” of the present invention is N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide, which is a compound represented by the structural formula of the above formula (1). The synthesis of agomelatine is described in EP 0447285.
The “ionic liquid” of the present invention refers to a Bronsted salt in the form of a room temperature viscous liquid formed from a compound having a carboxyl group and an organic amine compound. The easily soluble ionic liquid of agomelatine is one in which 3 g or more of agomelatin is dissolved in 100 g of ionic liquid. The slightly soluble ionic liquid of agomelatine refers to one in which agomelatin was dissolved in less than 3 g.
The patch of the present invention can be used by blending such agomelatine easily soluble ionic liquid. Furthermore, it is preferable to use a mixed ionic liquid in which an agomelatin hardly soluble ionic liquid is combined. Examples of such agomelatine easily soluble ionic liquids (systems of compounds having a carboxyl group) include decanoic acid ionic liquids, oleic acid ionic liquids, and salicylic acid ionic liquids. Can be used in combination. Moreover, the organic amine compound of the ionic liquid can be used by selecting one or more of diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine according to the acid compound. Furthermore, decanoic acid triisopropanolamine salt and oleic acid triisopropanolamine salt can be mentioned as particularly preferred agomelatin readily soluble ionic liquids.
As the poorly soluble ionic liquid of Agomelatine, for example, one or more of isostearic acid ionic liquid, lactic acid ionic liquid, and levulinic acid ionic liquid can be selected and used in combination. Moreover, the organic amine compound of the ionic liquid can select and use one or more from diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. Further, particularly difficult tolerated ionic liquids of agomelatine include diisopropanolamine isostearate and diisopropanolamine lactate.
The ionic liquid of the present invention contains an equimolar mixture of an organic carboxylic acid and an amine compound together with an equimolar Bronsted salt.

The “organic solvent” of the present invention is not only used as a transdermal absorption enhancer, but also refers to what is used for dissolving and dispersing an ionic liquid in which agomelatine is dissolved in a plaster, such as ethanol, Alcohols such as propanol and oleyl alcohol, such as ethylene glycol, propylene glycol, 1,3-butanediol, polyethylene glycol (macrogol), polyhydric alcohols such as glycerin, such as diethyl sebacate, isopropyl myristate, propylene carbonate, adipine Examples include esters such as diisopropyl acid and N-methylpyrrolidone (NMP). These organic solvents can be used in appropriate combination in order to achieve the above object. Preferably, one or more selected from N-methylpyrrolidone, diethyl sebacate, isopropyl myristate, propyl carbonate, and polyethylene glycol can be selected and used in combination.
Examples of the “filler” of the present invention include inorganic solid powder agents used for plaster pastes such as silicic anhydride, zinc oxide, titanium oxide, calcium carbonate, and kaolin. Further, organic solid powder reagents such as corn starch, crystalline cellulose, and stearic acid can be used. What is preferable as a filler of this invention can mention a corn starch and a crystalline cellulose as a silicic acid anhydride as an inorganic type agent, and an organic type agent. More preferable examples include crystalline cellulose and silicic anhydride. The addition amount of the filler is 3 to 10% by weight, preferably 3 to 7% by weight. As the filler, an inorganic solid powder reagent and an organic solid powder reagent can be used in combination.

The patch of the present invention may further contain additives such as antioxidants, disintegrants, surfactants, thickeners and the like as long as the effects of the present invention are not hindered. As these additives, commercially available reagents can be appropriately used according to the purpose.
Examples of the antioxidant include organic antioxidants such as sodium ascorbate, BHT, and propyl gallate, and inorganic antioxidants such as sodium thiosulfate, sodium bisulfite, sodium sulfite, and sodium pyrosulfite. it can.
Examples of the disintegrant include Kollidon (polyvinylpyrrolidone), carmellose sodium, sodium starch glycolate, partially pregelatinized starch, and the like.

Examples of the surfactant include a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant. Examples of the nonionic surfactant include sorbitan monolaurate. Sorbitan monopalmitate, sorbitan sesquioleate, glycerin monostearate, decaglyceryl monolaurate, hexaglycerin polyricinoleate, polyoxyethylene (9) lauryl ether, polyoxyethylene (2) lauryl ether, polyoxyethylene (4 , 2) lauryl ether, polyoxyethylene (5) nonylphenyl ether, polyoxyethylene (7,5) nonylphenyl ether, polyoxyethylene (10) nonylphenyl ether, polyoxyethylene (3) octylphenyl ether, polio Siethylene (10) octylphenyl ether, polyoxyethylene (10) oilylamine, polyoxy (5) oleylamine, polyoxy (5) oleic acid amide, polyoxyethylene (2) monolaurate, stearic acid monoglyceride, polyoxyethylene castor oil ( Hardened castor oil) and the like.
Examples of the anionic surfactant include sodium lauryl sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate, sodium cetyl sulfate, sodium lauroyl sarcosine, di-2-ethylhexyl sodium sulfosuccinate, polyoxyethylene (10) lauryl ether. Examples thereof include sodium phosphate, polyoxyethylene (4) sodium lauryl ether phosphate, polyoxyethylene (5) sodium cetyl ether phosphate, polyoxyethylene (6) sodium eurel ether phosphate, and the like.
Examples of the cationic surfactant include stearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, benzalkonium chloride, stearyl dimethyl benzyl ammonium chloride, and the like.
Examples of the amphoteric surfactant include lauryldimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, and the like. In addition to the above, lauroyl diethanolamide can also be used.
Furthermore, thickeners such as carbopol, ultraviolet absorbers, powders and the like can be added.

The phrase “the patch composition is non-aqueous” in the present invention means that the patch does not contain water as an essential component. That is, it refers to a tape agent.
A general-purpose base can be used for the plaster of the patch of the present invention, for example, an acrylic resin base, or a SIS (styrene-isoprene-styrene copolymer) resin and a tackifier, a softener. Etc. can be used. Preferable examples include a base having an SIS resin as an elastomer.
In addition, as a method for preparing the patch of the present invention, a method similar to that for the pressure-sensitive adhesive tape can be employed, and examples thereof include a solvent coating method. Examples of the solvent coating method include a method of preparing a plaster composition containing agomelatine, and coating and drying it directly on a support. Further, it is also possible to use a method in which the plaster composition is once coated on release paper and dried, and then peeled and transferred and adhered to a support.
The release paper is used for the purpose of protecting the pressure-sensitive adhesive layer. For example, polyethylene-coated fine paper, polyolefin-coated glassine paper, polyethylene terephthalate (hereinafter referred to as PET) film, polypropylene film, and the like treated with silicon can be used. is there.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples.

(Example 1) Solubility of agomelatin in ionic liquid In order to determine the solubility of agomelatin, 3 mg of agomelatin was weighed and added to each 100 mg of ionic liquid obtained from the carboxylic acid compound and amine compound of Table 1 below, The presence or absence of agomelatin remaining at room temperature was confirmed. The results are summarized in Table 1.

［注記］
　○：アゴメラチンが完全に溶解した。
　×：アゴメラチンの一部が溶解せずに残った。

[Note]
○: Agomelatine was completely dissolved.
X: A part of agomelatine remained without being dissolved.

As shown in Table 1 above, the readily soluble ionic liquid of agomelatine is a decanoic acid ionic liquid, a salicylic acid ionic liquid, or an oleic acid ionic liquid (triisopropanolamine salt). Moreover, the sparingly soluble ionic liquid of agomelatin is an isostearic acid type ionic liquid, a levulinic acid type ionic liquid, and a lactic acid type ionic liquid.
Therefore, the solubility of agomelatin can be adjusted by combining these easily soluble ionic liquid and hardly soluble ionic liquid. Furthermore, it is possible to improve transdermal absorbability by adjusting the solubility of agomelatine to near saturation by using an organic solvent.

(Example 2) Transdermal absorbability of a patch composition using an easily soluble ionic liquid of agomelatine (1) Formulation formulation 100 mg of each of the 8 types of readily soluble ionic liquids of Example 1 in an agomelatin were weighed and 10 mg of agomelatin After dissolving with stirring, 10 mg of BHT was added. Thereafter, 440 mg of terpene resin and 220 mg of SIS were added and stirred, and 220 mg of liquid paraffin was added to make 1 g. This composition was stretched on a PET film to produce a tape agent having a thickness of about 0.3 mm so that agomelatine was about 133 μg / cm ² .
(2) Evaluation Method An in vitro evaluation test using the Franz cell method of Test Example 2 was performed. The results are summarized as shown in Table 2 below.

　　　［注記］
　　　　　6時間後の累積透過濃度の単位：（μｇ／ｃｍ^２）

[Note]
Unit of cumulative transmission density after 6 hours: (μg / cm ² )

Of the 8 types of agomelatin readily soluble ionic liquids, 4 types of decanoic acid triisopropanolamine, decanoic acid triethanolamine, salicylic acid triisopropanolamine, and oleic acid triisopropanolamine are selected as ionic liquids with high transdermal absorbability. Further investigations were made.

(Example 3) Transdermal absorbability of agomelatin in patch composition using mixed ionic liquid (1) Formulation method Reagents were weighed according to the composition (w / w%) shown in Table 3 below, and ionic liquid (2 Agmelatin 10 mg was dissolved in seeds or 3 kinds, and NMP was added and stirred. 10 mg of BHT was added, 440 mg of terpene and 220 mg of SIS were further added and mixed and stirred, and then 220 mg of liquid paraffin was added to prepare a total composition of 1 g. This composition was stretched on a PET film to prepare a tape preparation according to Example 2. Using the tape, in vitro transdermal absorbability was evaluated by the Franz cell method of Test Example 2. The results are shown in Table 3.

［注記］
１）ＮＭＰ：Ｎ－メチル－２－ピロリドンを意味する。
２）ＳＩＳ：スチレン－イソプレン－スチレン共重合体を意味する。
３）ＢＨＴ：ジブチルヒドロキシトルエンを意味する。

[Note]
1) NMP: means N-methyl-2-pyrrolidone
2) SIS: means styrene-isoprene-styrene copolymer.
3) BHT: means dibutylhydroxytoluene.

(2) Results The results of Example 1 and the results of Table 3 above are shown together in FIG. As shown in FIG. 1 and Table 3, it was found that the use of a mixture of a plurality of ionic liquids improved the transdermal absorbability. In particular, test no. As shown in A056, it was shown that the combination of triisopropanolamine decanoate and triisopropanolamine oleate has high transdermal absorbability.

(Example 4) Change in transdermal absorbability of agomelatin in patch composition prepared by adding poorly soluble ionic liquid to agomelatine easily soluble ionic liquid and adjusting the solubility of agomelatine The ionic liquid used in Example 2 above was Since it is an easily soluble ionic liquid of agomelatine, it is considered that the solubility of agomelatin is high. Therefore, the isostearic acid-based ionic liquid and lactic acid-based ionic liquid, which are poorly soluble ionic liquids of Agomelatine, were added to reduce the solubility of Agomelatine, and changes in transdermal absorbability were examined.
Reagents were weighed out according to the composition (w / w%) shown in Table 4 below, and a tape preparation was produced according to the method of Example 2. Using the tape, the transdermal absorbability in Franz Cell was evaluated. The results are shown in Table 4.

［注記］
　略号は表３と同じ意味を表わす。

[Note]
The abbreviations have the same meaning as in Table 3.

As shown in the results in Table 4 above, test no. It was shown that transdermal absorbability is further improved than A056.

(Example 5) Effect of organic solvent in patch composition containing agomelatine The effect of the organic solvent in the mixed ionic liquid system of Example 4 was examined. As an organic solvent, diethyl sebacate (DES), isopropyl myristate (IPM), propylene carbonate, and polyethylene glycol (Macrogol 400) were used in addition to NMP.
Reagents were weighed out according to the composition (w / w%) shown in Table 5 below, and a tape preparation was produced according to the method of Example 3. Using the tape, the transdermal absorbability by the Franz-Cell method in Test Example 2 was evaluated. The results are shown in Table 5.

［注記］
　略号は表４と同じ意味を表わす。

[Note]
The abbreviations have the same meaning as in Table 4.

As shown in Table 5 above, the effect of adding an organic solvent was not particularly noticeable with respect to transdermal absorbability. However, with regard to skin irritation, the irritation decreased drastically when organic solvents other than NMP were added. For example, test no. The sample of A062 had weak skin irritation. Almost no skin irritation was seen in the A068 sample.
Therefore, using the A068 sample, the mouse in vivo test of Test Example 1 was performed to evaluate the change in blood concentration. As a result, in the A068 sample, the plasma concentration was 300 ng / ml 2 hours after application, and an inferior result was obtained as compared with the change in blood concentration during oral administration.

(Example 6) Effect of organic amine compound on transdermal absorbability of agomelatin In the mixed ionic liquid of Example 5 above, three kinds of organic amine compounds, triisopropanolamine, diisopropanolamine, and triethanolamine are used. . However, when alkanolamine is used, the maximum use amount (upper limit of use) is set as described in “Pharmaceutical Additives Dictionary 2007”. Therefore, the change in percutaneous absorption was evaluated using triethanolamine having a large maximum amount. Therefore, in the same manner as in Example 5, the reagents were weighed out according to the composition (w / w%) shown in Table 6 below, and a tape preparation was produced according to the method of Example 3. Using the tape, the transdermal absorbability by the Franz-Cell method in Test Example 2 was evaluated. The results are shown in Table 6.

［注記］
　略号は表４と同じ意味を表わす。

[Note]
The abbreviations have the same meaning as in Table 4.

As shown in Table 6 above, when only triethanolamine was used without using diisopropanolamine, for example, Test No. A067 and test no. As shown in contrast to A244-1, the transdermal absorbability was drastically reduced, showing only about 10% transdermal absorbability. Therefore, in order to add oleic acid as an organic acid and promote the ionic liquid formation of agomelatine, we investigated the formation of oleate of agomelatine in the system. As a result, test no. As shown in A244-1, the transdermal absorbability of agomelatin was improved by adding oleic acid. As a result, it was shown that transdermal absorbability was improved about 2.1 times.

(Example 7) Effect of substitution of NMP in dissolving solvent of agomelatine to dimethyl isosorbide In Examples 5 to 6 above, NMP is used as an organic solvent and used as a dissolving solvent of agomelatine. However, since NMP is easily scattered during the preparation of a tape preparation, and the stability of the preparation is not good, an alternative solvent was examined. As a result, it exchanged paying attention to dimethyl isosorbide (DMI), and evaluated the change in transdermal absorbability. Therefore, in the same manner as in Example 5, the reagents were weighed with the composition (w / w%) shown in Table 7 below, and a tape preparation was produced according to the method of Example 3. Using the tape, the transdermal absorbability by the Franz-Cell method in Test Example 2 was evaluated. The results are shown in Table 7.

［注記］
　略号は表４と同じ意味を表わす。

[Note]
The abbreviations have the same meaning as in Table 4.

As shown in Table 7 above, test no. A244-2 and test no. In contrast to A244-3, transdermal absorbability was improved about 1.3 times by replacing NMP with DMI. In addition, when the content of agomelatin was doubled to 2% by weight, Test No. A244-3 and test no. As shown in comparison with A244-4, the transdermal absorbability was improved about 1.5 times.

(Example 8) Effect of addition of filler in pressure-sensitive adhesive composition Previously, the composition of the ionic liquid used was mainly studied, but the effect of the pressure-sensitive adhesive composition on the transdermal absorbability is described below. investigated. Therefore, it was decided to evaluate the effect of the filler. Therefore, in the same manner as in Example 5, the reagents were weighed with the composition (w / w%) shown in Table 8 below, and a tape preparation was produced according to the method of Example 3. Using the tape, the transdermal absorbability by the Franz-Cell method in Test Example 2 was evaluated. The results are shown in Table 8.

［注記］
　略号は表４と同じ意味を表わす。

[Note]
The abbreviations have the same meaning as in Table 4.

As shown in Table 8 above, test no. When A260 was compared with Test No. A244 containing a filler, the transdermal absorbability was dramatically improved, indicating an approximately 6-fold increase in transdermal absorbability. Further, when Kollidon (polyvinylpyrrolidone) used as a disintegrant is added, as shown in Test No. A248, Test No. Compared with A260, it was shown that the transdermal absorbability was improved about 7 times. Further, when in vivo blood concentration evaluation using mice was performed based on Test Example 1, the effect of sustained release was also shown in FIG. 3 (Test No. A244) and FIG. 4 (Test No. A248). I can see that.

(Test Example 1) In vivo blood concentration evaluation test using mice (1) Experimental animals:
Wister mouse (male), 5 weeks old (2) Test method:
A 2 cm × 2 cm adhesive bandage type patch was prepared as a preparation sample of A068 (agomelatin, 133 μg / cm ² ). As the above 1 group of rats (6 animals), after removing the hair around the administration site (back to flank) of the mouse using an electric clipper [THRIVE, Model 5500 (0.05 mm), Daito Denki Kogyo Co., Ltd.] Shaving with an electric shaver (Cleancut, Seiko Syard Co., Ltd.). Three of the above preparation samples were attached to one animal, and blood was collected at 1, 2, 4, 8, 12, and 24 hours after administration.
200 μl of collected mouse plasma is added to a glass tube, and 200 μl of physiological saline is added to make it uniform. Next, 500 μl of diethyl ether is added, vortexed, centrifuged for 10 minutes, and the ether layer is recovered. Repeat the same ether weekly operation three times for the remaining aqueous layer. The extracted ether is collected and the solvent is distilled off under a high purity nitrogen stream. Evaporate the ether and dissolve the dry residue by adding 200 μl of water. Thereafter, the mixture was filtered through a 0.45 μm filter, and 10 μl of the filtrate was analyzed by HPLC.
(3) Results The results of the above analysis are summarized and FIG. 2 shows the transition of the concentration of agomelatine in plasma.

(Test Example 2) Transdermal absorbability evaluation test in Franz cell To compare the transdermal absorbability of the patch compositions of Examples 1 to 4, a Franz diffusion cell (permeation area: 1 cm) at a test temperature of 32 ° C. ^2. Receptor volume (8 mL) was used to conduct a transdermal absorbability test as follows.
(1) Rat skin: 5-week-old Wistar rat (male) abdominal excised skin (2) Receptor solution: physiological saline + 20% ethanol (3) Concentration measurement of permeation drug: HPLC-ES method (215 nm)
Commercially available rat abdominal frozen skin (5-week-old Wistar rat) is sandwiched between vertical diffusion cells (effective diffusion area: 1 cm ² ), and each sample shown in Tables 1 to 5 is placed on the stratum corneum side. On the side, saline + 20% ethanol solution was applied. Sampling was performed 1, 2, 4, 8, 12, and 24 hours after the start of the experiment, and 60 μL of the sample was measured by HPLC, and the cumulative amount of drug permeated at each time was measured. As a result, the effect of transdermal absorbability based on the difference in ionic liquid as shown in FIGS. 1 to 4 could be evaluated.

The patch composition of the present invention was able to improve transdermal absorbability by dissolving agomelatin in a plurality of fatty acid-based ionic liquids to obtain a patch composition. Furthermore, by adding a filler to the pressure-sensitive adhesive layer, the release of agomelatine from the pressure-sensitive adhesive layer is improved, the transdermal absorbability is improved, and the remaining amount of agomelatin in the pressure-sensitive adhesive layer may be reduced. Indicated. As a result, the effective utilization rate of agomelatin was greatly improved. Therefore, it was found that by using the patch composition of the present invention, a blood concentration comparable to that of a conventional oral agomelatin tablet can be obtained. Furthermore, an organic solvent was added to solve the skin irritation of the patch preparation. From these facts, by using the patch composition of the present invention, a new treatment method called transdermal administration of agomelatine has become possible. Further, by being a patch, agomelatine can avoid the first pass effect in the liver (FIRST PASS), and it has become possible to make a sustained release formulation of agomelatine.

Claims (14)

Agomelatin-containing patch composition comprising at least one ionic liquid selected from decanoic acid-based ionic liquid, salicylic acid-based ionic liquid, and oleic acid-based ionic liquid together with agomelatine. The patch composition containing agomelatin according to claim 1, wherein a filler is further added. The patch composition containing agomelatin according to claim 1 or 2, wherein the filler is added in an amount of 3 to 10% by weight. The agomelatin-containing patch composition according to any one of claims 1 to 3, wherein the filler is crystalline cellulose and / or silicic anhydride. The basic compound of the decanoic acid-based ionic liquid, salicylic acid-based ionic liquid, and oleic acid-based ionic liquid is one or more selected from diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine, Item 5. Agomelatin-containing patch composition according to any one of Items 1 to 4. The agomelatin-containing patch composition according to any one of claims 1 to 5, wherein the oleic acid ionic liquid is an oleic acid triisopropanolamine salt. Furthermore, one or more ionic liquids are selected and added from isostearic acid-based ionic liquid, levulinic acid-based ionic liquid, and lactic acid-based ionic liquid, according to any one of claims 1 to 6. A patch composition containing agomelatine. The basic compound of the isostearic acid-based ionic liquid, levulinic acid-based ionic liquid, or lactic acid-based ionic liquid is one or more selected from diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine, Item 8. Agomelatin-containing patch composition according to Item 7. Agomelatin, decanoic acid triisopropanolamine salt, decanoic acid triethanolamine salt, oleic acid triisopropanolamine salt, isostearic acid diisopropanolamine salt, isostearic acid triethanolamine salt, lactate triethanolamine salt, lactate diisopropanolamine salt The adhesive composition containing agomelatine according to claim 8, wherein one or more are selected from the inside. 10. The agomelatin-containing solution according to claim 1, wherein at least one selected from N-methylpyrrolidone, diethyl sebacate, isopropyl myristate, propylene carbonate, and polyethylene glycol is added as the organic solvent. Patch composition. The agomelatin-containing patch composition according to claim 9, comprising 1 to 10 parts by weight of the ionic liquid per 1 part by weight of agomelatine. The agomelatine-containing patch composition according to claim 9, comprising 5 to 10 parts by weight of the ionic liquid based on 1 part of agomelatine. The agomelatin-containing patch composition according to any one of claims 1 to 12, wherein the elastomer of the patch is SIS. The agomelatin-containing patch composition according to any one of claims 1 to 13, wherein the patch composition is non-aqueous.

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