JP2010285415A - Package of transdermal drug delivery system containing varenicline or pharmaceutically acceptable varenicline acid addition salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a transdermal drug delivery system containing varenicline or a pharmaceutically acceptable varenicline acid addition salt and being excellent in drug absorption and storage stability. <P>SOLUTION: A package of a transdermal drug delivery system reduced in the formation of a decomposition compound of drug varenicline and reduced especially, in the discoloration of a package with time, is provided by packaging a transdermal drug delivery system containing varenicline or a pharmaceutically acceptable salt of varenicline with an aluminum laminate sheet containing a polyacrylonitrile layer as the innermost layer. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a package for a transdermal drug delivery system containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt.

バレニクリンは、５，８，１４−トリアザテトラシクロ［１０．３．１．０^２，１１．０^４，９］−ヘキサデカ−２（１１），３，５，７，９−ペンタン、または７，８，９，１０−Ｔｅｔｒａｈｙｄｒｏ−６Ｈ−６，１０−ｍｅｔｈａｎｏａｚｅｐｉｎｏ［４，５−ｇ］ｑｕｉｎｏｘａｌｉｎｅとしても知られている。Varenicline has the following structure:

Varenicline, 5,8,14- triazacyclononane tetra cyclo [10.3.1.0 ^2,11. 0 ^4,9 ] -Hexadeca-2 (11), 3,5,7,9-pentane, or 7,8,9,10-Tetrahydro-6H-6,10-methanoazepino [4,5-g] quinoxaline Is also known.

  Varenicline is a partial agonist that has a high binding affinity for α4β2 nicotine receptor. When varenicline binds to α4β2 nicotine receptor in the brain, it blocks nicotine and suppresses the satisfaction of smoking. At the same time, it releases a smaller amount of dopamine than that released by the action of nicotine, reducing the symptoms of withdrawal and the longing for tobacco. The indication of varenicline tartrate preparations (0.5 mg tablets and 1 mg tablets) currently provided in Japan is an aid for smoking cessation for nicotine-dependent smokers.

  Regarding a transdermal drug delivery system for assisting smoking cessation, Japanese Patent Laid-Open No. 1-135717 (Patent Document 1) discloses a transdermal drug delivery system containing nicotine, which has already been used for several nicotine replacement therapies. There are commercially available formulations. In addition, a transdermal drug delivery system containing varenicline is disclosed in JP 2007-031436 (Patent Document 2), which describes advantages over tablets or capsules.

  Regarding the packaging of the preparation, for example, Japanese Utility Model Publication No. 61-002034 (Patent Document 3), Japanese Patent Application Laid-Open No. 61-171340 (Patent Document 4), Japanese Utility Model Application Publication No. 62-017244 (Patent Document 5), Japanese Patent Application Laid-Open No. 5-305108 (Patent Document 6). ), Etc. (Patent Documents 7 to 10), polyacrylonitrile packaging is used for packaging pharmaceuticals, foods, etc., and has gas barrier properties such as oxygen, chemical resistance, and non-adsorption of aromatic components It is known that it has excellent properties. The polyacrylonitrile film is superior to other general-purpose resin films in the barrier property of oxygen, and has an oxygen barrier property of about 200 to 1000 times as compared with, for example, a polyolefin film.

JP-A-1-135717 JP2007-031436 (WO2007 / 012963) Jikosho 61-002034 JP 61-171340 Shoko Sho 62-017244 JP 5-305108 Japanese Utility Model Sho 62-149337 WO99 / 35131 WO2005 / 072675 WO2005 / 072716

Problems to be solved by the invention

Although transdermal delivery of varenicline is expected to provide an auxiliary effect on sustained smoking cessation, in fact, the acid addition salt of varenicline is extremely hydrophilic and therefore poorly soluble in the base, and the required drug delivery rate In order to bring about, special ingenuity is necessary.
The present inventors have conducted intensive research and formulated varenicline with a basic compound (an alkaline component such as sodium hydroxide) in order to achieve a sufficient transdermal delivery rate of varenicline tartrate, an acid addition salt of varenicline. It was found that it is possible to increase the transdermal delivery rate by liberating. However, it was later found that such a preparation has poor storage stability of varenicline itself.

  The present invention is intended to solve the problem of such a transdermal drug delivery system containing varenicline, and particularly relates to a package for a transdermal delivery system containing varenicline, which improves storage stability. This is the issue.

Means for solving the problem

  The transdermal drug delivery system containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt is packaged with an aluminum laminated sheet whose innermost layer is a polyacrylonitrile layer, thereby reducing the generation of a degradation compound of drug varenicline, It was found that discoloration of the package over time can be prevented.

That is, the present invention provides a transdermal drug delivery system comprising at least a support, a pressure-sensitive adhesive layer containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt, a protective film, and an aluminum whose innermost layer is a polyacrylonitrile layer. A package for a transdermal drug delivery system packaged with a laminated sheet is provided.
In addition, the present invention provides the above package, wherein the varenicline or pharmaceutically acceptable vareniclic acid addition salt is varenicline tartrate.
Furthermore, the present invention provides the above-mentioned package encapsulating a storage stabilizer together with a transdermal drug delivery system.

The invention's effect

  The transdermal drug delivery system containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt is packaged with an aluminum laminated sheet whose innermost layer is a polyacrylonitrile layer, so that the storage stability of the drug varenicline is excellent and varenicline is decomposed. It is possible to provide a transdermal delivery system with less compound generation and less discoloration of the package over time.

Schematic diagram of a cross section of a package of the transdermal drug delivery system of the present invention Schematic diagram of a cross-section of a package encapsulating a storage stabilizer with the transdermal drug delivery system of the present invention

  Hereinafter, embodiments of the present invention will be specifically described. Unless otherwise specified, “%” means “mass%”.

The present invention relates to a package in which a transdermal drug delivery system containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt is packaged with an aluminum laminated sheet whose innermost layer is a polyacrylonitrile layer.
The transdermal drug delivery system comprises at least a support, an adhesive layer containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt, and a protective film.
The package can enclose a storage stabilizer along with the transdermal drug delivery system.

  Pharmaceutically acceptable acid addition salts of varenicline include tartaric acid, hydrochloric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, citric acid, tartaric acid, acetic acid, gluconic acid, fumaric acid, lactic acid, sulfuric acid, mesylic acid and the like. And tartaric acid addition salts are preferred. The content of varenicline or a pharmaceutically acceptable vareniclic acid addition salt is preferably in the range of 0.3 to 10% (converted as a free form) with respect to the components of the entire pressure-sensitive adhesive layer.

  The adhesive base is not particularly limited as long as it is generally used in a transdermal drug delivery system. Natural rubber adhesive, synthetic rubber adhesive, acrylic adhesive, rubber adhesive, silicone adhesive One type or two or more types selected from agents are exemplified. The adhesive base preferably has no carboxyl group.

  The synthetic rubber-based adhesive is styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-ethylene-butylene-styrene block copolymer (SEBS), or styrene-ethylene-propylene-styrene. Examples thereof include styrenic block copolymers such as block copolymer (SEPS), polyisoprene (PIB), polyisobutylene and the like.

  The acrylic pressure-sensitive adhesive contains at least one (meth) acrylate represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate, or the like. Copolymerized. The acrylic pressure-sensitive adhesive preferably has no carboxyl group as a functional group or is 10% or less as a ratio to the whole monomer from the viewpoint of the transdermal absorbability of the drug. Moreover, it is preferable from the point that there is little coloring over time of a formulation, and vinyl acetate is not contained as a monomer residue, and it is preferable that it is 10% or less as a ratio with respect to the whole monomer as a copolymerization monomer. An acrylic pressure-sensitive adhesive having no carboxyl group is more preferable.

  The said adhesive layer can also contain a tackifier, a softener, a solubilizer, an alkaline component, and other additive components as needed.

  The tackifier may be an alicyclic saturated hydrocarbon resin, a rosin derivative (eg, rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin or pentaerythritol ester of rosin), terpene resin, petroleum resin or Examples include maleic resin.

  The softener includes paraffin oil such as liquid paraffin, animal oil such as squalane and squalene, vegetable oil (for example, almond oil, olive oil, camellia oil, castor oil, tall oil, peanut oil, etc.), silicone oil, liquid rubber (for example, Polybutene or polyisoprene), aliphatic alcohols (isostearyl alcohol, octyldodecanol, etc.), liquid fatty acid esters (isopropyl myristate, hexyl laurate, diethyl sebacate or isopropyl sebacate), glycols (diethylene glycol, polyethylene glycol) , Propylene glycol, dipropylene glycol, etc.), triacetin, triethyl citrate, crotamiton and the like. Moreover, these softeners may be used alone or in combination of two or more.

  Examples of the solubilizer include aliphatic alcohols such as isostearyl alcohol, fatty acids such as capric acid, fatty acid derivatives such as propylene glycol monolaurate, isopropyl myristate, and lauric acid diethanolamide, and polyols such as propylene glycol and polyethylene glycol. Etc. are exemplified.

  The alkaline component is blended to neutralize the acid added to varenicline or the acid component having a free carboxyl group present in the pressure-sensitive adhesive layer, and 0.1 to 0.1 moles for neutralizing all of these acids. It is preferable to blend a double number of moles. The alkaline component is preferably sodium hydroxide, magnesium hydroxide, calcium hydroxide, aluminum hydroxide or the like.

  Examples of the other additive components include antioxidants, stabilizers such as ultraviolet absorbers, fillers, transdermal absorption accelerators, crystal precipitation inhibitors, and the like.

  The support is preferably capable of supporting the pressure-sensitive adhesive layer and having excellent flexibility. Supports are polyester (eg, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, etc.), polyolefin (eg, polyethylene, polypropylene, etc.), polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, nylon, polyurethane, cellulose derivatives. Films, fabrics (eg, woven fabrics, non-woven fabrics, etc.), porous membranes, foams, or the like, which are mainly formed from components selected from synthetic resins such as polyacrylonitrile, cotton, etc. Are illustrated.

  As the protective film, polyester (eg, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, etc.), polyolefin (eg, polyethylene, polypropylene, etc.), a resin film such as polyacrylonitrile, paper, etc. can be used. In order to facilitate peeling of the agent layer, it is preferable that the surface is subjected to a release treatment with silicone, Teflon or the like.

A method for producing a transdermal drug delivery system containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt may include, for example, heating varenicline or a pharmaceutically acceptable vareniclic acid addition salt and other components of the adhesive layer. After being melted and uniformly mixed, and coated on a protective film to form an adhesive layer, it can be bonded to a support and cut into a predetermined shape to produce a transdermal drug delivery system.
Alternatively, varenicline or pharmaceutically acceptable vareniclic acid addition salt and other components of the adhesive layer are dissolved in a solvent such as toluene, hexane, heptane, ethyl acetate, applied onto a protective film, and the solvent is dried. After the removal and formation of the pressure-sensitive adhesive layer, the transdermal drug delivery system can be produced by laminating the support and cutting it into a predetermined shape.

  The transdermal drug delivery system manufactured as described above is packaged in a bag made of an aluminum laminated sheet with the innermost layer being a polyacrylonitrile layer (see FIG. 1). This bag is manufactured by facing a packaging material having at least a barrier layer made of aluminum and a sealant layer made of polyacrylonitrile and joining the peripheral edges to each other. That is, this bag has a barrier layer made of aluminum and the innermost side is made of a polyacrylonitrile layer.

The barrier layer made of aluminum preferably has a thickness in the range of 1 to 30 μm in order to maintain gas barrier properties, prevent inconvenience such as pinhole generation, and suppress decomposition of varenicline.
The polyacrylonitrile (PAN) layer constitutes the innermost layer of the bag and is made of a resin mainly composed of a (co) polymer containing 50% or more of acrylonitrile units. The resin is formed by heating, ultrasonic vibration or the like. It is a sealant layer that can be bonded to each other by melting. What is generally called a polyacrylonitrile-based resin can be used for the polyacrylonitrile layer, and Zeklon (Mitsui Chemicals) can be exemplified as a commercially available resin. The thickness of the polyacrylonitrile layer is preferably 10 to 50 μm.

  An arbitrary intermediate layer made of a polyolefin resin, a polyester resin, or the like can be provided between the barrier layer and the polyacrylonitrile layer for curling prevention, pinhole prevention, bonding, and other purposes.

  In addition, on the outer side of the barrier layer, polyester resin, cellophane, vinyl for the purpose of preventing curling, preventing pinholes, surface gloss, printability, improving packaging strength, shielding light, preventing corrosion, adjusting sliding frictional force, etc. An arbitrary outer layer made of an alcohol (co) polymer, polypropylene, paper, or the like can be provided. If necessary, a bonding layer can be further provided between the outer layer and the barrier layer.

  The transdermal drug delivery system described above is more preferably packaged with an aluminum laminated sheet having a polyacrylonitrile layer as the innermost layer together with a storage stabilizer (see FIG. 2). As the storage stabilizer, an adsorbent, a desiccant, and an oxygen scavenger can be used. For example, adsorbents such as zeolite, silica gel, alumina, molecular sieve, and montmorillonite, and oxygen absorbers such as hydrosulfite and iron compounds. Examples thereof include desiccants such as an agent, calcium carbonate, and silica gel. Specifically, Sorb-It (Adsorbents & Desicants Corporation of America), Pharmakeep (Mitsubishi Gas Chemical Co., Ltd.), Ageless (Mitsubishi Gas Chemical Co., Ltd.), Vitalon (Tokiban Sangyo Co., Ltd.), etc. Illustrated.

  EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention in detail, this invention is not limited to a following example.

Example 1
17.6 g (87.8%) of Duro-Tak 387-2510, 2.0 g (10.0%) varenicline tartrate, 0.4 g (2.2%) sodium hydroxide, and the solvent methanol was added and mixed. A uniform solution was obtained. This solution was applied to the silicone release surface of a 75 μm thick polyethylene terephthalate film, which was a protective film, and the solvent was removed by drying in an air dryer. From the polyethylene terephthalate as a support on the formed adhesive layer, The film was laminated and appropriately cut to prepare a transdermal drug delivery system.
Next, two rectangular packaging material sheets in which cellophane, polyethylene, aluminum foil, and polyacrylonitrile (PAN) are laminated in this order are overlapped so that the PAN layers face each other, and one of the above preparations is sandwiched therebetween. The four peripheral edges of the packaging material were thermally bonded with a heat sealer to obtain a package for a transdermal drug delivery system.

(Example 2)
A transdermal drug delivery system was prepared as in Example 1.
Next, two rectangular packaging material sheets in which cellophane, polyethylene, aluminum foil, and polyacrylonitrile (PAN) are laminated in this order are overlapped so that the PANs face each other. A pharmak keep (manufactured by Mitsubishi Gas Chemical Co., Inc.) having a deoxygenating function was sandwiched, and the peripheral edges of the packaging material were thermally bonded with a heat sealer to obtain a package of a transdermal drug delivery system enclosing a storage stabilizer.

(Comparative Example 1)
A transdermal drug delivery system was prepared as in Example 1.
Next, two rectangular packaging sheets in which cellophane, polyethylene, aluminum foil, and low-density polyethylene (LDPE) are laminated in this order are overlapped so that the LDPEs face each other, and one of the above preparations is sandwiched therebetween. The four peripheral edges of the packaging material were thermally bonded with a heat sealer to obtain a package for a transdermal drug delivery system.

(Comparative Example 2)
A transdermal drug delivery system was prepared as in Example 1.
Next, two rectangular packaging material sheets in which cellophane, polyethylene, aluminum foil, and low density polyethylene (LDPE) are laminated in this order are overlapped so that the LDPEs face each other, and one of the above preparations and dried A pharmak keep (manufactured by Mitsubishi Gas Chemical Co., Ltd.) having both a deoxygenating function and a packaging material of a transdermal drug delivery system in which the four peripheral edges of the packaging material were thermally bonded with a heat sealer and enclosed with a storage stabilizer was obtained. .

(Test 1)
About the package of Example 1 and Comparative Example 1, the degradation product of varenicline was quantified by the following method for the prepared initial package and the package stored for 3 days in a constant temperature chamber at 80 ° C. The delivery system package was evaluated for discoloration over time.

(Method for quantifying varenicline degradation products)
For each package, open and remove the transdermal drug delivery system, extract the components from the 6.25 square cm formulation with an organic solvent to make a test solution, and use it for high performance liquid chromatography (ODS column, UV detector). Thus, varenicline and unknown compounds were searched. The amount of unknown compound was calculated from the sum of the chromatographic absorption areas of the unknown compound, where the theoretical amount of varenicline was 100.
(Evaluation method of coloration over time of transdermal drug delivery system)
About each package, it opened and took out the transdermal drug delivery system, and observed the external appearance, the inner surface of a packaging material, etc. visually.

経皮薬物送達システムの経時着色の評価結果

試験１の結果は上表１〜２のようになり、経皮薬物送達システムをＰＡＮ包装材にて包装した実施例１の包装体では、８０℃で３日間の過酷条件下での保存後においてバレニクリンに由来する分解物の生成率が４．７９％にとどまったのに対し、ＬＤＰＥ包装材を用いた比較例１の場合には、分解物の生成率が５．４６％と高い割合を示した。また、比較例１の包装体では包装材の内面に明らかな経時的変色がみとめられたのに対し、実施例１の包装体では経時的変色はみとめられなかった。Quantitative results of varenicline degradation compounds

Evaluation results of coloration over time of transdermal drug delivery system

The results of Test 1 are as shown in Tables 1 and 2 above. In the package of Example 1 in which the transdermal drug delivery system was packaged with PAN packaging material, after storage under severe conditions at 80 ° C. for 3 days. While the production rate of the degradation product derived from varenicline was only 4.79%, in the case of Comparative Example 1 using the LDPE packaging material, the production rate of the degradation product showed a high rate of 5.46%. It was. Further, in the packaging body of Comparative Example 1, clear discoloration over time was observed on the inner surface of the packaging material, whereas in the packaging body of Example 1, no discoloration over time was observed.

(Test 2)
About the package of Example 2 and Comparative Example 2, the degradation product of varenicline was quantified by the following method for the prepared initial package and the package stored for 3 days in a constant temperature chamber at 80 ° C. The discoloration over time of the delivery system package was evaluated as in Test 1.

経皮薬物送達システムの経時着色の評価結果

試験２の結果は上表３〜４のようになり、経皮薬物送達システムを保存安定剤とともにＰＡＮ包装材で包装した実施例２の包装体では、８０℃で３日間の過酷条件下での保存後においてバレニクリンに由来する分解物の生成率が２．１９％にとどまったのに対し、保存安定剤とともに包装したＬＤＰＥ包装材の比較例２の包装体では分解物の生成率が２．７１％と高い割合を示した。また、保存安定剤を入れた実施例２は、保存安定剤を入れなかった実施例１よりも更に優れた安定性を示した。
また、比較例２の包装体では包装材の内面に経時的変色がみとめられたのに対し、実施例２の包装体では経時的変色はみとめられなかった。Quantitative results of varenicline degradation compounds (when encapsulated with storage stabilizer)

Evaluation results of coloration over time of transdermal drug delivery system

The results of Test 2 are as shown in Tables 3 to 4 above. The package of Example 2 in which the transdermal drug delivery system was packaged with a PAN packaging material together with a storage stabilizer was subjected to severe conditions at 80 ° C. for 3 days. The production rate of degradation products derived from varenicline after storage remained at 2.19%, whereas the package of Comparative Example 2 of the LDPE packaging material packaged with the storage stabilizer had a degradation product production rate of 2.71. % Showed a high ratio. In addition, Example 2 in which a storage stabilizer was added showed even better stability than Example 1 in which no storage stabilizer was added.
In the package of Comparative Example 2, discoloration over time was observed on the inner surface of the packaging material, whereas in the package of Example 2, no discoloration over time was observed.

DESCRIPTION OF SYMBOLS 1 Package body of transdermal drug delivery system 2 Transdermal drug delivery system 3 Support body 4 Adhesive layer containing a drug 5 Protective film 10a Packaging material 10b Packaging material 11 Outer layer 12 Barrier layer 13 Intermediate layer 14 Polyacrylonitrile layer 20 Transdermal Packaged Storage Stabilizer 21a Encapsulated with Drug Delivery System 21a Packaging Sheet 21 for Storage Stabilizer Packaging Sheet 22 For Storage Stabilizer 22 Storage Stabilizer

Claims (3)

  A transdermal drug delivery system comprising at least a support, a pressure-sensitive adhesive layer containing varenicline or a pharmaceutically acceptable vareniclic acid addition salt, and a protective film is packaged with an aluminum laminated sheet whose innermost layer is a polyacrylonitrile layer. Package of skin drug delivery system.   The package according to claim 1, wherein the pharmaceutically acceptable vareniclic acid addition salt is varenicline tartrate.   The package according to claim 1 or 2, wherein a storage stabilizer is encapsulated together with the transdermal drug delivery system.

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