WO2013140821A1

WO2013140821A1 - Layered body for ptp or blister pack, and ptp or blister pack

Info

Publication number: WO2013140821A1
Application number: PCT/JP2013/001972
Authority: WO
Inventors: 高橋　正昭; 弘谷口; 小川　達也; 小泉　真一; 山本　光; みどり藤崎
Original assignee: 第一三共株式会社; 共同印刷株式会社
Priority date: 2012-03-23
Filing date: 2013-03-22
Publication date: 2013-09-26
Also published as: JPWO2013140821A1; TW201347988A; KR20140124790A; CN104169187A; JP6175425B2

Abstract

Provided is a layered body (40) for a PTP or blister pack in which an absorption layer (50) is layered on a substrate layer (70) via an adhesive layer (60). The absorption layer (50) has a configuration in which an outer skin layer (52), an intermediate layer (51), and an inner skin layer (53) are layered in the stated sequence, and the outer skin layer (52) is bonded to the substrate layer (70) via the adhesive layer (60). The outer skin layer (52) is composed of a polyethylene resin, the intermediate layer (51) is composed of a mixture of a polyethylene resin and an absorbent, and the inner skin layer (53) is composed of a blended resin having 25 to 50 mass% of a linear low-density polyethylene, and 75 to 50 mass% of a high-density polyethylene having a higher melting point as a material than the preheating temperature in the molding process. Preferably, the blended resin of the inner skin layer (53) has 10 to 50 mass% of a linear low-density polyethylene, and 90 to 50 mass% of a high-density polyethylene having a higher melting point as a material than the preheating temperature in the molding process.

Description

Laminate for PTP or blister pack and PTP or blister pack

The present invention relates to a PTP or blister pack laminate used for molding a PTP or blister pack, a PTP or blister pack molded using the same, and its usage.

Conventionally, PTP (Press-Through Package) is used as a packaging container for capsules containing solid preparations such as tablets and drugs. PTP or blister packs are also collectively referred to as blister packaging containers and are widely used for packaging pharmaceutical products.

The laminate for PTP or blister pack is a film or sheet material used for forming PTP or blister pack before the preparation is enclosed. A PTP or blister pack molding machine forms a dome-shaped (or bowl-shaped) pocket portion by applying heat (preheating) to a sheet-like laminate as a material while pressing it with a molding die.

The PTP or blister pack formed from the laminate is a package in which the preparation is sealed by thermally welding a lid material to the hem part extending around the periphery in a state where the preparation is accommodated inside the pocket portion. Become. If the PTP or blister pack is transparent, it is possible to easily visually recognize the preparation enclosed therein. Further, the encapsulated preparation can be easily taken out by pushing the PTP or blister pack together with a finger or the like so that the lid material breaks through. The name “press-through package” comes from this form of use.

There are various drugs that are active ingredients of preparations contained in PTP or blister packs, including drugs with low moisture resistance, drugs that are easily oxidatively decomposed, and drugs with strong odors. Therefore, it is desired that the PTP or blister pack has a function of absorbing liquid (water, etc.) and gas (water vapor, oxygen, smell, etc.). For example, there is a prior art in which an absorbent layer containing an absorbent is formed inside a PTP or blister pack in advance to give the molded PTP or blister pack an absorption function (International Publication WO2006 / 115264). : Patent Document 1). According to this prior art, even if a desiccant or the like is not included in the PTP or blister pack, the dry state of the medicine as a package is maintained, oxidation is prevented, and the odor is efficiently absorbed. I think it can be done.

Olmesartan medoxomil is used for hypertension or a disease derived from hypertension (more specifically, hypertension, heart disease [angina, myocardial infarction, arrhythmia, heart failure or hypertrophy), kidney disease [diabetic nephropathy, thread Spherical nephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]). This olmesartan medoxomil is a compound having a medoxomil group in the molecule, and the low molecular weight 2,3-butanedione (hereinafter referred to as “diacetyl”) is obtained by gradually cleaving the medoxomil ester by water to change into an active body. It is a generated compound. This diacetyl itself is known as a causative substance of a unique odor, and is considered to be an odor causative substance of a preparation containing olmesartan medoxomil.

In the above prior art, a film for PTP or blister pack is formed of a laminate, a barrier layer is disposed on the outermost layer, and a moisture absorbing layer is disposed on the inner layer. Further, the hygroscopic layer has a three-layer structure of a main hygroscopic layer and a sub hygroscopic layer, and the sub hygroscopic layer is disposed on the inner and outer (upper and lower sides in the stacking direction) with the main hygroscopic layer interposed therebetween. Of these, the outer sub-moisture absorbing layer enhances the adhesiveness with the barrier layer by lamination, and the inner sub-hygroscopic layer enhances the adhesiveness with the lid material by heat sealing.

In addition, the inventors of the present invention, when the barrier layer referred to in the prior art is a base material layer, the main moisture absorption layer is an intermediate layer, and the sub moisture absorption layers on both sides are an outer skin layer and an inner skin layer, PTP Or the following problems were faced in the laminated body for blister packs.
(1) When the material laminate is preheated in the molding process of PTP or blister pack, the inner skin layer facing the heating member may be fused to the heating member (improvement of preheat resistance).
(2) The inner skin layer in contact with the contents such as the preparation is required not only to have preheat resistance but also to have a property of allowing the odor and moisture to permeate efficiently and improving the absorbability in the intermediate layer (improvement of absorption characteristics).

In view of the above background, there is a demand for a technique that ensures the preheat resistance of a material in the molding process of PTP or blister pack and that sufficiently exhibits the function as a laminated body having an absorptivity.
International Publication WO2006 / 115264

As a result of intensive research, the inventors of the present invention have optimized the selection of the resin material used for the inner skin layer, and at the same time, optimized the mixing ratio (mass%) of the resin material, so that it can be used for PTP or blister packs. It came to invent a laminated body. This laminate for PTP or blister pack has (1) sufficient preheat resistance at the time of molding PTP or blister pack, and (2) has sufficient absorption characteristics depending on the purpose of use.

That is, one aspect of the present invention is a PTP or blister pack laminate comprising a base material layer and an absorption layer. The base material layer becomes the outermost layer during molding as a PTP or blister pack. Moreover, the absorption layer is laminated | stacked through the contact bonding layer on the base material layer, and faces at the time of the shaping | molding as PTP or a blister pack, and absorbs at least one of a liquid and gas. It is assumed that the PTP or blister pack laminate as a manufacturing raw material is preheated (preheated) from a heating member disposed facing the absorption layer in the process of forming the PTP or blister pack.

The above-mentioned absorption layer has a configuration in which an outer skin layer, an intermediate layer, and an inner skin layer are laminated in this order, and the outer skin layer is bonded to the base material layer via the adhesive layer. The outer skin layer is made of a polyethylene resin, and the intermediate layer is made of a mixture of a polyethylene resin and an absorbent. The inner skin layer is made of a blend resin having 25 to 50% by mass of linear low density polyethylene and 75 to 50% by mass of high density polyethylene having a melting point higher than the preheating temperature in the molding process.

More preferably, the inner skin layer is made of a blend resin having 10 to 50% by mass of linear low-density polyethylene and 90 to 50% by mass of high-density polyethylene having a melting point higher than the preheating temperature in the molding process. Become.

According to the above configuration, in any case, even if preheating is applied to the laminate of materials during the molding process of PTP or blister pack, fusion to the heating member does not occur (guarantee of preheat resistance). In addition, by optimizing the gas permeation rate and moisture permeability from the inner skin layer to the intermediate layer (mass of odor molecules, water molecules, etc. per unit time), sufficient absorption characteristics can be obtained depending on the purpose of use. Obtainable.

The above intermediate layer is composed of a mixture of a polyethylene resin and an absorbent, and forms the core of a functional layer that mainly absorbs moisture and odors. By appropriately changing the type of absorbent, it is possible to select the substance that the absorbent layer absorbs, and it is possible to suitably exhibit sufficient absorption characteristics depending on the combination of resin materials used for the inner skin layer and their mixing ratio it can. The absorbent is preferably a synthetic zeolite.

The PTP or blister pack which is another embodiment of the present invention is formed using the above-described PTP or blister pack laminate. That is, the PTP or blister pack is laminated with a base material layer constituting the outermost layer of the pocket portion containing the contents, and an adhesive layer on the base material layer, and faces at least one of liquid and gas facing the contents. And an absorption layer that absorbs water. The absorbent layer has a configuration in which an outer skin layer, an intermediate layer, and an inner skin layer are laminated in this order, and the outer skin layer is bonded to the base material layer through an adhesive layer, and the outer skin layer is made of polyethylene resin. Consists of. The intermediate layer is made of a mixture of a polyethylene resin and an absorbent. The inner skin layer is composed of a blend resin having 25 to 50% by mass of linear low-density polyethylene and 75 to 50% by mass of high-density polyethylene having a melting point higher than the preheating temperature in the molding process.

More preferably, also in the embodiment of PTP or blister pack, the inner skin layer is made of 10-50% by mass of linear low-density polyethylene and high-density polyethylene having a melting point higher than the preheating temperature in the molding process. It is composed of a blend resin having 90 to 50% by mass.

According to said PTP or blister pack, by using the material which has the advantage as a laminated body mentioned above, the quality as a PTP or blister pack or a package using the same is improved, and the formulation which is the content is The odor generated can be suitably absorbed.

The pharmaceutical uses of the present invention are as follows.
(1) A PTP package or blister pack comprising the PTP or blister pack described above and a preparation contained in the PTP or blister pack.
(2) The PTP or blister pack according to (1), wherein the preparation further contains one or more other drugs as active ingredients.
(3) Olmesartan medoxomil-containing preparation packaged in PTP or blister pack.
(4) The olmesartan medoxomil-containing preparation of (3), which further contains one or more other drugs as active ingredients.
(5) The olmesartan medoxomil-containing preparation according to (4), wherein the other drug is one or more compounds selected from amlodipine (including besylate salt), azelnidipine and hydrochlorothiazide.
(6) The olmesartan medoxomil-containing preparation according to any one of (3) to (5) for treating or preventing hypertension.
(7) The olmesartan medoxomil-containing preparation according to any one of (3) to (5), wherein the generation of odor generated from the contained olmesartan medoxomil preparation is reduced.
(8) A method for reducing odor generated from a preparation containing olmesartan medoxomil, which is packaged with PTP or blister pack.
(9) The method for reducing odor according to (8), wherein the preparation containing olmesartan medoxomil is a preparation containing olmesartan medoxomil further containing one or more of other drugs as an active ingredient.
(10) The method for reducing odor according to (9), wherein the other drug is one or more compounds selected from amlodipine (including besylate salt), azelnidipine and hydrochlorothiazide.
(11) Use of PTP or blister pack for olmesartan medoxomil-containing preparation packaging.
(12) Use of PTP or blister pack for odor-reducing packaging in olmesartan medoxomil-containing preparations.

The invention disclosed herein provides a laminate suitable for molding a PTP or blister pack having an absorption function. In addition, the quality and reliability of the PTP or blister pack formed using the laminate can be improved, the absorption function can be fully exhibited, and the odor generated from the preparation can be reduced. It becomes possible to provide a package that hardly senses odor when the preparation is taken out from the PTP package or the blister package.

FIG. 1 is a longitudinal sectional view schematically showing the structure of a blister package, FIG. 2 is a longitudinal sectional view schematically showing the structure of a laminate that is a material of PTP or blister pack, FIG. 3 is a list showing the brand, model number, manufacturer name, melting point, etc. of the resin used in the laminate, FIG. 4 is a list showing the verification results of the experimental samples (Nos. 1 to 14) regarding the layer configuration example, FIG. 5 is a diagram showing the absorption rate when each sample of the laminate is exposed to diacetyl gas for 10 hours, and FIG. 6 is a table showing the results of odor sensory tests with actual drugs.

Hereinafter, embodiments of a PTP or blister pack laminate, a PTP or blister pack using the same, a package using the PTP or blister pack, a usage, and the like will be described.

FIG. 1 is a longitudinal sectional view schematically showing the structure of a PTP package or blister package 10 in a form in which the preparation 20 is enclosed in a PTP or blister pack 40. The PTP package or blister pack 10 is an example of using a PTP or blister pack 40 formed using a PTP or blister pack laminate of materials. Such a PTP package or blister package 10 is suitable for applications in which a tablet, granular or capsule-shaped preparation 20 is individually packaged.

The shape of the PTP or blister pack 40 can be variously changed depending on the outer shape of the preparation 20 to be contained. In the example of FIG. 1, the PTP or blister pack 40 has a dome shape, but the PTP or blister pack 40 may have a hollow cylindrical shape, a truncated cone shape, a prismatic shape, or a truncated pyramid shape. Further, when the preparation 20 is a long and thin capsule, the PTP or blister pack 40 is formed into a long and thin hollow protruding shape according to the outer shape of the capsule.

Such a PTP or blister pack 40 is obtained by forming a film-like or sheet-like laminate (a laminate for PTP or blister pack) as a material (raw material). Examples of the method for forming the PTP or blister pack 40 from the laminate of materials include PTP forming methods such as a flat plate pressure forming method, a plug assist pressure forming method, a drum type vacuum forming method, and a plug forming method.

The PTP or blister pack 40 has a pocket portion 40a inside, and protects the formulation 20 in a state where the formulation 20 is accommodated in the pocket portion 40a. Further, a flat hem portion 40b extends around the pocket portion 40a, and the hem portion 40b serves as a base (or flange) of the PTP or blister pack 40.

FIG. 1 shows only a cross section of one blister package 10, but a plurality of PTP or blister packs 40 may be connected via, for example, a hem portion 40 b. For example, assuming that the skirt portion 40b is a single substrate, a plurality of PTPs or blister packs 40 are arranged in a matrix on the substrate. Half-cut lines and perforations (not shown) for dividing individual PTPs or blister packs 40 or their rows can be formed in the skirt portion 40b serving as a substrate.

The blister package 10 has a structure in which the preparation 20 is housed in a PTP or blister pack 40 and sealed with a lid 30. The lid member 30 is a film-like or sheet-like member having, for example, airtightness (gas barrier property and water vapor barrier property). For the lid member 30, PVC (Poly Vinyl Chloride; polyvinyl chloride) or EVA (Ethylene Vinyl Acetate; ethylene vinyl acetate copolymer resin) coat AL (aluminum) or the like can be used.

The lid member 30 and the PTP or blister pack 40 (hem portion 40b) are bonded together by heat-sealing them with their inner surfaces overlapped. If the adhesiveness is insufficient as it is, an adhesive layer or a heat-sealable resin layer may be further formed on either the lid member 30 or the PTP or blister pack 40.

The PTP package or the blister package 10 in particular the PTP package can extrude the formulation 20 from the outside by pushing the formulation 20 together with the PTP from the outside with the finger or the like, so that the formulation 20 inside can be taken out.

[Structure of laminate]
FIG. 2 is a longitudinal sectional view schematically showing the structure of a laminate that is a material of the PTP or blister pack 40. The laminated structure shown in FIG. 2 remains in the form after the laminated body of materials is formed as PTP or blister pack 40 (enclosed portion indicated by a two-dot chain line in FIG. 1: reference symbol II). Hereinafter, the structure of the laminated body (PTP or the laminated body for blister packs) used as the material of PTP or the blister pack 40 is demonstrated taking the laminated structure of FIG. 2 as an example.

The PTP or blister pack 40 includes a base material layer 70 in the outermost layer and an absorption film (absorption layer) 50 on the inner side facing the contents. The absorption film 50 is laminated on the base material layer 70 via the adhesive layer 60.

As the base material layer 70, PVC, PVC coated with polyvinylidene chloride (PVDC), PP, or the like can be used. The base material layer 70 may be a single layer, but may be composed of two or more layers including other layers such as an AL foil as long as the PTP moldability, gas barrier property, and water vapor barrier property are not impaired. The thickness is preferably 150 to 300 μm from the viewpoint of PTP moldability.

The absorption film 50 and the base material layer 70 are laminated via the adhesive layer 60 by dry lamination or sand lamination. As the adhesive layer 60, an adhesive for dry lamination, low density polyethylene (LDPE), linear low density polyethylene (LLDPE), or the like can be used. In order to facilitate lamination, an anchor coat layer may be provided on either or both of the absorption film 50 and the base material layer 70.

The absorption film 50 is a film having a three-layer structure. That is, the absorption film 50 includes an intermediate layer 51 and an outer skin layer 52 and an inner skin layer 53 sandwiching the intermediate layer 51. Among these, the intermediate | middle layer 51 makes the core as a functional layer which mainly bears absorption of a water | moisture content and an odor. Further, the outer skin layer 52 and the inner skin layer 53 are mainly formed as a skin layer of the intermediate layer 51 by being laminated inside and outside (up and down as viewed in the lamination direction) with the intermediate layer 51 interposed therebetween. The outer skin layer 52 is laminated with the base material layer 70 through the adhesive layer 60, and the inner skin layer 53 is disposed on the inner side facing the contents in the PTP or blister pack 40. The inner and outer skin layers 52 and 53 are not given an absorption function.

As the outer skin layer 52, a polyethylene resin such as LDPE or LLDPE can be used.
The intermediate layer 51 is composed of a mixture of a polyethylene resin and an absorbent, and the proportion of the absorbent in the entire mixture is preferably 10 to 30% by mass, and the proportion of polyethylene as the resin is preferably 70 to 90% by mass. . If it is said mass ratio, sufficient absorption characteristic can be suitably exhibited according to the combination of the resin material used for an inner skin layer, and those mixing ratios. As the absorbent, silica gel, zeolite, calcium oxide, magnesium sulfate, and the like can be appropriately selected depending on the object to be absorbed, such as water, water vapor, gas, and odor. In the present embodiment, zeolite having excellent odor absorption capability is preferable.

As zeolite, natural zeolite, artificial zeolite, synthetic zeolite and the like can be used. Since zeolite has a high absorption rate, it can quickly absorb moisture and odors. Molecular sieve, which is an example of zeolite, is a porous granular material used to separate materials according to the difference in molecular size, and has a structure with uniform pores. Absorbs molecules and acts as a kind of sieve. The pore (absorption port) diameter is preferably 0.3 nm to 1 nm. Usually, the molecular sieves having pore diameters of 0.3 nm, 0.4 nm, 0.5 nm, and 1 nm are respectively converted to molecular sieve 3A, molecular sieve 4A, and molecular sieve. 5A, referred to as molecular sieve 13X. The average particle size of the molecular sieve (particle size at an integrated value of 50% in the particle size distribution determined by the laser diffraction / scattering method) is, for example, about 10 μm. In the present embodiment, these zeolites can be appropriately used according to the properties of the contents packaged in the PTP or blister pack 40.

Moreover, it is preferable to use a hydrophobic zeolite particularly when absorbing odor. Hydrophobic zeolite is a generic term for a so-called high silica zeolite in which aluminum atoms in the crystal skeleton of the zeolite are reduced by dealumination to increase the silica-alumina ratio. Hydrophobic zeolite is a zeolite that loses its affinity for polar substances such as water and absorbs nonpolar substances such as odor more strongly. Particularly, hydrophobic molecular sieves have a pore diameter of 0.6 to 0.9 nm. Preferably, Abscents 1000, Abscents 2000, Abscents 3000 (above, manufactured by Union Showa Co., Ltd.), etc. The pore diameter can be confirmed by structural analysis by X-ray diffraction. The average particle size of the hydrophobic zeolite (particle size at an integrated value of 50% in the particle size distribution determined by the laser diffraction / scattering method) is, for example, 3 to 5 μm.

The inner skin layer is composed of a mixed resin obtained by mixing low density polyethylene (LDPE) and high density polyethylene (HDPE) having a melting point higher than the preheating temperature, and low density polyethylene (LDPE) occupying the mixed resin. Is 25 to 50% by mass, and the high-density polyethylene (HDPE) is the remaining 75 to 50% by mass.

[Example of layer structure]
The following is an example of the layer structure of the PTP or blister pack laminate. The material and thickness (layer thickness) of each layer in this layer configuration example are, for example, as follows.
Layer structure: Base material layer / anchor coat layer / adhesive layer / outer skin layer / intermediate layer / inner skin layer Base material layer: Material: PVC coated with PVDC (Product name: Sumilite VSL4515 Sumitomo Bakelite Manufactured), layer thickness: 230 μm
Anchor coat layer ··· AC agent for extrusion lamination (main agent: Tomoflex TM-265, curing agent: Tomoflex CATRT-37 manufactured by Toyo Morton), layer thickness: 2 µm
Adhesive layer: Material: LDPE, Layer thickness: 20 μm
Outer skin layer: Material: LLDPE (1), Layer thickness: 10 μm
Intermediate layer: Material: Absorbent and LLDPE (2), Layer thickness: 60 μm
Inner skin layer: Material: Mixed resin of LLDPE (1) and high-density polyethylene (HDPE), Layer thickness: 10 μm

In the above conditions, the notation “(1)”, “(2)”, etc. in parentheses following the abbreviation “LLDPE” of “linear low density polyethylene” are identifiers (serial numbers) of resins with different brands used. . The brand of resin used will be described later.

[Film forming conditions]
First, a predetermined amount of LLDPE (1) pellets and HDPE pellets, which are the materials of the inner skin layer 53, are put into a kneading extruder, mixed while melting the resin by heating, and then extruded to mix for the inner skin layer. Create pellets. Next, the pellets and absorbent of LLDPE (2), which is the material of the intermediate layer 51, are respectively put into a kneading extruder so as to have a predetermined absorbent content, and after mixing while melting the resin by heating, Extrude to produce mixed pellets for the intermediate layer.

The absorbent film 50 is formed by coextrusion molding by air-cooling inflation using the prepared inner skin layer mixed pellets as the inner skin layer 53 material and the intermediate layer mixed pellets as the intermediate layer 51 material. is there. The film forming conditions are as follows.
Processing machine name: Three-layer inflation molding machine Manufacturer: Plako Co., Ltd. Resin temperature: 180 ° C for both intermediate and inner skin layers
Take-up speed: 13m / min
The formed absorption film 50 is laminated with a base material layer 70 in which an anchor coat layer is formed by gravure printing on the surface to be bonded through an adhesive layer 60 by a sand laminating method, and this is laminated to a material of PTP or blister pack 40 (PTP or blister pack laminate). In FIG. 2, the anchor coat layer is omitted. (The same applies to the following.)

[PTP or blister pack molding conditions]
A PTP or blister pack 40 was formed using the above laminate. The molding conditions are as follows.
Machine name: FBP-600UC
Manufacturer: CKD Corporation Processing method: Plug assist molding Preheating set temperature: Heating plate 130 ° C
Plug temperature: 125 ° C
Processing speed: 250 shots / min

[Seal and measurement conditions]
After forming the PTP or blister pack 40, the lid member 30 was heat-sealed to complete the blister package 10. Seal conditions (measurement conditions) are as follows.
Sealing machine name: Thermal tilt tester Manufacturer: Toyo Seiki Seisakusho Co., Ltd. Sealing pressure: 0.15 MPa
Sealing temperature: 210 ° C
Sealing time: 0.2 seconds Sealing width: 10 mm

[Configuration of the lid 30]
The lid member has a structure shown in the following materials.
Manufacturer: Sumi Light Aluminum Foil Co., Ltd.
Product name: Printing aluminum foil (for CPP)
Material: Heat-resistant overcoat layer / AL (aluminum) 17 μm / Adhesive resin layer

[Used resin and absorbent]
FIG. 3 is a list showing the brand, model number, manufacturer name, melting point, etc. of the resin used in the laminate.

Here, the brand (product name) in FIG. 3 includes a registered trademark. Also, “LLDPE (1)” and “LLDPE (2)” shown in FIG. 3 correspond to “LLDPE (1)” and “LLDPE (2)” in the layer configuration example described above, respectively. .

Similarly, “PP (1)” and “PP (2)” shown in FIG. 3 are the abbreviations “PP” for “polypropylene” followed by “(1)”, “(2)”, etc. These are given in parentheses, and these mean identifiers (serial numbers) of resins of different brands used. The difference between “PP (1)” and “PP (2)” is in particular their melting point. That is, “PP (1)” has a melting point of 151 ° C., which is higher than the preheating temperature (130 ° C.) applied in the molding process of PTP or blister pack 40. In contrast, “PP (2)” has a melting point of 124 ° C., which is lower than the preheating temperature (130 ° C.).

The absorbent contained in the intermediate layer 51 is as follows.
Absorbent: Zeolite Product name / model: Abscents 3000 (Union Showa Co., Ltd.)

The inventors manufactured a plurality of experimental samples under the conditions of the above layer configuration example, and evaluated each sample from the viewpoint of preheat resistance and absorption characteristics. And the range suitable as an Example of this invention was verified about the layer structure example from the evaluation result.

FIG. 4 is a list showing the verification results of the experimental samples (Nos. 1 to 14) regarding the layer configuration example.

〔Evaluation item〕
For the inner skin layer 53, each experimental sample No. The absorption film 50 is actually blow-molded at the resin mixing ratios 1 to 14 (Nos. 1, 6, 10, and 14 are independent). The PTP 40 is actually formed using a laminate in which the absorption film 50 obtained from the laminate is laminated in the same manner as in the layer configuration example, and evaluated from the following three viewpoints (A), (B), and (C). went.

(A) Preheat resistance At the time of molding PTP40, the inner skin layer 53 was visually inspected to evaluate whether or not it was fused to the preheat plate (heating plate). The visual observation in the molding process is performed after the sheet-like laminate passes through the preheat plate, for example. The pass / fail evaluation was “◯” and “×”, and the pass “◯” was determined to correspond to the case where no fusion to the preheat plate occurred. Moreover, it was decided that “x” of failure was applicable when fusion to the preheat plate occurred.

(B) Diacetyl absorption capacity comparison test Each test sample's diacetyl absorption capacity comparison test measures the mass of the sample (sample) before and after absorption with respect to the sample's diacetyl gas absorption amount, and obtains it from the mass difference. The method was used. The procedure is shown below.
(1) Cut the sample into 5 cm × 10 cm, and (2) bend it in half with the absorption layer of the sample inside. (3) Measure and record the mass of the sample. (4) Prepare humidity-controlled salt (75% RH) with sodium chloride in a weighing bottle and place it in the bottom of the desiccator. (5) Put 5 ml of diacetyl in a weighing bottle and put it in the bottom of the desiccator. (6) Put the sample in the desiccator and cover the desiccator (to ensure airtightness with silicon). (7) Place the desiccator in a constant temperature bath at 40 ° C. (8) After the elapse of 2 hours, the desiccator is taken out of the thermostatic bath, and a sample is taken out and left at room temperature for 5 minutes. (9) Measure and record the mass of the sample. (10) Return to the previous step (6) and carry out in the same manner.

(C) Odor sensory test with an active drug In a PTP package applied to an active drug, it is required to secure and maintain the odor absorption capacity. Therefore, a PTP package was prepared by filling PTP with an active drug (olmesartan medoxomil 40 mg tablet), and an odor sensory test was conducted by 10 evaluators. The test method is as follows.
(1) Assuming severe conditions during storage and use, the PTP package is placed in a constant temperature bath at 40 ° C. in an environment of 75% RH. Do not use aluminum pillow outer packaging or desiccant.
(2) After 5 days, 1 week, and 2 weeks, the PTP package is taken out of the thermostatic chamber at each storage time point, and an odor sensory test is performed at room temperature.
(3) The PTP package is brought close to the tip of the nose and the odor at the time of taking out the tablet is evaluated.
The evaluation criteria of the odor sensory test are as follows.
The intensity of odor (specific odor) is classified into the following 5 levels.
1) Odorless, 2) Almost (or very slightly) 3) Slightly 4) 4) 5) Strong

Hereinafter, the verification result of each experimental sample will be specifically described.
First, experimental sample no. Evaluate groups 1-6. Experimental sample no. FIG. 4 shows the resin brands used for the inner skin layer 53 in 1 to 6 and the mixing ratio (% by mass) for each brand in the resin of the inner skin layer 53.

(A) Preheat resistance evaluation result Experimental sample No. 1, when the inner skin layer 53 is composed of LLDPE (1) alone, (A) “preheat resistance” is evaluated as “x”. It can be evaluated that this is because the melting point as a resin material is 126 ° C., which is largely related to being lower than the preheating temperature (130 ° C.). In this embodiment, the inner skin layer 53 is made of LLDPE or a mixed resin of LDPE and HDPE. Reference numeral 1 is a positioning as a comparative example compared with the embodiment of the present invention.

Next, the experiment sample No. When attention is focused on 2, (A) the evaluation result of “preheat resistance” is still “x”, and if it remains as it is, fusion to the preheat plate occurs. This means that even if the ratio of LLDPE (1) in the mixed resin is 75 mass% and HDPE is 25 mass%, sufficient preheat resistance is not obtained under the current PTP molding conditions.

Therefore, the experiment sample No. When paying attention to 3, 4 and 5, the proportion of HDPE in the mixed resin was determined as experimental sample No. By making it relatively higher than 2, the evaluation result of (A) “preheat resistance” becomes “◯”. For this reason, the experimental sample No. It can be seen that 3, 4 and 5 have sufficient preheat resistance.

Note that the experimental sample No. Reference numeral 6 denotes a structure in which the inner skin layer 53 is composed of HDPE alone, and is positioned as a comparative example compared with the example of the present invention. In this case, there is no problem with the preheat resistance.

(B) Diacetyl absorption capacity comparison test results FIG. The absorption rate (%) when 1 to 6 (excluding No. 5 in this case) is exposed to the diacetyl environment in the desiccator for 10 hours is shown. In FIG. 5, the horizontal axis represents the mixing ratio (% by mass) of LLDPE with respect to HDPE of the inner skin layer 53, and the vertical axis represents the diacetyl absorption rate (%). On the horizontal axis of FIG. 1 and the results of 75%, 50%, 25%, and 0% are respectively shown in the experimental sample Nos. 2, 3, 4 and 6 are supported. Further, the diacetyl absorption rate (% by mass) shown on the vertical axis of FIG. It represents the ratio (%) obtained by dividing the mass of diacetyl absorbed in 1 to 6 by the mass of the absorbent contained in each experimental sample.

As shown in FIG. 5, the absorption characteristics of diacetyl due to the difference in the mixing ratio of the resin have a high correlation between the mixing ratio of LLDPE and the diacetyl absorption rate, and the higher the mixing ratio of LLDPE, the higher the diacetyl absorption capacity. Experimental sample No. 1 was found to be the highest when diacetyl absorption ability was evaluated after a certain period of time. This means that LLDPE (1) alone has good gas permeability. Experimental sample No. 6 has the lowest diacetyl absorption capacity, which means that HDPE alone has the worst gas permeability.

(C) Odorous sensory test results with actual drugs FIG. 6 is a list showing the results of odor sensory tests with actual drugs. Here, in particular, four experimental sample Nos. The specimen is a PTP package prepared by using a laminate having each configuration of 4, 5, 6, and 10 and an active drug (olmesartan medoxomil 40 mg tablet). The experimental sample No. 10 (layer structure of PP (1) alone) is another experimental sample No. Evaluation was made for reference for comparison with 4, 5, and 6.

As described above, 10 people evaluated the PTP package placed in an environment of 40 ° C. and 75% RH in a constant temperature bath at each storage lapse time of “5 days later”, “1 week later”, and “2 weeks later”. Each person takes out the tablet at the tip of the nose, and the strength of the odor (specific odor) at that time is 1) odorless, 2) hardly (or very slightly), 3) slightly odor 4 ), 5) strong odor, and classified by absolute evaluation, and the results were scored.

As shown in the column of “Average score”, the sample number of each test sample is “5 days later” and “1 week later”. There was little smell in order of 4 <5 <10 <6. In addition, at the time of storage “after 2 weeks”, the experimental sample No. There was little smell in order of 5 <4 <10 <6.

Here, the experimental sample No. The average score of 10 evaluators with respect to 4 was 1.6 for both “after 5 days” and “after 1 week”, and 1.9 for “after 2 weeks”. It was rated as “I do n’t like it”. Experimental sample No. The average score of 5 was 1.9 for both “5 days later” and “1 week later”, and 1.4 for “after 2 weeks”, and “no odor” and “mostly unsatisfactory” at any storage time point. It became evaluation between.

In addition to this, the experimental sample No. As a result of conducting an odor sensory test with a PTP package produced using the laminate of 4 and the active drug (olmesartan medoxomil 40 mg tablet), 8 out of 10 people even in a 30 ° C environment for 3 months Was “odorless” and 2 out of 10 people received a rating of “almost no smell (or very little smell)”.

In the column of “Absorption characteristics” in FIG. The evaluation results of 1 to 6, 8, and 10 are summarized. “O” in the odor absorption performance is a sensory test with the above-mentioned active drug, and the average score is less than “almost unsatisfactory”. The ability is “sufficient”, and “x” indicates that the odor absorbing ability is “insufficient” in other cases.

[Comprehensive evaluation results]
The comprehensive evaluation results are shown below based on the evaluation results of the preheat resistance, the comparative test results of diacetyl absorption ability, and the odor sensory test results using the active drug (olmesartan medoxomil 40 mg tablet).

Experimental sample No. confirmed that no fusion occurred. 4 and no. In the composition of No. 5, the results of the sensory test of the smell by the diacetyl absorption ability and the actual drug were also good.

Based on the above results, in order to secure and maintain the odor absorption capacity in the normal pharmaceutical distribution environment, the experimental sample No. 4 or No. 5, that is, the mixing ratio of LLDPE is preferably 25% or more or 10% or more. Further, from the viewpoint of not causing fusion, the LLDPE mixing ratio is preferably 50% or less.

[Other comparative examples]
Experimental sample no. 7 to 9 are groups in which the inner skin layer 53 is composed of a mixed resin of LLDPE (1) and PP (1), and these are all positioned as comparative examples. Experimental sample No. 10 is an inner skin layer 53 made of a single resin of PP (1) and is similarly positioned as a comparative example. Experimental sample no. The brand of resin used for the inner skin layer 53 in 7 to 10 and the mixing ratio (% by mass) for each type in the resin of the inner skin layer 53 are as shown in FIG.

Experimental sample No. as a comparative example The only experimental sample No. in the group of 7-10. The evaluation of 10 (A) “preheat resistance” is “◯”. However, experimental sample no. As a result of conducting an odor sensory test using a PTP package prepared using 10 and an active drug (olmesartan medoxomil 40 mg tablet), the average score of 10 people “after 5 days” is 2.3, “1” The average scores of “after week” and “after 2 weeks” were both 2.2, and both exceeded the value of “almost no”. In the odor sensory test after 3 months, 5 out of 10 people “slightly smell”, 3 out of 10 “slightly smell”, 2 out of 10 “smell”, “no odor” (C), the odor sensory evaluation is “x”, indicating that the odor absorbing function is not exhibited.

As described above, the experimental sample No. For Nos. 7, 8, and 9, since (A) “preheat resistance” and the evaluation result is “x”, no. On behalf of No. 8, no. 4 and no. As a result of a comparative test of the diacetyl absorption capacity with No. 6, the diacetyl absorption capacity is N0.4> No. 6> No. It decreased to the order of 8, and it turned out that it is not suitable as a resin material of the inner skin layer 53. FIG.

Similarly, the experimental sample No. Reference numerals 11 to 13 are groups in which the inner skin layer 53 is made of a mixed resin of LLDPE (1) and PP (2), and these are all positioned as comparative examples. Experimental sample No. 14 is an inner skin layer 53 made of a resin of PP (2) alone, and is also positioned as a comparative example. Experimental sample no. The type of resin used for the inner skin layer 53 in 11 to 14 and the mixing ratio (mass%) by brand in the resin of the inner skin layer 53 are as shown in FIG.

Experimental sample No. as a comparative example In the groups 11 to 14, the evaluation results of (A) “Preheat resistance” were all “x”. Therefore, it is understood that (B) “diacetyl absorption characteristic” is not evaluated and is not suitable as a resin material for the inner skin layer 53.

[Range of Examples]
From the above, the experimental sample No. 3, 4 and 5 are examples of the layer configuration example. In the embodiment, the resin material used for the inner skin layer 53 is a mixed resin in which LLDPE (1) and HDPE having a higher melting point than the preheating temperature are mixed. The ratio of LLDPE (1) in the mixed resin is in the range of 25 to 50% by mass, and the ratio of HDPE is in the range of 75 to 50% by mass. More preferably, the ratio of LLDPE (1) in the mixed resin is in the range of 10 to 50% by mass, and the ratio of HDPE is in the range of 90 to 50% by mass.

In any case, in the above layer configuration example, the molding process of the PTP or blister pack 40 is performed by molding the laminate (raw material film) by setting the mixing ratio of the resin used for the inner skin layer 53 within the above range. Sufficient preheat resistance can be obtained. Moreover, the PTP or blister pack 40 obtained by molding from the laminate can exhibit good diacetyl absorption characteristics by packaging the preparation 20 and the like using this.

[References for pharmaceutical use]
Next, the pharmaceutical use of the present invention will be mentioned. The PTP or blister pack 40 of one embodiment is suitable for blister packaging of formulations containing olmesartan medoxomil. In particular, by packaging the preparation with the PTP or blister pack 40 of one embodiment, a method for reducing the odor generation of the olmesartan medoxomil-containing preparation can be realized, and therefore the PTP or blister pack 40 of one embodiment is used. Is preferred.

[PTP or blister pack usage]
(1) As shown in FIG. 1, the PTP or blister pack 40 can take a form in which an olmesartan medoxomil-containing preparation is included as the preparation 20.
(2) Further, the olmesartan medoxomil-containing preparation as the preparation 20 packaged in the PTP or blister pack 40 becomes the blister package 10 shown in FIG.
(3) In this way, by packaging the olmesartan medoxomil-containing preparation with PTP or blister pack 40, the generation of odor can be reduced. Therefore, the olmesartan medoxomil-containing preparation can be suitably marketed as a form of the blister package 10.
(4) PTP or blister pack 40 can be used to package olmesartan medoxomil-containing preparations.
(5) In addition, PTP or blister pack 40 can be used for odor-reducing packaging in olmesartan medoxomil-containing preparations.

Olmesartan medoxomil is used for hypertension or a disease derived from hypertension (more specifically, hypertension, heart disease [angina, myocardial infarction, arrhythmia, heart failure or hypertrophy), kidney disease [diabetic nephropathy, thread Spherical nephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]) is effective for prevention or treatment, and the method described in Japanese Patent No. 2082519 (US Pat. No. 5,616,599) and the like And can be manufactured easily.

In addition, the olmesartan medoxomil-containing preparation in the present invention may contain other active ingredients as necessary. Examples of the active ingredient include diuretics such as trichlormethiazide, hydrochlorothiazide, and benzylhydrochlorothiazide (Azelnidipine salt). Benidipine, Nitrendipine, Manidipine, Nicardipine, Nifedipine, Nildipine, Clinidipine, Efonidipine ), Calcium antagonists such as Felodipine; Pioglitazone, Rosiglitazone, Riboglitazone, MCC-555, NN-2344, BMS-298585, AZ-254, AZ-242L Insulin sensitizers such as TAK-559; pravastatin, simvastatin, atorvastatin, rosuvastatin, cerivastatin, pitavastatin, pitavastatin, pitavastatin, pitavastatin, pitavastatin HMG-CoA reduction Containing inhibitor; SMP-797, can be exemplified such as ACAT inhibitors such as pactimibe (Pactimibe), but is not limited thereto. The amount of these active ingredients is not particularly limited, and the amount usually used for a preparation may be used.

The olmesartan medoxomil-containing preparation of the present invention further comprises, as necessary, appropriate pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, etc. Can be included.

The olmesartan medoxomil-containing preparation in the present invention is preferably a solid preparation. For example, tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, fine granules, A powder, a pill, a chewable agent, a troche, etc. can be mentioned, Preferably it is a powder, a fine granule, a granule, a capsule, or a tablet, More preferably, it is a tablet.

The preparation method of the present invention includes The Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman et al .: LEA & FEIGER 1986, pages 3-99, 293H terd, 293-37, D (Second Edition) (Herbert A. Lieberman et al .: MARCEL DEKKER INC. 1989, pages 131-284) may be used, and there is no special limitation. .

The tablet of the present invention is prepared by, for example, granulating, drying and sizing the active ingredient together with excipients, binders, disintegrants, etc. by a method known per se, adding a lubricant etc., mixing, and tableting. To obtain tablets. Here, the granulation can be carried out by any of wet granulation, dry granulation, and heat granulation methods. Specifically, a high-speed agitation granulator, a fluidized granulator / dryer, an extrusion It is performed using a granulator, a roller compactor, etc. In addition, after granulation, operations such as drying and sizing may be performed as necessary. A mixture of the active ingredient and excipient, binder, disintegrant, lubricant, etc. can also be compressed directly. The tablet of the present invention may be provided with at least one film coating.

Coating is performed using, for example, a film coating apparatus, and examples of the film coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like. Can be mentioned.

[Test example]
An olmesartan medoxomil-containing preparation is packaged using PTP or blister pack 40, and blister pack 10 is obtained as an experimental sample. Then, after a certain period of time has passed for the experimental sample at room temperature or heat abuse conditions, sensory evaluation by human olfaction and quantitative evaluation of diacetyl can be performed. By such a test, it can be confirmed that the PTP or blister pack of the present invention can reduce the odor generation of the olmesartan medoxomil-containing preparation.
For determination of diacetyl, the gas in the pocket of the blister package 10 is collected with a syringe and injected into a gas chromatography to measure the concentration of the detected gas component (diacetyl). The measurement conditions for gas chromatography are shown below.

[Measurement conditions for gas chromatography]
Apparatus: Gas chromatograph Shimadzu GC-2014 (Shimadzu Corporation)
Detector: Flame ionization detector Analytical column: DB-WAX (Agilent Technology Co., Ltd., 0.53 mmid × 30 m, film thickness: 1.00 μm)
Column temperature: 50 ° C
Carrier gas: Helium flow rate: 5.0 mL / min
Inlet temperature: 200 ° C
Detector temperature: 230 ° C
Injection volume: 1.0 mL

The present invention can be implemented with various modifications and replacements without being limited to the above-described embodiments and examples. Moreover, it is needless to say that the configurations and materials of the laminate and the packaging container mentioned in the above-described embodiments and examples are all preferable examples, and can be implemented by appropriately modifying them.

[Explanation of symbols]
10 Blister pack 20 Formulation 30 Lid 40 PTP or blister pack 50 Absorption film (absorption layer)
51 Intermediate layer 52 Outer skin layer 53 Inner skin layer 60 Adhesive layer 70 Base material layer

Claims

A base material layer that is the outermost layer at the time of molding as a PTP or blister pack, and is laminated on the base material layer via an adhesive layer, and faces the contents at the time of molding as a PTP or blister pack, at least one of liquid and gas A layered body for PTP or blister pack to which preheating is applied from a heating member disposed opposite to the absorbent layer in the process of forming into PTP or blister pack,
The absorbent layer has a configuration in which an outer skin layer, an intermediate layer, and an inner skin layer are laminated in this order, and the outer skin layer is bonded to the base material layer via the adhesive layer,
The outer skin layer is made of polyethylene resin,
The intermediate layer is made of a mixture of a polyethylene resin and an absorbent,
The inner skin layer is a PTP made of a blend resin having 25 to 50% by mass of linear low density polyethylene and 75 to 50% by mass of high density polyethylene having a higher melting point as a material than the preheating temperature in the molding process. Or a laminated body for blister packs.
A base material layer that is the outermost layer at the time of molding as a PTP or blister pack, and is laminated on the base material layer via an adhesive layer, and faces the contents at the time of molding as a PTP or blister pack, at least one of liquid and gas A layered body for PTP or blister pack to which preheating is applied from a heating member disposed opposite to the absorbent layer in the process of forming into PTP or blister pack,
The absorbent layer has a configuration in which an outer skin layer, an intermediate layer, and an inner skin layer are laminated in this order, and the outer skin layer is bonded to the base material layer via the adhesive layer,
The outer skin layer is made of polyethylene resin,
The intermediate layer is made of a mixture of a polyethylene resin and an absorbent,
The inner skin layer is a PTP made of a blend resin having 10 to 50% by mass of linear low density polyethylene and 90 to 50% by mass of high density polyethylene having a melting point higher than the preheating temperature in the molding process. Or a laminated body for blister packs.
The laminate for PTP or blister pack according to claim 1 or 2, wherein the absorbent is a synthetic zeolite.
A PTP or blister pack formed using the PTP or blister pack laminate according to any one of claims 1 to 3.
A PTP package or a blister package comprising the PTP or blister pack according to claim 4 and a preparation contained in the PTP or blister pack.
The PTP package or blister package according to claim 5, wherein the formulation is a formulation containing two or more kinds of drugs as active ingredients.
An olmesartan medoxomil-containing preparation packaged in the PTP or blister pack according to claim 4.
The olmesartan medoxomil-containing preparation according to claim 7, further comprising one or more other drugs as active ingredients.
The olmesartan medoxomil-containing preparation according to claim 8, wherein the other drug is one or more compounds selected from amlodipine (including besylate salt), azelnidipine and hydrochlorothiazide.
10. Olmesartan medoxomil-containing preparation according to any one of claims 7 to 9 for treating or preventing hypertension.
The olmesartan medoxomil-containing preparation according to any one of claims 7 to 9, wherein the odor generated from the contained olmesartan medoxomil preparation is reduced.
A method for reducing odor generated from a preparation containing olmesartan medoxomil, which is packaged with the PTP or blister pack according to claim 4.
The method for reducing odor according to claim 12, wherein the preparation containing olmesartan medoxomil further contains one or more kinds of other drugs as an active ingredient.
The method for reducing odor according to claim 13, wherein the other drug is one or more compounds selected from amlodipine (including besylate salt), azelnidipine and hydrochlorothiazide.
Use of PTP or blister pack according to claim 4 for olmesartan medoxomil-containing preparation packaging.
Use of PTP or blister pack according to claim 4 for odor-reducing packaging in a preparation containing olmesartan medoxomil.