Adhesive skin patch

专利摘要:

公开号:ES2600007T9
申请号:ES11747417.1T
申请日:2011-02-23
公开日:2017-03-14
发明作者:Yoshihiro Iwao；Kensuke Matsuoka；Kazuhiro Aoyagi
申请人:Nitto Denko Corp；
IPC主号:

专利说明:

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DESCRIPTION
Cutaneo adhesive patch Technical field
The present invention relates to a transdermal adhesive patch suitable for the continuous administration of a drug with the exception of bisoprolol in a body through the surface of the skin.
Prior art
Recently, a transdermal therapeutic system (TTS) for the treatment or prevention of disease through transdermal drug absorption has been recognized as a drug delivery system (DDS). In TTS, not only has the drug been tried for local action but also the administration of the drug expected for systemic action, and to some extent it has already had a commercial reality.
Transdermal preparations can prevent, for example, the first-pass metabolism of the drug in the liver and various adverse reactions and, in addition, allow long-term and sustainable administration of the drug. Among them, an adhesive patch containing a drug in an adhesive that at the same time facilitates the administration of the drug and allows rigorous dose control has been developed considerably.
An adhesive patch generally includes a support that is formed of a woven fabric, a non-woven fabric, a plastic film or the like and, as laminated on the support, an adhesive layer containing the drug, and generally in a form that has a Laminated release coating on the adhesive layer, is held in a container formed of a packaging material of a resin film or the like, and is provided to the user.
As a characteristic aspect thereof, a recent trend towards adhesive patches is that a soft and velvety adhesive layer, for example an adhesive layer containing a large amount of a liquid component held therein, is used therein in order to improve the soft feel of the patch when adhering to the skin, or in order to reduce skin irritation that will be caused by removing the cornea layer when detaching the patch, or in order to increase skin solubility and permeability of the drug in the adhesive layer. In such adhesive patches, "cold flow" or, ie, the expulsion or detachment of the adhesive layer component from the exposed area of the adhesive layer of the adhesive patch becomes a problem.
The cold flow occurs depending on the characteristics of the adhesive layer, and frequently occurs during long-term storage in a state in which a load is applied to the adhesive patches for a long period of time or, that is, in a state in which an adhesive patch is packaged in a container.
When the cold flow occurs in an adhesive patch, the drug can exit along with the component of the adhesive layer from the exposed area of the adhesive layer of the adhesive patch and, consequently, the amount of the drug contained in the adhesive patch can be reduced, giving as a result therefore unfavorably reducing the effectiveness of the drug. In addition, the component of the adhesive layer that is ejected or detached may adhere to the inner face of the container, thereby causing negative influences on the adhesive patch because the adhesive patch could barely be removed from the container and because the patch Adhesive can peel off or it can get dirty during application to the skin. Also, in the case where the adhesive layer is thick, the tendency is noticeable since the amount of the component of the adhesive layer is large. Therefore, in adhesive patches, it is desirable that cold flow hardly occur and that the adhesive layer can maintain its original shape.
Against the above-mentioned problems, Patent Reference 1 describes a technique for a cutaneous adhesive material, in which the thickness of the cutaneous adhesive layer that is placed in the intermediate part of the support film is controlled so that it is within a range of 0.2 mm to 0.5 mm, and the peripheral part thereof is pressed to reduce the thickness of the skin adhesive layer in a range of 0.05 mm to 0.2 mm, to thereby avoid that the cutaneous adhesive layer be separated from the edges of the cutaneous adhesive material and prevent the edges of the cutaneous adhesive material from coming off.
More precisely, the method of producing the cutaneous adhesive material described in Patent Reference 1 is characterized in that a cutaneous adhesive layer is formed in a release sheet and a supporting film is laminated thereon, and the laminated sheet The result is sealed in two stages, in which after the first stage stamping, the pressure to form the thin peripheral part is carried out without heating. That is, in the case in which the laminated sheet is pressed first and, after the above, is sealed in the final form in one stage, the skin adhesive layer that is placed between the support film and the release sheet hardly it could move on both sides during the pressure, and even if the layer could move, it could not have a leakage path, and therefore, the part of the cutaneous adhesive layer adjacent to the peripheral part can be lifted by pressure. Therefore, to avoid the formation of the elevation, the method described in Patent Reference 1 is characterized in that the previous stamping in a larger size is followed by
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Pressed to extrude the skin adhesive layer adjacent to the peripheral part from the stamped edges, and the stamping of the second stage gives the final shape.
However, with respect to the cutaneous adhesive material described in Patent Reference 1, during storage thereof in a container, the opportunity for the exposed part of the adhesive layer, such as the edges of the cutaneous adhesive material, to be in contact with the inner surface of the container could not be sufficiently reduced, and therefore, in the case where the skin adhesive layer has been ejected or separated from the exposed part of the skin adhesive layer in the skin. container, the adhesion of the cutaneous adhesive material to the internal surface of the container could not be sufficiently prevented and, therefore, the cutaneous adhesive material could hardly be removed from the container. In addition, when the cutaneous adhesive material could come into contact with the fabrics and other materials while remaining adhered to the skin, the opportunity for the edges of the cutaneous adhesive material to rub against the fabrics and other materials could not be completely reduced, and the edges of the cutaneous adhesive material could come off. In addition, since the cutaneous adhesive layer in the peripheral part is thin, the adhesive capacity thereof to the skin in the peripheral part may be less with respect to that in the intermediate part.
Particularly, in an adhesive patch containing a drug liquid at room temperature, not only the cold flow of the components of the adhesive layer occurs but also a phenomenon of drug expulsion from the adhesive layer during long-term storage, so which drug content in the adhesive patch may decrease and cause a risk of reducing the effectiveness of the drug.
As another case of the development of an adhesive patch, Patent Reference 2 refers to a packaging bag containing the adhesive patch, in which the adhesive patch containing bisoprolol or a salt thereof in the adhesive layer thereof can be store stably, and describes that, when the relative humidity inside the packaging bag is at most 25%, then the stability of bisoprolol or a salt thereof becomes excellent. However, the patent reference does not describe anything that refers to the expulsion of bisoprolol or a salt thereof in the packaging bag and which refers to the influence of the cold flow of the adhesive layer component on stability, manageability and the adhesive patch adhesiveness, and even more, nothing related to the shape of the adhesive patch to solve the problems is investigated.
List of references
Patent References
Patent Reference 1: JP-A-2000-37413
Patent Reference 2: WO 2005/072716 Summary of the Invention Problems Solved by the Invention
The present invention has been made from the above situation and is intended to provide an adhesive patch that effectively inhibits the cold flow during storage, that is, the occurrence of the expulsion or separation of the adhesive layer component from the exposed area of the adhesive layer of the adhesive patch, as well as the occurrence of the expulsion of a drug from the adhesive layer to thereby prevent the reduction of the drug content.
Means to solve the problems
As a result of the regular investigations that were made to solve the problems mentioned above, the inventors have found the following. In an adhesive patch containing a different bisoprolol drug, when the support, the release liner and the adhesive layer that constitute the adhesive patch are each formed to have a rectangular flat shape while the entire adhesive patch is formed to have a rectangular flat shape, and the adhesive patch is formed to have a part that protrudes on the lateral support surface thereof in a corner of the adhesive patch, and also when the adhesive patch is formed to have an intermediate part that has a rectangular flat shape and a peripheral part in which the thickness of the adhesive patch is smaller than the thickness of the adhesive patch in the intermediate part while the protruding part is formed in a corner of the intermediate part, and in the case where the coating of release is formed to have a divided part and when the divided part does not pass through the part that protrudes from the corner, then during the storage of the adhesive patch in a container, the opportunity for the exposed part of the adhesive layer of the adhesive patch to be in contact with the inner surface of the container can be reduced, and therefore, the drug and other components of The adhesive layer is ejected or separated from the exposed part on the package. Based on these findings, the inventors have concluded the present invention.
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That is, the present invention relates to the following [1] to [7].
[1] An adhesive patch comprising a support, an adhesive layer containing a drug other than bisoprolol and which is placed on at least one side of the support, and a release liner that is placed on one side of the opposite adhesive layer next to it in which the support is placed,
wherein the support, the release liner and the adhesive layer each have a rectangular flat shape, and the entire adhesive patch has a rectangular flat shape, and
wherein, in one corner of the adhesive patch, the adhesive patch comprises a part that protrudes on a lateral support surface thereof.
[2] The adhesive patch according to [1], in which the adhesive patch comprises a peripheral part and an intermediate part having a rectangular flat shape, and in which a thickness of the adhesive patch in the peripheral part is smaller that a thickness of the adhesive patch in the intermediate part, and the protruding part is placed in a corner of the intermediate part.
[3] The adhesive patch according to [1], in which the adhesive patch comprises at least two protruding portions and comprises, between adjacent protruding parts, a composite band-type connection portion in which a thickness of the Adhesive patch is smaller than a thickness of the adhesive patch on the protruding parts.
[4] The adhesive patch according to [1], wherein the protruding part has a flat shape that is triangular, trapezoidal, semilunar or semicircular.
[5] The adhesive patch according to [1], wherein the release liner comprises a divided part that does not pass through the protruding part.
[6] The adhesive patch according to [1], wherein the adhesive layer contains an organic liquid component.
[7] The adhesive patch according to [1], in which the adhesive layer is not crosslinked.
Advantage of the invention
According to the invention, by storing the adhesive patch in a container, the opportunity for the exposed part of the adhesive layer of the adhesive patch to be in contact with the inner surface of the container can be reduced. Therefore, even when the drug and the other components of the adhesive layer have been ejected or separated from the exposed part of the adhesive patch in the package, the adhesive patch can still be prevented from adhering to the inner surface of the container , and therefore the content of the drug in the adhesive patch can be prevented from being reduced, and the adhesive patch can be easily removed from the package. Also, during the application to the skin, the opportunity for the edges of the adhesive patch to rub against clothing and other materials can be reduced, and therefore it is possible to obtain an adhesive patch in which the edges thereof are hardly they detach, the adhesive force to the skin is sufficient and rarely the detachment of the cutaneous surface occurs.
Brief description of the drawings
[Figure 1] Figure 1 is a schematic plan view of the adhesive patch of example 1 of the invention.
[Figure 2] Figure 2 (a) is a schematic cross-sectional view along I-I of the adhesive patch of Figure 1; Figure 2 (b) is a schematic cross-sectional view along II-II of the adhesive patch of Figure 1.
[Figure 3] Figure 3 is a schematic plan view of the adhesive patch of Example 2 of the invention.
[Figure 4] Figure 4 (a) is a schematic cross-sectional view along I-I of the adhesive patch of Figure 3; Figure 4 (b) is a schematic cross-sectional view along II-II of the adhesive patch of Figure 3.
[Figure 5] Figure 5 is a schematic plan view of the adhesive patch of Comparative Example 2 of the invention.
[Figure] Figure 6 (a) is a schematic cross-sectional view along I-I of the adhesive patch of Figure 5; Figure 6 (b) is a schematic cross-sectional view along II-II of the adhesive patch of Figure 5.
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Method of implementing the invention
The adhesive patch of the invention comprises a support, an adhesive layer containing a drug other than bisoprolol and which is placed on at least one side of the support, and a release liner that is placed on one side of the adhesive layer opposite the side of it on which the support is placed. The edges of the adhesive layer, more precisely, the side edges thereof, are exposed. The adhesive patch of the invention can be provided in any form of a type of matrix or type of deposit, such as a transdermal adhesive patch. Various dosage forms may be used herein, which include a patch type form, a tape type form, a sheet type form, etc.
The support, the release liner and the adhesive layer are each formed to have a rectangular flat shape, and the entire adhesive patch is formed to have a rectangular flat shape. In addition, the adhesive patch of the invention is formed so that it has a portion that projects over the lateral support surface thereof in a corner thereof. The term "rectangular (rectangular)" according to what was mentioned in this description means that it includes a case in which the corner is not rounded, and also a case in which the corner is partially rounded. In this case, the profile of the rectangle is composed of a rounded curved part and a linear part. The term "partially rounded" as referred to herein means that the ratio of the total length of the curved part to the total length of the linear part is preferably within a range of 0.1% to 40%, more preferably from 0.5% to 30%. In the invention, preferably, the adhesive patch has a rectangular flat shape that has a partially rounded corner, from the point of view of protecting the inner surface of the container or the skin surface from damage or wound by the corner of the patch adhesive, and from the point of view of the protection of clothing against adhesion to it. The protruding part that is provided on the lateral support surface is considered to fulfill the function as a pillar to press and support the packaging material within the container. The placement of the protruding part in the corner of the adhesive patch comprises the structure in which the protruding part of the adhesive patch can efficiently support the entire adhesive patch, and allows the protruding part to more effectively exhibit the pillar effect.
The protruding part mentioned above in the invention is formed on the lateral support surface at the corner of the adhesive patch. An outstanding portion is formed but preferably multiple protruding parts are formed, and more preferably, the protruding portions are formed in the respective corners. The expression "in the corner" in this description means that it includes not only the presence of the protruding part that adjoins the corner of the rectangular adhesive patch but also the presence of the protruding part in the vicinity of the corner. The expression "in the vicinity of" as referred to herein means that the narrowest distance between the profile of the corner and the profile of the protruding part, that is, the distance at the narrowest site between the profiled part of the corner and the profiled part of the protruding part is small. In the adhesive patch of the invention, the distance is preferably from 0.29 mm to 5 mm. The flat shape of the protruding part includes a triangular shape, a trapezoidal shape, a semilunar shape, a semicircular shape, etc. In the invention, these shapes include those deformed that have rounded corners. The "semilunar form" as referred to herein means a form surrounded by a small arc that has a small radius and a large arc that has a large radius; the "semicircular shape" means a shape surrounded by a semicircle and its diameter. In the adhesive patch of the invention, the part that protrudes on the lateral support surface in the corner can be formed, for example, by thickening the support at the site thereof corresponding to the protruding part and / or by thickening the adhesive layer on the site of it that corresponds to the part that protrudes. In the latter case, the thickness of the support and that of the release liner are substantially uniform. In the case where the thickness of the central part of the adhesive patch, that is, the thickness of the site where the diagonal lines of the rectangle intersect is taken as 100%, the thickness of the adhesive patch on the protruding part thereof is preferably from 110% to 300%, more preferably from 120% to 250%. The "thickness of the adhesive patch" is the total thickness of the support, the adhesive layer and the release coating that constitute the adhesive patch.
With respect to the size of the part that protrudes in the adhesive patch of the invention, preferably, the ratio of the occupied area of the protruding part is 2% to 90% or so of the entire surface of the support, preferably 2% to 85% or so. In the case in which the size of the protruding part is such that the ratio of the area occupied thereof is less than 2%, and when the adhesive patch is stored in a container, the protruding part could not fully support the inner surface of the container and the pillar effect of the protruding part could not be expected. On the other hand, when the size of the protruding part is such that the occupied area thereof is greater than 90%, then the necessary amount of the adhesive layer may increase and therefore the adhesive patch may be inexpensive.
In a preferred embodiment of the adhesive patch of the invention, the adhesive patch includes an intermediate part that has a rectangular flat shape and has a predetermined thickness of the adhesive patch, and also includes a peripheral part in which the thickness of the adhesive patch It is smaller than the thickness of the adhesive patch in the intermediate part, and the protruding part that will be provided on the lateral support surface is placed in the corner of the intermediate part. In the case where the adhesive patch has a part
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intermediate, the thickness of the adhesive patch in the intermediate part means the thickness of the aforementioned central part of the adhesive patch. When the thickness of the adhesive patch in the peripheral part is reduced, especially the thickness of the adhesive layer therein, then the chance of the side edges of the adhesive patch being in contact with the inner surface of the container can be reduced, and it can prevent the drug and other components of the adhesive layer from being ejected or separated from the exposed area of the adhesive layer of the adhesive patch. Accordingly, according to the adhesive patch of the invention, reduction of the drug content during storage can be avoided, and the adhesive patch can be easily removed from the package.
In addition, in the embodiment mentioned above, even when the adhesive capacity of the peripheral part could be reduced by decreasing the thickness of the adhesive layer in the peripheral part of the adhesive patch, the part that protrudes in which the thickness of the adhesive layer remains large is provided in the corner of the adhesive patch and, consequently, even if it remains adhered to the skin, the adhesive capacity to the skin of the adhesive layer can be compensated in the corner of the peripheral part that could be the starting point of skin shedding, and therefore, the adhesive patch can be prevented from peeling off the skin.
The flat shape of the peripheral part is preferably similar to a band having a width of 0.29 mm to 5 mm, more preferably 0.29 mm to 3.5 mm. The width of the peripheral part that is within the previous range makes it possible to avoid more effectively that the drug and other components of the adhesive layer are expelled or separated from the exposed area of the adhesive layer of the adhesive patch, and also allows to avoid with more efficiency that reduces the adhesive capacity of the peripheral part of the adhesive patch. To sufficiently exhibit the effect of the invention, preferably, the band-like part is provided on each peripheral side of the adhesive patch.
In the adhesive patch mentioned above, the thickness in the peripheral part of the adhesive patch is preferably at least 1.5 mm from the point of view of ensuring the minimum adhesive capacity thereof to the skin. On the other hand, the thickness in the intermediate part of the adhesive patch is, for example, 50 mm to 5000 mm, preferably 150 mm to 4000 mm. Within the ranges mentioned above, the adhesive capacity to the skin of the adhesive patch can be more effectively avoided, and in addition, since the adhesive layer can thereby easily retain its shape, it can be avoided. more effectively than the drug and other components of the adhesive layer are expelled or separated from the exposed area of the adhesive layer of the adhesive patch. Preferably, the difference between the thickness of the adhesive patch in the intermediate part and the thickness of the adhesive patch in the peripheral part is from 20 mm to 2000 mm. In the case mentioned above, the opportunity for the edges of the adhesive patch to rub against the container or clothing can be reduced, and a necessary adhesive capacity can also be provided to the adhesive layer in the intermediate portion.
The adhesive patch of the invention has a substantially flat flat shape and, as described above, the flat shape thereof is rectangular. Preferably, the length of one side of the adhesive patch is 10 mm to 100 mm, more preferably 15 mm to 80 mm. With respect to the expression "length of one side" as referred to herein, in the case where the corners of the adhesive patch are rounded, such a rounded adhesive patch becomes the corresponding completely rectangular shape without a rounded corner, and the Length indicates the length of one side of the rectangular shape.
Preferably, the adhesive patch of the invention includes at least two protruding parts. Also preferably, the adhesive patch includes, between the adjacent protruding parts therein, a composite connection portion in which the thickness of the adhesive patch is smaller than the thickness of the adhesive patch on the protruding parts. By having the composite connection part, the adhesive patch can be held securely by fingers when removed from the container, and therefore the adhesive patch can be easily removed from the container. The thickness of the adhesive patch in the composite connection part is preferably from 105% to 250%, more preferably from 110% to 200%, relative to the thickness of the adhesive patch in the central part, 100%. The term "adjacent" means that the two protruding parts are in a relationship in which they are provided along one side of the adhesive patch.
Without specifying it specifically, the flat shape of the composite connection part is preferably a band-like shape having a width of 0.5 mm to 3 mm or so. The composite connection part can be formed by prolonging the pressure time or by increasing the pressure or temperature in the formation by pressing the peripheral part of the adhesive patch, or by repeating the pressure stage twice or more, as which will be described below.
In the adhesive patch of the invention, the release liner may have a divided part. In this case, the divided part is thus provided so as not to pass through the protruding part provided in the corner of the adhesive patch. By making the release liner have a divided part, the adhesive layer can be exposed in the divided part. However, the divided part is thus provided so as not to pass through the protruding part mentioned above, and therefore the divided part can be prevented from receiving an external load from the outside of the container, and therefore, it can be prevented that The component of the adhesive layer is ejected or separated through the divided part. In addition, although the adhesive patch is stored in a container, the pressure that is provided to the divided part of the container can be effectively reduced due to the pillar effect of
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the protruding part of the adhesive patch, and therefore it is possible to prevent the drug and other components of the adhesive layer from being expelled or separated through the divided part. Consequently, the adhesive patch can be easily removed from the package and the drug content can be prevented from being reduced.
The divided part of the release liner is formed by forming a cutting line on the surface of the release liner opposite the surface of contact with the adhesive layer. The shape of the cutting line can be linear, curved or wavy, or it can also be a combination of those shapes. The cutting line can be a continuous or discontinuous line, or it can also be a combination of those lines. By having such part divided, the release liner in use can be easily removed from the adhesive patch.
Without being specifically defined, the support for use in the adhesive patch of the invention is preferably formed of a material through which components such as the drug contained in the adhesive layer do not penetrate and are lost from the back of the support, causing in this way the reduction of the content of those components, that is to say, is formed of a material impermeable to the components contained in the adhesive layer.
The support usable in the adhesive patch of the invention includes a single film of polyester resins such as polyethylene terephthalate, etc .; polyamide resins such as nylon, etc .; olefinic resins such as polyethylene, polypropylene, etc .; Vinyl resins such as ethylene vinyl acetate copolymer, polyvinyl chloride, polyvinylidene chloride, ionomer resin, etc .; acrylic resins such as ethylene-ethyl acrylate copolymer, etc .; fluorocarbon resins such as polytetrafluoroethylene, etc .; sheet metal or the like, and a laminated film thereof. The thickness of the support is generally 10 mm to 200 mm, preferably 15 mm to 150 mm, more preferably 20 mm to 100 mm. When the support thickness is at least 10 mm, then it can be favorably prevented that the components of the adhesive layer that have been ejected or separated from the exposed area of the adhesive layer of the adhesive patch drain to the surface on the side opposite to The adhesive layer On the other hand, when the thickness of the support is more than 200 mm, then the adhesive patch may feel rough when it adheres to the skin.
To improve the adhesiveness (anchoring capacity) between the support and the adhesive layer, preferably, the support is a laminated film of a non-porous film formed from the aforementioned material and a porous film, in which the adhesive layer is formed on the side of the porous film. Without being specifically defined, the porous film can be any one capable of improving the anchoring capacity between the support and the adhesive layer, including, for example, paper, woven fabric, non-woven fabric, mechanically perforated film, etc. Paper, woven fabric and non-woven fabric are especially preferred. The thickness of the porous film is preferably from 10 mm to 100 mm in view of the improvement of the anchoring capacity and the flexibility of the adhesive layer. In the case where woven fabric or nonwoven fabric is used as a porous film, its unit weight is preferably from 3 g / m2 to 50 g / m2, more preferably from 5 g / m2 to 30 g / m2 from the point of view of the improvement of anchoring capacity.
Of the support mentioned above, the most preferred support is a laminated film of a polyester based resin film (preferably a polyethylene terephthalate film) having a thickness of 1 mm to 45 mm, and a non-woven fabric made of polyester-based resin (preferably polyethylene terephthalate) having a thickness of 10 mm to 100 mm and a unit weight of 5 g / m2 at 30 g / m2.
Without being specifically defined, the adhesive constituting the adhesive layer in the adhesive patch of the invention includes an acrylic adhesive that includes an acrylic copolymer; a rubber type adhesive such as the styrene-diene-styrene block copolymer (for example, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, etc.), polyisoprene, polyisobutylene, polybutadiene , etc.; a silicone based adhesive such as silicone rubber, dimethylsiloxane base, diphenylsiloxane base, etc .; a vinyl ether based adhesive such as polyvinyl methyl ether, polyvinyl ethylene, polyvinyl isobutyl ether, etc .; a vinyl ester based adhesive such as copolymer of vinyl acetate-ethylene, etc .; a polyester based adhesive that includes a carboxylic acid component such as dimethyl terephthalate, dimethyl isophthalate, dimethyl phthalate or the like, and a polyalcohol component such as ethylene glycol or the like, etc. The adhesive layer that is formed of the adhesive can be crosslinked through physical radiation exposure crosslinking treatment such as UV irradiation, electron beam irradiation or the like, or through chemical crosslinking treatment with various crosslinking agents, or it can be also a non-crosslinked adhesive layer without any crosslinking treatment applied thereto.
Particularly, from the adhesive layer when using a rubber-like adhesive, the components of the adhesive layer tend to be easily ejected or separated. Therefore, the invention that is capable of effectively inhibiting the phenomenon is especially advantageous in the case where a rubber-like adhesive is used as the adhesive to constitute the adhesive layer. For the same reason, the invention is also advantageous in the case where an uncrosslinked adhesive layer is used.
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The rubber-like adhesive for use herein can be prepared by mixing the same components or different components that differ at the point of the average molecular weight, in order to achieve the suitable adhesive capacity and drug solubility. For example, a case of polyisobutylene is described. A mixture of a high molecular weight polyisobutylene having an average molecular weight in viscosity of 1,800,000 to 5,500,000, a medium molecular weight polyisobutylene having an average molecular weight in viscosity of 40,000 to 85,000, and optionally a low molecular weight polyisobutylene. The average molecular weight in viscosity as mentioned in the invention is a weight that is calculated as follows: When using a Ubbelohde viscometer, the flow time at 20 ° C of the polymer through a capillary tube is calculated, and the index Staudinger (J0) is derived from it according to the following Schulz-Blaschke formula (formula 1), and the value of J0 is entered into the following Mark-Houwink-Sakurada formula (formula 2) to calculate the value.
[Formula number 1]
Jo = T) sp / c (l + Ar | sp) (1)
In the previous formula, ^ 5P - ^
t: dissolution flow time (according to the Hagenbach-Couette compensation formula), t0: solvent flow time (according to the Hagenbach-Couette compensation formula), c: dissolution concentration ( g / cm3),
A: specific constant number for polymer dissolution.
[Formula number 2]
image 1
In the above formula, Mv is an average molecular weight in viscosity, and each of k and a are a specific constant number for the polymer.
For polyisobutylene, A = 0.31, k = 3.06 x 10-2, and a = 0.65 in the formulas mentioned above 1 and 2, and the value Mv can be calculated from the value J0.
In the case where polyisobutylene is used as the adhesive, a high molecular weight polyisobutylene is generally composed of a ratio of 10% by weight to 80% by weight, preferably from 10% by weight to 50% by weight, a medium molecular weight polyisobutylene is generally in a ratio of 0% by weight to 90% by weight, preferably from 10% by weight to 80% by weight, and a low molecular weight polyisobutylene is generally in a ratio of 0% by weight at 80% by weight, preferably from 0% by weight to 60% by weight.
To provide the suitable thickness thereto, the adhesive layer may contain, for example, a tackifying agent such as a rosin-based resin, a polyterpene resin, a chromane-indene resin, a petroleum-based resin, a terpene-phenolic resin, an xylene resin or the like. A single type or two or more different types of these may be used herein. Examples of the oil-based resin include the aliphatic oil resin (based on C5), aromatic oil resin (based on C9), copolymer type oil resin (based on C5-C9), resin of saturated alicyclic hydrocarbon obtained through the partial or complete hydrogenation of the aromatic oil resin (based on C9), etc. The saturated alicyclic hydrocarbon resin is preferably one having a softening point, as measured according to a ring and ball method, from 90 ° C to 150 ° C. The tackifying agent can be included in the adhesive layer in a ratio, for example, from 10% by weight to 40% by weight from the point of view of its ability to impart the suitable tackiness to the layer and the effect to the amount of it.
The adhesive layer may contain an organic liquid component miscible with the adhesive therein. The organic liquid component can plasticize the adhesive layer and can impart a smooth sensation to the layer. Consequently, in the case where an adhesive, such as the acrylic adhesive or the rubber-like adhesive mentioned above, is used as the adhesive to constitute the adhesive layer, the pain or irritation of the skin that can be reduced can be reduced. they will be caused by the adhesive ability to the skin of the adhesive patch when detaching the adhesive patch from the skin. Accordingly, any organic liquid component having a plasticizing effect can be used herein without specific limitation. From the point of view of improving the transdermal absorption capacity for the drug, the use of those having an effect that promotes absorption is preferred.
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In the invention, the organic liquid component preferably combined in the adhesive layer includes vegetable oils such as olive oil, castor oil, palm oil, etc .; animal oils and fats such as liquid lanolin, etc .; organic solvents such as dimethyldecyl sulfoxide, methyloctyl sulfoxide, dimethylsulfoxide, dimethylformamide, dimethylacetamide, dimethyl laurylamide, methylpyrrolidone, dodecyl pyrrolidone, etc .; surfactants such as fatty acid ester with polyoxyethylene sorbitan, fatty acid ester with sorbitan, fatty acid ester with polyoxyethylene, etc .; plasticizers such as diisopropyl adipate, phthalate, diethyl sebacate, etc .; hydrocarbons such as squalene, liquid paraffin, etc .; alkyl esters of fatty acids such as ethyl oleate, isopropyl palmitate, octyl palmitate, isopropyl myristate, isotridecyl myristate, ethyl laurate, etc .; esters of fatty acids with polyols such as fatty acid ester with glycerin, fatty acid ester with propylene glycol, etc .; ethoxylated stearyl alcohol; alkyl esters of pyrrolidonecarboxylic acid; as well as long chain aliphatic alcohols that include linear aliphatic alcohols such as 1-dodecanol, 1- tetradecanol, 1-hexadecanol, etc., and branched aliphatic alcohols such as 2-hexyl-1-decanol, 2-octyl-1 -dodecanol, 2-hexyl-1-tetradecanol, etc. One or two or more different types of these may be used herein either alone or in combination. The organic liquid component may contain, as constitutive ingredient thereof, any other non-liquid organic component at room temperature (25 ° C) as long as the component is liquid at room temperature (25 ° C) as a whole.
The organic liquid component may be included in the adhesive layer preferably in a ratio of 10% by weight to 60% by weight, more preferably from 15% by weight to 60% by weight, most preferably from 20% by weight to 60% by weight, with respect to the total weight of the adhesive layer. In the case where an adhesive layer contains an organic liquid component in a ratio of at least 10% by weight, the adhesive layer can be easily plasticized, and the components of the adhesive layer tend to be ejected or separated. Therefore, the invention is advantageous for such a case, in terms of effectively inhibiting the phenomenon. In the case where the organic liquid component is included in a ratio of more than 60% by weight, then the adhesive layer could hardly retain its constant shape in some cases.
In the adhesive patch of the invention, the adhesive layer contains a drug other than bisoprolol. Without being specifically defined, the drug can be any one other than bisoprolol, and it can be any of the systemic drugs or local action drugs. Transdermal drugs that are administrable to mammals, including humans, through their skin are preferred. Specifically, for example, such drugs include systemic anesthetics, antipsychotics, antidepressants, mood stabilizers, psychostimulants, narcotics, anxiolytics, antiepileptic drugs, migraine medications, antiemetics, anti-vertigo drugs, local anesthetics, muscle relaxants, agents autonomic, antispasmodic, remedies for Parkinson's disease, corticosteroids, non-steroidal anti-inflammatory drugs, analgesic-antipyretic drugs, anti-rheumatic drugs, antihistamphnic, anti-allergic, cardiotonic, anti-arrhythmic, diuretic, antihypertensive, vasoconstrictor, bronchodilators, bronchodilators , remedies for bronchial asthma, cough suppressants, expectorants, hormonal preparations, hematophic, hemostatic, antithrombotic drugs, hyperuricemic gout remedies, diabetes remedies, hypolipidemic drugs, antineoplasics, immunosuppressants, antimicro bianos, chemotherapeutics, antifungals, antivirals, antiparasitic drugs, narcotics, smoking cessation aids, etc. The adhesive patch of the invention may contain the drug other than bisoprolol as a free form or as a salt with an acid or a base. The drug salt includes alkali metal salts such as sodium salts, potassium salts, etc .; alkaline earth metal salts such as magnesium salts, calcium salts, etc .; salts of inorganic acids such as hydrochlorides, nitrates, sulfates, etc .; salts of organic acids such as acetates, citrates, smokers, maleates, etc .; salts with inorganic bases such as ammonium salts, etc .; salts with organic bases such as triethanolamine salts, pyridine salts, arginine salts, etc. The drugs can be produced according to the production methods that are already known.
The content of the drug other than bisoprolol is not specifically defined as long as it is in a range capable of presenting its pharmaceutical effect but not the decrease in adhesiveness or other properties of the adhesive layer. Preferably, it is contained in the adhesive layer in a ratio of 0.1% by weight to 60% by weight, more preferably from 0.5% by weight to 40% by weight. When the drug content is less than 0.1% by weight, then the therapeutic efficacy would not be sufficient in some cases. When it is more than 60% by weight, skin irritation may occur; and since the therapeutic efficacy is limited, the use of such a large amount would be economically disadvantageous.
Undefined specifically, the release coating includes translucent paper, polyethylene, polypropylene, polyester such as polyethylene terephthalate, etc., polystyrene, aluminum film, foamed polyethylene film, foamed polypropylene film, etc .; as well as the laminates that are selected from these, products processed or textured with silicone of these, etc. The thickness of the release liner is generally 10 mm to 200 mm, preferably 25 mm to 100 mm.
Among the release coatings mentioned above, preferred are those that were formed of a polyester resin (especially, polyethylene terephthalate) from the point of view of the barrier property and its cost. Particularly, in this case, the thickness of the coating is preferably from 25 mm to 100 mm, more or less, from the point of view of its manageability.
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Preferably, the release coating is processed for the treatment of improving the release capacity at its interface with the adhesive layer, so that the release coating can be easily released from the adhesive layer. The treatment for improving the release capacity can be achieved in accordance with known methods. For example, a treatment can be mentioned to form a layer for improving the release capacity according to a method of coating the bar coating, photogravure coating or the like, using a release agent that includes a curable silicone resin As its main ingredient. The thickness of the layer for improving the release capacity is preferably from 0.01 mm to 5 p.m from the point of view of ensuring the release capacity and the uniformity of the coating layer. The thickness of the release liner having a layer of improvement of the release capacity that is formed thereon is generally from 10 mm to 200 mm, preferably from 25 mm to 100 mm from the viewpoint of the handling of the liner.
In the adhesive patch of the invention, the release liner can be formed to have an extensible portion that extends outside the body of the adhesive patch (laminate of the adhesive layer containing a drug other than bisoprolol and the support). When the adhesive patch is packaged in a container, the extendable portion reduces the chance that the edges of the adhesive patch body will come into contact with the inner surface of the container; and therefore, even when the components of the adhesive layer are ejected or separated from the exposed area of the adhesive layer at the edge of the adhesive patch, it can be prevented from adhering to the inner surface of the container so that the adhesive patch It can barely be removed from the container. In view of the effect, preferably, the release liner has such part extended at least partially in the peripheral part of the body of the adhesive patch of the invention, more preferably it has the extended part in its entire peripheral part. The length of the extendable part of the release liner is preferably 0.5 mm to 10 mm or so, more preferably 1 mm to 3 mm or so, considering that the part can exhibit the aforementioned effect without having No negative influence on the packaging of adhesive patches.
The method of producing the adhesive patch of the invention is not specifically defined, whereby, therefore, any known method that is generally used in the art is used herein. For example, the above-mentioned adhesive, the organic liquid component and others, and a drug other than bisoprolol, dissolve or disperse in a solvent in that order. Then, if desired, a crosslinking agent is added to the solution or dispersion to prepare a composition to form an adhesive layer. This is applied on at least one side of a support and dried to form an adhesive layer thereon, and then a release coating is laminated under pressure thereon to produce the adhesive patch. Alternatively, the solution or dispersion can be applied on a release liner and dried to form the adhesive layer on the surface of the release liner, and after that a support is laminated under pressure on the adhesive layer to produce the adhesive patch. .
For coating with the composition by way of forming an adhesive layer, for example, any known coating applicator such as a photogravure roller coating applicator, a reverse roller coating applicator, a roller coating applicator can be used. contact, an immersion roller coating applicator, a rod coating applicator, a knife coating applicator, a rocfo coating applicator, etc. From the point of view of the acceleration of the crosslinking reaction and the improvement of the production efficiency, preferably, the composition is dried under heat. Depending on the type of support that will be coated with the composition, for example, a drying temperature of about 40 ° C to 150 ° C or so can be used herein.
After the adhesive patch has been produced in accordance with the method mentioned above, it can be aged at a temperature not less than room temperature in order to complete the crosslinking reaction or to improve the anchoring capacity between the layer Adhesive and support. The aging temperature is generally within a range of 25 ° C to 80 ° C, preferably within a range of 40 ° C to 70 ° C.
In the adhesive patch of the invention, in order to form the protruding parts on the lateral surface of the support at the corners thereof, any known method can be used. For example, a method of thickening the support at the site thereof corresponding to the protruding part, and / or a method of thickening the adhesive layer at the site thereof corresponding to the protruding part can be used.
To thicken the support at the site thereof corresponding to the protruding part, any other member can be placed at that support site, or the support itself can be formed so that it has the protruding part. Similarly, to thicken the adhesive layer at the site thereof corresponding to the protruding part, the composition that forms the adhesive layer can be applied twice to that site, or an adhesive layer that forms can be adhered to that site separately.
Then, the adhesive patch can be produced in another embodiment of the invention, which has a peripheral part and an intermediate part that has a rectangular flat shape and in which the thickness of the adhesive patch in the peripheral part is smaller than the thickness of the adhesive patch in the middle part and the protruding part
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which is placed in a corner of the intermediate part, for example according to the method mentioned below.
As described above, an adhesive layer is formed on at least one side of a support and then a release liner is laminated thereon, or an adhesive layer is formed on one side of a release liner and then a laminate is laminated. support therein, thereby preparing an adhesive patch printing precursor sheet (later referred to simply as "precursor sheet"). The precursor sheet is placed in a press bed so that the release liner thereof may be opposite the press bed, and is pressed to form it against a heated press die having a predetermined shape, on the support side Of the same. After being pressed to shape it, the sheet is stamped in a predetermined stamping position. The predetermined shape of the press die is a way capable of pressing at least the region corresponding to the rectangular peripheral part. Thus, by pressing the region corresponding to the peripheral part, the peripheral part is formed in which the thickness of the adhesive patch is smaller than the thickness in the intermediate part. The predetermined stamping position is a position that delineates the profile of the adhesive patch so that the region corresponding to the rectangular peripheral part of the adhesive patch could be included in the adhesive patch. In addition, the stamped sheet is then pressed and heated against a heated press die, to thereby form a part therein that protrudes in the corner of the intermediate part, or also form a composite part in the corresponding place. to the connection part between the protruding parts. The shape of the heated press die depends on the shape of the adhesive patch that will be formed, and as an example thereof, a flat shape can be mentioned as delineated by two concentric rectangles. For the continuous production of the adhesive patches, a stamping position to form the series of adhesive patches is simulated on the precursor sheet, and the pressing and stamping can be repeated continuously thereby efficiently producing the adhesive patches from the precursor sheet. .
When producing the adhesive patches of the invention according to the method mentioned above, preferably, in the pressing a heated press die is used. Pressing with a heated press die softens the support adjacent to the pressed region, whereby the adhesive layer in the pressed region moves to the corners of the adhesive patch and to the connecting part between the protruding parts formed for thereby promoting the projection in the corners and the encumbrance of the connection part. The protruding part and the composite part formed by the foregoing can retain their shape by cooling, for example, by spontaneous cooling or the like.
The temperature of the heated press die is preferably from 90 ° C to 180 ° C, more preferably from 120 ° C to 150 ° C. The pressure in the pressing is preferably from 1 x 104 N / m2 to 1 x 109 N / m2, more preferably from 1 x 106 N / m2 to 1 x 108 N / m2. The pressing time is preferably 0.05 seconds to 5 seconds, more preferably 0.1 seconds to 1 second. To form the composite connection part, the temperature of the press die varies depending on the thickness and composition of the adhesive layer and the shape, thickness and material of the support, but is preferably higher. For example, the temperature of the press die is 110 ° C to 180 ° C, the pressure in the pressing is 1 x 106 N / m2 to 1 x 108 N / m2, and the pressing time is 0, 05 seconds to 5 seconds. To efficiently form the composite connection part, preferably, the temperature of the press bed is within a range of 25 ° C to 50 ° C. When the temperature of the press bed is controlled to be within the previous range, it can be considered that the adhesive layer can be prevented from becoming too fluid due to the influence on it of the press matrix heated in the pressing, and by therefore, the aforementioned form of the adhesive patch can be formed in such a way efficiently.
The distance between the press die and the press bed is preferably the total thickness of the support, the adhesive layer in the peripheral part and the release liner ± 10 mm or so.
The material of the press die for pressing is not specifically defined, but preferably the press die is made of iron. A made of stainless steel would be deformed by heat and would be difficult to work. One made of aluminum and one made of brass would be easy to work but could have poor die durability, and therefore would often be unfavorable.
After pressing, printing to provide adhesive patches can be achieved in accordance with ordinary methods using a laser, a pressing blade or the like. The use of a press blade die assembly (male die and female die) that facilitates the control of the cutting dimension and alignment of the position and that provides good cutting edges is preferred.
In the case where the release liner has an extensible part, only the adhesive patch body is stamped first, and then the release liner is stamped, so that the extendable part is easily formed. The length of the extendable part can be controlled by controlling the dimensional difference between the male die and the female die of the pressing knife die assembly. The divided part of the release liner can be formed by cutting the middle part of the release liner in half with a die roller to thereby introduce a cutting line only into the release liner.
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Preferably, the adhesive patch of the invention is packaged in a container and stored as such. The package can be produced by using a packaging material generally used to package the adhesive patches. The packaging material includes, for example, polyolefin resin films such as polyethylene film, polypropylene film, polymethylpentene film, etc .; vinyl resin films such as polyvinyl chloride film, polyvinylidene chloride film, polyvinyl alcohol film, polystyrene film, polyacrylonitrile film, ionomer film, etc .; polyester based resin films such as polyethylene terephthalate film, etc .; polyamide based resin films such as nylon film, etc .; films of cellulosic resins such as cellophane, etc .; polycarbonate resin films, and their laminated films, and also the laminated films thereof and aluminum. The packaging of the adhesive patch in the package formed of the above packaging material, and sealed according to a known thermal sealing method or the like.
Examples
The invention is described in greater detail with reference to the following Examples and Comparative Examples; however, the invention is not limited by the following Examples.
<Preparation of the composition A that forms the adhesive layer>
(i) 95 parts by weight of 2-ethylhexyl acrylate (from Toa Gosei), 5 parts by weight of acrylic acid (from Toa Gosei), 100 parts by weight of ethyl acetate and 0.2 parts by weight of peroxide of benzoflo (“NYPER BW”, of NOF) were reacted in a separable flask equipped with a reflux condenser, a stirrer, a thermometer, a drip funnel and a nitrogen introduction duct, in a nitrogen atmosphere at 60 ° C for 15 hours, to prepare a solution of acrylic adhesive.
(ii) With respect to 40 parts by weight of the solid content of the acrylic adhesive solution, 40 parts by weight of isopropyl palmitate (from Croda Japan) as an organic liquid component and 20 parts by weight of isosorbide nitrate (from DKSH Japan) as a drug, they were mixed with the solution. Also, as the crosslinking agent, an isocyanate-based crosslinking agent ("CORONATE HL", from Nippon Polyurethane Industry) was mixed in the solution in a ratio of 0.05% by weight with respect to the solid content of the solution of acrylic adhesive, and ethyl acetate was added additionally for viscosity control to prepare a composition A that forms the adhesive layer. <Preparation of composition B forming the adhesive layer>
<Preparation of composition B forming the adhesive layer>
A high molecular weight polyisobutylene (average molecular weight in viscosity = 4 x 106, "OPPANOL B200", from BASF), a medium molecular weight polyisobutylene (average molecular weight in viscosity = 8.5 x 104, "OPPANOL B15N", BASF), as a tackifying agent, an alicyclic saturated hydrocarbon resin ("ARCON P-100", from Arakawa Chemical Industry, softening point (using the ring and ball method) = 100 ± 5 ° C), as a organic liquid component, isopropyl palmitate (from Croda Japan), and as a drug, tulobuterol (from Sumitomo Chemical), was mixed in hexane in a weight ratio of 15/20/25/30/10, and processed for viscosity control to prepare a composition B that forms the adhesive layer.
<Preparation of adhesive sheet A>
The composition A that forms the adhesive layer was applied on the release face of a release liner (75 mm thick) formed of polyethylene terephthalate (hereinafter this can be designated as "PET") so that the thickness of The adhesive layer after it was dried could be 200 mm, and then dried with a dryer (100 ° C, 3 minutes), thereby forming an adhesive layer on the release liner. Then, as a support, a laminate of a PET-made film that has a thickness of 3.5 mm and a non-woven fabric made of PET that is approximately 35 mm thick and has a unit weight of 12 g / m2 (thickness total, approximately 40 mm) adhered under pressure to the face of the lining formed by the adhesive layer keeping the non-woven fabric made of PET facing the adhesive layer, thereby preparing an adhesive sheet. The adhesive sheet was kept statically in a thermostatic chamber at 70 ° C for 48 hours to thereby promote the crosslinking reaction of the adhesive layer. The release liner only of the adhesive sheet that was prepared in this way is cut along a corrugated line, thereby preparing an adhesive sheet A having a divided part.
<Preparation of adhesive sheet B>
The composition B that forms the adhesive layer was applied on the release face of a release coating made of PET (thickness 75 mm) so that the thickness of the adhesive layer after it dried could be 200 mm, and then It was dried with a dryer (70 ° C, 2 minutes), thereby forming an adhesive layer on the release liner. As a support, a laminate of a film made of PET that has a thickness of 3.5
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mm and a non-woven fabric made of PET having a thickness of approximately 35 mm and a unit weight of 12 g / m2 (total thickness, approximately 40 mm) adhered under pressure to the face of the coating formed by the adhesive layer maintaining the non-woven fabric made of PET facing the adhesive layer, thereby preparing an adhesive sheet. The release liner only of the adhesive sheet that was prepared in this way is cut along a wavy line, thereby preparing an adhesive sheet B having a divided part.
<Preparation of adhesive sheet C>
Composition A that forms the adhesive layer was applied on the release face of a release coating made of PET (thickness 75 mm) so that the thickness of the adhesive layer after it dried could be 180 mm, and then it was dried with a dryer (100 ° C, 3 minutes), thereby producing a laminate A having the adhesive layer laminated on the release liner. A laminate of a PET-made film having a thickness of 3.5 mm and a non-woven fabric made of PET that has a thickness of approximately 35 mm and a unit weight of 12 g / m2 (total thickness, approximately 40 mm) It was used as a support, and the composition A that forms the adhesive layer was applied on the non-woven side made of PET of the laminate so that the thickness of the adhesive layer after it dried could be 60 mm and the Its width could be 10 mm, and it was dried with a dryer (100 ° C, 3 minutes), thereby producing a laminate B having the adhesive layer laminated on the support. Laminate A and laminate B were adhered together under pressure so that the sides of the adhesive layer of the two could be opposite, thereby producing an adhesive sheet. The adhesive sheet was kept statically in a thermostatic chamber at 70 ° C for 48 hours to thereby promote the crosslinking reaction of the adhesive layer. The intermediate part of the release liner corresponding to the laminate B (thick part) of the prepared adhesive sheet is cut along a wavy line, thereby producing an adhesive sheet C having a divided part.
<Preparation of adhesive sheet D>
The composition B that forms the adhesive layer was applied on the release face of a release coating made of PET (75 mm thick) so that the thickness of the adhesive layer after drying could be 180 mm, and then Dry with a dryer (70 ° C, 2 minutes), thereby producing a laminate C having the adhesive layer laminated on the release liner. A laminate of a PET-made film having a thickness of 3.5 mm and a non-woven fabric made of PET that has a thickness of approximately 35 mm and a unit weight of 12 g / m2 (total thickness, approximately 40 mm) It was used as a support, and the composition B that forms the adhesive layer was applied on the non-woven side made of PET of the laminate so that the thickness of the adhesive layer after drying could be 60 mm and the width of the it could be 10 mm, and dried with a dryer (70 ° C, 2 minutes), thereby producing a laminate D having the adhesive layer laminated on the support. Laminate C and laminate D were bonded together under pressure so that the sides of the adhesive layer of the two could be opposite, thereby producing an adhesive sheet. The intermediate part of the release liner corresponding to the laminate D (thick part) of the prepared adhesive sheet is cut along a wavy line, thereby producing an adhesive sheet D having a divided part.
<Adhesive patch production>
[Example 1]
Adhesive sheet A was placed in a press bed having a surface temperature of 30 ° C. Using a heated rectangular press die (external dimension: 32 mm x 32 mm, radius of the arcuate curved part (later referred to as simply "R"): 5 mm, internal dimension: 28 mm x 28 mm, R: 1 mm , made of iron), the support surface of the adhesive sheet A was heated under pressure (heating temperature: 150 ° C, press die pressure: 2 x 107 N / m2, heating and pressing time: 0, 3 seconds) so that the split part of the release liner could be almost in the center of the adhesive patch. Using a pressing blade, the adhesive patch body and the release liner were stamped together from the heated and pressed adhesive sheet A so that the heated and pressed region could correspond to the peripheral part of the adhesive patch that will be obtained later, producing thereby an adhesive patch of Example 1.
[Example 2]
An adhesive patch of Example 2 was produced in the same manner as in Example 1, except that the heating and pressure conditions were changed to: a heating temperature of 100 ° C, a press die press of 2 x 107 N / m2, and a heating and pressing time of 0.3 seconds.
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[Example 3]
An adhesive patch of Example 3 was produced in the same manner as in Example 1, for which, however, adhesive sheet B was used instead of adhesive sheet A.
[Example 4]
An adhesive patch of Example 4 was produced in the same manner as in Example 2, for which, however, adhesive sheet B was used instead of adhesive sheet A.
[Comparative Example 1]
An adhesive patch of Comparative Example 1 was produced in the same manner as in Example 1, for which, however, the heating and pressing treatment with the press die was omitted.
[Comparative Example 2]
An adhesive patch of Comparative Example 2 was produced by stamping the adhesive sheet C to have a flat shape, as in Comparative Example 1.
[Comparative Example 3]
An adhesive patch of Comparative Example 3 was produced in the same manner as in Example 3, for which, however, the heating and pressing treatment with the press die was omitted.
[Comparative Example 4]
An adhesive patch of Comparative Example 4 was produced by stamping the adhesive sheet D to have a flat shape, as in Comparative Example 2.
<Adhesive patch packaging>
The adhesive patch of Examples 1 and 2 and Comparative Examples 1 and 2 was sealed and packaged in a container (external dimension: 95 mm x 95 mm, internal dimension: 85 mm x 85 mm) formed of a packaging material whose outer layer was a PET film that is 12 mm thick, the inner layer was a resin film based on polyacrylonitrile that is 30 mm thick, and the central layer was aluminum that is 7 mm thick. The adhesive patch of Examples 3 and 4 and Comparative Examples 3 and 4 was sealed and packaged in a container formed from the aforementioned packaging material and having an external dimension of 65 mm x 65 mm and an internal dimension: 55 mm x 55 mm.
[Test Example 1] Evaluation of the shape of the adhesive patch:
The flat shape of the adhesive patch of Examples 1 to 4 and Comparative Examples 1 to 4 was observed. In addition, the adhesive patch was frozen in liquid nitrogen and extracted quickly, and cut with a trimmer blade at low temperature in the vertical direction of the face of the support (6). Using a digital microscope, the cutting face was observed to measure each thickness (total thickness of the support (6), of the adhesive layer (7) and of the release liner (8) in the peripheral part (1), intermediate part ( 2), protruding part (3) and in the composite connection part (4) At the same time, the width of the peripheral part (1) was measured.The results are shown in Table 1, and in figures 1 to 6.
Table 1
 Sample  Patch shape Overhanging part Composite connection part Intermediate part Peripheral part
 adhesive  Position, number, shape Relationship of occupied area (%) Thickness (pm) Thickness (pm) Width (mm) Thickness (pm) Thickness (pm) Width (mm)
 Example 1  Rectangle (30 mm square) R = 3 mm at the corners of the intermediate part, four, semilunar shape 16 520 400 1.5 310 120 2
 Example 2  Rectangle (30 mm square) R = 3 mm at the corners of the intermediate part, four, semilunar shape 11 460 310 180 2
 Comparative Example 1  Rectangle (30 mm square) R = 3 mm none “- - 310“
 Comparative Example 2  Rectangle (30 mm square) R = 3 mm in the divided part of the release liner, band type (10 mm width) 34 340 280
 Example 3  Rectangle (30 mm square) R = 3 mm at the corners of the intermediate part, four, semilunar shape 16 510 380 1.5 300 120 2
 Example 4  Rectangle (30 mm square) R = 3 mm at the corners of the intermediate part, four, semilunar form 11 460 300 180 2
 Comparative Example 3  Rectangle (30 mm square) R = 3 mm none “- - 300
 Comparative Example 4  Rectangle (30 mm square) R = 3 mm in the divided part of the release liner, band type (10 mm width) 34 340 280
* In the Table, "semilunar form" means a rounded semilunar form in the corner
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Figure 1 schematically shows the flat shape of the adhesive patch of Example 1. Figures 2 (a) and (b) each schematically show the cross-sectional profile of the adhesive patch of Example 1, as cut from the support surface (6) in the vertical direction along line II and line II-II, respectively, in figure 1. As is evident from Table 1 and figures 1 and 2, the adhesive patch of this Example has a peripheral part (1) having a width of 2 mm and an intermediate part (2) within the peripheral part. The external shape of the adhesive patch is a rectangle (30 mm x 30 mm) rounded at the corners of it (R = 3 mm), and on the contour thereof, the ratio of the total length of the curved parts to the total length of the linear parts was approximately 19.6%. Each flat shape of the support (6), the release liner (8) and the adhesive layer (7) was also a rounded rectangle at the corners, and the flat shape of the intermediate part (2) was also a rounded rectangle in The corners At each corner thereof, the rectangular adhesive patch has a semilunar protruding part (3) rounded at the corner thereof, therefore having four such parts protruding in total. Among the adjacent protruding parts (3), the adhesive patch had a composite band-type connection part (4) in which the thickness of the adhesive patch was smaller than the thickness of the adhesive patch on the protruding part (3) . In addition, the divided part (5) of the release liner was thus arranged so as not to overlap with the four protruding parts (3). The protruding part (3) and the composite connection part (4) were formed by changing the thickness of the adhesive layer (7) on the lateral surface of the support (6) of the adhesive patch.
Next, Figure 3 schematically shows the flat shape of the adhesive patch of Example 2. Figures 4 (a) and (b) each schematically show the cross-sectional profile of the adhesive patch of Example 2, as cut from the surface of the support (6) in the vertical direction along line II and line II-II, respectively, in figure 3. As is evident from Table 1 and figures 3 and 4, the shape and Similar of the adhesive patch of this Example were the same as the shape and similar of the adhesive patch of Example 1 except that the former did not have the band-like composite part (4) between adjacent protruding parts (3).
On the other hand, according to what was shown in Table 1, each external shape of the adhesive patch and the like of Comparative Example 1 had a rounded rectangular flat shape at the corners thereof. However, the adhesive patch that is produced here did not have the peripheral part (1) and the inner intermediate part (2) that had the adhesive patch of Example 1, and also, the adhesive patch that is produced here does not it had the protruding part (3) in the corner part of the rectangle thereof. In the contour of the external shape of the adhesive patch of this Comparative Example, the ratio of the total length of the curved parts to the total length of the linear parts was approximately 19.6%, and was at the same level as in the adhesive patch of Example 1.
Figure 5 schematically shows the flat shape of the adhesive patch of Comparative Example 2. Figures 6 (a) and (b) each schematically show the cross-sectional profile of the adhesive patch of Comparative Example 2, as cut from the surface of the support (6) in the vertical direction along the Line II and Line II-II, respectively, in Figure 5. As is evident from Table 1 and Figures 5 and 6, each outer shape of the adhesive patch and the like of Comparative Example 2 had a rectangular flat shape. rounded at the corners thereof, and had the protruding part (3) that is 10 mm wide, in which, however, the protruding part (3) was arranged in the divided part (5) of the lining of release. In the contour of the external shape of the adhesive patch of this Comparative Example, the ratio of total length of the curved parts to the total length of the linear parts was approximately 19.6%, and was at the same level as in the patch adhesive of Example 1.
Then, according to what was shown in Table 1, the shape and others of the adhesive patch of Example 3 were the same as the shape and others of the adhesive patch of Example 1; and the shape and others of the adhesive patch of Example 4 were the same as the shape and others of the adhesive patch of Example 2.
Also as evident from Table 1, similar to the adhesive patch of Comparative Example 1, the adhesive patch of Comparative Example 3 did not have the peripheral part (1), the internal intermediate part (2) and the protruding parts (3 ) in the corners of the rectangle. Similar to the adhesive patch of Comparative Example 2, the adhesive patch of Comparative Example 4 had the protruding part (3) having a width of 10 mm, in which, however, the protruding part was placed in the divided part ( 5) of the release liner. In the contour of the external shape of the adhesive patch of these Comparative Examples, the ratio of the total length of the curved parts to the total length of the linear parts was approximately 19.6%, and was at the same level as in the adhesive patch of Example 1.
[Test Example 2] Evaluation of the amount of drug ejected from the adhesive patch:
The adhesive patch of Examples 1 to 4 and Comparative Examples 1 to 4 was stored at 60 ° C for 1 month, and then in the package in which the adhesive patch had been packaged, the drug that adhered to the material of the The package was extracted with methanol and quantified through high performance liquid chromatography (HPLC). Table 2 shows the ratio of the amount of drug that adheres to the package to the amount of drug in the adhesive patch of the Examples and Comparative Examples.
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Table 2
 Sample  Amount of drug adhered to the container (mg / bag) Ratio of drug adhered to the container to drug contained in the adhesive patch (%)
 Example 1  68 0.2
 Example 2  123 0.4
 Comparative Example 1  514 1.6
 Comparative Example 2  826 2.8
 Example 3  14 0.1
 Example 4  22 0.1
 Comparative Example 3  90 0.5
 Comparative Example 4  123 0.7
Table 2 shows that, in the adhesive patches of Examples 1 and 2, the amount of isosorbide nitrate that adhered to the package was 1/4 or less, compared to that in the adhesive patches of Comparative Examples 1 and 2 . Also in the adhesive patches of Examples 3 and 4, the amount of tulobuterol that adhered to the package was 1/5 or less of the amount thereof in the adhesive patches of Comparative Examples 3 and 4. In the adhesive patches of Comparative Examples 2 and 4, which had the protruding part (3) in the divided part (5), it was not only remarkable that the drug was ejected from the exposed area of the adhesive layer at the edge of the peripheral part of the adhesive patch but also that the drug was ejected from the exposed area of the adhesive layer in the divided part (5), and therefore, the ratio of the drug that adhered to the container was high. The results in Table 2 confirm that in the adhesive patches of the invention, not only was it favorably avoided that the drug was ejected from the exposed area of the adhesive layer at the edge of the peripheral part of the adhesive patch but also that the drug was ejected. of the exposed area of the adhesive layer in the divided part (5).
[Example of 3 Test] Evaluation of the easy removal of the adhesive patch from the package:
The adhesive patch of Examples 1 to 4 and Comparative Examples 1 to 4 was stored at 60 ° C for 1 month, as packaged in a container. Then, the container was opened by scissors cutting two sides of it. From the open part, the adhesive patch was removed by pressing the corner thereof, and evaluated to determine the ease of removing the adhesive patch from the package, according to the following evaluation criteria with 1 to 5 evaluation points. The results of the evaluation are shown in Table 3.
<Evaluation criteria>
5: Extremely easy to remove.
4: Slightly caught, but it is possible to remove it.
3: Trapped, but it is possible to remove it.
2: Visibly trapped, but it is possible to remove it.
1: The adhesive patch is attached to the container and it was difficult to remove.
Table 3
 Sample  Easy to remove the adhesive patch from the container
 Example 1  5
 Example 2  4
 Comparative Example 1  one
 Comparative Example 2  one
 Example 3  5
 Example 4  4
 Comparative Example 3  one
 Comparative Example 4  one
As can be seen from Table 3, the adhesive patches of Examples 1 to 4 were easy to remove from the package, but the adhesive patches of Comparative Examples 1 to 4 adhered to the inner surface of the container and were difficult to remove. of the container The adhesive patches of Examples 1 and 3 had the composite connection part (4), and therefore were easier to remove from the package than the adhesive patches of Examples 2 and 4 that do not have the composite connection part (4 ).
5
10
fifteen
twenty
25
30
35
40
Four. Five
fifty
55
[Test Example 4] Evaluation of the expulsion or separation of the components of the adhesive layer from the exposed area of the adhesive layer in the divided part and at the peripheral edge of the adhesive patch:
The adhesive patch that was removed from the package in Test Example 3 was visually checked to determine the state of expulsion or separation of the components of the adhesive layer from the exposed area of the adhesive layer in the divided part (5) and at the edge peripheral of the adhesive patch, and was evaluated according to the following evaluation criteria with 1 to 5 evaluation points. The results of the evaluation are shown in Table 4.
<Evaluation criteria>
5: In the exposed area of the adhesive layer in the divided part and in the peripheral edge of the adhesive patch, absolutely no component of the adhesive layer is ejected or separated.
4: From the entire length of the exposed area of the adhesive layer in the divided part and at the peripheral edge of the adhesive patch, the components of the adhesive layer were ejected or separated by less than 1/4.
3: From the entire length of the exposed area of the adhesive layer in the divided part and at the peripheral edge of the adhesive patch, the components of the adhesive layer were ejected or separated in 1/4 to less than 1/2.
2: From the full length of the exposed area of the adhesive layer in the divided part and on the peripheral edge of the adhesive patch, the components of the adhesive layer were ejected or separated in 1/2 to less than 3/4.
1: From the entire length of the exposed area of the adhesive layer in the divided part and at the peripheral edge of the adhesive patch, the components of the adhesive layer were ejected or separated by 3/4 or more.
Table 4
 Sample  Expulsion or separation of the components of the adhesive layer
 Split part  Peripheral edge of the adhesive patch
 Example 1  5 5
 Example 2  5 4
 Comparative Example 1  twenty-one
 Comparative Example 2  eleven
 Example 3  5 5
 Example 4  5 4
 Comparative Example 3  3 1
 Comparative Example 4  twenty-one
As can be seen from Table 4, in the adhesive patches of Examples 1 to 4, the components of the adhesive layer were ejected or separated little from the exposed area of the adhesive layer in the divided part (5) and at the edge peripheral adhesive patch. On the other hand, in the adhesive patches of Comparative Examples 1 to 4, the components of the adhesive layer were ejected or visibly separated from the exposed area of the adhesive layer and at the peripheral edge of the adhesive patch, and especially in the adhesive patches. of Comparative Examples 2 and 4, the components of the adhesive layer were also ejected or visibly separated from the exposed area of the adhesive layer in the divided part (5) in comparison with the adhesive patches of Comparative Examples 1 and 3.
Although the invention has been described in detail and with reference to the specific embodiments thereof, it will be apparent to the person skilled in the art that various changes and modifications may be made therein without departing from the scope of the invention. This application is based on the application of 'Japanese Patent No. 2010043100 filed on February 26, 2010, and its complete contents are incorporated herein by reference.
Industrial applicability
As described in detail above in accordance with the invention, an adhesive patch containing a drug other than bisoprolol is provided and the drug and other components of the adhesive layer are prevented from being expelled or separated from the exposed area of the adhesive layer such as the edge of the adhesive patch or the divided part. As a result, when the adhesive patch is packaged in a container and stored in the container for a long period of time, the adhesive patch is prevented from adhering to the inner face of the container and preventing the drug content from being reduced in The adhesive patch during storage. In addition, the invention provides an adhesive patch that can be easily removed from the package, and while adhered to the skin, the opportunity for the adhesive patch to rub against clothing and others, and therefore the edge thereof, is hardly reduced.
10
fifteen
twenty
It detaches and the adhesive patch can have a sufficient adhesive capacity to the skin and it is difficult to detach from the cutaneous surface.
Description of the numerical references
1 peripheral part
2 Intermediate part
3 protruding part
4 Composite connection part
5 Split part
6 Support
7 Adhesive layer
8 Release Coating

权利要求:
Claims (7)
[1]
5
10
fifteen
twenty
25
30

1. Adhesive patch comprising a support, an adhesive layer containing a drug that excludes bisoprolol and disposed on at least one side of the support, and a release liner disposed on one side of the adhesive layer opposite the side thereof. on which the support is arranged,
wherein the support, the release liner and the adhesive layer each have a rectangular flat shape and the adhesive patch as a whole has a rectangular flat shape, and
wherein, in one corner of the adhesive patch, the adhesive patch comprises a part that protrudes on a lateral support surface thereof formed by thickening the support and / or thickening the adhesive layer.
[2]
2. Adhesive patch according to claim 1, wherein the adhesive patch comprises a peripheral part and an intermediate part having a flat rectangular shape, and in which a thickness of the adhesive patch in the peripheral part is smaller than a thickness of the adhesive patch on the intermediate part, and the protruding part is placed in a corner of the intermediate part.
[3]
3. Adhesive patch according to claim 1, wherein the adhesive patch comprises at least two protruding parts and comprises, between said adjacent protruding parts, a composite part of the strip type connection in which a thickness of the adhesive patch is smaller than a thickness of the adhesive patch on the protruding parts.
[4]
4. Adhesive patch according to claim 1, wherein the protruding part has a flat shape that is triangular, trapezoidal, semilunar or semicircular.
[5]
5. Adhesive patch according to claim 1, wherein the release liner comprises a divided part that does not pass through the protruding part.
[6]
6. Adhesive patch according to claim 1, wherein the adhesive layer contains an organic liquid component.
[7]
7. Adhesive patch according to claim 1, wherein the adhesive layer is not crosslinked.

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同族专利:

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NZ602035A|2013-07-26|

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KR101717320B1|2017-03-16|

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RU2012141031A|2014-04-10|

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EP2540288B9|2017-02-15|

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JP5412323B2|2014-02-12|

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WO2011105457A1|2011-09-01|

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EP2540288A1|2013-01-02|

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AU2011221292A1|2012-09-13|

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CN102781433B|2014-09-17|

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CA2791196A1|2011-09-01|

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US20120323191A1|2012-12-20|

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MX2012009913A|2012-11-23|

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KR20130055560A|2013-05-28|

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US9326952B2|2016-05-03|

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CA2791196C|2017-02-28|

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ES2600007T3|2017-02-06|

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EP2540288B1|2016-08-10|

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EP2540288A4|2015-04-29|

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CN102781433A|2012-11-14|

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BR112012021528A2|2016-07-05|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP2010043100|2010-02-26|

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JP2010043100A|JP5412323B2|2010-02-26|2010-02-26|Patch preparation|

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PCT/JP2011/054043|WO2011105457A1|2010-02-26|2011-02-23|Adhesive skin patch|

---