WO2017146106A1 - Method for producing oral cavity patch - Google Patents

Method for producing oral cavity patch Download PDF

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Publication number
WO2017146106A1
WO2017146106A1 PCT/JP2017/006633 JP2017006633W WO2017146106A1 WO 2017146106 A1 WO2017146106 A1 WO 2017146106A1 JP 2017006633 W JP2017006633 W JP 2017006633W WO 2017146106 A1 WO2017146106 A1 WO 2017146106A1
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Prior art keywords
layer
drug
tableting pressure
powder
tableting
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PCT/JP2017/006633
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French (fr)
Japanese (ja)
Inventor
利博 中西
靖久 古瀬
隆明 義永
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久光製薬株式会社
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Priority to JP2018501739A priority Critical patent/JP6548809B2/en
Publication of WO2017146106A1 publication Critical patent/WO2017146106A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the present invention relates to a method for producing an intraoral patch.
  • This application claims priority based on Japanese Patent Application No. 2016-034522 for which it applied to Japan on February 25, 2016, and uses the content here.
  • Patent Document 1 discloses a tablet for use as an intraoral patch comprising two layers, a drug layer and an adhesive layer, which is applied to an oral mucosa such as a palate.
  • Such a bilayer tablet (laminated tablet) can be produced using a known laminated tableting machine. First, the first layer powder is filled into a mortar and lightly compressed with an upper punch and a lower punch. Subsequently, the second layer powder is overlaid and filled on the first layer powder compressed in the die, and lightly compressed with an upper punch and a lower punch. Finally, the compressed first layer powder and second layer powder are strongly compressed with the upper and lower eyelids to obtain a bilayer tablet.
  • the drug layer as the first layer is blended with an elution control component for continuously eluting the drug at a ratio of 10% by mass or more, and the adhesive layer as the second layer.
  • An adhering component for adhering the preparation to the oral mucosa is blended in a proportion of 25 to 75% by mass.
  • the elution control component is, for example, hydroxypropylcellulose or hypromellose.
  • the adhering component is, for example, carmellose sodium or povidone.
  • the elution control components such as hydroxypropylcellulose and hypromellose are powders with good moldability, but the adhering components such as carmellose sodium and povidone are powders with poor moldability. For this reason, the moldability is greatly different between the tableting powder of the first layer and the tableting powder of the second layer. In the production of a two-layer tablet, if the moldability of each layer is different, compression molding of each layer works preferentially, the adhesive force at the boundary surface between both layers becomes weak, and delamination tends to occur.
  • the present invention has been made in view of the above circumstances, and an object thereof is to provide a method for producing an intraoral patch capable of reducing the occurrence of delamination between a drug layer and an adhesive layer. To do.
  • the method for producing an oral patch is at least selected from the group consisting of hydroxyalkylalkylcellulose, hydroxypropylcellulose, sodium carboxyalkylcellulose, ethylcellulose, hydrogenated castor oil, and sucrose fatty acid ester.
  • a method for producing an oral patch comprising a drug layer comprising a single drug release controlling agent, and an adhesive layer containing carboxyalkyl cellulose or a carboxyalkyl cellulose salt and polyvinylpyrrolidone as an adhesive. Then, the first layer powder constituting the drug layer is filled in the die of a tableting machine, and the drug layer is formed by compressing the first layer powder with a tableting pressure of 0.2 to 1.2 kN.
  • the second layer powder constituting the adhesion layer is filled on the drug layer in the die, and the drug layer and The second layer powder is compressed with a tableting pressure of 6.0 to 26 kN to form the adhesive layer, and the drug layer and the adhesive layer are compressed with a tableting pressure of 7.5 to 26 kN. To do.
  • the diameter of the oral patch in which the drug layer and the adhesive layer are compressed with a tableting pressure of 7.5 to 26 kN is the thickness of the oral patch. It may be 4 times or more.
  • the occurrence of delamination between the drug layer and the adhesive layer can be reduced.
  • the intraoral patch includes a drug layer and an adhesive layer.
  • the drug layer contains a drug release controlling agent consisting of at least one selected from the group consisting of hydroxyalkylalkylcellulose, hydroxypropylcellulose, sodium carboxyalkylcellulose, ethylcellulose, hydrogenated castor oil, and sucrose fatty acid ester.
  • the compounding amount of the drug release controlling agent is not particularly limited as long as it can delay the dissolution of the drug from the drug layer or the collapse of the drug layer.
  • the content of the drug release controlling agent is 10% by mass or more based on the total mass of the components of the drug layer.
  • the drug layer includes a pH regulator, a refreshing agent such as l-menthol, a sweetener, a corrigent, a coloring agent, an adsorbent, a stabilizer, a flavoring agent (fragrance), and the like. It may contain components.
  • the adhesion layer usually contains an adhesive as a component that adheres to the oral mucosa.
  • the adhesion layer comprises, as an adhesion agent, a group consisting of carboxyalkyl cellulose, carboxyalkyl cellulose salt, alginic acid, alginate, poly (N-vinyl lactam), polyvinyl alcohol, hydroxypropyl cellulose, carboxyvinyl polymer, pullulan and pregelatinized starch. Contains at least one selected.
  • the adhesion layer contains carboxyalkyl cellulose or carboxyalkyl cellulose salt and polyvinyl pyrrolidone as an adhesion agent.
  • the content of the adhesive is preferably 25 to 75% by mass based on the total mass of the adhesive layer components.
  • the intraoral patch according to this embodiment is a tablet, which is a two-layer tablet (laminated tablet) composed of two layers of a drug layer and an adhesive layer.
  • the intraoral patch is formed in a thin disk shape having a substantially circular outer periphery, and both the front surface and the back surface thereof are formed flat.
  • the thickness of the oral patch is, for example, 1.0 to 2.5 mm, preferably 1.5 to 2.0 mm. Among them, the thickness of the drug layer as the first layer is 0.67 to 1.67 mm, and the thickness of the adhesion layer as the second layer is 0.33 to 0.83 mm.
  • the diameter of the oral patch is, for example, 5 to 15 mm, preferably 7 to 10 mm.
  • the intraoral patch according to the present embodiment is preferably formed as thin as possible in consideration of ease of application in the oral cavity and less uncomfortable feeling when applied.
  • a shape is represented by a ratio of diameter to thickness (diameter / thickness), it is approximately 4 or more.
  • the drug layer and adhesive layer of the tablet further contain components commonly used in tablets such as excipients such as lactose hydrate, binders such as crystalline cellulose, and lubricants such as stearate and talc. You may do it.
  • excipients such as lactose hydrate
  • binders such as crystalline cellulose
  • lubricants such as stearate and talc. You may do it.
  • FIG. 1 is a diagram showing a method for producing an intraoral patch 30 according to this embodiment.
  • (A) to (e) of FIG. 1 show each step of tableting.
  • the first layer powder 10 constituting the drug layer 11 and the second layer powder 20 constituting the adhesion layer 21 are prepared.
  • each component is weighed based on a predetermined blending ratio and mixed to obtain a first layer powder 10 which is a tableting powder for the first layer.
  • each component is weighed based on a predetermined
  • These first layer powder 10 and second layer powder 20 are respectively set in the hopper of the tableting machine 1.
  • the tableting machine 1 compresses the first layer powder 10 and the second layer powder 20.
  • the first layer powder 10 is filled into the die 2 from the hopper of the tableting machine 1 (see FIG. 1A).
  • the first layer powder 10 is compressed with a tableting pressure (first tableting pressure) of 0.2 to 1.2 kN by the upper punch 3 and the lower punch 4 of the tableting machine 1 to form the drug layer 11 (FIG. 1 (b)).
  • the second layer powder 20 is filled onto the drug layer 11 in the die 2 from the hopper of the tableting machine 1 (see FIG. 1C).
  • the upper layer 3 and the lower layer 4 are used to compress the second layer powder 20 with a tableting pressure (second tableting pressure) of 6.0 to 26 kN to form the adhesion layer 21 (see FIG. 1 (d)).
  • the drug layer 11 and the adhesive layer 21 are compressed by the upper punch 3 and the lower punch 4 with a tableting pressure (third tableting pressure) of 7.5 to 26 kN.
  • the intraoral patch 30 can be manufactured (refer FIG.1 (e)).
  • Example 1 In this example, the ranges of the first tableting pressure and the second tableting pressure were examined by changing the magnitudes of the first tableting pressure and the second tableting pressure to reduce delamination.
  • Example formation procedure Varying tablet pressures of the first tableting pressure and second tableting pressure were changed to produce tablets for oral patch of sample numbers A1 to A60.
  • each component shown in Table 1 was weighed and mixed based on the respective blending ratios to obtain a first layer powder.
  • the adhesion layer each component shown in Table 1 was weighed based on the blending ratio and mixed to obtain a second layer powder.
  • the first layer powder and the second layer powder were set in a tableting machine, and tableting was performed by the process shown in FIG.
  • evaluation results The evaluation results for each sample number are shown in Table 2. As shown in Table 2, when the first tableting pressure was 1.4 kN or more, the evaluation criteria were not satisfied regardless of the magnitude of the second tableting pressure. When the first tableting pressure was 1.0 to 1.2 kN, the degree of delamination varied depending on the magnitude of the second tableting pressure. When the first tableting pressure was 0.8 kN or less, the evaluation criteria were satisfied regardless of the magnitude of the second tableting pressure.
  • the second layer powder is stacked without compressing the first layer powder, so that the layer interface between the first layer and the second layer is disturbed in the two-layer tablet. End up. Since this is not preferable in appearance, this condition is not suitable as a manufacturing condition.
  • the upper limit of the second tableting pressure is 26 kN due to the allowable pressure limit of the punch of the tableting machine.
  • the first tableting pressure is 0.2 to 1.2 kN
  • the second tableting pressure is 5 to 26 kN
  • the third tableting pressure is 18.5 kN.
  • Example 2 In the present example, the range of the second tableting pressure and the third tableting pressure that can reduce delamination was examined by changing the magnitudes of the second tableting pressure and the third tableting pressure and using the friability as an index.
  • Example formation procedure Varying tablet pressures of the second tableting pressure and third tableting pressure were changed to produce tablets for oral patch of sample numbers B1 to B7.
  • each component shown in Table 3 was weighed based on the blending ratio and mixed to obtain a first layer powder.
  • each component shown in Table 3 was weighed based on the blending ratio and mixed to obtain a second layer powder.
  • the first layer powder and the second layer powder were set in a tableting machine, and tableting was performed by the process shown in FIG.
  • Example numbers B1 to B7 of the oral patch consisting of two layers having a diameter of 8 mm, a drug layer thickness of 1.3 mm, and an adhesive layer thickness of 0.6 mm.
  • the friability (mass percentage of reduced mass with respect to the initial mass) was measured according to the “Tablet friability test method” described in the reference information of the 16th revision Japanese Pharmacopoeia. Using the friability as an index, delamination was evaluated based on the following evaluation criteria. ⁇ : Abrasion degree is 3.0% or less ⁇ : Abrasion degree exceeds 3.0%
  • the first tableting pressure is 1.0 kN
  • the second tableting pressure is 6.0 to 26 kN
  • the third tableting pressure is 7.5 to 26 kN.
  • the first tableting pressure is 0.2 to 1.2 kN
  • the second tableting pressure is 6.0 to 26 kN
  • the third The tableting pressure is 7.5 to 26 kN.
  • the tablets produced in Example 1 and Example 2 described above have a diameter of 8 mm and a thickness of 1.9 mm (the sum of the drug layer thickness of 1.3 mm and the adhesive layer thickness of 0.6 mm). .
  • it is a thin disc-shaped bilayer tablet having a diameter of 4 times or more with respect to the thickness, it is difficult to cause delamination by applying the method for producing an oral patch according to the above-described embodiment.

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Abstract

A method for producing an oral cavity patch comprising a drug layer and an adhesive layer involves: filling a first layer powder that constitutes the drug layer into a mortar of a tableting machine; compressing the first layer power with a tableting pressure of 0.2-1.2 kN to form the drug layer; filling a second layer powder that constitutes the adhesive layer onto the drug layer inside the mortar; compressing the drug layer and the second layer powder with a tableting pressure of 6.0-26 kN to form the adhesive layer; and compressing the drug layer and the adhesive layer with a tableting pressure of 7.5-26 kN.

Description

口腔内貼付剤の製造方法Method for producing oral patch
　本発明は、口腔内貼付剤の製造方法に関する。
　本願は、２０１６年２月２５日に、日本国に出願された特願２０１６－０３４５２２号に基づき優先権を主張し、その内容をここに援用する。 The present invention relates to a method for producing an intraoral patch.
This application claims priority based on Japanese Patent Application No. 2016-034522 for which it applied to Japan on February 25, 2016, and uses the content here.
　従来、口腔粘膜に貼付して使用する製剤（口腔内貼付剤）が広く用いられている。例えば、特許文献１には、口腔内貼付剤として、薬物層および付着層の二層からなり、口蓋などの口腔内の粘膜に貼付して使用するための錠剤が開示されている。 Conventionally, preparations (oral patches) that are applied to the oral mucosa have been widely used. For example, Patent Document 1 discloses a tablet for use as an intraoral patch comprising two layers, a drug layer and an adhesive layer, which is applied to an oral mucosa such as a palate.
　このような二層錠（積層錠）は、公知の積層打錠機を用いて製造することができる。まず、第一層粉末を臼内に充填し、上杵および下杵により軽く圧縮する。続いて、第二層粉末を臼内において圧縮された第一層粉末の上に重ねて充填し、上杵および下杵により軽く圧縮する。最後に、圧縮された第一層粉末および第二層粉末を上杵および下杵により強く圧縮することで、二層錠が得られる。 Such a bilayer tablet (laminated tablet) can be produced using a known laminated tableting machine. First, the first layer powder is filled into a mortar and lightly compressed with an upper punch and a lower punch. Subsequently, the second layer powder is overlaid and filled on the first layer powder compressed in the die, and lightly compressed with an upper punch and a lower punch. Finally, the compressed first layer powder and second layer powder are strongly compressed with the upper and lower eyelids to obtain a bilayer tablet.
日本国特許第５７７５９７０号公報Japanese Patent No. 5775970
　特許文献１に記載の口腔内貼付剤は、第一層である薬物層に、薬物を持続溶出させるための溶出制御成分が１０質量％以上の割合で配合され、第二層である付着層に、製剤を口腔粘膜に付着させるための付着成分が２５～７５質量％の割合で配合されている。ここで、溶出制御成分は、例えばヒドロキシプロピルセルロースやヒプロメロースなどである。また、付着成分は、例えばカルメロースナトリウムやポビドンなどである。 In the oral patch described in Patent Document 1, the drug layer as the first layer is blended with an elution control component for continuously eluting the drug at a ratio of 10% by mass or more, and the adhesive layer as the second layer. An adhering component for adhering the preparation to the oral mucosa is blended in a proportion of 25 to 75% by mass. Here, the elution control component is, for example, hydroxypropylcellulose or hypromellose. The adhering component is, for example, carmellose sodium or povidone.
　溶出制御成分であるヒドロキシプロピルセルロースやヒプロメロースなどは、成形性が良い粉末であるが、付着成分であるカルメロースナトリウムやポビドンなどは、成形性が悪い粉末である。このため、第一層の打錠末と第二層の打錠末とでは、成形性が大きく異なっている。二層錠の製造において、各層の成形性が異なると、各層単独の圧縮成形が優位に働いて両層の境界面での接着力が弱くなり、層間剥離が生じやすくなる。 The elution control components such as hydroxypropylcellulose and hypromellose are powders with good moldability, but the adhering components such as carmellose sodium and povidone are powders with poor moldability. For this reason, the moldability is greatly different between the tableting powder of the first layer and the tableting powder of the second layer. In the production of a two-layer tablet, if the moldability of each layer is different, compression molding of each layer works preferentially, the adhesive force at the boundary surface between both layers becomes weak, and delamination tends to occur.
　本発明は、上記の事情を鑑みてなされたものであり、薬物層と付着層との間の層間剥離の発生を低減することが可能な口腔内貼付剤の製造方法を提供することを目的とする。 The present invention has been made in view of the above circumstances, and an object thereof is to provide a method for producing an intraoral patch capable of reducing the occurrence of delamination between a drug layer and an adhesive layer. To do.
　本発明の一態様によれば、口腔内貼付剤の製造方法は、ヒドロキシアルキルアルキルセルロース、ヒドロキシプロピルセルロース、カルボキシアルキルセルロースナトリウム、エチルセルロース、硬化ヒマシ油、およびショ糖脂肪酸エステルからなる群より選ばれる少なくとも一つからなる薬物放出制御剤を含有する薬物層と、付着剤として、カルボキシアルキルセルロースまたはカルボキシアルキルセルロース塩と、ポリビニルピロリドンとを含有する付着層と、を備える口腔内貼付剤の製造方法であって、前記薬物層を構成する第一層粉末を打錠機の臼内に充填し、前記第一層粉末を０．２～１．２ｋＮの打錠圧で圧縮して前記薬物層を成形し、前記付着層を構成する第二層粉末を前記臼内の前記薬物層の上に充填し、前記薬物層および前記第二層粉末を６．０～２６ｋＮの打錠圧で圧縮して前記付着層を成形し、前記薬物層および前記付着層を７．５～２６ｋＮの打錠圧で圧縮することを特徴とする。 According to one aspect of the present invention, the method for producing an oral patch is at least selected from the group consisting of hydroxyalkylalkylcellulose, hydroxypropylcellulose, sodium carboxyalkylcellulose, ethylcellulose, hydrogenated castor oil, and sucrose fatty acid ester. A method for producing an oral patch comprising a drug layer comprising a single drug release controlling agent, and an adhesive layer containing carboxyalkyl cellulose or a carboxyalkyl cellulose salt and polyvinylpyrrolidone as an adhesive. Then, the first layer powder constituting the drug layer is filled in the die of a tableting machine, and the drug layer is formed by compressing the first layer powder with a tableting pressure of 0.2 to 1.2 kN. The second layer powder constituting the adhesion layer is filled on the drug layer in the die, and the drug layer and The second layer powder is compressed with a tableting pressure of 6.0 to 26 kN to form the adhesive layer, and the drug layer and the adhesive layer are compressed with a tableting pressure of 7.5 to 26 kN. To do.
　上記の口腔内貼付剤の製造方法において、前記薬物層および前記付着層が７．５～２６ｋＮの打錠圧で圧縮された前記口腔内貼付剤の直径は、前記口腔内貼付剤の厚さの４倍以上であってもよい。 In the method for producing an oral patch, the diameter of the oral patch in which the drug layer and the adhesive layer are compressed with a tableting pressure of 7.5 to 26 kN is the thickness of the oral patch. It may be 4 times or more.
　上記の口腔内貼付剤の製造方法によれば、薬物層と付着層との間の層間剥離の発生を低減することができる。 According to the above method for producing an intraoral patch, the occurrence of delamination between the drug layer and the adhesive layer can be reduced.
本発明の一実施形態に係る口腔内貼付剤の製造方法を示す図である。It is a figure which shows the manufacturing method of the intraoral patch which concerns on one Embodiment of this invention.
　以下、本発明の一実施形態について説明する。 Hereinafter, an embodiment of the present invention will be described.
　まず、本実施形態に係る口腔内貼付剤について説明する。口腔内貼付剤は、薬物層と付着層とを備える。 First, the intraoral patch according to this embodiment will be described. The intraoral patch includes a drug layer and an adhesive layer.
　薬物層は、ヒドロキシアルキルアルキルセルロース、ヒドロキシプロピルセルロース、カルボキシアルキルセルロースナトリウム、エチルセルロース、硬化ヒマシ油、およびショ糖脂肪酸エステルからなる群より選ばれる少なくとも１つからなる薬物放出制御剤を含有する。薬物放出制御剤の配合量は、薬物層からの薬物の溶出または薬物層の崩壊を遅延させることができる量であれば、特に限定されない。好ましくは、薬物放出制御剤の含有量は、薬物層の成分の総質量基準で１０質量％以上である。 The drug layer contains a drug release controlling agent consisting of at least one selected from the group consisting of hydroxyalkylalkylcellulose, hydroxypropylcellulose, sodium carboxyalkylcellulose, ethylcellulose, hydrogenated castor oil, and sucrose fatty acid ester. The compounding amount of the drug release controlling agent is not particularly limited as long as it can delay the dissolution of the drug from the drug layer or the collapse of the drug layer. Preferably, the content of the drug release controlling agent is 10% by mass or more based on the total mass of the components of the drug layer.
　薬物層に含有させる薬物としては、口内殺菌薬や口臭除去薬（消臭剤）、抗炎症薬、歯周病治療薬などを使用することができる。また、薬物層は、上述した成分の他に、ｐＨ調節剤、ｌ－メントールなどの清涼化剤、甘味剤、矯味剤、着色剤、吸着剤、安定化剤、着香剤（香料）などの成分を含有していてもよい。 As the drug to be contained in the drug layer, oral bactericides, oral malodor removal drugs (deodorants), anti-inflammatory drugs, periodontal disease treatment drugs, and the like can be used. In addition to the above-mentioned components, the drug layer includes a pH regulator, a refreshing agent such as l-menthol, a sweetener, a corrigent, a coloring agent, an adsorbent, a stabilizer, a flavoring agent (fragrance), and the like. It may contain components.
　付着層は、通常、口腔粘膜に付着する成分として付着剤を含有する。付着層は、付着剤として、カルボキシアルキルセルロース、カルボキシアルキルセルロース塩、アルギン酸、アルギン酸塩、ポリ（Ｎ－ビニルラクタム）、ポリビニルアルコール、ヒドロキシプロピルセルロース、カルボキシビニルポリマー、プルラン及びアルファー化デンプンからなる群より選ばれる少なくとも１つを含有する。好ましくは、付着層は、付着剤として、カルボキシアルキルセルロースまたはカルボキシアルキルセルロース塩と、ポリビニルピロリドンとを含有する。付着剤の含有量は、付着層成分の総質量基準で、好ましくは２５～７５質量％である。 The adhesion layer usually contains an adhesive as a component that adheres to the oral mucosa. The adhesion layer comprises, as an adhesion agent, a group consisting of carboxyalkyl cellulose, carboxyalkyl cellulose salt, alginic acid, alginate, poly (N-vinyl lactam), polyvinyl alcohol, hydroxypropyl cellulose, carboxyvinyl polymer, pullulan and pregelatinized starch. Contains at least one selected. Preferably, the adhesion layer contains carboxyalkyl cellulose or carboxyalkyl cellulose salt and polyvinyl pyrrolidone as an adhesion agent. The content of the adhesive is preferably 25 to 75% by mass based on the total mass of the adhesive layer components.
　本実施形態に係る口腔内貼付剤は錠剤であり、薬物層と付着層との二層からなる二層錠（積層錠）である。口腔内貼付剤は、略円形の外周を有する薄い円盤状に形成され、その表面および裏面はともに平坦に形成されている。口腔内貼付剤の厚さは、例えば１．０～２．５ｍｍであり、好ましくは１．５～２．０ｍｍである。そのうち、第一層である薬物層の厚さは、０．６７～１．６７ｍｍであり、第二層である付着層の厚さは、０．３３～０．８３ｍｍである。また、口腔内貼付剤の直径は、例えば５～１５ｍｍであり、好ましくは７～１０ｍｍである。 The intraoral patch according to this embodiment is a tablet, which is a two-layer tablet (laminated tablet) composed of two layers of a drug layer and an adhesive layer. The intraoral patch is formed in a thin disk shape having a substantially circular outer periphery, and both the front surface and the back surface thereof are formed flat. The thickness of the oral patch is, for example, 1.0 to 2.5 mm, preferably 1.5 to 2.0 mm. Among them, the thickness of the drug layer as the first layer is 0.67 to 1.67 mm, and the thickness of the adhesion layer as the second layer is 0.33 to 0.83 mm. The diameter of the oral patch is, for example, 5 to 15 mm, preferably 7 to 10 mm.
　本実施形態に係る口腔内貼付剤は、口腔内への貼付のしやすさや、貼付したときの違和感の少なさなどを考慮すると、できるだけ薄く形成されることが好ましい。このような形状を直径と厚さとの比（直径／厚さ）で示すと、概ね４以上となる。 The intraoral patch according to the present embodiment is preferably formed as thin as possible in consideration of ease of application in the oral cavity and less uncomfortable feeling when applied. When such a shape is represented by a ratio of diameter to thickness (diameter / thickness), it is approximately 4 or more.
　なお、錠剤の薬物層および付着層は、乳糖水和物などの賦形剤や、結晶セルロースなどの結合剤、ステアリン酸塩やタルクなどの滑沢剤などの錠剤で慣用される成分をさらに含有していてもよい。 The drug layer and adhesive layer of the tablet further contain components commonly used in tablets such as excipients such as lactose hydrate, binders such as crystalline cellulose, and lubricants such as stearate and talc. You may do it.
　次に、本実施形態に係る口腔内貼付剤の製造方法について説明する。図１は、本実施形態に係る口腔内貼付剤３０の製造方法を示す図である。図１の（ａ）～（ｅ）は、打錠の各工程を示している。 Next, a method for producing an intraoral patch according to this embodiment will be described. FIG. 1 is a diagram showing a method for producing an intraoral patch 30 according to this embodiment. (A) to (e) of FIG. 1 show each step of tableting.
　まず、薬物層１１を構成する第一層粉末１０および付着層２１を構成する第二層粉末２０を準備する。薬物層１１について、所定の配合割合に基づいて各成分を秤量し、混合して、第一層用の打錠末である第一層粉末１０とする。また、付着層２１について、所定の配合割合に基づいて各成分を秤量し、混合して、第二層用の打錠末である第二層粉末２０とする。これらの第一層粉末１０および第二層粉末２０を、打錠機１のホッパーにそれぞれセットする。 First, the first layer powder 10 constituting the drug layer 11 and the second layer powder 20 constituting the adhesion layer 21 are prepared. About the drug layer 11, each component is weighed based on a predetermined blending ratio and mixed to obtain a first layer powder 10 which is a tableting powder for the first layer. Moreover, about the adhesion layer 21, each component is weighed based on a predetermined | prescribed mixture ratio, it mixes and it is set as the 2nd layer powder 20 which is the tableting powder for 2nd layers. These first layer powder 10 and second layer powder 20 are respectively set in the hopper of the tableting machine 1.
　次に、打錠機１により第一層粉末１０および第二層粉末２０の打錠を行う。まず、第一層粉末１０を打錠機１のホッパーから臼２内に充填する（図１（ａ）参照）。打錠機１の上杵３および下杵４により、第一層粉末１０を０．２～１．２ｋＮの打錠圧（第一打錠圧）で圧縮し、薬物層１１を成形する（図１（ｂ）参照）。次に、第二層粉末２０を打錠機１のホッパーから臼２内の薬物層１１の上に充填する（図１（ｃ）参照）。上杵３および下杵４により、第二層粉末２０を６．０～２６ｋＮの打錠圧（第二打錠圧）で圧縮し、付着層２１を成形する（図１（ｄ）参照）。そして、上杵３および下杵４により、薬物層１１および付着層２１を７．５～２６ｋＮの打錠圧（第三打錠圧）で圧縮する。これにより、口腔内貼付剤３０を製造することができる（図１（ｅ）参照）。 Next, the tableting machine 1 compresses the first layer powder 10 and the second layer powder 20. First, the first layer powder 10 is filled into the die 2 from the hopper of the tableting machine 1 (see FIG. 1A). The first layer powder 10 is compressed with a tableting pressure (first tableting pressure) of 0.2 to 1.2 kN by the upper punch 3 and the lower punch 4 of the tableting machine 1 to form the drug layer 11 (FIG. 1 (b)). Next, the second layer powder 20 is filled onto the drug layer 11 in the die 2 from the hopper of the tableting machine 1 (see FIG. 1C). The upper layer 3 and the lower layer 4 are used to compress the second layer powder 20 with a tableting pressure (second tableting pressure) of 6.0 to 26 kN to form the adhesion layer 21 (see FIG. 1 (d)). The drug layer 11 and the adhesive layer 21 are compressed by the upper punch 3 and the lower punch 4 with a tableting pressure (third tableting pressure) of 7.5 to 26 kN. Thereby, the intraoral patch 30 can be manufactured (refer FIG.1 (e)).
　以下、実施例を挙げて本発明をさらに説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited thereto.
　〔実施例１〕
　本実施例では、第一打錠圧および第二打錠圧の大きさを変え、層間剥離が低減できる第一打錠圧および第二打錠圧の範囲を検討した。 [Example 1]
In this example, the ranges of the first tableting pressure and the second tableting pressure were examined by changing the magnitudes of the first tableting pressure and the second tableting pressure to reduce delamination.
　（試料の形成手順）
　第一打錠圧および第二打錠圧の大きさを変えて、試料番号Ａ１～Ａ６０の口腔内貼付剤の錠剤を製造した。まず、薬物層について、表１に示す各成分をそれぞれの配合割合に基づいて秤量し、混合して、第一層粉末とした。同様に、付着層について、表１に示す各成分をそれぞれの配合割合に基づいて秤量し、混合して、第二層粉末とした。第一層粉末および第二層粉末を打錠機にセットし、図１に示す工程により打錠を行った。 (Sample formation procedure)
Varying tablet pressures of the first tableting pressure and second tableting pressure were changed to produce tablets for oral patch of sample numbers A1 to A60. First, for the drug layer, each component shown in Table 1 was weighed and mixed based on the respective blending ratios to obtain a first layer powder. Similarly, for the adhesion layer, each component shown in Table 1 was weighed based on the blending ratio and mixed to obtain a second layer powder. The first layer powder and the second layer powder were set in a tableting machine, and tableting was performed by the process shown in FIG.
　まず、第一層粉末８０ｍｇを臼内に充填し、表２に示す各試料番号の第一打錠圧で圧縮し、薬物層を成形した。次に、第二層粉末４０ｍｇを臼内に充填し、表２に示す各試料番号の第二打錠圧で圧縮し、付着層を成形した。そして、薬物層および付着層を１８．５ｋＮの第三打錠圧で圧縮した。なお、第三打錠圧は、試料番号に関わらず一定である。これにより、直径８ｍｍ、薬物層の厚さ１．３ｍｍ、および付着層の厚さ０．６ｍｍである二層からなる口腔内貼付剤の錠剤（試料番号Ａ１～Ａ６０）を製造した。 First, 80 mg of the first layer powder was filled in the mortar and compressed with the first tableting pressure of each sample number shown in Table 2 to form a drug layer. Next, 40 mg of the second layer powder was filled in the mortar and compressed with the second tableting pressure of each sample number shown in Table 2 to form an adhesion layer. The drug layer and adhesive layer were then compressed with a third tableting pressure of 18.5 kN. The third tableting pressure is constant regardless of the sample number. This produced tablets (sample numbers A1 to A60) of an oral patch comprising two layers having a diameter of 8 mm, a drug layer thickness of 1.3 mm, and an adhesive layer thickness of 0.6 mm.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　（評価方法）
　第十六改正日本薬局方の参考情報に記載された「錠剤の摩損度試験法」を参考として、上記により製造された錠剤を６．５ｇにできるだけ近い量に相当する錠数をドラムに入れ、回転数２５ｒｐｍにて３００回転させた。回転終了後、初期質量に対して層間剥離しなかった錠剤の質量百分率を算出した。この質量百分率を、次の評価基準に基づいて評価した。
　　○：層間剥離しなかった錠剤の割合が９５％以上
　　×：層間剥離しなかった錠剤の割合が９５％未満 (Evaluation methods)
With reference to the “Tablet friability test method” described in the reference information of the 16th revision Japanese Pharmacopoeia, the number of tablets corresponding to an amount as close as possible to 6.5 g of the tablets produced as described above is placed in a drum. The rotation was performed 300 times at a rotation number of 25 rpm. After the completion of rotation, the mass percentage of the tablets that did not delaminate relative to the initial mass was calculated. This mass percentage was evaluated based on the following evaluation criteria.
○: The proportion of tablets that did not delaminate was 95% or more. ×: The proportion of tablets that did not delaminate was less than 95%.
　（評価結果）
　各試料番号に対する評価結果を表２に示す。表２に示すように、第一打錠圧が１．４ｋＮ以上の場合には、第二打錠圧の大きさに関わらず評価基準を満足しなかった。第一打錠圧が１．０～１．２ｋＮの場合には、第二打錠圧の大きさに応じて層間剥離の程度が変化した。第一打錠圧が０．８ｋＮ以下の場合には、第二打錠圧の大きさに関わらず評価基準を満足した。 (Evaluation results)
The evaluation results for each sample number are shown in Table 2. As shown in Table 2, when the first tableting pressure was 1.4 kN or more, the evaluation criteria were not satisfied regardless of the magnitude of the second tableting pressure. When the first tableting pressure was 1.0 to 1.2 kN, the degree of delamination varied depending on the magnitude of the second tableting pressure. When the first tableting pressure was 0.8 kN or less, the evaluation criteria were satisfied regardless of the magnitude of the second tableting pressure.
　なお、第一打錠圧が０ｋＮの場合は、第一層粉末を圧縮成形しないまま第二層粉末を重ねるため、二層錠において第一層と第二層との間の層境界面が乱れてしまう。これは外観上好ましくないため、この条件は製造条件として不適である。また、第二打錠圧は、打錠機の杵の耐圧許容限界により２６ｋＮが上限である。 In addition, when the first tableting pressure is 0 kN, the second layer powder is stacked without compressing the first layer powder, so that the layer interface between the first layer and the second layer is disturbed in the two-layer tablet. End up. Since this is not preferable in appearance, this condition is not suitable as a manufacturing condition. The upper limit of the second tableting pressure is 26 kN due to the allowable pressure limit of the punch of the tableting machine.
　以上の結果より、適切な打錠圧の範囲として、第一打錠圧は０．２～１．２ｋＮ、第二打錠圧は５～２６ｋＮ、第三打錠圧は１８．５ｋＮである。 From the above results, as the appropriate tableting pressure range, the first tableting pressure is 0.2 to 1.2 kN, the second tableting pressure is 5 to 26 kN, and the third tableting pressure is 18.5 kN.
　〔実施例２〕
　本実施例では、第二打錠圧および第三打錠圧の大きさを変え、摩損度を指標として、層間剥離が低減できる第二打錠圧および第三打錠圧の範囲を検討した。 [Example 2]
In the present example, the range of the second tableting pressure and the third tableting pressure that can reduce delamination was examined by changing the magnitudes of the second tableting pressure and the third tableting pressure and using the friability as an index.
　（試料の形成手順）
　第二打錠圧および第三打錠圧の大きさを変えて、試料番号Ｂ１～Ｂ７の口腔内貼付剤の錠剤を製造した。まず、薬物層について、表３に示す各成分をそれぞれの配合割合に基づいて秤量し、混合して、第一層粉末とした。同様に、付着層について、表３に示す各成分をそれぞれの配合割合に基づいて秤量し、混合して、第二層粉末とした。第一層粉末および第二層粉末を打錠機にセットし、図１に示す工程により打錠を行った。 (Sample formation procedure)
Varying tablet pressures of the second tableting pressure and third tableting pressure were changed to produce tablets for oral patch of sample numbers B1 to B7. First, for the drug layer, each component shown in Table 3 was weighed based on the blending ratio and mixed to obtain a first layer powder. Similarly, with respect to the adhesion layer, each component shown in Table 3 was weighed based on the blending ratio and mixed to obtain a second layer powder. The first layer powder and the second layer powder were set in a tableting machine, and tableting was performed by the process shown in FIG.
　まず、第一層粉末８０ｍｇを臼内に充填し、１．０ｋＮの第一打錠圧で圧縮し、薬物層を成形した。なお、第一打錠圧は、試料番号に関わらず一定である。次に、第二層粉末４０ｍｇを臼内に充填し、表４に示す各試料番号の第二打錠圧で圧縮し、付着層を成形した。そして、薬物層および付着層を表４に示す各試料番号の第三打錠圧で圧縮した。これにより、直径８ｍｍ、薬物層の厚さ１．３ｍｍ、および付着層の厚さ０．６ｍｍである二層からなる口腔内貼付剤の錠剤（試料番号Ｂ１～Ｂ７）を製造した。 First, 80 mg of the first layer powder was filled in the die and compressed with a first tableting pressure of 1.0 kN to form a drug layer. The first tableting pressure is constant regardless of the sample number. Next, 40 mg of the second layer powder was filled into the mortar and compressed with the second tableting pressure of each sample number shown in Table 4 to form an adhesion layer. Then, the drug layer and the adhesive layer were compressed with the third tableting pressure of each sample number shown in Table 4. This produced tablets (sample numbers B1 to B7) of the oral patch consisting of two layers having a diameter of 8 mm, a drug layer thickness of 1.3 mm, and an adhesive layer thickness of 0.6 mm.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　（評価方法）
　第十六改正日本薬局方の参考情報に記載された「錠剤の摩損度試験法」に準じて摩損度（初期質量に対する減少質量の質量百分率）を測定した。摩損度を指標として、層間剥離を、次の評価基準に基づいて評価した。
　　○：摩損度が３．０％以下
　　×：摩損度が３．０％を超える (Evaluation methods)
The friability (mass percentage of reduced mass with respect to the initial mass) was measured according to the “Tablet friability test method” described in the reference information of the 16th revision Japanese Pharmacopoeia. Using the friability as an index, delamination was evaluated based on the following evaluation criteria.
○: Abrasion degree is 3.0% or less ×: Abrasion degree exceeds 3.0%
　（評価結果）
　各試料番号に対する評価結果を表４に示す。表４に示すように、第二打錠圧および第三打錠圧が大きいほど層間剥離が低減した。なお、第二打錠圧および第三打錠圧は、打錠機の杵の耐圧許容限界により２６ｋＮが上限である。 (Evaluation results)
The evaluation results for each sample number are shown in Table 4. As shown in Table 4, delamination was reduced as the second tableting pressure and the third tableting pressure were increased. Note that the upper limit of the second tableting pressure and the third tableting pressure is 26 kN due to the allowable pressure limit of the punch of the tableting machine.
　以上の結果より、適切な打錠圧の範囲として、第一打錠圧は１．０ｋＮ、第二打錠圧は６．０～２６ｋＮ、第三打錠圧は７．５～２６ｋＮである。 From the above results, as the appropriate tableting pressure range, the first tableting pressure is 1.0 kN, the second tableting pressure is 6.0 to 26 kN, and the third tableting pressure is 7.5 to 26 kN.
　上述した実施例１および実施例２の結果より、適切な打錠圧の範囲として、第一打錠圧は０．２～１．２ｋＮ、第二打錠圧は６．０～２６ｋＮ、第三打錠圧は７．５～２６ｋＮである。 From the results of Example 1 and Example 2 described above, as the appropriate tableting pressure range, the first tableting pressure is 0.2 to 1.2 kN, the second tableting pressure is 6.0 to 26 kN, and the third The tableting pressure is 7.5 to 26 kN.
　また、上述した実施例１および実施例２において製造した錠剤は、直径が８ｍｍで厚さが１．９ｍｍ（薬物層の厚さ１．３ｍｍおよび付着層の厚さ０．６ｍｍの和）である。このように厚さに対して直径が４倍以上ある薄い円盤状の二層錠であっても、上述した実施形態に係る口腔内貼付剤の製造方法を適用して、層間剥離が生じにくい錠剤を好適に製造することができる。 Further, the tablets produced in Example 1 and Example 2 described above have a diameter of 8 mm and a thickness of 1.9 mm (the sum of the drug layer thickness of 1.3 mm and the adhesive layer thickness of 0.6 mm). . In this way, even if it is a thin disc-shaped bilayer tablet having a diameter of 4 times or more with respect to the thickness, it is difficult to cause delamination by applying the method for producing an oral patch according to the above-described embodiment. Can be suitably manufactured.
　以上、本発明の好ましい実施形態を説明したが、本発明はこれら実施形態に限定されることはない。本発明の趣旨を逸脱しない範囲で、構成の付加、省略、置換、およびその他の変更が可能である。 The preferred embodiments of the present invention have been described above, but the present invention is not limited to these embodiments. Additions, omissions, substitutions, and other modifications can be made without departing from the spirit of the present invention.
　上記実施形態に係る口腔内貼付剤の製造方法によれば、薬物層と付着層との間の層間剥離の発生を低減することができる。 According to the method for producing an intraoral patch according to the above embodiment, it is possible to reduce the occurrence of delamination between the drug layer and the adhesive layer.
　１　打錠機
　２　臼
　３　上杵
　４　下杵
　１０　第一層粉末
　１１　薬物層
　２０　第二層粉末
　２１　付着層
　３０　口腔内貼付剤 DESCRIPTION OF SYMBOLS 1 Tableting machine 2 Dice 3 Upper punch 4 Lower punch 10 First layer powder 11 Drug layer 20 Second layer powder 21 Adhesive layer 30 Oral patch

Claims (2)

  1. 　ヒドロキシアルキルアルキルセルロース、ヒドロキシプロピルセルロース、カルボキシアルキルセルロースナトリウム、エチルセルロース、硬化ヒマシ油、およびショ糖脂肪酸エステルからなる群より選ばれる少なくとも一つからなる薬物放出制御剤を含有する薬物層と、付着剤として、カルボキシアルキルセルロースまたはカルボキシアルキルセルロース塩と、ポリビニルピロリドンとを含有する付着層と、を備える口腔内貼付剤の製造方法であって、
    　前記薬物層を構成する第一層粉末を打錠機の臼内に充填し、
    　前記第一層粉末を０．２～１．２ｋＮの打錠圧で圧縮して前記薬物層を成形し、
    　前記付着層を構成する第二層粉末を前記臼内の前記薬物層の上に充填し、
    　前記薬物層および前記第二層粉末を６．０～２６ｋＮの打錠圧で圧縮して前記付着層を成形し、
    　前記薬物層および前記付着層を７．５～２６ｋＮの打錠圧で圧縮する
    　口腔内貼付剤の製造方法。     A drug layer containing a drug release control agent consisting of at least one selected from the group consisting of hydroxyalkylalkylcellulose, hydroxypropylcellulose, sodium carboxyalkylcellulose, ethylcellulose, hydrogenated castor oil, and sucrose fatty acid ester, and an adhesive An adhesive layer containing a carboxyalkyl cellulose or a carboxyalkyl cellulose salt and polyvinylpyrrolidone, and a method for producing an oral patch,
    Fill the first layer powder constituting the drug layer in the die of the tablet machine,
    The first layer powder is compressed with a tableting pressure of 0.2 to 1.2 kN to form the drug layer,
    Filling the drug layer in the die with the second layer powder constituting the adhesion layer,
    The adhesive layer is formed by compressing the drug layer and the second layer powder with a tableting pressure of 6.0 to 26 kN,
    A method for producing an intraoral patch, wherein the drug layer and the adhesive layer are compressed with a tableting pressure of 7.5 to 26 kN.
  2. 　請求項１に記載の口腔内貼付剤の製造方法であって、
    　前記薬物層および前記付着層が７．５～２６ｋＮの打錠圧で圧縮された前記口腔内貼付剤の直径は、前記口腔内貼付剤の厚さの４倍以上である
    　口腔内貼付剤の製造方法。     A method for producing an intraoral patch according to claim 1,
    The diameter of the intraoral patch in which the drug layer and the adhesive layer are compressed with a tableting pressure of 7.5 to 26 kN is 4 times or more the thickness of the oral patch. Production of an oral patch Method.
PCT/JP2017/006633 2016-02-25 2017-02-22 Method for producing oral cavity patch WO2017146106A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006527184A (en) * 2003-06-06 2006-11-30 エティファーム Orally dispersible multilayer tablets
WO2014192918A1 (en) * 2013-05-31 2014-12-04 久光製薬株式会社 Oral cavity patch

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006527184A (en) * 2003-06-06 2006-11-30 エティファーム Orally dispersible multilayer tablets
WO2014192918A1 (en) * 2013-05-31 2014-12-04 久光製薬株式会社 Oral cavity patch

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