JP5466379B2 - Film-form preparation and method for producing film-form preparation - Google Patents

Description

  The present invention relates to a film-form preparation and a method for producing the film-form preparation, and particularly to a film-form preparation containing a drug for oral administration and a production method suitable for the production of the film-form preparation.

  In recent years, with the progress of aging, the number of people who have difficulty swallowing tends to increase. Therefore, there is a strong demand for the development of a preparation that can orally administer drug components to patients who are difficult to swallow the drug. Therefore, the present inventors have advanced research and development on a film-form preparation in which a drug component is contained in an edible film, and have made a proposal. The film-like preparation proposed by the present inventors rapidly disintegrates or dissolves in the oral cavity, and has a practical strength with no handling problems, so that the swallowing function is reduced due to aging or disease. In addition, it is a preparation that is easy to take for people with low swallowing function such as children.

  The invention relating to the above film-form preparation does not fall under the literature known invention because it is before publication of the application.

  However, rapid disintegration or dissolution in the oral cavity is a necessary characteristic for a preparation that can be easily taken by persons with difficulty in swallowing, but when the taste or smell of the drug component is bad, There was a risk that the taste and smell spread quickly inside, making it difficult to take. In addition, even when the drug component is irritating, there is a risk of discomfort such as numbness of the tongue accompanying disintegration or dissolution of the film-form preparation in the oral cavity.

  Accordingly, in view of the above circumstances, the present invention has a problem of providing a film-form preparation in which the perception of the taste, smell, and irritation of the drug component is suppressed, and a production method suitable for the production of the film-form preparation. To do.

  In order to solve the above-mentioned problems, the film-form preparation according to the present invention has the following: “on the surface of a powder matrix containing a drug component for oral administration, gold, silver, platinum, aluminum, copper, titanium, magnesium, silicon, oxidation Silicon, aluminum oxide, titanium oxide, magnesium oxide, cellulose, collagen, zein, shellac, agar, high molecular starch, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxy A powdered formulation with a vapor-deposited coating layer deposited with at least one selected from propylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate is formed into a film with an edible water-soluble film-forming agent The film is contained in the substrate "is intended.

  The “drug component” is not particularly limited as long as it is for oral administration, but those having a bad taste, those having a strong odor, and those having an irritation are highly significant in applying the present invention. For example, diphenhydramine hydrochloride with strong bitterness and irritation, alum with bitter taste, quinine, acetaminophen, epinastine, clarithromycin, strong odor L-methionine, L-ethylcysteine hydrochloride, irritation ibuprofen, bisacodyl Can do.

  The “powder matrix containing a drug component” is a matrix of a powdery formulation, and refers to a formulation referred to as “Powders” in the Japanese Pharmacopoeia. According to the 15th revision Japanese Pharmacopoeia, "powder" is a powder or finely divided preparation by adding the drug component as it is or by adding additives such as excipients, binders, and disintegrants to the drug component, In the particle size test, it is defined as a preparation that passes through the entire size of No. 18 sieve (850 μm) and remains in No. 30 sieve (500 μm) at 5% or less of the total. In the Japanese Pharmacopoeia, “Granules” made of pharmaceuticals in granular form pass through the entire No. 10 sieve (1700 μm), and the remaining amount on the No. 12 sieve (1400 μm) is 15% or less of the total quantity There is a distinction between powder and granule by defining that the product passing through No. 42 sieve (355 μm) is 15% or less of the total amount. In the present invention, since the “powder preparation” is contained in the “film preparation”, the particle diameter of the “powder matrix” is limited by the thickness of the film substrate. Therefore, the “powder base” of the present invention has a small particle size as described later among the preparations classified as “powder” in the Japanese Pharmacopoeia.

  The “deposition coating layer” can be formed by physical vapor deposition (PVD) such as vacuum vapor deposition, ion plating, sputtering, or chemical vapor deposition (CVD). The deposited film layer is formed “on the surface of the powder matrix”, but is not a requirement until it is formed so as to cover the entire surface of the powder matrix. This is because it is difficult to completely prevent the adjacent powder bases from overlapping each other during vapor deposition, and thus it is impractical to completely cover the surface of the powder base with the vapor deposition coating layer.

  "Gold, silver, platinum, aluminum, copper, titanium, magnesium, silicon, silicon oxide, aluminum oxide, titanium oxide, magnesium oxide, cellulose, collagen, zein, shellac, agar, high molecular starch, polyvinyl acetal diethylaminoacetate, aminoalkyl "Methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate" are all substances that are permitted to be added to foods or preparations for oral administration. It is. In addition, all of these substances are insoluble or sparingly soluble in water.

  Examples of the “edible water-soluble film forming agent” include sodium caseinate, gelatin, soy protein, starch, pectin, arabinoxylan, soy polysaccharide, sodium alginate, carrageenan, glucomannan, xanthan gum, pullulan, dextrin, hypromellose (HPMC). Old Japanese Pharmacopoeia “hydroxypropylmethylcellulose”), hydroxypropylcellulose (HPC), water-soluble hydroxyethylcellulose (HEC), methylcellulose (MC), carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), sodium polyacrylate, Polyacrylamide (PAA), polyethylene oxide (PEO), polyethylene glycol (PEG) and the like can be used. Further, a plurality of types of film forming agents can be appropriately blended and used.

  In addition to the edible water-soluble film forming agent, the film substrate can contain other components. For example, by adding triethyl citrate, glycerin, sorbitol, triacetin, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate, macrogol, glyceryl monostearate, mannitol, etc. as a plasticizer In addition, the flexibility of the film substrate can be increased and the occurrence of cracks and tears can be prevented.

  If the thickness of the film substrate is 50 to 100 μm, it is easy to disintegrate or dissolve in the oral cavity and is not bulky in the oral cavity. In addition, if the particle size of the powder preparation contained in the film base is too large, it is difficult to stably hold the powder preparation in the film base, so the particle diameter (diameter) of the powder preparation is the thickness of the film base. The thickness is desirably 3/4 or less of the thickness, and more desirably 1/2 or less of the thickness of the film substrate.

  According to the above configuration, according to the present invention, the film substrate formed of the water-soluble film forming agent is easily disintegrated or dissolved in the oral cavity, while the powdered preparation contained in the film substrate is not dissolved in water. By forming an insoluble or hardly soluble vapor deposition film layer, elution of the drug component into the oral cavity is suppressed. Therefore, even if the film substrate is disintegrated or dissolved by moisture in the oral cavity, it is difficult to feel the taste, smell and irritation of the drug component in the oral cavity. Thereby, even a drug component having a strong taste, smell, or irritation can be contained in a film-form preparation that is easily disintegrated or dissolved in the oral cavity and orally administered to a person with difficulty in swallowing.

  In addition, if the drug component elutes in the oral cavity, the drug component may be absorbed from the mucous membrane in the oral cavity, and depending on the type of drug component, the medicinal effect appears too early compared to when absorbed in the stomach or intestine There was a concern. In contrast, in the present invention, since the elution of the drug component in the oral cavity is suppressed by the vapor deposition film layer, the drug component is absorbed from the oral mucosa even if the film substrate is disintegrated or dissolved by moisture in the oral cavity. It is possible to prevent the possibility that the medicinal effect will appear too early.

  Further, since the coating layer made of a substance insoluble or hardly soluble in water is formed by vapor deposition, even a fine powder matrix has good film forming properties. Further, in the vapor deposition, the film thickness can be easily controlled by the vapor deposition time, so that the vapor deposition film layer can be a thin film as much as necessary and sufficient for obtaining the above-described effects. For example, the film thickness of a vapor deposition film layer can be 0.5-5 micrometers.

  In addition, metals such as gold, silver, and platinum, and metal oxides such as aluminum oxide and titanium oxide are excellent in light resistance. Therefore, when a vapor-deposited film layer is formed with these materials, the deterioration of drug components due to light is suppressed. Preparation. Thereby, for example, a drug component unstable to light such as mecobalamin can be stably contained in the preparation.

  In addition, since polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer E are gastric soluble, when a vapor-deposited film layer is formed with these substances, the film-form preparation itself may rapidly disintegrate or dissolve in the oral cavity, It can be set as the formulation which absorbs a drug component from the stomach. On the other hand, since the methacrylic acid copolymer L, the methacrylic acid copolymer LD, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate are enteric, when a vapor-deposited film layer is formed with these substances, the film-form preparation itself is Even if it rapidly disintegrates or dissolves in the oral cavity, it can be made into a preparation that absorbs the drug component from the intestine.

  By the way, in order to suppress the perception of the taste, smell, and irritation of the drug component, the film-form preparation has a laminated structure of a plurality of films, and the layer containing the drug component is made difficult to feel the taste, smell, and irritation of the drug component. It can also be envisaged to cover with a masking layer for the purpose. However, in that case, since the entire preparation is thickened by the provision of the masking layer, the thickness of the layer containing the drug component is limited in consideration of ease of taking. Therefore, the content of the drug component in one film-form preparation is small, and the number of film-form preparations to be taken as a single dose increases. On the other hand, in the present invention, the powder matrix containing the drug component is coated with the vapor deposition film layer, so that the taste and smell of the drug component are masked in units of powder. Therefore, it is not necessary to laminate a film-like masking layer as described above, and a film-form preparation can be composed of only a drug-containing layer, so that the content of the drug component in one film can be increased. It becomes possible. Thereby, in order to take a single dose of the drug component, the number of film-form preparations to be taken can be reduced. Alternatively, even if the size (thickness, length and width) of the film-form preparation is reduced, a sufficient amount of the drug component can be taken, and the film-form preparation is not bulky in the oral cavity and is easier to take. Become.

  Next, the method for producing a film-form preparation according to the present invention is described as follows: “On the surface of a powder matrix containing a drug component for oral administration, gold, silver, platinum, aluminum, copper, titanium, magnesium, silicon, silicon oxide, Aluminum oxide, titanium oxide, magnesium oxide, cellulose, collagen, zein, shellac, agar, high molecular starch, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropyl methylcellulose A vapor deposition step in which at least one selected from phthalate and hydroxypropylmethylcellulose acetate succinate is vapor-deposited to form a powdery formulation with a vapor-deposited film layer, and the powdery formulation is an edible water-soluble film forming agent A suspension preparation step for preparing a suspension suspended in an aqueous solution, and a film formation step for forming a film-form preparation by casting the suspension on a base surface and drying to form a film. "".

  With the above configuration, the present invention produces a powdery formulation in which a vapor-deposited coating layer insoluble or hardly soluble in water is formed on the surface of the powder matrix, and the powdery formulation is further contained in a water-soluble film substrate. It is suitable as a method for producing a film-form preparation, and a film-form preparation having the above-mentioned excellent effects can be produced.

  As described above, as an effect of the present invention, it is possible to provide a film-form preparation in which the perception of the taste, smell, and irritation of the drug component is suppressed, and a production method suitable for producing the film-form preparation.

  Hereinafter, a film-form preparation that is the best embodiment of the present invention and a method for producing the film-form preparation will be described with reference to FIGS. 1 to 3. Here, FIG. 1 (a) is a cross-sectional view schematically showing the configuration of the film-form preparation of the present embodiment, FIG. 1 (b) is an enlarged view of the range A in FIG. 1 (a), and FIG. FIG. 3 is a cross-sectional view schematically showing a configuration of a powdery preparation contained in the film-form preparation of FIG. 1, and FIG. 3 is a process diagram showing a method for producing the film-form preparation of FIG.

  As shown in FIG. 1 (a), the film-form preparation 1 of the present embodiment was contained in a film base 2 formed into a film form using an edible water-soluble film-forming agent as a main raw material, and the film base 2 A powdery preparation 10. Here, as shown in FIG. 1B and FIG. 2, the powder preparation 10 includes a powder matrix 11 containing a drug component, and a vapor-deposited coating layer 12 formed on the surface of the powder matrix 11 by vapor deposition. It has.

  Note that FIG. 1B is a schematic illustration, but the powder preparation 10 is monodispersed in the film substrate 2, but actually a plurality of particles are aggregated and dispersed. There is also.

  As shown in FIG. 3, the manufacturing method of the film-form preparation 1 of this embodiment includes a deposition step S1 in which a vapor-deposited coating layer is formed on the surface of a powder matrix containing a drug component to form a powder-form preparation, and the powder-form preparation comprises A suspension preparation step S2 for preparing a suspension suspended in an aqueous solution of an edible water-soluble film forming agent, a casting step S3 for casting the suspension on a base surface, and a suspended suspension It comprises a drying step S4 for drying the turbid liquid, and includes a film forming step for forming a suspension into a film to obtain a film-like preparation, and a peeling step S5 for peeling the film-like preparation from the base surface.

  If it demonstrates in detail, in this embodiment, vapor deposition process S1 is performed by sputtering. For sputtering, for example, a rotating barrel type sputtering apparatus (not shown) can be used.

  Further, in the sputtering apparatus, a flow path for allowing the powder matrix to flow along the inner peripheral surface of the rotating barrel is formed. Therefore, by storing the powder matrix containing the drug component in this flow path and rotating the roller that supports the rotating barrel, the powder matrix flows in the flow path as the rotating barrel rotates, and the fluidized bed Form. When a high voltage is applied between the sputtering source and the flow path, the inside of the rotating barrel is decompressed and argon gas is introduced, the atoms knocked out of the sputtering source by the collision of the generated plasma reach the flow path, and the powder base A vapor deposition film layer is formed on the surface. At this time, since the fluidized bed of the powder matrix is formed in the flow path, uneven formation of the deposited film layer is reduced. In addition, a vapor deposition film layer can be formed in the thickness of 0.5-5 micrometers.

  Here, when the thickness of the film-form preparation is about 100 μm and the vapor-deposited film layer having the above thickness is formed, the particle diameter of the powder-form preparation is set to 70 μm or less, preferably 45 μm or less. Can be 3/4 or less of the thickness of a film-form preparation, desirably 1/2 or less. In addition, when the thickness of the film-form preparation is about 50 μm and the deposited film layer having the above thickness is formed, if the particle diameter of the powder base is 32 μm or less, preferably 20 μm or less, the particle diameter of the powder-form preparation is The thickness of the film-form preparation can be 3/4 or less, desirably 1/2 or less. In addition, when the particle diameter of the powder base is too small, it becomes difficult to handle in the vapor deposition step S1 and the like, so the particle diameter of the powder base is desirably 5 μm or more.

  In the suspension preparation step S2, an aqueous solution of an edible water-soluble film forming agent, a liquid in which additives such as a disintegrant and a plasticizer are dissolved or dispersed in water or an organic solvent, and a vapor deposition film in the vapor deposition step S1 The powdery preparation with the layer formed is mixed to prepare a suspension in which the powdery preparation is sufficiently dispersed. In this step, heat treatment or defoaming treatment can be appropriately performed as necessary.

  In the casting step S3, the prepared suspension is uniformly coated on a base surface on which a base film (PP, made of PET) is fixed on a smooth plane. Since the thickness of the film depends on the concentration, viscosity, and coating speed of the suspension, the film thickness is appropriately adjusted so as to obtain a desired thickness. In the drying step 4, the suspension coated on the base film is dried in a hot air drier maintained at a predetermined temperature.

  And if a base film is peeled in peeling process S5, the film-form formulation containing the powdery formulation in which the vapor deposition film layer was formed can be obtained.

  As described above, according to the film-form preparation of the present embodiment, a film substrate mainly composed of an edible water-soluble film-forming agent is easily disintegrated or dissolved in the oral cavity, but is contained in the film substrate. The powdered preparation has a vapor-deposited film layer formed of a metal that is hardly soluble in water. As a result, elution of the drug component contained in the powdered preparation is suppressed in the oral cavity, and even if the film substrate is disintegrated or dissolved by moisture in the oral cavity, the taste, smell, and irritation of the drug component are felt in the oral cavity. In addition to being difficult, it is possible to prevent the drug component from being absorbed from the oral mucosa and causing the drug effect to appear too quickly.

  In addition, since the taste and odor of drug components are masked in powder units by a thin vapor-deposited coating layer, the film-form preparation is contained in a single film compared to the case where a masking layer is provided as a laminated structure of multiple films. The content of the drug component can be increased.

  Moreover, in this embodiment, since the vapor deposition film layer is formed by sputtering using a rotating barrel, a thin vapor deposition film layer with less unevenness is formed. Thereby, compared with the case where a vapor deposition film layer is formed thickly, the volume of one powdery formulation becomes small, and it becomes possible to make a film-form formulation contain many powdery formulations. That is, even if the size of the film-form preparation is reduced or the number of sheets taken at one time is reduced, it becomes easy to ingest necessary drug components as a single dose.

The powder base obtained by pulverizing the powder of acetaminophen was subjected to silver sputtering under the following conditions using a rotating barrel type sputtering apparatus to obtain a powdery formulation in which a silver deposited film layer was formed.
Degree of vacuum: 0.8Pa
Output: 0.5kW
Sputtering time: 520 seconds

  When the obtained powdery preparation was taken as it was, the bitterness peculiar to acetaminophen was hardly felt in the oral cavity. Moreover, the film-form preparation was manufactured as follows using this powder-form preparation.

First, an aqueous solution of HPMC as a water-soluble film forming agent, a crystalline cellulose as a disintegrant, and a solution in which other components are dissolved or dispersed in water or an organic solvent, and a shear-milled L -A 5 wt% aqueous dispersion of HPC (low-substituted hydroxypropyl cellulose) was mixed and defoamed to obtain the following formulation to prepare a suspension. Next, the prepared suspension was uniformly coated on a base film (PP, made of PET) fixed on a smooth plane, dried with warm air to form a film, and then peeled off from the base film. The thickness of the obtained film-form preparation was about 50 μm.
Powder formulation: 10% by mass
HPMC: 8.5% by mass
Crystalline cellulose: 63.2% by mass
L-HPC: 3.0% by mass
Other: 15.3 mass%

  In addition, the ratio of each component in said prescription is the weight% with respect to the total weight of a film-form preparation, and is a numerical value as solid content. Also, as HPMC, Metrows (trade name) 60SH-50 manufactured by Shin-Etsu Chemical Co., Ltd., Asahi Kasei's Ceraos (trade name) as crystalline cellulose, and L-HPC as L with a molar substitution degree of 0.3 -HPC (Shin-Etsu Chemical LH-21) was used.

  When the film-form preparation was cut into a size of about 2 cm × about 3 cm and taken by several subjects, the film-form preparation dissolved rapidly in the oral cavity from all the subjects, but almost no bitterness was felt. The answer was obtained.

  The present invention has been described with reference to the preferred embodiments. However, the present invention is not limited to the above-described embodiments, and various improvements can be made without departing from the scope of the present invention as described below. And design changes are possible.

  For example, in the above embodiment, the case where the vapor deposition film layer is made of metal is exemplified, but the present invention is not limited to this. For example, gastric organic compounds such as polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer E, or enteric properties such as methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, etc. A vapor-deposited film layer can also be comprised with these organic compounds. When a film-form preparation comprising such a deposited film layer is contained in a film-form preparation, the drug component remains in the stomach even if the film substrate formed of the water-soluble film-forming agent disintegrates or dissolves rapidly in the oral cavity. Or it can be absorbed from the intestine.

(A) It is sectional drawing which shows the structure of the film-form preparation of this embodiment typically, (b) It is an enlarged view of A range. It is sectional drawing which shows typically the structure of the powdery formulation contained in the film-form preparation of FIG. It is process drawing which shows the manufacturing method of the film-form formulation of FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Film-form preparation 2 Film base 10 Powder-form preparation 11 Powder base 12 Deposition film layer S1 Deposition process S2 Suspension preparation process S3 Casting process (film formation process)
S4 Drying process (filming process)

Claims (2)

At least one selected from gold, silver, platinum, aluminum, copper, titanium, magnesium, aluminum oxide, titanium oxide, and magnesium oxide is provided on the surface of a powder matrix containing a drug component for oral administration and having a particle size of 5 μm to 32 μm. A film-form preparation characterized in that a powder-form preparation comprising a vapor-deposited film layer is contained in a film substrate formed into a film form having a thickness of 50 to 100 μm with an edible water-soluble film-forming agent. At least one selected from gold, silver, platinum, aluminum, copper, titanium, magnesium, aluminum oxide, titanium oxide, and magnesium oxide on the surface of a powder matrix containing a drug component for oral administration and having a particle size of 5 μm to 32 μm Vapor deposition, a vapor deposition step to form a powdered formulation with a vapor deposition film layer,
A suspension preparation step of preparing a suspension in which the powder preparation is suspended in an aqueous solution of an edible water-soluble film-forming agent;
A film- formation preparation comprising: forming a film-form preparation having a thickness of 50 μm to 100 μm by casting the suspension on a base surface and drying to form a film. Method.

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