JP5674480B2 - Intraoral film-form base and preparation - Google Patents

Description

  The present invention relates to an oral film-form base that dissolves rapidly in the oral cavity, and a preparation containing a drug in the base, and more specifically, fine particles of sugar and sugar alcohol are dispersed in the base. The present invention relates to an oral film-form base and a preparation in which a drug is well absorbed by a digestive organ or oral mucosa by being rapidly dissolved in the oral cavity.

  Currently, as pharmaceuticals to be applied orally, solid preparations such as naked tablets, coated tablets, capsules, powders, granules, and liquid preparations such as liquid preparations and emulsions have been put on the market. As preparations that disintegrate in the oral cavity and are absorbed in the digestive tract, orally disintegrating tablets and fast-dissolving oral film-form preparations are already on the market.

  Over 10 products of over-the-counter (OTC) have already been sold overseas as film, tape or sheet preparations that can be applied to the oral cavity and taken up by saliva without being chewed. In Japan, one product is sold as an ethical drug and is also sold as an over-the-counter drug.

  Regarding such a film-form preparation, hydroxypropylcellulose or a mixture of hydroxypropylcellulose and polyvinylpyrrolidone, a preparation base obtained by dissolving a tannin substance in a solvent and then removing the solvent (Patent Document 1), water-soluble And a coating layer (a) comprising a non-water-absorbing polysaccharide and a softening agent, a drug layer (b) comprising a drug and an edible water-soluble polymer, a drug layer comprising a drug, an edible water-soluble polymer and a tannin substance ( a film-like troche obtained by laminating c) in the order of a, b, c, b and a (Patent Document 2), a drug and an edible polymer substance, and the breaking strength of the film is 200 to 3000 g / φ7 mm The film has a tensile strength of 200 to 3000 g / 15 mm and dissolves in the oral cavity within 60 seconds (patent text) 3) An oral film preparation (patent document 4) characterized by blending either pregelatinized starch and / or pullulan, enzyme-modified starch and plasticizer, water-soluble less than about 1 g / 4 mL at room temperature A soluble film preparation (Patent Document 5) containing an active ingredient having a property and having a water content of less than about 15% by weight, a drug, an edible water-soluble film-forming agent, and a molar substitution degree from 0.05 A technique such as a film-form preparation (Patent Document 6) characterized by containing 1.0 low-substituted hydroxypropylcellulose is disclosed. In addition, as a rapidly soluble preparation that rapidly disintegrates and dissolves in the oral cavity or the like, a technique is disclosed in which a drug, a saccharide, and polyvinylpyrrolidone are dissolved or dispersed in an organic solvent and then removed by removing the organic solvent ( Patent Document 7).

However, the film-form bases and preparations disclosed so far are those in which a drug is dispersed or dissolved in a water-soluble polymer, and sugar and sugar alcohol blends have also been reported (Patent Document 3, In Patent Document 4), sugars and sugar alcohols are used in a state where they are dissolved in a solvent or recrystallized. Therefore, conventional oral film-form bases or preparations have a sticky feeling caused by a water-soluble polymer when applied to the oral cavity, and stickiness is also a problem when touched by fingers. It was. Also, Patent Document 7 relating to a rapid-dissolving preparation does not show a technique for dispersing saccharide fine particles, and does not show a film-form preparation.
JP-A-7-189933 JP 2001-288074 A JP 2004-43450 A JP-A-2005-21124 Special table 2007-528876 gazette JP 2008-169138 A JP 11-116465 A

  Therefore, in the present invention, it has a rapid dissolution profile in the oral cavity and sufficient film strength, and further, the feeling of stickiness due to the water-soluble polymer in the oral cavity is reduced, and the tactile sensation when taken on the fingers is also improved. The object was to obtain an intraoral film-like base and preparation.

  As a result of intensive studies to solve the above problems, the present inventors have found that an edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more, and a sugar and a sugar alcohol that are not soluble in the organic solvent. Using one or more kinds, a film-form base in which one or more kinds of sugar and sugar alcohol are dispersed in the organic solvent as fine particles is obtained, and a preparation using the same has a rapid dissolution profile and sufficient in the oral cavity. It has been found that the film has a strength and the touch when applied to the oral cavity and the touch when taken on the fingers are improved, and the present invention has been completed.

That is, the present invention relates to the following [1] to [10].
[1] One or more edible polymers that are soluble in water and an organic solvent having a solubility parameter of 9.7 or more, and monosaccharide to hexasaccharide sugars having an average particle size of 0.1 μm to 60 μm And an edible polymer that contains one or more particles selected from the group consisting of these sugar alcohols and is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is polyvinylpyrrolidone and hydroxy An oral film-form base which is one or more selected from the group consisting of propylcellulose.
[2] The oral film-form base according to [1] above, wherein the average particle size of one or more particles selected from the group consisting of sugar and these sugar alcohols is 0.1 μm to 30 μm. .
[3] The oral film-form base according to the above [1] or [2], wherein the polyvinylpyrrolidone has a weight average molecular weight of 2,500 to 3,000,000.
[4] The oral film-form base according to the above [1] or [2], wherein the hydroxypropylcellulose has a weight average molecular weight of 10,000 to 1,200,000.
[5] The intraoral film-form base according to the above [1], [2] or [4], wherein the hydroxypropyloxy group substitution degree of hydroxypropylcellulose is 50% to 100%.
[6] An intraoral film-form preparation obtained by adding a drug to the film-form base described in any one of [1] to [5] above.
[7] A method for producing an oral film-form base according to [1] above, wherein water and one kind of edible polymer soluble in an organic solvent having a solubility parameter of 9.7 or more Alternatively, two or more types are dissolved, and one or more types of particles selected from the group consisting of monosaccharide to hexasaccharide sugars and sugar alcohols having an average particle diameter of 0.1 μm to 60 μm are dispersed, A thin layer of the obtained dispersion is formed and dried, and the edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose. 1 or 2 types or more, The manufacturing method of an intraoral film-form base characterized by the above-mentioned.
[8] The method for producing an intraoral film-form preparation described in [6] above, wherein the drug, water, and an edible polymer 1 soluble in an organic solvent having a solubility parameter of 9.7 or more Dissolve seeds or two or more kinds, and disperse one or more kinds of particles selected from the group consisting of monosaccharide to hexasaccharide sugars having an average particle diameter of 0.1 μm to 60 μm and sugar alcohols thereof. A thin layer of the obtained dispersion is formed and dried, and the edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose A method for producing an intraoral film-form preparation, wherein the preparation is one or more kinds.
[9] In one part or more of an organic solvent having a solubility parameter of 9.7 or more, water or one or more edible polymers that are soluble in the organic solvent are dissolved, and the solution has an average particle size of One or two or more kinds of particles selected from the group consisting of monosaccharide to hexasaccharide of 0.1 μm to 60 μm and these sugar alcohols were dispersed in the remainder of the organic solvent having a solubility parameter of 9.7 or more. In addition to the mixture, a thin layer of the resulting dispersion is formed and dried, and the edible polymer soluble in water and an organic solvent having a solubility parameter of 9.7 or higher is polyvinylpyrrolidone and hydroxypropyl A method for producing an intraoral film-like base, characterized in that it is one or more selected from the group consisting of cellulose.
[10] Some of the organic solvent solubility parameter is 9.7 or more, the water and organic solvent to dissolve one or more edible polymer that is soluble, the solution solubility parameter 9 .1 or more selected from the group consisting of monosaccharide to hexasaccharide sugars having an average particle size of 0.1 μm to 60 μm and these sugar alcohols , while dissolving or dispersing the drug in the remainder of the organic solvent of 7 or more In addition to the dispersion of two or more kinds of particles , the mixture is mixed, and a thin layer of the resulting dispersion is formed and dried. The edible material is soluble in the above water and an organic solvent having a solubility parameter of 9.7 or more. The method for producing an oral film-form preparation, wherein the polymer is one or more selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose.

  In the oral film-form base and preparation according to the present invention, one or more selected from sugar and sugar alcohol are dispersed in the form of particles, and a rapid dissolution profile in the oral cavity and sufficient film strength Have In addition, the sticky feeling caused by the water-soluble polymer when applied to the oral cavity is reduced, and the characteristics such as touch feeling when picked up by a finger are clearly improved as compared with conventional products. That is, by dispersing one or more selected from sugar and sugar alcohol uniformly in the film in the form of particles, film properties such as tensile strength and bending resistance required as a base and preparation can be obtained. Without loss, it is possible to clearly improve only the properties necessary for improving the dosage of the preparation, such as disintegration in the oral cavity, feel when applied to the oral cavity, and feel of the film.

FIG. 1 is a schematic view showing an embodiment of an intraoral film base and a preparation according to the present invention. FIG. 2 is a schematic diagram showing how the tack duration time is measured. FIG. 3 is a diagram (magnification: 1000 times) showing the surface of the intraoral film-form base of Example 21 of the present invention. FIG. 4 is a diagram (magnification: 1000 times) showing the surface of the oral film-form base of Example 22 of the present invention. FIG. 5 is a diagram (magnification: 500 times) showing the surface of the oral film-form base of Example 23 of the present invention.

Explanation of symbols

1a One or two or more kinds of particles selected from the group consisting of monosaccharide to hexasaccharide sugars and sugar alcohols thereof 1b Edible polymer, or film containing edible polymer and drug 2a probe 2b double-sided tape 2c Test piece 2d Collagen film 2e Rubber 2f Test stand

BEST MODE FOR CARRYING OUT THE INVENTION

  The oral film-form base according to the present invention has one or more edible polymers that are soluble in water and an organic solvent having a solubility parameter of 9.7 or more, and an average particle size of 0.1 μm to 60 μm. 1 type or 2 or more types of particle | grains chosen from the group which consists of the sugar of the monosaccharide-hexasaccharide which are these, and these sugar alcohol. FIG. 1 schematically shows an embodiment of the base, in which one or more particles (1a) of the sugar and sugar alcohol are contained in the film (1b) containing the edible polymer. It is thought that it is in a state of being uniformly dispersed. In the case of an intraoral film-form preparation according to the present invention, one or more particles (1a) of sugar and sugar alcohol are uniformly dispersed in a film (1b) containing an edible polymer and a drug. It is thought that.

  In the present invention, as an edible polymer that is soluble in both water and an organic solvent having a solubility parameter of 9.7 or more, the organic compound having film-forming ability and edible, and in which sugar and sugar alcohol do not dissolve. Any solvent that can be dissolved in a solvent can be used without particular limitation. In the present invention, “edible” means that it can be administered orally and is pharmaceutically acceptable.

  Among them, polyvinylpyrrolidone is sufficiently soluble in water and an organic solvent having a solubility parameter of 9.7 or more, can be rapidly dissolved in the oral cavity, and can be used in production. (Hereinafter referred to as “PVP”) and hydroxypropylcellulose (hereinafter referred to as “HPC”) are preferred. In addition, since the hygroscopic property with respect to relative humidity is lower than HPP and is preferable from a practical viewpoint, HPC is more preferable.

  In the present invention, the PVP used as the edible polymer preferably has a weight average molecular weight of 2,500 to 3,000,000, and more preferably 2,500 to 1,200,000. If the weight average molecular weight is less than 2,500, the stability and hygroscopicity of the resulting base and the preparation may be reduced. Conversely, if it exceeds 3,000,000, the solubility parameter is 9.7 or more. There is a possibility that the solubility in an organic solvent may decrease.

  In addition, the HPC used as the edible polymer in the present invention preferably has a weight average molecular weight of 10,000 to 1,200,000, more preferably 10,000 to 370,000. If the weight average molecular weight is less than 10,000, the stability and hygroscopicity of the resulting base and the preparation may be reduced. Conversely, if it exceeds 1,200,000, the solubility parameter is 9.7 or more. There is a possibility that the solubility in an organic solvent may decrease.

  In addition, the weight average molecular weights of the PVP and HPC can be obtained by gel permeation chromatography analysis.

  The HPC used as the edible polymer in the present invention preferably has a hydroxypropoxy group substitution degree of 50% to 100%. Here, the degree of substitution of the hydroxypropoxy group is a value quantified by the quantification method described in the “Hydroxypropylcellulose” section of the 15th revision Japanese Pharmacopoeia / Pharmaceutical Articles. Furthermore, the thing whose substitution degree of the said hydroxypropoxy group is 53.4% or more is preferable. This is because when the degree of substitution of the hydroxypropoxy group is less than 53.4%, the solubility in water and an organic solvent having a solubility parameter of 9.7 or more may be deteriorated. Further, the upper limit of the hydroxypropoxy substitution degree of HPC used in the present invention is more preferably about 77.5% as defined in the 15th revised Japanese Pharmacopoeia / Pharmaceutical Articles.

  These edible polymers may be used alone or in combination of two or more. As the edible polymer, it is convenient to use a commercially available product provided for pharmaceutical use. It is appropriate that the amount of one or more of these edible polymers is 10 to 80% by weight with respect to the total weight of the oral film base or preparation according to the present invention. It is more preferable to set it to -70 weight%. If the blending amount of the edible polymer is less than 10% by weight, the film becomes brittle and does not exhibit sufficient strength, and if it exceeds 80% by weight, a sticky feeling derived from the polymer in the oral cavity tends to occur. Because.

  In addition to the above edible polymers that are soluble in both water and organic solvents having a solubility parameter of 9.7 or more, edible polymers that are soluble only in water, water and organic solvents. An appropriate amount of edible polymers that do not dissolve can also be used in combination. Examples of such edible polymers include acacia gum, gum arabic, sodium alginate, casein, xanthan gum, guar gum, dextran, tragacanth gum, starch, pullulan, pectin, and other natural products, crystalline cellulose, methylcellulose, ethylcellulose, Semi-synthetic polymer compounds such as carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl starch sodium, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, low-substituted hydroxypropyl cellulose, and synthetic polymer compounds such as polyvinyl alcohol and carboxyvinyl polymer A commercially available product that is provided for pharmaceuticals can be used.

  In the present invention, edible polymers soluble in both water and organic solvents having a solubility parameter of 9.7 or more, monosaccharide to hexasaccharide sugars and particles of these sugar alcohols as shown below Is used.

  Examples of monosaccharides include aldoterose such as erythrose and throse, ribose, lyxose, aldose pentose such as xylose and arabinose, allose, talose, gulose, glucose, altrose, mannose, galactose, idose and other aldohexoses, erythrulose Keto pentose such as ketotetrose, xylulose and ribulose, ketohexose such as psicose, fructose, sorbose and tagatose. Disaccharides include α-diglucosides such as trehalose, cordobiose, nigerose, maltose, isomaltose, β-diglucosides such as isotrehalose, sophorose, laminaribiose, cellobiose, gentiobiose, and α, β-diglucosides such as neotrehalose. , Lactose, sucrose, isomaltulose (palatinose) and the like. Examples of trisaccharides include raffinose. Examples of trisaccharide to hexasaccharide oligosaccharides include fructooligosaccharide, galactooligosaccharide, xylo-oligosaccharide, isomaltoligosaccharide, chitin oligosaccharide, chitosan oligosaccharide, oligoglucosamine, and cyclodextrin. And cyclic oligosaccharides.

  Examples of monosaccharide sugar alcohols include tetritols such as erythritol, D-threitol, and L-threitol, pentitols such as D-arabinitol and xylitol, D-idinol, galactitol (dulcitol), D-glucitol (sorbitol), mannitol, and the like. And cyclitols such as hexitol and inositol. Examples of disaccharide sugar alcohols include maltitol, lactitol, and reduced palatinose (isomalt), and examples of oligosaccharides include pentaerythritol and reduced maltose starch syrup.

  From the viewpoint of imparting easy solubility in the oral cavity to the base and the preparation, monosaccharides to trisaccharides and sugar alcohols thereof are preferably used. Furthermore, lactose, erythritol, xylitol, mannitol, and reduced palatinose (isomalt) having low hygroscopicity are more preferable. In the present invention, one or more of the above-mentioned monosaccharide to hexasaccharide sugars and these sugar alcohols are selected and used.

  In this invention, what contains the particle | grains which have an average particle diameter of 0.1 micrometer-60 micrometers is used as 1 type (s) or 2 or more types selected from said monosaccharide-hexasaccharide sugar and these sugar alcohol. As said saccharide | sugar and sugar alcohol, what contains 30-80 weight% of particles which have the said average particle diameter with respect to the total content of the saccharide | sugar and sugar alcohol in a base or a formulation is preferable. If the average particle size of one or more selected from sugar and sugar alcohol is less than 0.1 μm, each particle may be aggregated, and the flexibility of the film base or formulation is uneven depending on the site There is a possibility. On the other hand, if the average particle diameter exceeds 60 μm, the flexibility of the preparation may also be uneven depending on the site when it is contained in a film-like base or preparation having a practical thickness. Furthermore, the 1 type (s) or 2 or more types selected from saccharide | sugar and sugar alcohol have a more preferable thing containing the particle | grains which have an average particle diameter of 0.1-30 micrometers.

Here, the average particle diameter of one type or two or more types of particles selected from sugar and sugar alcohol refers to a 50% by volume average particle size measured by a laser scattering particle size distribution analyzer as follows.
That is, 10 mg of sugar or sugar alcohol particles were added to 3 mL of a chloroform solution of 0.2% by weight of polyoxyethylene monolaurate and sufficiently dispersed by ultrasonic waves. This dispersion is added to chloroform so that the transmittance in a laser scattering type particle size distribution measuring apparatus (LA-950, manufactured by Horiba, Ltd.) is 75% to 85%, and 50 volume% average particle diameter is measured by a wet method. did.

  It is appropriate that 1 to 80% by weight of one or more kinds of particles selected from monosaccharide to hexasaccharide and these sugar alcohols is blended with respect to the total weight of the base or the preparation, It is more preferable to add 10 to 60% by weight. If the blending amount of one or more kinds of particles selected from the sugar and sugar alcohol is less than 1% by weight, the dissolution profile in the mouth, film strength, mouth In the sticky feeling derived from the water-soluble polymer in the inside, sufficient improvement in the tactile feel when taken on the finger is not seen, and if it exceeds 80% by weight, unless the average particle size of the sugar and sugar alcohol particles is considerably reduced, There is a possibility that the shape retention of the base or the preparation may be lowered. For the purpose of the present invention, as the sugar and sugar alcohol, it is convenient to use commercially available products provided for pharmaceuticals, and those having an average particle size in the above range are sized. It can also be used, and a commercially available product can be used after being sized so that the average particle diameter is in the above range. The average particle diameter can be adjusted by pulverization, granulation by a dry granulation method, wet granulation method, etc., classification using a sieve or a classifier.

  With respect to the solubility of edible polymers and sugars and sugar alcohols used in the present invention in water or organic solvents having a solubility parameter of 9.7 or higher, in this specification, it is necessary to dissolve 1 g of solute at 20 ° C. When water or the organic solvent is 100 mL or more, the expression “does not dissolve” is used, and when water or the organic solvent necessary to dissolve 1 g of solute is less than 5 mL, it is “soluble”. Expression is used. The expression “easily soluble” is used when the water or the organic solvent necessary for dissolving 1 g of solute is less than 3 mL. The sugar and sugar alcohol used in the present invention have low solubility in the organic solvent, but it is known that the solubility decreases as the temperature of the organic solvent increases. And can stabilize the particle state of sugar and sugar alcohol.

  In addition to one or more selected from the group consisting of the edible polymer and sugar and sugar alcohol, the oral film-form base and preparation according to the present invention may optionally include a plasticizer such as polyethylene glycol, Surfactants, stabilizers, preservatives, antioxidants, fragrances, flavoring agents, sweetening agents, coloring agents, and the like can be appropriately blended.

  The drug that can be blended in the oral film-form preparation according to the present invention is not particularly limited as long as it can be administered orally, and includes, for example, antineoplastic, anti-inflammatory, antiallergic, antidiabetic, Lipidemia treatment, bone / calcium metabolism, antihypertensive, angina treatment, antiarrhythmic, vasodilator, diuretic, bronchodilator, bronchial asthma, antitussive, expectorant, digestive stomach Drugs, gastrointestinal function regulators, peptic ulcer drugs, bowel disease drugs, laxatives, antipsychotics, antidepressants, mood stabilizers, psychostimulants, sleeping pills, anti-anxiety drugs, antiepileptic drugs, migraine treatment Drugs, antiemetics, antipruritics, Parkinson's disease drugs, cerebral circulation / metabolism improving drugs, anti-dementia drugs, antibacterial drugs, antiviral drugs, antifungal drugs, frequent urination / urination disorder drugs, urinary incontinence drugs, etc. Can be mentioned. The amount of these drugs varies depending on the type and titer of the drug, the symptoms of the patient to be applied, etc., but considering the required dose etc., it is usually 0.1 to 60% by weight with respect to the total weight of the preparation. It is.

  Specific examples of the above-mentioned drugs include zolmitriptan, diphenhydramine, tamsulosin, granisetron, tolterodine, scopolamine, famotidine, candesartan cilexetil, pioglitazone, amlodipine, donepezil, and salts thereof.

  Since the film-form preparation according to the present invention is applied to the oral cavity, a drug without bitterness is suitable as the drug used in the present invention. It can be used by adding bitterness masking techniques, bitterness masking agents, sweeteners, flavoring agents, and fragrances. Moreover, since many sugars and sugar alcohols used in the present invention exhibit sweetness, a masking effect on the bitterness of the drug can be expected.

  Although the thickness of the film-form base and formulation which concern on this invention is not specifically limited, 30-300 micrometers is preferable. If the thickness is less than 30 μm, the film strength may be reduced, and the handling of the preparation may be deteriorated. If the thickness exceeds 300 μm, it takes time to dissolve in the oral cavity and may not be easily dissolved. As the planar shape of the film base and the preparation, a normal form can be adopted, and examples thereof include a rectangle, a square, a circle, and an ellipse.

  The intraoral film-form base according to the present invention has one or more edible polymers that are soluble in an organic solvent having a solubility parameter of 9.7 or more, water, and an average particle size. One or two or more kinds of particles selected from the group consisting of monosaccharide to hexasaccharide of 0.1 μm to 60 μm and these sugar alcohols are dissolved or dispersed to form a thin layer of the obtained dispersion. And dried. When obtaining an oral film-form preparation, an organic solvent having a solubility parameter of 9.7 or more, one or more drugs, water, and one or more edible polymers that are soluble in the organic solvent, and an average particle size is One or two or more kinds of particles selected from the group consisting of monosaccharide to hexasaccharide sugars of 0.1 μm to 60 μm and these sugar alcohols can be dissolved or dispersed and produced in the same manner as described above.

  More preferably, it is produced as follows. First, a predetermined amount of edible polymer is dissolved in a part of an organic solvent having a solubility parameter of 9.7 or more in which the polymer is soluble. Separately, in the remainder of the organic solvent, one or two or more kinds of particles selected from the group consisting of sugar and sugar alcohol are adjusted in advance by a process such as pulverization, granulation, classification, etc. Disperse. To this, the organic solvent solution of the edible polymer is added and mixed with other additive components such as a plasticizer if necessary, and an appropriate amount is spread on a release film made of polystyrene or polyethylene terephthalate. Dry to obtain a film base. In the above, the organic solvent in which the edible polymer is dissolved is preferably about 1 to 2 times the amount of the edible polymer. In the case of an oral film-form preparation, the drug is dissolved or dispersed in the remainder of the organic solvent having a solubility parameter of 9.7 or more, and one or more kinds of particles selected from sugar and sugar alcohol are further dispersed. Thereafter, a solution in which an edible polymer is dissolved in a part of the organic solvent is added to this together with other additive components such as a plasticizer, if necessary. An appropriate amount of this liquid is spread and dried on the release film in the same manner as described above, cut into a desired shape and size, and hermetically sealed as necessary to obtain an oral film-form preparation.

  As the organic solvent having the solubility parameter of 9.7 or more used for the production of the oral film-form preparation according to the present invention, sugar or sugar alcohol is not dissolved, but edible polymer may be dissolved, for example, Examples include methanol, ethanol, isopropanol, propylene glycol, methylene chloride, and acetone. One selected from these may be used alone, or two or more may be used in combination. Furthermore, lower alcohols such as methanol, ethanol and isopropanol, methylene chloride and acetone are preferably used, and purified water can be added if the amount is small. Further, when bubbles are generated in the solution at the time of preparation, the solution is left to stand overnight or defoamed by vacuum degassing.

In the present invention, the “solubility parameter” refers to the square root (SP value) of heat of vaporization (cal / cm ³ ) necessary for evaporating a 1 mol volume of liquid. The solubility parameter values of the organic solvent and water that can be used in the present invention are shown in Table 1. In addition, it is preferable that it is 9.7-20, and, as for the solubility parameter of the organic solvent used in this invention, it is more preferable that it is 9.7-15. If the solubility parameter exceeds 20, sugar or sugar alcohol may be dissolved, which is not preferable for the purpose of the present invention.

  The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.

  After pulverizing the sugar and sugar alcohol particles used in the Examples and Comparative Examples, the particles were sieved through a 32 μm, 50 μm or 90 μm sieve, and the 50% by volume average particle size was measured with a laser scattering particle size distribution measuring device. Used as an index of the particle size of the fine particles. Table 2 shows the 50 vol% average particle diameter of the sugar and sugar alcohol particles used.

[Examples 1 and 2]
About the intraoral film-form preparation which concerns on this invention, the composition of Example 1 and 2 is shown in Table 3 with the composition of Comparative Example 1 and 2. FIG.

The oral film-form preparations of Examples 1 and 2 were prepared as follows. In Table 3, HPC (weight average molecular weight = about 30,000, substitution degree of hydroxypropoxy group = 53.4-77.5%) or PVP K-30 (weight average molecular weight = about) was added to 70.5 parts by weight of ethanol. 40,000) 47.0 parts by weight were added and dissolved by stirring to prepare an ethanol solution of HPC or PVP K-30. To the remaining ethanol, 9.0 parts by weight of zolmitriptan was added and dissolved by stirring, and 40.0 parts by weight of D-mannitol fine particles obtained by passing a 32 μm sieve in advance were added and stirred ultrasonically. This was stirred and mixed with an ethanol solution of HPC or PVP K-30 and 4.0 parts by weight of polyethylene glycol, sufficiently defoamed, and then stretched and dried on a polyethylene terephthalate release film to give a film having a thickness of about 100 μm. Manufactured. The obtained film was cut into a 3 cm ² rectangle to obtain a film-form preparation.

Moreover, the oral film-form preparations of Comparative Examples 1 and 2 were prepared as follows. In Table 3, 9.0 parts by weight of zolmitriptan was added to 33.3 parts by weight of ethanol and dissolved by heating. In purified water, 47.0 parts by weight of pullulan or hydroxypropylmethylcellulose, 4.0 parts by weight of polyethylene glycol, and 40.0 parts by weight of D-mannitol fine particles obtained by previously sieving a 32 μm sieve were added and dissolved by stirring. The prepared ethanol solution of zolmitriptan was added and dissolved by stirring while heating at 45 ° C. After sufficiently defoaming this solution, it was stretched and dried on a polyethylene terephthalate release film to produce a film having a thickness of about 100 μm. The obtained film was cut into a 3 cm ² rectangle to obtain a film-form preparation.

[Examples 3 to 10]
Then, the composition of Examples 3-10 about the intraoral film-form preparation of this invention was shown in Table 4. In the same manner as in the oral film-form preparations of Examples 1 and 2, these were prepared by dissolving zolmitriptan in ethanol, and then adding and dispersing fine particles of sugar or sugar alcohol that had previously been sieved through a 32 μm sieve. A solution prepared by adding HPC to 70.5 parts by weight, and polyethylene glycol were added and mixed by stirring. After sufficient defoaming, this was stretched and dried on a release film made of polyethylene terephthalate to give a film having a thickness of about 100 μm. And the obtained film was cut into a 3 cm ² rectangle and prepared.

[Comparative Examples 3 to 13]
The compositions for Comparative Examples 3 to 13 are shown in Table 5.

  Regarding the oral film-form preparation of Comparative Example 3, in Table 5, zolmitriptan and polyethylene glycol were dissolved in ethanol, and an ethanol solution of HPC was added thereto to obtain a film-form preparation as in Example 1.

  Moreover, about the intraoral film-form preparation of Comparative Examples 4-13, it prepared as follows. Zolmitriptan was added to ethanol and dissolved by heating. In purified water, HPC (weight average molecular weight = about 30,000, substitution degree of hydroxypropoxy group = 53.4-77.5%), polyethylene glycol, and sugar or sugar alcohol fine particles previously sieved through a 32 μm sieve are added. In addition, the mixture was dissolved by stirring, and the ethanol solution of zolmitriptan prepared earlier was added, and dissolved by stirring while heating at 45 ° C. This solution was sufficiently degassed and then stretched and dried on a release film made of polyethylene terephthalate.

When prepared by the above method, except for Comparative Examples 3, 5, 7, 12, and 13, the produced film is too brittle and soft, so it cannot be peeled off from the polyethylene terephthalate release film, and a film-form preparation is obtained. I could not. For Comparative Examples 3, 5, 7, 12, and 13, the obtained films were cut into 3 cm ² rectangles to obtain film-form preparations.

[Examples 11 to 20]
The compositions of Examples 11 to 20 for the oral film-form preparation according to the present invention are shown in Table 6.

The oral film-form preparations of Examples 11 to 16 were prepared as follows. That is, in Table 6, HPC (weight average molecular weight = about 30,000, hydroxypropoxy group substitution degree = 53.4-77.5%) was added to 1.5 times by weight of ethanol and dissolved by stirring. An ethanol solution was prepared. The remaining ethanol is stirred and dissolved, and D-mannitol fine particles, the above-mentioned HPC ethanol solution and polyethylene glycol are added and stirred and mixed, and this is stretched and dried on a polyethylene terephthalate release film to a thickness of about 100 μm. The obtained film was cut into a 3 cm ² rectangle to obtain a film-form preparation.

Moreover, the intraoral film-form preparation of Examples 17-20 was prepared as follows. That is, the drugs in Table 6, D-mannitol fine particles and polyethylene glycol were added to ethanol and dispersed by sonication for 10 minutes, and then HPC (weight average molecular weight = about 30,000, hydroxypropoxy group substitution degree = 53.4-77.5%) was added and dissolved by stirring. This solution was stretched and dried on a polyethylene terephthalate release film to produce a film having a thickness of about 70 μm, and the resulting film was cut into a 3 cm ² rectangle to obtain a film-form preparation.

[Examples 21 to 26]
Table 7 shows the compositions of Examples 21 to 26 for the oral film-form base according to the present invention.

These were prepared as follows. That is, in Table 7, HPC (weight average molecular weight = about 30,000, substitution degree of hydroxypropoxy group = 53.4-77.5%) is 1.5 times by weight for Examples 21 to 23 and 26, In Examples 24 and 25, the solution was stirred and dissolved in 1 weight-fold ethanol to prepare an ethanol solution of HPC. After adding D-mannitol fine particles to the remaining ethanol and sonicating and dispersing, the ethanol solution of HPC and polyethylene glycol were added and mixed by stirring, and this was stretched and dried on a release film made of polyethylene terephthalate, A film having a thickness of about 100 μm was produced, and the obtained film was cut into a 3 cm ² rectangle to obtain a film-like base.

  For the oral film-form preparations and bases of the examples and comparative examples of the present invention, the peel strength test and the softness test were conducted with respect to film strength, stickiness in the mouth, dissolution profile in the mouth, and feel when taken on the fingers. Measurement and evaluation were performed by performing a degree test, a tensile strength test, a tack duration test, an oral disintegration test, and a sensory evaluation (tactile sensation). Further, the average particle diameter of the sugar and sugar alcohol fine particles dispersed in the film base was measured using a microscope. Each test method is shown below.

(1) Evaluation of peelability When preparing a film-form preparation or base, the peelability from a polyethylene terephthalate release film was evaluated and scored according to the following evaluation criteria.

[Evaluation criteria]
Can be easily peeled; 4 points can be peeled; 3 points can be peeled off but is difficult to peel off; 2 points can be peeled off but the film is damaged; 1 point cannot be peeled at all; 0 points

(2) Bending test This test was conducted in accordance with “Japanese Industrial Standard (JIS) L1096 General Textile Testing Method, 8.19 Bending Softness, 8.19.1 A Method (45 ° Cantilever Method)”. First, five test pieces of 20 mm × 150 mm were sampled from each sample of the example and the comparative example, one end has a 45 ° slope, the surface is smooth, and the short side of the test piece is the base line of the scale. Put it to fit. Next, the test piece is gently slid in the direction of the slope by an appropriate method, and the position of the other end when the center point of one end of the test piece is in contact with the slope A is read on the scale. The bending resistance is indicated by the length (mm) when the test piece is moved, measured by reversing the front and back and front and back of each of the five test pieces, and calculating the average value of each to obtain the bending resistance. It was. The evaluation criteria were set as follows, considering the bending resistance (about 60 mm) of the film-form preparation (Comparative Example 3) when no sugar was added. In addition, the thing which was not able to peel from a peeling film on the physical property of the prepared sample and was unable to obtain a film-form preparation was set to 0 point.

[Evaluation criteria]
4 points 60 ± 20 mm or more and less than 30 mm; 3 points 60 ± 30 mm or more and less than 40 mm; 2 points 60 ± 40 mm or more; 1 point

(3) Tensile strength test This test was performed in accordance with "Japanese Industrial Standard (JIS) K7127 Plastic Film and Sheet Tensile Test Method". Each film-form preparation or base was cut into 12 mm × 50 mm to obtain test pieces, which were sufficiently dried in a desiccator and then subjected to the test. The test was performed using a small desktop tensile tester (manufactured by Shimadzu Corp., EZ TEST-100M) at a test speed of 60 mm / min. Since almost no elongation was observed for the test piece subjected to the test, the tensile yield strength obtained by the measurement was obtained as the tensile strength. Each sample was repeatedly measured three times, and the average value was obtained as the tensile strength. The obtained tensile strength was scored according to the following evaluation criteria. In addition, the thing which was not able to peel from a peeling film on the physical property of the prepared sample and was unable to obtain a film-form preparation was set to 0 point.

[Evaluation criteria]
Tensile strength = 10N or more and less than 20N; 4 points Tensile strength = 5N or more and less than 10N; 3 points Tensile strength = 2N or more and less than 5N; 2 points Tensile strength = less than 2N; 1 point

(4) Tack continuation test This test was performed using a rheometer (SUN SCIENTIFIC, CR-2000) by cutting each film-form preparation or base into a circle having a diameter of 12 mm to obtain a test piece. Here, “tack” refers to a force that adheres to an adherend when it is brought into contact with the adherend in a short time with a light force. The appearance of the test is shown in FIG. That is, the test piece 2c is stuck on the probe 2a having a diameter of 12 mm with a double-sided tape 2b. Separately, a rubber 2e is placed on the test table 2f, and a collagen film 2d soaked in water is placed thereon. 200 μL of purified water is added to the test piece, the probe 2a to which the test piece 2c is attached is lowered and brought into contact with the collagen film 2d, and then raised. At that time, the tack duration after the initial tack obtained when the probe 2a was separated from the collagen film 2d was measured from the recording paper using calipers. The measurement results were scored according to the following evaluation criteria. In addition, due to the physical properties of the prepared sample, those that could not be peeled off from the release film and could not obtain a film-form preparation were cut together with the release film, and the release film side was affixed to the double-sided tape of the probe. The measurement was performed in the same manner.

[Evaluation criteria]
Tack duration measurement value = less than 2 mm; 4 points Tack duration measurement value = 2 mm or more and less than 3 mm; 3 points Tack duration measurement value = 3 mm or more and less than 4 mm; 2 points Tack duration measurement value = 4 mm or more; 1 point

(5) Oral disintegration test 900 mL of a phosphate buffer solution of pH 6.8 is put into a 1000 mL glass petri dish, and a stainless steel sieve (Φ4 mm) is turned upside down and stirred in a stirrer (300 rpm). The temperature of this solution is controlled at 37 ± 2 ° C. using a constant temperature water circulator, and a test piece (3 cm ² ) is submerged therein, and at the same time, a 3 cm × 3 cm stainless steel wire mesh (mesh size 5 mm) is placed as a weight. It was. The appearance of the test piece was observed visually, and the time from when the test piece was submerged until the test piece completely collapsed was measured with a stopwatch. Each sample was measured three times, and the average value was taken as the oral disintegration time. The oral disintegration time was scored according to the following evaluation criteria. In addition, the thing which was not able to peel from a peeling film on the physical property of the prepared sample and was unable to obtain a film-form preparation was set to 0 point.

[Evaluation criteria]
Oral disintegration time = less than 10 seconds; 4 points Oral disintegration time = 10 seconds to less than 15 seconds; 3 points Oral disintegration time = 15 seconds to less than 20 seconds; 2 points Oral disintegration time = 20 seconds or more; 1 point

(6) Sensory evaluation (feel)
Each film-form preparation or base was cut into test pieces, and the panelists were touched with a finger to draw a circle for 5 seconds, and evaluated whether the surface was sticky or not according to the following evaluation criteria. . In addition, the thing which was not able to peel from a peeling film on the physical property of the prepared sample and was unable to obtain a film-form preparation was set to 0 point.

[Evaluation criteria]
4 points Feels not sticky; 3 points Feels uncomfortable with the feeling of stickiness; 2 points It is quite sticky and the film remains on the finger; 1 point

(7) Measurement of average particle diameter of sugar alcohol fine particles in film-form base Regarding the oral film-form bases of Examples 21 to 23 of the present invention, the added D-mannitol fine particles A to C in the film-form base The particle diameter was measured using a microscope (VHX-600, manufactured by Keyence Corporation). The 50 volume% average particle diameter was calculated | required from the result measured about 200 particles.

  Table 8 shows the results of the evaluations and tests of the above (1) to (6) for the oral film-form preparations of Examples 1 to 10.

  In Table 8, good evaluation was obtained in each evaluation item for any oral film-form preparation except that the sensory evaluation result for the intra-oral film-form preparation of Example 4 was slightly worse. That is, the oral film-form preparations of Examples 1 to 10 of the present invention exhibit good peelability, have sufficient strength and good oral disintegration, have little stickiness and good tactile sensation. It was shown that there is.

  Table 9 shows the results of the evaluations and tests of the above (1) to (6) for the oral film-form preparations of Comparative Examples 1 to 13.

  In Table 9, the oral film-form preparation of Comparative Example 1 prepared by dissolving pullulan, which is an edible polymer that is water-soluble but hardly soluble in ethanol, in purified water has good evaluation in all items. It was not obtained. In addition, the oral film-form preparation of Comparative Example 2 using hydroxypropylmethylcellulose, which is an edible polymer that is water-soluble but hardly soluble in ethanol, has low strength against bending deformation and has a sticky feeling. It was. In the oral film-form preparation of Comparative Example 3 in which no sugar or sugar alcohol fine particles were blended, the disintegration property in the oral cavity was poor and the gooey feeling was remarkable. In the oral film-form preparations of Comparative Examples 4 to 12 prepared by dissolving HPC in purified water, a film having sufficient strength could not be obtained. In the oral film-form preparation of Comparative Example 13 prepared by dissolving HPC in purified water and not containing sugar or sugar alcohol fine particles, the disintegration property in the oral cavity was poor and the sticky feel was also remarkable.

  Table 10 shows the results of the evaluations and tests of the above (1) to (6) for the oral film-form preparations of Examples 11 to 20.

  In Table 10, about the intraoral film-form preparation of Examples 11 to 20 of the present invention, good evaluation was obtained in each item, and even when various drugs were blended, sufficient film strength and good oral cavity were obtained. It was shown to have internal disintegration and tactile sensation.

  Table 11 shows the results of the evaluations and tests of the above (1) to (6) for the oral film-form bases of Examples 21 to 26.

  In Table 11, about the intraoral film-form base of Examples 21-26 of this invention, except the tack duration about the film-form base of Example 24, and the tensile strength of the film-form base of Example 26 Good evaluation was obtained.

  Table 12 shows the average particle size measurement results for the oral film-form bases of Examples 21 to 23. 3 to 5 show photographs under the microscope.

  As is clear from Table 12, in the oral film-form bases of Examples 21 to 23 of the present invention, the 50% by volume average particle diameter of the D-mannitol fine particles was also compared with that in the film-form base before addition. It was shown that D-mannitol was not dissolved in the base but was dispersed in the form of fine particles. As shown in FIGS. 3 to 5, good dispersion of the D-mannitol fine particles could be confirmed by observation of the oral film-form bases of Examples 21 to 23 with a microscope.

Industrial availability

  According to the present invention, an intraoral film-form base having sufficient film strength, showing a rapid dissolution profile in the oral cavity, reduced stickiness in the oral cavity, and improved tactile sensation when taken on the fingers And formulations can be provided.

  This application is based on international application PCT / JP2009 / 051511 filed in accordance with the Patent Cooperation Treaty, the contents of which are incorporated in full herein.

Claims (10)

One or more edible polymers that are soluble in water and an organic solvent having a solubility parameter of 9.7 or more, monosaccharide to hexasaccharide sugars having an average particle size of 0.1 μm to 60 μm, and these Containing one or more particles selected from the group consisting of sugar alcohols,
An oral film-form base in which the edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is one or more selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose. . The intraoral film-form base of Claim 1 whose average particle diameter of 1 type, or 2 or more types of particle | grains chosen from the group which consists of saccharide | sugar and these sugar alcohols is 0.1 micrometer-30 micrometers. The intraoral film-form base of Claim 1 or 2 whose weight average molecular weights of polyvinylpyrrolidone are 2,500-3,000,000. The oral film-form base according to claim 1 or 2, wherein the hydroxypropylcellulose has a weight average molecular weight of 10,000 to 1,200,000. The oral film-form base according to claim 1, 2, or 4, wherein the hydroxypropoxy group substitution degree of hydroxypropyl cellulose is 50% to 100%. An oral film-form preparation comprising a drug in the oral film-form base according to any one of claims 1 to 5. It is a manufacturing method of the intraoral film-form base of Claim 1,
The solubility parameter 9.7 or more organic solvents, together with dissolving one or more of the edible polymer that is soluble in water and organic solvents, monosaccharides average particle diameter is 0.1μm~60μm ~ Disperse one or more kinds of particles selected from the group consisting of hexasaccharide sugars and these sugar alcohols, form a thin layer of the resulting dispersion and dry,
The edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is one or more selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose. The manufacturing method of an inner film-form base. A method for producing an oral film-form preparation according to claim 6,
In the organic solvent having a solubility parameter of 9.7 or more, the drug, water, or one or more edible polymers that are soluble in the organic solvent are dissolved, and the average particle size is 0.1 μm to 60 μm. Disperse one or more particles selected from the group consisting of monosaccharide to hexasaccharide sugars and these sugar alcohols, form a thin layer of the resulting dispersion, and dry.
The edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is one or more selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose. A method for producing an inner film-form preparation. In a part of the organic solvent having a solubility parameter of 9.7 or more, water and one or more edible polymers soluble in the organic solvent are dissolved, and the solution has an average particle size of 0.1 μm. In addition to one or two or more kinds of particles selected from the group consisting of monosaccharide to hexasaccharide of ˜60 μm and these sugar alcohols dispersed in the remainder of the organic solvent having a solubility parameter of 9.7 or more Mixed and formed a thin layer of the resulting dispersion and dried,
The edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is one or more selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose. The manufacturing method of an inner film-form base. In a part of the organic solvent having a solubility parameter of 9.7 or more, one or more edible polymers that are soluble in water and the organic solvent are dissolved, and the solution is dissolved in a solubility parameter of 9.7 or more. 1 or 2 or more types selected from the group consisting of monosaccharide to hexasaccharide sugars having an average particle size of 0.1 μm to 60 μm and these sugar alcohols , while dissolving or dispersing the drug in the remainder of the organic solvent In addition to the dispersed particles , the mixture is mixed, and a thin layer of the resulting dispersion is formed and dried.
The edible polymer that is soluble in water and an organic solvent having a solubility parameter of 9.7 or more is one or more selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose. A method for producing an inner film-form preparation.