JP4898113B2 - Oral administration - Google Patents

Description

  The present invention relates to an oral administration agent.

  Orally administered drugs have lower medication compliance due to various causes such as discomfort due to drug bitterness and astringency, nausea and vomiting due to medication, and medication rejection. For example, in the case of solid preparations (for example, tablets, capsules, etc.), which are common dosage forms for oral administration, it is difficult to swallow them as they are, so usually they must be taken with a large amount of water, resulting in reduced compliance. To do. Particularly in elderly people and infants, solid preparations cannot be swallowed, and medication compliance is often reduced. In the case of a solid preparation, there is a risk of accidentally clogging the trachea and a risk of sticking to the esophagus to form an esophageal tumor.

Therefore, an oral administration agent having a drug-containing layer and a water-swellable gel-forming layer, wherein the water-swellable gel-forming layer is provided in the outermost layer of the oral administration agent has been developed (Patent Document) 1). The water-swellable gel-forming layer provided in the outermost layer of the oral administration agent swells and gels with moisture such as saliva in the patient's mouth, and the oral administration agent is easy to swallow in size, shape, elasticity, viscosity To a dosage form having Therefore, the patient can easily take the oral administration agent. In addition, since the risk of the oral administration agent becoming clogged in the trachea of the patient during taking is reduced, it can be safely taken even if the patient is an elderly person or an infant. Furthermore, the water-swellable gel-forming layer provided in the outermost layer of the oral administration agent swells and gels with moisture such as saliva in the patient's mouth, and the taste of the drug contained in the drug-containing layer (for example, bitterness) , Astringency), odor, etc. can be masked.
International Publication WO02 / 087622

  An object of the present invention is to provide an orally-administered agent with improved ease of swallowing, ease and safety, and masking effects such as drug taste and odor.

  To solve the above problems, the present invention provides an oral administration comprising a drug-containing layer, a water-swellable gel-forming layer, and an intermediate layer provided between the drug-containing layer and the water-swellable gel-forming layer. The drug-containing layer contains a poorly water-soluble polymer as a base, the intermediate layer contains polyvinylpyrrolidone, and the water-swellable gel-forming layer is directly laminated on the intermediate layer. The oral administration agent provided in the outermost layer of the oral administration agent is provided.

  In the present invention, the “outermost layer” means a layer constituting the outer surface of the oral administration agent when the oral administration agent is in the oral cavity of a patient or the like. Therefore, the “outermost layer” includes not only the layer constituting the outer surface of the orally-administered agent before administration but also the outer surface of the orally-administered agent before administration, but the oral-administered agent when in the oral cavity of the patient. A layer constituting the outer surface is also included. For example, even when another layer is provided as an outer layer of the water-swellable gel-forming layer, if this outer layer is decomposed or dissolved by moisture such as saliva in the patient's mouth, In the oral cavity, the water-swellable gel-forming layer constitutes the outer surface of the orally-administered agent, so that the water-swellable gel-forming layer is provided in the outermost layer of the orally-administered agent.

The water-swellable gel-forming layer provided on the outermost layer of the orally administered agent swells and gels with moisture such as saliva in the patient's mouth, and the orally administered agent has a size, shape, elasticity, viscosity, etc. that are easy to swallow. The dosage form changes. Accordingly, the patient can easily take the oral preparation. In addition, since the risk of the oral administration agent becoming clogged in the trachea of the patient during taking is reduced, it can be safely taken even if the patient is an elderly person or an infant. In the case of a patient who has little saliva and the water-swellable gel-forming layer does not sufficiently gel, the same effect can be exhibited by taking it together with a small amount of water or pre-dipping in water before administration. The amount of water required at this time is very small compared to the amount of water required when taking solid preparations such as tablets and capsules.
In addition, the water-swellable gel-forming layer provided in the outermost layer of the orally-administered agent swells and gels with moisture such as saliva in the oral cavity of the patient, and the taste of the drug contained in the drug-containing layer (for example, bitterness, Astringency), odor, etc. can be masked.

  In particular, in the oral administration agent of the present invention, the water-swellable gel-forming layer is gelled because the water-swellable gel-forming layer is provided on the outermost layer of the oral administration agent in a state of being directly laminated on the intermediate layer. In this case, the water-swellable gel-forming agent contained in the water-swellable gel-forming layer interacts with the polyvinylpyrrolidone contained in the intermediate layer, and the strength is higher than when the water-swellable gel-forming layer gels alone. A large gel is formed. Therefore, in the oral administration agent of the present invention, the ease of swallowing, ease and safety at the time of taking are improved, and the masking effect such as the taste and smell of the drug is improved.

  When the water-swellable gel-forming layer swells and gels with water such as saliva in the oral cavity of the patient, the drug contained in the drug-containing layer is dissolved by the water reaching the drug-containing layer, There is a risk of elution. When the drug elutes from the orally administered agent in the patient's oral cavity, masking of the taste, smell, etc. of the drug becomes insufficient. In the oral administration agent of the present invention, since the poorly water-soluble polymer is contained as a base in the drug-containing layer, the drug contained in the drug-containing layer is protected from moisture by the poorly water-soluble polymer. Elution of the drug can be prevented. Therefore, in the oral administration agent of the present invention, the masking effect such as drug taste and smell is improved.

  In the oral administration agent of the present invention, the amount of the poorly water-soluble polymer contained in the drug-containing layer is not particularly limited, but is preferably 10% by mass or more of the drug-containing layer. When the amount of the poorly water-soluble polymer contained in the drug-containing layer is in the above range, the drug can be effectively prevented from being eluted from the orally administered agent. The upper limit of the amount of the poorly water-soluble polymer contained in the drug-containing layer is a value obtained by subtracting the minimum drug content from 100% by mass.

  In the oral administration agent of the present invention, the poorly water-soluble polymer is not particularly limited, but is preferably polyvinyl alcohol. Since polyvinyl alcohol has a masking effect such as the taste and odor of the drug, when polyvinyl alcohol is contained in the drug-containing layer, it is possible to effectively prevent the drug from eluting from the orally administered agent. It is possible to effectively mask the taste, smell, etc. of the drug contained in the drug-containing layer.

In the oral administration agent of the present invention, the K value of polyvinylpyrrolidone is not particularly limited, but is preferably 30 or more.
The interaction between the polyvinylpyrrolidone contained in the intermediate layer and the water-swellable gel-forming agent contained in the water-swellable gel-forming layer increases as the K value of the polyvinylpyrrolidone contained in the intermediate layer increases. The strength of the gel increases. When the K value of polyvinylpyrrolidone contained in the intermediate layer is 30 or more, a gel having a sufficiently high strength can be formed. As a result, the ease of swallowing, ease and safety when taking an orally administered agent are further improved, and masking effects such as the taste and smell of the drug are further improved. These effects become more remarkable when the K value of polyvinylpyrrolidone contained in the intermediate layer is 90 or more.

In the oral administration agent of the present invention, the water-swellable gel-forming agent contained in the water-swellable gel-forming layer is not particularly limited, but is preferably polyacrylic acid.
If the water-swellable gel-forming agent contained in the water-swellable gel-forming layer is polyacrylic acid, the interaction with the polyvinyl pyrrolidone contained in the intermediate layer will be sufficient, and a sufficiently strong gel will be formed can do. As a result, the ease of swallowing, ease and safety when taking an orally administered agent are further improved, and masking effects such as the taste and smell of the drug are further improved.

In the oral administration agent of the present invention, the oral administration agent is preferably a film preparation.
When the oral administration agent of the present invention is a film-form preparation, the water content in the preparation can be kept low, so that the drug contained in the drug-containing layer (especially compared to the jelly-form preparation containing a large amount of water) The stability of drugs that are easily hydrolyzed can be improved. Furthermore, handling of the preparation becomes easy and the packaging cost of the preparation can be reduced.

  Further, when the oral administration agent of the present invention is a film-form preparation, even if the drug amount of the drug-containing layer increases and the film strength of the drug-containing layer decreases, the water-swellable gel-forming layer and / or the intermediate layer By imparting film-forming properties, the strength of the film-form preparation as a whole can be maintained. Therefore, the drug-containing layer can contain a wide variety of drugs ranging from a very small amount of drug to a large amount of drug, and an insoluble and bulky drug that tends to cause a decrease in film strength.

  ADVANTAGE OF THE INVENTION According to this invention, the oral administration agent which improved the masking effects, such as the ease of swallowing at the time of taking, ease and safety | security, and the taste and smell of a drug, is provided.

Hereinafter, the present invention will be described in detail.
One embodiment of the oral administration agent of the present invention is shown in FIG.
As shown in FIG. 1, the orally administered agent 1a according to this embodiment includes a drug-containing layer 11a, water-swellable gel-forming layers 13a and 13b, a drug-containing layer 11a, and a water-swellable gel-forming layer 13a. The intermediate layer 12a is provided, and the intermediate layer 12b is provided between the drug-containing layer 11a and the water-swellable gel-forming layer 13b. The water-swellable gel-forming layers 13a and 13b are respectively intermediate layers 12a and 12b. It is provided in the outermost layer of the orally-administered agent 1a in a state where it is directly laminated on.

  The orally administered agent 1a is preferably a film-form preparation (sheet-form preparation). When the orally-administered agent 1a is a film-form preparation, the water content in the preparation can be kept low. Therefore, compared to a jelly-form preparation containing a large amount of water, the drug contained in the drug-containing layer 11a (especially water) It is possible to improve the stability of drugs that are easily decomposed. In addition, the preparation can be handled easily and the packaging cost of the preparation can be reduced.

The drug-containing layer 11a is a layer containing a drug to be administered.
The thickness of the drug-containing layer 11a can be appropriately adjusted within a range that can be administered orally. When the orally administered agent 1a is a film-form preparation, the thickness of the drug-containing layer 11a is preferably 0.1 to 1000 μm, and more preferably 10 to 200 μm. When the thickness of the drug-containing layer 11a is less than 0.1 μm, it becomes difficult to form a film with high accuracy (that is, the drug content of the drug-containing layer 11a varies), while the thickness of the drug-containing layer 11a If the thickness exceeds 1000 μm, the film becomes stiff and difficult to take.

  The drug-containing layer 11a contains a poorly water-soluble polymer as a base for holding the drug to be administered in a desired state in the drug-containing layer 11a. Thereby, the drug contained in the drug-containing layer 11a is protected from moisture by the poorly water-soluble polymer. Therefore, when the water-swellable gel-forming layers 13a and 13b swell and gel with water such as saliva in the patient's mouth, the drug contained in the drug-containing layer 11a is caused by the water reaching the drug-containing layer 11a. It is possible to prevent dissolution and elution from the orally administered agent 1a.

  The poorly water-soluble polymer contained in the drug-containing layer 11a is not particularly limited. For example, polyvinyl alcohol, ethyl cellulose, hydroxypropyl methylcellulose, acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, carboxymethylcellulose, Hydroxypropyl starch, (meth) acrylic acid dimethylaminoethyl / (meth) acrylic acid copolymer, (meth) acrylic acid / ethyl acrylate copolymer, (meth) acrylic acid / (meth) acrylic acid methyl copolymer, (meth) acrylic acid Ethyl / (meth) acrylated trimethylammonium copolymer, dimethylaminoethyl (meth) acrylate / (meth) acrylated methyl copolymer, ( T) Acrylic acid / acrylated ethyl copolymer, polyvinyl acetal diethylaminoacetate, polyvinyl acetate, gelac, etc., and one or more of these can be selected and used. It is preferable to use alone or use polyvinyl alcohol in combination with other poorly water-soluble polymers. Since polyvinyl alcohol has a masking effect such as the taste and smell of a drug, when polyvinyl alcohol is contained in the drug-containing layer 11a, it is possible to effectively prevent the drug from being eluted from the orally administered agent 1a. In addition, the taste and smell of the drug contained in the drug-containing layer 11a can be effectively masked.

  The amount of the poorly water-soluble polymer contained in the drug-containing layer 11a is usually 10% by mass or more, preferably 15% by mass or more, more preferably 20% by mass or more of the drug-containing layer 11a. When the amount of the poorly water-soluble polymer contained in the drug-containing layer 11a is in the above range, the drug can be effectively prevented from being eluted from the orally administered agent 1a. The upper limit of the amount of the poorly water-soluble polymer contained in the drug-containing layer 11a is a value obtained by subtracting the minimum drug content from 100% by mass. For example, when the minimum content of the drug is 0.01% by mass of the drug-containing layer 11a, the upper limit value of the content of the poorly water-soluble polymer is 99.99% by mass of the drug-containing layer 11a.

  The drug-containing layer 11a may contain only a poorly water-soluble polymer as a base, but may contain a water-soluble polymer together with the poorly water-soluble polymer. Examples of the water-soluble polymer include polyvinylpyrrolidone, vinyl acetate-vinylpyrrolidone copolymer, polyethylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, xanthan gum, gum arabic, starch, gelatin, dextrin, dextran and the like. It is done. The amount of the water-soluble polymer contained in the drug-containing layer 11a is usually 50% by mass or less, preferably 30% by mass or less, more preferably 20% by mass or less of the drug-containing layer 11a. Note that the lower limit of the content of the water-soluble polymer is zero.

The drug contained in the drug-containing layer 11a is a drug to be administered to a patient or the like, and is not particularly limited as long as it can be administered orally. As drugs that can be administered orally, for example, drugs acting on the central nervous system include hypnotics such as amobarbital, estazolam, triazolam, nitrazepam, pentobarbital; amitriptine hydrochloride, imipramine hydrochloride, oxazolam, chlordiazepoxide, chlorpromazine, diazepam, sulpiride, Psychotropic drugs such as haloperidol; antiparkinson drugs such as trihexyphenidyl and levodopa; analgesics and anti-inflammatory drugs such as aspirin, isopropylantipyrine, indomethacin, diclofenac sodium, mefenamic acid, streptokinase, streptodornase, serrapeptase, and pronase A central nervous system metabolism stimulator such as ATP and vinpocetine; as drugs acting on the respiratory tract, expectorants such as carbocysteine and promhexine hydrochloride; hydrochloric acid Anti-asthmatic drugs such as zelastine, oxatomide, theophylline, terbutaline sulfate, tranilast, procaterol hydrochloride, ketotifen fumarate; drugs acting on the circulatory system include cardiotonic drugs such as aminophylline, digitoxin, digoxin; adimarin, disopyramide, procainamide hydrochloride Antiarrhythmic agents such as methiletine hydrochloride; amyl nitrite, alprenolol hydrochloride, isosorbide nitrate, nicorandil, oxyfedrine, dipyridamole, dirazep hydrochloride, diltiazem hydrochloride, nitroglycerin, nifedipine, verapamil hydrochloride; Peripheral vasodilators such as kalidinogenase; atenolol, captopril, clonidine hydrochloride, metoprolol tartrate, spironolactone, triamterene, trichlormethiazide, nicardipine, hydrochloride hydrochloride Anti-hypertensive drugs such as larazine, hydrochlorothiazide, prazosin hydrochloride, furosemide, propranolol hydrochloride, enalapril maleate, methyldopa, labetalol hydrochloride, reserpine; anti-arteriosclerotic drugs such as clofibrate, dextran sulfate, nicomol, niceritrol; blood and hematopoietic agents Hemostatic drugs such as sodium carbazochrome sulfonate and tranexamic acid; Antithrombotic drugs such as ticlopidine hydrochloride and warfarin potassium; Antianemic drugs such as iron sulfate; Azulene, aldioxa, cimetidine, hydrochloric acid as drugs acting on the digestive system Antiulcer drugs such as ranitidine, famotidine, teprenone, rebamipide; domperidone,
Antiemetics such as metoclopramide; sedatives such as sennoside; digestive enzyme preparations; therapeutic drugs for liver diseases such as glycyrrhizin and liver extract preparations; antidiabetic drugs such as glibenclamide, chlorpropamide, and tolbutamide Drugs for the treatment of gout such as allopurinol and colchicine; acetazolamide as a drug in the ophthalmic field; anti-vertigo drugs such as diphenidol hydrochloride and betahistine mesylate as a drug in the otorhinology; isoniazid, ethambutol hydrochloride Ofloxacin, erythromycin stearate, cefaclor, norfloxacin, fosfomycin calcium, minocycline hydrochloride, rifampicin, rokitamycin, etc .; as antineoplastic agents, cyclophosphamide, tegafur, etc .; as immunosuppressants, Zathioprine, etc .; as hormones and endocrine therapeutic agents, lutein hormone, salivary gland hormone, thiamazole, prednisolone, betamethasone, liothyronine, levothyroxine, etc .; bioactive substances (ortachoids) as diphenhydramine hydrochloride, clemastine fumarate, chlorinated D-maleate Antihistamines such as phenylamine; vitamins such as alphacalcidol, cobamide, tocopherol nicotinate, mecoparamine, etc. are listed, and one or more of these are selected and used according to the therapeutic / preventive purpose be able to.

  The amount of the drug contained in the drug-containing layer 11a is not particularly limited and can be appropriately adjusted according to the type of drug, but is usually 90% by mass or less, preferably 85% by mass or less of the drug-containing layer 11a. Preferably it is 80 mass% or less. When the drug content exceeds 90% by mass, the film strength decreases when the orally administered preparation 1a is a film-form preparation. The lower limit of the drug content is appropriately set according to the type of drug to be contained in the drug-containing layer 11a, and is usually about 0.01% by mass.

  The drug-containing layer 11a can contain a wide variety of drugs ranging from a very small amount of drug to a large amount of drug. Here, a small dose means that a single dose is 1 mg or less, and a large dose means that a single dose is 300 mg or more.

  Even when the orally-administered agent 1a is a film-form preparation, the drug-containing layer 11a has a wide variety of drugs ranging from a very small amount to a large amount of drug, and an insoluble and bulky drug that tends to cause a decrease in film strength. Can be contained. This is because the drug-containing layer 11a, the intermediate layers 12a and 12b, and the water-swellable gel-forming layers 13a and 13b are formed as separate layers. Even if the film strength of the containing layer 11a is lowered, the strength of the film-form preparation as a whole can be maintained by imparting film-forming properties to the intermediate layers 12a and 12b and the water-swellable gel-forming layers 12a and 12b. Because it can.

The intermediate layers 12a and 12b are layers containing polyvinyl pyrrolidone.
The intermediate layers 12a and 12b may contain only polyvinyl pyrrolidone, or may contain a base that can hold the polyvinyl pyrrolidone in the intermediate layer 11 in a desired state. The amount of polyvinyl pyrrolidone contained in the intermediate layers 12a and 12b is usually 10% by mass or more, preferably 20% by mass or more, more preferably 40% by mass or more of the intermediate layers 12a and 12b.

  The thicknesses of the intermediate layers 12a and 12b can be appropriately adjusted within a range that can be administered orally. When the orally administered agent 1a is a film-form preparation, the thickness of the intermediate layers 12a and 12b is preferably 1 to 80 μm, and more preferably 10 to 50 μm. When the thickness of the intermediate layers 12a and 12b is less than 1 μm, it is difficult to form a film with high accuracy (that is, the polyvinyl pyrrolidone content of the intermediate layers 12a and 12b varies), while the intermediate layers 12a and 12b When the thickness exceeds 80 μm, the film becomes stiff and difficult to take.

  Examples of the base contained in the intermediate layers 12a and 12b include crystalline cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate. Cellulose such as succinate, carboxymethylethyl cellulose and derivatives thereof or pharmaceutically acceptable salts thereof (for example, sodium salt); starch such as α-starch, oxidized starch, sodium carboxymethyl starch, hydroxypropyl starch, dextrin, dextran And derivatives thereof; sucrose, maltose, lactose, glucose, fructose, pullulan, Sugars such as suntan gum and cyclodextrin; sugar alcohols such as xylitol, mannitol, sorbitol; dimethylaminoethyl (meth) acrylate / (meth) acrylic acid copolymer, (meth) acrylic acid / ethyl acrylate copolymer, (meth) acrylic Acid / (meth) acrylate methyl copolymer, (meth) ethyl acrylate / (meth) acrylated trimethylammonium copolymer, dimethylaminoethyl (meth) acrylate / (meth) acrylated methyl copolymer, (meth) acrylic acid Acrylic acid derivatives such as acrylated ethyl copolymer; shellac; polyvinyl acetal diethylaminoacetate; polyvinyl acetate; polyvinyl alcohol; vinyl acetate-vinyl pyrrolidone copolymer; gum arabic, tragaca Natural rubbers such as ant gum; polyglucosamines such as chitin and chitosan; proteins such as gelatin, casein and soy protein; titanium oxide; calcium monohydrogen phosphate; calcium carbonate; talc; stearate; magnesium metasilicate aluminate; Examples thereof include magnesium silicate, silicic anhydride, glycerin, and the like, and one or more of these can be selected and used.

  The K value of polyvinylpyrrolidone contained in the intermediate layers 12a and 12b is not particularly limited, but is preferably 30 or more, more preferably 60 or more, and most preferably 90 or more. When the water-swellable gel-forming layers 13a and 13b are gelled, the water-swellable gel-forming agent contained in the water-swellable gel-forming layers 13a and 13b interacts with the polyvinyl pyrrolidone contained in the intermediate layers 12a and 12b. In addition, a gel having a higher strength than the case where the water-swellable gel-forming layers 13a and 13b are gelated alone is formed. The interaction between the water-swellable gel-forming agent contained in the water-swellable gel-forming layers 13a and 13b and the polyvinyl pyrrolidone contained in the intermediate layers 12a and 12b is the same as that of polyvinyl pyrrolidone contained in the intermediate layers 12a and 12b. The larger the value, the larger and the strength of the gel formed. When the K value of the polyvinyl pyrrolidone contained in the intermediate layers 12a and 12b is 30 or more, a gel having sufficiently high gel strength can be formed. This improves ease of swallowing, ease and safety when taking the orally-administered agent 1a, and improves masking effects such as drug taste and odor. This effect becomes more remarkable when the K value of polyvinylpyrrolidone contained in the intermediate layers 12a and 12b is 90 or more.

The K value is the intrinsic viscosity of the polymer solution, and is also called the K value of Fikencher.
The K value can be obtained as a value of K that satisfies the following expression.
lnη _r = {75K ² /(1+1.5KC)+K}×C
[Wherein η _r represents relative viscosity, and C represents solute concentration (% (w / v)). ]

  The water-swellable gel-forming layers 13a and 13b contain a water-swellable gel-forming agent and can swell with moisture to form a gel.

  The thickness of the water-swellable gel-forming layers 13a and 13b can be appropriately adjusted within a range that can be administered orally, but when the orally-administered agent 1a is a film-form preparation, it is preferably 10 to 1000 μm, More preferably, it is 15-500 micrometers. When the thickness of the water-swellable gel-forming layers 13a and 13b is less than 10 μm, gel formation is insufficient, and the masking effect such as the taste and smell of the drug by the water-swellable gel-forming layers 13a and 13b is insufficient. On the other hand, when the thickness of the water-swellable gel-forming layers 13a and 13b exceeds 1000 μm, when administered into the oral cavity of a patient or the like, the saliva alone does not sufficiently swell to form a gel and is difficult to take. Become.

  The type of the water-swellable gel-forming agent contained in the water-swellable gel-forming layers 13a and 13b is not particularly limited as long as it can swell with water to form a gel, and is a crosslinked one. Or it may not be crosslinked.

  Examples of the water-swellable gel-forming agent include carboxyvinyl polymer, starch and derivatives thereof, agar, alginic acid, arabinogalactan, galactomannan, cellulose and derivatives thereof, carrageen, dextran, tragacanth, gelatin, pectin, hyaluronic acid, gellan gum , Collagen, casein, xanthan gum, etc., and one or more of these can be selected and used.

  The water-swellable gel-forming agent contained in the water-swellable gel-forming layers 13a and 13b is preferably a carboxyvinyl polymer, particularly polyacrylic acid, and is a cross-linked carboxyvinyl polymer, particularly cross-linked polyacrylic acid. Is more preferable. Polyacrylic acid does not adversely affect the film-forming ability of the film-forming agent, and can exhibit a moderate gel strength during swelling. Moreover, polyacrylic acid can interact with the polyvinylpyrrolidone contained in the intermediate layers 12a and 12b at the time of gel formation, and can form a gel with high gel strength.

  Crosslinking can be performed with a crosslinking agent depending on the type of molecule to be crosslinked. As a polyacrylic acid crosslinking agent, for example, a polyvalent metal compound can be used. Specific examples of the polyvalent metal compound include calcium chloride, magnesium chloride, aluminum chloride, aluminum sulfate, potassium alum, iron chloride alum, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, aluminum phosphate, citric acid. Examples thereof include iron oxide, magnesium oxide, calcium oxide, zinc oxide, and zinc sulfate. Among these, when a trivalent metal compound is used, the degree of cross-linking of polyacrylic acid increases, and when an interaction between cross-linked polyacrylic acid and polyvinyl pyrrolidone occurs, a gel with high gel strength is formed. Can do.

  The amount of the water-swellable gel-forming agent contained in the water-swellable gel-forming layers 13a and 13b can be appropriately adjusted according to the type of the water-swellable gel-forming agent, but preferably the water-swellable gel-forming agent is formed. It is 15-70 mass% of a layer.

  When the orally administered agent 1a is a film-form preparation, it is preferable that the water-swellable gel-forming layers 13a and 13b contain a film-forming agent in order to improve the film-forming properties of the water-swellable gel-forming layers 13a and 13b. .

  The type of the film forming agent is not particularly limited as long as it has film forming ability. Specific examples of the film forming agent include polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, hydroxyalkyl cellulose (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose), alkylcellulose (for example, Methyl cellulose, ethyl cellulose), carboxyalkyl cellulose (for example, carboxymethyl cellulose), (meth) acrylic acid and esters thereof, xanthan gum, carrageenan, alginic acid, etc., and one or more of these should be selected and used Can do.

  The amount of the film-forming agent contained in the water-swellable gel-forming layers 13a and 13b can be adjusted as appropriate according to the type of the film-forming agent, but preferably 30 of the water-swellable gel-forming layers 13a and 13b. It is -85 mass%.

  The film forming agent contained in the water-swellable gel-forming layers 13a and 13b is preferably water-soluble. When the film-forming agent is water-soluble, water easily enters the water-swellable gel-forming layers 13a and 13b, and the water-swellable gel-forming layers 13a and 13b are rapidly swollen and gel-formed in the oral cavity. Can do.

  Examples of the water-soluble film-forming agent include polyvinyl alcohol; hydroxyalkyl cellulose such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose; polyvinylpyrrolidone; xanthan gum; carrageenan;

  The water-swellable gel-forming layers 13a and 13b may contain a plasticizer in order to impart appropriate flexibility to the water-swellable gel-forming layer. Examples of the plasticizer include propylene glycol, polyethylene glycol, glycerin, sorbitol, glycerin triacetate, diethyl phthalate, triethyl citrate, lauric acid, sucrose, and the like. Can be used.

  The water-swellable gel-forming layers 13a and 13b may contain a masking agent capable of masking the taste and smell of the drug contained in the drug-containing layer 11a. When the water-swellable gel-forming layers 13a and 13b contain a masking agent, the masking effect such as the taste and smell of the drug by the water-swellable gel-forming layers 13a and 13b can be improved. As the masking agent, for example, those that give acidity such as citric acid, tartaric acid, fumaric acid, sweeteners such as saccharin, glycyrrhizic acid, sucrose, fructose, mannitol, refreshing agents such as menthol, mint oil, peppermint, spearmint, Natural or synthetic fragrance | flavor etc. are mentioned, Among these, 1 type or 2 types can be selected and used.

  When the water-swellable gel-forming layers 13a and 13b contain polyvinyl alcohol or the like as a film forming agent, these film forming agents can also serve as a masking agent. Thus, it is preferable to use a film forming agent having a masking effect, and it is also preferable to use a water-swellable gel forming agent having a masking effect.

  The water-swellable gel forming layers 13a and 13b may contain a preservative such as methyl hydroxybenzoate and propyl hydroxybenzoate; a colorant such as an edible lake colorant.

  Since mixing of additives into the water-swellable gel-forming layers 13a and 13b generally reduces the strength of the water-swellable gel-forming layers 13a and 13b, water enters the water-swellable gel-forming layers 13a and 13b. The water-swellable gel-forming agent is likely to swell and form gel due to the water that has entered the water-swellable gel-forming layers 13a and 13b.

  As shown in FIG. 1, in the oral administration agent 1a, the water-swellable gel-forming layers 13a and 13b are provided in the outermost layer of the oral administration agent 1a.

  The water-swellable gel-forming layers 13a and 13b provided in the outermost layer of the orally administered agent 1a swell and gel with moisture such as saliva in the patient's mouth, and the orally administered agent 1a has a size, shape, It changes into a dosage form with elasticity, viscosity, etc. Therefore, the patient can easily take the orally administered agent 1a. In addition, since the risk of the oral administration agent becoming clogged in the trachea of the patient during taking is reduced, it can be safely taken even if the patient is an elderly person or an infant. For patients with low saliva and water-swellable gel-forming layers 13a and 13b that are not sufficiently gelled, the same effect can be achieved by taking with a small amount of water or pre-dipping in water before administration. Can do. The amount of water required at this time is very small compared to the amount of water required when taking solid preparations such as tablets and capsules.

  In addition, the water-swellable gel-forming layers 13a and 13b provided in the outermost layer of the orally administered agent 1a swell and gel with moisture such as saliva in the oral cavity of the patient, and the drug contained in the drug-containing layer 11a. The taste (for example, bitterness, astringency), smell, etc. can be masked.

  In particular, in the orally-administered agent 1a, the water-swellable gel-forming layers 13a and 13b are provided in the outermost layer of the orally-administered agent 1a while being directly laminated on the intermediate layers 12a and 12b, respectively. When the forming layers 13a and 13b are gelled, the water-swellable gel-forming agent contained in the water-swellable gel-forming layers 13a and 13b interacts with the polyvinylpyrrolidone contained in the intermediate layers 12a and 12b, thereby causing water swelling. A gel having a higher strength than the case where the gelling layers 13a and 13b are gelated alone is formed. Therefore, in the orally administered agent 1a, ease of swallowing, ease and safety at the time of taking are improved, and masking effects such as drug taste and odor are improved.

  Further, when the water-swellable gel-forming layers 13a and 13b swell and gel with water such as saliva in the patient's mouth, even if the water reaches the drug-containing layer 11a, it is contained in the drug-containing layer 11a. The drug is protected from moisture by the poorly water-soluble polymer contained in the drug-containing layer 11a, and can prevent the drug from eluting from the orally administered agent 1a. Therefore, the masking effect such as the taste and smell of the drug is improved.

The orally administered agent 1a can be produced, for example, according to the following first method and second method.
[First method]
The water-swellable gel-forming layer forming solution, the intermediate layer-forming solution, and the drug-containing layer forming solution are applied to the upper side of the predetermined layer, sprayed, etc., and then dried, and the water-swellable gel-forming layer, the intermediate layer, and the drug-containing layer are specified. Laminate in order. At this time, as the water-swellable gel-forming layer forming liquid, a solution to which a water-swellable gel-forming agent and a film-forming agent are added (the solvent is, for example, purified water or ethanol), and as the intermediate layer-forming liquid, polyvinylpyrrolidone. A solution (solvent is, for example, purified water, ethanol, etc.) is used, and a solution containing a drug and a poorly water-soluble polymer (solvent, for example, purified water, ethanol, etc.) is used as the drug-containing layer forming solution. The laminate in which the water-swellable gel-forming layer, the intermediate layer, and the drug-containing layer are laminated in a predetermined order may be punched into an arbitrary shape such as a circle, an ellipse, or a polygon.

[Second method]
A water-swellable gel-forming layer forming solution is applied to the upper side of a holding substrate such as a plastic film or a mount, sprayed, etc., and dried to form a water-swellable gel-forming layer. The intermediate layer forming solution is applied, sprayed, etc., and dried to produce an intermediate A in which a water-swellable gel forming layer and an intermediate layer are sequentially laminated on a holding substrate. On the other hand, the drug-containing layer forming liquid is applied, sprayed, etc. on the upper side of the holding substrate and dried to produce intermediate B in which the drug-containing layer is laminated on the holding substrate. After heat-sealing the drug-containing layers of the two intermediates B, one holding substrate is peeled off, the drug-containing layer and the intermediate layer of the intermediate A are heat-sealed, and the other holding substrate is The drug-containing layer and the intermediate layer A of the intermediate A are heat-sealed. The laminate in which the water-swellable gel-forming layer, the intermediate layer, and the drug-containing layer are laminated in a desired order may be punched into an arbitrary shape such as a circle, an ellipse, or a polygon.

  The orally administered agent 1a may have a functional layer other than the drug-containing layer, the intermediate layer, and the water-swellable gel-forming layer, for example, an adhesive layer. The adhesive layer is provided between the layers (for example, between the drug-containing layer and the intermediate layer, between the drug-containing layer and the drug-containing layer, and between the water-swellable gel-forming layer and the holding substrate).

  The adhesive contained in the adhesive layer is not particularly limited as long as it is a pharmaceutically acceptable adhesive. Examples of the adhesive that exhibits adhesiveness when used in a state including a solvent include, for example, Hydrophilic cellulose such as carboxyvinyl polymer, polyacrylic acid such as sodium polyacrylate or pharmaceutically acceptable non-toxic salt thereof, acrylic acid copolymer or pharmaceutically acceptable salt thereof, carboxymethyl cellulose and sodium salt Derivatives, pullulan, povidone, karaya gum, pectin, xanthan gum, tragacanth, alginic acid, gum arabic, acidic polysaccharides or derivatives thereof, or pharmaceutically acceptable salts thereof, and the like, and exhibit adhesiveness by heating (that is, heat fusion) Possible adhesives include, for example, homopolymers such as vinyl acetate and polyvinylpyrrolidone. Rimmer, copolymers such as of vinyl acetate and vinyl pyrrolidone.

  Examples of other functional layers include a layer for adjusting the film thickness. When the orally administered agent of the present invention is a film-form preparation, the ease of handling of the orally administered agent of the present invention can be improved by providing such a layer and adjusting the film thickness.

  The orally-administered agent 1a has two water-swellable gel-forming layers 13a and 13b. However, as long as the water-swellable gel-forming layer is located in the outermost layer of the orally-administered agent, the orally-administered agent of the present invention has water-swellability. The number of gel forming layers is not particularly limited.

  FIG. 2 shows an embodiment in which the oral administration agent of the present invention has one water-swellable gel-forming layer. As shown in FIG. 2, the orally administered agent 1b includes a drug-containing layer 11a, a water-swellable gel-forming layer 13a, and an intermediate layer 12a provided between the drug-containing layer 11a and the water-swellable gel-forming layer 13a. Have When administering the oral administration agent 1b, as shown in FIG. 3, the outermost layer of the oral administration agent 1b can be covered with the water-swellable gel-forming layer 13a by bending the oral administration agent 1b. The same effect as 1a is exhibited.

  FIG. 4 shows an embodiment in which the oral administration agent of the present invention has four water-swellable gel-forming layers. As shown in FIG. 4, the orally-administered drug 1c is composed of a drug-containing layer 11a, a water-swellable gel-forming layer 13c laminated on the lower side of the drug-containing layer 11a, and a lower side of the water-swellable gel-forming layer 13c. The water-swellable gel-forming layer 13a laminated via the intermediate layer 12a, the water-swellable gel-forming layer 13d laminated on the upper side of the drug-containing layer 11a, and the intermediate layer 12b on the upper side of the water-swellable gel-forming layer 13d And a water-swellable gel-forming layer 13b laminated through the layers.

  In the orally administered agent 1a, as shown in FIG. 5, one drug-containing layer 11a may be formed by the drug-containing layers 11a 'and 11a' 'formed side by side.

Although the orally administered agent 1a has one drug-containing layer, the number of drug-containing layers that the orally administered agent of the present invention has is not particularly limited.
When the orally administered agent of the present invention has a plurality of drug-containing layers, the drug-containing layers can be laminated directly or via an adhesive layer.

  One embodiment in the case where the oral administration agent of the present invention has two drug-containing layers is shown in FIG. As shown in FIG. 6, the orally-administered drug 1d was laminated with two drug-containing layers 11a and 11b laminated via an adhesive layer 14 and an intermediate layer 12a below the drug-containing layer 11a. It has a water-swellable gel-forming layer 13a and a water-swellable gel-forming layer 13b laminated on the upper side of the drug-containing layer 11b via an intermediate layer 12b.

  The orally-administered agent 1a is a layered drug in which a plurality of layers are laminated in a flat shape, but the orally-administered agent of the present invention may have any shape as long as it is layered, for example, a flat one The shape may be folded (see FIG. 3).

  Oral administration agent 1a may be in a state of being held on a holding base material, or may be in a state of being peeled off from the holding base material.

Hereinafter, the present invention will be described in more detail with reference to production examples and test examples.
[Production Example 1] Production of orally administered drug Manufacture of the product of the present invention (1) Preparation of water-swellable gel-forming layer forming liquid (coating liquid A) Coating liquid A was prepared in order to form a water-swellable gel-forming layer. 280 g of purified water was taken, 0.3 g of calcium chloride was added therein, and stirred to completely dissolve. Next, 11.25 g of polyacrylic acid (Carbopol 974P (BF Goodrich)) was slowly added with stirring and stirred for about 1 hour to completely dissolve. Next, 33.75 g of polyvinyl alcohol (Gosenol EG-05T (Nippon Synthetic Chemical)) was slowly added with stirring, and the mixture was completely dissolved by stirring for about 1 hour while heating to 70 ° C. Next, 4 g of glycerin (Kanto Chemical) was added and stirred for about 5 minutes.

  Polyacrylic acid is cross-linked by calcium ions generated by the ionization of calcium chloride, and the cross-linked polyacrylic acid serves as a water-swellable gel-forming agent, and polyvinyl alcohol serves as a film-forming agent.

(2) Formation of a water-swellable gel-forming layer Using an applicator with a gap adjusted so that the coating liquid A is sufficiently degassed and the coating amount after drying is 20 g / m ² (thickness 16 μm), A polyethylene terephthalate film (manufactured by Lintec Corporation, product name: SP-PET3801) was spread-coated on the surface opposite to the silicone resin release surface and dried at 80 ° C. for 5 minutes to form a water-swellable gel-forming layer. .

(3) Preparation of intermediate layer forming liquid (coating liquid B) A coating liquid B was prepared in order to form an intermediate layer. 46.4 g of purified water and 2.6 g of ethanol are taken, 0.6 g of titanium oxide is added therein, and after sufficiently dispersed using a homogenizer, polyvinylpyrrolidone (PVP K-90 (ISP Japan)) is added therein. ) 16.3 g and 4.0 g of glycerin (Kanto Chemical) were slowly added with stirring and stirred for about 20 minutes to completely dissolve. The K value of PVP K-90 is 90.

(4) Formation of intermediate layer Using the applicator with the gap adjusted so that the coating liquid B is sufficiently degassed and the coating amount after drying is 30 g / m ² (thickness 38 μm), (2) The film was spread and applied on the water-swellable gel-forming layer formed in Step 1, and dried at 80 ° C. for 5 minutes to form an intermediate layer. In this way, two sheets of intermediate A in which the water-swellable gel-forming layer was laminated on the polyethylene terephthalate film and the intermediate layer was laminated on the water-swellable gel-forming layer were produced.

(5) Preparation of drug-containing layer forming solution (coating solution C) Coating solution C was prepared in order to form a drug-containing layer. 10 g of purified water was taken, and 15 g of diphenhydramine hydrochloride, which is an antihistamine, was added therein and dissolved completely. Next, 45.8 g of a 15% by mass polyvinyl alcohol (GOHSENOL EG-40 (Nippon Synthetic Chemical)) aqueous solution was slowly added with stirring to completely dissolve the solution.

(6) Formation of drug-containing layer Polyethylene terephthalate using an applicator in which the gap was adjusted so that the coating amount after drying of coating solution C was 103 g / m ² (thickness 80 μm) The film (Lintec Co., Ltd., product name: SP-PET3801) was spread-coated on the surface opposite to the silicone resin release-treated surface, and dried at 90 ° C. for 10 minutes to form a drug-containing layer. In this way, two sheets of intermediate B in which the drug-containing layer was laminated on the polyethylene terephthalate film were produced.

(7) Manufacture of Orally Administered by Thermal Fusion The drug-containing layers of the two intermediates B were thermally fused at 100 ° C., 1 kgf / cm ² , and 1 second. Next, one polyethylene terephthalate film of the two heat-bonded intermediates B was peeled off, and heat-welded with the intermediate layer of the one intermediate A under the conditions of 100 ° C., 1 kgf / cm ² and 1 second. Next, the other polyethylene terephthalate film of the two intermediates B that had been heat-sealed was peeled off and heat-sealed with the intermediate layer of the other intermediate A at 100 ° C., 1 kgf / cm ² , for 1 second. . Thus, an oral administration agent (product of the present invention) in which a water-swellable gel-forming layer, an intermediate layer, a drug-containing layer, an intermediate layer, and a water-swellable gel-forming layer were sequentially laminated was produced.

2. Production of Comparative Product In the same manner as in the above (1) and (2), 2 sheets of Intermediate C in which a water-swellable gel-forming layer was laminated on a polyethylene terephthalate film were produced. The drug-containing layers of the two intermediates B were heat-sealed at 100 ° C., 1 kgf / cm ² , and 1 second. Next, the polyethylene terephthalate film of one of the two heat-bonded intermediates B is peeled off, and heat-sealed with the water-swellable gel-forming layer of the intermediate C at 100 ° C., 1 kgf / cm ² for 1 second. It was. Next, the other polyethylene terephthalate film of the two heat-bonded intermediates B is peeled off, and heat-sealed with the water-swellable gel-forming layer of the intermediate C at 100 ° C., 1 kgf / cm ² , for 1 second. It was. Thus, an oral administration agent (Comparative Product 1) in which a water-swellable gel-forming layer, a drug-containing layer, and a water-swellable gel-forming layer were sequentially laminated was produced.
In addition, an oral administration agent (Comparative Product 2) was produced by replacing polyvinyl alcohol, which is the base of the drug-containing layer, with polyvinylpyrrolidone in the product of the present invention.

[Test Example 1]
After punching out an orally-administered drug into a circular shape with a diameter of 15 mm, the subject 10 randomly picked it up and taking it without water, and evaluated the following five levels of gelling ability and drug taste masking ability: Evaluated according to.

[Evaluation criteria for gelation ability]
5 ... Swells and gels sufficiently in a short time 4 ... Swells and gels 3 ... Swells and gels but dissolves over time 2 ... Slightly swells and gels but short Dissolves over time 1 ... Dissolves without swelling or gelation

[Evaluation criteria for masking ability]
5 ... Does not feel the taste of the drug 4 ... Almost does not feel the taste of the drug 3 ... I feel the taste of the drug, but there is no problem in taking the drug 2 ... Taste of the drug immediately after taking the drug I feel the taste of the drug within the time it takes to take 1 ... I feel the taste of the drug immediately after taking it

  As shown in Table 1, the product of the present invention was superior in gelling ability and drug taste masking ability to Comparative Products 1 and 2.

It is sectional drawing which shows one Embodiment of the oral administration agent of this invention. It is sectional drawing which shows another embodiment of this invention. It is sectional drawing which shows the aspect at the time of administration of the oral administration agent shown in FIG. It is sectional drawing which shows another embodiment of the oral administration agent of this invention. It is sectional drawing which shows another embodiment of the oral administration agent of this invention. It is sectional drawing which shows another embodiment of the oral administration agent of this invention.

Explanation of symbols

1a, 1b, 1c, 1d ... Orally administered agent 11a, 11b ... Drug-containing layers 12a, 12b ... Intermediate layers 13a, 13b, 13c, 13d ... Water-swellable gel-forming layers

Claims (6)

An oral administration agent comprising a drug-containing layer, a water-swellable gel-forming layer, and an intermediate layer provided between the drug-containing layer and the water-swellable gel-forming layer,
The drug-containing layer is based on polyvinyl alcohol, ethylcellulose, hydroxypropylmethylcellulose, acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, carboxymethylcellulose, hydroxypropyl starch, dimethylaminoethyl (meth) acrylate ( (Meth) acrylic acid copolymer, (meth) acrylic acid / ethyl acrylate copolymer, (meth) acrylic acid / (meth) methyl acrylate copolymer, (meth) acrylic acid / (meth) acrylated trimethylammonium copolymer, (meta ) Dimethylaminoethyl acrylate / methyl methacrylate (meth) acrylate copolymer, (meth) acrylic acid / ethyl acrylate copolymer, Containing one or more kinds selected vinyl acetal diethylamino acetate, polyvinyl acetate and Jerakku,
The intermediate layer contains polyvinylpyrrolidone;
The oral administration agent provided in the outermost layer of the oral administration agent in a state where the water-swellable gel-forming layer is directly laminated on the intermediate layer. Polyvinyl alcohol, ethylcellulose, hydroxypropylmethylcellulose, acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, carboxymethylcellulose, hydroxypropyl starch, dimethylaminoethyl (meth) acrylate ( (Meth) acrylic acid copolymer, (meth) acrylic acid / ethyl acrylate copolymer, (meth) acrylic acid / (meth) methyl acrylate copolymer, (meth) acrylic acid / (meth) acrylated trimethylammonium copolymer, (meta ) Dimethylaminoethyl acrylate / methyl methacrylate (meth) acrylate copolymer, (meth) acrylic acid / ethyl acrylate copolymer, Vinyl acetal diethylamino acetate, one or more kinds of the total amount is orally administered agent according to claim 1, wherein 10 mass% or more of the drug-containing layer is selected from polyvinyl acetate and Jerakku. The oral administration agent according to claim 1 or 2, wherein the drug-containing layer contains polyvinyl alcohol as a base .   The oral administration agent according to any one of claims 1 to 3, wherein the polyvinyl pyrrolidone has a K value of 30 or more.   The oral administration agent according to any one of claims 1 to 4, wherein the water-swellable gel-forming agent contained in the water-swellable gel-forming layer is polyacrylic acid.   The oral administration agent according to any one of claims 1 to 5, wherein the oral administration agent is a film-form preparation.

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