JP4953673B2 - 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 provided on both sides of the drug-containing layer, wherein the water-swellable gel-forming layer is provided in the outermost layer of the oral administration agent. Orally administered drugs have been developed (see 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

  The present inventor made an oral administration agent having a drug-containing layer containing a water-soluble drug and a water-swellable gel-forming layer, and then caused the moisture remaining in the oral administration agent, the moisture in the environment, etc. It was confirmed that a phenomenon occurs in which the water-soluble drug contained in the drug-containing layer migrates to another layer over time. The water-soluble drug moves to the whole oral administration agent over time, and the water-soluble drug transferred to the water-swellable gel-forming layer is retained in the water-swellable gel-forming layer. When such an orally administered agent is taken, the water-soluble drug retained in the water-swellable gel-forming layer is trapped as it is in the water-swellable gel-forming layer that has been gelled by the water in saliva and has become difficult to dissolve in water. Therefore, there is a problem that elution of the water-soluble drug held in the water-swellable gel-forming layer is delayed.

  Accordingly, the present invention relates to an oral administration that can prevent a delay in elution of a water-soluble drug from an oral administration agent in an oral administration agent having a drug-containing layer containing a water-soluble drug and a water-swellable gel-forming layer. The purpose is to provide an agent.

  In order to solve the above-mentioned problem, the oral administration agent of the present invention is an oral administration agent having a drug-containing layer containing a water-soluble drug and a water-swellable gel-forming layer. The total amount of the gel forming layer is 5 to 15% by mass of the oral administration agent.

  When the ratio of the total amount of the water-swellable gel-forming layer contained in the orally administered agent is in the range of 5 to 15% by mass, it is possible to prevent delay of elution of the water-soluble drug from the orally administered agent. For example, when the dissolution of a drug from the oral administration agent of the present invention was measured using the dissolution test method (paddle method) described in the 14th revision Japanese Pharmacopoeia, 85% of the water-soluble drug contained in the drug-containing layer The above can be eluted within 15 minutes.

  The oral administration agent of the present invention is, for example, a single layer of water-swellable gel-forming layer or a plurality of layers laminated directly or via a water-soluble intermediate layer directly or via a water-soluble intermediate layer. A water-swellable gel-forming layer is provided. When the orally-administered agent has such a configuration, the elution of the water-soluble drug from the orally-administered agent tends to be delayed, but in the orally-administered agent of the present invention, the elution of the water-soluble drug from the orally-administered agent is likely to occur. Delay can be prevented.

The oral administration agent of the present invention preferably has a water-swellable gel-forming layer as the outermost layer.
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.

The oral administration agent of the present invention is preferably a film-form 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 orally administered agent 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 film-forming property in the water-swellable gel-forming layer and / or intermediate layer 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.

  According to the present invention, an oral administration agent having a drug-containing layer containing a water-soluble drug and a water-swellable gel-forming layer, which can prevent delay of elution of the water-soluble drug from the oral administration agent. An oral dosage is provided.

Hereinafter, embodiments of the present invention will be described with reference to the drawings.
As shown in FIG. 1, an oral administration agent 1a according to an embodiment of the oral administration agent of the present invention is directly laminated on a drug-containing layer 11a containing a water-soluble drug and one surface side of the drug-containing layer 11a. Water-swellable gel-forming layer 12a and a single-layer water-swellable gel-forming layer 12b laminated directly on the other surface side of drug-containing layer 11a, The total amount of the water-soluble gel-forming layer (the total amount of the water-swellable gel-forming layers 12a and 12b) is 5 to 15% by mass of the orally administered agent 1a.

  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 size of the orally administered agent 1a can be appropriately adjusted within a range in which it can be administered orally. When orally administered pharmaceutical composition 1a is a film preparation, usually 25～2500Mm ^2, preferably 50 to 1000 mm ^2, more preferably 100 to 500 mm ^2.

The basis weight (mass per unit area) of the orally administered agent 1a can be appropriately adjusted within a range in which it can be administered orally. When orally administered pharmaceutical composition 1a is a film preparation, the basis weight of the orally-administered agent 1a is preferably 15~1000g / ^{m 2,} more preferably from 60~600g / ^{m 2,} 80~400g / and particularly preferably m ^2. When the basis weight of the orally-administered agent 1a is less than 15 g / m ² , the film may become brittle, whereas when the basis weight of the orally-administered agent 1a exceeds 1000 g / m ² , the film becomes stiff and difficult to take. .

  The water-swellable gel-forming layers 12a and 12b contain a water-swellable gel-forming agent and can swell with moisture to form a gel.

  The basis weight of the water-swellable gel-forming layers 12a and 12b is such that the total amount of the water-swellable gel-forming layers contained in the oral administration agent 1a (the total amount of the water-swellable gel-forming layers 12a and 12b) is the same as that of the oral administration agent 1a. It is essential to adjust so that it may become 5-15 mass%. When the total amount of the water-swellable gel-forming layer contained in the orally-administered agent 1a is less than 5% by mass of the orally-administered agent 1a, gel formation becomes insufficient, and the taste of the drug by the water-swellable gel-forming layers 12a and 12b , Masking effect such as odor is insufficient. On the other hand, when the total amount of the water-swellable gel-forming layer contained in the orally-administered agent 1a exceeds 15% by mass of the orally-administered agent 1a, when the orally-administered agent 1a is taken, the water-swellable gel-forming layers 12a and 12b The water-soluble drug that has been transferred and retained is trapped as it is in the water-swellable gel-forming layers 12a and 12b that have become gelled by water in the saliva and have become difficult to dissolve in water. There arises a problem that the elution of the water-soluble drug held in 12a and 12b is delayed.

When the orally-administered agent 1a is a film-form preparation, the total basis weight of the water-swellable gel-forming layers 12a and 12b contained in the orally-administered agent 1a is preferably ² to 150 g / m ² , and preferably 3 to 90 g / m ^2. m ² is more preferable, and 4 to 60 g / m ² is particularly preferable. If the basis weight of either the water-swellable gel-forming layer 12a or 12b is less than 1 g / m ² , gel formation becomes insufficient, and the water-swellable gel-forming layers 12a and 12b have a masking effect such as the taste and smell of the drug. However, when the basis weight of either the water-swellable gel-forming layer 12a or 12b exceeds 75 g / m ² , the saliva alone swells sufficiently when administered into the oral cavity of a patient or the like. A gel cannot be formed, making it difficult to take. That is, each basis weight of the water-swellable gel-forming layers 12a and 12b is preferably ¹ to 75 g / m ² .

  The type of the water-swellable gel-forming agent contained in the water-swellable gel-forming layers 12a and 12b 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 12a and 12b 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.

  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.

  The total amount of the water-swellable gel-forming agent contained in the water-swellable gel-forming layers 12a and 12b is not particularly limited and can be appropriately adjusted according to the type of the water-swellable gel-forming agent. Preferably, it is 15 to 70% by mass of the water-swellable gel-forming layers 12a and 12b.

  When the orally administered agent 1a is a film-form preparation, it is preferable to contain a film-forming agent in the water-swellable gel-forming layers 12a and 12b in order to improve the film-forming property of the water-swellable gel-forming layers 12a and 12b. .

  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 12a and 12b can be appropriately adjusted according to the type of film-forming agent, etc., but preferably 30 of the water-swellable gel-forming layers 12a and 12b. It is -85 mass%.

  The film forming agent contained in the water-swellable gel-forming layers 12a and 12b is preferably water-soluble. If the film-forming agent is water-soluble, water easily enters the water-swellable gel-forming layers 12a and 12b, and the water-swellable gel-forming layers 12a and 12b 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 12a and 12b 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 12a and 12b may contain a masking agent that can mask the taste, smell, etc. of the drug contained in the drug-containing layer 11a. When the water-swellable gel-forming layers 12a and 12b contain a masking agent, the masking effect such as the taste and smell of the drug by the water-swellable gel-forming layers 12a and 12b can be improved. Masking agents include, for example, those that give sour taste such as citric acid, tartaric acid, fumaric acid, sweeteners such as saccharin, glycyrrhizic acid, sucrose, fructose, mannitol, acesulfame potassium, menthol, mint oil, peppermint, spearmint, etc. Examples thereof include naturalizing agents, natural or synthetic fragrances, and one or two of these can be selected and used.

  When the water-swellable gel-forming layers 12a and 12b 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 12a and 12b 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 12a and 12b generally reduces the strength of the water-swellable gel-forming layers 12a and 12b, water can enter the water-swellable gel-forming layers 12a and 12b. 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 12a and 12b.

In the orally administered agent 1a, the gel fraction of the water-swellable gel-forming layers 12a and 12b calculated by the following steps (1) to (10) is preferably 40% or more. When the gel fraction of the water-swellable gel-forming layers 12a and 12b is 40% or more, when the water-swellable gel-forming layers 12a and 12b swell and gel with water such as saliva in the patient's mouth, The shape, elasticity, viscosity and the like of the orally administered agent 1a can be kept moderate. In addition, when the gel fraction of the water-swellable gel-forming layers 12a and 12b is 40% or more, the problem of delayed elution of the water-soluble drug due to traps in the water-swellable gel-forming layer is likely to occur. In 1a, this problem is solved.
Step (1): The water-swellable gel-forming layer is separated from the orally administered agent, and the separated water-swellable gel-forming layer is cut into two pieces (A) and (B).
Step (2): The mass (a) of the fragment (A) is measured.
Step (3): The fragment (A) is dried at 105 ° C. for 4 hours, and the mass (b) of the fragment (A) after drying is measured.
Step (4): The moisture content (c) per unit mass of the fragment (A) before drying is calculated based on the formula: c = (ab) / a.
Step (5): The mass (d) of the fragment (B) is measured.
Step (6): The mass (e) of components other than water contained in the fragment (B) is calculated based on the formula: e = d−d × c.
Step (7): The fragment (B) is put in a nylon bag (120 mesh, mass (f)), sealed, and immersed in 0.9% physiological saline for 24 hours.
Step (8): The nylon bag taken out from the physiological saline solution after 24 hours of immersion is dried at 105 ° C. for 4 hours, and the mass (g) of the dried nylon bag is measured.
Step (9): The mass (h) of the fragment (B) present in the nylon bag after drying is calculated based on the formula: h = g−f.
Step (10): The gel fraction (i) of the fragment (B) is calculated based on the formula: i = (h / e) × 100.

  As shown in FIG. 1, in the orally-administered agent 1a, the water-swellable gel-forming layers 12a and 12b are provided in the outermost layer of the orally-administered agent 1a while being directly laminated on the drug-containing layer 11a. The water-swellable gel-forming layers 12a and 12b 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 12a and 12b that are not sufficiently gelled, exhibit the same effect by taking them 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 12a and 12b 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.

The drug-containing layer 11a is a layer containing a water-soluble drug to be administered.
The basis weight of the drug-containing layer 11a is such that the total amount of the water-swellable gel-forming layer contained in the orally-administered agent 1a (the total amount of the water-swellable gel-forming layers 12a and 12b) is 5 to 15% by mass of the orally-administered agent 1a. It is essential to adjust so that. That is, the amount of the drug-containing layer 11a (the total amount when there are a plurality of drug-containing layers) is adjusted to 85 to 95% by mass of the orally administered agent 1a. When the orally administered agent 1a is a film-form preparation, the basis weight of the drug-containing layer 11a is preferably 13 to 950 g / m ² . If the basis weight of the drug-containing layer 11a is less than 13 g / m ² or more than 950 g / m ² , the basis weight of the water-swellable gel-forming layer cannot be set within the optimum range described above.

  The drug-containing layer 11a may be composed of only the drug to be administered, but normally the water-soluble drug is in a desired state (that is, the water-soluble drug from the drug-containing layer 11a by water that has entered the orally-administered agent 1a). As a base for holding the drug-containing layer 11a), a pharmaceutically acceptable excipient, binder, disintegrant, masking agent, colorant, plasticizer, etc. may be contained. . Examples of the base include cellulose such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, and the like. And derivatives thereof or pharmaceutically acceptable salts thereof (for example, sodium salts); starch and derivatives thereof such as α-starch, oxidized starch, sodium carboxymethyl starch, hydroxypropyl starch, dextrin, dextran; pullulan, xanthan gum, Sugars such as cyclodextrin; dimethylamino methacrylate Ethyl / methacrylic acid copolymer, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, ethyl methacrylate / methacrylated trimethylammonium copolymer, dimethylaminoethyl methacrylate / methacrylated Acrylic acid derivatives such as methyl copolymer, methacrylic acid / acrylated ethyl copolymer; shellac; polyvinyl acetal diethylaminoacetate; polyvinyl acetate; polyvinyl alcohol; polyvinyl pyrrolidone; vinyl acetate-vinyl pyrrolidone copolymer; gum arabic, tragacanth rubber, etc. Natural rubbers; polyglucosamines such as chitin and chitosan; and proteins such as gelatin, casein and soy protein. One type or two or more types can be selected and used. In addition, the drug-containing layer 11a has titanium oxide, calcium monohydrogen phosphate, calcium carbonate, talc, stearate, magnesium aluminate metasilicate, magnesium silicate, anhydrous silica for the purpose of coloring and improving shape retention. One or more kinds of inorganic fillers such as acids can be selected and added. Further, the drug-containing layer 11a is provided with propylene glycol, polyethylene glycol, glycerin, sorbitol, glycerin triacetate, diethyl phthalate, triethyl citrate, lauric acid, sucrose in order to impart appropriate flexibility to the drug-containing layer 11a. One or two of plasticizers such as these can be selected and added.

  The total amount of the base contained in the drug-containing layer 11a is an amount capable of forming the drug-containing layer 11a, and the amount can be appropriately adjusted according to the type of the base. The content of the containing layer 11a is usually 20% by mass or more, preferably 60% by mass or more, and more preferably 70% by mass or more. When the total content of the base is less than 20% by mass, the drug-containing layer 11a is not sufficiently formed. In addition, the upper limit of the total content of the base can be appropriately set according to the content of the drug.

  The water-soluble 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 is a water-soluble drug that can be administered orally. As water-soluble drugs that can be administered orally, for example, drugs acting on the central nervous system include hypnotics such as sodium pentobarbital; psychotropic drugs such as amitriptine hydrochloride, imipramine hydrochloride, chlorpromazine, levomepromazine; pronase, dipotassium glycyrrhizinate, loxoprofen Analgesics and anti-inflammatory drugs such as sodium; central nervous system metabolism stimulators such as adenosine triphosphate disodium; migraine treatments such as dimethothiazine mesylate; expectorants such as ethylcysteine hydrochloride as drugs acting on the respiratory tract An anti-asthma drug such as corintheophylline, terbutaline sulfate, tranilast, procaterol hydrochloride; a cardiotonic drug such as aminophylline; an antiarrhythmic drug such as procainamide hydrochloride, mexiletine hydrochloride; alprenolol hydrochloride, salt Antianginal drugs such as dilazep, diltiazem hydrochloride, and trimetazidine hydrochloride; peripheral vasodilators such as kallidinogenase; antihypertensive drugs such as captopril, clonidine hydrochloride, metoprolol tartrate, hydralazine hydrochloride, propranolol hydrochloride; dextran sodium sulfate, pravastatin sodium, etc. Anti-arteriosclerotic agents; blood and hematopoietic agents, hemostatic agents such as tranexamic acid; anti-thrombotic agents such as ticlopidine hydrochloride and warfarin potassium; anti-anemic agents such as iron sulfate; hydrochloric acid as a drug acting on the digestive system Anti-ulcer drugs such as ranitidine and rabeprazole sodium; Antiemetics such as metoclopramide; Digestive enzyme preparations; Liver extract hydrolyzate, glucuronolactone, diisopropylamine dichloroacetate treatments; Picosulfate and other laxatives; Ship Anti-diabetic drugs such as acarbose and voglibose as drugs acting on the skin; anti-vertigo drugs such as betahistine mesylate and isosorbide as drugs in the otolaryngology area; isoniazid, ethambutol hydrochloride, erythromycin lactopionate as chemotherapeutic drugs and antibiotics, Fosfomycin sodium, etc .; antineoplastic agent, cyclophosphamide, etc .; hormones and endocrine therapeutic agents, thiamazole, sodium prednisolone phosphate, betamethasone sodium phosphate, etc .; bioactive substance (ortachoid), diphenhydramine hydrochloride, hydrochloric acid Antihistamines such as cetirizine and D-chlorpheniramine maleate; cetotiamine hydrochloride, thiamine hydrochloride, cobamide, pyridoxine hydrochloride, hydrosocobalamin acetate, nicotinamide, panthenol And vitamins such as calcium pantothenate, sodium phosphate riboflavin, ascorbic acid and the like, and derivatives thereof, and one or more of these can be selected and used depending on the purpose of treatment / prevention, etc. . The drug-containing layer 11a may contain a drug other than the water-soluble drug.

  The amount of the water-soluble drug contained in the drug-containing layer 11a is not particularly limited, but is usually 80% by mass or less, preferably 40% by mass or less, more preferably 30% by mass or less of the drug-containing layer 11a. is there. When the drug content exceeds 80% 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 can contain a wide variety of drugs ranging from a very small dose to a large amount of drug. This is because the drug-containing layer 11a and the water-swellable gel-forming layers 12a and 12b are formed as separate layers, so that the drug content of the drug-containing layer 11a increases and the film strength of the drug-containing layer 11a decreases. This is because the strength of the film-form preparation as a whole can be maintained by imparting film-forming properties to the water-swellable gel-forming layers 12a and 12b.

The orally administered agent 1a can be produced, for example, according to the following production method.
[First production method]
A coating liquid for forming a water-swellable gel-forming layer or drug-containing layer is applied to a holding substrate (for example, a plastic film or a mount) or an upper side of a predetermined layer, sprayed, etc., and then dried to be water-swellable. The gel forming layer and the drug-containing layer are laminated in a predetermined order. At this time, as a coating liquid for forming a water-swellable gel-forming layer, a solution containing a water-swellable gel-forming agent, a film-forming agent or the like (a solvent is, for example, purified water, ethanol, etc.) As a coating solution for forming a layer, a solution to which a drug, a base, or the like is added (a solvent is, for example, purified water or ethanol) can be used.

[Second production method]
The coating liquid for forming the water-swellable gel-forming layer is applied on the upper side of the holding substrate, sprayed, etc., dried to form the water-swellable gel-forming layer, and then on the upper side of the water-swellable gel-forming layer. A coating solution for forming the drug-containing layer is applied, sprayed, etc., and dried to form the drug-containing layer. In this way, an intermediate in which the water-swellable gel-forming layer and the drug-containing layer are sequentially laminated on the holding substrate is manufactured, and the intermediate drug-containing layers are heat-sealed.

  In the first production method and the second production method, the laminate in which the water-swellable gel-forming 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. .

In the orally administered agent 1a, a water-soluble intermediate layer may be provided between the drug-containing layer 11a and the water-swellable gel-forming layer 12a, or between the drug-containing layer 11a and the water-swellable gel-forming layer 12b. Good.
For example, as shown in FIG. 2, an oral administration agent 1b according to an embodiment of the oral administration agent of the present invention has a drug-containing layer 11a and a water-soluble intermediate layer 13a on one surface side of the drug-containing layer 11a. Provided with one water-swellable gel-forming layer 12a and one water-swellable gel-forming layer 12b provided on the other surface side of the drug-containing layer 11a via a water-soluble intermediate layer 13b. The total amount of the water-swellable gel-forming layer contained in the orally-administered agent 1b (the total amount of the water-swellable gel-forming layers 12a and 12b) is 5 to 15% by mass of the orally-administered agent 1b.

  The basis weight of the water-soluble intermediate layers 13a and 13b is such that the total amount of the water-swellable gel-forming layer contained in the oral administration agent 1b (the total amount of the water-swellable gel-forming layers 12a and 12b) is 5 to 15% by mass. Adjust to. That is, the total amount of the drug-containing layer 11a (all drug-containing layers when there are a plurality of drug-containing layers) and the water-soluble intermediate layers 13a and 13b is adjusted to 85 to 95% by mass of the orally administered agent 1b. . The mass ratio between the drug-containing layer 11a (all drug-containing layers when there are a plurality of drug-containing layers) and the water-soluble intermediate layers 13a and 13b is appropriately selected within the range of 100: 0 to 20:80.

  The components contained in the water-soluble intermediate layers 13a and 13b are not particularly limited as long as they are water-soluble. Various functions such as a function as an adhesive layer, a function as a layer for adjusting the film thickness, and the like can be imparted to the water-soluble intermediate layers 13a and 13b. When the water-soluble intermediate layers 13a and 13b are provided with a function as an adhesive layer, the water-soluble intermediate layers 13a and 13b contain an adhesive. The adhesive contained in the water-soluble intermediate layers 13a and 13b is not particularly limited as long as it is a pharmaceutically acceptable adhesive. As an adhesive that exhibits adhesiveness when used in a state containing a solvent. Is, for example, carboxyvinyl polymer, polyacrylic acid such as sodium polyacrylate or a pharmaceutically acceptable non-toxic salt thereof, an acrylic acid copolymer or a pharmaceutically acceptable salt thereof, carboxymethylcellulose and sodium salt, etc. Hydrophilic cellulose 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 ( Examples of adhesives that can be heat-sealed include, for example, vinyl acetate, polyvinyl chloride Homopolymers pyrrolidone, copolymers such as of vinyl acetate and vinyl pyrrolidone.

  In the orally administered agents 1a and 1b, one water-swellable gel forming layer 12a is provided on one surface side of the drug-containing layer 11a, and one water-swelling gel-forming layer 12a is provided on the other surface side of the drug-containing layer 11a. Although the swellable gel-forming layer 12b is provided, the number of water-swellable gel-forming layers provided on one or the other surface side of the drug-containing layer 11a is not particularly limited, and is two or more. Also good.

  For example, as shown in FIG. 3, an oral administration agent 1c according to an embodiment of the oral administration agent of the present invention includes a drug-containing layer 11a and two pieces of water provided on one surface side of the drug-containing layer 11a. Water having swelling gel-forming layers 12a and 12a ′ and two water-swelling gel-forming layers 12b and 12b ′ provided on the other surface side of the drug-containing layer 11a and contained in the orally-administered drug 1c The total amount of the swellable gel-forming layer (the total amount of the water-swellable gel-forming layers 12a, 12a ′, 12b and 12b ′) is 5 to 15% by mass of the orally administered agent 1c.

  When a plurality of water-swellable gel-forming layers are provided on one or the other surface side of the drug-containing layer 11a, the water-swellable gel-forming layers may be directly laminated with each other (see FIG. 3) or a water-soluble intermediate You may laminate | stack through the layer.

  For example, as shown in FIG. 4, an oral administration agent 1d according to an embodiment of the oral administration agent of the present invention includes a drug-containing layer 11a and two water provided on one side of the drug-containing layer 11a. The swellable gel-forming layers 12a and 12a ′, the two water-swellable gel-forming layers 12b and 12b ′ provided on the other surface side of the drug-containing layer 11a, and the water-swellable gel-forming layers 12a and 12a ′ Water-soluble intermediate layer 14a provided therebetween and water-soluble intermediate layer 14b provided between water-swellable gel-forming layers 12b and 12b ′, and water-swellable gel formation contained in orally administered drug 1d The total amount of the layers (the total amount of the water-swellable gel-forming layers 12a, 12a ′, 12b and 12b ′) is 5 to 15% by mass of the orally administered agent 1d.

  The basis weight, components, functions, and the like of the water-soluble intermediate layers 14a and 14b are the same as those of the water-soluble intermediate layers 13a and 13b.

In the orally administered agents 1a to 1d, the drug-containing layer 11a may be formed of a plurality of drug-containing layers.
For example, as shown in FIG. 5, an oral administration agent 1e according to an embodiment of the oral administration agent of the present invention includes a drug-containing layer 11a formed from side-by-side drug-containing layers 11a ′ and 11a ″. One water-swellable gel-forming layer 12a provided on one surface side of the drug-containing layer 11a, and one water-swellable gel-forming layer 12b provided on the other surface side of the drug-containing layer 11a The total amount of the water-swellable gel-forming layer contained in the orally-administered agent 1e (the total amount of the water-swellable gel-forming layers 12a and 12b) is 5 to 15% by mass of the orally-administered agent 1e.

When the drug-containing layer 11a is formed from a plurality of drug-containing layers, the drug-containing layers may be directly stacked on each other or may be stacked via a water-soluble intermediate layer.
For example, as shown in FIG. 6, an orally administered agent 1f according to an embodiment of the orally administered agent of the present invention includes a drug-containing layer 11a formed from drug-containing layers 11a ′ and 11a ″ that are directly laminated to each other. One water-swellable gel-forming layer 12a provided on one surface side of the drug-containing layer 11a, and one water-swellable gel-forming layer 12b provided on the other surface side of the drug-containing layer 11a The total amount of the water-swellable gel-forming layer contained in the orally-administered agent 1f (the total amount of the water-swellable gel-forming layers 12a and 12b) is 5 to 15% by mass of the orally-administered agent 1f.

  The orally administered agents 1a to 1f are layered drugs in which a plurality of layers are laminated in a flat shape, but may have any shape as long as they are layered. Moreover, the orally administered agents 1a to 1f 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 Production of Invention Products 1 to 4 (1) Preparation of Water-Swellable Gel-Forming Layer Forming Solution (Coating Solution A) Coating solution A was prepared to form a water-swellable gel-forming layer. 280 g of purified water (Japanese Pharmacopoeia purified water (Otsuka Pharmaceutical)) was taken, 0.3 g of calcium chloride (calcium chloride H (Tonda Pharmaceutical)) was added, and the mixture was stirred and completely dissolved. Next, 11.25 g of polyacrylic acid (Carbopol 974P (Noveon, Inc.)) was slowly added with stirring, and the mixture was completely dissolved by stirring for about 1 hour. 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. using a water bath. Subsequently, 4 g of glycerin (Japanese Pharmacopoeia concentrated glycerin (Asahi Denka Kogyo)) and 0.4 g of acesulfame potassium (Sanet (Maruzen Pharmaceutical)) were added and stirred for about 5 minutes.
Polyacrylic acid is a water-swellable gel-forming agent and can be crosslinked by calcium ions generated by the ionization of calcium chloride. Polyvinyl alcohol is a film forming agent.

(2) Formation of water-swellable gel-forming layer After sufficiently defoaming coating liquid A, using an applicator whose gap is adjusted so that the coating amount after drying is 5 g / m ² or 10 g / m ² , Spread coating on the opposite side of the silicone resin release surface of polyethylene terephthalate film (product of Lintec Co., Ltd., product name: SP-PET3811), and drying at 80 ° C. for 5 minutes to form a water-swellable gel-forming layer It was. Thus, the intermediate A ₁ in which the water-swellable gel-forming layer (5 g / m ² , gel fraction 47.9%) was laminated on the polyethylene terephthalate film, and the water-swellable gel-forming layer (on the polyethylene terephthalate film ( 10 g / ^{m 2,} the gel fraction 47.9%) was prepared intermediate _{a 2} which are stacked.
The gel fraction of the water-swellable gel-forming layer was calculated by the following steps (1) to (10), and the gel fraction of the fragment (B) was defined as the gel fraction of the water-swellable gel-forming layer.
Step (1): The water-swellable gel-forming layer is separated from the orally administered agent, and the separated water-swellable gel-forming layer is cut into two pieces (A) and (B).
Step (2): The mass (a) of the fragment (A) is measured.
Step (3): The fragment (A) is dried at 105 ° C. for 4 hours, and the mass (b) of the fragment (A) after drying is measured.
Step (4): The moisture content (c) per unit mass of the fragment (A) before drying is calculated based on the formula: c = (ab) / a.
Step (5): The mass (d) of the fragment (B) is measured.
Step (6): The mass (e) of components other than water contained in the fragment (B) is calculated based on the formula: e = d−d × c.
Step (7): The fragment (B) is put in a nylon bag (120 mesh, mass (f)), sealed, and immersed in 0.9% physiological saline for 24 hours.
Step (8): The nylon bag taken out from the physiological saline solution after 24 hours of immersion is dried at 105 ° C. for 4 hours, and the mass (g) of the dried nylon bag is measured.
Step (9): The mass (h) of the fragment (B) present in the nylon bag after drying is calculated based on the formula: h = g−f.
Step (10): The gel fraction (i) of the fragment (B) is calculated based on the formula: i = (h / e) × 100.

(3) was prepared coating solution B ₁ to form the prepared drug-containing layer of the drug-containing layer forming liquid (Coating Liquid B). Take 60 g of purified water (Japanese Pharmacopoeia purified water (Kominato Pharmaceutical)), add 1 g of nicotinamide, a water-soluble drug, and 0.5 g of titanium oxide (Taipeku CR-50 (Ishihara Sangyo)), and homogenizer Was dissolved and dispersed. Next, 17.34 g of polyvinyl pyrrolidone (Prasudone K-90 (ISP Japan)) was added with stirring and completely dissolved. Next, 3.06 g of glycerin (Japanese Pharmacopoeia concentrated glycerin (Asahi Denka)) was added and stirred for about 5 minutes.

It was prepared coating liquid B ₂ in order to form a drug-containing layer. Take 60 g of purified water (Japanese Pharmacopoeia purified water (Kominato Pharmaceutical)), add 1 g of nicotinamide, a water-soluble drug, and 0.5 g of titanium oxide (Taipeku CR-50 (Ishihara Sangyo)), and homogenizer Was dissolved and dispersed. Next, 26.65 g of polyvinyl pyrrolidone (Prasudone K-90 (ISP Japan)) was added with stirring and completely dissolved. Next, 4.7 g of glycerin (Japanese Pharmacopoeia concentrated glycerin (Asahi Denka)) was added and stirred for about 5 minutes.

(4) was thoroughly degassed forming coating solution _{B 1} and _{B 2} of the drug-containing layer, the coating amount after drying for _{B 1} is such that the 120 g / ^{m 2,} dried for _{B 2} Using an applicator in which the gap is adjusted so that the coating amount is 180 g / m ² , it is spread-coated on the water-swellable gel-forming layer of the intermediate A ₁ or A ₂ and dried at 80 ° C. for 6 minutes. A containing layer was formed. Thus, an intermediate B ₁ in which a water-swellable gel-forming layer (5 g / m ² ) and a drug-containing layer (120 g / m ² ) are sequentially laminated on the polyethylene terephthalate film, and the water-swellable gel-forming layer on the polyethylene terephthalate film. (5 g / m ² ) and drug-containing layer (180 g / m ² ) sequentially laminated on intermediate B ₂ , polyethylene terephthalate film, water-swellable gel-forming layer (10 g / m ² ) and drug-containing layer (120 g / m ² ) Intermediate B ₃ in which m ² ) is sequentially laminated, and Intermediate B in which a water-swellable gel-forming layer (10 g / m ² ) and a drug-containing layer (180 g / m ² ) are sequentially laminated on a polyethylene terephthalate film. ₄ was produced.

(5) Manufacture of orally-administered drug by thermal fusion At 100 ° C., 1 kgf / cm ² , for 1 second, between the drug-containing layers of the two intermediates B ₁ and between the drug-containing layers of the two intermediates B ₂ , the drug-containing layer between the two intermediate B _3, or two of the drug-containing layer between the intermediate B ₄ were heat sealed. Thus, an oral administration agent (invention product 1) in which a water-swellable gel-forming layer (5 g / m ² ), a drug-containing layer (120 g / m ² ), and a water-swellable gel-forming layer (5 g / m ² ) are sequentially laminated. , Ratio of the total amount of the water-swellable gel-forming layer contained in the oral administration agent: 7.7% by mass), water-swellable gel-forming layer (5 g / m ² ), drug-containing layer (180 g / m ² ) and water swelling sex gel-forming layer (5 g / m ²⁾ are sequentially stacked oral dosage (percentage of the total amount of the present invention product 2, the water-swellable gel-forming layer contained in the oral dosage: 5.3 wt%), water swelling Orally administrable agent (present product 3, orally administrable agent) in which a water-soluble gel-forming layer (10 g / m ² ), a drug-containing layer (120 g / m ² ) and a water-swellable gel-forming layer (10 g / m ² ) are sequentially laminated Of the total amount of the water-swellable gel-forming layer contained in the water: 14.3% by mass) Stratification (10 g ^{/ m} 2), the drug-containing layer (180 g / ^{m 2)} and the water-swellable gel-forming layer (10 g / ^{m 2)} are sequentially stacked orally administered agent (present invention product 4, contained in the oral dosage The ratio of the total amount of the water-swellable gel-forming layer: 10.0% by mass) was produced.

2. Manufacture of Comparative Example Product 1 After sufficiently defoaming coating solution A, the silicone resin release treatment surface of the polyethylene terephthalate film using an applicator whose gap was adjusted so that the coating amount after drying was 17 g / m ^2. A water-swellable gel-forming layer (17 g / m ² ), a drug-containing layer (120 g / m ² ), and a water-swellable gel are formed in the same manner as in the product 1 of the present invention except that it is spread-coated on the opposite surface of An oral administration agent (comparative product 1, ratio of the total amount of the water-swellable gel-forming layer contained in the oral administration agent: 22.1% by mass) in which layers (17 g / m ² ) were sequentially laminated was produced.

[Test Example 1]
Samples of the present invention products 1 to 4 and comparative product 1 punched out to 13.5 mm in length and 13.5 mm in width are used as test pieces, individually placed in an aluminum bag, and stored for a certain period of time at a temperature of 40 ° C. and a humidity of 75%. did. After a certain period of time, the dissolution rate of water-soluble drugs from products 1 to 4 and comparative product 1 of the present invention 15 minutes after the start of the test using the dissolution test method (paddle method) described in the 14th revised Japanese Pharmacopeia Was measured. At this time, 900 mL of purified water at 37 ° C. was used as a test solution, and the paddle rotation speed was 50 rpm. The results are shown in Table 1.

  As shown in Table 1, in the products 1 to 4 of the present invention, the dissolution rate of the water-soluble drug 15 minutes after the start of the test was 85% or more regardless of the storage period, whereas in the comparative product 1 When the storage period was 3 months or longer, the dissolution rate of the water-soluble drug 15 minutes after the start of the test was less than 85%. From these results, it was found that the products 1 to 4 of the present invention can prevent the delay of elution of the water-soluble drug from the oral administration agent.

It is sectional drawing which shows one Embodiment of the oral administration agent of this invention. It is sectional drawing which shows one Embodiment of the oral administration agent of this invention. It is sectional drawing which shows one Embodiment of the oral administration agent of this invention. It is sectional drawing which shows one Embodiment of the oral administration agent of this invention. It is sectional drawing which shows one Embodiment of the oral administration agent of this invention. It is sectional drawing which shows one Embodiment of the oral administration agent of this invention.

Explanation of symbols

1a, 1b, 1c, 1d, 1e, 1f ... Orally administered agent 11a ... Drug-containing layers 12a, 12b ... Water-swellable gel-forming layers 13a, 13b ... Water-soluble intermediate layers 14a, 14b ..Water-soluble intermediate layer

Claims (3)

In an orally administered agent that is a film-form preparation having a drug-containing layer containing a water-soluble drug and a water-swellable gel-forming layer,
The oral administration agent, wherein the total amount of the water-swellable gel-forming layer contained in the oral administration agent is 5 to 15% by mass of the oral administration agent.   A single water-swellable gel-forming layer or a plurality of water-swellable gel-forming layers laminated to each other directly or via a water-soluble intermediate layer is provided on the drug-containing layer. The oral administration agent according to claim 1.   The oral administration agent according to claim 1, wherein the outermost layer has a water-swellable gel-forming layer.

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