JP2010120877A - Oral administration preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral administration preparation that is easy to swallow and releases a medicine at a target portion, particularly in intestines. <P>SOLUTION: The oral administration preparation includes a medicine-containing layer containing a medicine, a disintegration-controlling layer provided on each side of the medicine-containing layer and a gel-like layer that is provided on each of the disintegration-controlling layers on the opposite side to the medicine-containing layer and is like a gel containing an aqueous liquid, where the disintegration-controlling layer is constituted of a material comprising an enteric material that is dissolved when brought into contact with body fluid within the intestines. Preferably, the content of the aqueous liquid in the gel-like layer is 30-99.9 mass%. Preferably, the content of water contained in the aqueous liquid is at least 30 mass%. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to an oral administration agent.

  Examples of the orally-administered drug containing a drug and taken from the mouth include a solid solid preparation and a jelly-like (gel-like) semi-solid preparation. In general, solid preparations (eg, tablets, capsules, etc.) are difficult to swallow as they are, and usually must be taken with a large amount of water. Especially in the elderly and infants, it is often difficult to swallow the solid preparation. In the case of a solid preparation, there is a risk of accidentally clogging the trachea and a risk of sticking to the esophagus.

  On the other hand, since the semi-solid preparation is in a jelly form, it is easy to swallow and is easy for elderly people and infants to take. However, the semi-solid preparation contains a large amount of water, and thus has a drawback that the contained drug is easily decomposed and altered.

  In order to solve such a problem, a film-form preparation has been developed in which a saliva is absorbed and swelled in the outermost layer to provide a gel-like layer (for example, Patent Document 1).

  However, such a film-form preparation may become viscous immediately after the gel layer absorbs saliva, and may adhere to the oral mucosa, particularly the upper mucous membrane of the oral cavity where the saliva is relatively small. There was a problem. In addition, there is a problem that it may be difficult to take unless the preparation is kept in the oral cavity for the time of swelling with saliva.

WO2002 / 087622

  An object of the present invention is to provide an orally administered agent that is easy to swallow and can release a drug in the intestine.

Such an object is achieved by the present inventions (1) to (7) below.
(1) a drug-containing layer containing a drug;
A disintegration control layer provided on each side of the drug-containing layer;
Provided on the side opposite to the drug-containing layer of each collapse control layer, and has a gel-like gel layer containing an aqueous liquid,
The orally administered agent, wherein the disintegration control layer is composed of a material containing an enteric material that dissolves by contact with a bodily fluid in the intestine.

  (2) The oral administration agent according to (1), wherein the content of the aqueous liquid in the gel layer is 30 to 99.9% by mass.

  (3) The oral administration agent according to (1) or (2), wherein the content of water contained in the aqueous liquid is 30% by mass or more.

  (4) The oral administration agent according to any one of (1) to (3) above, wherein the gel layer has a hydrogen ion index of 2 to 5.

  (5) The oral administration agent according to any one of (1) to (4), wherein the enteric material contains an enteric polymer.

  (6) The orally administered agent according to (5), wherein the enteric polymer is an enteric acrylic acid copolymer or an enteric cellulose derivative.

  (7) The oral administration agent according to any one of (1) to (6), wherein the drug-containing layer is covered with the collapse control layer.

  ADVANTAGE OF THE INVENTION According to this invention, the oral administration agent which can be swallowed easily and can release a drug in intestines can be provided.

Hereinafter, the present invention will be described in detail based on preferred embodiments.
FIG. 1 is a cross-sectional view showing a preferred embodiment of the oral administration agent of the present invention.

  As shown in FIG. 1, an orally-administered drug 1 includes a drug-containing layer 11 containing a drug, a disintegration control layer 12 a laminated on one surface of the drug-containing layer 11, and the other surface of the drug-containing layer 11. The disintegration control layer 12b, the gel-like layer 13a provided on the surface of the disintegration control layer 12a opposite to the drug-containing layer 11, and the disintegration control layer 12b provided on the surface opposite to the drug-containing layer 11 It is comprised with the laminated body which has the obtained gel-like layer 13b.

  In the present invention, the form of the oral administration agent 1 is not particularly limited as long as it has the above layers, and may be in the form of a film (sheet) or a block.

Hereinafter, each layer which comprises the oral administration agent 1 is demonstrated in detail.
<Drug-containing layer 11>
The drug-containing layer 11 is a layer containing a drug to be administered.

  The drug contained in the drug-containing layer 11 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 that act on the central nervous system include hypnotics such as amobarbital, estazolam, triazolam, nitrazepam, pentobarbital, amitryptine hydrochloride, imipramine hydrochloride, oxazolam, chlordiazepoxide, chlorpromazine, diazepam, sulpiride, Psychotropic drugs such as haloperidol, antiparkinson drugs such as trihexyphenidyl and levodopa, aspirin, isopropylantipyrine, indomethacin, diclofenac sodium, mefenamic acid, streptokinase, streptodolase, serrapeptase, pronase and other analgesics and anti-inflammatory drugs , ATP, vinpocetine and other central nervous system metabolic stimulants, and drugs acting on the respiratory tract include expectorants such as carbocysteine and promhexine hydrochloride, hydrochloric acid Anti-asthma drugs such as zelastine, oxatomide, theophylline, terbutaline sulfate, tranilast, procaterol hydrochloride, ketotifen fumarate, and drugs acting on the circulatory system include cardiotonic drugs such as aminophylline, digitoxin, digoxin, adimarin, disopyramide, procainamide hydrochloride Antiarrhythmic drugs such as mexiletine hydrochloride, amyl nitrite, alprenolol hydrochloride, isosorbide nitrate, nicorandil, oxyfedrine, dipyridamole, dirazep hydrochloride, diltiazem hydrochloride, nitroglycerin, nifedipine, verapamil hydrochloride, Peripheral vasodilators such as caridinogenase, atenolol, captopril, clonidine hydrochloride, metoprolol tartrate, spironolactone, triamterene, trichlormethiazide, nicardipine, 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 As hemostatic agents such as sodium carbazochrome sulfonate and tranexamic acid, antithrombotic agents such as ticlopidine hydrochloride and warfarin potassium, antianemic agents such as iron sulfate, and drugs acting on the digestive system, such as azulene, aldioxa, cimetidine, hydrochloric acid Anti-ulcer drugs such as ranitidine, famotidine, teprenone, rebamipide, antiemetics such as domperidone and metoclopramide, shallow drugs such as sennoside, digestive enzyme preparations, glycyrrhizin, liver extract preparations, etc. In addition, as drugs that act on metabolic diseases, antidiabetic drugs such as glibenclamide, chlorpropamide, tolbutamide, gout treatment drugs such as allopurinol and colchicine, as drugs in the ophthalmic area, acetazolamide, as drugs in the otolaryngological area, difenidol hydrochloride, Anti-vertigo drugs such as betahistine mesylate, chemotherapeutic drugs and antibiotics such as isoniazid, ethambutol hydrochloride, ofloxacin, erythromycin stearate, cefaclor, norfloxacin, fosfomycin calcium, minocycline hydrochloride, rifampicin, rokitamycin, etc. Phosphamide, tegafur, etc .; immunosuppressive drugs, azathioprine, etc., hormones and endocrine therapeutic drugs, luteinizing hormone, salivary gland hormone, thiamazole, prednisolone Betamethasone, liothyronine, levothyroxine, etc., bioactive substances (autocoid) such as diphenhydramine hydrochloride, clemastine fumarate, chlorpheniramine maleate, antihistamines such as alphacalcidol, cobamide, tocopherol nicotinate, mecoparamine, etc. Vitamins and the like can be mentioned, and these can be used alone or in combination of two or more according to the purpose of treatment or prevention.

  In particular, in the present invention, the orally administered agent 1 is capable of releasing a drug in the intestine. For this reason, as the drug contained in the drug-containing layer 11, it is preferable to use a drug that exhibits an effect by being absorbed in the intestine.

  Further, the drug-containing layer 11 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.

  The content of the drug in the drug-containing layer 11 is not particularly limited and can be appropriately adjusted according to the type of drug and the volume of the drug-containing layer 11, but is preferably 0.01 to 70% by mass, More preferably, the content is 0.01 to 40% by mass, and still more preferably 0.01 to 35% by mass. Thereby, a sufficient amount of drug can be included in the oral administration agent 1 while making the physical strength of the oral administration agent 1 excellent.

  The oral administration agent 1 contains a relatively large amount of drug as described above in the drug-containing layer 11 or contains an insoluble and bulky drug that tends to lower the physical strength of the drug-containing layer 11. Even so, it has sufficient physical strength. This is because the orally-administered agent 1 has the disintegration control layers 12a and 12b on both surfaces of the drug-containing layer 11, and these disintegration control layers 12a and 12b impart sufficient physical strength to the orally-administered agent 1. it is conceivable that.

  Moreover, the drug-containing layer 11 may contain a base (base for the drug-containing layer). The base (drug-containing layer base) has a function of holding the drug to be administered in a desired state in the drug-containing layer 11 and adjusting the shape and physical strength of the drug-containing layer 11. The base that can be used for the drug-containing layer 11 is not particularly limited. For example, crystalline cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate , Cellulose such as hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and derivatives thereof or pharmaceutically acceptable salts thereof (for example, sodium salt), α-starch, oxidized starch, sodium carboxymethyl starch, hydroxypropyl starch, dextrin , Starches such as dextran and their derivatives, sucrose, maltose, lactose, grapes , Sugars such as fructose, pullulan, xanthan gum, cyclodextrin, xylitol, mannitol, sorbitol, dimethylaminoethyl methacrylate / (meth) acrylic acid copolymer, (meth) acrylic acid / ethyl acrylate copolymer, (meth) acrylic acid / (Meth) acrylic acid methyl copolymer, (meth) ethyl acrylate / (meth) acrylated trimethylammonium copolymer, (meth) acrylic acid dimethylaminoethyl / (meth) acrylated methyl copolymer, (meth) acrylic acid / acrylic Acrylic acid derivatives such as ethyl oxychloride copolymer, shellac, polyvinyl acetal diethylaminoacetate, polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone, vinyl acetate-vinyl pyrrolidone copolymer, Natural rubbers such as rabia gum and tragacanth rubber, polyglucosamines such as chitin and chitosan, proteins such as gelatin, casein and soy protein, titanium oxide, calcium monohydrogen phosphate, calcium carbonate, talc, stearate, and metasilicate aluminate Examples thereof include magnesium, magnesium silicate, silicic anhydride, and the like, and one or more of these can be used in combination according to the purpose.

  The content of the base in the drug-containing layer 11 is not particularly limited, but is preferably 30 to 99.9% by mass, more preferably 60 to 99.9% by mass, and 65 to 99.0% by mass. % Is more preferable. As a result, the physical strength of the drug-containing layer 11 can be made particularly easily sufficient while a sufficient amount of drug is contained in the drug-containing layer 11.

  The thickness of the drug-containing layer 11 can be appropriately adjusted within a range that can be administered orally. The thickness of the drug-containing layer 11 is not particularly limited, but is preferably 0.5 to 5000 μm, more preferably 10 to 3000 μm, and still more preferably 50 to 1000 μm, for example. As a result, the drug-containing layer 11 can have a particularly small variation in drug content and thickness at each site. Moreover, the flexibility as the whole oral administration agent 1 can be made sufficient, and it becomes especially easy to take the oral administration agent 1.

<Collapse control layers 12a, 12b>
The collapse control layer 12a is provided between the drug-containing layer 11 and the gel layer 13a. The collapse control layer 12b is provided between the drug-containing layer 11 and the gel layer 13b. In the present invention, the collapse of the collapse control layer means that the shape of the collapse control layer collapses due to dissolution, outflow, decomposition, etc. of the components of the collapse control layer.

  The collapse control layers 12a and 12b are layers that can be collapsed in the intestine by contacting the body fluid in the intestine. For this reason, the disintegration control layer 12a and the disintegration control layer 12b disintegrate in the intestine, whereby the drug-containing layer 11 can be dissolved in contact with the body fluid in the intestine, and the drug is released into the intestine.

  In addition, the disintegration control layers 12a and 12b are layers having a function of preventing contact between the moisture contained in the gel layers 13a and 13b and the drug contained in the drug-containing layer 11, and preventing decomposition and alteration of the drug. It is.

  Furthermore, the disintegration control layers 12a and 12b also have a function of preventing the contact between the drug-containing layer 11 and saliva, prevent dissolution of the drug contained in the drug-containing layer 11 in the oral cavity, and improve the taste of the drug ( For example, bitterness, astringency, numbness), odor, etc. can be masked. It also has a function of preventing contact between the drug-containing layer 11 and gastric juice, and can prevent unintended release of the drug in the stomach.

  On the other hand, when the orally administered agent does not have such a disintegration control layer, the water contained in the gel layer may penetrate into the drug-containing layer, and the drug in the drug-containing layer may be decomposed or altered. There is sex. In addition, there is a possibility that the drug is released from other than the target site through the gel layer.

  In the present embodiment, the collapse control layer 12 a and the collapse control layer 12 b are joined at their ends extending from a portion where the drug-containing layer 11 is present. For this reason, the periphery of the drug-containing layer 11 is covered with the collapse control layers 12a and 12b. As a result, the drug-containing layer 11 is prevented from inadvertently eluting and altering the drug inadvertently in contact with body fluid or moisture in the gel layer.

  Hereinafter, since the collapse control layer 12a and the collapse control layer 12b have the same configuration, the collapse control layer 12a will be described as a representative.

  In the present invention, the disintegration control layer 12a includes an enteric material that dissolves by contact with a bodily fluid in the intestine. By including such an enteric material, the disintegration control layer 12a disintegrates in contact with the bodily fluid in the intestine.

  The enteric material is a material that does not substantially dissolve in an aqueous liquid contained in the gel layers 13a and 13b described later. In addition, that it does not melt | dissolve substantially means that the solubility with respect to 100 g of the said aqueous liquid in normal temperature is 0.01 g or less.

  The enteric polymer that can be used for the disintegration control layer 12a is not particularly limited, and examples thereof include enteric cellulose derivatives, enteric acrylic acid copolymers, enteric maleic copolymers, enteric polyvinyls. A derivative | guide_body, a shellac, etc. are mentioned, It can use combining 1 type (s) or 2 or more types.

  Specific examples of enteric cellulose derivatives include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylacetate maleate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, cellulose Examples thereof include acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl cellulose, ethyl hydroxyethyl cellulose phthalate, hydroxymethyl cellulose ethyl phthalate, and cellulose acetate phthalate.

  In addition, enteric acrylic copolymers include methacrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl acrylate copolymer, styrene / acrylic acid copolymer, methyl acrylate / acrylic acid copolymer, acrylic acid Examples thereof include a methyl / methacrylic acid copolymer, a butyl acrylate / styrene / acrylic acid copolymer, and a methyl acrylate / methacrylic acid / octyl acrylate copolymer.

  The enteric maleic acid copolymer includes vinyl acetate / maleic anhydride copolymer, styrene / maleic anhydride copolymer, styrene / maleic ester copolymer, vinyl methyl ether / maleic anhydride. Copolymer, ethylene / maleic anhydride copolymer, vinyl butyl ether / maleic anhydride copolymer, acrylonitrile / methyl acrylate / maleic anhydride copolymer, butyl acrylate / styrene / maleic anhydride A copolymer etc. are mentioned.

  Examples of enteric polyvinyl derivatives include polyvinyl acetate phthalate, polyvinyl butyrate phthalate, and polyvinyl alcohol acetate phthalate.

  Among the above-described materials, the enteric material is preferably an enteric acrylic copolymer or an enteric cellulose derivative. Thereby, the disintegration control layer 12a is preferably prevented from being disintegrated in the oral cavity or stomach, and can be quickly dissolved in the intestine by contact with body fluids. Further, the influence of the aqueous liquid in the gel layer 13a can be made sufficiently small. Among the above-mentioned, when using any one of methacrylic acid / methyl methacrylate copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose as an enteric material, the above effects are more remarkable. It will be something.

  Moreover, the mass average molecular weight of the enteric polymer is not particularly limited, but is preferably 5,000 to 500,000, and more preferably 10,000 to 300,000. Thereby, while being able to make the influence of the aqueous liquid in the gel-like layer 13a small enough, in the intestines, it can melt | dissolve quickly by contacting with a bodily fluid. Moreover, the adhesiveness with the layer which the collapse control layer 12a adjoins can be made especially excellent.

  Moreover, it is preferable that it is 60-99 mass%, and, as for content of the enteric material in the decay | disintegration control layer 12a, it is more preferable that it is 75-95 mass%. Thereby, the disintegration control layer 12a is preferably prevented from being disintegrated in the oral cavity or stomach, and can be quickly dissolved in the intestine by contact with body fluids.

  The collapse control layer 12a preferably contains a certain amount of plasticizer. As a result, cracking of the collapse control layer 12a can be prevented, and adhesion between the gel layer 13a and the drug-containing layer 11 can be improved. During swallowing, the gel layer 13a and the collapse control layer 12a It is possible to reliably prevent peeling between the drug-containing layer 11 and the collapse control layer 12a.

  The material that can be used as a plasticizer for the collapse control layer 12a is not particularly limited, and examples thereof include propylene glycol, polyethylene glycol, polypropylene glycol, glycerin triacetate, diethyl phthalate, triethyl citrate, and lauric acid. Among these, one kind or a combination of two or more kinds can be used.

  Moreover, when the collapse control layer 12a contains a plasticizer, the content thereof is preferably 1 to 40% by mass of the collapse control layer 12a, and more preferably 5 to 25% by mass.

  The collapse control layer 12a preferably contains a certain amount of a hydrophobic substance. Thereby, it can prevent effectively that a water | moisture content permeates through the collapse control layer 12a from the gel-like layer 13a to the medicine containing layer 11. FIG.

  The material that can be used as the hydrophobic substance is not particularly limited, and examples thereof include solid waxes, that is, fats and oils, waxes, hydrocarbons, higher fatty acids, higher fatty acid esters, and the like. A combination of the above can be used. Particularly preferred are beeswax and carnauba wax.

  Moreover, when the collapse control layer 12a contains a hydrophobic substance, the content thereof is preferably 5 to 40% by mass of the collapse control layer 12a, and more preferably 10 to 30% by mass.

  Moreover, the decay control layer 12a may contain a base other than the enteric material as described above (a base for the decay control layer).

The material that can be used as the base of the disintegration control layer 12a is not particularly limited. For example, starch such as α-starch, oxidized starch, sodium carboxymethyl starch, hydroxypropyl starch, dextrin, dextran, and derivatives thereof, Sucrose, maltose, lactose, glucose, fructose, pullulan, xanthan gum, cyclodextrin, xylitol, mannitol, sorbitol and other sugars, polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone, vinyl acetate-vinyl pyrrolidone copolymer, gum arabic, tragacanth gum, etc. Natural rubbers, polyglucosamines such as chitin and chitosan, proteins such as gelatin, casein, soybean protein, titanium oxide, calcium monohydrogen phosphate, calcium carbonate, talc, stearate Magnesium aluminometasilicate, magnesium silicate, silicic acid and the like anhydride, according to the purpose, can be used singly or in combination of two or more of them.
Moreover, when the collapse control layer 12a contains a base, the content is preferably 1 to 25% by mass.

  In addition, the decay control layer 12a may include a drug different from the drug included in the drug-containing layer 11. By making the drugs contained in the disintegration control layer 12a and the drug-containing layer 11 different, the oral administration agent 1 can release different drugs at different timings.

  The collapse control layer 12a may include components other than the materials described above. For example, the disintegration control layer 12a has a preservative such as methyl hydroxybenzoate and propyl hydroxybenzoate, a colorant such as an edible lake colorant, and a masking agent such as a sweetener at 5% by mass or less of the disintegration control layer 12a. It may be included.

  Moreover, it is preferable that the collapse control layer 12a is hard to collapse in a body cavity other than the intestine. Specifically, it is preferable that the disintegration control layer 12a is hard to disintegrate in the oral cavity and stomach. This reliably prevents the drug in the drug-containing layer 11 from being released into the body cavity due to the collapse of the collapse control layer 12a in the body cavity other than the intestines. As a result, the orally administered agent 1 can release the drug in the intestine more reliably.

More specifically, the collapse control layer 12a is made of artificial saliva at 37 ° C. (NaCl: 0.08 mass%, KCl: 0.12 mass%, MgCl ₂ : 0.01 mass%, CaCl based on purified water). ₂ : 0.01% by mass, K ₂ HPO ₄ : 0.03% by mass: 0.01% by mass, CMC-Na: 0.10% by mass) It is preferable that it does not collapse within 10 minutes.

  More specifically, the disintegration control layer 12a is less than 120 minutes with respect to the test solution first solution (pH: 1.2) of the disintegration test method defined in the 37 ° C Japanese Pharmacopoeia. It must be something that does not collapse.

  More specifically, the disintegration control layer 12a disintegrates in less than 10 minutes with respect to the test liquid second liquid (pH: 6.8) of the disintegration test method defined in the 37 ° C Japanese Pharmacopoeia. It is preferable that the material disintegrates in less than 3 minutes.

  Since the collapse control layer 12a has the above properties, the collapse control layer 12a is reliably prevented from being collapsed by saliva and gastric juice in the oral cavity and stomach. This reliably prevents the drug in the drug-containing layer 11 from being dissolved and released in the oral cavity and stomach. Further, in the intestine, the disintegration control layer 12a is suitably disintegrated, and the drug in the drug-containing layer 11 is suitably released into the intestine.

  Moreover, the thickness of the disintegration control layer 12a is not particularly limited, and can be appropriately adjusted according to the site where the drug is released in the intestine, but is preferably 1 to 200 μm, more preferably 5 to 100 μm. preferable. Thereby, the orally-administered drug 1 can release the drug more reliably in the intestine.

<Gel-like layer>
The gel-like layer 13a is provided on the surface opposite to the drug-containing layer 11 of the collapse control layer 12a. The gel layer 13b is provided on the surface of the disintegration control layer 12b opposite to the drug-containing layer 11.

  Hereinafter, since the gel layer 13a and the gel layer 13b have substantially the same configuration, the gel layer 13a will be described as a representative.

  The gel layer 13a is a layer that contains an aqueous liquid and forms a gel. The gel state refers to properties such as elastic jelly and soft jelly. Thus, by having a gel-like layer in the outermost layer, the orally-administered drug 1 can be easily swallowed.

  The aqueous liquid contained in the gel layer 13a is a liquid mainly composed of water. Specifically, the content of water contained in the aqueous liquid is preferably 30% by mass or more, more preferably 50% by mass or more, and further preferably 70% by mass or more. Thereby, while being able to make the influence on the said collapse control layer smaller, the swallowability of the oral administration agent 1 can be made higher.

  The aqueous liquid may contain components other than water. Examples of components other than water include polyhydric alcohols such as propylene glycol, butylene glycol, and polyethylene glycol, sugar alcohols such as glycerin and sorbitol, alcohols such as ethanol, and the like. By including such a component, when the orally-administered agent 1 is placed in the oral cavity, saliva secretion is promoted, and the swallowability of the orally-administered agent 1 can be further improved.

  The aqueous liquid may contain a surfactant such as polyoxyethylene fatty acid esters and glycerin fatty acid esters, and a long-chain alcohol such as hexyldecanol. Moreover, fats and oils etc. may be contained with the above surfactants.

  The content of the aqueous liquid in the gel layer 13a is preferably 30 to 99.9% by mass, more preferably 50 to 99.5% by mass, and 70 to 99.2% by mass. Is more preferable. Thereby, the swallowability of the oral administration agent 1 can further be improved.

  The gel-like layer 13a includes a gel-forming agent that swells by absorbing moisture to form a gel. By including such a gel-forming agent, the gel-like layer 13a becomes a gel and can impart good swallowability to the orally-administered agent 1.

  Examples of the gel forming agent include, but are not limited to, alginic acid and its derivatives, agar, gelatin, carrageenan, pectin, guar gum, locust bean gum, gum arabic, gellan gum, xanthan gum, tragacanth, hyaluronic acid, sesbania gum, pullulan, Examples thereof include natural polysaccharides such as karaya gum and rhamzan gum; starch and derivatives thereof; cellulose and derivatives thereof; polyacrylic acid and derivatives thereof, and the like, and one or more of these can be used in combination.

  The alginic acid and its derivatives include alginic acid, alginic acid such as sodium salt, potassium salt, triethanol salt and ammonium salt of alginic acid, and alginic acid ester such as propylene glycol alginate.

  Among these, the gel-forming agent is preferably a polymer containing a carboxyl group such as alginic acid and its derivatives, polyacrylic acid and its derivatives, and particularly preferably contains alginic acid and its derivatives. Alginic acid and its derivatives are components having a tendency to decrease the dissolution rate in water such as saliva after becoming a gel. For this reason, the shape of the gel-like layer 13a is more reliably maintained in the oral cavity, and high swallowability can be more effectively maintained. Moreover, the site | part in a body cavity can be more reliably controlled for the time when the collapse control layer 12a collapses.

  The content of the gel forming agent in the gel layer 13a can be appropriately adjusted according to the type of the gel forming agent and the like, but is preferably 0.1 to 70% by mass, and preferably 0.5 to 50% by mass. More preferably, it is 0.8-30 mass%. Thereby, the swallowability of the oral administration agent 1 can further be improved.

  Moreover, in the gel-like layer 13a, the crosslinking agent may be contained as needed. As the crosslinking agent, a compound that generates a polyvalent metal ion is preferable. For example, aluminum hydroxide, aluminum silicate, calcium chloride, dicalcium phosphate, magnesium chloride, aluminum chloride, aluminum sulfate, potash alum, iron chloride alum, ammonium Multivalent metal salts such as alum, ferric sulfate, aluminum phosphate, iron citrate, magnesium oxide, calcium oxide, zinc oxide, zinc sulfate and the like can be mentioned. The polyvalent metal ions can form a salt with a plurality of carboxyl groups in the gel forming agent, and can crosslink the gel forming agent.

  The gel layer 13a may contain a retarder such as a polyvalent carboxylic acid such as citric acid or tetrasodium edetacetate.

  In addition to the above components, the gel layer 13a may contain a pH adjuster, a plasticizer, an emulsifier, an antioxidant, an antiseptic, a fragrance, a colorant, a sweetener, a bitter agent, an acidulant and the like. Good.

  The hydrogen ion exponent pH of the gel-like layer 13a as described above is preferably 2 to 5, and more preferably 3 to 4.5. Thereby, it can prevent effectively that the material which comprises the disintegration control layer 12a melt | dissolves in the gel-like layer 13a, improving the swallowability of the oral administration agent 1. FIG. As a result, dissolution / degeneration of the drug contained in the drug-containing layer 11 can be effectively prevented.

  The thickness of the gel layer 13a can be appropriately adjusted within a range that can be administered orally, but is preferably 10 to 1000 μm, and more preferably 15 to 500 μm.

  In the oral administration agent 1 shown in FIG. 1, the disintegration control layer is exposed at the end of the oral administration agent 1, but the end of the oral administration agent 1 may be covered with a gel layer.

Oral administration agent 1 can be manufactured according to the following manufacturing methods, for example.
2 and 3 are process diagrams showing an example of the method for producing the oral administration agent of the present invention.

(Disintegration control layer forming sheet creation process)
First, a coating liquid containing a constituent material for the collapse control layer (coating liquid for the collapse control layer) is prepared.

  The coating liquid for a collapse control layer can be prepared by dispersing or dissolving the components constituting the collapse control layer as described above in a liquid medium such as purified water or ethanol.

  Next, after applying and spraying the coating liquid for disintegration control layers on a flat plate, it is dried. As a result, a collapse control layer forming sheet 12b 'as shown in FIG. 2A is formed. In the same manner, the collapse control layer forming sheet 12a 'is also formed.

(Intermediate production process (drug encapsulation process))
Next, as shown in FIG. 2 (b), a recess (pocket) is formed in the center of the collapse control layer forming sheet 12b 'by embossing at room temperature or under heating.

  Next, the drug-containing layer forming material is put into the recess, and the drug-containing layer 11 is formed as shown in FIG.

  Next, as shown in FIG. 2 (d), the collapse control layer forming sheet 12a is formed on the surface of the collapse control layer forming sheet 12b 'on which the drug containing layer 11 is formed, on the side where the drug containing layer 11 is formed. 'Overlap.

  Next, as shown in FIG.2 (e), the part by which the recessed part of the sheet | seat for two collapse control layers formation is not formed is thermocompression-bonded. Thereby, the intermediate body 14 which has the medicine containing layer 11, the decay control layer 12a, and the decay control layer 12b is obtained.

(Gel-like layer preparation process)
First, a solution for a gel layer composed of the constituent material of the gel layer as described above is prepared.

  Next, the gel layer solution is applied to a flat plate to form a gel layer forming layer 13b 'as shown in FIG.

  Next, as shown in FIG. 3G, the intermediate body 14 is placed at the center of the formed gel layer forming layer 13b '.

  Next, as shown in FIG. 3 (h), a gel layer solution is applied on the intermediate body 14 and the gel layer forming layer 13b ′ so as to cover the intermediate body 14, thereby forming the gel layer layer. Layer 13a ′ was formed. Then, the oral administration agent 1 provided with the medicine containing layer 11, the disintegration control layers 12a and 12b, and the gel-like layers 13a and 13b is obtained by cutting as necessary.

  As mentioned above, although this invention was demonstrated about embodiment of illustration, this invention is not limited to this.

  For example, the oral administration agent of the present invention may have an arbitrary layer between the gel layer and the drug-containing layer.

For example, the shape of the drug-containing layer may be powder, compressed tablet, liquid, or the like.
For example, you may have an adhesive layer etc. which improve the adhesiveness of a disintegration control layer and a drug containing layer.

  In addition, for example, a moisture-proof layer made of a hydrophobic substance may be provided between the drug-containing layer and each collapse control layer and / or between the gel layer and each collapse control layer.

Next, specific examples of the oral administration agent of the present invention will be described.
1. Production of Orally Administered Example (Example 1)
(A) Sheet preparation process for collapse control layer formation First, the coating liquid A containing the structural component of the collapse control layer was prepared.

  Ethanol: A methacrylic acid-methyl methacrylate copolymer (Eudragit L100, manufactured by Pharma Polymers, Inc., mass average molecular weight: 135000): 70 parts by mass as an enteric material was added to 180 parts by mass, and dissolved by stirring. Next, polyethylene glycol # 1500: 10 parts by mass and beeswax: 20 parts by mass were sequentially added and dissolved to obtain a coating liquid A.

Next, the coating liquid A is sufficiently defoamed and spread-applied on a flat plate using an applicator in which a gap is adjusted so that the coating amount after drying is 50 g / m ^2, and is applied at 90 ° C. for 5 minutes. A sheet for forming a collapse control layer was obtained by drying. The average thickness of the collapse control layer forming sheet was 40 μm.

(B) Preparation process of drug-containing layer forming material Blue No. 1 (dummy drug): To 5 parts by mass, carboxymethylcellulose (NS-300, manufactured by Nichirin Chemical Co., Ltd.): 95 parts by mass is added, and uniform in a mortar. To obtain a drug-containing layer forming material.

(C) Drug encapsulation process (intermediate preparation process)
The collapse control layer forming sheet obtained as described above was placed on a smooth metal plate having a circular hole having a diameter of 11 mm. A portion covering the hole of the collapse control layer forming sheet was pressed with a cylindrical pin having a diameter of 8 mm to form a truncated cone-shaped recess (pocket) having a depth of 2 mm.

  Next, 50 mg of the drug-containing layer forming material was placed in the pocket of the collapse control layer forming sheet.

Next, another collapse control layer forming sheet is overlapped on the surface where the pockets of the collapse control layer forming sheet are formed, and two overlapping collapse control layer forming sheet pockets are formed. The unexposed portion was thermocompression bonded at 110 ° C. and 1 kg / cm ² for 3 seconds to enclose the drug. As a result, an intermediate having a drug-containing layer and two disintegration control layers was obtained.

(D) Gel layer preparation step First, 12 parts by mass of sodium alginate (Duck Algin NSPLL, manufactured by Kibun Food Chemifa) was added to 400 parts by mass of water and dissolved to obtain an aqueous sodium alginate solution.

  Next, a second calcium phosphate dispersion in which 1.3 parts by mass of second calcium phosphate is dispersed in 200 parts by mass of water is added to the aqueous sodium alginate solution, and gluconodeltalactone as a pH adjuster: 12 A pH adjusting solution in which 200 parts by mass of water was dissolved was added, and the mixture was stirred and mixed to obtain a gel layer solution.

  Next, the obtained solution for gel layer was poured into a mold and molded into a flat plate having a thickness of 1 mm to form a layer for forming a gel layer.

  Next, while the gelation of the gel layer solution did not proceed, the intermediate obtained as described above was placed on the molded layer for gel layer formation.

  Further, the solution for the gel layer was poured into the mold so as to cover the intermediate, and the whole was molded into a flat plate shape having a thickness of 4 mm. The gel-like layer was formed when the gel-like layer solution was completely gelled. The surface pH of the gel layer was measured with a surface pH meter (manufactured by Toa DKK Corporation) and found to be 3.7.

  Thereafter, the intermediate sandwiched between the gel layers was taken out from the mold and cut into a circle having a diameter of 15 mm so that the drug-containing layer of the intermediate was the center to obtain an orally administered agent.

(Examples 2 to 6)
An orally administered agent was obtained in the same manner as in Example 1 except that the types and contents of each material of the gel layer and the disintegration control layer were changed as shown in Table 1.

(Comparative Example 1)
The drug-containing layer forming material prepared in the same manner as in Example 1 was encapsulated in a commercially available No. 2 capsule to obtain an oral administration agent.

(Comparative Example 2)
An orally administered agent was obtained in the same manner as in Example 1 except that the disintegration control layer was not provided.

(Comparative Example 3)
(A) Water-swellable gel-forming layer preparation step 0.9 parts by mass of calcium chloride (Japanese Pharmacopoeia calcium chloride, manufactured by Tomita Pharmaceutical Co., Ltd.) was added to 900 parts by mass of purified water, and dissolved by sufficiently stirring. . Next, 33.8 parts by mass of polyacrylic acid (Carbopol 974P, manufactured by CBC) was slowly added with stirring, and the mixture was stirred for about 1 hour. Next, polyvinyl alcohol (GOHSENOL EG40, manufactured by Nippon Synthetic Chemical Co., Ltd.): 56.5 parts by mass is slowly added with stirring. After the addition, the mixed solution to which each material has been added is heated to 70 ° C. to obtain about 1 Stir for hours. Next, glycerin (Japanese Pharmacopoeia Concentrated Glycerin, manufactured by Asahi Denka Kogyo Co., Ltd.): 8 parts by mass and acesulfame potassium (Sanet A type, manufactured by Maruzen Pharmaceutical Co., Ltd.): 0.8 part by mass are added and stirred for about 10 minutes. A coating liquid B was obtained.

Next, the coating liquid B is sufficiently defoamed, spread-coated on a flat plate so that the coating amount after drying is 20 g / m ^2, and dried at 80 ° C. for 10 minutes. A gel-forming layer was formed.

(B) Drug-containing layer formation step Blue: No. 1 (dummy drug): 4.1 parts by mass was added to ethanol: 400 parts by mass, and sufficiently dissolved using a disper. Thereafter, 68.25 parts by mass of polyvinylpyrrolidone (PVP K-90, manufactured by IS Japan) was slowly added with stirring, and the mixture was stirred for about 30 minutes. Next, glycerin (Japanese Pharmacopoeia Concentrated Glycerin, manufactured by Asahi Denka Kogyo Co., Ltd.): 8.1 parts by mass was added and stirred for about 10 minutes to obtain a coating liquid C.

Next, the coating liquid C was sufficiently defoamed and spread on the water-swellable gel-forming layer so that the coating amount after drying was 80 g / m ² and dried to form a drug-containing layer.

(C) Thermocompression bonding / cutting step As described above, two water-swellable gel-forming layers having a drug-containing layer formed thereon are prepared and stacked so that the drug-containing layers face each other at 100 ° C., 1 kg / cm ^2. For 2 seconds.

  This was cut into a circle having a diameter of 15 mm to obtain an orally-administered agent having a dried water-swellable gel-forming layer as the outermost layer.

Tables 1 and 2 show the constituent materials and the contents of each layer in each example and each comparative example. In the table, “MM” is methacrylic acid-methyl methacrylate copolymer, “HPMCP” is hydroxypropylmethylcellulose phthalate (HP-55S, manufactured by Shin-Etsu Chemical Co., Ltd., mass average molecular weight: 76000), and “PEG” is , polyethylene glycol # 1500, "TEC" is triethyl citrate, "M", beeswax, "C", carnauba wax, "AGNa" is sodium alginate, "PAA" means polyacrylic acid, "CaHPO _4" is , Dicalcium phosphate, “CaCl ₂ ” represents calcium chloride, “GDL” represents glucono delta lactone, and “G” represents glycerin.

  In addition, as a result of measuring the solubility of the enteric material used for the disintegration control layer using a McIlvine buffer (pH 4.0) having a pH comparable to the surface pH of the gel layer, it was found that The solubility of the polymer in 100 g of McIlvaine buffer (pH 4.0) was 0.01 g or less. Further, the solubility of hydroxypropylmethylcellulose phthalate in 100 g of McIlvaine buffer (pH 4.0) was 0.01 g or less.

2. Evaluation of swallowing ability
(2-1) Gargle and wash the oral cavity. Two minutes later, the orally administered preparations of each Example and each Comparative Example were placed in the oral cavity without water and swallowed immediately. The ease of swallowing was evaluated according to the following four criteria. In addition, evaluation was performed 5 times and the average value was calculated | required as comprehensive evaluation.

4 …… Can be taken very easily without water.
3 …… Can be taken without water.
2 ... I would like to take it with water if possible.
1 ... Cannot be taken without water.

  (2-2) Gargle and wash the oral cavity. Two minutes later, the orally administered preparations of each Example and each Comparative Example were placed in the oral cavity without water, swallowed after 20 seconds, and the ease of swallowing according to the same four-stage criteria as in (2-1) above evaluated. In addition, evaluation was performed 5 times and the average value was calculated | required as comprehensive evaluation.

3. Adhesion evaluation (3-1) Gargle was performed and the oral cavity was washed. Two minutes later, the oral administration agents of each Example and each Comparative Example were placed in the oral cavity without water and swallowed immediately.
The above operation was performed 5 times and evaluated according to the following three-stage criteria.

○ …… Never adhered out of 5 doses.
Δ: 1 to 2 times of 5 degrees
× …… Fixed more than 3 times out of 5 doses.

(3-2) Gargle and wash the oral cavity. Two minutes later, the oral preparations of each Example and each Comparative Example were placed in the oral cavity without water and swallowed after 20 seconds.
The above operation was performed 5 times, and evaluation was performed according to the same three-stage criteria as in (3-1) above.

4). Evaluation of disintegration property of the disintegration control layer The disintegration property of the disintegration control layer used in each example was visually evaluated by a method according to the disintegration test method defined in the 15th revised Japanese Pharmacopoeia.

First, the coating liquid A for preparing the collapse control layer used in each example was spread on a flat plate using an applicator in which a gap was prepared so that the coating amount after drying was 50 g / m ^2. After coating and drying at 90 ° C. for 5 minutes, the flat plate was removed to obtain a film composed of a collapse control layer. A sample was obtained by punching this film into a circle having a diameter of 15 mm.

The test solution was artificial saliva (NaCl: 0.08% by mass, KCl: 0.12% by mass, MgCl ₂ : 0.01% by mass, CaCl ₂ : 0.01% by mass, K ₂ HPO with respect to purified water). ₄ : 0.03 mass%: 0.01 mass%, CMC-Na: 0.10 mass% added liquid), test liquid first liquid (pH: 1.2), and test liquid second liquid (pH: 6.8), and the test was conducted in the same manner as the capsule operating method, and the time until the sample completely disintegrated in each test solution was measured. In addition, the test performed the same test 3 times about each test liquid, calculated | required the average value of 3 times of tests, and evaluated it according to the following 4 steps | standards.

[Evaluation criteria for disintegration using artificial saliva]
◎ …… No disintegration or time until disintegration was 10 minutes or more.
○ …… Time to collapse was 5 minutes or more and less than 10 minutes.
Δ: Time until collapse was 3 minutes or more and less than 5 minutes.
X: Time until collapse was less than 3 minutes.

[Evaluation Criteria for Disintegration Using Test Solution 1]
◎ …… It took 120 minutes or more to collapse.
X: Time until collapse was less than 120 minutes.

[Evaluation criteria for disintegration using test liquid 2]
◎ …… Time to collapse was less than 3 minutes.
○ …… The time until collapse was 3 minutes or more and less than 10 minutes.
Δ: Time until collapse was 10 minutes or more and less than 20 minutes.
X: It did not collapse or the time until collapse was 20 minutes or more.

5). Evaluation of Drug Dissolution The drug dissolution was evaluated for the orally administered preparations of each Example and each Comparative Example by a method according to the dissolution test method (rotating basket method) prescribed in the 15th revision Japanese Pharmacopoeia.

  As the test solution, the test solution was artificial saliva (described above), the test solution first solution (pH: 1.2), and the test solution second solution (pH: 6.8). The time until the drug started to dissolve in each test solution (the time until the blue dye of the dummy drug contained in the drug-containing layer was eluted in each test solution) was measured. In addition, the test performed the same test 3 times about each test liquid, calculated | required the average value of 3 times of tests, and evaluated it according to the following 4 steps | standards. Further, the time until the drug started to elute was measured by visually confirming that each test solution was colored blue.

[Evaluation criteria for dissolution using artificial saliva]
A: The drug did not elute or the time until the drug eluted was 10 minutes or longer.
○ The time until the drug was eluted was 5 minutes or more and less than 10 minutes.
Δ: Time until the drug was eluted was 3 minutes or more and less than 5 minutes.
X: Time until the drug was eluted was less than 3 minutes.

[Evaluation criteria for dissolution using test solution 1]
A: It took 120 minutes or more for the drug to elute.
X: The time until the drug was eluted was less than 120 minutes.

[Evaluation criteria for dissolution using test solution 2]
◎ …… It took less than 3 minutes for the drug to elute.
○: It took 3 minutes or more and less than 10 minutes for the drug to elute.
Δ: Time until the drug was eluted was 10 minutes or more and less than 20 minutes.
X: The drug did not elute or the time until the drug elutes was 20 minutes or more.
These results are shown in Table 2.

  As shown in Table 2, the oral administration agent of each Example was easy to swallow even if taken immediately without water. In addition, the orally administered agent of each example can suitably release the drug in a solution having a pH close to that of the body fluid in the intestine (test solution second solution), and can produce artificial saliva and acidic solution (test solution first). In 1 liquid), it was difficult to release the drug. That is, the oral administration agent of each Example was capable of releasing a drug in the intestine without releasing the drug in the oral cavity and stomach.

  On the other hand, in the comparative example, a satisfactory result was not obtained. In particular, the orally administered preparations of Comparative Examples 1 and 3 could not be taken immediately without water. In addition, the orally administered agent of Comparative Example 2 was easy to release the drug with artificial saliva and easy to release the drug in the oral cavity.

It is sectional drawing which shows suitable embodiment of the oral administration agent of this invention. It is process drawing which shows an example of the manufacturing method of the oral administration agent of this invention. It is process drawing which shows an example of the manufacturing method of the oral administration agent of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Oral administration agent 11 ... Drug containing layer 12a, 12b ... Disintegration control layer 12a ', 12b' ... Disintegration control layer forming sheet 13a, 13b ... Gel-like layer 13a ', 13b '... Gel layer forming layer 14 ... Intermediate

Claims (7)

A drug-containing layer containing a drug;
A disintegration control layer provided on each side of the drug-containing layer;
Provided on the side opposite to the drug-containing layer of each collapse control layer, and has a gel-like gel layer containing an aqueous liquid,
The orally administered agent, wherein the disintegration control layer is composed of a material containing an enteric material that dissolves by contact with a bodily fluid in the intestine.   The oral administration agent according to claim 1, wherein the content of the aqueous liquid in the gel layer is 30 to 99.9% by mass.   The oral administration agent according to claim 1 or 2, wherein the content of water contained in the aqueous liquid is 30% by mass or more.   The oral administration agent according to any one of claims 1 to 3, wherein the gel layer has a hydrogen ion index of 2 to 5.   The orally administered agent according to any one of claims 1 to 4, wherein the enteric material contains an enteric polymer.   The oral administration agent according to claim 5, wherein the enteric polymer is an enteric acrylic copolymer or an enteric cellulose derivative.   The orally administered agent according to any one of claims 1 to 6, wherein the drug-containing layer is covered with the disintegration control layer.

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