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`69 Publication number:
`
`0 651 997 A1
`
`®
`
`EUROPEAN PATENT APPLICATION
`published in accordance with Art.
`158(3) EPC
`
`@ Appiication number: 92924919.1
`
`@ Date of filing: 15.12.92
`
`International application number:
`PCT/J P92/01631
`
`International publication number:
`WO 93/12769 (08.07.93 93/16)
`
`Priority: 24.12.91 JP 356898/91
`20.11.92 JP 335076/92
`
`Date of publication of application:
`10.05.95 Bulletin 95/19
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IE IT LI LU NL
`PT SE
`
`@ Int. 01.6: A61K 9/20, A61K 47/36,
`A61 K 47/10, A61 K 47/26,
`A61 K 9/00
`
`® Applicant: YAMANOUCHI PHARMACEUTICAL
`CO. LTD.
`No. 3-11 Nihonbashi-Honcho, 2-chome
`Chuo-ku
`
`Tokyo 103 (JP)
`
`® Inventor: MASAKI, Katsuhiro
`1754-3, Taziri
`Yaizu-shi
`
`Shizuoka 425 (JP)
`Inventor: BAN, Kazutoshi
`48-1, thurni
`Yaizu-shi
`
`Shizuoka 425 (JP)
`
`Representative: Geering, Keith Edwin et aI
`REDDIE & GROSE
`16 Theobalds Road
`
`London WC1X 8PL (GB)
`
`
`
`@ INTRABUCCALLY DISINTEGRATING PREPARATION AND PRODUCTION THEREOF.
`
`@ A solid preparation soluble in the buccal cavity, which is composed of a sugar comprising lactose and/or
`manitol and 0.1-1.2 w/w°/o, based on the sugar, of agar and an active ingredient and has a density of 400-1000
`mg/ml and such a strength as to withstand the handling in the manufacture thereof.
`It has such a sufficient
`practical solubility in the buccal cavity that even the aged or children having difficulty in swallowing a solid
`preparation, such as a tablet, can take it.
`It has an exceedingly high strength as compared with conventional
`open matrix structures and hence can withstand satisfactorily carrying and PTP packaging.
`
`EP0651997A1
`
`Rank Xerox (UK) Business Services
`(3.10/3.09/3.3.4I
`
`

`

`EP 0 651 997 A1
`
`TECHNICAL FIELD
`
`This invention relates to a solid preparation which has a practically sufficient strength for the handling
`similar to the case of common tablets and also has a practically sufficient solubility or disintegration
`property in the buccal cavity, and to a process for producing the same.
`
`BACKGROU ND ART
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`Since dosage forms in which easy swallowing by patients is taken into consideration are scarce in spite
`of the existence of various known dosage forms of pharmaceutical preparations for oral administration use,
`great concern has been directed toward the development of a dosage form which can be easily handled
`especially by the aged or children having difficulty in swallowing a solid preparation.
`For example, in the case of tablets and capsules frequently used as oral preparations, many patients of
`the aged or children having weak swallowing power are unwilling to take these solid preparations
`complaining that the drug is difficult to swallow or stops in the pharynx or gullet.
`In the case of powders and granules, they are difficult to swaliow because of their aptness to remain in
`the buccal cavity and therefore to cause a unpleasant feeling in the mouth. In some cases, the aged will be
`choked with powders or feel a pain or unpieasantness due to granules gotten in between false teeth.
`In
`addition, powders and granules have to be used after tearing each package, but the aged or children often
`have difficulty in tearing the package or spill a portion of its contents.
`To take these oral preparations, it is necessary to use water, and the aged or children especially require
`a large volume of water in many cases because of the swallowing difficulty. However, there is a situation
`that
`it
`is necessary to drink water moderately, especially before retire to bed because of the urination
`problem at night.
`In addition,
`in the case of patients who have to take oral preparations constantly while
`making daily life, water can hardly be obtained in certain cases depending on circumstances,
`thus
`sometimes entailing decline in the compliance.
`Syrups and the like are regarded as desirable dosage forms for the aged or children, but the aged or
`children who have difficulty in measuring the necessary volume cannot be expected to use such
`preparations in correct dose.
`In addition, since there are many aged patients who can hardly take liquid
`preparations to mouths by themselves, such dosage forms cannot always be regarded as suitable dosage
`forms for the aged and children when trouble at the time of drug-taking is taken into consideration, except
`for a case in which a patient can ask a nurse for a helping hand.
`On the basis of
`the above, when the forthcoming social condition of advanced age is taken into
`consideration, development of a dosage form which can be used easily especially by the aged seems to be
`an immediate need, because the morbidity rate of chronic diseases increases with advance in age and
`patients of advanced age have a tendency to take drugs for a long period of time. Also,
`in order to keep the
`quality of
`life,
`it
`is desirable to develop a dosage form which can be easily swallowed and handled
`according to the ability and life condition of each patient.
`Several pharmaceutical preparations which dissolve or disintegrate in the buccal cavity are known as
`suitable dosage forms for the aged, children or patients who dislike drug taking. For example, JP-B-62—
`50445 discloses a solid preparation having an open matrix network structure which is obtained by freezing
`an aqueous solution containing gelatin as the main component and a pharmaceutical substance and then
`sublimating the solvent. (The term "JP-B" as used herein means an "examined Japanese patent publica-
`tion".) According to this patent publication, the open matrix network structure has a density of 10 to 200
`mg/ml and disintegrates rapidly in water within 10 seconds by a tablet disintegration test. It also discloses
`that spitting of
`the preparation by patients who dislike drug-taking can be prevented, because the
`preparation disintegrates rapidly within 1
`to 2 seconds in the buccal cavity of the patient and is swallowed
`together with saliva.
`However, because of the rapidly disintegrating property, this open matrix structure has an insufficient
`strength and is so brittle that its hardness cannot be measured. In consequence, usual Press Through Pack
`(blister packaging) and the like from which tablets can be easily taken out cannot be applied to this
`preparation, which therefore requires a specific seal-peeling type packaging, and the preparation is
`extremely difficult to handle because of its aptness to cause breakage and cracking during its delivery or
`carrying or when it is taken out from its package at the time of its use. Being sensitive to moisture,
`it also
`has a problem of causing stickiness on the surface of the preparation even when it
`is merely put on the
`hand.
`In consequence, this dosage form is not practically appropriate because of its difficulty in handling
`especially by the aged or children.
`
`

`

`EP 0 651 997 A1
`
`JP-A—2-30014 discloses a molded tablet which is produced by temporarily mixing solid components
`such as sugar, active ingredient and the like with a small volume of a volatile liquid binder sufficient to form
`a slightly wet lump and putting the thus formed lump into a mold by force to evaporate the liquid binder.
`(The term "JP-A" as used herein means an "unexamined published Japanese patent application")
`However, since this molded tablet is prepared by forced pack molding of a clayey material and drying, air
`contamination and the like cannot be avoided,
`thus causing irregularities in the drug content, shape,
`hardness and the like and entailing inferior practicability.
`In addition,
`the production process is not
`applicable to industrial tablet production, because it requires a special mold packing apparatus.
`JP-A—3-56412 discloses an intrabuccally dissolving preparation which is obtained by freeze-drying
`sugars. However, since this preparation has low hardness,
`it cannot be applied to conventional Press
`Through Pack (blister packaging) and has low practicability from the viewpoint of preparation handling.
`In
`addition, its production process has low industrial productivtty, because the highly viscous suspension to be
`filled in a mold cannot be applied to the usual
`liquid filling apparatus,
`thus requiring a special
`filling
`apparatus, and because irregularities in the shape, weight and the like of the final preparation occur.
`
`DISCLOSURE OF THE INVENTION
`
`The inventors of the present invention have conducted extensive studies to develop new dosage forms
`which can be swallowed easily, handled easily and taken in correct dose and therefore is applicable to the
`aged and children and, as the result, have succeeded in developing a new dosage form which is easily
`swallowable without water because of its rapidly disintegrating nature in the buccal cavity and also can
`easily be handled and taken out from packages.
`In addition, this dosage form is excellent in industrial productivity, has uniformity in its drug content and
`shape and, therefore, is practically useful.
`That ts, the present invention relates to an intrabuccally disintegrating solid preparation which com-
`prises an active ingredient, a sugar comprising lactose and/or mannitol and 0.12 to 1.2 W/W°/o, based on the
`solid components, of agar and which has a density of 400 mg/ml to 1,000 rng/rnl and a sufficient strength
`for the handling. The solid preparation of the present
`invention has high practicability because of
`its
`advantages in that it can be swallowed easily without water due to its rapidly disintegrating nature in the
`buccal cavity, it has a strength sufficient enough to withstand the handling and, therefore, can be applied to
`usual Press Through Pack (blister packaging) and the like from which tablets can be taken out easily and it
`has no particular limitations with regard to its delivery and carrying and its handling after take out from
`packages.
`The present invention also relates to a process for the production of an intrabuccally disintegrating solid
`preparation having a sufficient strength for the handling, which comprises suspending an active ingredient
`and a sugar comprising lactose and/or mannitol
`in a 0.3 to 2.0 w/w% agar aqueous solution used in an
`amount of 40 to 60 w/w% based on the solid components, filling the suspension in a mold to solidify it into
`a jelly form, and subsequently drying the jell. According to the inventive production process, the phar-
`maceutical preparation of the present invention can be produced with excellent uniformities of preparation
`weight, active ingredient content and shape.
`In addition, since vacuum drying, aeration drying and the like
`can be used,
`the production process is free from complex drying-related operation and therefore is
`excellent in industrial productivity.
`The following describes the present invention in detail.
`The sugar which constitutes the preparation of the present invention is lactose and/or mannitol having
`excellent dispersibility in water and proper solubility. One of these sugars may be used alone or a mixture
`of them may be used. A structural body having desired hardness and disintegration rate (dissolution rate)
`can be obtained regardless of their mixing ratio. However, such a structure of interest cannot be obtained
`when other sugars such as sucrose, glucose, sorbitol and the like are used, and the dissolution rate
`decreases remarkably even when these other sugars are used in combination with lactose and/or mannitol.
`The sugar of the inventive preparation seems to form the desired structural body because the partly
`dissolved sugar binds the undissolved sugar during the water-removing step which is carried out after
`solidification of the sugar and an active ingredient under such a condition that the sugar is dispersed in
`water
`(partly dissolved).
`In consequence,
`the present
`invention is characterized in that
`lactose and/or
`mannitol having excellent dispersibility and proper solubility is used as a sugar.
`Though it varies depending on the quality and quantity of the active ingredient to be used, the sugar
`may be used in the inventtve preparation in an amount of at least 50 w/w%, preferably 80 w/w% or more,
`more preferably 90 w/w% or more, based on the total solid components.
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`EP 0 651 997 A1
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`According to the present invention, 0.12 to 1.2 w/w% of agar is used based on the solid components
`(namely an active ingredient, sugars and the like). By the addition of agar, the following advantages are
`obtained.
`
`(1) Because of the nature of aqueous agar solution to solidify rapidly into the form of a jelly at room
`temperature, the aforementioned suspension solidifies in a jelly form within a short tirrre when it is filled
`in a mold, thus rendering possible prevention of precipitation of solid components in the suspension and
`formation of a uniform structural body having a desired hardness.
`(2) Agar itself also has an effect to improve strength of the pharmaceutical preparation by forming a part
`of the structural body.
`(3) Since the suspension is solidified in the form of a jelly, expansion of the dried surface in the drying
`step under a reduced pressure condition can be suppressed,
`thus rendering possible prevention of
`hardness reduction and irregular shape which are generated by the expansion.
`(4) When drying is effected especially under a reduced pressure or with aeration, agar molecules are
`partly shifted to the upper surface of the preparation together with water molecules, thus resulting in the
`improvement of strength of the preparation surface structure.
`(5) Since the suspension solidifies rapidly into the form of a jelly after its filling in a mold, irregularity in
`shape does not occur, thus rendering possible easy operations thereafter such as transfer of the mold,
`drying and the like.
`Though gelatin and the like are also known as substances which solidify into the form of a jelly, a
`desirable preparation may not be obtained when these substances are used because of their inferior
`operabilities such as inappropriate temperature for jelly-like solidification and prolonged period of time
`necessary for the solidification, as well as inappropriate hardness and solubility of the resulting preparation
`after its drying.
`Though types of agar are not particularly limited, those listed in the Japanese Pharmacopoeia may be
`used preferably. Examples of the listed agar include agar powders PS-7 and PS—8 (manufactured by Ina
`Shokuhin).
`Agar may be used in an amount of from 0.12 to 1.2 w/w%, preferably from 0.2 to 0.4 w/w%, based on
`the solid components.
`In order to produce the structural body of the present invention, a sugar comprising lactose and/or
`mannitol is suspended in an aqueous agar solution, filled in a mold, solidified into a jelly-like form and then
`dried. The aqueous agar solution may have a concentration of from 0.3 to 2.0%, preferably from 0.3 to
`0.8%. The aqueous agar solution may be used in such an amount that the blending ratio of agar based on
`the solid components becomes 0.12 to 1.2 w/w%, but preferably 40 to 60 w/w% of agar solution based on
`the solid components.
`Concentration of the aqueous agar solution if smaller than 0.3% would bear no advantageous effect of
`the agar blending. Also,
`the concentration if
`larger
`than the above range would entail delay in the
`disintegration rate of the resulting preparation in the buccal cavity.
`Active ingredients to be applied to the preparation of the present invention are not particularly limited,
`provided that they are able to be dissolved or suspended in the aqueous agar solution, with their preferred
`examples including drugs for use in patients having difficulty in swallowing tablets, the aged and children;
`drugs for use in patients who require drug taking without water during daily life; preparations for use in
`patients whose water drinking is limited; and drugs for use in potions.
`Illustrative examples of drugs having high utility values include:
`)carbonyl]-4,5,6,7-tetrahydro-1H-
`serotonin 5HT3 receptor antagonists such as (R)-5-[(1-methyl-3-indolyl
`benzimidazole hydrochloride and salts thereof, ondansetron, granisetron and the like,
`non-steroidal anti-infammatory drugs such as indometacin,
`ibuprofen,
`ibufenac, alclofenac, diclofenac,
`mefenamic acid, flurbiprofen, flufenamic acid, ketoprofen, phenylbutazone, methyl salicylate and the like,
`steroidal anti-infammatory drugs such as cortisone, hydrocortisone, prednisolone, dexamethasone, be-
`tamethasone dipropionate, betamethasone valerate, prednisolone, triamcinolone, fluocinolone acetonide and
`the like,
`trichlormethiazide, cyclopen-
`diuretic drugs such as bendroflumethiazide, polythiazide, methyclothiazide,
`thiazide, pentylhydrochlorothiazide, hydrochlorothiazide, bumetanide and the like,
`lorazepam, prazepam,
`antipsychotic drugs such as emonapride, diazepam, nitrazepam,
`flunitrazepam,
`fludiazepam, clonazepam, chlorpromazine hydrochloride,
`reserpine, clofluperol,
`trifluperidol, haloperidol,
`moperone and the like,
`hypnotic drugs such as barbital, thiopental, phenobarbital, cyclobarbital and the like,
`antiepileptic drugs such as ethosuximide, sodium valproate, acetazolamide, meprobamate and the like,
`antiparkinsonism drugs such as chlorzoxazone, levodopa and the like,
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`EP 0 651 997 A1
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`antiemetic drugs such as metoclopramide, metoclopramide hydrochloride and the like,
`hormone drugs such as insulin, testosterone, methyltestosterone, progesterone, estradiol and the like,
`analgesic drugs such as morphine, aspirin, codeine, acetaniiide, aminopyrine and the like,
`sulfa drugs such as sulfamine, sulfamonomethoxine, sulfamethizole and the like,
`coronary vasodilators such as nitroglycerin, isosorbide dinitrate, pentaerythrityl tetranitrate, propatylnitrate,
`dipyridamole, papaverine HCI and the like,
`H2 receptor antagonists such as famotidine, cimetidine, ranitidine HCl, roxatidine acetate HCl and the like,
`antiarrhythmic drugs such as ajimalin, pindolol, propranolol, guinidine, amrinone, milrinone and the like,
`cardiotonic drugs such as caffeine, digoxin, digitoxin and the like,
`calcium antagonists such as nicardipine HCl, diltiazem HCI, nivadipine, nifedipine, nitrendipine, nisoldipine,
`nimodipine, niludipine and the like,
`antihistaminic drugs such as diphenhydramine HCl, carbinoxamine, diphenylpyrallin, phenbenzamine, chlor-
`pheniramine maleate, brompheniramine maleate, diphenylimidazol, clemizole and the like,
`antibiotics such as tetracycline, oxytetracycline, metacycline, doxycycline, minocycline, chloramphenicols,
`erythromycins, lincomycin, penicillin G, clindamycin, kanamycin, chloramphenicol, fradiomycin, streptomy-
`cin, gentamycin and the like,
`antitumor drugs such as 5-fluorouracil, uracil, cytarabine, floxuridine, busulfan, actinomycin, bleomycin,
`mitomycin and the like,
`antidiabetic drugs such as glibenclamide and the like,
`gout treating drugs such as allopurinol, colchicine, benzbromarone and the like,
`antiallergic drugs such as ketotifen fumarate, sodium cromoglicate, amlexanox and the like,
`antihypertensive drugs such as clonidine, guanethidine sulfate, amosulalol HCl, alacepril, delapril HCl,
`enalapril maleate and the like,
`central nervous system acting drugs such as indeloxazine HCl, tiapride HCl, bifemelane HCl and the like,
`skeletal muscle relaxants such as sodium dantrolene and the like,
`antispasmodic drugs such as eberidine HCI, tizanidine HCl, butylscopolamine, atropine methylbromide and
`the like,
`antihyperlipemic drugs such as simvastatin, sodium pravastatin and the like,
`bronchodilators such as formoterol fumarate, salbutamol sulfate, procaterol HCl and the like,
`a-adrenergic receptor blockers such as tamsulosin hydrochloride and prazasin,
`blood sugar lowering drugs,
`oral contraceptives, and
`animal drugs having antipyretic-analgestic-antiinflammatory activities, peptic antiulcer activities and the like
`or animal organ drugs for treating reproductive organ and the like.
`Active ingredients are not particularly limited, and not only pharmaceutical drugs but also various other
`substances can be applied to the preparation of the present invention making use of its characteristic
`nature, which include for example diagnostic drugs such as a contrast medium and the like, healthy food,
`physiologically functional
`food and buccals such as a bad breath eliminating drug, a dental plaque
`disclosing agent and the like.
`The active ingredient may be used in an amount of 50 w/w% or less, preferably 20 w/w% or less, more
`preferably 10 w/w% or less, based on the total solid components, though it varies depending on the nature
`of each active ingredient to be used.
`In general, preferred active ingredients to be applied are those which do not generate unpleasant taste
`at the time of their dissolution. When a component which generates unpleasant taste is used, it is preferable
`to employ a proper taste-concealing treatment.
`In addition, if necessary, the aqueous agar solution may further have a perfume (menthol, for instance),
`a sweetener (Aspartame (trade name), for instance), a coloring agent, an stabilizer, a preservative and the
`like.
`
`The solid preparation of the present invention may have a density approximately in the range of from
`400 to 1,000 mg/ml, though it varies depending on the blending ratio of components. A density of from 600
`to 900 mg/ml
`is preferable in view of
`the relationship between strength and solubility of
`the solid
`preparation.
`invention has such a sufficient strength for the handling and,
`the present
`The solid preparation of
`therefore, can be put
`into practical use in the same manner as the case of usual tablets. The term "a
`sufficient strength for the handling" as used herein means a strength which can withstand at least the usual
`Press Through Pack (blister packaging), and such a strength will also withstand other handling such as
`delivery, carrying and the like.
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`EP 0 651 997 A1
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`Hardness in the lengthwise direction of tablets may be used as an index of the strength which is
`applicable to Press Through Pack (blister packaging), namely a strength necessary to take out a preparation
`by pushing it out of a cover sheet of usual Press Through Pack (blister packaging). Such a hardness varies
`depending on the size and shape of tablets and may preferably be 1.0 kg or more when the tablet has a
`diameter of about 8.0 mm, 1.5 kg or more for a diameter of about 10.0 mm and 2.0 kg or more for a
`diameter of about 12.0 mm. The solid preparation of the present invention has a strength which can fully
`withstand its taking out from Press Through Pack (blister packaging) regardless of its size.
`The term "intrabuccally disintegrating property" as used herein means a practically sufficient disintegra-
`tion or solubilization of
`the preparation by saliva in the buccal cavity without
`taking water. The term
`"practically sufficient disintegration or solubilization" means that the preparation disintegrates or dissolves
`generally within approximately 5 to 20 seconds in the buccal cavity, though there are individual variations.
`The structural body of the inventive preparation chiefly made of a sugar rapidly becomes brittle due to
`saliva in the buccal cavity and gradually disintegrates or solubilizes, and the disintegration or solubiiization
`becomes more quick when an intrabuccal pressure, namely a pressure between the upper jaw and tongue,
`a "licking" movement of tongue, or the like, is applied to the preparation.
`The preparation of the present invention does not show rapid disintegration, because its disintegration
`in water by a tablet disintegration test is approximately 1 to 2 minutes, though it varies depending on the
`shape. As described above, however, the inventive preparation has a practically sufficient disintegrating or
`solubiiizing property in the buccal cavity.
`A person of parched mouth or having a small quantity of saliva in the buccal cavity may use the
`inventive preparation with the aid of cold or hot water in an amount sufficient to wet the buccal cavity.
`Also,
`the inventive preparation may be swallowed together with a small amount of water after the
`preparation is disintegrated or solubilized in the buccal cavity or under a partly disintegrated or solubilized
`condition. Even by such a way of drug-taking, merits of the preparation of the present invention such as
`easy swallowing, small amount of water to be used and the like can be given.
`Of course, the inventive preparation can be taken together with water with no problems similar to the
`case of usual tablets. The preparation of the present invention can be used by any of these drug-taking
`means in accordance with each patient's choice or condition, provided that there are no limitations with
`respect to the active ingredient contained therein.
`The following describes a process for the production of the preparation of the present invention.
`An aqueous agar solution is prepared by the usual way, for example, by adding water to agar powder
`and dissolving the agar by heating.
`Lactose and/or mannitol and an active ingredient are added to the aqueous agar solution to obtain a
`uniform suspension. If necessary, a sweetener, a perfume, a coloring agent, a preservative and the like may
`also be added optionally.
`Next, the thus obtained suspension is filled in a mold in the usual way. Filling may be carried out at
`around room temperature. The filling temperature if too high would require a prolonged period of time for
`the solidification of the suspension into a jelly form, and the temperature if too low would disturb smooth
`filling due to solidification of the suspension prior to its filling. The temperature may preferably be in the
`range of from 15 to 30 “C.
`The mold to be used is not particularly limited, and those made of metals or resin films may be used.
`Preferred mold is a resin film sheet having a number of hollows, which is used for the enclosure of tablets
`by Press Through Pack (blister packaging).
`After filling and drying the suspension in the resin film sheet, a cover sheet for use in usual Press
`Through Pack (blister packaging) is adhered to the resulting resin film sheet, thereby easily obtaining
`packages of the solid preparation of the present invention. The material of the sheet has no particular
`limitation, and may be selected from polypropylene, polyvinyl chloride, polyvinylidene chloride and the like.
`Though the shape of the mold is not particularly limited, the hollow of the mold may preferably have a
`globular shape.
`Since the suspension filled in the mold solidifies into a jelly form within a short period of
`subsequent shifting and transfer of the mold or drying step can be made easily.
`The suspension surface solidifies within 1
`to 2 minutes at room temperature to form a predetermined
`shape,
`though the time varies depending on the size and shape of the preparation.
`If necessary,
`the
`suspension can be solidified into a jelly form within more shorter time at a low temperature.
`Next, the preparation thus solidified into a jelly form is dried. Drying may be effected by any means,
`provided that it does not spoil characteristics of the solid preparation of the present invention. Preferably,
`the drying may be effected under reduced pressure or with aeration. The reduced pressure or aeration
`drying may be carried out at a temperature within such a rage that the preparation solidified into a jelly form
`
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`EP 0 651 997 A1
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`does not freeze or re-dissolved, preferably at about 25 to 35 “C in the case of reduced pressure drying or
`about 3 to 15°C in the case of aeration drying.
`In the case of reduced pressure drying, it may be effected
`near vacuum condition of -750 mmHg or below.
`Drying time may be optionally decided depending on the drying method, drying condition and the size
`and shape of the preparation. For example,
`it may be 2 to 5 hours in the case of reduced pressure drying
`or 1 to 6 days in the case of aeration drying.
`
`INDUSTRIAL APPLICABILITY
`
`The solid preparation of the present invention has the following utility.
`(1) It shows practically sufficient disintegration or solubilization in the buccal cavity without water and can
`be swallowed easily (easy to administer).
`(2) Since means to take the preparation can be selected at will according to each person's ability, choice
`and condition (e.g., without water, with the aid of a small amount of water or together with water similar to
`the case of tablets), improvement in the compliance can be expected.
`(3) Since it does not stick on the hand when taken out of its package similar to the case of usual tablets
`due to its resistance against moisture, it can be handled easily.
`(4) It can be taken in correct dose, because it is uniform in both weight and active ingredient content and
`can be used with no measuring effort at the time of its use or without causing spilling when taken out of
`its package.
`(5) It can be taken out from its package easily, because it has a sufficient strength for the handling and,
`therefore, can be packaged by any packaging means for easy to take out which is commonly applied to
`tablets (e.g. Press Through Pack (blister packaging».
`(6) It can be handled in the same manner as commonly used tablets even at the time of its packaging,
`transferring or carrying.
`invention is a new dosage form having high
`In consequence,
`the solid preparation of the present
`practicability, because it can be taken easily due to its practically sufficient disintegration or solubilization in
`the buccal cavity even without water, can be handled easily in the same manner as commonly used tablets
`and, especially,
`is applicable to the aged, patients having difficulty in swallowing, and children.
`In addition,
`the preparation of the present invention can be used advantageously by persons who require drug-taking
`during their daily life, because it can be carried, easily taken out from its package and swallowed without
`water.
`
`invention is effective in industrially
`the present
`the production process of the preparation of
`Also,
`manufacturing the aforementioned useful solid preparation. The production process of the present invention
`is characterized in that an appropriate concentration of aqueous agar solution is used in an amount of from
`40 to 60 w/w% based on solid components, thereby effecting quick solidification of a suspension, which is
`quantitatively filled in a mold,
`into a jelly form at room temperature. This renders possible not only easy
`handling of the mold in the subsequent production steps but also production of a preparation having desired
`strength and infrabuccally disintegrating function, which is uniform in its weight and active ingredient
`content, has no irregularity in its shape and is uniform in its inner structural body.
`In addition, since the drying step is effected when the suspension is solidified into a jelly form,
`irregularity in shape does not occur, special apparatus is not required and a uniform preparation from which
`water is thoroughly removed can be obtained even by inexpensive and simple reduced pressure drying or
`aeration drying, thus resulting in high industrial productivity.
`Since piastic containers for Press Through Pack (blister packaging) can be used as the mold in the
`production process of the present invention, Press Through Pack (blister packaging) can be obtained easily
`by adhering cover sheets to the containers in the usual way after drying of the jellied suspension.
`The following illustratively describes utility of the solid preparation of the present invention.
`
`(1) Disintegration or solubilization property
`
`Disintegration or solubilization of the solid preparation of the present invention in water was measured in
`accordance with the tablet disintegration test (The Japanese Pharmacopoeia). Each of the data shown in
`Table 1
`is an average of 6 tablets. Disintegration time in the buccal cavity (average of 10 volunteers) is also
`shown in the table.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`

`

`EP 0 651 997 A1
`
`Table 1
`
`Tablet disintegration test
`
`Exampie No. of the present invention
`
`Results of tablet disintegration test
`
`29
`
`Example 1
`2 (a)*1
`2 (by?
`3
`
`23 seconds
`13.6
`29.8
`28
`58
`34
`49
`
`Note)
`*1 Disintegration time in the buccal cavity in Example 2 (a) was found to be 10 seconds.
`’2 Disintegration time in the buccal cavity in Example 2 (b) was found to be 11 seconds.
`
`Thus, the solid preparation of the present invention showed about 13 to 120 seconds of disintegration
`time by the tablet disintegration test. Though there were individual variations, disintegration time in the
`buccal cavity was approximately 5 to 20 seconds.
`
`(2) Hardness
`
`Hardness of the preparation of the present invention was measured using a hardness meter. The results
`are s