JP5080856B2 - Tablets for oral administration - Google Patents

Description

  The present invention comprises an inner core and a coating layer covering the inner core, the inner core does not contain a drug and can be chewed, and the coating layer contains a drug and is rapidly disintegrating in the oral cavity. About.

  In recent years, application to various orally disintegrating tablets has been attempted, but in general, when a drug having a bitter taste is used to produce an orally rapidly disintegrating tablet, the tablet disintegrates rapidly, Immediately spreads in the mouth and feels bitter. Moreover, when excipient | fillers and artificial sweeteners, such as D-mannitol, are added, there exists a tendency for bitterness to increase further by the quick feeling of sweetness. Therefore, recently, when preparing a preparation of a drug having a bitter taste, means such as masking are applied by a separate manufacturing process. However, the equipment and processes used for masking increase, and many of the additives used for masking are insoluble in water, so there is a problem that drug release is greatly delayed in the evaluation of solubility (dissolution test, etc.). .

  On the other hand, photolabile drugs are generally produced as film-coated tablets. The hardness of the tablet can be easily increased by increasing the tableting pressure. However, when the tableting pressure is increased, the center portion of the tablet does not collapse at all, and the core remains in the oral cavity. In manufacturing as an intraoral quick disintegrating tablet, it is necessary to disintegrate quickly, and thus the hardness of the tablet cannot be increased, and the film coating cannot be performed because of insufficient hardness. Therefore, it has been impossible to make an intraoral quick disintegrating tablet from a photolabile drug.

JP 2000-302672 A JP 2002-338500 A

  An object of this invention is to provide the tablet for oral administration which reduces the bitterness of a medicine, without impairing the rapid disintegration property in an oral cavity. Another object of the present invention is to provide a tablet for oral administration that reduces the bitterness of the drug and improves the light stability without impairing the rapid disintegration property in the oral cavity.

  As a result of intensive studies to solve the above-described problems, the present inventors have found that a tablet having a chewable tablet containing no drug as an inner core has an excellent bitterness reducing effect. Furthermore, the present inventors have found that by making a dry-coated tablet, the tableting pressure is transmitted only to the external surface, and the rapid disintegration property of the coating layer is maintained. Based on these findings, further research has been conducted and the present invention has been completed.

That is, the present invention
[1] It comprises an inner core and a coating layer covering the inner core, the inner core does not contain a drug and can be chewed, and the coating layer contains a drug and is rapidly disintegrating in the oral cavity. Tablets for oral administration,
[2] The tablet for oral administration according to the above [1], wherein the inner core is a chewable tablet,
[3] The tablet for oral administration according to any one of [1] to [2], wherein the drug has a bitter taste,
[4] The tablet for oral administration according to any one of [1] to [3], wherein the disintegration time of the coating layer is within 30 seconds,
[5] The tablet hardness is 2 to 15 kgf, and the tablet for oral administration according to any one of [1] to [4], and [6] Further, the surface of the coating layer is coated. The tablet for oral administration according to any one of the above [1] to [5],
About.

  According to the present invention, after the external coating layer containing the drug rapidly disintegrates, the bitter taste masking effect can be obtained by the remaining inner core when the bitter taste of the drug spreads in the oral cavity. Further, even if the hardness of the tablet is increased, the rapid disintegration property is not impaired, so that the tablet can be easily coated even when the outer coating layer contains a light-unstable drug. Furthermore, since the tablet for oral administration of the present invention can be taken without water, it can be taken easily.

  The present invention comprises an inner core and a coating layer covering the inner core, the inner core does not contain a drug and can be chewed, and the coating layer contains a drug and is rapidly disintegrating in the oral cavity. The present invention relates to tablets for oral administration.

  Examples of the drug used in the present invention include nourishing tonics, antipyretic analgesics, antipsychotics, anxiolytics, antidepressants, hypnotic sedatives, antispasmodics, central nervous system agonists, brain metabolism improving agents, brain Circulation improving agent, antiepileptic agent, sympathomimetic agent, gastrointestinal agent, antacid, antiulcer agent, antitussive expectorant, antiemetic agent, respiratory promoting agent, bronchodilator, allergic agent, dental oral agent, antihistamine, Cardiotonic agent, arrhythmia agent, diuretic, antihypertensive agent, vasoconstrictor, coronary vasodilator, peripheral vasodilator, hyperlipidemic agent, biliary agent, antibiotic, chemotherapeutic agent, diabetes agent, bone 1 or 2 types selected from anti-porosis agents, anti-rheumatic drugs, skeletal muscle relaxants, antispasmodics, hormones, alkaloid narcotics, sulfa drugs, gout treatments, anticoagulants, anti-neoplastic agents The above components are used.

  For example, vitamin A, vitamin D, vitamin E (eg, d-α-tocopherol acetate), vitamin B1 (eg, dibenzoylthiamine, fursultiamine hydrochloride), vitamin B2 (eg, riboflavin butyrate), vitamins Vitamins such as B6 (such as pyridoxine hydrochloride), vitamin C (such as ascorbic acid, sodium L-ascorbate), vitamin B12 (such as hydroxocobalamin acetate, cyanocobalamin), minerals such as calcium, magnesium, iron, proteins, amino acids, oligosaccharides, Contains crude drugs.

  Antipyretic analgesics and anti-inflammatory agents include, for example, aspirin, acetaminophen, etenzamide, ibuprofen, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, caffeine, anhydrous caffeine , Serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminopyrine, ketoprofen, indomethacin, bucolome, pentazocine and the like. Examples of psychotropic drugs include chlorpromazine, reserpine and the like. Examples of the anxiolytic drug include alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include imipramine, maprotiline hydrochloride, amphetamine and the like. Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like. Antispasmodic agents include, for example, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, and the like. Examples of central nervous system drugs include citicoline. Examples of the brain metabolism improving agent include meclofenixate hydrochloride. Examples of the cerebral circulation improving agent include vinpocetine. Examples of the antiepileptic agent include phenytoin and carbamazepine. Examples of the sympathomimetic agent include isoproterenol hydrochloride. The gastrointestinal drugs include, for example, gastrointestinal agents such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, cinnamon oil, etc., berberine chloride, resistant lactic acid bacteria, bifidobacteria and the like.

  Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like. Examples of the anti-ulcer agent include famotidine, lansoprazole, omeprazole, rabeprazole, cimetidine, ranitidine hydrochloride and the like. Examples of the antitussive expectorant include cloperastine hydrochloride, dextromelt fan hydrobromide, theophylline, potassium guaiacol sulfonate, guaifenesin, and codeine phosphate. Examples of the antiemetic include diphenidol hydrochloride and metoclopramide. Examples of the respiratory accelerator include levallorphan tartrate. Examples of bronchodilators include theophylline and salbutamol sulfate. Examples of allergic drugs include amlexanox and seratrodast. Examples of the dental and oral medicine include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like. Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isothipentyl hydrochloride, dl-chlorpheniramine maleate, and the like. Examples of the cardiotonic agent include caffeine and digoxin. Examples of the arrhythmic agent include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of the diuretic include isosorbide, furosemide, hydrochlorothiazide and the like. Examples of antihypertensive agents include delapril hydrochloride, captopril, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, and perindopril erbumine. Examples of the vasoconstrictor include phenylephrine hydrochloride. Examples of the coronary vasodilator include carbochromene hydrochloride, molsidomine, and perapamil hydrochloride. Examples of peripheral vasodilators include cinnarizine. Examples of the hyperlipidemia agent include cerivastatin sodium, simvastatin, pravastatin sodium, atorvastatin calcium hydrate and the like. Examples of the bile agent include dehydrocholic acid and trepeptone. Antibiotics include, for example, cephem series such as cephalexin, cefaclor, amoxicillin, pimecillinam hydrochloride, cefotiam hexetyl hydrochloride, cefadroxyl, cefixime, cefditoren pivoxil, cefteram pivoxil, cefpodoximiproxetil, ampicillin, dicycline acid, And synthetic antibacterial agents such as enoxacin, monobactams such as carmonam sodium, penems and carbapenems.

  Examples of the chemotherapeutic agent include sulfamethizole. Examples of the agent for diabetes include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone and the like. Examples of the osteoporosis agent include ipriflavone. Examples of skeletal muscle relaxants include metocarbamol. Examples of antispasmodic agents include meclizine hydrochloride and dimenhydrinate. Antirheumatic drugs include methotrexate, bucillamine and the like. Examples of hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like. Alkaloid narcotics include opium, morphine hydrochloride, tocone, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride, and the like. Examples of the sulfa drugs include sulfisomidine and sulfamethizole. Examples of anti-gout drugs include allopurinol and colchicine. Examples of the blood coagulation inhibitor include dicumarol. Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin and the like. When the present invention is applied to a drug having a strong bitter taste, the effect is more exhibited.

  The amount of the above-mentioned drug is usually selected as appropriate depending on the type of drug or pharmaceutical use (indication), and is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount. It is usually 0.01 to 90% by weight, preferably 0.1 to 50% by weight, based on the total amount of the tablet.

  The uncoated tablet that is the inner core of the tablet of the present invention can be produced by the same method as that for a normal tablet. In other words, additives such as known excipients and binders are mixed and compressed as it is (direct powder compression method, direct compression method), or granulated into granules and used as they are or as additives Can be mixed and compression molded (wet and dry granule compression method, indirect compression method). Such an inner core can be produced using a commercially available tableting machine such as a rotary tableting machine used for the production of ordinary pharmaceuticals. An inner core tablet is 1 to 90 weight% normally with respect to the tablet whole quantity, Preferably it is 10 to 50 weight%. Although the magnitude | size of an inner core uncoated tablet is not specifically limited, Usually, a diameter (maximum diameter when a planar shape is not circular) is 4-10 mm, Preferably it is 5-7 mm. The thickness of the inner core is not particularly limited, but when the inner core diameter is 1, it is about 0.1 to 1, preferably about 0.2 to 0.6. The inner core tablet of the present invention is a chewable tablet that does not contain a drug, and the chewability of the chewable tablet can be influenced by the shape, thickness, etc. of the tablet, the size of the inner core tablet as described above, By making the thickness, ease of chewing is ensured.

  As an inner core component used in the present invention, an excipient is a main component, and in addition to this, for example, a disintegrant, a lubricant, a binder, a sour agent, a sweetener, a fragrance, a colorant and the like can be added. Examples of excipients used as the main component include saccharides and sugar alcohols, and examples of such saccharides and sugar alcohols include glucose, fructose, galactose, D-sorbitol, D-mannitol, sucrose, and maltose. , Lactose, isomaltose, palatinose, maltulose, lactulose, maltitol, lactitol, palatinit, xylitol, erythritol, trehalose and the like. Examples of the disintegrant include carboxymethyl starch sodium, carmellose calcium, croscarmellose sodium, carmellose, starch, crystalline cellulose, powdered cellulose and the like. Examples of the lubricant include magnesium stearate, magnesium silicate, carmellose, light anhydrous silicic acid, stearic acid, calcium stearate, talc, macrogol and the like. Examples of the binder include gum arabic, carmellose, carmellose sodium, gelatin, simple syrup, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like. Examples of the acidulant include organic acids such as citric acid, tartaric acid, lactic acid, acetic acid, and phosphoric acid, and salts thereof. Examples of the sweetening agent include aspartame, dipotassium glycyrrhizinate, sodium saccharin and the like. Examples of the fragrances include L-menthol, caramel, and various fruit fragrances. Examples of the colorant include titanium oxide, edible bengara, tartrazine, and indigo carmine.

The coating layer of the tablet of the present invention can be produced in the same manner as the inner core tablet by mixing the excipient and other additives with the drug. Such a tablet can be produced using a dry-coated tableting machine that is used in the production of ordinary dry-coated tablets. Pressure during tableting is usually 200~1000kgf / cm ^2, preferably 250~900kgf / cm ^2. The weight ratio of the inner core to the coating layer is 1: 1.1 to 1:20, preferably 1: 1.5 to 1:10, more preferably 1: 2 to 1: 5. The size of the entire tablet is not particularly limited, but usually the diameter (maximum diameter when the planar shape is not circular) is 7 to 15 mm.

  The tablet of this invention is manufactured so that hardness (kgf) may be 2-15 kgf. Here, the hardness of the tablet of the present invention is a value measured by a commonly used tablet hardness measuring device (for example, a tablet weight / thickness / hardness measuring device (trade name: TM5-5) manufactured by Kikusui Seisakusho Co., Ltd.). And is represented by the pressure (kgf) when the tablet disintegrates. Such desired hardness can be easily obtained by adjusting the compression pressure at the time of tableting, components of the inner core, and the like. If the hardness is lower than this range, the tablet is likely to be damaged in the process of manufacturing, packaging, and distribution. If the hardness is higher than this range, the hardness is too high and the tablet is difficult to chew.

  In the present invention, when the drug is unstable to light, the tablet obtained above can be further coated. Examples of photolabile drugs include vitamin A, vitamin D, vitamin K (menatetrenone, phytonadione, etc.), vitamin B2, vitamin B6, vitamin B12, carbamazepine, nifedipine, sofalcone and the like. Coating can be performed using a commonly used coating agent and coating apparatus. As a coating agent, what melt | dissolves in an oral cavity is preferable, For example, cellulose derivatives, such as hydroxymethylpropylcellulose, hydroxymethylcellulose, methylcellulose, are mentioned suitably. Further, macrogol or titanium oxide can be added to the coating agent. Moreover, as a coating apparatus, a tablet coating apparatus, a fluidized bed granulation coating apparatus, etc. can be used, for example.

  In the present invention, the rapid disintegrating property in the oral cavity means that the outer coating layer rapidly disintegrates in the oral cavity when taken, and “rapidly” specifically means within 45 seconds, preferably Within 30 seconds.

  Hereinafter, the present invention will be described with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto.

[Example 1]
D-mannitol (Rocket Japan Co., Ltd.) 300g, Hydroxypropylcellulose (Nihon Soda Co., Ltd.) 10g, Aspartame (Ajinomoto Co., Ltd.) 50g, Crystalline cellulose (Asahi Kasei Chemicals Co., Ltd.) 100g are granulated. Granulation is performed using 110 g of granulation liquid obtained by dissolving 50 g of tartaric acid (product name: High Speed Mixer FS-2, manufactured by Fukae Pautech Co., Ltd.) and tartaric acid (manufactured by Showa Kako Co., Ltd.) in 60 g of purified water. The granulated product was dried and then sized to obtain a sized product. 51 parts of the obtained sized product, 10 parts of carboxymethyl starch sodium (manufactured by Rocket Japan Co., Ltd.), 10 parts of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation), 22 parts of D-mannitol (manufactured by Merck Japan Co., Ltd.) , 5 parts of sodium hydrogen carbonate (Tokuyama) and 2 parts of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) were mixed to obtain tableting granules for inner core. An inner core uncoated tablet having a diameter of 6 mm and a weight of 85 mg was produced by a rotary tableting machine (trade name: VIRG, manufactured by Kikusui Seisakusho Co., Ltd.). In the obtained inner core tablet, 60 g of famotidine (manufactured by Koa Shoji Co., Ltd.), 1422 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.), 540 g of carmellose (manufactured by Gotoku Pharmaceutical Co., Ltd.) and magnesium stearate (Taihei Chemical Industry Co., Ltd.) )) 18 g of mixed powder was 340 mg per tablet, and it was compression coated with a tableting pressure (280 kgf / cm ² ) using a dry tableting machine (trade name: LIBRA2, manufactured by Kikusui Seisakusho Co., Ltd.), diameter 11 mm A dry-coated tablet weighing 425 mg (containing 10 mg of famotidine per tablet) was obtained.

[Example 2]
A dry-coated tablet having a diameter of 11 mm and a weight of 425 mg (containing 10 mg of famotidine per tablet) was obtained in the same manner as in Example 1 except that the tableting pressure was 540 kgf / cm ² .

[Example 3]
Except that the tableting pressure was 650 kgf / cm ² , a dry-coated tablet having a diameter of 11 mm and a weight of 425 mg (containing 10 mg of famotidine per tablet) was obtained in the same manner as in Example 1.

[Example 4]
A dry-coated tablet having a diameter of 11 mm and a weight of 425 mg (containing 10 mg of famotidine per tablet) was obtained in the same manner as in Example 1 except that the tableting pressure was 770 kgf / cm ² .

[Example 5]
Except that the tableting pressure was 880 kgf / cm ² , a dry-coated tablet having a diameter of 11 mm and a weight of 425 mg (containing 10 mg of famotidine per tablet) was obtained in the same manner as in Example 1.

[Test Example 1]
The following tests were conducted on the dry-coated tablets obtained in Examples 1 to 5.
(1) The tablet hardness was measured with 20 tableted tablets using a tablet weight / thickness / hardness measuring device (trade name: TM5-5, manufactured by Kikusui Seisakusho Co., Ltd.).
(2) The tablet friability was measured by the 15th revision Japanese Pharmacopoeia tablet friability test method.
(3) Nucleated tablets were included in the mouths of healthy subjects (three in each example), and the disintegration time of the outer coating layer was confirmed in a natural state. The average value and standard deviation of each disintegration time were determined for the dry-coated tablets obtained in Examples 1-5. The results are shown in Table 1.

  As is clear from Table 1, it was confirmed that an increase due to the tableting pressure showed an extremely fast disintegration even when the hardness was 10 or more. Moreover, there was almost no delay in disintegration due to pressure increase.

[Example 6]
The dry-coated tablet obtained in Example 5 was subjected to 5 parts hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) using a tablet coating machine (trade name: Hi-Coater HCT-30, manufactured by Freund Sangyo Co., Ltd.), Macrogol. 6000 (manufactured by NOF Corporation) 0.5 parts, titanium oxide (manufactured by Freund Sangyo Co., Ltd.) 4 parts, Japanese Pharmacopoeia ethanol (manufactured by Konishi Co., Ltd.) 46.25 parts, purified water 46.25 parts Coating was performed with a coating solution obtained by mixing and dispersing to obtain coated dry coated tablets having a weight of 435 mg (containing 10 mg of famotidine per tablet).

[Test Example 2]
The following tests were conducted on the coated dry coated tablets of Example 6.
(1) The tablet hardness was measured with 20 tableted tablets using a tablet weight / thickness / hardness measuring device (trade name: TM5-5, manufactured by Kikusui Seisakusho Co., Ltd.).
(2) Nucleated tablets were included in the mouths of healthy subjects (3 persons), and the disintegration time of the outer coating layer was confirmed in a natural state. The average value and standard deviation of the disintegration time of the dry-coated tablets obtained in Example 6 were determined. The results are shown in Table 2.

  In the coating process, it was easy to coat because of the strength of the dry-coated tablet. Further, as is clear from Table 2, the disintegration time was within 30 seconds even with the coated dry coated tablets.

[Comparative Example 1]
30g of Famotidine (manufactured by Koa Shoji Co., Ltd.) and 205.5g of D-mannitol (manufactured by Rocket Japan Co., Ltd.) in a fluidized bed granulator / dryer (trade name: Flow coater FLO-1, manufactured by Freund Sangyo Co., Ltd.) Then, 103 g of a solution in which 3 g of dextrin was dissolved in 100 g of purified water was sprayed, granulated, and dried to obtain a granulated product. 79.5 parts of the granulated product, 20 parts of carmellose (manufactured by Gotoku Pharmaceutical Co., Ltd.) and 0.5 part of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) were mixed to obtain a tableting agent. An intraoral rapidly disintegrating tablet having a diameter of 7 mm and a weight of 100 mg was obtained at 0.65 t using a rotary tableting machine (trade name: VIRG, manufactured by Kikusui Seisakusho Co., Ltd.). In addition, 3 healthy subjects were included in the mouth, and the decay time was 18 seconds on average in a natural state.

[Test Example 3]
For the dry-coated tablet obtained in Example 5 and the intraoral quick disintegrating tablet obtained in Comparative Example 1, a sensory evaluation test of bitterness was conducted by a total of five panelists. For the dry-coated tablet, after the coating layer disintegrates in the mouth, for the rapidly disintegrating tablet in the oral cavity, the test results on the remaining bitterness after the tablet disintegrates in the mouth are shown. The sensory evaluation was made by comparing the intensity of bitterness with the following criteria.
(Evaluation criteria for bitterness)
Not bitter: 1 point, slightly bitter: 2 points, bitter: 3 points, very bitter: 4 points

  As is apparent from Table 3, it was confirmed that after the outer coating layer collapses, the inner core remains and functions as a foamed tablet, so that bitterness due to the drug remaining on the tongue and in the oral cavity is reduced. .

  ADVANTAGE OF THE INVENTION By this invention, the tablet for oral administration which reduces the bitterness of a drug can be provided, without impairing the rapid disintegration property in an oral cavity.

FIG. 1 shows a cross-sectional view of the tablet of the present invention.

Explanation of symbols

1 inner core 2 drug 3 coating layer

Claims (5)

An inner core having a diameter (maximum diameter when the planar shape is not circular) is 4 to 10 mm and a coating layer covering the inner core, the inner core does not contain a drug and can be chewed, and the coating layer contains a drug. A dry-coated tablet for oral dissolution, characterized by containing and rapidly disintegrating in the oral cavity. Inner core is dry-coated tablet for oral dissolution of claim 1, wherein a chewable tablet. 3. The dry- coated tablet for intraoral dissolution according to claim 1 or 2, wherein the coating layer is coated with a film. The dry- coated tablet for intraoral dissolution according to any one of claims 1 to 3, wherein the drug has a bitter taste. The coated tablet for oral dissolution according to any one of claims 1 to 4, wherein the disintegration time of the coating layer is within 30 seconds.