JPWO2018074496A1 - Composition for controlling drug elution in vivo - Google Patents

Abstract

The present invention relates to a novel substance having a drug elution control action in vivo, a novel drug elution control agent in vivo, a solid preparation with controlled drug elution, and any one of these production methods The above provision is an issue. In the infrared absorption spectrum obtained when the present invention contains tannic acid and a drug (if desired, further an inert carrier and / or a lower alcohol) and measured with a Fourier transform infrared spectrophotometer, There are provided a complex, a complex-containing solid preparation, a production method thereof, and the like, wherein at least one of the peaks due to the functional group is not detected.

Description

  The present invention relates to a composition for drug elution control or a drug elution control agent in vivo, a solid preparation containing the same, and a method for producing them. Representative dosage forms as solid preparations are tablets such as orally disintegrating tablets and chewable tablets.

  The most widely used dosage form for internal solid preparations is a tablet, which is taken with water, disintegrates in the digestive tract such as the stomach and intestine, and is absorbed in the digestive tract such as the stomach and intestine. In recent years, orally disintegrating tablets and chewable tablets, which are attracting attention as easy-to-drink formulations for infants, children and the elderly, can be taken without water, disintegrate in the oral cavity, and are absorbed in the digestive tract such as the stomach and intestine Is done. Therefore, if the medicinal component develops an unpleasant taste such as bitterness or puffy taste in the oral cavity, it deteriorates the feeling of medication and causes a decrease in medication adherence and compliance, so masking the unpleasant taste There is a need to.

  Many methods have been reported for masking the unpleasant taste of medicinal ingredients, such as functional masking methods that add high sweeteners, taste-masking agents, cooling agents, etc., and films containing water-insoluble polymers. A physical masking method for coating is generally known.

  As a sensory masking method, there is known a method (Patent Document 1) for suppressing drug discomfort when taken by combining a drug having an unpleasant taste and sucralose as a sweetener. In some cases, an unpleasant taste cannot be concealed only by the addition of sucralose, so that there is a problem that the bitterness reducing effect is not sufficient.

  As a method of physical masking, a method of masking the unpleasant taste by preparing a granular pharmaceutical composition containing a drug exhibiting an unpleasant taste, a waxy substance and a sugar alcohol (Patent Document 2) is known. In addition, there is a problem that an apparatus for melt granulation is required and it cannot be applied to an unstable drug that is decomposed by heat at the time of melting. In addition, the bitterness can be reduced by preparing a fine-grain preparation by spray-coating an aqueous suspension composed of ethylcellulose and a water-soluble plasticizer as a bitterness-inhibiting layer on the core containing a pharmacologically active ingredient having a bitter taste. A masking method (Patent Document 3) is known, but when a tablet is prepared by compressing it, there is a problem that the coating film is destroyed and bitterness is felt at the time of taking.

  As described above, various methods for masking the unpleasant taste of conventional medicinal ingredients have been studied. However, depending on the type of medicinal ingredient, there are cases where it is difficult to respond technically. Was demanded.

JP 2001-342151 A JP 2000-327590 A JP 2000-53563 A

  The present invention relates to a novel substance having a drug elution control action in vivo, a novel drug elution control agent in vivo, a solid preparation with controlled drug elution, and any one of these production methods The above provision is an issue.

  As a result of intensive studies to solve the above problems, the present inventors have found that (1) tannic acid and drug-containing complex, (2) tannic acid, drug and inert carrier-containing complex holding carrier, and (3) tannic acid And / or (4) It has been found that a solid preparation in which these are blended solves the above-mentioned problems, and further research has been made based on this finding, and the present invention has been completed.

That is, the present invention relates to the following inventions.
Item 1. In the infrared absorption spectrum obtained when (I) tannic acid and drug, or (II) tannic acid, drug and lower alcohol, and measured with a Fourier transform infrared spectrophotometer, the peak due to the functional group of the drug A complex characterized in that at least one of them is not detected.
Item 2. Item 14. The complex according to Item 1, which is characterized by the FT-IR spectrum shown in Fig. 14, 15, 18, or 21.
Item 3. In the infrared absorption spectrum obtained when (III) tannic acid, drug and inert carrier, or (IV) tannic acid, drug, inert carrier and lower alcohol are measured with a Fourier transform infrared spectrophotometer A complex holding carrier, wherein at least one of peaks due to a functional group of a drug is not detected.
Item 4. Item 4. The complex holding carrier according to Item 3, wherein the insoluble carrier is silicic acid, cellulose, starch, calcium, saccharide or sugar alcohol.
Item 5. Item 5. A composition for controlling drug elution in vivo, comprising the complex according to item 1 or 2, or the complex holding carrier according to item 3 or 4.
Item 6. Item 5. A solid preparation containing the complex according to item 1 or 2, or the complex-holding carrier according to item 3 or 4.
Item 7. Item 7. The solid preparation according to Item 6, which is a tablet.
Item 8. Item 8. The solid preparation according to Item 6 or 7, which is an orally disintegrating tablet or a chewable tablet.
Item 9. A drug elution control agent in vivo, comprising tannic acid.
Item 10. (A) The method for producing a complex according to item 1 above, comprising the step of mixing a drug and tannic acid with a lower alcohol, and (B) the step of removing the lower alcohol in the mixture. .
Item 11. (C)
(C-1) spraying or adding tannic acid-containing lower alcohol to a mixture of drug and inert carrier,
(C-2) a step of immersing an inert carrier in a drug and tannic acid-containing lower alcohol, or
(C-3) a step of spraying or adding a drug and a tannic acid-containing lower alcohol to an inert carrier, and
(D) removing the lower alcohol in the mixture;
A method for producing a tannic acid and drug-containing complex holding carrier, comprising:
Item 12. A method for producing a solid preparation, comprising the step of mixing the complex according to Item 1 or 2 or the complex holding carrier according to Item 3 or 4 and an excipient.

  The present invention relates to a novel substance having a drug elution control action in vivo, a novel drug elution control agent in vivo, a solid preparation with controlled drug elution, and any one of these production methods The above can be provided.

FIG. 1 shows the results of dissolution tests (test solution: water) of the tablets of Examples 1 and 2 and Comparative Examples 1 and 2. FIG. 2 shows the results of dissolution tests (test solution: dissolution test first solution (pH 1.2)) of the tablets of Examples 1 and 2 and Comparative Examples 1 and 2. FIG. 3 shows the results of dissolution tests (test solution: water) of the tablets of Examples 3 and 4 and Comparative Examples 3 and 4. FIG. 4 shows the results of the dissolution test (test solution: dissolution test first solution (pH 1.2)) of the tablets of Examples 3 and 4 and Comparative Examples 3 and 4. FIG. 5 shows the results of the tablet dissolution test (test solution: water) of Examples 5 and 6 and Comparative Example 5. FIG. 6 shows the results of the tablet dissolution test (test solution: dissolution test first solution (pH 1.2)) of Examples 5 and 6 and Comparative Example 5. FIG. 7 shows the results of the tablet dissolution test (test solution: water) of Examples 7 and 8 and Comparative Example 6. FIG. 8 shows the results of the tablet dissolution test (test solution: dissolution test first solution (pH 1.2)) of Examples 7 and 8 and Comparative Example 6. FIG. 9 shows the results of the tablet dissolution test (test solution: water) of Examples 9 and 10 and Comparative Examples 7 and 8. FIG. 10 shows the results of the tablet dissolution test (test solution: dissolution test first solution (pH 1.2)) of Examples 9 and 10 and Comparative Examples 7 and 8. FIG. 11 shows IR spectrum data of tannic acid (simple substance). FIG. 12 shows IR spectrum data of loperamide hydrochloride (simple substance). FIG. 13 shows IR spectrum data of a mixture of tannic acid and loperamide hydrochloride (mass ratio 1: 1). FIG. 14 shows IR spectrum data of complex 1 (mass ratio 1: 1) of tannic acid and loperamide hydrochloride. FIG. 15 shows IR spectrum data of complex 2 (mass ratio 1: 1) of tannic acid and loperamide hydrochloride. FIG. 16 shows IR spectrum data of ketotifen fumarate (simple substance). FIG. 17 shows IR spectrum data of a mixture of tannic acid and ketotifen fumarate (mass ratio 1: 1). FIG. 18 shows IR spectrum data of a complex of tannic acid and ketotifen fumarate (mass ratio 1: 1). FIG. 19 shows IR spectrum data of fexofenadine hydrochloride (simple substance). FIG. 20 shows IR spectrum data of a mixture of tannic acid and fexofenadine hydrochloride (mass ratio 1: 1). FIG. 21 shows IR spectrum data of a complex of tannic acid and fexofenadine hydrochloride (mass ratio 1: 1).

Complex The present invention contains tannic acid and a drug, and in an infrared absorption spectrum obtained when measured with a Fourier transform infrared spectrophotometer, at least one of peaks due to a functional group of the drug is not detected. And a complex (hereinafter also referred to as a complex of the present invention).
The complex of the present invention may consist essentially of tannic acid and a drug, may consist essentially of tannic acid, a drug and a lower alcohol, or consist of tannic acid and a drug. It may be composed of tannic acid, drug and lower alcohol, may contain components other than tannic acid and drug, and contains components other than tannic acid, drug and lower alcohol May be substantially composed of tannic acid and drug, substantially composed of tannic acid, drug and lower alcohol, composed of tannic acid and drug, or composed of tannic acid, drug and lower alcohol It is preferable that it consists of tannic acid and a drug. “Substantially consists of tannic acid and drug” and “substantially consists of tannic acid, drug and lower alcohol” means other components that do not have a fundamental influence on the drug elution control action in vivo (for example, , A solvent such as water).

[Tannic acid]
Tannic acid can be extracted from various plant materials. For example, water or ethanol can be extracted from persimmon fruit, chestnut astringent skin, pentaploid, gallic, cod powder, leguminous tamarind seed skin, or mimosa bark. Preferably, tannic acid extracted from pentaploid or gallic acid listed in the 17th revised Japanese Pharmacopoeia can be used. Tannic acid may be an unpurified product or a purified product, but a purified product is more preferable.

[Drug]
The drug used in the present invention is not particularly limited. Specifically, hydrocortisone, prednisolone, parameterzone acetate, beclomethasone propionate, flumethasone pivalate, betamethasone, betamethasone valerate, dexamethasone, triamcinolone, triamcinolone Corticosteroids such as acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, indomethacin, ketoprofen, acetaminophen, mefenamic acid, flufenamic acid, diclofenac or its salt, alclofenac, oxy Fenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, methyl salicylate, camphor, Anti-inflammatory analgesics such as dak, tolmetine sodium, naproxen, fenbufen, felbinac, loxoprofen, glycyrrhetinic acid, phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, hypnotic sedatives such as flunitrazepam, lorazepam, haloperidol, orfenadine , Diazepam, fludiazepam, flunitrazepam, chlorpromazine and other tranquilizers, clonidine, clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, bufuranol, indenolol, nilvadipine, nimodipine, lofedixin, nitrendipine, nipradilol, bucmolol, antihypertensive Agent, hydrochlorothiazide, bendroflumethiazide, cyclobe Antihypertensive diuretics such as thiazide, antibiotics such as penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, anesthetics such as lidocaine, dibucaine hydrochloride, benzocaine, ethyl aminobenzoate, benzalkonium Antibacterial and antifungal substances such as chloride, nitrofurazone, nystatin, acetosulfamine, pentamycin, amphotericin B, pyrrolnitrin, clotrimazole, vitamin A, vitamin E (tocopherol acetate), vitamin K, ergocalciferol, Vitamins such as cholecalciferol, octothiacin, riboflavin butyrate, antiepileptics such as nitrazepam, meprobamate, and clonazepam, nitroglycerin, nitroglycol, and isosodium nitrate Coronary vasodilators such as rubid, propatyl nitrate, dipyridamole, molsidomine, cromoglycic acid or salts thereof, tranilast, repirinast, amlexanox, ibudilast, tazanolast, pemirolast or salts thereof, ketotifen, azelastine, oxatomide, mequitazine, epinastine or salts thereof , Antiallergic agents such as astemizole, diphenhydramine or its salts, antihistamines such as chlorpheniramine and diphenylimidazole, dextromethorphan hydrobromide, dextromethorphan, terbutaline, terbutaline sulfate, ephedrine, ephedrine hydrochloride, salbutamol sulfate Salt, salbutamol, isoproterenol hydrochloride, isoproterenol, isoproterenol sulfate, etc. Drugs, sex hormones such as progesterone and estradiol, antidepressants such as doxepin, cerebral circulation improving agents such as hydergine, ergot alkaloids, and ifenprodil, antiemetics such as metoclopramide, clebopride, domperidone, scopolamine, scopolamine hydrobromide And anti-ulcer agents.
In the present invention, the drug may be paraphrased as a medicinal ingredient, a drug substance and the like.

[Lower alcohol]
In the present invention, examples of the lower alcohol include ethanol, glycerin, isopropanol and the like, and ethanol is particularly preferable.
When the complex contains a lower alcohol, the lower alcohol in the complex may be 10% by mass or less, or 1% by mass or less. Further, the lower alcohol in the composite may be more than 0% by mass and 10% by mass or less, or more than 0% by mass and 1% by mass or less.

(Mass ratio)
In the complex of the present invention, the mass ratio of tannic acid to drug may be, for example, (tannic acid) :( drug) may be 1: (0.01-100), or 1: (0.1 10), 1: (0.5-2), 1: (0.66-1.5), but 1: 1 is particularly preferable. .

〔nature〕
The complex of the present invention exhibits one physicochemical property as a complex, for example, while a mixture of a plurality of substances (drugs, tannic acid, etc.) maintains the chemical properties of the substance alone. In the complex according to the present invention, at least one of peaks due to a functional group of a drug is not detected in an infrared absorption spectrum obtained when measured with a Fourier transform infrared spectrophotometer.
As the Fourier transform infrared spectrophotometer (FT-IR), for example, FT / IR-6100 type A (JASCO, serial number: A018861020) can be used.
Measurement conditions such as a light source, a detector, the number of integrations, decomposition, zero filing, apodization, gain, aperture, scan speed, and filter may be set as appropriate. For example, the following measurement conditions may be used.
<Measurement conditions>
Light source: Standard light source detector: TGS
Integration count: 16
Decomposition: 4cm ^-1
Zero filling: On
Apodization: Cosine
Gain: Auto (16)
Aperture: Auto (7.1mm)

The horizontal axis of the infrared absorption spectrum is the wave number (cm ⁻¹ ). The vertical axis of the infrared absorption spectrum may be transmittance (T,%) or absorbance.

  The functional group in the “peak due to the functional group of the drug” is not particularly limited as long as it is a functional group possessed by the drug used. Examples of such functional groups include hydroxyl groups, ether groups, amide groups, amino groups, azo groups, guanidino groups, aldehyde groups, carboxy groups, acyl groups, sulfo groups, thiol groups, sulfonic acid groups, fluoro groups, chloro groups, bromo groups. , Iodo group, nitroso group, nitro group, cyano group, ester group, ketone group, pyridyl group and the like. The functional group is preferably a group (carbonyl group) having —CO— such as an amide group, an ester group, a ketone group, or an aldehyde group.

“The peak due to the functional group of the drug is not detected” means that, for example, when measured with a Fourier transform infrared spectrophotometer, in the infrared absorption spectrum of the complex of the present invention, (1) the infrared absorption spectrum of the drug alone The peak at the specific wave number (cm ⁻¹ ) in which the peak was detected in ( ¹ ) is not detected, and / or (2) it falls under (1) above and is obtained by stirring and mixing the drug and tannic acid. The peak at the specific wave number (cm ⁻¹ ) where the peak was detected in the infrared absorption spectrum of the mixture containing the drug and tannic acid was not detected. When determining whether it is detected, an error of several cm ⁻¹ (for example, 3 cm ⁻¹ or less) may be considered. That is, comparing the infrared absorption spectra of two samples, if a peak is recognized at a wave number different by several cm ^−1, it may be determined that a peak is detected at the same wave number. The number of peaks due to the functional group of the drug that is not detected may be at least 1, and may be 2, 3, 4, 5, 6, 7, 8, 9, 10, or the like.

The present invention encompasses complexes containing tannic acid and a drug characterized by the FT-IR spectrum shown in FIG. 14, 15, 18, or 21. Complexes containing tannic acid and drug characterized by the FT-IR spectrum shown in FIG. 14, 15, 18 or 21 are the FT-IR spectrum shown in FIG. 14, 15, 18 or 21, respectively. Complexes containing tannic acid and drug characterized by FT-IR spectra where peaks are observed at different wavenumbers by a few cm ^{-1 in} comparison may be included.
The complex containing tannic acid and the drug characterized by the FT-IR spectra shown in FIGS. 14 and 15 is produced from loperamide hydrochloride and tannic acid as raw materials. The amide group possessed by loperamide hydrochloride The peak due to is not detected.
The complex containing tannic acid and the drug characterized by the FT-IR spectrum shown in FIG. 18 is produced from ketotifen fumarate and tannic acid as raw materials. The ketone group possessed by ketotifen fumarate The peak due to is not detected.
The complex containing tannic acid and the drug characterized by the FT-IR spectrum shown in FIG. 21 is produced using fexofenadine hydrochloride and tannic acid as raw materials. Fexofenadine hydrochloride has A peak due to a carboxy group is not detected.

  In addition, the composite in the present invention may have different behaviors with respect to temperature of the composite, solubility in a solvent, or dispersibility in comparison with that of a single substance, for example.

〔Production method〕
The present invention comprises (A) a step of mixing a drug and tannic acid using a lower alcohol, and (B) a step of removing the lower alcohol in the mixture, thereby producing the complex of the present invention Includes methods. In the step (A), mixing may be performed by means such as heating and stirring. In this case, the mixture obtained in the step (A) is preferably a solution in which the drug and tannic acid are dissolved in the lower alcohol, preferably uniformly. Alternatively, in step (A), the tannic acid-containing lower alcohol may be sprayed or added to the drug, preferably uniformly. In this case, in the mixture obtained by the step (A), the drug is preferably covered with a layer of tannic acid-containing lower alcohol. Alternatively, in the step (A), the drug may be immersed in the tannic acid-containing lower alcohol, preferably uniformly. In this case, in the mixture obtained by the step (A), the drug is preferably covered with a layer of tannic acid-containing lower alcohol.
The mass of the lower alcohol is not particularly limited as long as it can dissolve both the tannic acid and the drug. For example, the mass of the lower alcohol may be about 0.1 to 1000 times the total mass of the tannic acid and the drug. Good.
Step (B) may be after step (A) or at the same time as step (A).
Examples of means for removing in the step (B) include solvent distillation, drying (spray drying, freeze drying, etc.) and the like. For drying, a commercially available spray dryer, a freeze dryer (such as a liquid nitrogen freeze dryer) or the like can be appropriately selected and used. The spray dryer is, for example, a rotary atomizer type (disk type), nozzle type (pressure nozzle type, two-fluid nozzle type, etc.), two-point collection type, cyclone collection type, or bag filter collection type, or A combination thereof may be used. Removing the lower alcohol means, for example, making the amount of the lower alcohol in the complex 1% by mass or less.
In the complex obtained by the steps (A) and (B), the drug may be covered with a layer of tannic acid.
In the production method of the present invention, only the drug, tannic acid and lower alcohol may be used as raw materials, and other components may be further used.

In more detail, the manufacturing method of the composite_body | complex of this invention can be classified into the following four, for example.
As a first production method, after adding the drug to an appropriate amount of lower alcohol, tannic acid is gradually added while dispersing, and the drug is dissolved. At this time, means such as heating and stirring are used. And can be done efficiently. Further, when the drug to be dissolved is easily oxidized by oxygen, it is possible to replace the inside of the production environment with an inert gas such as nitrogen gas. Further, the lower alcohol is removed from the solution to produce the complex of the present invention. At this time, a method of distilling off the solvent under heating or / and reduced pressure, a method of spray drying the solution, the solution It is also possible to use a method of instantly freezing the liquid with liquid nitrogen or the like and then drying it.
As a second production method, a solution in which tannic acid is dissolved in an appropriate amount of lower alcohol is uniformly sprayed on the drug. As the production apparatus used at this time, a fluidized bed granulator is preferable. In addition, when a fluidized bed granulator is used, solvent removal by drying can be simultaneously performed during the treatment, and accordingly, the composite of the present invention is generated.
As a third production method, a solution in which tannic acid is dissolved in an appropriate amount of lower alcohol is uniformly added to the drug. As the production apparatus used at this time, a stirring and mixing granulator is preferable. In the case of using a stirring and mixing granulator, it is necessary to carry out solvent removal by drying using a shelf-type drying device or a fluidized bed granulator after the treatment, and accordingly, the composite of the present invention Is generated.
As a fourth production method, the drug is uniformly immersed in a solution in which tannic acid is dissolved in an appropriate amount of lower alcohol. After the drug is put into the solution and immersed, the lower alcohol is removed to form the complex of the present invention. At this time, the method of distilling off the solution under heating or / and reduced pressure It is also possible to use a method of spray-drying the solution, a method of freeze-drying the solution with liquid nitrogen or the like, and then freeze-drying.
Although the target complex of the present invention can be obtained in a semi-solid, solid, or powder state by each method, it is preferably obtained in a powder form from the viewpoint of an additive for a solid preparation.

Complex holding carrier The present invention contains tannic acid, a drug and an inert carrier, and in an infrared absorption spectrum obtained by measurement with a Fourier transform infrared spectrophotometer, at least one of peaks due to a functional group of the drug A complex holding carrier (hereinafter also referred to as a complex holding carrier of the present invention) characterized in that no one is detected.
The complex holding carrier of the present invention may be composed of tannic acid, drug and inert carrier, or may be composed of tannic acid, drug, inert carrier and lower alcohol, tannic acid, drug And a component other than tannic acid, a drug, an inert carrier and a lower alcohol, but may comprise components other than tannic acid, a drug, an inert carrier, and an inert carrier. Or a tannic acid, a drug, an inert carrier and a lower alcohol, and more preferably a tannic acid, a drug and an inert carrier.

[Inert carrier]
The inert carrier is not particularly limited as long as it can be used in the field of pharmaceuticals or foods. Examples of the inert carrier include silicic acids, celluloses, starches, calciums, sugars, sugar alcohols and the like.
Examples of the silicic acid include light anhydrous silicic acid, magnesium aluminate metasilicate, silicon dioxide, synthetic aluminum silicate, and calcium silicate. A particularly preferred silicic acid is calcium silicate.
Examples of celluloses include crystalline cellulose, powdered cellulose, and low-substituted hydroxypropylcellulose. Particularly preferred celluloses are crystalline cellulose.
Examples of the starches include wheat starch, rice starch, corn starch, potato starch, and tapioca starch, and dextrin obtained by enzymatic degradation, acid degradation, and alkaline degradation of these starches. A particularly preferred starch is corn starch.
Examples of calcium include calcium hydrogen phosphate (dibasic calcium phosphate), anhydrous calcium hydrogen phosphate (anhydrous dicalcium phosphate), and calcium dihydrogen phosphate (primary calcium phosphate). Particularly preferred calcium is calcium hydrogen phosphate.
Examples of the saccharide include lactose hydrate, anhydrous lactose, sucrose, purified sucrose, fructose, glucose, and trehalose. A particularly preferred saccharide is lactose hydrate.
Examples of sugar alcohols include mannitol, erythritol, sorbitol, xylitol, trehalose, maltitol, and lactitol. A particularly preferred sugar alcohol is mannitol.

[Lower alcohol]
When the complex holding carrier contains a lower alcohol, the lower alcohol in the complex holding carrier may be 10% by mass or less, or 1% by mass or less. Further, the lower alcohol in the composite may be more than 0% by mass and 10% by mass or less, or more than 0% by mass and 1% by mass or less.

(Mass ratio)
In the complex holding carrier of the present invention, the mass ratio of tannic acid and drug may be, for example, (tannic acid) :( drug) may be 1: (0.01-100), or 1: (0 .1-10), 1: (0.5-2), 1: (0.66-1.5), or 1: 1. Is particularly preferred.
In the complex holding carrier of the present invention, the mass ratio of tannic acid and inert carrier may be, for example, (tannic acid) :( inactive carrier) is 1: (0.01-100), It may be 1: (0.1-10), 1: (1-10), 1: (4-9), particularly 1: 6 preferable.
In the complex holding carrier of the present invention, the mass ratio of tannic acid, drug, and inert carrier is, for example, (tannic acid) :( drug) :( inactive carrier) is 1: (0.01-100) : (0.01-100) may be sufficient, 1: (0.1-10): (0.1-10) may be sufficient, 1: (0.5-2): (1- 10) or 1: (0.66-1.5) :( 4-9), but 1: 1: 6 is particularly preferable.

〔Production method〕
The present invention comprises (C) a step of mixing a drug, tannic acid and an inert carrier with a lower alcohol, and (D) a step of removing the lower alcohol in the mixture, It includes a method for producing a complex holding carrier. In the step (C), mixing may be performed by means such as heating and stirring. In this case, the mixture obtained in the step (C) is preferably a solution in which the drug, tannic acid and inert carrier are preferably uniformly dissolved in the lower alcohol. Alternatively, in step (C), the tannic acid-containing lower alcohol may be sprayed or added to the mixture of drug and inert carrier, preferably uniformly. In this case, it is preferable that the drug in the mixture obtained by the step (C) is covered with a tannic acid-containing lower alcohol layer. Alternatively, in the step (C), the inert carrier may be preferably immersed uniformly in the drug and the tannic acid-containing lower alcohol. In this case, it is preferable that the drug in the mixture obtained by the step (C) is covered with a tannic acid-containing lower alcohol layer. Alternatively, in step (C), the drug and tannic acid-containing lower alcohol may be sprayed or added to the inert carrier, preferably uniformly. In this case, it is preferable that the drug in the mixture obtained by the step (C) is covered with a tannic acid-containing lower alcohol layer. Alternatively, in the step (C), the drug and the inert carrier may be preferably immersed uniformly in the tannic acid-containing lower alcohol. In this case, it is preferable that the drug in the mixture obtained by the step (C) is covered with a tannic acid-containing lower alcohol layer.
Step (D) may be after step (C) or at the same time as step (C).
The mass of the lower alcohol may be any mass that can dissolve both tannic acid and drug, and is not particularly limited. For example, the mass is about 0.1 to 1000 times the total mass of tannic acid, drug and inert carrier. It may be.
Examples of means for removing in the step (D) include solvent distillation, drying (spray drying, freeze drying, etc.) and the like. For drying, a commercially available spray dryer, a freeze dryer (such as a liquid nitrogen freeze dryer) or the like can be appropriately selected and used. The spray dryer is, for example, a rotary atomizer type (disk type), nozzle type (pressure nozzle type, two-fluid nozzle type, etc.), two-point collection type, cyclone collection type, or bag filter collection type, or A combination thereof may be used. Removing the lower alcohol means, for example, making the amount of the lower alcohol in the complex 1% by mass or less.
In the complex holding carrier obtained by the steps (C) and (D), the drug may be covered with a tannic acid-containing layer.
In the production method of the present invention, only the drug, tannic acid, inert carrier, and lower alcohol may be used as raw materials, or other components may be further used.

The details of the method for producing the complex holding carrier of the present invention can be classified into the following five, for example.
As a first production method, a solution in which tannic acid is dissolved in an appropriate amount of lower alcohol is uniformly sprayed on a drug and an inert carrier. As a production apparatus used at this time, a fluidized bed granulator is preferable. In the case of using a fluidized bed granulator, the solvent removal by drying can be carried out simultaneously during the treatment, and accordingly, the composite holding carrier of the present invention is produced.
As a second production method, a solution in which tannic acid is dissolved in an appropriate amount of lower alcohol is uniformly added to a drug and an inert carrier. As a production device used at this time, a stirring and mixing granulator is used. preferable. In the case of using a stirring and mixing granulator, it is necessary to carry out solvent removal by drying using a shelf-type drying device or a fluidized bed granulator after the treatment, and accordingly, the composite of the present invention A holding carrier is produced.
As a third production method, after adding the drug to an appropriate amount of lower alcohol, tannic acid is gradually added while dispersing, and the drug is dissolved. At this time, means such as heating and stirring are used. And can be done efficiently. In addition, when the drug to be dissolved is easily oxidized by oxygen, it can be replaced with an inert gas such as nitrogen gas. Furthermore, after putting an inert carrier into the above solution and immersing it, the lower alcohol is removed to produce the complex-supporting carrier of the present invention. At this time, heating or / and under reduced pressure is performed. It is also possible to use a method of distilling off the solution, a method of spray-drying the solution, a method of instantly freezing the solution with liquid nitrogen or the like, and then freeze-drying.
As a fourth production method, after adding the drug to an appropriate amount of lower alcohol, the tannic acid is gradually added while being dispersed to dissolve the drug. At this time, means such as heating and stirring are used. And can be done efficiently. In addition, when the drug to be dissolved is easily oxidized by oxygen, it can be replaced with an inert gas such as nitrogen gas. Further, the above solution is uniformly sprayed onto an inert carrier to remove the lower alcohol to produce the composite holding carrier of the present invention. The production apparatus used at this time includes a fluidized bed granulator. preferable. In the case where a fluidized bed granulator is used, solvent removal by drying can be performed simultaneously during the treatment.
As a fifth production method, after adding the drug to an appropriate amount of lower alcohol, the tannic acid is gradually added while dispersing, and the drug is dissolved. At this time, means such as heating and stirring are used. And can be done efficiently. In addition, when the drug to be dissolved is easily oxidized by oxygen, it can be replaced with an inert gas such as nitrogen gas. Further, the above solution is uniformly added or added to an inert carrier to remove the lower alcohol to produce the complex-supported carrier of the present invention. An apparatus is preferred. In the case of using a stirring and mixing granulator, it is necessary to remove the solvent by drying using a shelf-type drying device or a fluidized bed granulator after the treatment.
By the respective methods, the target complex-supporting carrier of the present invention can be obtained in a semi-solid, solid or powder state, but it is preferably obtained in a powder form from the viewpoint of an additive for a solid preparation.

In vivo drug elution control agent and in vivo drug elution control composition The present invention comprises (1) an in vivo drug elution control agent containing tannic acid, and (2) the complex of the present invention. A composition for controlling drug elution in a living body, and (3) a composition for controlling drug elution in a living body containing the complex holding carrier of the present invention ((1) to (3) are collectively referred to below) , Also referred to as a control agent of the present invention).
Further, the present disclosure includes (i) tannic acid for controlling drug elution in vivo, (ii) the complex of the present invention for controlling drug elution in vivo, and (iii) drug elution in vivo. A complex holding carrier of the present invention for control, (iv) a method for controlling drug elution in vivo, comprising a step of administering tannic acid to a mammal including human, (v) a complex of the present invention for human A method for controlling the dissolution of a drug in vivo, comprising the step of administering to a mammal including: (vi) a method for controlling the dissolution of a drug in vivo, comprising the step of administering the complex-holding carrier of the present invention to a mammal including human. (Vii) use of tannic acid for producing a drug elution control agent in vivo, (viii) use of the complex of the present invention for a composition for controlling drug elution in vivo, (ix) in vivo For maintaining the complex of the present invention for production of a drug elution control composition (X) the use of tannic acid for in vivo drug elution control, (xi) the use of the complex of the invention for in vivo drug elution control, and (xii) in vivo It includes one or more selected from the use of the complex holding carrier of the present invention for drug elution control. Examples of mammals including humans include humans, mice, rats, rabbits, guinea pigs, dogs, cats, monkeys, and the like.

〔effect〕
The control agent or the like of the present invention can control elution of a drug contained in a solid preparation in vivo. Controlling the elution of a drug in a living body means, for example, delaying the elution of the drug in the oral cavity, or delaying the elution of the drug in the oral cavity, and the elution behavior of the drug in the digestive tract. It means having no effect. The solid preparation is preferably a tablet such as an intraoral rapidly disintegrating tablet or chewable tablet.

  For elution of the drug in the oral cavity, for example, a solid preparation containing the control agent of the present invention is prepared, and the solid preparation is subjected to a general test method of the Japanese Pharmacopoeia using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.). Performed according to a certain dissolution test method 2 (paddle method) (test solution: water), and at each time point of 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, etc. after the start of the test, It can be determined as the drug elution amount from the solid preparation.

For elution of the drug in the digestive tract, for example, a solid preparation containing the control agent of the present invention is prepared, and the solid preparation is subjected to a general test method of the Japanese Pharmacopoeia using a dissolution tester (manufactured by Toyama Sangyo). (Test solution: pH 1.2 dissolution test first solution) 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes after the start of the test The amount of drug dissolved out from the solid preparation can be determined at each time point such as 60 minutes.
The digestive tract refers to, for example, the stomach; the small intestine such as the duodenum, jejunum, and ileum; the cecum, the colon (the ascending colon, the transverse colon, the descending colon, the sigmoid colon, and the like), and the large intestine such as the rectum;

Solid formulation This invention includes the solid formulation (henceforth the solid formulation of this invention) containing the control agent of this invention, etc. The solid preparation of the present invention is preferably an internal solid preparation. Moreover, as an internal solid agent, it is preferable that they are tablets, such as an intraoral quick disintegrating tablet and a chewable tablet.

When the control agent of the present invention contains the complex of the present invention, the solid preparation of the present invention contains additives other than drugs and tannic acid to the extent that the effects of the present invention are not impaired. Also good.
When the control agent of the present invention contains the complex-supporting carrier of the present invention, the solid preparation of the present invention does not impair the effects of the present invention with additives other than drugs, tannic acid and inert carriers. It may be contained in a degree.

  The content of the control agent or the like of the present invention is preferably about 1% by mass or more, more preferably about 5% by mass or more, and still more preferably about 10% by mass or more based on the total amount of the solid preparation. That is, when the solid preparation of the present invention contains components other than the control agent of the present invention, the content other than the control agent of the present invention is preferably about 99% by mass or less based on the total amount of the solid preparation, About 95% by mass or less is more preferable, and about 90% by mass or less is even more preferable. Within the above range, practically sufficient in vivo drug elution controllability, moldability and disintegration can be obtained.

[Excipient]
Excipients include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, isomalt; sugars such as lactose hydrate, anhydrous lactose, sucrose, purified sucrose, fructose, glucose, glucose hydrate, trehalose, etc. Starches such as corn starch, potato starch, wheat starch and rice starch; amino acids such as glycine and alanine; silicic acids such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and calcium silicate; crystals Celluloses such as cellulose and powdered cellulose; talc; titanium oxide and the like. As the excipient, sugar alcohols and saccharides are preferable in that the granulated material is rapidly disintegrated in the oral cavity, and among these, mannitol and lactose hydrate are more preferable. The content of the excipient is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the solid preparation. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a solid formulation, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. One type of excipient may be used alone, or two or more types may be used. The excipient can further improve the drug elution controllability, moldability and disintegration properties in vivo.

[Binder]
The binder has, for example, an action of bonding the granulated materials to each other during compression. Examples of the binder include magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, and the like. Among these, magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, and crystalline cellulose are preferable. The content of the binder is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the solid preparation. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a solid formulation, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. Within the above range, practically sufficient in vivo drug elution controllability, moldability and disintegration can be obtained. A binder may be used individually by 1 type and may use 2 or more types.

[Disintegrant]
The disintegrant is, for example, a component that swells with water or a component that collapses with water. Disintegrants include crospovidone, carmellose calcium, carmellose, alginic acid, croscarmellose sodium, low-substituted hydroxypropylcellulose, corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, carboxy Examples include methyl starch sodium. Of these, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, and low-substituted hydroxypropylcellulose are preferred. The content of the disintegrant is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the solid preparation. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a solid formulation, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. If it is the said range, practically sufficient moldability and disintegration can be obtained. A disintegrating agent may be used individually by 1 type, and may use 2 or more types.

  The solid preparation of the present invention is generally used for pharmaceuticals and foods such as lubricants, coloring agents, corrigents, sweeteners, fragrances, preservatives, etc., in addition to excipients, binders and disintegrants. Appropriate amounts of additives can be included. Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like. Examples of the colorant include food dyes, food lake dyes, iron sesquioxide, and yellow iron sesquioxide. Examples of the corrigent include citric acid hydrate, tartaric acid, malic acid, ascorbic acid and the like. Examples of the sweetening agent include aspartame, acesulfame potassium, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose and the like. Examples of the fragrances include fennel oil, orange oil, chamomile oil, spearmint oil, cinnamon oil, clove oil, mint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roman chamomile oil, menthol and the like. Examples of preservatives include benzoic acid, sodium benzoate, benzyl benzoate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, sodium propyl paraoxybenzoate, paraoxybenzoic acid Examples thereof include methyl and methyl sodium paraoxybenzoate. The content of the additive is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the solid preparation. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a solid formulation, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. An additive may be used individually by 1 type and may use 2 or more types.

〔Production method〕
This invention includes the manufacturing method of the solid formulation characterized by including the process (henceforth a mixing process) which mixes the control agent of this invention, etc., and an excipient | filler.
In addition to the excipient, if necessary, for example, a binder, a disintegrant, a lubricant and the like (and, if desired, other components) may be used as a raw material for mixing.

In the manufacturing method of a solid formulation, the process (henceforth a granulation process) granulated using the obtained mixture after the mixing process may be included.
As a granulation method, a wet granulation method using a stirring and mixing granulator or a fluidized bed granulator is generally used. A method using a stirring and mixing granulator is preferable because of its simplicity. In the present invention, a commercially available product may be appropriately selected and used as the stirring and mixing granulator and / or the fluidized bed granulator.

  The wet granulation treatment method is, for example, a treatment in which each component is kneaded with a solvent and then granulated. Examples of this treatment include crushing granulation method, extrusion granulation method, stirring granulation method, rolling granulation method and the like. In this treatment, alcohols such as ethanol and isopropanol and water are used as a solvent.

  In the manufacturing method of a solid formulation, the process (henceforth a compression molding process) of compressing and molding the obtained granulated material after the granulation process may be included. For the compression molding, a method and an apparatus generally used for molding a tablet such as a commercially available rotary tableting machine and a single tableting machine can be used. The compression pressure in this compression molding is preferably about 1 kN or more, more preferably about 2 kN or more, and even more preferably about 4 kN or more. Moreover, about 60 kN or less is preferable, about 30 kN or less is more preferable, and about 15 kN or less is still more preferable. If it is this range, the burden of the mortar at the time of tableting is small, and also it is easy to maintain the tableting pressure at the time of tableting.

  In the solid preparation manufacturing method, prior to the compression molding step, drying using a fluidized bed dryer, shelf type drying device, etc .; sizing using a screen mill, jet mill, hammer mill, pin mill, sieve, vibrating sieve, etc. You may attach | subject to operation required for manufacture of this solid formulation. Commercially available products may be appropriately selected and used for the fluidized bed dryer, shelf dryer, screen mill, jet mill, hammer mill, pin mill, sieve and / or vibrating sieve.

〔effect〕
In the solid preparation of the present invention, the elution of the drug contained in the solid preparation in the living body is controlled. The controlled dissolution of the drug in the living body means, for example, that the dissolution of the drug in the oral cavity is controlled to be slow, or the dissolution of the drug in the oral cavity is slow, and It means being controlled so as not to be affected by the dissolution behavior of the drug in the digestive tract.

  Drug dissolution in the oral cavity is carried out using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) in accordance with the dissolution test method method 2 (paddle method), which is a general test method of the Japanese Pharmacopoeia (test solution: water), solid The elution amount of the drug from the preparation can be determined at each time point such as 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes after the start of the test.

  Elution of the drug in the gastrointestinal tract is carried out using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) according to dissolution test method method 2 (paddle method), which is a general test method of the Japanese Pharmacopoeia (test solution: pH 1.2 1), and the amount of drug dissolution from the solid preparation can be determined at each time point such as 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes after the start of the test. it can.

  The solid preparation of the present invention may further have an appropriate moldability that is not problematic in practice and / or may have excellent disintegration properties in the oral cavity. “Excellent disintegration” means, for example, that the disintegration time and / or water absorption time is short.

The solid preparation of the present invention has a hardness (particularly, a hardness measured using a tablet hardness meter (manufactured by Toyama Sangyo Co., Ltd.)) of preferably 545 N or more, more preferably 50 N or more, and 60 N or more. Is more preferable, 70N or more is more preferable, 80N or more is more preferable, 90N or more is more preferable, and 100N or more is even more preferable.
The solid preparation of the present invention has a disintegration time (particularly, disintegration time measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.)) of 30 seconds or less according to the disintegration test method prescribed in the 17th revised Japanese Pharmacopoeia Description It is preferably 20 seconds or less, and more preferably 15 seconds or less.
In the solid preparation of the present invention, 6 mL of water is placed in a petri dish having a diameter of 6.5 cm, and a tissue paper that does not dissolve in water is folded in four, and after it is completely wetted, one tablet is added to the tablet. The water absorption time required for the entire solid preparation to be moistened is preferably 30 seconds or less, more preferably 25 seconds or less, and even more preferably 20 seconds or less.

  EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated in more detail, these do not limit this invention at all.

(1-1) Production of solid preparation (solid preparation for internal use; tablet) Example 1
Based on the composition shown in Table 1 below, loperamide hydrochloride and tannic acid are dissolved in an appropriate amount of absolute ethanol, and then spray-dried with a spray dryer (Palvis Mini Spray GB-22, Yamato Kagaku) (intake air temperature). 150 ° C.) to obtain a composite. Separately, based on the composition shown in Table 1 below, mannitol and hydroxypropyl cellulose were added to a stirring and mixing granulator (Mechanomyl MM-20N, Okada Seiko), mixed, and then tannic acid was dissolved in an appropriate amount of absolute ethanol The liquid was gradually added and granulated. Next, the granulated product was dried with a shelf dryer (OFW-450B, ASONE), and then the dried product was sized using a sieve (18 mesh). Further, based on the above composite and the composition shown in Table 1 below, magnesium metasilicate aluminate, crospovidone and magnesium stearate were added to and mixed with this granulated product, and then rotary tableting was performed. Using a machine (VELA5, Kikusui Seisakusho), tablets with a tableting pressure of about 8 kN and a tablet diameter of 8 mm and a mass of 220 mg were obtained.

Example 2
Based on the composition shown in Table 1 below, loperamide hydrochloride and tannic acid were dissolved in an appropriate amount of absolute ethanol, and then magnesium aluminate metasilicate was added and mixed. Next, this mixed product was dried with a shelf dryer to obtain a composite holding carrier. Separately, based on the composition shown in Table 1 below, mannitol and hydroxypropyl cellulose are put into a stirring and mixing granulator, mixed, and then a solution in which tannic acid is dissolved in an appropriate amount of absolute ethanol is gradually added and granulated. did. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Furthermore, after adding and mixing crospovidone and magnesium stearate based on the above composite holding carrier, and the composition shown in Table 1 below, to this sized product, using a rotary tableting machine, With a tableting pressure of about 8 kN, a tablet having a tablet diameter of 8 mm and a mass of 220 mg was obtained.

Comparative Example 1
Based on the composition shown in Table 1 below, mannitol and hydroxypropyl cellulose were charged into a stirring and mixing granulator and mixed, and then a solution of tannic acid dissolved in an appropriate amount of absolute ethanol was gradually added to granulate. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Furthermore, based on the composition shown in Table 1 below, loperamide hydrochloride, magnesium aluminate metasilicate, crospovidone, tannic acid and magnesium stearate were added to and mixed with this granulated product, followed by rotary tableting. A tablet with a tablet diameter of 8 mm and a mass of 220 mg was obtained with a tableting pressure of about 8 kN.

Comparative Example 2
Based on the composition shown in Table 1 below, loperamide hydrochloride was dissolved in an appropriate amount of absolute ethanol, and then magnesium aluminate metasilicate was added and mixed. Next, this mixed product was dried with a shelf dryer to obtain a composite holding carrier. Separately, based on the composition shown in Table 1 below, mannitol and hydroxypropyl cellulose are put into a stirring and mixing granulator, mixed, and then a solution in which tannic acid is dissolved in an appropriate amount of absolute ethanol is gradually added and granulated. did. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Further, after adding and mixing tannic acid, crospovidone and magnesium stearate based on the above composite holding carrier and the composition shown in Table 1 below, to this sized product, a rotary tableting machine With a tableting pressure of about 8 kN, a tablet with a tablet diameter of 8 mm and a mass of 220 mg was obtained.

(2-1) Evaluation of dissolution [drug: loperamide hydrochloride]
The measurement is carried out using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) in accordance with dissolution test method method 2 (paddle method), which is a general test method of the Japanese Pharmacopoeia (test solution: water), and loperamide hydrochloride from tablets. The elution rate (%) of was calculated. Specifically, one tablet was taken, and the test was conducted at 50 rpm by the second dissolution test method (paddle method) using 900 mL of the test solution. After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes after the start of the dissolution test, accurately take 10 mL of the dissolution solution and immediately add 10 mL of the test solution heated immediately to 37 ± 0.5 ° C. Carefully replenished. The eluate was filtered through a membrane filter having a pore size of 0.45 μm or less, and the filtrate was used as a sample solution. Separately, quantified loperamide hydrochloride is dried at 105 ° C. for 4 hours, about 33 mg of which is accurately weighed and dissolved in methanol to make exactly 100 mL. 1 mL of this solution was accurately weighed, and the test solution was added to make exactly 100 mL, which was used as a standard solution. The amount of loperamide hydrochloride was measured using liquid chromatography.
Furthermore, the test solution was changed from water to the first solution for dissolution test (pH 1.2), and the same procedure was followed except for the dissolution test.

<Quantitative conditions by liquid chromatography>
Detector: UV absorptiometer (measurement wavelength: 214 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 7.5 cm is filled with 3 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature mobile phase around 40 ° C .: Dissolve 1.0 g of sodium 1-pentanesulfonate in 400 mL of water, and add 600 mL of methanol, 50 mL of acetonitrile and 1 mL of phosphoric acid.
Flow rate: Adjust so that the retention time of loperamide is about 3 minutes.
Injection volume: 10 μL

(3-1) Evaluation of physical properties <Hardness test>
In the test, the hardness was measured using a load cell type tablet hardness tester (Okada Seiko Co., Ltd.), and the number of tests was 10 tablets.
<Disintegration test>
In the test, the disintegration time was measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.) with reference to the disintegration test method stipulated in the 17th revised Japanese Pharmacopoeia manual, and the number of tests was 6 tablets.
<Water absorption test>
In the test, 6 mL of water was placed in a petri dish with a diameter of 6.5 cm, and a tissue paper that did not dissolve in water was folded in four, and after it was completely wetted, a tablet was placed on it. The water absorption time required for the entire tablet to be wet was measured, and the number of tests was 3 tablets.

(4-1) Evaluation results Table 1 below shows the measurement results of the compositions, hardness, disintegration time, and water absorption time of the tablets of Examples 1 and 2 and Comparative Examples 1 and 2.

  From the results of physical property evaluation in Table 1, the disintegration time and water absorption time were less than 30 seconds in both Examples 1 and 2, but in Comparative Example 1, the disintegration time and in Comparative Example 2 were disintegration time and water absorption time. Both were over 30 seconds. Regarding hardness, it was the same in Examples 1 and 2 and Comparative Examples 1 and 2, and there was no particular problem of moldability. Therefore, it was confirmed that the solid preparations of Examples 1 and 2 were superior in disintegration and water absorption than the solid preparations of Comparative Examples 1 and 2.

  In addition, Table 2 and FIG. 1 show the results of dissolution tests (test solution: water) of the solid preparations of Examples 1 and 2 and Comparative Examples 1 and 2.

  Solid formulation of Example 1 using loperamide hydrochloride and tannic acid-containing complex, and solid of Example 2 using loperamide hydrochloride, tannic acid and a magnesium metasilicate aluminate-containing complex holding carrier as an inert carrier Compared with the solid preparation of Comparative Example 1 using untreated loperamide hydrochloride and the solid preparation of Comparative Example 2 in which loperamide hydrochloride was adsorbed on an inert carrier, the preparation was suppressed from dissolution of loperamide hydrochloride. It was. In more detail, the elution of loperamide hydrochloride was suppressed more in the solid preparation of Example 1 than in the solid preparation of Example 2.

  In addition, Table 3 and FIG. 2 show the results of dissolution tests (test solution: first solution of dissolution test at pH 1.2) of the solid preparations of Examples 1 and 2 and Comparative Examples 1 and 2.

  The dissolution behavior of loperamide hydrochloride in the solid preparations of Examples 1 and 2 and Comparative Examples 1 and 2 was almost the same.

(1-2) Production of solid preparation (solid preparation for internal use; tablet) Example 3
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate, mannitol and hydroxypropyl cellulose are put into a stirring granulator and mixed, and then tannic acid is dissolved in an appropriate amount of absolute ethanol The liquid was gradually added and granulated. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 4 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Example 4
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate and mannitol were added to a stirring and mixing granulator and mixed, and then a solution of tannic acid dissolved in an appropriate amount of absolute ethanol was gradually added. In addition to granulation. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 4 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Example 5
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate, anhydrous calcium hydrogen phosphate, and hydroxypropyl cellulose are put into a stirring and mixing granulator, mixed, and then added to an appropriate amount of absolute ethanol. The liquid in which tannic acid was dissolved was gradually added and granulated. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 4 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Example 6
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate and anhydrous calcium hydrogen phosphate are put into a stirring granulator and mixed, and then tannic acid is dissolved in an appropriate amount of anhydrous ethanol The liquid was gradually added and granulated. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 4 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Example 7
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate, lactose hydrate and hydroxypropyl cellulose were added to a stirring and mixing granulator, mixed, and then tannin was added to an appropriate amount of absolute ethanol. The solution in which the acid was dissolved was gradually added and granulated. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 4 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Example 8
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate and lactose hydrate were put into a stirring and mixing granulator, mixed, and then tannic acid was dissolved in an appropriate amount of absolute ethanol. The liquid was gradually added and granulated. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 4 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Comparative Example 3
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate, mannitol and hydroxypropylcellulose were added to a stirring and mixing granulator, mixed, and then an appropriate amount of absolute ethanol was gradually added. Granulated. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Furthermore, based on the composition shown in Table 4 below, to this sized product, crospovidone, magnesium aluminate metasilicate, aspartame, citric acid, menthol, fragrance and magnesium stearate were added and mixed, then the rotary type Using a tableting machine, tablets with a tableting pressure of about 8 kN and a tablet diameter of 8 mm and a mass of 220 mg were obtained.

Comparative Example 4
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate, and mannitol were charged into a stirring and mixing granulator, mixed, and granulated by gradually adding an appropriate amount of absolute ethanol. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Furthermore, based on the composition shown in Table 4 below, to this sized product, crospovidone, magnesium aluminate metasilicate, aspartame, citric acid, menthol, fragrance and magnesium stearate were added and mixed, then the rotary type Using a tableting machine, tablets with a tableting pressure of about 8 kN and a tablet diameter of 8 mm and a mass of 220 mg were obtained.

Comparative Example 5
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate, anhydrous calcium hydrogen phosphate, and hydroxypropyl cellulose were put into a stirring and mixing granulator, mixed, and then an appropriate amount of anhydrous ethanol was added. Gradually added. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Furthermore, based on the composition shown in Table 4 below, to this sized product, crospovidone, magnesium aluminate metasilicate, aspartame, citric acid, menthol, fragrance and magnesium stearate were added and mixed, then the rotary type Using a tableting machine, tablets with a tableting pressure of about 8 kN and a tablet diameter of 8 mm and a mass of 220 mg were obtained.

Comparative Example 6
Based on the composition shown in Table 4 below, ketotifen fumarate, magnesium aluminate metasilicate, lactose hydrate and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, an appropriate amount of absolute ethanol is gradually added. In addition to granulation. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Furthermore, based on the composition shown in Table 4 below, to this sized product, crospovidone, magnesium aluminate metasilicate, aspartame, citric acid, menthol, fragrance and magnesium stearate were added and mixed, then the rotary type Using a tableting machine, tablets with a tableting pressure of about 8 kN and a tablet diameter of 8 mm and a mass of 220 mg were obtained.

(2-2) Evaluation of dissolution [drug: ketotifen fumarate]
Measurement is carried out using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) according to dissolution test method method 2 (paddle method), which is a general test method of the Japanese Pharmacopoeia (test solution: water), and ketotifen fumarate from tablets. The elution amount of the salt was determined, and the elution rate was calculated from the result. Specifically, one tablet was taken, and the test was conducted at 50 rpm by the second dissolution test method (paddle method) using 900 mL of the test solution. After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes from the start of dissolution test, accurately take 10 mL of eluate and immediately refill with 10 mL of test solution heated to 37 ± 0.5 ° C with care. did. The eluate was filtered through a membrane filter having a pore size of 0.45 μm or less to obtain a sample solution. Separately, ketotifen fumarate for quantification was dried at 105 ° C. for 4 hours, and about 15 mg thereof was accurately weighed and dissolved in a test solution to make exactly 200 mL. 2 mL of this solution was accurately weighed, and the test solution was added to make exactly 100 mL, which was used as a standard solution. The amount of ketotifen fumarate was measured using liquid chromatography. Further, two kinds of test solutions were selected: water and a first dissolution test first solution (pH 1.2).

<Quantitative conditions by liquid chromatography>
Detector: UV absorptiometer (measurement wavelength: 295 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 15 cm was packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature mobile phase around 40 ° C .: 2.0 g of sodium lauryl sulfate dissolved in 450 mL of water and 550 mL of acetonitrile and 1 mL of phosphoric acid were used as the mobile phase.
Flow rate: Adjusted so that the retention time of ketotifen was about 4 minutes.
Injection volume: 50 μL

(3-2) Evaluation of physical properties <Hardness test>
In the test, the hardness was measured using a load cell type tablet hardness tester (Okada Seiko Co., Ltd.), and the number of tests was 10 tablets.
<Disintegration test>
In the test, the disintegration time was measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.) with reference to the disintegration test method stipulated in the 17th revised Japanese Pharmacopoeia manual, and the number of tests was 6 tablets.
<Water absorption test>
In the test, 6 mL of water was placed in a petri dish with a diameter of 6.5 cm, and a tissue paper that did not dissolve in water was folded in four, and after it was completely wetted, a tablet was placed on it. The water absorption time required for the entire tablet to be wet was measured, and the number of tests was 3 tablets.

(4-2) Evaluation results Table 4 below shows the measurement results of the composition, hardness, disintegration time, and water absorption time of the solid preparations of Examples 3 to 8 and Comparative Examples 3 to 6.

  From the results of the physical property evaluation in Table 4, in the solid preparations of Examples 3 to 8, the disintegration time and the water absorption time were less than 30 seconds, but in the solid preparations of Comparative Examples 3, 5 and 6, the water absorption time was It was more than 30 seconds. In the solid preparation of Comparative Example 4, the disintegration time and water absorption time were less than 30 seconds, but many molding defects were observed. Therefore, the solid preparations of Examples 3 to 8 were more excellent in disintegration, water absorption and moldability than the solid preparations of Comparative Examples 3 to 6.

  The results of the dissolution test (test solution: water) of Examples 3 and 4 and Comparative Examples 3 and 4 are shown in Table 5 and FIG.

  The solid preparations of Examples 3 and 4 using ketotifen fumarate, tannic acid, and an inert carrier mannitol and magnesium metasilicate aluminate-containing composite carrier were used in Comparative Examples 3 and 4 where no complex carrier was used. Compared to the solid preparation of Comparative Example 4, elution of ketotifen fumarate was suppressed.

  In addition, Table 6 and FIG. 4 show the results of the dissolution test (test solution: first solution of dissolution test (pH 1.2)) of Examples 3 and 4 and Comparative Examples 3 and 4.

  The dissolution behavior of ketotifen fumarate in the solid preparations of Examples 3 and 4 and Comparative Examples 3 and 4 was almost the same.

  The results of the dissolution test (test solution: water) of Examples 5 and 6 and Comparative Example 5 are shown in Table 7 and FIG.

  The solid preparations of Examples 5 and 6 using a ketotifen fumarate, tannic acid, and a composite holding carrier with anhydrous calcium hydrogen phosphate and magnesium aluminate metasilicate as an inert carrier do not use the composite holding carrier. In comparison with the solid preparation of Comparative Example 5, elution of ketotifen fumarate was suppressed.

  In addition, Table 8 and FIG. 6 show the results of the dissolution test (test solution: dissolution solution first solution (pH 1.2)) of Examples 5 and 6 and Comparative Example 5.

  The dissolution behavior of ketotifen fumarate in the solid preparations of Examples 5 and 6 and Comparative Example 5 was almost the same.

  The results of the dissolution test (test solution: water) of Examples 7 and 8 and Comparative Example 6 are shown in Table 9 and FIG.

  The solid preparations of Examples 7 and 8 using ketotifen fumarate, tannic acid, lactose hydrate as an inert carrier, and a magnesium aluminate-containing composite carrier were used as comparative examples in which the complex carrier was not used. Compared to 6, ketotifen fumarate elution was suppressed.

  Table 10 and FIG. 8 show the results of dissolution tests (test solution: first solution of dissolution test (pH 1.2)) of Examples 7 and 8 and Comparative Example 6.

  The dissolution behavior of ketotifen fumarate in the solid preparations of Examples 7 and 8 and Comparative Example 6 was almost the same.

(1-3) Production of solid preparation (internal solid agent; tablet) Example 9
Based on the composition shown in Table 11 below, mannitol, magnesium aluminate metasilicate and hydroxypropyl cellulose were charged into a stirring and granulating machine, mixed, and then tannic acid and loperamide hydrochloride were dissolved in an appropriate amount of absolute ethanol. The liquid was gradually added and granulated. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 11 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Example 10
Based on the composition shown in Table 11 below, mannitol and magnesium aluminate metasilicate were put into a stirring and mixing granulator and mixed, and then a solution of tannic acid and loperamide hydrochloride dissolved in an appropriate amount of absolute ethanol was gradually added. In addition, it was granulated. Next, this granulated product was dried with a shelf dryer to obtain a composite holding carrier. Furthermore, after this composite holding carrier was sized using a sieve (18 mesh), the sized product was subjected to crospovidone, magnesium aluminate metasilicate, aspartame, based on the composition shown in Table 11 below. Add citric acid, menthol, fragrance, and magnesium stearate, mix, and use a rotary tableting machine to obtain a tablet with a tableting pressure of about 8 kN and a diameter of 8 mm and a mass of 220 mg. It was.

Comparative Example 7
Based on the composition shown in Table 11 below, mannitol, magnesium aluminate metasilicate and hydroxypropylcellulose were added to a stirring and mixing granulator, mixed, and then slowly added with appropriate amounts of absolute ethanol and loperamide hydrochloride. Grained. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Furthermore, crospovidone, magnesium aluminate metasilicate, aspartame, citric acid, menthol, fragrance and magnesium stearate were added to and mixed with this sized product based on the composition shown in Table 11 below, and then the rotary type Using a tableting machine, tablets with a tableting pressure of about 8 kN and a tablet diameter of 8 mm and a mass of 220 mg were obtained.

Comparative Example 8
Based on the composition shown in Table 11 below, mannitol and magnesium aluminate metasilicate were charged into a stirring and mixing granulator, mixed, and then slowly granulated with appropriate amounts of anhydrous ethanol and loperamide hydrochloride. Next, after this granulated product was dried with a shelf dryer, the dried product was sized using a sieve (18 mesh). Further, based on the composition shown in Table 11 below, loperamide hydrochloride, magnesium aluminate metasilicate, crospovidone, tannic acid and magnesium stearate were added to and mixed with this granulated product, followed by rotary tableting. A tablet with a tablet diameter of 8 mm and a mass of 220 mg was obtained with a tableting pressure of about 8 kN.

(2-3) Evaluation of dissolution [drug: loperamide hydrochloride]
The measurement is carried out using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) in accordance with dissolution test method method 2 (paddle method), which is a general test method of the Japanese Pharmacopoeia (test solution: water), and loperamide hydrochloride from tablets. The elution amount was obtained, and the elution rate was calculated from the result.
Specifically, one tablet was taken, and the test was conducted at 50 rpm by the second dissolution test method (paddle method) using 900 mL of the test solution. After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes from the start of dissolution test, accurately take 10 mL of eluate and immediately refill with 10 mL of test solution heated to 37 ± 0.5 ° C with care. did. The eluate was filtered through a membrane filter having a pore size of 0.45 μm or less to obtain a sample solution. Separately, quantified loperamide hydrochloride was dried at 105 ° C. for 4 hours, and about 22 mg thereof was accurately weighed and dissolved in methanol to make exactly 100 mL. 5 mL of this solution was accurately weighed and the test solution was added to make exactly 100 mL. 5 mL of this solution was accurately weighed, and the test solution was added to make exactly 100 mL, which was used as a standard solution. The amount of loperamide hydrochloride was measured using liquid chromatography. Furthermore, two types of test solutions were selected: water and the first dissolution test first solution (pH 1.2).

<Quantitative conditions by liquid chromatography>
Detector: UV absorptiometer (measurement wavelength: 214 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 7.5 cm was packed with 3 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 40 ° C. Mobile phase: A solution obtained by dissolving 1.0 g of sodium pentanesulfonate in 400 mL of water and adding 600 mL of methanol, 50 mL of acetonitrile and 1 mL of phosphoric acid was used as the mobile phase.
Flow rate: Adjusted so that the retention time of loperamide was about 3 minutes.
Injection volume: 50 μL

(3-3) Evaluation of physical properties <Hardness test>
In the test, the hardness was measured using a load cell type tablet hardness tester (Okada Seiko Co., Ltd.), and the number of tests was 10 tablets.
<Disintegration test>
In the test, the disintegration time was measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.) with reference to the disintegration test method stipulated in the 17th revised Japanese Pharmacopoeia manual, and the number of tests was 6 tablets.
<Water absorption test>
In the test, 6 mL of water was placed in a petri dish with a diameter of 6.5 cm, and a tissue paper that did not dissolve in water was folded in four, and after it was completely wetted, a tablet was placed on it. The water absorption time required for the entire tablet to be wet was measured, and the number of tests was 3 tablets.

(4-3) Evaluation Results The measurement results of the compositions, hardness, disintegration time, and water absorption time of the solid preparations of Examples 9 and 10 and Comparative Examples 7 and 8 are shown in Table 11 below.

  From the results of the physical property evaluation in Table 11, the disintegration time and the water absorption time were less than 30 seconds in Examples 9 and 10, but the water absorption time in the solid preparation of Comparative Example 7 was 30 seconds or more. In Comparative Example 8, the disintegration time and water absorption time were less than 30 seconds, but many molding defects were observed. Therefore, the solid preparations of Examples 9 and 10 were more excellent in disintegration, water absorption, and moldability than Comparative Examples 7 and 8.

  The results of the dissolution test (test solution: water) of Examples 9 and 10 and Comparative Examples 7 and 8 are shown in Table 12 and FIG.

  The solid preparations of Examples 9 and 10 using the complex holding carrier with loperamide hydrochloride, tannic acid and inert carrier mannitol are comparative examples using hydroxypropyl cellulose which is a water-soluble binder instead of tannic acid 7 and the comparative example 8 which did not use tannic acid, elution of loperamide hydrochloride was suppressed.

  Table 13 and FIG. 10 show the results of dissolution tests (test solution: first solution of dissolution test (pH 1.2)) of Examples 9 and 10 and Comparative Examples 7 and 8.

  The dissolution behavior of ketotifen fumarate in the solid preparations of Examples 9 and 10 and Comparative Examples 7 and 8 was almost the same.

  When the test solution is water, the state in the oral cavity is assumed, and in the case of the dissolution test first solution (pH 1.2), the state in the stomach is assumed. From the test results of the water in the test solution, it can be said that when tannic acid is blended, elution of the drug is suppressed and the bitter taste of the drug in the oral cavity is masked as compared with the case where tannic acid is not blended. Moreover, from the test results of the first dissolution test solution (pH 1.2), the dissolution of the drug is not suppressed regardless of the presence or absence of tannic acid, and there is no difference in the absorption of the drug in the stomach. It can be said. Therefore, by adopting the present invention, it was shown that the bitter taste of the drug in the oral cavity is masked and there is no difference in the absorption of the drug in the stomach.

(5) Physicochemical properties of the complex Loperamide hydrochloride, ketotifen fumarate, or fexofenadine hydrochloride and tannic acid are dissolved in an appropriate amount of absolute ethanol, and then spray dryer (Palvis mini spray GB-22 , Yamato Kagaku) and spray-dried (intake air temperature 150 ° C.) to obtain a composite, which was used as a sample. In order to check whether the complex and the stirring mixture are different, the mixture obtained by thoroughly stirring and mixing loperamide hydrochloride, ketotifen fumarate, or fexofenadine hydrochloride and tannic acid in a plastic bag is also a sample. Used as.
Using FT / IR-6100 type A (JASCO, serial number: A018861020), tannic acid (single), loperamide hydrochloride (single), and a mixture of tannic acid and loperamide hydrochloride (mass ratio 1: 1) ), A complex of tannic acid and loperamide hydrochloride (mass ratio 1: 1, n = 2), ketotifen fumarate (simple substance), a mixture of tannic acid and ketotifen fumarate (mass ratio 1: 1), Complex of tannic acid and ketotifen fumarate (mass ratio 1: 1), fexofenadine hydrochloride (simple substance), mixture of tannic acid and fexofenadine hydrochloride (mass ratio 1: 1), and tannic acid The IR spectrum of the complex with fexofenadine hydrochloride (mass ratio 1: 1) was measured, and from the obtained spectra, the complex and the mixture It was confirmed whether there is a difference of physicochemical properties.

<Measurement conditions>
Light source: Standard light source detector: TGS
Integration count: 16
Decomposition: 4cm ^-1
Zero filling: On
Apodization: Cosine
Gain: Auto (16)
Aperture: Auto (7.1mm)
Scanning speed: Auto (2mm / sec)
Filter: Auto (10000Hz)

Tannic acid (single), loperamide hydrochloride (single), a mixture of tannic acid and loperamide hydrochloride (mass ratio 1: 1), and a complex of tannic acid and loperamide hydrochloride (mass ratio 1: 1, n = 2) IR spectrum measurement results are shown in Table 14 and FIGS.
Loperamide hydrochloride (simple substance) and a mixture of tannic acid and loperamide hydrochloride have a peak with a wave number of 1623 cm ⁻¹ , which is considered to be derived from the amide group possessed by loperamide hydrochloride. However, it was confirmed that the peak was not detected in the complex of tannic acid and loperamide hydrochloride (mass ratio 1: 1, n = 2). From the above, it was confirmed that there was a difference in physicochemical properties between the composite and the mixture, and both were different.

IR spectrum measurement of ketotifen fumarate (simple substance), mixture of tannic acid and ketotifen fumarate (mass ratio 1: 1), and complex of tannic acid and ketotifen fumarate (mass ratio 1: 1) The results are shown in Table 15 and Figs. In Table 15, the IR spectrum measurement result of tannic acid (single substance) is shown again.
A ketotifen fumarate salt (single) and a mixture of tannic acid and ketotifen fumarate have a peak at a wave number of 1650 cm ⁻¹ , which is considered to be derived from a carbonyl group possessed by ketotifen fumarate. However, it was confirmed that the peak was not detected in the complex of tannic acid and ketotifen fumarate (mass ratio 1: 1). From the above, it was confirmed that there was a difference in physicochemical properties between the composite and the mixture, and both were different.

Of fexofenadine hydrochloride (simple substance), a mixture of tannic acid and fexofenadine hydrochloride (mass ratio 1: 1), and a complex of tannic acid and fexofenadine hydrochloride (mass ratio 1: 1). The IR spectrum measurement results are shown in Table 16 and FIGS. In Table 15, the IR spectrum measurement result of tannic acid (single substance) is shown again.
A mixture of fexofenadine hydrochloride (simple substance) and tannic acid and fexofenadine hydrochloride has a peak with a wave number of 1706 to 1707 cm ⁻¹ , which is considered to be derived from a carbonyl group of fexofenadine hydrochloride. However, it was confirmed that the peak was not detected in the complex of tannic acid and fexofenadine hydrochloride (mass ratio 1: 1). From the above, it was confirmed that there was a difference in physicochemical properties between the composite and the mixture, and both were different.

  The solid preparation of the present invention can be produced without using a complicated production process or a special production apparatus, and masks a drug having an unpleasant taste. Therefore, it is suitable for industrial large-scale production, and at the same time can be widely used as a solid preparation in which various drugs can be blended.

Claims (12)

  In the infrared absorption spectrum obtained when (I) tannic acid and drug, or (II) tannic acid, drug and lower alcohol, and measured with a Fourier transform infrared spectrophotometer, the peak due to the functional group of the drug A complex characterized in that at least one of them is not detected.   The complex of claim 1 characterized by the FT-IR spectrum shown in FIG. 14, 15, 18, or 21.   In the infrared absorption spectrum obtained when (III) tannic acid, drug and inert carrier, or (IV) tannic acid, drug, inert carrier and lower alcohol are measured with a Fourier transform infrared spectrophotometer A complex holding carrier, wherein at least one of peaks due to a functional group of a drug is not detected.   The complex holding carrier according to claim 3, wherein the insoluble carrier is silicic acid, cellulose, starch, calcium, saccharide or sugar alcohol.   A composition for controlling drug elution in vivo, comprising the complex according to claim 1 or 2 or the complex holding carrier according to claim 3 or 4.   A solid preparation containing the complex according to claim 1 or 2 or the complex holding carrier according to claim 3 or 4.   The solid preparation according to claim 6, which is a tablet.   The solid preparation according to claim 6 or 7, which is an orally disintegrating tablet or a chewable tablet.   A drug elution control agent in vivo, comprising tannic acid.   The method for producing a complex according to claim 1, comprising: (A) a step of mixing a drug and tannic acid with a lower alcohol; and (B) a step of removing the lower alcohol in the mixture. . (C)
(C-1) spraying or adding tannic acid-containing lower alcohol to a mixture of drug and inert carrier,
(C-2) a step of immersing an inert carrier in a drug and tannic acid-containing lower alcohol, or
(C-3) a step of spraying or adding a drug and a tannic acid-containing lower alcohol to an inert carrier, and
(D) removing the lower alcohol in the mixture;
A method for producing a tannic acid and drug-containing complex holding carrier, comprising:   A method for producing a solid preparation, comprising a step of mixing the complex according to claim 1 or 2 or the complex holding carrier according to claim 3 or 4 and an excipient.