TW201818969A - Composition for in vivo drug dissolution control - Google Patents

Abstract

The present invention is to provide a novel substance having in vivo drug dissolution control action, a novel in vivo drug dissolution control agent, a solid preparation controlled drug dissolution, and any one of these production methods. The present invention provides a complex having tannic acid and a drug (optionally, an inert carrier and/or a lower alcohol), a solid preparation having the complex, production methods thereof, and the like. The complex is characterized in that at least one of the peaks due to the functional groups of the drug is not detected in the infrared absorption spectrum obtained when measured with a Fourier transform infrared spectrophotometer.

Description

 Drug dissolution control composition in living body  

The present invention relates to a drug elution controlling composition or a drug elution controlling agent in a living body, and a solid preparation containing the same, and a method for producing the same. Further, a representative dosage form of the solid preparation is a lozenge such as an orally disintegrating ingot and a chewable ingot.

The most commonly used dosage form for oral solids is a tablet, which can be taken with water, collapsed in the digestive tract such as the stomach and intestines, and absorbed in the digestive tract such as the stomach and intestines. In recent years, dosage forms that are easy to drink for young children, children, and elderly people are attracting attention. Intraoral disintegration tablets and chewable tablets can be taken without water, collapsed in the oral cavity, and absorbed in the digestive tract such as the stomach and intestines. Therefore, when the medicinal ingredient exhibits an unpleasant taste such as bitterness or bitterness in the oral cavity, the feeling of ingestion is deteriorated, which causes a decrease in medication adherence or compliance, and therefore it is necessary to cover it. Uncomfortable taste.

There are many reports on methods for masking the unpleasant taste of medicinal ingredients, such as a functional masking method in which a high-flavoring agent, a flavoring agent, a cooling agent, or the like is added, or a film containing a water-insoluble polymer is effective. The physical masking method of ingredient coverage is generally known.

As a functional masking method, a method of combining a drug having an unpleasant taste with a sucralose belonging to a sweetener to suppress the discomfort of the drug at the time of administration is known (Patent Document 1), but it is considered to be effective. The type of the component, if only sucralose is added, there is a case where the unpleasant taste cannot be concealed, and thus the effect of reducing the bitterness is insufficient.

A method of masking the unpleasant taste of a drug which exhibits an unpleasant taste by preparing a granular pharmaceutical composition containing a waxy substance and a sugar alcohol (Patent Document 2), but In addition to the apparatus for melt granulation, there is a problem that it cannot be applied to a unstable drug which is decomposed due to heat at the time of melting. Further, it is known that a fine particle preparation prepared by spraying an aqueous suspension of ethyl cellulose and a water-soluble plasticizer as a bitterness-suppressing layer is prepared for a core portion of a pharmacologically active ingredient containing bitterness, thereby masking its bitterness. In the method (Patent Document 3), when the tablet is prepared by tableting, the cover film is broken, and there is a problem of bitterness when taken.

As described above, various methods for masking the unpleasant taste of the medicinal ingredients have been reviewed. However, depending on the type of the medicinal ingredient, there is a technical difficulty, and there is a need for a better method.

 [Advanced technical literature]  

[Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open Publication No. 2001-342151

[Patent Document 2] Japanese Patent Laid-Open Publication No. 2000-327590

[Patent Document 3] Japanese Patent Laid-Open Publication No. 2000-53563

The present invention is a novel substance which provides a controlling action for drug dissolution in a living body, a novel drug dissolution controlling agent in a living body, a solid preparation in which dissolution of a drug is controlled, and any one or more of the manufacturing methods. Question.

In order to solve the above problems, the inventors of the present invention have found that (1) a complex containing tannic acid and a drug, (2) a complex holding carrier containing tannic acid, a drug, and an inert carrier, and (3) tannin The above-mentioned problem can be solved by the acid, and/or (4) the solid preparation prepared by the above, and based on this finding, the research is further advanced to complete the present invention.

That is, the present invention relates to the following invention.

[Item 1] A composite comprising (I) tannic acid and a drug or (II) tannic acid, a drug, and a lower alcohol, wherein the infrared absorption spectrum obtained by measurement by a Fourier transform infrared spectrophotometer is At least one of the peaks of the functional group of the drug is not detected.

[Item 2] The composite according to the above item 1 having the characteristics of the FT-IR spectrum shown in Fig. 14, Fig. 15, Fig. 18, or Fig. 21.

[Item 3] A composite retention carrier comprising (III) tannic acid, a drug and an inert carrier or (IV) tannic acid, a drug, an inert carrier and a lower alcohol, wherein the carrier is measured by Fourier transform infrared spectrophotometry In the infrared absorption spectrum obtained at a predetermined time, at least one of the peaks of the functional groups of the drug is not detected.

[Claim 4] The composite retention carrier according to the above item 3, wherein the insoluble carrier is a decanoic acid, a cellulose, a starch, a calcium, a saccharide or a sugar alcohol.

[Claim 5] The composition for controlling a drug elution in a living body, comprising the composite according to the above item 1 or 2, or the composite retention carrier according to the above item 3 or 4.

[Embodiment 6] A solid preparation comprising the composite according to the above item 1 or 2, or the composite retention carrier according to the above item 3 or 4.

[Claim 7] The solid preparation according to the above item 6, which is a tablet.

[Claim 8] The solid preparation according to the above item 6 or item 7, which is an intraoral collapsed ingot or a chewable ingot.

[Item 9] A drug dissolution controlling agent in a living body, which contains tannic acid.

[10] The method for producing a composite according to the above item 1, which comprises (A) a step of mixing a drug and tannic acid as a lower alcohol, and (B) a step of removing a lower alcohol in the mixture.

[11th] A method for producing a complex retention carrier containing tannic acid and a drug, which comprises (C) (C-1) a lower alcohol containing tannic acid, sprayed or added in a mixture of a drug and an inert carrier. Step, (C-2) a step of impregnating an inert carrier in a lower alcohol containing a drug and tannic acid, or (C-3) a step of spraying or adding a lower alcohol containing a drug and tannic acid to an inert carrier And (D) a step of removing the lower alcohol in the mixture.

[12] A method for producing a solid preparation, comprising the composite according to the above item 1 or 2, or the composite retention carrier according to the above item 3 or 4, and an excipient. step.

The present invention can provide a novel substance having a control effect of drug dissolution in a living body, a novel drug dissolution controlling agent in a living body, a solid preparation in which a drug is controlled to be eluted, and any one or more of the above-described methods.

Fig. 1 shows the results of dissolution test (test liquid: water) of the tablets of Examples 1 and 2, and Comparative Example 1 and Comparative Example 2.

Fig. 2 shows the results of elution tests (test liquid: dissolution test first liquid (pH 1.2)) of the tablets of Examples 1 and 2 and Comparative Example 1 and Comparative Example 2.

Fig. 3 shows the results of dissolution test (test liquid: water) of the tablets of Example 3 and Example 4, Comparative Example 3, and Comparative Example 4.

Fig. 4 shows the results of elution tests (test liquid: dissolution test first liquid (pH 1.2)) of the tablets of Example 3 and Example 4, Comparative Example 3, and Comparative Example 4.

Fig. 5 shows the results of dissolution test (test liquid: water) of the tablets of Example 5, Example 6, and Comparative Example 5.

Fig. 6 shows the results of elution tests (test liquid: dissolution test first liquid (pH 1.2)) of the tablets of Example 5, Example 6, and Comparative Example 5.

Fig. 7 shows the results of dissolution test (test liquid: water) of the tablets of Example 7 and Example 8 and Comparative Example 6.

Fig. 8 shows the results of elution tests (test liquid: dissolution test first liquid (pH 1.2)) of the tablets of Example 7 and Example 8 and Comparative Example 6.

Fig. 9 shows the results of dissolution test (test liquid: water) of the tablets of Example 9 and Example 10, and Comparative Example 7 and Comparative Example 8.

Fig. 10 shows the results of elution tests (test liquid: dissolution test first liquid (pH 1.2)) of the tablets of Example 9 and Example 10, and Comparative Example 7 and Comparative Example 8.

Figure 11 shows IR spectrum data of tannic acid (monomer).

Figure 12 shows IR spectrum data of loperamide hydrochloride (monomer).

Figure 13 shows IR spectrum data of a mixture of tannic acid and loperamide hydrochloride (mass ratio 1:1).

Figure 14 shows IR spectrum data of complex 1 (mass ratio 1:1) of tannic acid and loperamide hydrochloride.

Figure 15 shows IR spectrum data of complex 2 (mass ratio 1:1) of tannic acid and loperamide hydrochloride.

Figure 16 shows IR spectral data of ketotifen fumarate (monomer).

Figure 17 shows IR spectrum data of a mixture of tannic acid and ketotifen fumarate (mass ratio 1:1).

Figure 18 shows IR spectrum data of a complex of tannic acid and ketotifen fumarate (mass ratio 1:1).

Figure 19 shows IR spectrum data of Fexofenadine hydrochloride (monomer).

Figure 20 shows IR spectrum data of a mixture of tannic acid and fexofenadine hydrochloride (mass ratio 1:1).

Figure 21 shows IR spectrum data of a complex of tannic acid and fexofenadine hydrochloride (mass ratio 1:1).

Complex

The present invention includes a complex comprising tannic acid and a drug, characterized in that at least one of the peaks of the functional group of the drug is not detected in the infrared absorption spectrum obtained by measurement by a Fourier transform infrared spectrophotometer ( Hereinafter, it is also referred to as a composite of the present invention.).

The complex of the present invention may be substantially composed of tannic acid or a drug, and may be substantially composed of tannic acid, a drug or a lower alcohol, and may be composed of tannic acid or a drug, and may be composed of tannic acid, The drug may be formed by a drug or a lower alcohol, and may contain a component other than tannic acid or a drug, and may contain a component other than tannic acid, a drug, or a lower alcohol, but is substantially composed of tannic acid or a drug. Essentially made up of tannic acid, drugs and lower alcohols, it is better from tannins and drugs, or tannic acid, drugs and lower alcohols. It is better by tannic acid and drugs. . "Substantially made up of tannic acid and drugs" and "substantially made up of tannic acid, drugs and lower alcohols" means that it may also contain other ingredients that do not affect the drug dissolution control in the body in principle. (for example, a solvent such as water).

 [tannic acid]  

Tannic acid can be extracted from various plant materials. For example, it is extracted with water or ethanol from the fruit of the persimmon, the molt of the chestnut, the gallnut, the gallnut, the root powder of Aralia elata, the seed skin of the tamarind of the leguminous tree, or the bark of the acacia tree. Ideally, tannic acid extracted from gallnuts or gallnuts included in the 17th corrected Japanese Pharmacopoeia may be used. Tannic acid is either an unfinished product or a refined product, but a refined product is preferred.

 Drug  

The drug to be used in the present invention is not particularly limited, and specific examples thereof include hydrocorticosterone, prednisolone, paramethasone acetate, and beclomethasone dipropionate. , flumethasone pivalate, betamethasone, betamethasone valerate, dexamethasone, triamcinolone, triamcinolone acetonide ), fluocinolone, fluocinolone acetate, fluocinolone acetate, clobetasole propionate and other corticosteroids; indomethacin, ketopro Ketoprofen, acetaminophen, Mefenamic acid, flufenamic acid, diclofenac or its salt, aclofenac, oxyphenbutazone ), Phenylbutazone, Ibuprofen, flurbiprofen, salicylic acid, methyl salicylate, camphor, sulindac, tolmetine sodium ( Tolm Etin sodium), naproxen, fenbufen, Felbinac, loxoprofen, Glycyrrhetinic acid and other anti-inflammatory analgesics; phenobarbital ( Phenobarbital), amobabaral, cyclobarbital, triazolam, Nitrazepam, flutrazepam, Lorazepam Hypnotic sedatives such as haloperidol; Fluphenazine, thioridazine, Diazepam, fludiazepam, flunitrazepam , chlorpromazine (Chlorpromazine) and other neuroleptics; Clonidine, clonidine hydrochloride, pindolol, propranolol (propranolol), propranolol hydrochloride, bufuralol (Bufuralol), indenolol, nilvadipine, nimodipine, lofexidine, nitrendipine, nipradil, buccolo Anti-hypertensive agents such as bucumolol and nifedipine; hydrochlorothiazide Orothiazide), benzflufluaziazine (bendroflumethiazide), cyclopentthiazide (cyclopenthiazide) and other antihypertensive diuretics; penicillin, tetracycline, oxytetracycline, fladiomycin, erythromycin, chloramphenicol Anti-biomass; lidocaine, dibucaine hydrochloride, benzocaine, ethyl benzoate, etc., benzalkonium chloride , nitrofurazone, nystatin, acetosulfamine, pentamycin, amphotericin B, pyrrolnitrin, clotrimazole, etc. Fungal substances; vitamin A, vitamin E (tocopherol acetate), vitamin K, ergocalciferol, cholecalciferol, octotiamine, riboflavin and other vitamins Anti-epileptic agents such as nitrazepam, meprobamate, and clonazepam; nitroglycerin, digested glycol, isosorbide dinitrate, propatyl nitrate, Waiting for Pilida (dipyrid Coronary vasodilators such as amole), molsidomine, sodium cromoglicate or its salts, tranilast, repirinast, amlexanox, iso Ibudilast, tazanolast, pemimolast or its salt, ketotifen, azelastine, Oxatomide, mequitine An antiallergic agent such as mequitazine, epinastine or a salt thereof, fexofenadine, astemizole, diphenhydramine or its salt, chlorine Antihistamines such as chlorpheniramine and diphenylimidazole; dextromethorphan hydrobromide, dextromethorphan, terbutaline, terbutaline Sulfate, ephedrine, ephedrine hydrochloride, salbutamol sulfate, salbutamol, isoproterenol hydrochloride, isoproterenol, isoproterenol sulfate and other antitussives Progesterone, estradiol, etc. Hormone; antidepressants such as doxepin; cerebral circulation improvers such as hydergine, ergot alkaloid, and ifenprodil; metoclopramide, An excretion agent or an anti-ulcer agent such as clebopride, domperidone, scopolamine, or scopolamine.

In the present invention, the drug may be referred to as a medicinal ingredient, a drug or the like.

 [lower alcohol]  

In the present invention, examples of the lower alcohol include ethanol, glycerin, and isopropanol. In particular, ethanol is preferred.

The lower alcohol in the composite when the composite contains a lower alcohol may be 10% by mass or less, and may be 1% by mass or less. In addition, the lower alcohol in the composite may be contained in an amount of more than 0% by mass and not more than 10% by mass, and may be more than 0% by mass and not more than 1% by mass.

 [mass ratio]  

In the complex of the present invention, the mass ratio of tannic acid to the drug, for example, (tannic acid): (drug) is 1: (0.01 to 100), and 1: (0.1 to 10) is also possible, 1: (0.5 to 2) is also possible, 1: (0.66 to 1.5) is also possible, but 1:1 is particularly good.

 [property]  

The composite of the present invention, for example, a mixture of a plurality of substances (drugs, tannic acid, etc.) exhibits a physicochemical property as a whole of the composite while maintaining the chemical properties of each of the monomers of the substance. In the infrared absorption spectrum obtained by the Fourier transform type infrared spectrophotometer, at least one peak of the functional group of the drug is not detected in the complex in the present invention.

For the Fourier transform infrared spectrophotometer (FT-IR), for example, FT/IR-6100 type A (Japan Spectroscopic, serial number: A018861020) can be used.

Light source, detector, integrated count, decomposition, zero filling, apodization, gain, aperture, scan speed, filter, etc. set up. For example, the following measurement conditions are also possible.

 <Measurement conditions>  

Light source: standard light source

Detector: TGS

Total number of calculations: 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 a transmittance (T, %) or an absorbance.

The functional group in the "spike of the functional group of the drug" is not particularly limited as long as it is a functional group of the drug to be used. Examples of the functional group include a hydroxyl group, an ether group, a decylamino group, an amine group, an azo group, a decyl group, an aldehyde group, a carboxyl group, a thiol group, a sulfo group, a thiol group, a sulfonic acid group, and the like. Fluoryl, chloro, bromo, iodo, nitroso, nitro, cyano, ester, keto, pyridyl and the like. As the functional group, a group having a -CO- group such as a decyl group, an ester group, a ketone group or an aldehyde group (carbonyl group) is preferred.

"The peak of the functional group of the drug is not detected", for example, when measured by a Fourier transform infrared spectrophotometer, in the infrared absorption spectrum of the composite of the present invention, (1) the infrared absorption spectrum of the drug monomer The peak of the specific wave number (cm ^-1 ) of the spike detected in the middle is not detected, and/or (2) conforms to the above (1), and contains the mixture of the drug and the tannic acid. A spike of a specific wave number (cm ^-1 ) of a spike detected in an infrared absorption spectrum of a mixture of a drug and tannic acid was not detected. When judging whether or not to detect, it is also possible to consider an error of several cm ^-1 (for example, 3 cm ^-1 or less). In other words, when the infrared absorption spectrum of the two samples is compared, when the peak in the wave number of the difference number cm ^-1 is recognized, it is determined that the peak of the same wave number is detected. The number of peaks of the functional group of the drug not detected may be at least one, and may be 2, 3, 4, 5, 6, 7, 8, 9, 10, or the like.

The present invention includes a complex comprising tannic acid and a drug having the FT-IR spectral characteristics shown in Fig. 14, Fig. 15, Fig. 18, or Fig. 21. The composite containing tannic acid and a drug having the FT-IR spectral characteristics shown in Fig. 14, Fig. 15, Fig. 18, or Fig. 21 may include and have a picture, Fig. 14, Fig. 15, and The FT-IR spectrum shown in Fig. 18 or Fig. 21 respectively shows a combination of tannic acid and a drug characterized by an FT-IR spectrum characteristic of a peak having a wavenumber difference within a few cm ^-1 .

A complex containing tannic acid and a drug having the FT-IR spectral characteristics shown in Figs. 14 and 15 is produced by using loperamide hydrochloride and tannic acid as raw materials. The peak of the guanamine group of loperamide hydrochloride was not detected.

A complex containing tannic acid and a drug having the characteristics of the FT-IR spectrum shown in Fig. 18, which was produced by using ketotifen fumarate and tannic acid as raw materials, but was not detected. Ketotifen fumarate has a spike of a keto group.

A complex containing tannic acid and a drug having the characteristics of the FT-IR spectrum shown in Fig. 21, which is produced by using fexofenadine hydrochloride and tannic acid as raw materials, cannot be detected. Sofenadine hydrochloride has a sharp peak of a carboxyl group.

In the composite according to the present invention, for example, the action of the composite on the temperature or the solubility or dispersibility to the solvent may be different depending on the substance monomer.

 〔Production method〕  

The present invention comprises a method for producing a composite of the present invention, which comprises the steps of (A) mixing a drug and tannic acid with a lower alcohol, and (B) removing the lower alcohol in the mixture. In the step (A), it may be mixed by means of heating, stirring or the like. At this time, the mixture obtained in the step (A) is preferably a drug and a tannic acid in a lower alcohol, preferably a solution which is uniformly dissolved. Alternatively, in the step (A), a lower alcohol containing tannic acid, preferably a uniform spray or addition, may be used in the medicine. At this time, the mixture obtained in the step (A) is preferably covered with a layer of a drug which is a lower alcohol containing tannic acid. Alternatively, in the step (A), in the lower alcohol containing tannic acid, the drug may preferably be uniformly impregnated. At this time, it is preferred that the mixture obtained in the step (A) is covered with a layer of a drug which is a lower alcohol containing tannic acid.

The quality of the lower alcohol is not particularly limited as long as it can dissolve both the tannic acid and the drug. For example, the quality of tannic acid and the total mass of the drug may be about 0.1 to 1000 times.

Step (B) may also be carried out after step (A), and may be carried out simultaneously with step (A).

In the step (B), for example, the solvent may be distilled off, dried (spray-dried, freeze-dried, etc.) or the like. In the case of drying, a dryer such as a commercially available spray dryer or freeze dryer (such as a liquid nitrogen freeze dryer) can be suitably used. The spray dryer is, for example, a rotary atomizing type (disc type), a nozzle type (pressure nozzle method, two-fluid nozzle method, etc.), a two-point collection type, a cyclone collection method, or a bag type filtration-collection method, or the like. A combination or the like is also possible. The removal of the lower alcohol is, for example, a reduction in the amount of the lower alcohol in the composite to 1% by mass or less.

From the complex obtained in the steps (A) and (B), the drug may be covered with a layer of tannic acid.

In the production method of the present invention, a drug, a tannic acid, or a lower alcohol may be used as a raw material, and other components may be used.

More specifically, the method for producing the composite of the present invention can be classified into the following four types, for example.

In the first production method, after the medicine is put into an appropriate amount of the lower alcohol, the tannic acid is gradually added during the dispersion, and the medicine is dissolved. In this case, it can be efficiently carried out by means of heating or stirring. Further, when the dissolved drug is easily oxidized by oxygen, the inert gas such as nitrogen may be used instead of the gas in the production environment. Further, the lower alcohol is removed from the solution to form the composite of the present invention. In this case, the solution may be spray-dried by heating or distilling off the solvent under reduced pressure. A method in which the liquid nitrogen or the like is instantaneously frozen and then dried.

The second production method is a solution in which a tannin acid is dissolved in an appropriate amount of a lower alcohol in a uniform spray of the drug, and the production apparatus used at this time is preferably a fluidized bed granulator.

Further, when a fluidized bed granulator is used, the composite of the present invention can be produced by simultaneously removing the solvent by drying during the treatment.

The third production method is to uniformly add a solution in which a drug dissolves tannic acid in an appropriate amount of a lower alcohol, and in the case of the production apparatus used, a stirring and mixing granulation apparatus is preferred. Further, when a stirring mixing granulation apparatus is used, it is necessary to remove the solvent by drying using a tray type drying apparatus or a fluidized bed granulation apparatus after the treatment to form the composite of the present invention.

In the fourth manufacturing method, the drug is uniformly immersed in a solution obtained by dissolving tannic acid in an appropriate amount of a lower alcohol. After the drug is immersed in the solution, the lower alcohol is removed to form the composite of the present invention. In this case, the solution may be spray-dried by heating or/or decompressing the solution under reduced pressure. A method in which the above solution is instantaneously frozen in liquid nitrogen or the like and then freeze-dried.

The composite of the present invention can be obtained in the form of a semisolid, a solid, or a powder by a separate method, but it is preferably obtained in the form of a powder from the viewpoint of being an additive of a solid preparation.

Composite retention carrier

The present invention comprises a composite retention carrier (hereinafter also referred to as a composite retention carrier of the present invention) characterized by comprising: tannin, a drug and an inert carrier, and infrared rays obtained by measurement by a Fourier transform infrared spectrophotometer In the absorption spectrum, at least one of the peaks of the functional groups of the drug is not detected.

The composite retention carrier of the present invention may be formed by tannic acid, a drug and an inert carrier, and may be formed by tannic acid, a drug, an inert carrier and a lower alcohol, and may contain a tannin, a drug or an inert carrier. The component may also be a component other than tannic acid, a drug, an inert carrier and a lower alcohol, but may be formed by tannic acid, a drug and an inert carrier or by tannic acid, a drug, an inert carrier and a lower alcohol. Preferably, it is better by tannins, drugs and inert carriers.

 [inert carrier]  

The inert carrier is not particularly limited as long as it can be used in the fields of medicines, foods, and the like. Examples of the inert carrier include citric acid, cellulose, starch, calcium, sugar, sugar alcohol, and the like.

Examples of the phthalic acid include light anhydrous citric acid, magnesium metasilicate aluminate, cerium oxide, synthetic aluminum silicate, and calcium citrate. A particularly preferred tannin is calcium citrate.

As the cellulose, for example, crystalline cellulose, powdered cellulose, and low-substituted hydroxypropylcellulose can be mentioned. A particularly preferred class of cellulose is crystalline cellulose.

Examples of the starch include wheat starch, rice starch, corn starch, potato starch, and tapioca starch, and dextrin obtained by decomposition of the enzyme, acid decomposition, and alkali decomposition. A particularly good starch is corn starch.

Examples of the calcium include calcium hydrogen phosphate (calcium phosphate), anhydrous calcium hydrogen phosphate (anhydrous calcium phosphate), and calcium dihydrogen phosphate (first calcium phosphate). A particularly good calcium is calcium hydrogen phosphate.

Examples of the saccharide include lactose hydrate, anhydrous lactose, white sugar, refined white sugar, fructose, glucose, and sucrose. A particularly preferred sugar is lactose hydrate.

As the sugar alcohol, for example, mannitol, erythritol, sorbitol, xylitol, sucrose, maltitol, and lactitol can be mentioned. A particularly preferred sugar alcohol is mannitol.

 [lower alcohol]  

When the composite retaining carrier contains a lower alcohol, the composite retains the lower alcohol in the carrier in an amount of 10% by mass or less, and may be 1% by mass or less. Further, the lower alcohol in the composite may be more than 0% by mass and may be 10% by mass or less, and may be more than 0% by mass and not more than 1% by mass.

 [mass ratio]  

In the composite retention carrier of the present invention, the mass ratio of tannic acid to the drug, for example, (tannic acid): (drug) is 1: (0.01 to 100), and 1: (0.1 to 10) may also be used. , 1: (0.5 to 2) is also possible, 1: (0.66 to 1.5) is also possible, but it is particularly good at 1:1.

In the composite retention carrier of the present invention, the mass ratio of tannic acid to an inert carrier, for example, (tannic acid): (inert carrier) is 1: (0.01 to 100), and 1: (0.1 to 10) It is also possible that 1: (1 to 10) is also possible, and 1: (4 to 9) is also possible, but 1:6 is particularly preferable.

In the composite retention carrier of the present invention, the mass ratio of tannic acid to the drug to the inert carrier, for example, (tannic acid): (drug): (inert carrier) is 1: (0.01 to 100): (0.01 to 100) Yes, 1: (0.1 to 10): (0.1 to 10) Yes, 1: (0.5 to 2): (1 to 10) Yes, 1: (0.66 to 1.5): (4 to 9) Yes, but it is especially good at 1:1:6.

 〔Production method〕  

The present invention comprises a method for producing a composite retention carrier of the present invention, which comprises the steps of (C) mixing a drug, tannic acid and an inert carrier with a lower alcohol, and (D) removing the lower alcohol in the mixture. . In the step (C), it may be mixed by means of heating, stirring or the like. At this time, the mixture obtained in the step (C) is preferably a solution of a drug, tannic acid or an inert carrier in a lower alcohol, preferably a homogeneous one. Alternatively, in the step (C), a lower alcohol containing tannic acid may be sprayed or added to the mixture of the drug and the inert carrier, preferably uniform. At this time, it is preferred that the drug in the mixture obtained in the step (C) is covered with a layer of a lower alcohol containing tannic acid. Alternatively, in the step (C), in the lower alcohol containing a drug and tannic acid, the inert carrier may be impregnated, preferably as a homogeneous one. At this time, it is preferred that the drug in the mixture obtained in the step (C) is covered with a layer of a lower alcohol containing tannic acid. Alternatively, in the step (C), a lower alcohol containing a drug and tannic acid may be sprayed or added to the inert carrier, and it may be uniform. At this time, it is preferred that the drug in the mixture obtained in the step (C) is covered with a layer of a lower alcohol containing tannic acid. Alternatively, in the step (C), in the lower alcohol containing tannic acid, the drug and the inert carrier may be impregnated, preferably as a homogeneous one. At this time, it is preferred that the drug in the mixture obtained in the step (C) is covered with a layer of a lower alcohol containing tannic acid.

Step (D) may also be carried out after step (C), and may also be carried out simultaneously with step (C).

The quality of the lower alcohol is not particularly limited as long as it can dissolve both the tannic acid and the drug, and for example, the mass of the tannic acid, the drug, and the inert carrier may be about 0.1 to 1000 times the total mass.

In the step (D), the means for removing may, for example, be a solvent and dried (spray drying, freeze drying, etc.). In the case of drying, a dryer such as a commercially available spray dryer or freeze dryer (such as a liquid nitrogen lyophilizer) can be suitably used. The spray dryer is, for example, a rotary mist type (disc type), a nozzle type (pressurizing nozzle method, a two-fluid nozzle method, etc.), a two-point collecting type, a cyclone collecting method, or a bag type filtering-collecting method, or Combinations of these, etc. are also possible. The removal of the lower alcohol is, for example, a reduction in the amount of the lower alcohol in the composite to 1% by mass or less.

The composite obtained by the steps (C) and (D) holds the carrier, and the drug may be covered with a layer containing tannic acid.

In the production method of the present invention, a drug, a tannic acid, an inert carrier, and a lower alcohol may be used as a raw material, and other components may be used.

Moreover, the method for producing a composite holding carrier of the present invention can be classified into the following five types in detail, for example.

In the first production method, a solution in which tannic acid is dissolved in an appropriate amount of a lower alcohol is uniformly sprayed in a drug and an inert carrier, but in the case of the manufacturing apparatus used at this time, a fluidized bed granulator is preferred. Further, when a fluidized bed granulator is used, the solvent can be removed by drying during the treatment, and the composite retaining carrier of the present invention can be produced in the process.

In the second production method, a solution in which tannic acid is dissolved in an appropriate amount of a lower alcohol is uniformly added to the drug and the inert carrier. However, in the production apparatus used at this time, a stirring and mixing granulation apparatus is preferred. Further, when a stirring mixing granulation apparatus is used, it is necessary to carry out drying to remove the solvent by using a tray drying apparatus or a fluidized bed granulation apparatus after the treatment, and in the process, the composite holding carrier of the present invention is produced.

In the third production method, after the drug is introduced into an appropriate amount of the lower alcohol, the tannic acid is gradually added to disperse the drug, and the drug is dissolved. In this case, it can be efficiently carried out by means of heating or stirring. Further, when the dissolved drug is easily oxidized by oxygen, it may be first replaced with an inert gas such as nitrogen. Further, after the inert solution is introduced into the solution, the lower alcohol is removed, and the composite of the present invention is kept in a carrier. In this case, a method of distilling off the solution under heating or/under reduced pressure may be used. A method in which the above solution is spray-dried, a method in which the solution is instantaneously frozen by liquid nitrogen or the like, and then freeze-dried.

In the fourth production method, after the drug is introduced into an appropriate amount of the lower alcohol, the tannic acid is gradually added to the dispersion, and the drug is dissolved. In this case, the method can be carried out efficiently by heating or stirring. Further, when the dissolved drug is easily oxidized by oxygen, it may be first replaced with an inert gas such as nitrogen. Further, after the above solution is uniformly sprayed on an inert carrier, the lower alcohol is removed, and the composite of the present invention is kept in a carrier. In the case of the production apparatus used, a fluidized bed granulator is preferred. Further, when a fluidized bed granulating apparatus is used, it is also possible to simultaneously remove the solvent by drying during the treatment.

In the fifth production method, after the drug is introduced into an appropriate amount of the lower alcohol, the tannic acid is gradually added to disperse the drug, and the drug is dissolved. In this case, the method can be carried out efficiently by heating or stirring. Further, when the dissolved drug is easily oxidized by oxygen, it may be first replaced with an inert gas such as nitrogen. Further, after the above solution is uniformly added or added to the inert carrier, the lower alcohol is removed, and the composite of the present invention is kept in a carrier. The production apparatus used in this case is preferably a stirring and mixing granulator. Further, when a stirring mixing granulation apparatus is used, it is necessary to use a tray drying apparatus and a fluidized bed granulation apparatus to dry and remove the solvent after the treatment.

The composite retaining carrier of the present invention can be obtained in a semi-solid, solid, powder state by various methods, but it is preferably obtained in the form of a powder from the viewpoint of being an additive of a solid preparation.

Drug dissolution controlling agent in living body and drug dissolution controlling composition in living body

The present invention comprises (1) a drug dissolution controlling agent in a living body containing tannic acid, (2) a drug dissolution controlling composition in a living body containing the complex of the present invention, and (3) a compound containing the present invention. The drug elution controlling composition in the living body of the carrier (hereinafter, (1) to (3) are collectively referred to as a controlling agent of the present invention, etc.).

Further, the present disclosure encompasses: (i) tannic acid for drug dissolution control in a living body, (ii) a complex of the present invention for drug dissolution control in a living body, and (iii) for use in living a complex retention carrier of the present invention for drug dissolution control in vivo, (iv) a drug dissolution control method in vivo for the step of administering tannic acid to mammals including humans, (v) including the present invention The drug dissolution control method in the living body of the step of administering the mammal to the human body including the human, (vi) includes the step of administering the complex of the present invention to the mammal, including humans. a drug dissolution control method in vivo, (vii) use of tannic acid for producing a drug dissolution controlling agent in a living body, (viii) a complex of the present invention for producing a drug dissolution controlling composition in a living body Use of (ix) a composite retention carrier for the manufacture of a drug dissolution controlling composition in a living body, (x) use of a tannic acid for controlling dissolution of a drug in a living body, ( Xi) for controlling drugs in living organisms The use of the composite of the present invention in which the dissolution is carried out, and (xii) one or more selected from the use of the composite retention carrier of the present invention for controlling the dissolution of the drug in the living body. Further, mammals including humans include, for example, human, mouse, rat, rabbit, guinea pig, dog, cat, monkey, and the like.

 [effect]  

The control agent or the like of the present invention can control the dissolution of the drug contained in the solid preparation in the living body. Controlling the dissolution of the drug in the body, for example, means delaying the dissolution of the drug in the oral cavity, or delaying the dissolution of the drug in the oral cavity and not affecting the dissolution behavior of the drug in the digestive tract. Further, the solid preparation is preferably a tablet such as an orally disintegrating ingot chewable tablet.

For the dissolution of the drug in the oral cavity, for example, a solid preparation containing the control agent of the present invention or the like is prepared, and a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) is used for the solid preparation, and a dissolution test method according to the general test method of the Japanese Pharmacopoeia is used. The second method (stirring method) was carried out (test liquid: water), and the drug was solidified at various points such as 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after the start of the test. The amount of dissolution of the formulation.

For the dissolution of the drug in the digestive tract, for example, a solid preparation containing the control agent of the present invention or the like is prepared, and a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) is used for the solid preparation, and a dissolution test according to the general test method of the Japanese Pharmacopoeia is used. Method 2 (stirring method) (test solution: dissolution test first solution at pH 1.2), 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes after the start of the test At each time point, the amount of dissolution of the drug from the solid preparation was determined.

Further, the digestive tract refers to, for example, the stomach; the small intestine such as the duodenum, the jejunum, and the ileum; the cecum, the colon (upward colon, transverse colon, descending colon, sigmoid colon, etc.), the large intestine such as the rectum, and the like.

Solid preparation

The present invention includes a solid preparation (hereinafter also referred to as a solid preparation of the present invention) containing the control agent or the like of the present invention. The solid preparation of the present invention is preferably an internal solid solution. Further, in the case of the internal solid preparation, it is preferred to use a tablet such as an orally disintegrating ingot or a chewable ingot.

When the control agent of the present invention or the like contains the composite of the present invention, the solid preparation of the present invention may contain an additive other than a drug or tannic acid to the extent that the effects of the present invention are not impaired.

When the control agent of the present invention or the like contains the composite retention carrier of the present invention, the solid preparation of the present invention may contain an additive other than a drug, tannic acid, and an inert carrier to the extent that the effects of the present invention are not impaired.

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. In other words, when the solid preparation of the present invention contains a component other than the control agent or the like of the present invention, the content of the control agent other than the solid preparation of the present invention is preferably about 99% by mass or less, and preferably about 95% by mass or less based on the total amount of the solid preparation. Preferably, it is more preferably about 90% by mass or less. When it is in the above range, it is possible to obtain practically sufficient drug elution controllability, moldability, and chipping property in the living body.

 [excipient]  

Examples of the excipient include sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, and isomalt; lactose hydrate, anhydrous lactose, white sugar, and refined white sugar. , fructose, glucose, glucose hydrate, sugar and other sugars; corn starch, potato starch, wheat starch, rice starch and other starches; glycine acid, alanine and other amino acids; light anhydrous citric acid, synthetic aluminum citrate , tannic acid such as magnesium bismuth aluminate, calcium citrate; cellulose such as crystalline cellulose and powdered cellulose; talc; titanium oxide, and the like. The excipient is preferably a sugar alcohol or a saccharide at a point where the granule is rapidly collapsed in the oral cavity, and among them, mannitol and lactose hydrate are preferred. 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. Further, the total amount of the solid preparation is preferably about 30% by weight or less, more preferably about 20% by weight or less, still more preferably about 10% by weight or less. One type of the excipient may be used alone or two or more types may be used. By means of the excipient, the drug dissolution controllability, moldability and collapse property in the living body can be further enhanced.

 [adhesive]  

The binder, for example, is a person who bonds the granules to each other when compressed. Examples of the binder include magnesium metasilicate aluminate, synthetic aluminum niobate, light anhydrous citric acid, calcium citrate, crystalline cellulose, powdered cellulose, and low-substituted hydroxypropylcellulose. Among them, magnesium metasilicate aluminate, synthetic aluminum citrate, light anhydrous citric acid, calcium citrate, and crystalline cellulose are preferred. 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. Further, the total amount of the solid preparation is preferably about 30% by weight or less, more preferably about 20% by weight or less, still more preferably about 10% by weight or less. When it is in the above range, it is practically possible to obtain sufficient drug elution controllability, moldability, and chipping property in the living body. One type of the adhesive may be used alone or two or more types may be used.

 [cracking agent]  

The breaker is, for example, a component which hydrates when it contains water, or a component which hydrates and collapses. As the breaker, crospovidone, carmellose calcium, carmellose, alginic acid, croscarmellose sodium (croscarmellose) can be mentioned. Sodium), low-substituted hydroxypropylcellulose, cornstarch, potato starch, wheat starch, rice starch, partially alpha (alpha) starch, alpha-starch starch, sodium carboxymethyl starch, and the like. Among them, cross-linked polyvinylpyrrolidone, carboxymethylcellulose, carmellose calcium, croscarmellose sodium, and low-substituted hydroxy Propyl cellulose is preferred. The content of the breaker 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. Further, the total amount of the solid preparation is preferably about 30% by weight or less, more preferably about 20% by weight or less, still more preferably about 10% by weight or less. If it is in the above range, sufficient moldability and collapse property can be obtained practically. One type of the breaker may be used alone or two or more types may be used.

The solid preparation of the present invention may contain an appropriate amount of a lubricant, a coloring agent, a flavoring agent, a sweetener, a flavoring agent, a preservative, etc., in addition to an excipient, a binder, and a breaker. . The lubricant may, for example, be magnesium stearate, calcium stearate, talc, sucrose fatty acid ester or sodium stearyl fumarate. Examples of the coloring agent include food coloring matter, edible lake coloring matter, triiron dioxide, yellow triiron dioxide, and the like. The flavoring agent may, for example, be citric acid hydrate, tartaric acid, malic acid or ascorbic acid. As the sweetener, aspartame, acesulfame potassium, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose and the like can be mentioned. For spices, it can be fennel ( Feneniculum vulgar , Fennel) oil, orange oil, chamomile Roman oil, spearmint, cinnamon oil, clove oil, peppermint oil, bergamot oil ( Bergamot oil), eucalyptus oil, lavender oil, lemon oil, rose oil, chamomile Roman oil, menthol, and the like. As the preservative, there may be mentioned benzoic acid, sodium benzoate, benzyl benzoate, isobutyl p-oxybenzoate, isopropyl p-oxybenzoate, ethyl p-oxybenzoate, and butyl p-oxybenzoate. Ester, propyl p-oxybenzoate, sodium propyl p-oxybenzoate, methyl p-oxybenzoate, sodium methyl p-oxybenzoate, and the like. 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. Further, the total amount of the solid preparation is preferably about 30% by weight or less, more preferably about 20% by weight or less, still more preferably about 10% by weight or less. One type of the additive may be used alone or two or more types may be used.

 〔Production method〕  

The present invention comprises a method for producing a solid preparation, which comprises the step of mixing a control agent or the like of the present invention and an excipient (hereinafter also referred to as a mixing step).

In addition to the excipients, for example, a binder, a breaker, a lubricant, or the like (and other components to be determined) may be used as a raw material for mixing.

In the method for producing a solid preparation, after the mixing step, a step of granulating using the obtained mixture (hereinafter also referred to as a granulation step) may be included.

In the method of granulation, a wet granulation treatment method using a stirring mixing granulator or a fluidized bed granulator is general. In the case where the simplicity is excellent, a method using a stirring mixing granulator is preferred. Further, in the present invention, the agitation mixing granulator and/or the fluidized bed granulator may be suitably selected from commercially available products.

In the wet granulation treatment method, for example, each component is kneaded with a solvent, and then subjected to granulation treatment. The treatment may be a crush granulation method, an extrusion granulation method, a stirring granulation method, a rotary granulation method or the like. Further, in this treatment, an alcohol such as ethanol or isopropyl alcohol or water can be used as the solvent.

In the method for producing a solid preparation, after the granulation step, a step of compression-molding the obtained granules (hereinafter also referred to as a compression molding step) may be included. In the compression molding, a commercially available rotary tableting machine, a single punch tableting machine, or the like, which is generally used for molding a tablet, can be used. Further, the compression pressure in the compression molding is preferably about 1 kN or more, more preferably about 2 kN or more, and still more preferably about 4 kN or more. Further, it is preferably about 60 kN or less, more preferably about 30 kN or less, and still more preferably about 15 kN or less. If it is in this range, the burden of the mortar and the pestle at the time of tableting is small, and it is easy to maintain the tableting pressure at the time of tableting.

In the method for producing a solid preparation, drying using a fluidized bed dryer, a tray drying device, or the like is performed before the compression molding step; using a sieve mill, a jet mill, a hammer mill, a nail mill, a sieve, It is also possible to perform operations necessary for the production of a solid preparation such as a vibrating sieve or the like. A fluidized bed dryer, a tray drying device, a screen mill, a jet mill, a hammer mill, a nail mill, a sieve, and/or a vibrating sieve can be suitably selected for use in a commercial product.

 [effect]  

The solid preparation of the present invention is such that the dissolution of the drug contained in the solid preparation in the living body is controlled. The dissolution of the drug in the living body is controlled, for example, by controlling to delay dissolution of the drug in the oral cavity, or by controlling to delay dissolution of the drug in the oral cavity and having no effect on the dissolution behavior of the drug in the digestive tract.

The dissolution of the drug in the oral cavity is carried out by using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) and the second method (stirring method) of the dissolution test method (test solution: water) according to the general test method of the Japanese Pharmacopoeia. The amount of the drug to be eluted from the solid preparation was determined at various points such as 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after the start of the test.

The dissolution of the drug in the digestive tract is carried out by using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) in accordance with the second test method (stirring method) of the dissolution test method according to the general test method of the Japanese Pharmacopoeia. (Test solution: pH 1.2) In the first test for the dissolution test, the amount of the drug to be eluted from the solid preparation was determined at various points such as 0 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after the start of the test.

The solid preparation of the present invention may have moderate moldability which is practically free from problems, and/or may have excellent collapse properties in the oral cavity. It is excellent in collapse property, for example, it means that the collapse time and/or the water absorption time are short.

The solid preparation of the present invention preferably has a hardness (especially, a hardness measured by a tablet hardness tester (manufactured by Toyama Sangyo Co., Ltd.) of 45 N or more, preferably 50 N or more, more preferably 60 N or more, and more preferably 70 N or more, 80 N. The above is even better, 90N or more is better, and 100N or more is even better.

In the solid preparation of the present invention, according to the correction of the collapse time of the collapse test method specified in the Japanese Pharmacopoeia, the damage time (in particular, the collapse time measured by the collapse tester (manufactured by Toyama Sangyo Co., Ltd.)) is used. It is preferably 30 seconds or less, 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 one sheet of water-insoluble toilet paper folded in a quarter size is placed, and after completely wetting, a lozenge is placed thereon. The water absorption time required for the entire solid preparation to be wetted is preferably 30 seconds or less, more preferably 25 seconds or less, and still more preferably 20 seconds or less.

[Examples]

Hereinafter, the present invention will be described in more detail by way of examples and comparative examples, but the invention is not limited thereto.

(1-1) Manufacture of solid preparation (endogenous solid preparation; lozenge)  Example 1  

According to the composition shown in the first table shown below, loperamide hydrochloride and tannic acid were dissolved in an appropriate amount of absolute ethanol, followed by a spray dryer (Pulvis Minispray GB-22, Yamato Science). Spray drying (inhalation temperature 150 ° C) gave a composite. In addition, mannitol and hydroxypropylcellulose were placed in a stirring and mixing granulator (Mechanomill MM-20N, Okada Seiko) according to the composition shown in the first table shown below, and the tannins were slowly added after mixing. The acid is dissolved in a solution of an appropriate amount of absolute ethanol for granulation. Next, the granulated product was dried in a tray dryer (OFW-450B, As One Co., Ltd.), and the dried product was sized by using a sieve (18 mesh). Further, the above-mentioned composite is added to the whole granule, and magnesium bismuth aluminate, crosslinked polyvinylpyrrolidone and magnesium stearate are added in accordance with the composition shown in the first table shown below. Thereafter, using a rotary tableting machine (VELA5, Kikusui Seisakusho Co., Ltd.), a tablet having a diameter of 8 mm and a mass of 220 mg was obtained at a tableting pressure of about 8 kN.

 Example 2  

According to the composition shown in the first table shown below, loperamide hydrochloride and tannic acid were dissolved in an appropriate amount of absolute ethanol, and then magnesium metasilicate aluminate was added and mixed. Next, the mixture was dried in a tray dryer to form a composite holding carrier. Further, mannitol and hydroxypropylcellulose are placed in a stirring and mixing granulator according to the composition shown in Table 1 to be described later, and after mixing, a solution in which an appropriate amount of absolute ethanol is dissolved in tannic acid is gradually added. Granulation. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). In addition, the above-mentioned composite holding carrier is added to the whole granule, and the crosslinked polyvinylpyrrolidone and magnesium stearate are added according to the composition shown in the first table shown later, and after mixing, the rotary type is used. Ingot machine, with a tableting pressure of about 8 kN, obtained a tablet having a diameter of 8 mm and a mass of 220 mg.

 Comparative example 1  

According to the composition shown in the first table shown below, mannitol and hydroxypropylcellulose are put into a stirring and mixing granulator, and after mixing, a solution of tannic acid dissolved in an appropriate amount of absolute ethanol is gradually added for granulation. . Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in the granulated product, loperamide hydrochloride, magnesium metasilicate aluminate, crosslinked polyvinylpyrrolidone, tannic acid, and the like are added according to the composition shown in the first table shown below. Magnesium stearate, after mixing, was subjected to a tableting press at a pressure of about 8 kN using a rotary tableting machine to obtain a tablet having a diameter of 8 mm and a mass of 220 mg.

 Comparative example 2  

According to the composition shown in the first table shown below, loperamide hydrochloride was dissolved in an appropriate amount of absolute ethanol, and then magnesium metasilicate aluminate was added and mixed. Next, the mixture was dried in a tray dryer to form a composite holding carrier. Further, mannitol and hydroxypropylcellulose are placed in a stirring and mixing granulator according to the composition shown in Table 1 to be described later, and after mixing, a solution in which an appropriate amount of absolute ethanol is dissolved in tannic acid is gradually added. Granulation. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in the whole granule, the above-mentioned composite holding carrier is added, and tannic acid, crosslinked polyvinylpyrrolidone, and magnesium stearate are added according to the composition shown in Table 1 to be described later, and after mixing, Using a rotary tableting machine, a tablet having a diameter of 8 mm and a mass of 220 mg was obtained at a tableting pressure of about 8 kN.

(2-1) Evaluation of dissolution property [drug: loperamide hydrochloride]

The measurement was carried out by using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), and the second method (stirring method) (test liquid: water) of the dissolution test method according to the general test method of the Japanese Pharmacopoeia, and calculating the loperamide from the tablet. (Loperamide) The dissolution rate (%) of the hydrochloride. Specifically, one tablet was taken, and 900 mL of the test liquid was used, and the test was performed at 50 rotations per minute in accordance with the second method of the dissolution test method (stirred slurry method). After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after the start of the dissolution test, 10 mL of the eluate was correctly taken out, and 10 mL of the test solution heated at 37 ± 0.5 ° C was carefully added. The eluate was filtered through a membrane filter having a pore diameter of 0.45 μm or less, and the filtrate was used as a sample solution. Further, the amount of loperamide hydrochloride was quantitatively dried at 105 ° C for 4 hours, and about 33 mg was accurately weighed and dissolved in methanol to make 100 mL correctly. The solution was accurately weighed to 1 mL, and the test solution was added to make it 100 mL correctly as a standard solution. Further, the amount of loperamide hydrochloride was measured using a liquid chromatograph.

In addition, the test solution was changed from water to the first test solution (pH 1.2) of the dissolution test, and the dissolution test was carried out in the same manner.

 <Quantitative conditions of liquid chromatograph>  

Detector: UV spectrophotometer (measuring wavelength: 214 nm)

Column: A stainless steel tube having an inner diameter of 3.0 mm and a length of 7.5 cm was filled with a 3 μm liquid chromatograph using an octadecyl ruthenium oxide gel.

Column temperature: a certain temperature around 40 ° C

Mobile phase: 1.0 g of sodium 1-pentanesulfonate was dissolved in 400 mL of water, and 600 mL of methanol, 50 mL of acetonitrile, and 1 mL of phosphoric acid were added.

Flow: Adjust to maintain the loperamide for about 3 minutes.

Injection volume: 10μL

(3-1) Evaluation of physical properties  <hardness test>  

In the test, the hardness was measured using a load cell type tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), and the number of tests was set to 10 spindles.

 <disintegration test>  

In the test, the collapse test method specified in the Japanese Pharmacopoeia's prescription was revised, and the collapse time was measured using a collapse tester (manufactured by Toyama Industrial Co., Ltd.), and the number of tests was set to 6 spindles.

 <Water absorption test>  

In the test, 6 mL of water was placed in a Petri dish having a diameter of 6.5 cm, and one sheet of water-insoluble toilet paper folded into a quarter size was placed, and after completely wetting it, a tablet was placed thereon, and the tablet was measured. The water absorption time required for the entire wetness was set to 3 spindles.

(4-1) Evaluation results

The measurement results of the composition, hardness, collapse time, and water absorption time of the tablets of Example 1 and Example 2 and Comparative Example 1 and Comparative Example 2 are shown in the first table below.

As a result of the physical property evaluation of the first table, the collapse time and the water absorption time were both less than 30 seconds in Example 1 and Example 2, but in Comparative Example 1, the collapse time, and in Comparative Example 2, the collapse time and The water absorption time is more than 30 seconds. Regarding the hardness, 1 and 2, and Comparative Example 1 and Comparative Example 2 were equivalent, and there was no problem of special moldability. Therefore, it was confirmed that the solid preparations of Example 1 and Example 2 were excellent in both collapse property and water absorbability as compared with the solid preparations of Comparative Example 1 and Comparative Example 2.

In addition, the results of the dissolution test (test liquid: water) of the solid preparations of Example 1 and Example 2, and Comparative Example 1 and Comparative Example 2 are shown in Tables 2 and 1 .

The solid preparation of Example 1 using loperamide hydrochloride and a tannic acid-containing complex, and the hemiplegic using loperamide hydrochloride, tannic acid and an inert carrier The solid preparation of Example 2 of the magnesium aluminate complex retaining carrier, the solid preparation of Comparative Example 1 using untreated loperamide hydrochloride, and the loperamide hydrochloride The dissolution of loperamide hydrochloride was inhibited as compared with the solid preparation of Comparative Example 2 in which the salt was adsorbed on an inert carrier. Further, in detail, in the solid preparation of Example 1, the dissolution of loperamide hydrochloride was suppressed as compared with the solid preparation of Example 2.

In addition, the results of the dissolution test (test solution: dissolution test first liquid of pH 1.2) of the solid preparations of Example 1 and Example 2, and Comparative Example 1 and Comparative Example 2 are shown in Tables 3 and 2.

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

(1-2) Manufacture of a solid preparation (internal solid preparation; lozenge)  Example 3  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate, mannitol and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, slowly A solution of tannic acid dissolved in an appropriate amount of absolute ethanol is added for granulation. Next, the granulated product is dried in a tray dryer to obtain a composite to hold the carrier. Further, the composite is held in a carrier, and after sizing using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in the fourth table shown below. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, using a rotary tableting machine, with a spindle pressure of about 8kN, one spindle has a diameter of 8mm and its mass is 220mg. Lozenges.

 Example 4  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate and mannitol are put into a stirring and mixing granulator, and after mixing, slowly added to an appropriate amount of absolute ethanol. A solution of tannic acid is dissolved for granulation. Next, the granulated product was dried in a tray dryer to obtain a composite holding carrier. Further, the composite is held in a carrier, and after sizing using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in the fourth table shown below. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, using a rotary tableting machine, with a spindle pressure of about 8kN, one spindle has a diameter of 8mm and its mass is 220mg. Lozenges.

 Example 5  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate, anhydrous calcium hydrogen phosphate and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, the mixture is slowed down. A solution of tannic acid dissolved in an appropriate amount of absolute ethanol is slowly added for granulation. Next, the granulated product was dried in a tray dryer to obtain a composite holding carrier. Further, the composite is held in a carrier, and after sizing using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in the fourth table shown below. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, using a rotary tableting machine, with a spindle pressure of about 8kN, one spindle has a diameter of 8mm and its mass is 220mg. Lozenges.

 Example 6  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate and anhydrous calcium hydrogen phosphate are put into a stirring and mixing granulator, and after mixing, slowly added in an appropriate amount of anhydrous Ethanol dissolves the solution of tannic acid for granulation. Next, the granulated product was dried in a tray dryer to obtain a composite holding carrier. Further, the composite is held in a carrier, and after sizing using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in the fourth table shown below. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, using a rotary tableting machine, with a spindle pressure of about 8kN, one spindle has a diameter of 8mm and its mass is 220mg. Lozenges.

 Example 7  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate, lactose hydrate and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, slowly A solution of tannic acid dissolved in an appropriate amount of absolute ethanol is added for granulation. Next, the granulated product was dried in a tray dryer to obtain a composite holding carrier. Further, the composite is held in a carrier, and after sizing using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in the fourth table shown below. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, using a rotary tableting machine, with a spindle pressure of about 8kN, one spindle has a diameter of 8mm and its mass is 220mg. Lozenges.

 Example 8  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate and lactose hydrate are put into a stirring and mixing granulator, and after mixing, slowly added to an appropriate amount of absolute ethanol. A solution of tannic acid is dissolved for granulation. Next, the granulated product is dried in a tray dryer to obtain a composite to hold the carrier. Further, the composite is held in a carrier, and after sizing using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in the fourth table shown below. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, use a rotary tableting machine to produce a spindle with a diameter of 8 mm and a mass of 220 mg at a pressure of about 8 kN. Lozenges.

 Comparative example 3  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate, mannitol and hydroxypropyl cellulose were put into a stirring and mixing granulator, and after mixing, slowly added. A suitable amount of absolute ethanol is used for granulation. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in the whole granule, a crosslinked polyvinylpyrrolidone, magnesium metasilicate aluminate, aspartame, citric acid, menthol, perfume, and stearin are added according to the composition shown in Table 4 to be shown later. Magnesium acid, after mixing, was subjected to a tableting press at a pressure of about 8 kN using a rotary tableting machine to obtain a tablet having a diameter of 8 mm and a mass of 220 mg.

 Comparative example 4  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate and mannitol were placed in a stirring and mixing granulator, and after mixing, an appropriate amount of absolute ethanol was gradually added thereto. grain. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in the whole granule, a crosslinked polyvinylpyrrolidone, magnesium metasilicate aluminate, aspartame, citric acid, menthol, perfume, and stearin are added according to the composition shown in Table 4 to be shown later. Magnesium acid, after mixing, was subjected to a tableting press at a pressure of about 8 kN using a rotary tableting machine to obtain a tablet having a diameter of 8 mm and a mass of 220 mg.

 Comparative Example 5  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate, anhydrous calcium hydrogen phosphate and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, the mixture is slowed down. A suitable amount of absolute ethanol is slowly added for granulation. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in the whole granule, a crosslinked polyvinylpyrrolidone, magnesium metasilicate aluminate, aspartame, citric acid, menthol, perfume, and stearin are added according to the composition shown in Table 4 to be shown later. Magnesium acid, after mixing, was subjected to a tableting press at a pressure of about 8 kN using a rotary tableting machine to obtain a tablet having a diameter of 8 mm and a mass of 220 mg.

 Comparative Example 6  

According to the composition shown in the fourth table shown below, ketotifen fumarate, magnesium metasilicate aluminate, lactose hydrate and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, slowly An appropriate amount of absolute ethanol was added for granulation. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in the whole granule, a crosslinked polyvinylpyrrolidone, magnesium metasilicate aluminate, aspartame, citric acid, menthol, perfume, and stearin are added according to the composition shown in Table 4 to be shown later. Magnesium acid, after mixing, was subjected to a tableting press at a pressure of about 8 kN using a rotary tableting machine to obtain a tablet having a diameter of 8 mm and a mass of 220 mg.

(2-2) Evaluation of dissolution property [drug: ketotifen fumarate]

In the measurement, the dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) was used, and the second method (stirred slurry method) (test liquid: water) of the dissolution test method according to the general test method of the Japanese Pharmacopoeia was used to obtain the ketotifen from the tablet. The amount of dissolution of the fumarate was calculated from the results. Specifically, one tablet was taken, and 900 mL of the test liquid was used, and the test was carried out at 50 rotations per minute in accordance with the second method (stirring method) of the dissolution test method. After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes from the start of the dissolution test, 10 mL of the solution was correctly taken out, and 10 mL of the test solution heated at 37 ± 0.5 ° C was carefully added. The eluate was filtered through a membrane filter having a pore diameter of 0.45 μm or less to prepare a sample solution. Further, the ketotifen fumarate was quantitatively dried at 105 ° C for 4 hours, and about 15 mg was accurately weighed, dissolved in the test solution, and correctly made into 200 mL. The solution was accurately weighed 2 mL, and the test solution was added to make it 100 mL correctly as a standard solution. Further, the amount of ketotifen fumarate was measured using a liquid chromatograph. In addition, the test liquid is two types, such as water selection and the first solution (pH 1.2) of the dissolution test.

 <Quantitative conditions of liquid chromatograph>  

Detector: UV spectrophotometer (measuring wavelength: 295 nm)

Column: A stainless steel tube having an inner diameter of 3.0 mm and a length of 15 cm was filled with a 5 μm liquid chromatograph using an octadecyl ruthenium oxide gel.

Column temperature: a certain temperature around 40 ° C

Mobile phase: 2.0 g of sodium lauryl sulfate was dissolved in 450 mL of water, and 550 mL of acetonitrile and 1 mL of phosphoric acid were added and used as a mobile phase.

Flow: Adjust to maintain the Ketutifen hold time of about 4 minutes.

Injection volume: 50μL

(3-2) Evaluation of physical properties  <hardness test>  

In the test, the hardness was measured using a load-weight tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), and the number of tests was set to 10 spindles.

 <disintegration test>  

In the test, the collapse test method specified in the Japanese Pharmacopoeia's prescription was revised, and the collapse time was measured using a collapse tester (manufactured by Toyama Industrial Co., Ltd.), and the number of tests was set to 6 spindles.

 <Water absorption test>  

In the test, 6 mL of water was placed in a Petri dish having a diameter of 6.5 cm, and one sheet of water-insoluble toilet paper folded into a quarter size was placed, and after completely wetting it, a tablet was placed thereon, and the tablet was measured. The water absorption time required for the entire wetness was set to 3 spindles.

(4-2) Evaluation results

The measurement results of the composition, hardness, collapse time, and water absorption time of the solid preparations of Examples 3 to 8 and Comparative Examples 3 to 6 are shown in Table 4 below.

As a result of evaluation of the physical properties of the fourth table, in the solid preparations of Examples 3 to 8, the collapse time and the water absorption time were less than 30 seconds, but the solid preparations of Comparative Example 3, Comparative Example 5, and Comparative Example 6, The water absorption time is more than 30 seconds. Further, in the solid preparation of Comparative Example 4, the collapse time and the water absorption time were less than 30 seconds, but there were many molding failures. Therefore, in the solid preparations of Examples 3 to 8, the chipping property, the water absorbability, and the moldability were superior to those of the solid preparations of Comparative Examples 3 to 6.

The results of the dissolution test (test liquid: water) of Example 3 and Example 4, and Comparative Example 3 and Comparative Example 4 are shown in Tables 5 and 3.

The solid preparations of Examples 3 and 4 were maintained using a combination of mannitol and magnesium metasilicate aluminate containing ketotifen fumarate, tannic acid and an inert carrier, and without using a composite retention carrier The dissolution of ketotifen fumarate was inhibited in Comparative Example 3 and the solid preparation of Comparative Example 4.

Further, the results of the dissolution test (test liquid: dissolution test first liquid (pH 1.2)) of Example 3 and Example 4, Comparative Example 3, and Comparative Example 4 are shown in Tables 6 and 4.

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

The results of the dissolution test (test liquid: water) of Example 5, Example 6, and Comparative Example 5 are shown in Tables 7 and 5.

A composite comprising a mixture of anhydrous chromomolybdate and tannic acid aluminate ketotifen fumarate, tannic acid and an inert carrier, and a solid preparation of the carrier, and a comparative example 5 of the carrier without the use of a composite retention carrier In comparison with the solid preparation, the dissolution of ketotifen fumarate was inhibited.

Further, the results of the dissolution test (test liquid: dissolution test first liquid (pH 1.2)) of Examples 5 and 6 and Comparative Example 5 are shown in Tables 8 and 6.

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

The results of the dissolution test (test liquid: water) of Example 7 and Example 8 and Comparative Example 6 are shown in Tables 9 and 7.

The solid preparations of Examples 7 and 8 were maintained using a complex of lactose hydrate and magnesium metasilicate aluminate containing ketotifen fumarate, tannic acid and an inert carrier, and remained without the use of a composite. In Comparative Example 6 of the carrier, dissolution of ketotifen fumarate was inhibited.

The results of the dissolution test (test liquid: dissolution test first solution (pH 1.2)) of Example 7 and Example 8 and Comparative Example 6 are shown in Tables 10 and 8.

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

(1-3) Manufacture of a solid preparation (internal solid preparation; lozenge)  Example 9  

According to the composition shown in Table 11 below, mannitol, magnesium metasilicate magnesium silicate and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, slowly added to an appropriate amount of anhydrous ethanol to dissolve the single sheet. A solution of chloric acid and loperamide hydrochloride is granulated. Next, the granulated product is dried in a tray dryer to obtain a composite to hold the carrier. Further, the composite is held in a carrier, and after sieving using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in Table 11 which will be shown later. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, using a rotary tableting machine, with a spindle pressure of about 8kN, one spindle has a diameter of 8mm and its mass is 220mg. Lozenges.

 Example 10  

According to the composition shown in Table 11 below, mannitol and magnesium metasilicate aluminate are put into a stirring and mixing granulator. After mixing, slowly add an appropriate amount of absolute ethanol to dissolve tannic acid and loperidine. A solution of the amine (Loperamide) hydrochloride is granulated. Next, the granulated product was dried in a tray dryer to obtain a composite holding carrier. Further, the composite is held in a carrier, and after sieving using a sieve (18 mesh), a crosslinked polyvinylpyrrolidone or a bismuthic acid aluminate is added to the whole granule according to the composition shown in Table 11 which will be shown later. Magnesium, aspartame, citric acid, menthol, perfume and magnesium stearate, after mixing, using a rotary tableting machine, with a spindle pressure of about 8kN, one spindle has a diameter of 8mm and its mass is 220mg. Lozenges.

 Comparative Example 7  

According to the composition shown in Table 11 below, mannitol, magnesium metasilicate magnesium silicate and hydroxypropyl cellulose are put into a stirring and mixing granulator, and after mixing, an appropriate amount of absolute ethanol and Lopper are slowly added. Loperamide hydrochloride is granulated. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in this whole granule, cross-linked polyvinylpyrrolidone, magnesium metasilicate aluminate, aspartame, citric acid, menthol, perfume, and stearin are added according to the composition shown in Table 11 which will be shown later. Magnesium acid, after mixing, was subjected to a tableting press at a pressure of about 8 kN using a rotary tableting machine to obtain a tablet having a diameter of 8 mm and a mass of 220 mg.

 Comparative Example 8  

According to the composition shown in Table 11 below, mannitol and magnesium metasilicate aluminate are put into a stirring and mixing granulator, and after mixing, an appropriate amount of absolute ethanol and loperamide salt are gradually added. The acid salt is granulated. Next, the granulated product was dried in a tray dryer, and the dried product was sized by using a sieve (18 mesh). Further, in the granulated product, loperamide hydrochloride, magnesium metasilicate aluminate, crosslinked polyvinylpyrrolidone, tannic acid, and the like are added according to the composition shown in Table 11 below. Magnesium stearate, after mixing, was subjected to a tableting press at a pressure of about 8 kN using a rotary tableting machine to obtain a tablet having a diameter of 8 mm and a mass of 220 mg.

(2-3) Evaluation of dissolution property [drug: loperamide hydrochloride]

The measurement was carried out by using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.), and the second method (stirring method) (test liquid: water) of the dissolution test method according to the general test method of the Japanese Pharmacopoeia, and determining the loperidine from the tablet. The elution amount of the amine (loperamide) hydrochloride was calculated from the results.

Specifically, one tablet was taken, and 900 mL of the test liquid was used, and the test was carried out at 50 rotations per minute in accordance with the second method (stirring method) of the dissolution test method. After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes from the start of the dissolution test, 10 mL of the solution was correctly taken out, and 10 mL of the test solution heated at 37 ± 0.5 ° C was carefully added. The eluate was filtered through a membrane filter having a pore diameter of 0.45 μm or less to prepare a sample solution. Further, the amount of loperamide hydrochloride was quantitatively dried at 105 ° C for 4 hours, and about 22 mg was accurately weighed and dissolved in methanol to make it 100 mL correctly. The solution was accurately weighed to 5 mL, and the test solution was added to make it 100 mL correctly. The solution was accurately weighed 5 mL, and the test solution was added to make it 100 mL correctly as a standard solution. Further, the amount of loperamide hydrochloride was measured using a liquid chromatograph. In addition, the test liquid is selected from two types, such as water and the first solution (pH 1.2) of the dissolution test.

 <Quantitative conditions by liquid chromatography>  

Detector: UV spectrophotometer (measuring wavelength: 214 nm)

Column: an inner diameter of 3.0 mm, a 7.5 cm long stainless steel tube filled with a 3 μm liquid chromatograph using an octadecyl ruthenium oxide gel.

Column temperature: a certain temperature around 40 ° C

Mobile phase: 1.0 g of sodium pentane sulfonate was dissolved in 400 mL of water, and 600 mL of methanol, 50 mL of acetonitrile and 1 mL of phosphoric acid were added as a mobile phase.

Flow: Adjust to maintain the loperamide for about 3 minutes.

Injection volume: 50μL

(3-3) Evaluation of physical properties  <hardness test>  

In the test, the hardness was measured using a load-weight tablet hardness tester (manufactured by Okada Seiko Co., Ltd.), and the number of tests was set to 10 spindles.

 <disintegration test>  

In the test, the collapse test method specified in the Japanese Pharmacopoeia of the 17th Amendment was used, and the collapse time was measured using a collapse tester (manufactured by Toyama Sangyo Co., Ltd.), and the number of tests was set to 6 spindles.

 <Water absorption test>  

In the test, 6 mL of water was placed in a Petri dish having a diameter of 6.5 cm, and one sheet of water-insoluble toilet paper folded into a quarter size was placed, and after completely wetting it, a tablet was placed thereon, and the tablet was measured. The water absorption time required for the entire wetness was set to 3 spindles.

(4-3) Evaluation results

The measurement results of the composition, hardness, collapse time, and water absorption time of the solid preparations of Example 9 and Example 10, and Comparative Example 7 and Comparative Example 8 are shown in the following Table 11.

As a result of the physical property evaluation of the eleventh table, the collapse time and the water absorption time were less than 30 seconds in Example 9 and Example 10, but the water absorption time of the solid preparation of Comparative Example 7 was 30 seconds or longer. Further, in Comparative Example 8, the collapse time and the water absorption time were less than 30 seconds, but there was a large amount of molding failure. Therefore, the solid preparations of Example 9 and Example 10 were excellent in collapsibility, water absorbability, and moldability as compared with Comparative Example 7 and Comparative Example 8.

The results of the dissolution test (test liquid: water) of Example 9 and Example 10, and Comparative Example 7 and Comparative Example 8 are shown in Tables 12 and 9.

The solid preparations of Examples 9 and 10 were maintained using a composite of mannitol from loperamide hydrochloride, tannic acid and an inert carrier, and water-soluble instead of tannic acid. In Comparative Example 7 of the hydroxypropylcellulose of the binder and Comparative Example 8 in which no tannic acid was used, the elution of loperamide hydrochloride was suppressed.

Further, the results of the dissolution test (test liquid: dissolution test first liquid (pH 1.2)) of Example 9 and Example 10, Comparative Example 7, and Comparative Example 8 are shown in Tables 13 and 10.

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

When the test liquid is water, it is conceivable in the state of the oral cavity, and when it is the first liquid (pH 1.2) of the dissolution test, it can be assumed to be in the stomach. From the test results of the test liquid being water, the dissolution of the drug was suppressed when the tannic acid was formulated, and the bitterness of the drug in the oral cavity was masked. Further, the test liquid was the result of the test of the first solution (pH 1.2) of the dissolution test, and the dissolution of the drug was not inhibited with or without the presence of tannic acid, and it was said that there was no difference in drug absorption in the stomach. Therefore, it was revealed that the bitterness of the drug in the oral cavity was masked by the use of the present invention, and there was no difference in drug absorption in the stomach.

(5) Physicochemical properties of the composite

Loperamide hydrochloride, ketotifen fumarate, and fexofenadine hydrochloride and tannic acid were dissolved in an appropriate amount of absolute ethanol, followed by a spray dryer (Pulvis Minispray GB- 22, Yamato Science), spray drying (inhalation temperature 150 ° C), to obtain a composite, and use this composite as a sample. In order to confirm whether the complex is different from the stirred mixture, loperamide hydrochloride, ketotifen fumarate, and fexofenadine hydrochloride and tannic acid are fully contained in the plastic bag. The mixture obtained by stirring and mixing was also used as a sample.

Using FT/IR-6100 type A (Japan Spectrophotometry, serial number: A018861020), tannic acid (monomer), loperamide hydrochloride (monomer), tannic acid, and Luo were measured under the following conditions. a mixture of loteramide hydrochloride (mass ratio 1:1), a complex of tannic acid and loperamide hydrochloride (mass ratio 1:1, n=2), ketone a mixture of fenfumate (monomer), tannic acid and ketotifen fumarate (mass ratio 1:1), a complex of tannic acid and ketotifen fumarate (mass ratio 1: 1), a mixture of fexofenadine hydrochloride (monomer), tannic acid and fexofenadine hydrochloride (mass ratio 1:1), and tannic acid and fexofenadine hydrochloride The IR spectrum of the salt complex (mass ratio 1:1) confirmed the difference in physicochemical properties between the composite and the mixture from the respective spectra obtained.

 <Measurement conditions>  

Light source: standard light source

Detector: TGS

Total number of calculations: 16

Decomposition: 4cm ^-1

Zero filling: On

Apodization: Cosine

Gain: Auto(16)

Aperture: Auto (7.1mm)

Scan rate: Auto (2mm/sec)

Filter: Auto (10000Hz)

a mixture of tannic acid (monomer), loperamide hydrochloride (monomer), tannic acid and loperamide hydrochloride (mass ratio 1:1), and single The results of IR spectroscopy of a complex of linonic acid with loperamide hydrochloride (mass ratio 1:1, n=2) are shown in Table 14 and Figures 11 to 15.

Loperamide hydrochloride (monomer) and a mixture of tannic acid and loperamide hydrochloride have a peak of wave number 1623 cm ^-1 and can be considered to be from loperamide. ) Hydrochloride all of the guanamine groups. 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 the two were different.

a mixture of ketotifen fumarate (monomer), tannic acid and ketotifen fumarate (mass ratio 1:1), and a complex of tannic acid with ketotifen fumarate (quality) The IR spectrum measurement results of the ratio of 1:1 are shown in Table 15 and Figures 16 to 18. Further, the results of IR spectrum measurement of tannic acid (monomer) are again described in Table 15.

The mixture of ketotifen fumarate (monomer) and tannic acid and ketotifen fumarate has a peak of wave number 1650 cm ^-1 and is considered to be derived from all carbonyl groups of 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 the two were different.

a mixture of fexofenadine hydrochloride (monomer), tannic acid and fexofenadine hydrochloride (mass ratio 1:1), and a combination of tannic acid and fexofenadine hydrochloride The results of IR spectrum measurement of the body (mass ratio 1:1) are shown in Table 16 and Figure 19 to Figure 21. Further, in the fifteenth table, the results of IR spectrum measurement of tannic acid (monomer) are again described.

The mixture of fexofenadine hydrochloride (monomer), and tannic acid and fexofenadine hydrochloride has a peak of wave number 1706 to 1707 cm ^-1 and can be considered to be derived from fexofenadine hydrochloride. Salt all carbonyl. However, it was confirmed in the complex of tannic acid and fexofenadine hydrochloride (mass ratio 1:1) that the peak was not detected. From the above, it was confirmed that there was a difference in physicochemical properties between the composite and the mixture, and the two were different.

 [Industry use possibility]  

The solid preparation of the present invention can be manufactured without using a complicated manufacturing step or a special manufacturing apparatus, and further concealing a drug having an unpleasant taste. Therefore, it is suitable for industrial mass production, and at the same time, it can be widely used as a solid preparation which can be formulated with various drugs.

Claims (12)

 A complex comprising (I) tannic acid and a drug or (II) a combination of tannic acid, a drug, and a lower alcohol, wherein the infrared absorption spectrum obtained by a Fourier transform infrared spectrophotometer is used for the drug At least one of the peaks of the functional group is not detected.    The composite according to claim 1, which has the characteristics of the FT-IR spectrum shown in Fig. 14, Fig. 15, Fig. 18, or Fig. 21.    A composite retention carrier comprising (III) tannic acid, a drug and an inert carrier or (IV) tannic acid, a drug, an inert carrier and a lower alcohol complex carrier, wherein the Fourier transform infrared spectrophotometer is used. In the infrared absorption spectrum obtained at a predetermined time, at least one of the peaks of the functional groups of the drug is not detected.    The composite retention carrier according to claim 3, wherein the insoluble carrier is a tannin, a cellulose, a starch, a calcium, a sugar or a sugar alcohol.    A composition for controlling a drug elution in a living body, which comprises the composite according to claim 1 or 2, or the composite retaining carrier according to item 3 or 4 of the patent application.    A solid preparation comprising the composite according to claim 1 or 2 or the composite retention carrier according to item 3 or 4 of the patent application.    A solid preparation according to claim 6, which is a tablet.    The solid preparation according to claim 6 or 7, which is an orally disintegrating ingot or a chewable ingot.    A drug dissolution controlling agent in a living body containing tannic acid.    A method for producing a composite according to the invention of claim 1, which comprises (A) a step of mixing a drug and tannic acid with a lower alcohol, and (B) removing the mixture The step of lower alcohol.    A method for producing a composite retention carrier, which is a method for producing a composite retention carrier comprising tannic acid and a medicament, which comprises (C) (C-1) a lower alcohol containing tannic acid, a drug and an inert carrier a step of spraying or adding a mixture, (C-2) a step of impregnating an inert carrier in a lower alcohol containing a drug and tannic acid, or (C-3) a lower alcohol containing a drug and tannic acid, being inert The step of spraying or adding the carrier, and (D) the step of removing the lower alcohol in the mixture.    A method for producing a solid preparation, comprising the step of mixing the composite according to claim 1 or 2 or the composite holding carrier according to item 3 or 4 of the patent application with an excipient.