JPH09157158A - Preparation compounded with galenical - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the preparation prepared by compounding a galenical extract with a medicine-adsorbed ion exchange resin resinate without affecting the release of the medicine from the resinate, and to provide a method for preparing the preparation. SOLUTION: This preparation containing the medicine-adsorbed ion exchange resin resinate and the galenical extract is prepared by compounding the medicine-adsorbed ion exchange resin resinate and the galeical extract containing an ionic substance in an amount of the equality: F=B(eq)/A(eq) (0<=F<=0.3) [A(eq) is the ion exchange capacity of the medicine-adsorbed ion exchange resin resinate; B(eq) is the ion equivalent of the ionic substance contained in the galenical extract].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aqueous suspension preparation comprising a resinate in which a drug having an effective effect on a living body is bound to an ion-exchange resin and particles coated with a release-controlling membrane. The present invention relates to an aqueous suspension preparation characterized by being blended.

[0002]

2. Description of the Related Art Liquid preparations are generally superior in absorption after administration as compared with solid preparations, are easy to drink, and are excellent preparations applicable to the elderly and children who cannot take solid preparations. In addition, a liquid drug with sustained release is effective for a drug having a short half-life and a drug having a narrow effective blood concentration range, and it is also an effective drug for enhancing patient compliance, but the number is currently very high. Very few. As a method of preparing this sustained-release liquid preparation, there is a method of binding a drug to an ion exchange resin and coating it with a release-controlling film (US Pat. Nos. 2990332 and 3138525). Furthermore, as a method for preventing cracking of the release-controlling membrane due to swelling of the ion exchange resin during dispersion in water, a method of adding a solvating agent into the drug-ion exchange resin complex (resinate) (US Pat. No. 42217).
78 and 4847077), and a method for increasing the theoretical ion adsorption amount of the drug bound to the ion exchange resin to 80% or more (Japanese Patent Publication No. 7-5458). As described above, conventionally, various types of aqueous suspension formulations using a drug-ion exchange resin complex are known, but in these aqueous suspension formulations,
There are no examples of formulations containing crude drug extracts. Crude drugs have been used since ancient times as medical drugs and folk medicines, and their safety has been confirmed, and there are some that exhibit various medicinal effects. Furthermore, the medicinal components are multi-components including unknown ones that have not been identified and act as a complex agent, so that one crude drug often has a broad pharmacological action. Therefore, by adding a crude drug to a preparation, it is possible to enhance the drug effect and to add a wide range of drug effect. From this point of view, an attempt was made to design a formulation in which an extract of crude drug was mixed with an aqueous suspension formulation containing a resinate in which the drug was bound to an ion-exchange resin. It has been confirmed that this may cause deterioration of the formulation and a decrease in potency, and that the sustained-release liquid formulation cannot achieve the drug release as designed and changes.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have proposed an aqueous suspension preparation in which an extract of a crude drug is added to an aqueous suspension preparation of resinate in which a drug having an effective effect on a living body is bound to an ion exchange resin. Therefore, intensive studies were conducted to obtain an aqueous suspension preparation that does not affect the drug release from the resinate and can be stored for a long period of time. As a result, when a crude drug extract is blended with a resinate, there is no problem with a crude drug extract component that does not affect drug release from the resinate, but when drug release occurs from the resinate, the crude drug extract extract is blended. It was found that the above-mentioned problems can be solved by removing ions from the resin, whereby the drug release from the resinate can be performed as designed.

[0004]

Means for Solving the Problems The present invention (1) is a preparation characterized by containing an ion-exchange resin resinate adsorbing a drug and a crude drug extract, and (2) an aqueous suspension preparation. (3) The resinate (3) is a resinate coated with a water-permeable polymer film, and the aqueous suspension preparation (2) is (4) the crude drug is a crude drug selected from Onji, Senega and Kyoukyo. The aqueous suspension preparation according to (3) above, (5) the aqueous suspension preparation according to (2) or (3) above, wherein the drug is dihydrocodeine or methylephedrine, and (6) the water-permeable polymer is an aminoalkyl methacrylate copolymer. (3) The aqueous suspension preparation according to the above (3). The present invention also provides (7) relational expression F = B (eq) / A (eq) [where 0 ≦ F ≦ 0.3] [wherein A (eq) is an ion exchange resin resinate adsorbing a drug. , B (eq) represents the ionic equivalent of the ionic substance contained in the crude drug extract. ] The manufacturing method of the preparation characterized by mix | blending the crude drug extract containing the quantity of ionic substances represented by these, and the ion-exchange resin resinate which adsorbed the drug, and (8) contained in the crude drug extract The production method according to (7) above, which has a step of adjusting the amount of the ionic substance to be generated by an ion exchange resin. The ion-exchange resin resinate adsorbed with the drug to be incorporated in the preparation of the present invention is one in which a desired drug is adsorbed on an ion-exchange resin according to a conventional method, and as the ion-exchange resin used, an insoluble porous synthetic polymer, For example, a copolymer of styrene and divinylbenzene may be mentioned. The acidic ion exchange resin (H type) adsorbs a basic drug, and the basic ion exchange resin (OH type) adsorbs an acidic drug. In the present invention, a strongly acidic or strongly basic ion exchange resin is used. It is preferable. The degree of cross-linking of the ion exchange resin composed of styrene-divinylbenzene copolymer is determined by the amount of divinylbenzene used.
It is preferable to use -16%, especially 8-14%. These ion-exchange resins are available from Diaion (Mitsubishi Kasei Co., Ltd.), Dowex (Dow Chemical Co., Ltd.),
It is commercially available under the trade name of Amberlite (Rohm and Haas Co., Ltd.) and the like, and can be appropriately selected and used from these. The average particle size of the ion exchange resin is 5 to
It is preferably 1000 μm, and particularly preferably 10 to 300 μm, and if desired, a commercially available product can be used after being finely granulated with a pulverizer such as an atomizer.

[0005] As a drug, as a substance that binds to an ion exchange resin, a basic drug has pKa6 to 10 and especially pKa.
7.5-10, ionic drugs in the range of pKa 2-5 for acidic drugs may be arbitrarily selected according to the purpose, for example, respiratory tract agents: dihydrocodeine phosphate, codeine phosphate. , Noscapine hydrochloride, potassium guaiacol sulfonate, clopilastine fendizoate, dextromethorphan hydrobromide, cloperastine hydrochloride, etc., antitussive and expectorant; bronchodilators such as dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, dl- Antihistamines such as chlorpheniramine maleate, drugs for digestive tract: scopolamine hydrobromide,
Gastrointestinal antispasmodics such as methixene hydrochloride and dicyclomine hydrochloride, central nervous system drugs: phenothiazine derivatives such as chlorpromazine hydrochloride which is an antipsychotic agent; phenothiazine analogues such as chlorprothixene hydrochloride; benzodiazepine derivatives such as chlordiazepoxide hydrochloride which is anxiolytic Imipramine-based drugs such as imipramine hydrochloride, which is an antidepressant; sodium salicylate, which is an antipyretic / analgesic agent; phenobarbital sodium, which is a hypnotic
Cardiovascular drugs: etafenone hydrochloride, which is a coronary dilator;
Antiarrhythmic agents, such as procainamide hydrochloride; Ca antagonists, such as verapamil hydrochloride; antihypertensive agents, such as hydrazine hydrochloride, propranolol hydrochloride, flonidin hydrochloride, etc .; peripheral vasodilators / constrictors, such as trazoline hydrochloride, antibiotics: macrolides Oleandomycin phosphate, etc .;
Tetracycline-based tetracycline hydrochloride, etc .; Streptomycin-based fradiomycin sulfate, etc .; Penicillin agent dicloxacillin sodium, pibmesirinam hydrochloride, carbenicillin indanyl sodium, etc.
Chemotherapeutic agents: sulfa drug, sulfisomidine sodium, etc .; antituberculosis drug, kanamycin sulfate, etc .; antiprotozoal drug, amodiaquine hydrochloride, etc.

In particular, dihydrocodeine phosphate, dl-
Basic respiratory tract drugs such as methylephedrine hydrochloride and phenylpropanolamine, or chlorpheniramine,
An excellent effect of sustained release can be obtained with antihistamines such as diphenhydramine. A good resinate can be obtained by combining these drugs alone or by combining two or more kinds having the same selectivity and binding property of the ion exchange resin and binding them to the ion exchange resin. In the present invention, the relative molar number is 80% or more, particularly 85 to 100%, when the maximum adsorption amount of strong base ion (sodium ion etc.) or strong acid ion (chlorine ion etc.) to each ion exchange resin is 100%. What adsorbed the above drug is preferable.

The resinate of the present invention can be produced by a conventional method, for example, as follows. The drug salt is reacted with an ion exchange resin in an aqueous solvent in which both the drug salt and the free form can be dissolved to obtain an aqueous solution of the drug free form. Examples of the aqueous solvent include water or an organic solvent which can be freely dissolved in water, for example, an aqueous solution of monohydric alcohols such as methyl alcohol, ethyl alcohol and isopropanol, and ketones such as acetone and methyl ethyl ketone. The aqueous solvent includes an aqueous solution containing 5 to 95%, preferably 10 to 90% of an organic solvent. Particularly, in the case of a salt of a basic drug, an aqueous solution of 40 to 85% of ethanol or isopropanol is used, and an aqueous solution of an acid drug is used. In this case, it is preferable to use a 5-30% ethanol aqueous solution. The reaction with the ion exchange resin is performed by adding an ion exchange resin corresponding to the drug salt dissolved in a water-soluble solvent and stirring. In this case, the ion exchange resin is preferably used in an amount of about 1.0 to 2.0 times the required equivalent amount of the drug salt. The reaction can be carried out at room temperature or can be heated to about 70 ° C. if desired. The reaction time is about 0.5 to 6 hours. After the reaction, the ion-exchange resin is removed by an ordinary means to obtain an aqueous solution of the free drug substance. The drug-resin complex can be produced by adding an ion-exchange resin having a predetermined particle size and a degree of crosslinking to the above aqueous solution and reacting them. The reaction is usually performed by stirring at room temperature for 0.5 to 3 hours.

The resinate thus obtained may be covered with a water-permeable polymer film. Examples of the water-permeable polymer film include a sustained-release film that uniformly releases a drug, an enteric film that suppresses drug release for a certain period, and the like.
A biocompatible water-permeable polymer such as a cellulosic polymer or an acrylic polymer is selected. Specific examples thereof include cellulosic polymers such as ethyl cellulose, nitrocellulose, benzyl cellulose, hydroxypropyl cellulose, and cellulose acetate, and acrylic polymers such as polyacrylate, polymethacrylate, and aminoalkyl methacrylate. In particular, aminoalkyl methacrylate copolymers are advantageously used as sustained release coatings. Further, the water-permeable polymer film may be a coating of the entire surface of the resinate depending on the purpose,
It may be partially coated. The coating with such a water-permeable polymer is one type of organic solvent capable of dissolving the polymer, such as ethanol, toluene, chloroform, methyl ethyl ketone, methylene chloride, isopropanol, cyclohexane, methanol, ethylene chloride, dimethylformamide, ethyl acetate, etc. Alternatively, two or more kinds are mixed and used. Further, water may be added to these solvents and mixed solvents for use.

In addition, a stabilizer such as a plasticizer or an antioxidant may be added in any amount. Examples of the plasticizer include dibasic acid esters such as phthalic acid esters, glycol esters, fatty acid esters, polyethylene glycol, surfactants, glycerin and derivatives thereof. Further, as the antioxidant, 2 (3) -t-butyl-4-hydroxyanisole (BHA), 3,5-di-t-butyl-
Examples thereof include 4-hydroxytoluene (BHT), tocopherol acetate, tocopherol, ascorbic acid and its derivatives. For example, when the water-permeable polymer is an acrylic polymer, it is dissolved in methylene chloride, chloroform, etc., and the drug-resin complex is added and suspended therein. Microcapsules are produced from this suspension by a spray drying method which is a physical or mechanical production method. Another method is to dissolve the polymer in a good solvent,
To this, for example, a phase separation agent selected from polybutadiene, polydimethylsiloxane, phenylmethylsiloxane, methacrylic polymer, etc. is added in an arbitrary amount, a poor solvent is added with stirring, and a physicochemical method, that is, a phase separation method Capsules can be manufactured. Furthermore, the microcapsules can be produced by, for example, a chemical method such as an interfacial polymerization method. The particle size of the sustained-release microcapsules obtained by either method is 5 to 1,000.
The thickness is preferably μm, and particularly preferably 10 to 300 μm.

The crude drug extract contained in the preparation of the present invention includes:
A herb, which has various medicinal effects, is extracted with an aqueous solvent such as water, alcohol, or a mixed solution thereof, or an organic solvent such as acetone or ether, a decoction, an extract, a flow extract, a tincture, and the like. In the present invention, the type of crude drug to be used is not particularly limited, and specific examples thereof include a medicinal part of a plant such as ephedra, nantenjitsu, spruce, carrot, ondi, licorice, kyokyou, senega, fennel, gooh. , Mesophyll, loquat, and the like for medicinal purposes in animals, extracts of Acacia catechu, and the like. When the aqueous suspension preparation is an antitussive expectorant, ondi, senega, and kyokyo are preferable, but not limited thereto. These crude drugs are
You may mix and mix 1 type or more.
When the ions derived from the crude drug component in the crude drug extract adversely affect the release of the drug, the crude drug extract, which is obtained by adding a treatment step with an ion exchange resin to the purification of the crude drug extract, is used. In this case, the relationship between the exchange capacity A (eq) of the resinate or the coated resinate mixed with the crude drug and the ion equivalent B (eq) of the ionic substance contained in the crude drug mixed is F = B (eq) / When A (eq), F is 0 ≦ F ≦ 0.3, preferably 0 ≦ F ≦ 0.2, more preferably 0 ≦ F ≦ 0.1. Perform processing. As a specific method for treating the crude drug component with an ion exchange resin, a column of a strongly acidic cation exchange resin and a strongly basic anion exchange resin is prepared according to a conventional method, and a liquid extracted from the crude drug is sequentially passed through ( Column chromatography), or
There is a method in which a crude drug extract, a strongly acidic cation exchange resin and a strongly basic anion exchange resin are put in the same container and stirred. In either case, the acidic cation exchange resin uses the H type and the basic anion exchange resin uses the OH type. The amount of the acidic cation exchange resin and the basic anion exchange resin used is not particularly limited with respect to the amount of 1/50 times the amount of the drug substance and the upper limit, preferably 1/10 times to 20 times.
Double, and more preferably 1/4 to 5 times. The method for treating the crude drug is not limited to the method using the above ion exchange resin, and may be a charge-retaining substance (for example, an ion exchange cellulose, an ion exchange dextran, an ion exchanger such as an ion exchange agarose, an ion exchange membrane, etc.) Applying the electroseparation method that uses the principle of electrophoresis, the method of adding a substance that has a small solubility product with the ions to be removed and separating it by precipitation, the method of removing it by heat treatment, the method of separating using the molecular sieving effect, etc. It is possible to do so, and it is also possible to combine a plurality of these methods.

The formulation of the present invention can be obtained by blending the crude drug extract with the drug ion-exchange resin resinate obtained as described above. Here, the resinate may be coated with a controlled release membrane. The resinate and the coated resinate may be mixed and blended. It is one of the preferred embodiments from the viewpoint of ingestability to produce the preparation of the present invention in the form of an aqueous suspension preparation, but in this case as well, the resinate and the coated resinate are mixed as dispersed particles to be mixed with the crude drug extract. You may mix it. As the aqueous solvent, purified water or the like prescribed by the Japanese Pharmacopoeia may be used, and if necessary, a suspending agent, a pH adjusting agent, a preservative, a coloring agent, a flavoring agent and the like can be added in appropriate amounts. As the suspending agent, xanthan gum, locust bean gum, guar gum, pullulan, natural thickeners such as tragacanth gum and semi-synthetic thickeners such as methylcellulose, synthetic thickeners such as polyvinylpyrrolidone, as a pH adjuster. Is citric acid, tartaric acid,
Malic acid, acetic acid, oxalic acid, benzoic acid, tannic acid, lactic acid,
Gluconic acid, fumaric acid, sorbic acid, erythorbic acid,
And its salts, as a flavoring agent, sucrose, fructose,
Lactose, sorbitol, xylitol, mannitol, glycerin, corn syrup, fructose corn syrup, reduced maltose and the like, and preservatives include benzoic acid, paraoxybenzoic acid esters, sorbic acid, dehydroacetic acid, chlorhexidine, chlorobutanol and the like. However, one or more of these may be blended. Furthermore, a nonionic drug may be added to the aqueous solvent,
A substance which is insoluble in the aqueous solvent may be added.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described more specifically with reference to the following Reference Examples, Comparative Examples and Examples. Reference Example 1 i) Preparation of methylephedrine resinate After dissolving 14 g of methylephedrine hydrochloride in 150 ml of 60% methanol solution, anion exchange resin (O
H type; Diaion SAN1 (manufactured by Mitsubishi Kasei)) 70g
Was added and stirred for 1 hour. After this, the slurry is filtered off and the ion-exchange resin filtered off is added to 300 ml of 60%.
Wash with a methanol solution and mix the washing solution with the previous filtrate to 60%
It was made up to 500 ml with a methanol solution. The total content of the hydrochloride and the free base in 500 ml of this solution was determined by high performance liquid chromatography (HPLC) by the titration method. Methylephedrine as the hydrochloride was not observed, and 100% free salt was obtained. Had been converted. The content was 13.8 g in terms of methylephedrine hydrochloride, which was 9
The recovery rate was 8.6%.

Next, 450 ml of this solution was added to a cation exchange resin (H having a divinylbenzene content of 8% (crosslinking degree of 8%)).
Type; Diaion SKNUPC (Mitsubishi Kasei) 24.
3 g (the amount of adsorption of methyl ephedrine was 90% of the theoretical saturated adsorption amount of the ion exchange resin) was added, and the mixture was stirred and reacted for 1 hour. After the reaction, the resinate was collected by filtration and dried. When methyl ephedrine in the filtrate after the reaction was measured, it was not detected. Therefore, the total amount of the free base type methylephedrine in the solution is bound to the ion exchange resin. ii) Preparation of coated resinate Methylephedrine resinate obtained in i) above 2.
8g to 5ml of methylene chloride Aminoalkylmethacrylate copolymer RS (Eudragit RS100
(Manufactured by Roehm Pharma)) 1 g was dispersed in a dissolved solution. This slurry was spray dried to obtain microcapsules. The sustained-release property of methylephedrine from the obtained microcapsules was evaluated by dissolution test (JP XI paddle method: the eluent was 0.2M NaCl containing 0.05% Tween80).
As a result of evaluation using a solution (500 ml), it showed a good sustained release property, and it was observed by a scanning electron microscope after the dissolution test that the microcapsule film had a so-called rupture such as crack or breakage.
Was not observed at all.

Reference Example 2 i) Preparation of dihydrocodeine resinate After dissolving 10 g of dihydrocodeine phosphate in 250 ml of 50% ethanol solution, 30 g of the same anion exchange resin (OH type) as in Reference Example 1 was added to this solution and stirred for 2 hours. I did. Then, the slurry is filtered off, and the ion-exchange resin filtered off is washed with 300 ml of 50% ethanol solution, the washing solution is mixed with the above filtrate, and the mixture is washed with 50% ethanol solution to 500%.
ml. The total content of phosphate and free base in 500 ml of this solution was determined by high performance liquid chromatography with the titration method to determine the content of free base, and dihydrocodeine as the phosphate was not observed, and it was converted to 100% free base. Was there. The content was 9.8 g in terms of dihydrocodeine phosphate, and the recovery rate was 98.0%. Next, 450 ml of this solution was added to a cation exchange resin (H type; Diaion SK) having a divinylbenzene content of 8% (crosslinking degree of 8%).
NUPC (manufactured by Mitsubishi Kasei) 25.69 g (the adsorption of dihydrocodeine is 85 of the theoretical saturated adsorption amount of the ion exchange resin)
%) Was added and the mixture was stirred and reacted for 1 hour. After the reaction, the resinate was collected by filtration and dried. On the other hand, when dihydrocodeine in the filtrate was measured, it was not detected. Therefore, the total amount of the free base type dihydrocodeine in the solution is bound to the ion exchange resin.

Ii) Preparation of the coated resinate The dihydrocodeine resinate 3.3 obtained in i) above.
g to 8 ml of acetone aminoalkyl methacrylate copolymer RS (Eudragit RS100 (Roehm P
harma)) 0.8 g and aminoalkyl methacrylate copolymer RL (Eugiragit RS100L)
0.2 g was dispersed in the dissolved solution. This slurry was spray dried to obtain microcapsules. The sustained release property of dihydrocodeine from the obtained microcapsules was determined by a dissolution test (JP XI paddle method: the eluate was 0.05%).
As a result of evaluation using a 0.2M NaCl solution containing Tween 80 (500 ml), a good sustained release property was obtained, and by observation with a scanning electron microscope after the elution test, the occurrence of so-called rupture such as cracking or breaking of the microcapsule coating was observed. , Was not recognized at all.

Reference Example 3 i) Preparation of methyl ephedrine / dihydrocodeine mixed resinate A free base solution of dihydrocodeine phosphate and methylephedrine hydrochloride was used as an anion exchange resin (OH type) according to Reference Examples 1-i) and 2-i). Used to prepare each. Next, both free base solutions were mixed with a cation exchange resin (the same as in Reference Examples 1 and 2) so that the molar ratio of the mixture was dihydrocodeine: methylephedrine = 17.8: 82.2, and the bound drug was adsorbed. The amount is 95 of the theoretical saturated adsorption amount of the ion exchange resin.
% To prepare a resinate. After the reaction, the resinate was collected by filtration and dried. On the other hand, when dihydrocodeine and methylephedrine in the filtrate were measured, they were not detected. Therefore, the free base type dihydrocodeine and methylephedrine in the solution are all bound to the ion exchange resin. ii) Preparation of coated resinate 40 g of the dihydrocodeine-methylephedrine-containing resinate obtained in i) above was mixed with methylene chloride 66.
Aminoalkyl methacrylate copolymer RS (Eudragit RS10 in 7 ml and 26.7 ml of 50% ethanol)
0 (manufactured by Roehm Pharma)) was dispersed in the solution. This slurry was spray dried to obtain microcapsules. The sustained release properties of dihydrocodeine and methylephedrine from the obtained microcapsules were evaluated by the dissolution test (JP X
II Paddle method: However, the eluate was evaluated by using 0.2M NaCl solution containing 0.05% Tween 80 (900 ml), and as a result, good sustained release was shown.

Comparative Example 1 Method) A resinate containing dihydrocodeine and methylephedrine was prepared in the same manner as in Reference Example 3-i), added to each of the following formulations, and an aqueous suspension preparation was prepared according to a conventional method. [Table 1]. Preparation of each formulation, 5 ℃, 25 ℃, 4
It was stored at 0 ° C. and 60 ° C. for 1 week, and the drug released from the resinate was quantified. The quantification was performed by HPLC.

[0018]

[Table 1] * The amount of each crude drug is 1.7g of Onji, 1.3g of kyokyo and 1.3g of Senega in terms of the original drug, which is 2 / the maximum daily dose.
This corresponds to the single dose calculated from the triple volume. 5 for each prescription
When stored at ℃, 25 ℃, 40 ℃, 60 ℃ for 1 week,
The free percentages of dihydrocodeine and methylephedrine from the ion exchange resin are shown in [Table 2]. As shown in [Table 1], the aqueous suspension preparation containing no galenical components (formulation 1) had a release amount of dihydrocodeine and methylephedrine of 10% or less after storage for 1 week at all temperatures. In the aqueous suspension preparations (prescriptions 2 to 4) containing the aqueous extracts of Astragalus sinensis, Kyokyo and Senega, the release amount was obviously increased for all the drugs, and 50 to 6 at all temperatures.
It showed 0% release, indicating that the galenical component significantly affects the binding between the drug and the ion exchange resin.

[0019]

[Table 2] Comparative Example 2 Method) A resinate containing dihydrocodeine and methylephedrine was prepared according to the above Reference Example 3-i) and blended in each of the following formulations [Table 3]. Formulation 1 is an aqueous suspension formulation containing no galenical ingredients, Formulation 2 is an Onji aqueous extract, and Formulation 3 is an kyokyou aqueous extract.
Formulation 4 was an aqueous suspension formulation containing a Senega aqueous extract. Each formulation was stored at 40 ° C. for up to 3 weeks and the drug released from the resinate was quantified by HPLC. The release rate (%) of dihydrocodeine and methylephedrine from the ion exchange resin for each formulation is shown in [Table 4].

[Table 3] * The amount of each crude drug is 1.7g of Onji, 1.3g of kyokyo and 1.3g of Senega in terms of the original drug, which is 2 / the maximum daily dose.
This corresponds to the single dose calculated from the triple volume. In the aqueous suspension formulation of crude drug component-free formulation 1, the release amount of dihydrocodeine and methylephedrine remained unchanged for up to 3 weeks,
It was around 10%. On the other hand, in the formulations 2 to 4 in which the Onji aqueous extract, the kyoza aqueous extract and the Senega aqueous extract were respectively mixed, both dihydrocodeine and methylephedrine showed 50-60% release in all the formulations.

[0020]

[Table 4]

Comparative Example 3 A resinate containing dihydrocodeine and methylephedrine was prepared according to Reference Example 3-i) and blended in each of the following formulations [Table 5]. Formulation 1 is an aqueous suspension formulation containing no crude drug components, Formulation 2 is an Onji-style extract formulation, Formulation 3 is a Kyokyo-style extract formulation, and Formulation 4 is an aqueous suspension formulation containing a Senega-style extract. It was Each formulation was stored at 40 ° C for 2 weeks to quantify the drug released from the resinate. The quantification was performed by HPLC.

[0022]

[Table 5] * The amount of each crude drug is 1.7g of Onji, 1.3g of kyokyo and 1.3g of Senega in terms of the original drug, which is 2 / the maximum daily dose.
This corresponds to the single dose calculated from the triple volume. 40 for each prescription
The free% of dihydrocodeine and methylephedrine from the ion exchange resin when stored at 2 ° C for 2 weeks [Table 6]
It was shown to. In the aqueous suspension preparation containing no galenical component of Formulation 1, the free amounts of dihydrocodeine and methylephedrine were around 10%. In Formulations 2 to 4 containing Onji-style extract, Kyoukyo-style extract, and Senega-style extract, respectively, dihydrocodeine and methylephedrine,
All formulations showed 50-60% release. It was shown that the blending of the crude drug significantly affects the binding between the drug and the ion exchange resin not only in the aqueous extract but also in the flow extract.

[Table 6]

Example 1 Treatment Method of Onji Water Extract Using Ion Exchange Resin and Confirmation of Saponin 1) Preparation of Crude Drug Extract Liquid 700 ml of deionized water was added to 100 g of chopped Onji,
Extraction was performed under stirring at 50 ° C. for 90 minutes. Solid-liquid separation was performed by sieving, and the residue was washed with 300 ml of deionized water. The extract and the washing solution were combined and filtered with a filter paper to obtain 836 ml of a filtrate. 2) Preparation of water extract and saponin fraction A crude drug extract solution containing 10 g of the original drug was freeze-dried to obtain 1.7 g of the water extract (extract yield 17%) (A). A crude drug extract containing 40 g of the original drug was added to n-butanol 10
The extract was extracted three times with 0 ml, and the obtained extract was concentrated under reduced pressure to obtain 1.5 g of a water-extracted saponin fraction (yield 3.75%, converted to the original drug) (B). Cation exchange resin (H type; Diaion SKNUP)
C (Mitsubishi Kasei)) and anion exchange resin (OH type; Diaion SAN1 (Mitsubishi Kasei)) 12.5g inner diameter 12
mm column, each packed with 50 g of drug substance
The crude drug extract (418 ml) was passed in order from the cation exchange resin column to the anion exchange resin column. The column was then washed with deionized water and combined with the previous flow-through to give 465 ml of process liquid. The treatment liquid for 10 g of the original drug was freeze-dried to obtain 1.6 g of water extract (treated) (C) of extract yield 16%. N-Butanol 1 with 40 g
The extract was extracted 3 times with 00 ml, and concentrated under reduced pressure to obtain 1.2 g of a water extract (treated) saponin fraction (yield 3.00%, converted to the original drug) (D).

3) Saponin qualitative test The saponin qualitative test was performed on each sample obtained in the above 2) by the following thin layer chromatograph (TLC). 2) above on a thin layer plate (Kieselgel 60F ₂₅₄ ; Merck)
(A), (B), (C) and (D) obtained in step (4) were dissolved in a 20% methanol solution and spotted, and a developing solvent (first liquid: chloromethane: methanol: water (64:50: 10); second
Liquid: n-butanol: acetic acid: water (4: 1: 5)) about 80m
After developing, spray Kieselgel reagent (1 ml of 50% ethanol / sulfuric acid solution and 10 ml of 2% p-hydroxybenzaldehydemethanol solution just before use) as a coloring reagent, and heat on a hot plate at 100 ° C for 5 minutes. Colored. As a result, saponin was confirmed in all. 4) Effect of treated water extract on ion exchange resin 825 ml of the crude drug extract obtained according to 1) above is used in 25 g (wet) of strongly acidic cation exchange resin (1/4 times the amount of the original drug).
Then, the column was washed with deionized water, and both were combined to obtain 900 ml of a treatment liquid. Exactly 1000 ml of this was prepared with deionized water, and then divided into 5 equal parts (2.
0g equivalent), each with a strong acid cation exchange resin 5,1
Five strong acids used after passing through a column packed with 0, 20, 40 and 80 g (wet) (equivalent to 1/4, 1/2, 1, 2, 4 times the amount of the original drug, respectively) The cation exchange resin column was washed with 50 ml of 1N NaOH and then with deionized water until the passing solution became neutral, and the resin adsorbate was recovered. After acidifying the recovered solution with hydrochloric acid, add 1/3 of n-butanol to
It was extracted twice to obtain a recovered ion-exchange resin. The amount of saponin in the resin adsorbate was confirmed by TLC described in 3) above. As a result, saponin was not found regardless of the amount of ion exchange resin used. Therefore, it was proved that the galenical component was not adsorbed to the ion exchange resin by the treatment with 1/4 times the amount of the crude drug.

Example 2 Treatment of Kyokyo Aqueous Extract Using Ion Exchange Resin and Confirmation of Saponin 1) Preparation of Crude Herbal Extract According to Example 1, 100 ml of chopped Kyokyo was prepared to prepare 700 ml of Kyokyo extract. It was 2) Preparation of water extract and saponin fraction Using the kyoto extract obtained in 1) above, Example 1-
The following treatments were obtained by each treatment described in 2). 3.7 g of Kyokyo water extract (extract yield 37%); 1.0 g of Kyokyo water extract saponin fraction (2.5% yield)
%, Converted value to crude drug); Kikyo water extract (treated) 3.2 g (extract yield 3)
7%); Kyokyo water extract (treated) saponin fraction 0.6 g
(Yield 1.5%, converted value to crude drug); 3) Qualitative test of kyokusaponin According to the TLC test described in Example 1-2), the qualitative test of kyokusaponin for each sample obtained in 2) above. As a result, the saponin was confirmed in all. In this test, Platycodin D was used as a standard of kyokusaponin.

Example 3 1) Preparation of Senega water extract To 70 g of crude drug (diced), 490 ml of deionized water was added, and the mixture was extracted with stirring at 50 ° C. for 1.5 hours. The extract and the residue were separated by filtration, washed with 210 ml of deionized water, and the extract and the wash were combined and concentrated under reduced pressure. A soft extract was obtained due to the concentration operation (extract yield 32.7 g, extract yield 21.6).
%). 2) Treatment with ion-exchange resin The same operation as in 1) above was performed on 130 g of crude drug (diced), the extract solution and the washing solution were combined, and 60 g (wet wet resin) of each of the strong-acid and strong-basic ion-exchange resins in that order. ) Was passed through the column at a rate of 20 ml / min. After passing, it was freeze-dried and water extract (treated) 13.8 g (yield 0.42)
%, Converted value to original drug).

Example 4 1) Preparation of kyoto-style extract 25 g (v / v)% ethanol 30 per 100 g crude drug (diced)
0 ml was added and the mixture was left standing at room temperature for 2 days. Filter the leachate to 16
7 ml was obtained. The filtrate was concentrated under reduced pressure, ethanol was distilled off, and then freeze-dried to obtain a kyokyo-ryu extract (extract yield 42.3).
%). 2) Treatment with ion-exchange resin The same operation as in 1) above was performed on 200 g of crude drug (diced), and the leachate was depressurized to distill off ethanol. Then, in the order of strong acid and strong basic ion exchange resin, 70 g each
After passing through a column filled with (wet) at a rate of 20 ml per minute, lyophilization was performed to obtain a kyoto-style extract (treated) (extract yield 0.47 g, converted value to the original drug).

Example 5 1) Preparation of senega flow extract 10 (v / v)% ethanol 700 per 70 g of crude drug (diced)
ml was added and the mixture was left standing at room temperature for 24 hours. The leachate was filtered, the residue was washed with 10 (v / v)% ethanol, combined with the above filtrate to 875 ml, and concentrated under reduced pressure to give a soft extract (extract yield 27%). 2) Treatment with ion-exchange resin The same operation as in 1) was performed on 130 g of crude drug (diced), the leachate and the washing solution were combined, and ethanol was distilled off under reduced pressure. Then, after passing through a column filled with 60 g (wet) of strong acid and strong basic ion exchange resin in this order at a rate of 20 ml / min, the flow-through solution is freeze-dried to obtain a Senega flow extract (treated). Obtained (extract yield 9.8%, value converted to crude drug).

Example 6 Preparation of Onji Flow Extract In the same manner as in Example 5, onji flow extract (extract yield 2
3.3%) and treated Onji flow extract (extract yield 1
Both were obtained as freeze-dried powders (0.9%, converted value to the original drug).

Example 7 A resinate containing dihydrocodeine and methylephedrine was prepared according to Reference Example 3-i) and blended in each of the following formulations [Table 7]. Formulation 1 is an aqueous suspension formulation containing no galenical ingredients, Formulation 2 is an aqueous suspension formulation containing Ondi aqueous extract treated with an ion exchange resin, and Formulation 3 is an kyokyou aqueous solution treated with an ion exchange resin. Aqueous suspension formulation containing the extract, Formulation 4 was an aqueous suspension formulation containing the Senega aqueous extract treated with an ion exchange resin. Each formulation was stored at 40 ° C for up to 3 weeks, and the drug released from the resinate was HP-treated over time.
It was quantified by LC.

[0031]

[Table 7] * The amount of each crude drug is 1.7g of Onji, 1.3g of kyokyo and 1.3g of Senega in terms of the original drug, which is 2 / the maximum daily dose.
This corresponds to the single dose calculated from the triple volume. It has been confirmed that the treatment does not affect saponin. 4 for each prescription
Dihydrocodeine when stored at 0 ° C for up to 3 weeks,
The release rate (%) of methylephedrine from the ion exchange resin is shown in [Table 8]. In the aqueous suspension preparation of Formulation 1 containing no crude drug component, the free amounts of dihydrocodeine and methylephedrine remained unchanged for up to 3 weeks and were around 10%. In the aqueous suspension preparation containing the aqueous extract of the crude drug treated with the ion exchange resin of the formulations 2 to 4, the formulation 1
The release amount was similar to that of the above-mentioned case, and showed an effect of remarkably improving the release of the drug, as compared with the aqueous crude drug extract of the comparative example 2 which was not treated with the ion exchange resin and compounded.

[Table 8]

Example 8 A resinate containing dihydrocodeine and methylephedrine was prepared according to Reference Example 3-i) and blended in each of the following formulations [Table 9]. Formulation 1 is an aqueous suspension formulation containing no galenical components, and Formulation 2 is an aqueous suspension formulation containing an Onji flow extract treated with an ion exchange resin.
Formulation 3 was an aqueous suspension formulation containing the zelkova flow extract treated with the ion exchange resin, and Formulation 4 was an aqueous suspension formulation containing the Senega flow extract treated with the ion exchange resin. Each formulation was stored at 40 ° C. for 2 weeks and the drug released from the resinate was quantified by HPLC over time.

[0033]

[Table 9] * The amount of each crude drug is 1.7g of Onji, 1.3g of kyokyo and 1.3g of Senega in terms of the original drug, which is 2 / the maximum daily dose.
This corresponds to the single dose calculated from the triple volume. It has been confirmed that the treatment does not affect saponin. 4 for each prescription
The free% of dihydrocodeine and methylephedrine released from the ion exchange resin when stored at 0 ° C. for 2 weeks is shown in [Table 1].
0]. In the aqueous suspension preparation containing no galenical component of Formulation 1, the free amounts of dihydrocodeine and methylephedrine were around 10%. The aqueous suspension preparations containing the flow extract of the crude drug treated with the ion exchange resins of the prescriptions 2 to 4 showed the same free amount as in the case of the prescription 1 and were not treated with the ion exchange resin of the comparative example 3. Compared with the blended crude drug extract, it showed an effect of remarkably improving drug release.

[Table 10]

Example 9 A resinate containing dihydrocodeine and methylephedrine and particles obtained by applying a sustained-release film (aminoalkylmethacrylate) were mixed in the same manner as in Reference Example 3 and blended into the following formulations. [Table 11].
Formulation 1 is an aqueous suspension formulation which is not blended with galenical components and has a sucrose concentration of 55%, and Formulation 2 is a formulation of ondi aqueous extract treated with an ion exchange resin and a sucrose concentration is 55%. % Of the aqueous suspension formulation,
Formulation 3 contains Onji aqueous extract treated with ion exchange resin, 0.15% locust bean gum,
It was an aqueous suspension preparation formulated so that sucrose was 40%. Each formulation was stored at 40 ° C. for 1 month to quantify the drug released from resinate and particles with sustained release membrane on resinate. The quantification was performed by HPLC.

[0035]

[Table 11] * The crude drug content is 6.7g of Onji in terms of the original drug and 1
It corresponds to 2 days calculated from 2/3 times the maximum daily amount. It has been confirmed that the treatment does not affect saponin. The free% of dihydrocodeine and methylephedrine from the ion exchange resin after storage at 40 ° C. for 1 month in each formulation is shown in [Table 11]. Releasing of each drug was almost the same in the formulations 1 to 3, and it was revealed that the ondi component can be compounded without affecting the resinate and the coated resinate by treating with the ion exchange resin.

[Table 12]

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Claims (8)

[Claims] 1. A preparation comprising a drug-adsorbed ion exchange resin resinate and a crude drug extract. 2. The preparation according to claim 1, which is an aqueous suspension preparation. 3. The aqueous suspension preparation according to claim 2, wherein the resinate is a resinate coated with a water-permeable polymer film. 4. The aqueous suspension preparation according to claim 3, wherein the crude drug is a crude drug selected from Onji, Senega and Kyoukyo. 5. The aqueous suspension preparation according to claim 2 or 3, wherein the drug is dihydrocodeine or methylephedrine. 6. The aqueous suspension preparation according to claim 3, wherein the water-permeable polymer is an aminoalkyl methacrylate copolymer. 7. A relational expression F = B (eq) / A (eq) [where 0 ≦ F ≦ 0.3] [wherein A (eq) is the exchange capacity of the ion exchange resin resinate onto which a drug is adsorbed. B (eq) represents the ion equivalent of the ionic substance contained in the crude drug extract. ] The manufacturing method of the preparation characterized by mix | blending the crude drug extract containing the quantity of ionic substances represented by these, and the ion exchange resin resinate which adsorbed the drug. 8. The method according to claim 7, which comprises a step of adjusting the amount of ionic substances contained in the crude drug extract with an ion exchange resin.