JPH0225414A - Peroral drug having prolonged action - Google Patents

Abstract

PURPOSE:To obtain a slowly releasing peroral drug having prolonged action by inserting a drug active component in the form of an organic cation between layers of the basic structure of a stevensite-type magnesium sodium phyllosilicate. CONSTITUTION:A stevensite-type magnesium sodium phyllosilicate solely containing Mg, Na and Si as metal components is used as a base agent and a drug active component is integrated into a gap between the layers of the phyllosilicate to obtain the objective material. In the figure, the base agent B has a three-layer structure composed of a tetrahedral layer S of SiO4 an octahedral layer M of Mg(Na)O6 and a tetrahedral layer S of SiO4 and the drug active component D is inserted into the basic three-layer structures in the form of cation. Since the active component of the drug is slowly released by the acid and anion in the digestive fluid, the shock and stomach injury in the drug administration can be decreased.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a long-acting oral preparation, and more specifically, to a long-acting oral preparation, in which an active pharmaceutical ingredient is contained in the form of an organic cation between the layers of the basic structure of stevensite-type sodium magnesium phyllosilicate. The present invention relates to a long-acting oral preparation in which the active pharmaceutical ingredient is gradually released by the acid or acid anion in the digestive juices.

(Prior Art) Conventionally, long-acting oral preparations include hard seratin capsules filled with several types of granules whose release time is adjusted by coating with a fatty film (Smith, Klein and French Co., Ltd. 5 pansule ■), Parent-child tablets with an inner core and an outer layer, with the outer layer dissolving in the gastrointestinal tract and the inner core gradually eroding from the surface; others are covered with drug microcapsules, and the drug is gradually released through the microcapsule membrane. What is done is known.

(Problems to be solved by the invention) However, most of the conventional long-acting oral preparations are in the form of tablets or capsules, and their manufacturing is more complicated than that of ordinary drugs. It had some problems.

In addition, conventional long-acting oral drugs are designed to release the active ingredient of the drug based mainly on the elapsed time from the time of oral administration, so the active ingredient does not necessarily remain in the target organ. Another problem was that it was not always released.

Therefore, the object of the present invention is to have a sustained release property of active pharmaceutical ingredients in the gastrointestinal tract, a long-lasting medicinal effect, a flavor-correcting and odor-correcting property, and a long-lasting drug that can be used in any dosage form. Oral preparations are available.

(Means for Solving the Problems) According to the present invention, a metal component is incorporated in the form of an organic cation between a stevensite-type sodium magnesium phyllosilicate consisting essentially of magnesium, sodium, and silicon, and a layer of the sodium magnesium phyllosilicate. Provided is a long-acting oral preparation characterized by comprising an active pharmaceutical ingredient.

(Function) The long-acting oral preparation of the present invention is characterized by using stevensite-type magnesium sodium phyllosilicate (hereinafter simply referred to as synthetic stevensite) as a base whose metal components are substantially only magnesium, sodium, and silicon. This synthetic stevensite has a 5104 tetrahedral layer-
Mg(Na)06 octahedral layer 310 It has a basic layer structure of 4 tetrahedral layers, and has a layered structure in which this basic layer structure is laminated in the C-axis direction.

The Mg(sa)O6 octahedral layer that exists in the middle of the basic layer means that some of the Mg atoms in this octahedral layer are replaced with Na, and the remaining part is vacant. do. Furthermore, some other Mg atoms may be substituted with hydrogen atoms. Na ions are present between the laminated layers of the basic layer structure to compensate for the lack of valence charge due to the Mg atoms being substituted with Na and the remaining Mg atoms being vacant positions. are doing. This Na
Ions have ion-exchange properties with organic cations, and the active pharmaceutical ingredients are easily incorporated between the laminated layers in the form of organic cations.

In FIG. 1 schematically showing the long-acting oral preparation of the present invention,
Base B has a 5in4 tetrahedral layer S, Mg(Na)0. It consists of a three-layer structure of an octahedral layer M and a 5in4 tetrahedral layer S, and the active drug ingredient is incorporated in the form of a cation between this basic three-layer structure. When this long-acting oral preparation is administered into the gastric fluid, a part of the active drug ingredients are solubilized and eluted by reaction with chloride ions, and the basic three-layer structure itself also reacts with hydrochloric acid, forming amorphous silica. It is broken down into the forms of magnesium chloride and sodium chloride, with the result that all the active pharmaceutical ingredients are leached into the gastric juices. The reaction between this basic three-layer structure and hydrochloric acid generally proceeds gradually over several hours, although it depends on the size of the crystals of the basic three-layer structure, so that the release of the active drug ingredient also occurs gradually over several hours.

Therefore, the long-acting oral preparation of the present invention has the advantage that sustained drug efficacy can be obtained with only one oral administration, and there is no shock or gastric damage that would occur if the active drug ingredients were dissolved all at once. It will be done. In addition, the component used as the base material is magnesium silicate, which is conventionally widely used as an excipient, coating agent, lubricant, etc., with part of it replaced with sodium, so it is virtually harmless. Moreover, it shows the effect of reducing gastric damage during drug administration.

(Preferred Embodiment of the Invention) Synthetic stevensite The synthetic stevensite used in the present invention substantially has the following formula (1), where X and y are a number of 2 or more under the condition that x + y < 3. , y is a number from O to 01, and 2 is a number greater than O and up to 1.0.

The chemical composition of formula (1) is determined as follows.

From the compositional analysis of the synthetic mineral, the number of Mg atoms (X) and the total number of Na atoms (y+z) per Si4 atom are determined. Next, the number of Na atoms (y) present in the layer is determined from a composition analysis of the synthetic mineral whose cations are ion-exchanged with ammonium ions. In this way, the number of atoms (x, yZ) in formula (1) can be determined. Here, Z is simply the number of exchangeable Na atoms existing between the layers and the attached N.
It is the sum of the number of atoms (α) of a.

In the present invention, X+y is smaller than 3, and particularly preferably in the range of 2 or more. X has a value of 2 or more within the range that satisfies this condition, and is preferably in the range of 2.6 to 28. y also has a value of 0 to 01 within the range that satisfies the above conditions, and is particularly preferably in the range of 0 to 005. The value of O generally ranges from 0 to 1. Theoretically, the value of the cation exchange capacity (z-α) is expressed by the following formula % formula % (2) where α simply represents the number of Na atoms attached.

It is expressed as

The cation exchange capacity of the synthetic stevensite used in the present invention is generally 0.20 to 1.58 mEquivalent (
meq)/g, especially 0.2 to 1. o meq/g. Due to this ion exchange capacity, it has the function of an ion exchange material for various cations or an ionic adsorbent for cationic substances, so it can absorb the active ingredients of drugs as described below in the form of organic cations. The exchangeable Na atoms located between the layers are exchanged, and the active ingredient of the drug is incorporated into the synthetic steven site.

The synthetic stevensite used in the present invention is obtained by subjecting an aqueous mixture containing basic magnesium carbonate and a combination of sodium silicate or amorphous silica and sodium hydroxide to a hydrothermal treatment.

By selecting basic magnesium carbonate as the magnesium raw material, stevensite can be synthesized.
Furthermore, production with high yield and high purity becomes possible. Any basic magnesium carbonate can be used, but if magnesium carbonate, magnesium hydroxide, or a mixture thereof is used, production of stevensite in high yield and purity cannot be expected. As the basic magnesium carbonate, it is particularly desirable to use hydromagnesite, which has a chemical composition represented by the following formula 4% (3) and an ASTM No 25-5
It has an X-ray diffraction image assigned to No. 13.

As the raw material for the St and Na components, a sodium silicate aqueous solution is advantageously used, but combinations of amorphous silica and sodium hydroxide and amorphous silica and sodium silicate can also be used. As sodium silicate, sodium silicate of the formula % (4) is used, where n is a number from 1 to 5, in particular from 2.0 to 3.5. Further, as the amorphous silica, silica hydrosil, hydrogel, xerogel, wet amorphous silica, vapor phase amorphous silica, etc. are used.

The ratio of basic magnesium carbonate to sodium silicate or amorphous silica and sodium hydroxide is preferably such that the atomic ratio of magnesium to silicate is 3=7 to 55 (Mg:Si). Also, it is preferable to use more than the stoichiometric amount of sodium. When sodium silicate is used, an excess of sodium will be present in the system even without the addition of special sodium hydroxide.

Prior to the hydrothermal reaction, the raw materials used are mixed as uniformly as possible to form a homogenized aqueous slurry.
Desirable from the standpoint of improving yield and purity. This homogeneous mixing is preferably carried out under strong shear stirring, and for this purpose, a high-speed staged mixer, ball mill, sand mill, colloid mill, ultrasonic irradiation, etc. can be used. The solids concentration in the aqueous mixture is generally preferably in the range 1 to 30% by weight, particularly 5 to 15% by weight.

In addition, a small amount of sodium silicate has the effect of uniformly dispersing basic magnesium carbonate in an aqueous solution, so when using sodium silicate as a raw material, it is necessary to disperse basic magnesium carbonate with sodium silicate in advance. Even if you add the remaining ingredients after mixing the slurry,
The purpose of uniform mixing can be achieved. The sodium silicate used in this case is preferably used in an amount of 0.01 to 10% by weight based on the aqueous slurry.

This mixture is placed in an autoclave and subjected to hydrothermal treatment. The hydrothermal treatment conditions may be relatively mild compared to conventional methods, for example, generally at a temperature of 100 to 300°C, particularly 150 to 200°C, and at a temperature of 0 to 100 kg/c.
It is preferable to carry out the reaction under a pressure of m2 (gauge), especially 6 to 40 kg/cm2G. Reaction time is generally 0.5 to 20
Time order is sufficient. The synthetic stevensite obtained by the reaction is separated from the mother liquor, washed with water, and dried to obtain a product.

Pharmaceutical Ingredients The active ingredients of the pharmaceutical ingredients used in the present invention exist in the form of organic cations, and generally exist in the form of acid addition salts such as hydrochloride, bromate, and sulfate. Suitable examples include, but are not limited to:

Central nervous system drugs: Chlorpromazine hydrochloride, thioridazine hydrochloride, imibramine hydrochloride, amitributyline hydrochloride, Peripheral nervous system drugs: scopolamine hydrobromide, methylbenactidine bromide, papaverine hydrochloride, trihexyphenidyl hydrochloride, Allergy drugs (antihistamines) Diphenhydramine hydrochloride, chlorpheniramine maleate, sibbutadine hydrochloride, alimeazine tartrate, promethacin hydrochloride, cardiovascular drugs etylefrine hydrochloride, procainamide hydrochloride, quinidine sulfate, propranolol hydrochloride, guanethidine sulfate, hytaralazine hydrochloride, insorbide nitrate, prenylamine lactate, Herabamil hydrochloride, respiratory drugs dextromethorphan hydrobromide, amproxol hydrochloride, ephedrine hydrochloride, di-methylephedrine hydrochloride, gastrointestinal drugs berberine chloride, atropin sulfate, metabolic drugs pyridoxine hydrochloride, hydroxocobalamin hydrochloride, Antibiotics kanamycin sulfate, frasiomycin sulfate, oxytetracycline hydrochloride, lincomycin hydrochloride, polyxin B sulfate, the above drug active ingredients are 0.01 per synthetic steven site.
It can be contained in a range of 50 wt% to 50 wt%, especially 0.1 to 10 wt%, and when fast-acting drug active ingredients are also required, part of the drug active ingredients may be contained in a free form other than intercalation compounds. It may be contained.

In addition, the active pharmaceutical ingredients incorporated between the layers of synthetic smectite are
It is not limited to a single ingredient, and there is no problem in incorporating a plurality of active ingredients as long as their combination is not contraindicated.

Manufacturing method The method for manufacturing the sustained-acting oral preparation of the present invention involves dissolving synthetic stevensite powder in water at a concentration of 0.1 to 10 wt% and swelling it with a high-shear dispersion machine, which varies depending on the chemicals used. is generally a drug ingredient from 001 to 4.
By adding a 0 wt % aqueous solution and stirring at 20 to 100° C. for 1 to 5 hours, the chemical component is incorporated between the layers of the synthetic stevensite in the form of an organic cation. The synthetic stevensite into which organic cations have been incorporated loses its swelling properties and settles, so it is subjected to separation operations such as centrifugation and filtration to remove moisture and dry. agent can be obtained.

The above method is just an example; for example, the synthetic stevensite can be used in the form of a slurry rather than a dispersion, or the drug component can be added in the form of a powder rather than an aqueous solution. The long-acting oral preparation of the present invention can be obtained without impairing the excellent effects of the drug.

Figure 2 of the attached drawings is an X-ray diffraction diagram of synthetic stevensite, and Figure 3 is an X-ray diffraction diagram of a long-acting oral preparation in which berberine chloride is incorporated between the layers of synthetic stevensite according to Example 1.
This is a line diffraction image.

Comparison of these X-ray diffraction images shows that the plane index [001] of the synthetic stevensite is a 9-11 plane spacing, which is a property common to smectites, and the peak intensity is weak. on the other hand,
In the berberine-containing long-acting oral preparation of the present invention, the interval of the plane index [001] is increased and the peak intensity is clear, so it is clear that an organic cation is introduced into the correlation.

The long-acting oral preparation of the present invention may be in a dosage form known per se, such as a solid oral dosage form such as a capsule, granule, pill, powder, tablet, or troche, syrup, suspension, or emulsion. It can be administered orally in the form of a liquid oral dosage form such as. Of course, when formulating, known additives, excipients, binders, thickeners,
A type of lubricant, disintegrant, wetting agent, solvent, solubilizing agent, surfactant, emulsifier, suspending agent, stabilizer, preservative, coloring agent, sweetener, aromatic agent, isotonic agent, buffering agent Alternatively, more than one species can be blended.

The oral dosage varies considerably depending on the type of active pharmaceutical ingredient, but it may be administered in a manner that the active pharmaceutical ingredient is administered at a commonly administered dose known per se.

(Effects of the Invention) According to the long-acting oral preparation of the present invention, since the active ingredient of the drug is chemically supported between the layers of synthetic stevensite, it is hardly released unless it is by anion components such as digestive juices. , exhibits excellent durability. Furthermore, the synthetic stevensite used has fewer impurities and is superior in the amount of drug supported than natural products, so it is possible to obtain a product containing a large amount of active ingredients in a small amount. Furthermore, it can be obtained in powder form and can be molded into any shape.

(Example) Example 1 Commercially available basic magnesium carbonate (TT manufactured by Tokuyama Soda) 14.
5 g (magnesia content: 6 g) is placed in about 150 ml of water, and 54 g of No. 3 sodium silicate (silica content: 12 g) is added and stirred to prepare a dispersion slurry.

This dispersed slurry is placed in an autoclave having an internal volume of 1°C. Hydrothermal treatment is carried out at 170° C. for 5 hours while stirring.

Occasionally exhaust the gas generated during the process. After the reaction was completed, the contents were taken out after being allowed to cool, filtered and dried to obtain 46 g of product.

The cation exchange capacity (C, E, C) of the synthetic stevensite powder obtained by grinding this product with a sample mill is 0.
．． At 38 meq/g, B, E, T specific surface area is 468
m2/g.

Then, as this base material, synthetic Stevensite powder 1.0
Disperse g in 500 ml of distilled water, heat and stir at 50'C to swell. This contains 0.1 berherin chloride.
g was added thereto, and the mixture was further heated and stirred at 90°C for 3 hours. Water was distilled off at 90° C. under reduced pressure to obtain a yellow solid, which was ground in a mortar to a powder of 325 mesh or less to obtain a preparation according to the present invention.

This preparation did not have the characteristic bitterness of berberine chloride. Furthermore, the results of the persistence test shown in Figure 4 show that the amount of helverin chloride released into the simulated gastric fluid increases over time, and therefore, when administered as an oral preparation, the drug's active ingredient It is understood that the drug shows a long-lasting action and effect.

The various test methods used in the present invention are shown below.

1. X-ray diffraction A sample powder dried at 105° C. was measured under the following conditions using a 4036AI model X-ray diffractometer manufactured by Rigaku Denki Co., Ltd.

a. Condition target for X-ray diffraction Cu Filter Old detector SC Voltage 40kVP Current 20mA Count full scale 4000G/S time constant
1 sec scanning speed 1°/min chart speed
1 cm/min radiation angle
1/6゜Slit width 0.3mm Glancing angle 6゜Measurement diffraction angle range 1゜~12゜(2θ) The interplanar spacing (d) is the diffraction angle (2θ) calculated from the midpoint of the half width.
θ) using the following formula.

d = (-) 5in-' (θ) However, λ is the X-ray wavelength 1.542 people 2, BET specific surface area Automatic BET (specific surface area) measuring device (CARLOERBA
Sorptomatic 5eries 1800
).

3. Weigh out 0.20 g of the sustainability test preparation, and use artificial gastric fluid whose temperature was adjusted to a constant 37°C (°゛11th revised Japanese Pharmacopoeia゛p90.19).
83) Pour into 100 ml of test solution 1st solution described by Legal Shoten. After a predetermined period of time under electromagnetic stirring, the solution was sampled into a 10 mm quartz cell, and a υVID manufactured by JASCO Corporation was used.
The temperature of the active drug ingredient released from the formulation into the artificial gastric fluid is measured using an EC650 spectrophotometer under the measurement conditions shown in Table 1.

4. Cation Exchange Capacity (C, E, C) Based on Test Method Tl S-413 published by Japan Foundry Association, Tokai Branch, Inorganic Sand Mold Research Group.

Example 2 Sample No. of the preparation obtained in the same manner as in Example 1 except that the amount of berberine chloride supported on the base synthetic stevensite was varied to 0.2 g and 2.0 g, respectively.
, 2-1 and 2-2, the results are shown in FIG.

As is clear from FIG. 4, it is understood that by increasing the amount of berberine chloride supported, a preparation having both immediate action and long-lasting effect can be obtained.

Example 3 A preparation obtained in the same manner as in Example 1 except that 5 g of papaverine hydrochloride O, and 0.08 g of hydralazine hydrochloride were each supported on the synthetic stevensite base instead of berberine chloride as the active drug ingredient. Sample No. 3~
The results are shown in FIG. 5 for No. 1, No. 3-2. As is clear from FIG. 5, it was found to exhibit persistence similar to berberine chloride.

[Brief explanation of the drawing]

FIG. 1 schematically shows the long-acting oral preparation of the present invention, where S is a 5in4 tetrahedral layer and M is Mg(Na)Os.
The octahedral layer, B represents a synthetic stevensite having a 5-M-5 three-layer structure, and D represents an active drug ingredient. FIG. 2 is an X-ray diffraction image of synthetic stevensite, and FIG. 3 is an X-ray diffraction image of a long-acting oral preparation in which berberine chloride was incorporated between the layers of synthetic stevensite according to Example 1. Figures 4 and 5 show the results of the persistence test of the long-acting oral preparations according to the present invention obtained in each Example, and the numbers in the figures indicate the sample number of each formulation. Patent applicant Mizusawa Chemical Industry Co., Ltd.

Claims (1)

[Claims] (1) Consisting of a stevensite-type sodium magnesium phyllosilicate whose metal components are essentially only magnesium, sodium, and silicon, and a known active pharmaceutical ingredient incorporated in the form of an organic cation between the layers of the sodium magnesium phylosilicate. A long-acting oral agent characterized by: