JPS63162619A - Delayed soluble granule and sustained release complex granule using said granule - Google Patents

Abstract

PURPOSE:To obtain a delayed soluble granule capable of providing sustained release composite granule having stable bioavailability (BAV) characteristics for a long period, by coating the surface of a rapidly soluble granule homogeneously containing a drug, polyvinylpyrrolidone (PVP) based polymer and powerful disintegrating agent with a polyacid enteric substance. CONSTITUTION:A delayed soluble granule, obtained by coating the surface of a rapidly soluble granule homogeneously containing a drug, polyvinylpyrrolidone (PVP) based polymer and powerful disintegrating agent, e.g. crosslinked sodium carboxymethyl cellulose (CMC-Na), with a polyacid enteric substance, e.g. methacrylic acid.ethyl acrylate copolymer, and having an enteric film of a uniform thickness having a complex of the PVP based polymer with the enteric substance formed on the surface part thereof. The above-mentioned granule is capable of disintegrating in a short time after dissolving the enteric film without migration of the drug into the enteric film and extremely reducing dispersion of bioavailability (BAV). The aimed homogeneous sustained release complex tablet having reproducibility and BAV characteristics is obtained by using the afore-mentioned granule with a rapidly soluble granule.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Application Field The present invention relates to slow-dissolving granules having good physical properties and long-lasting composite granules using the same. More specifically, slow-dissolving granules characterized in that they are coated with a drug and a polyvinylpid enteric material, and the surface portion thereof is formed with a complex of the polyvinylpyrrolidone polymer and the polyacid enteric material; The present invention relates to a long-lasting composite granule consisting of slow-dissolving granules of the same type and fast-dissolving granules that are not coated with an enteric coating.

<Prior art> Among the long-acting drug preparations, the surface of ordinary fast-dissolving preparations is coated with (
・When a so-called enteric substance is applied by coating or other method, it exists stably without dissolving in the strongly acidic gastric digestive fluid, but as it moves into the intestinal tract, it disintegrates when it comes into contact with the weakly alkaline digestive fluid IC. - Various methods using so-called enteric-coated preparations that can be eluted have been studied and put into practical use.

For example, there are the following methods. That is, powdered drugs are placed around a rolling core material, and various excipients, binders,
A method of manufacturing a granular preparation by spray coating with a disintegrant, etc., or a powdered drug and various excipients.

It is a method of kneading a disintegrant, a binder, etc. with a quick-drying solvent such as alcohol and extruding it through the pores of a basket to form cylindrical granules.
The formulation is first manufactured.

Next, the table below uses this fast-dissolving preparation as a base material.

A slow-dissolving (enteric-coated) preparation is made by uniformly coating the surface with a solution of an enteric-coated substance using a spray method.

(The fast-dissolving and slow-dissolving preparations obtained.

They are mixed in a specific ratio to form multiple pellets, which are then administered orally. Since early blood concentration is achieved by slowly soluble components, this technique for sustaining drug blood concentration is
In particular, it has been put to practical use in fields such as antibiotics, and has received awards (
For example, see Japanese Patent Application Laid-open No. 139713/1983).

However, in the prior art, l! When coating with a solution of a soluble substance, the film is often applied non-uniformly, with thicker and thinner parts forming in some places. If there is a thin part, naturally that part will be dissolved first, and if intestinal digestive juices enter from this part, the preparation will disintegrate due to swelling of the contents, especially disintegrants and excipients, so it will not be encapsulated. The drug in the granule is released more quickly than in other granules.

Furthermore, even if the film is crack-free immediately after production, if it is stored for a long period of time, it is often observed that the film cracks, probably due to the influence of humidity or mechanical stress.

Therefore, if there is not only uniformity in the film thickness but also defects such as cracks in the film, the disintegration and elution behavior of the granules will be abnormally accelerated, and uniform and reproducible elution characteristics will never be obtained.

Another drawback of the prior art is that while storing the formulation! /
There is a problem that the contents migrate into the cyII-soluble film. The drug in the contents is generally of low molecular weight, and there are many cases in which it migrates relatively quickly into the enteric coating coated on the outside.

Drug migration depends on the material of the enteric coating and the material used.

This differs depending on the compatibility and affinity between the contents and the coating, but this results in the "protective effect of the enteric coating on the contents from gastric digestive juices." Furthermore, as a problem with the conventional technology, One example of this is the lack of disintegrating power of slow-dissolving preparations. Even if the enteric coating is eluted by intestinal digestive fluids, if the contents (i.e., fast-dissolving preparations) are not well eluted into the digestive fluids and are of such a nature that they are gradually dissolved from the outside, No matter how carefully the dissolution and rupture properties of the enteric coating itself are examined, BAV with good reproducibility cannot be obtained. That is, reproducible BAY cannot be expected for a preparation in which the rate-limiting step for absorption into the body from the intestinal tract is not the dissolution of the enteric coat, but the dissolution of the contents.

Therefore, as mentioned above, once the film dissolves, the enteric granules should have good properties (such as disintegration) in a short period of time due to the infiltrating digestive juices. The contents (i.e. fast-dissolving [
8) requires the presence of a strong disintegrant, but there has been almost no systematic study of the strong disintegrant that can be incorporated into enteric-coated fast-dissolving granules.

<Problems to be Solved by the Invention> Problems in which the prior art is incomplete, that is, problems to be solved by the present invention are listed below.

B. The thickness of the enteric coating is not uniform.P. The contents, especially the drug, migrate into the outer enteric coating, increasing the variation in BAY.C. After the enteric coating has dissolved, the IcBA
Increased variation in Y = occurrence of defects such as cracks in the Ii% soluble film, etc., and intensive studies were conducted to solve these problems all at once and economically.

<Means for solving the problem> The surface of the fast-dissolving granules is coated with a polyacid enteric material, and the surface portion is coated with the polyvinylvinylene polymer and the polyacid enteric material. and long-lasting composite granules comprising slow-dissolving granules and fast-dissolving granules not provided with an enteric coating.

The long-lasting composite granule in the present invention is composed of fast-dissolving granules and slow-dissolving granules, and is used by mixing 90 to 10 parts of slow-dissolving granules to io to 90 parts of blood granules. More preferably, it is 20 to 60 parts of fast dissolving granules and 80 to 40 parts of slow dissolving granules. In the fast-dissolving granules used to produce the slow-dissolving granules of the present invention.

One of the essential components is a polyvinylpyrrolidone-based polymer (hereinafter referred to as PvP-based polymer) of a polyvinylbisilidone homopolymer or a polyvinylpyrrolidone-containing copolymer.
Contains.

The fast-dissolving granules of the present invention refer to granules that have not been subjected to any special sustaining treatment or III-solubility treatment, and refer to fine granules and granules produced according to conventional methods.

The fast-dissolving granules of the present invention contain drugs and excipients (usually commonly used lactose, sucrose, cornstarch, etc.).

Powder K consisting of the disintegrant and the above-mentioned disintegrating agent, a binder for binding these powders (PvP polymer is essential in the present invention, but in addition to the above, 1. Powders, oligosaccharides, etc. may be used in combination) to form granules, but this powder is sprayed around the core material, especially the spherical core agent (non-pareil), and a binder is sprayed. Granulation is preferred because uniform spherical granules are obtained.

The PvP polymer of the present invention is used as a binder when producing the fast-dissolving granules of the present invention from finely pulverized powder consisting of a drug, various excipients, and a disintegrant. Usually, the PvP polymer is sprayed as a solution dissolved in an organic solvent so that the content thereof is about 0.5 to xo% based on the amount of powder.

Examples of the PvP polymers used include PVP K-15 with various polymerization degrees, which are sold by General 7 Nilin & Film Co., Ltd. in the United States, BASF Co., Ltd. in West Germany, etc.
,PVP K-301PVP K-60゜PVP K-
90 can be used, but especially PVP with a high degree of polymerization can be used.
Tsuklade such as K-60-IpPVP K-90 will be awarded. Other copolymers such as polyvinyl bipridone/vinyl acetate copolymer and polyvinyl pyrrolidone/styrene copolymer may also be used.

Furthermore, as another essential component of the fast-dissolving granules used to produce the slow-dissolving granules of the present invention, it is necessary to contain a strong disintegrant as described below. As a strong disintegrant, as a result of various studies, we found that low-substituted hydoxyp p-pilcel p-su (manufactured by Shin-Etsu Chemical Co., Ltd.; low-substituted hydroxyp σ-pyle ether of cercese, which has hydroxypyl pyl groups of 5 to !Contains 6 weight SS degrees, L-RP
It is abbreviated as C. ) and croscarmegyes sodium (manufactured by Asahi Kasei Corporation; partially crosslinked sodium carboxymethyl cellulose, trade name: 7 Cudeinlu) were found to be suitable for use.

When these disintegrants come into contact with water, they rapidly swell to several times their own volume within a very short period of time, within a few minutes, and can therefore effectively disintegrate the surroundings. It is sufficient that its content is 1 to 10% in the rapidly dissolving granules.

The slow-dissolving granules of the present invention are granulated by sufficiently drying the fast-dissolving granules granulated as described above, and then coating them with an enteric substance.

As the enteric substance used in the present invention, the following polyacid substances having a large number of carboxyl groups in their molecules are used.

Examples of polyacid materials include methacrylic acid/ethyl acrylate copolymer (Eudragit L-30D, manufactured by Nishi WRa-M 77-Ima Co., Ltd.); Eudragit L or Eudragit S), hydroxypropyl methylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd. + HP
-50t HP-55tHP-558ft), Hydroxypropyl methylcellulose acetate 7 tallate (manufactured by Shin-Etsu Chemical Co., Ltd., As-LGt Al5
-LP, As-MG, As-Ml”.

As-HG, A3-HF, etc.), carboxymethylethyl cellulose (70 manufactured by Indo Santo Co., Ltd.).

Acetic heptatarate cell p-su, polymethyl vinyl ether/maleic anhydride copolymer (manufactured by GAF, USA)
139, AN-169, etc.) may be used.

Among these, Eudragit L, Eudragit S j
HP-55 and the like are preferred materials.

These are coated with a suitable dust dispersing agent. Usually, a solution dissolved in a solvent is coated by a known method such as a spray method.

<Function> In the present invention, the first problem is to improve the uniformity of the coating when coating the surface of the rapidly dissolving granules with an enteric coating. As mentioned above, quick-dissolving granules are usually made up of powdered chain components brought together by a binder and are inherently extremely porous. When spray coating a solution containing a coating agent on such a substrate, it is very likely that the solution will necessarily undergo a spotty process in the substrate. The method is to increase the thickness step by step, and the thickness increases by repeating drying and coating. Therefore, in the early stages, the well-formed film is redissolved by the sprayed solvent, which is a major cause of non-uniform coating. In particular, when the matrix of fast-dissolving granules is not spherical, such as a cylinder, extreme care is required to form a uniform film over the entire surface, which is a major cause of individual differences between workers. It has become.

The inventors of the present invention have conducted extensive research into ways to solve this problem.

In the present invention, the PvP polymer is uniformly contained in the fast-dissolving granules, and the enteric material coated thereon is a polyacid compound containing a large amount of carboxyl groups in the molecule. This is the first essential requirement.

PvP polymers are vinyl polymers with a large number of beerydon rings in their side chains, and are polyfusilad compounds such as polyacrylic acid copolymers.

When it comes into contact with maleic anhydride copolymers, etc., it reacts almost instantaneously and forms a complex (cornplex) that is insoluble in organic solvents.
) is well known to form (Benkutswi, (B@nk1 B-) v Hiemische Lahuitrang (Ch@w, Ztg) 78.41 (1954)
(See) The present inventors focused on this phenomenon and conducted the following model experiment.

A solution of polymethyl methacrylate/polymethacrylic acid copolymer (Eudragitsu L-too) using the same mixed solvent as above was gradually added to a solution of PVP K-90 dissolved in a mixed solvent of Impropatol/methylene chloride. When the solvent was added to the solution, an eight-colored gel-like substance was immediately formed on the contact surface where the liquid came into contact, and it was confirmed that this gel never redissolved even if new solvent was added.

Therefore, when polyacid is actually spray-coated onto the above-mentioned fast-dissolving granules, a similar gelation reaction occurs near the surface, and a thin insoluble layer is first uniformly formed. and.

Since this gel-like substance is not re-dissolved by the polyacid solution coated in the first step, it can effectively prevent the coating liquid from locally enlarging deeply within the granules. As a result, it became possible to obtain an extremely uniform coating film.

In fact, when the obtained enteric granules were divided into two parts and an electron micrograph of the cross section was taken, it was found that an extremely homogeneous film was formed on one surface. For comparison, we made fast-dissolving granules without using PVP, coated the surface with Eudragi L-100 to produce so-called enteric-coated granules, and similarly took and observed electron micrographs. , the uniformity of the enteric coating thickness is Pv
It was considerably worse than when P was included.

The film of the present invention obtained in this way has very little drug migration, does not crack during storage, and is extremely stable over a long period of time, probably because the inner surface is homogeneously covered with a layer of gel-like complex. The elution characteristics could be maintained.

Although the gel-like complex of polyacid and PvP polymer does not dissolve in organic solvents as mentioned above, it is easily redissolved in weakly alkaline water, so it is difficult to function as an enteric coating. No impact.

However, since it is a gel-like substance and is in a dried state, it is necessary to use a strong disintegrant in combination with K in order to fully exhibit its function as a slow-dissolving granule with good reproducibility.

As mentioned earlier, once the polyacid film is dissolved, it is essential that the granules are disintegrated in a short time by the digestive juices contained in the bottle.
This property is particularly required for the slow-dissolving granules of the present invention, and is the second essential requirement of the present invention.

As mentioned above, L-HPC and Acidityl can be suitably used as strong disintegrants.

After examining various disintegrants used in ordinary preparations, we found that in addition to the two items mentioned above, carboxymethyl cellulose calcium (e.g., ECG manufactured by Gotoku Pharmaceutical Co., Ltd.)
505) had relatively good disintegration properties, but it was further coated with a KM-soluble film to form slow-dissolving granules.
It has been found that the enteric coated film cracks when stored at room temperature for a long period of time, making it impossible to meet the object of the present invention.

Slow-dissolving granules based on fast-dissolving granules using L-RPC and Acdituru do not undergo such changes over time and can maintain their properties over a long period of time. Their disintegration power is extremely excellent, and when the fast-dissolving granules are added to the eluate, the granules appear to burst and disintegrate, rather than the cylindrical granules obtained by the meat granulation method.

The most preferred are spherical granules that are nearly perfect spheres produced using a centrifugal fluid coating machine.

When spherical granules are formed, the uniformity of the enteric coating is extremely excellent, and the quality is not affected by differences in the skill of the granulation workers, making it possible to obtain the desired stable quality. In addition, if it is in the form of a rattan granule, it is the most suitable form of the preparation since it is less unevenly distributed in the gastrointestinal tract and has a long-lasting effect.

Furthermore, in the present invention, in addition to the above-mentioned fast-dissolving granules and slow-dissolving granules, it is also possible to combine other slow-dissolving granules with different drug elution behavior to form composite granules of three or more types. It goes without saying that the third component used in this case must also be granules with excellent stability and reproducibility.

The formulation technology of the present invention can be used for essentially any drug that can be administered orally, and can be said to be a particularly useful means for drugs that are highly mobile within the formulation. To list the drugs that can be used as an example, Cef-7 Rexin, Cef-10 Glycine, and Cef-1 Radin! Cephadroxil, ampicillin, 7 moxicillin naciclacillin! Antibiotics such as ceftuxil, chemotherapeutic agents such as nor7jixacin, off0xazine, enoxacin, pipemic acid, and bisimide, antipyretic, analgesic, and antiinflammatory agents such as fenbufen, pranoprofen, flurbiproen, etc. , Pindolor.

Prazosin hydrochloride - antihypertensive agents substituted with meticlane, labetalol hydrochloride, etc., anti-allergy agents such as tranilast, nianidivine, nicardipine hydrochloride,
Cardiovascular agents such as ifenprodil and vinpocetine, urinary and reproductive agents such as frapoxate hydrochloride, and gout treatment agents such as penzbroma-pun and purinol. The present invention is not limited to these types of drugs.

<Examples> Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference Example 1 PVP-90 (GAF Corp. II, USA) was mixed with a mixed solvent of impulpyl alcohol and methicin 1ride (mixed weight ratio: 1).
:1) to create a solution with a concentration of 1.5% (by weight, the same hereinafter). Take this solution in a beaker and add Eudragi L-100 (manufactured by Rohm Pharma, Germany).
Copolymer of methacrylate and methyl methacrylate,
A solution in which copolymerization molar ratio 1:1) was dissolved in the same mixed solvent IC7 at a concentration of 7 was gradually added. A slightly cloudy glue-like substance was immediately formed at the fold interface between both liquids. When the entire liquid was stirred with a glass rod, the entire liquid became glue-like. Even if only the above-mentioned mixed solvent was newly added to this solution, the solution did not return to a homogeneous solution.

Furthermore, when a 5% solution of HP-55 (Shin-Etsu Chemical Co., Ltd. 11) in the same solvent as above was added as a polyfusilad polymer, exactly the same phenomenon was observed.

Centrifugal flow coating machine (7a manufactured by India Industry ■ t C
F-36011 experimental machine) Cranu m with uniform particle size
zkII and transfer it to Jt TS”) pVPK
=9o f) A 1 spherical nucleating agent (non-barrail) was granulated by spraying a 1% aqueous solution and sprinkling with Corn Star+t.

It was dried in warm air at 50°C and then sieved to size the particles. The obtained non-barrel had a spherical shape close to a perfect sphere with an average particle diameter of about 650 pm.

Separately, 7 moxicillin 80, which is a penicillin antibiotic,
(parts by weight, same hereinafter) and 20 parts of corn starch were prepared.

Using the above-mentioned non-barrail as a core material, sprinkle the powder around it, set the slit air temperature to room temperature, and perform PVP.
Granulation was performed by spraying K-90 (IF) i, s% Imp a panol solution. The obtained granules were dried in hot air at 50° C. to remove the solvent to produce fast-dissolving granules.

This was used as a control example. This granule contains 4701F (1i1) per 1.9 reta of amoxicillin. It contains about 1% of PVP K-90.

The thus-obtained granules were mixed with gastric fluid Siminiresilane solution (H1, H1,
2) was used to examine the elution behavior.

On the other hand, five types of disintegrants shown in Table 1 below were added to the powder, and granulation was carried out in the same manner as in the control example in Examples 1 to 2.
Comparative Examples 1 to 3), Comparing the above elution behavior #1. I discussed it.

The additive ratio is 80 parts of drug.

15 parts of corn starch and 5 parts of disintegrant were used.

Ti
e, T*n (minutes) are summarized in Table 1K.

Table 1 Note) CMC-Ca: S image and tag outside a sillerose/calcium Gotoku Pharmaceutical ■ Avicel: Crystalline cellulose Asahi Kasei Industries ■ Back As shown in Table 1, fast-dissolving granules without disintegrant (control In Example), it took an extremely long time to disintegrate, and it was found that the enteric strain granules obtained therefrom could not fulfill the purpose of the present invention. However, 5cl in powder with disintegrant
The samples containing b disintegrated faster than the control samples, although there were differences in degree, and it could be observed with the naked eye that the granules were bursting and disintegrating, just like bob corn.

Examples 3-4. Comparative Examples 4-6 Examples 1-2. Five types of fast-dissolving granules granulated with powder containing 5% disintegrant obtained in Comparative Examples 1 to 3.

Same < CF-360m coated armor, 2k each
No. 17 was used to coat the enteric film.

As the enteric substance, Eudragit L-100σ) inpropyl alcohol/methylene chloride mixed solvent (
Coating was carried out using a 7-chip solution with a mixing weight ratio of 1:l. In this case, the slit air temperature was kept at 40°C. Approximately lθ% of lθ% lubricant was added to EudraKid L-100. did.

In both cases, the enteric substance is on the spherical granules with approximately 2077? The coating was continued until the coating was applied to a thickness of 0.1 mm, and the resulting granules were thoroughly dried in a hot air dryer at 50°C and further sieved to obtain slow-dissolving granules with uniform particle size. Ta. Each of the present granules sfl contained approximately 400 to 400 (potency) of the drug (Examples 3 to 4, Comparative Examples 4 to 6) These slow-dissolving granules were placed in a polyethylene packaging bag, and
An accelerated aging test was carried out for 6 months in a constant temperature and humidity chamber at 0°C and humidity of 75°C.

And for each granule before and after the time course test.

Intestinal fluid simulated solution specified by the Japanese Pharmacopoeia (H7
, 5, and a temperature of 37°C).

As in Example 1, the time required for half of the contained drug to be eluted (Tso minutes) was compared as shown in Table 2.

Table 2 Note) The range of values measured five times each is shown.

As is clear from Table 2, the slow-dissolving granules of the present invention
HPC, 7 with cudeine as a disintegrant (Example 3~
4) I) The Tsm value was sufficiently fast and showed stable physical properties with small variations.

Regarding CMC-C&C Comparative Example 5), the elution of samples after the aging test may be abnormally fast, and when the surface was closely observed under a microscope, it was confirmed that there were cracks in the enteric coating. It was done. Avicel (Comparative Example 6) Ic probably has poor compatibility with the pvp binder, but compared to Tll, which is a fast-dissolving granule, when it is made into a slow-dissolving granule, the elution becomes much worse, and moreover, over time. The change was huge.

Examples 5-6 Comparison 7-9 Examples 3-4. Slowly soluble granules 51 obtained in Comparative Examples 4 to 6
! For Class I, the elution of the drug into the gastric fluid before and after the time-course test was measured by incubating the gastric fluid for 30 minutes in a cimit solution. Although there was a slight leakage from the soluble film, it was found that there was almost no change over time, but CMC-C
It was found that in the slow-dissolving granule bundle using A (Comparative Example 8), the resistance to gastric juices became extremely poor, especially after aging, and a considerable amount of the drug leaked through the enteric coating in the stomach. As mentioned in Comparative Example 5, this seems to be due to cracks in the film.
It was cut in half with a knife, the cross section was photographed under a microscope, and the thickness of the enteric coating was measured. Measurements are made for one granule at 7
Implemented in some places. As a result, the average film thickness was 23.7 μm, and the variation (standard deviation value) of all measured values was 2.5 μm.
This resulted in a uniform coating thickness.

On the other hand, when producing fast-dissolving granules by the method shown in Example 1, Hydroxypropylene Cellulose 1 (manufactured by Co., Ltd.) was used as a binder instead of PVP K-90. The resulting fast-dissolving granules also contained about 1% RPC-L.

These granules were coated with Eudragi L-100 in exactly the same manner as in Example 3 to produce slow-dissolving granules. H of the cut surface of the five obtained granules
When microphotographs were taken and the average value and variation of the thickness of the film were measured, the average value of the thickness was 22.2 μm and the standard deviation value was 4.2 μm, indicating that the uniformity of the thickness was extremely high. It has become KM.

Example 8 Using the spherical nucleating agent (Memberleil) obtained in Example 1, rapidly dissolving fine particles having the following composition were manufactured by the following method. (Parts represent weight.) N-(3.4-dimethoxycinnamoyl)7 ntranilic acid 5 parts corn starch 57 parts nonvalyl
3 6 parts total
Thoroughly crush the mixture of ioo drug and corn starch using a hammer mill. PV
3% inpropylfluid of PK-90; - The stock solution was sprayed, and granulation was carried out in a centrifugal fluid coating granulator (model CF-360) in the same manner as in Example 1 while sprinkling with the above powder. . It was thoroughly dried in a hot air dryer at 50°C.

After drying, the granules were classified and spherical particles that passed through a 12-mesh screen but did not pass through a 24-mesh screen were defined as fast-dissolving granules.

Next, when producing the above-mentioned fast-dissolving granules using the same method, granulation was carried out by changing part of the Tokumo p-Fushi starch to 7 Kudeisol. The composition of the finally obtained fast-dissolving granules was as follows.

Drugs 5 parts corn starch 52 parts nonvaleryl 36 parts accdenle 5 parts total
surface K of the two types of rapidly dissolving granules thus obtained, the same <Eudragid dissolved in a mixed solvent of equal amounts of inpropyl alcohol and methylene chloride in a CF-360m coating machine) L-1
Each was coated with a lacquer of a 6% (IL amount) solution of 0.00. In addition.

A small amount of plasticizer and silica gel were mixed and dispersed in this lacquer. Sending hot air at 65℃, rotor 12
Coating was carried out at a constant feed rate while rotating with an Orpm to transfer the granules. After coating, the solvent was thoroughly removed in a hot air dryer at 50°C, the particles were sized and passed through a 12mm/3-screen.
Particles that did not pass through a 4-mesh screen were obtained.

The thickness of the film coated on the surface of the two types of enteric granules thus obtained was measured using the same method as in Example 7, and it was found that both were coated with a Kffi film with an average thickness of 25 μm. It was found that the standard deviation of the variation was approximately 2.4 μm, indicating that the coating was extremely uniform.

Further, the dissolution behavior of the drug was measured for each of the two types of enteric-coated granules using the dissolution test method Kjllll specified in the Japanese Pharmacopoeia. The eluate is a so-called JGZ solution with a pH of 6.8, which simulates intestinal fluid.

The elution curve was repeatedly measured and graphed, and the time (T, .) required for the amount of drug to elute was calculated, and the results were as shown in Table 4.

Table 4 Granules containing Acdenle had a significantly greater T of about 1.5 minutes than those without. A shortening of the period was recognized.

The fast-dissolving granules obtained in Example 1 and the slow-dissolving granules obtained in Example 3 were mixed, and the titer ratio of 7 moxicillin/moxicillin contained in each was 3 nia. A multi-granule sustained-release preparation with a total content of 7 moxicillin of 5009 (power 11 ali) was prepared. On the other hand, we recruited 24 healthy adult male volunteers and conducted an oral administration experiment. The subjects were divided into two groups of 12 people each, and BAV was compared using a cross-over method using ordinary amoxicillin capsules that had not been subjected to slow-release processing as a control drug. As the BAY parameter, the area under the curve (AUC) of the obtained blood drug concentration/time curve was measured, and the results are shown in Table 5.

Table 5 From Table 5, the formulation 1 of the present invention under the same drug administration conditions
The AUG of single administration and capsule administration were almost the same, and extremely excellent durability of drug efficacy was observed.

Next, the preparation of the present invention, which had been stored at room temperature for 36 months while packaged in a polyethylene/aluminum laminated film, was taken out and treated with the control drug and AU in exactly the same manner.
When the comparative experiment of G was repeated, the results shown in Table 6 were obtained.

Table 6 In other words, the long-lasting composite granules of the present invention completely retained their ability even after being stored for a long period of 3 years.
It was proven to be a stable formulation.

<Effects of the Invention> In the slow-dissolving granules obtained by the technique of the present invention, the enteric coating component does not penetrate excessively into the middle of the fast-dissolving granules, resulting in an extremely uniform skin [0 property]. Become. Since an effective barrier layer is necessarily formed on the inside of the enteric coating that can prevent the contents from migrating to the outer surface, it is extremely stable and can maintain AVIrj properties over a long period of time.

Furthermore, the strong disintegrant present in the fast-dissolving granules enables the rapid dissolution of the drug as the enteric coating dissolves, thereby making it possible to provide good AV% properties.

It is known that the shortening of the elution time by the simulated intestinal fluid seen in the so-called in vitro experimental examples shown in Example 8 etc. occurs more rapidly in the actual human body, and it is extremely stable. % property can be obtained. In particular, for drugs whose absorption sites are limited to the duodenum and upper small intestine, the BAY of slow-dissolving granules is important to have a certain dissolution behavior as quickly as possible with the increase in H of the digestive fluid in the gastrointestinal tract. This is an essential requirement to increase the durability of the composite granules.

Claims (1)

[Claims] 1. The surface of fast-dissolving granules uniformly containing a drug, a polyvinylpyrrolidone polymer, and a strong disintegrant as essential components is coated with a polyacid enteric material, and the surface portion is coated with the polyvinylpyrrolidone. A slow-dissolving granule characterized by forming a complex of a polyacid enteric substance and a polyacid enteric substance. 2. The slow-dissolving granule according to claim 1, wherein the disintegrant is a low-substituted hydroxypropyl ether of cellulose and/or partially cross-linked carboxymethyl cellulose sodium. 3. (a) Fast-dissolving granules uniformly containing the drug, a polyvinylpyrrolidone polymer, and a strong disintegrant as essential components, and (b) The surface of the fast-dissolving granules is coated with a polyacid enteric substance. A long-lasting composite granule comprising slow-dissolving granules characterized in that a complex of the polyvinylpyrrolidone complex and the polyacid enteric substance is formed on the surface portion. 4. The long-lasting composite granule according to claim 3, wherein the disintegrant is a low-substituted hydroxypropyl ether of cellulose and/or partially cross-linked carboxymethyl cellulose sodium.