JPS62226926A - Long acting complex granule - Google Patents

Abstract

PURPOSE:The titled complex granule having high durability, obtained by combining slow-acting granules which have an intermediate layer consisting of a substance to prevent a drug from transferring to the outside and a layer made of an enteric coated substance with rapid-acting granules. CONSTITUTION:Long acting complex granules consisting of slow-acting granules obtained by providing the surface of granules containing one or more of pyridonecarboxylic acid antibacterial agent (e.g. norfloxacin) or cephem antibiotic (e.g. cephalexin) as a drug with an intermediate layer comprising a substance (e.g. amino acid, protein or saccharide) to prevent the drug from transferring to the outside as a main constituent unit and forming a layer comprising an enteric coated substance (e.g. cellulose acetate phthalate) as a main constituent component on the intermediate layer and rapid-acting granules. The formation of the intermediate layer in the slow-cating granules makes elution of the drug in a first solution hard and causes no migration of the drug to the surface in the interior of the granules even by long-term preservation.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a long-lasting composite granule. More specifically, it consists of fast-acting granules that dissolve quickly in the stomach, and slow-acting granules that are difficult to dissolve in the stomach but are controlled to dissolve in the intestines. The present invention relates to a stable composite granule that can maintain its concentration over a long period of time and whose properties hardly change during storage.

(Prior Art) Various so-called long-acting preparations are known in order to maintain blood or urine concentrations of drugs for as long as possible. For example, orally administrable constituents such as cephalexin, cephaloglidine, cephalazine, cefadroxil, ampicillin, cyclacillin, amoxicillin, and cefaclor are expected to be highly effective against many infectious diseases; Many drugs have a short duration in the blood and require administration 4 times a day, or every 6 hours, which is complicated.

Therefore, we obtained naked granules containing the drug as a fast-acting ingredient;
A long-acting composite granule is known in which enteric-coated granules are prepared by applying enteric coating to granules containing a drug as a slow-acting ingredient, and these are mixed in an appropriate ratio.

Such composite granules have a good effect on sustaining blood concentration, and therefore, especially when the drug is an antibacterial substance or antibiotic, there is a risk of bacterial regrowth if the patient does not take the drug as directed by the doctor. It is commonly used as a preparation designed to improve so-called compliance because it can prevent reproduction as much as possible and requires fewer doses.

Enteric-coated granules are commonly used in the following manner.

Coating the bare granules containing the drug in a suitable coating device such as a coating pan, fluidized fluid granulator, centrifugal fluid granulator, etc., and coat the enteric polymeric substance with a suitable solvent such as ethanol, isopropanol, acetone, methylene chloride, etc. Bone grafting can be done by spraying a solution containing more than the seeds and drying it.

In order to obtain a long-lasting preparation, enteric-coated granules require that the drug is difficult to dissolve in the stomach and that the drug dissolves relatively rapidly at 11H in the intestinal region.

(Problems to be Solved by the Invention) However, according to the study results of the present inventors, it has been found that the surface of fast-acting granules containing one or more of pyridonecarboxylic acid-based antibacterial agents or cephem-based antibiotics can be coated with a conventional method. If the enteric coating is directly coated with a substance that dissolves in alkaline conditions, such as methyl methacrylate-methacrylic acid copolymer, even though the enteric coating is completely coated, When a dissolution test was performed using the simulated gastric digestive liquid (PI-11,2, hereinafter referred to as the first liquid) described in the pharmacopoeia, most of the drug contained inside the granules passed through the enteric coating in a short period of time. An inconvenient phenomenon was discovered in which it could be eluted into external fluids.

This fact means that delayed-release granules cannot be produced by simply utilizing conventional techniques for the drug used in the present invention.

As a result of various studies to improve the above drawbacks, the inventors of the present invention found that
By providing an intermediate layer made of a specific substance inside the layer whose main component is an enteric-coated substance, the drug is difficult to dissolve in the first liquid, and even after long-term storage, the drug inside the granules moves to the surface.・There is no passage, and artificial intestinal digestive fluid (IIH6
, 8, hereinafter referred to as the second liquid), it has been discovered that excellent enteric-coated granules can be obtained whose elution behavior does not significantly change compared to conventional methods, and the present invention has been achieved.

(Means for Solving the Problems) That is, the present invention has the following features: (A) A drug is externally coated on the surface of granules containing one or more of pyridonecarboxylic acid antibacterial agents or cephem antibiotics as drugs. Delayed-release granules obtained by providing an intermediate layer containing a substance that prevents migration as a main component, and further providing a layer containing an enteric polymer substance as a main component on top of the intermediate layer, and (B) containing a drug. This is a long-acting composite granule consisting of fast-acting granules and fast-acting granules.

The fast-acting granules of the present invention can be obtained using conventionally commonly used crushing granulation, extrusion granulation, dry fluidized granulation, etc., but the granules obtained by these methods generally have a The shape is often columnar or has significant irregularities, and when a slow-release coating is applied, the coating tends to become uneven, making it difficult to achieve the original purpose and causing problems such as a significant drop in yield. many.

Therefore, it is a preferred embodiment that the fast-acting granules are substantially spherical.

The drug contained in the slow-acting granules of the present invention is a pyridonecarboxylic acid antibacterial agent or a cephem antibiotic.

Examples of pyridonecarboxylic acid antibacterial agents include norfloxacin, ofloxacin, and enoxacin.

Selected from pipemic acid, pyromidic acid, etc.

Examples of cephem antibiotics include cefatridine propylene glycol and cefuroxazine.

Selected from such as cefaclor, cefadroxil, cephalexin, and cefrazine. Although these drugs can be used alone or in combination of two or more, they are usually used alone.

When formulating the drug, the drug may be used as is, or the drug and a suitable excipient such as corn may be used.

It is also preferable to use it in combination with lactose or the like.

The spherical granules containing the pyridonecarboxylic acid antibacterial agent or cephem antibiotic can be obtained, for example, by the following method.

It may be either a pyridonecarboxylic acid antibacterial agent, a cephem antibiotic, a drug or a composition containing a drug), or a non-medicinal ingredient, but lactose is preferred.

A nucleating agent consisting of a carbohydrate such as granulated sugar, or a non-medicinal ingredient such as an inorganic substance such as calcium phosphate or light anhydrous silicic acid, or a nucleating agent consisting of a non-medicinal ingredient such as a nucleating agent consisting of a non-medicinal ingredient, is applied using centrifugal force and jet air using a centrifugal fluid coating granulator, for example. On top of the spherical nucleating agent obtained by transferring the same non-pharmacological nucleating agent, preferably more finely powdered, or a covering ingredient such as corn starch or crystalline cellulose, while being transferred by a flow. Spherical granules can be obtained by coating with a coating component containing a pyridonecarboxylic acid antibacterial agent or a cephem antibiotic.

The method for coating the surface of the nucleating agent or spherical nucleating agent with the pyridonecarboxylic acid-based antibacterial agent or the cephem-based antibiotic is not particularly limited, and a known spray coating method or the like can be adopted, but the centrifugal fluid coating method described above may be used. preferable. Specifically, a predetermined amount of a nucleating agent or spherical nucleating agent is put into a centrifugal fluid coating granulator, and while this nucleating agent is rotated by centrifugal force (due to the rotation of the rotor), the nucleating agent is simultaneously rotated by the granulator. A syrup liquid or ethanol made by a suitable mixture of sucrose and water, for example, is blown up to a controlled height by an air flow blown from between the side wall and the rotating body (slit), and from a spray gun located above it. For example, an organic polymer such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or polyvinyl alcohol is dissolved in a relatively low-boiling organic solvent such as isopropanol, acetone, methyl ethyl ketone, or methidine chloride, or water. A solution (binder) is sprayed to wet the nucleating agent, and then a coated powder (drug or Spherical granules with a desired particle size can be obtained by introducing a mixed powder composition (composed of a drug, an excipient, etc.), adhering it to the moist core agent, and drying it for a certain period of time.

The granules can be used as fast-acting granules.

The slow-release granules of the present invention can then be produced by the following method.

First, an intermediate layer containing a substance having the effect of inhibiting drug migration as a main component is provided on the surface of the granules obtained earlier. It is also possible to use the granules at this stage as fast-acting granules.

In this case, as mentioned above, if the surface of the granule is significantly uneven, in order to make it a slow-acting granule that is difficult to dissolve in the stomach, it is necessary to coat it with a relatively large amount of a substance that has the effect of blocking drug migration. It is also possible to do so. However, in this case, sufficient care should be taken to control the effect of delaying elution.

Therefore, slow-acting granules are spherical granules obtained by the method described above, in which the nucleating agent or spherical nucleating agent is put into a centrifugal fluid coating granulator and coated while being rolled by centrifugal force and jetted air flow. As mentioned above, the method using granules is a preferred embodiment.

The substance constituting the intermediate layer that prevents the drug of the present invention from migrating to the outside preferably has a substance having low compatibility with the drug as a main component.

When granules containing a drug are directly coated with an enteric polymeric substance as in the conventional method, the elution of the drug during immersion in the first liquid is significant, and the objective of obtaining a long-lasting preparation cannot be achieved. The cause is not clear, but when a solution of an enteric polymer substance is sprayed, the solvent penetrates into the inside of the granule, and when it dries, at least a portion of the drug is transferred to the outside along with the solvent. As a result of drug transfer to the enteric polymer coating, if a dissolution test is performed with the first liquid even after sufficient drying, at least a portion of the drug contained inside the granules will pass through the enteric coating and elute into the external liquid. You might also say that.

When an intermediate layer made of a substance with low compatibility with the drug is provided on the surface of the granules containing the drug as in the present invention, it is difficult for the solvent to penetrate inside the granules even when a solution of an enteric polymer substance is sprayed. It is believed that a layer of material that is less compatible with the drug may result in blocking drug migration.

Furthermore, substances that are easily water-soluble or easily disintegrate in water are preferred because they do not impair dissolution in the intestines.

Examples of substances with low compatibility with drugs that make up the intermediate layer include amino acids and their salts such as glycine, sodium daltamate, sodium caseinate, gelatin, and proteins; inositol, fructose, xylitol,
Sorbitol, potato starch, wheat starch,
rice starch.

These include sugars such as hydroxypropyl starch; inorganic salts such as sodium chloride and sodium sulfate; and polymeric substances such as polyvinyl alcohol, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and crystalline cellulose. Even if these are used alone, 2
It is also possible to use more than one species in combination.

The intermediate layer can be provided by spraying and drying a solution of the above-mentioned substance on the surface of the granules, or by introducing a predetermined amount of the granules into a centrifugal flow type coating granulation method and applying centrifugal force (by rotation of a rotor). ), while at the same time the space between the side wall of the granulator and the rotating body (slit)
An air stream blows up to a controlled height from a spray gun located above, for example, a syrup made by a suitable mixture of sucrose and water, or ethanol, isopropanol, acetone, methyl ethyl ketone, methylene chloride. For example, methyl cellulose, hydroxypropyl cellulose, etc., in relatively low boiling point organic solvents such as water, etc.

A solution (binder) in which an organic polymer such as hydroxypropyl methylcellulose, polyvinylpyrrolidone, or polyvinyl alcohol is dissolved is sprayed to moisten the granules, and then the coating powder is added to the intermediate layer from the unintroduced port located above the granulator. One example is a method in which a powder containing a layer-forming material is introduced, adhered to the wet granules, and dried for a certain period of time.

The amount of the intermediate layer applied may vary depending on the properties of the drug, the process of applying the enteric coating, etc., but is generally about 10 to 100% by weight based on the granules.

In the present invention, the granules obtained by the methods described above are coated with an intermediate layer on the surface of the granules, which are difficult to dissolve in gastric juice and are coated with digestive fluid in the intestine (artificial intestinal digestive fluid, i.e., second fluid). It is necessary to manufacture granules (delayed-release granules) that have the property of being easily dissolved in the Japanese Pharmacopoeia (Japanese Pharmacopoeia specifies a buffer solution of pl-46.8, which is often used in laboratories). It is.

Examples of substances that are difficult to dissolve in the stomach and dissolve in the digestive fluids in the intestines (enteric-coated substances) include cellulose acetate phthalate,
Cellulose acetate succinate, methyl cellulose phthalate, carboxymethyl ethyl cellulose, methyl methacrylate-methacrylic acid copolymer (product name:
Examples include polymeric substances with excellent film-forming ability, such as ethyl acrylate and methacrylic acid copolymers.

As enteric substances, those that dissolve at pH 5.5 or higher are preferred, and those that dissolve at pH 6.0 or higher are particularly preferred because they last for a long time.

The method for coating the enteric substance is not particularly limited, and any known method may be used, but the granules coated with the intermediate layer may be spray-coated with a solution or suspension of the enteric substance using a centrifugal flow coating method. A method of drying is preferred. As the solvent, in addition to water, organic solvents such as ethanol, isopropanol, methylene chloride, and acetin are used alone or in combination.

The coating amount of the enteric substance is 2 to 50% by weight, preferably 5 to 35% by weight, based on the granules in which the intermediate layer is applied on the fast-acting granules.
It is about % by weight.

In the present invention, by performing such a coating operation multiple times as necessary, a more significant effect can be exerted on the dissolution properties of the first liquid (pH approximately 1.2) and the second liquid (DHHO28). .

In the present invention, in order to achieve a sustained effect, various methods can be used depending on the drug used and the desired duration, but the potency of the medicinal ingredient among all the drugs contained in the fast-acting granules and slow-acting granules The ratio is 20-80%, preferably 20-50
It is preferable to formulate a formulation in which % is contained in fast-acting granules and the rest is contained in slow-acting granules.

With this level of potency ratio, a good initial blood concentration of the drug can be achieved and an effective blood concentration can be maintained for a long time.

There may be one type of delayed-release granule or two or more types. For example, if two types of delayed-release granules each using two types of enteric substances with different solubility rlH are used together, the durability of the drug effect can be further varied.

As for the method of blending granules for each dose, accuracy can be ensured by weighing and blending each granule for each packaging unit, but preferably, a predetermined amount of both granules is mixed in large quantities in advance, and - A method of dividing into packaging units is adopted.

The composite granules of the present invention may be packaged, for example, in stick packaging or sachets to form one packaging unit.

If granules of approximately constant size are used as the composite granules of the present invention, there is an advantage that they can be packaged easily and smoothly during the day. The preferred content of composite granules in one packaging unit is usually 500~
5000 Ing is orally administered several times a day depending on the disease.

As explained in detail so far, the technical objective of the present invention is that when using a specific drug in slow-release granules, the main substance is contained under the enteric coating to prevent the drug from migrating to the outside during storage. The main feature is that an intermediate layer is provided as a constituent component, and an enteric coating is further applied thereon. This is combined with fast-acting granules.

For example, the drug used in the fast-acting granules may be the same drug as in the slow-acting granules to maintain the blood concentration of the drug, or a drug different from the slow-acting granules (for example, antibacterial agents other than pyridone carboxylic acid, By using antibiotics other than cephems, a variety of medicinal effects can be exerted. In addition, the species of these drugs, their quantitative ratios, the species of granules,
The effects can be further diversified by forming composite granules that combine a large number of their quantitative ratios.

It goes without saying that the present invention also includes the use of such composite granules by providing them with a suitable outer package such as a capsule.

(Effects of the Invention) The long-acting composite granules of the present invention, which are composed of fast-acting granules and slow-acting granules, can prolong the duration of the drug concentration in the blood compared to oral administration of ordinary fast-acting preparations alone. Moreover, it is a drug that is stable over a long period of time, and the medicinal drug present inside the slow-acting granules does not migrate into the enteric coat in a short period of time and impair the intended proximal effect. It is a composite granule formulation.

<Example) The present invention will be explained in detail with reference to Examples below.

Example 1 (Manufacture of fast-acting granules) 500 g of granules, etc. were placed in a stretch-flow type coating granulator (inner volume: approximately 10 mm), and the rotor was rotated to 150 to 170 mm.
While rotating at r, p, m, blow air from Surin 1 (air amount 150/min, air temperature 15-50℃)
), the above-mentioned granules, etc. (nucleating agent) are blown up with air and rolled by a centrifugal horn, and then a 1% aqueous solution of polyvinylpyrrolidone is sprayed from a spray gun at a rate of 2.5 me/min).
Further, 8009 1-corn starch was gradually added through the inlet where the coating powder was not introduced, the nucleating agent was coated with this, granulation was performed, and after drying with hot air at 50 to 60° C., a spherical nucleating agent was obtained.

300 g of the spherical nucleating agent obtained as described above was transferred to a centrifugal fluid coating granulator, and a 3% isopropanol solution of polyvinylpyrrolidone was sprayed thereon to form a mixture containing norfloxacin and corn starch as the main components. Spherical granules were granulated while gradually adding 523 g of mixed powder. Dry with hot air at 50-60°C to form granules with 500%
Fast-acting spherical granules containing 1 oomg of norfloxacin in m9 were obtained.

(Manufacture of slow-acting granules) Next, 400 g of the fast-acting spherical granules were similarly put into a centrifugal fluid coating granulator, and while being transferred, 176 g of powdered sucrose (44 parts by weight of saccharose per 100 parts by weight of fast-acting granules) was transferred. ) of hydroxypropylcellulose from a spray gun while gradually adding
% aqueous solution to form an intermediate layer.
Dry with hot air at ℃.

400 g of the thus obtained fast-acting granules with an intermediate layer applied to the surface were placed in the same centrifugal fluid coating granulator, and while the rotor was rotating at 100 to 250 r, p, m, air was blown through the slits. (Air @4001
/min, air temperature 45°C), the above granules were blown up with air and rolled by centrifugal force as a whole, and Eudragid L-10 containing a small amount of fatty acid ester monoglyceride (plasticizer) and light silicic anhydride was added to the granules.
0 6% isopropanol-methylene chloride solution (
While spraying (mixing ratio 1:1) from a spray gun (spray amount 5 to 30 d/ll 1 in), the granules were sequentially removed from the granulator when a predetermined amount of enteric coating was coated.
It was dried with hot air at 50 to 60°C.

By the above operations, delayed-release granules were obtained in which 15.30.35.40 parts by weight of the enteric coating composition was coated on 100 parts by weight of the granules provided up to the intermediate layer.

Comparative Example 1 300 g of the fast-acting spherical granules obtained in Example 1 were similarly charged into a centrifugal flow type coating granulator, and directly coated with an enteric coating as described below without applying an intermediate layer.

As in Example 1, the rotor was heated at 100 to 250 r, p,
While rotating at IIl, air is blown through the slit (air amount 400 M/min, air temperature 45°C), the above granules are blown up by the air and transferred as a whole by centrifugal force, and a small amount of fatty acid ester monoglyceride (plastic Spray a 6% isopropanol-methylene chloride solution (mixing ratio 1:1) of Eudragit L-100 containing light anhydrous silicic acid and light silicic anhydride from a spray gun (
When a predetermined amount of the enteric coating was coated at a spray rate of 5 to 30 d/min, the granules were sequentially removed from the granulator and dried with hot air at 50 to 60°C. Fast-acting granules 1
00 parts by weight, the enteric coating composition was added to 15.30.4 parts by weight.
Granules coated with 0 parts by weight were obtained.

Example 2 <Production of fast-acting granules) While transferring the spherical nucleating agent 300 (j) obtained in Example 1 to a centrifugal fluid coating granulator, a 3% isopropyl alcohol solution of polyvinylpyrrolidone was sprayed thereon. Spherical granules were granulated while gradually adding 536 g of mixed powder mainly composed of cefatridine propylene glycol and corn starch.
The product was dried with hot air at 0.degree. C. to obtain fast-acting spherical granules containing 441 g of cefatridine propylene glycol in 1000 ml of spherical granules.

(Manufacture of slow-acting granules) Next, 500 g of the fast-acting spherical granules were similarly put into a centrifugal fluid coating granulator and powdered while transferring the saccharose 2009 (40 parts by weight of saccharose for 100 parts by weight of fast-acting granules). A 5% aqueous solution of hydroxypropylcellulose was sprayed from a spray gun while gradually adding
It was dried with hot air at 60°C. The thus obtained granules 5009, in which an intermediate layer was applied to the surface of the fast-acting granules, were placed in the same centrifugal flow type coating granulator, and the rotor was rotated at 100 to 2
While rotating at 50 r, p, m, blow air through the slit (air amount 400 degrees/min, air temperature 45°C),
The above granules are blown up with air and rolled by centrifugal force, and then a 6% isopropanol-methylene chloride solution of Eudragit L-100 containing a small amount of fatty acid ester monoglyceride (plasticizer) and light silicic anhydride ( While spraying granules (mixing ratio 1:1) from a spray gun (spray volume 5-30 m/min), when a predetermined amount of enteric coating is coated, the granules are taken out from the granulator and heated to 50-60°C. Dry with hot air.

By the above operations, delayed-release granules were obtained in which the 100-layer most part of the granules, which had been provided up to the middle layer, was coated with 15.20.25 parts by weight of the enteric coating composition.

Comparative Example 2 300 g of the fast-acting spherical granules obtained in Example 2 were charged into a centrifugal flow type coating granulator, and directly coated with an enteric coating as described below without applying an intermediate layer.

Similarly to Example 2, the rotor was heated at 100 to 250 r, p,
While rotating at speed m, air is blown through the slit (air amount 400/min, air temperature 45°C), the above granules are blown up by the air and rolled by centrifugal force as a whole, and a small amount of fatty acid Nistel monoglyceride is added to the granules. (plasticizer) and light silicic anhydride.
Spray 100% 6% isopropanol-methylene chloride solution (mixing ratio 1:1) from a spray gun (spray volume 5 to 30 ml/min).When a predetermined amount of enteric coating is coated, spray the granulator. The granules were taken out and dried with hot air at 50 to 60°C. Fast-acting granules 10
15.20.25 parts by weight of enteric coating composition
Part by weight coated granules were obtained.

Example 3 (Manufacture of fast-acting granules) 300 g of the spherical nucleating agent obtained in Example 1 was put into a centrifugal fluid coating granulator, and while being transferred, a 3% isopropyl alcohol solution of polyvinylpyrrolidone was sprayed onto it. , spherical granules were granulated while gradually adding 534 g of a mixed powder containing cefatridine propylene glycol and corn starch as main components. After that 50~
It was dried with hot air at 60° C. to obtain fast-acting spherical granules containing 1009 ofloxacin in 500 rng of granules.

(Manufacture of slow-acting granules) Next, the fast-acting spherical granules 4009 were similarly introduced into a centrifugal fluid coating granulator, and while being transferred, the saccharose 160! ? (40 parts by weight of saccharose per 100 parts by weight of quick-acting granules) was gradually added, and a 5% aqueous solution of hydroxypropylcellulose was sprayed from a spray gun to form an intermediate layer.
Hot air drying was performed at ~60°C.

400 g of the thus obtained fast-acting granules with an intermediate layer on the surface were placed in the same centrifugal fluid coating granulator, and while rotating the rotor at 100 to 250 r, p, m, air was blown through the slits (air Amount 4001/mi
n, air temperature 45°C), the above granules were blown up by air and rolled by centrifugal force, and then Eudragit L-100 6 containing a small amount of fatty acid ester monoglyceride (plasticizer) and light silicic anhydride was added. % isopropanol-methylene chloride solution (mixing ratio 1:
Spray 1) from a spray gun (spray amount 5-30
d/min> When a predetermined amount of enteric coating is coated, the granules are taken out from the granulator and
Dry with hot air at ℃.

By the above operations, delayed-release granules were obtained in which 15.25 parts by weight of the enteric coating composition was coated on 100 parts by weight of the granules provided up to the intermediate layer.

Comparative Example 3 300 g of the fast-acting spherical granules obtained in Example 3 were charged into a centrifugal fluid coating granulator, and directly coated with an enteric coating as described below without applying an intermediate layer. Similarly to Example 3, while rotating the rotor at 100 to 25 Or, p, m, air was blown through the slit (air amount 40
0 degrees/min, air temperature 45°C), the above granules are blown up with air and rolled by centrifugal force as a whole, and Eudragid L- containing a small amount of fatty acid ester monoglyceride (plasticizer) and light silicic anhydride is added to the granules. 10
0 6% isopropanol-methylene chloride solution (
While spraying (mixing ratio 1:1) from a spray gun (spray amount 5 to 30 d/min), when a predetermined amount of enteric coating was coated, the granules were sequentially extracted from the granulator,
It was dried with hot air at 50 to 60°C.

1 part by weight of the enteric coating composition per 100 parts by weight of the fast-acting granules.
5. Granules coated with 20 layers were obtained.

Example 4 The delayed-release granules obtained in Examples 1 to 3 and Comparative Examples 1 to 3 and the granules coated with the enteric coating composition were tested by dissolution test method 1 (rotating basket method) described in the Japanese Pharmacopoeia. liquid first
An elution test was conducted using the solution (pH 1, 2) and the second solution (pH 8).

As shown in Table 1, when pyridonecarboxylic acid antibacterial agents such as norfloxacin and ofloxacin, or cephem antibiotics such as cefatridine propylene glycol are used as drugs, enteric-coated granules can be added directly onto conventional fast-acting granules. Compared to granules coated with a film, the slow-release granules of the present invention have an intermediate layer on the surface and are further coated with an enteric coat.
It can be seen that the drug elution rate at 2> was significantly reduced.

Even in the second liquid (1) H6,8) corresponding to l)H of fatty meat, the drug is eluted relatively rapidly without any problem.

(Left below) -30 Example 5 The slow-release granules obtained in Example 1 and Example 2 were heated at 40°C.
The sample was left in a 75% RH atmosphere for one month, and its elution behavior was measured.

As shown in Table 2, it can be seen that the dissolution behavior of the slow-release granules of the present invention is stable with almost no change even after one month at 40° C. and 75% RH.

(Leaving space below) Example 6 150q of the granules with the intermediate layer obtained in Example 1 were put into a centrifugal fluid coating granulator, and the rotor was
While rotating at 0 to 150 r, p, m, air is blown through the slit (air ii 4001/min, air temperature 70°C), and while the granules are blown up by the air, they are rolled as a whole by centrifugal force. Spray 6% isopropanol methylene chloride (mixing ratio 1:1) of Eudragit L-100 containing a small amount of fatty acid ester monoglyceride (plasticizer) and light anhydrous silicic acid from a spray gun (spray amount 5-30 d/min) L ,
When the solid content of the enteric coating composition was 3.75'j, that is, 2.5 parts by weight of the enteric coating composition was coated on 100 parts by weight of the granules, the spraying was temporarily stopped and the spraying was continued for 30 minutes while being transferred. After drying, the coating solution was sprayed again.

The above operation was repeated six times in total to obtain delayed-release granules in which 100 parts by weight of the granules were coated with 15 parts by weight of the enteric coating composition.

The slow-acting granules obtained by performing the coding operation multiple times are as shown in Table 3.
The dissolution rate after a 3-hour dissolution test was 32%.

In the second solution (f) H6,8>, the drug (
It is a granule with excellent elution of norfloxacin).

Claims (1)

[Claims] 1. (A) A substance that prevents the drug from migrating to the outside on the surface of the granules containing one or more of pyridonecarboxylic acid antibacterial agents or cephem antibiotics as drugs. (B) fast-acting granules containing the drug; and (B) fast-acting granules containing the drug. Long-acting composite granules. 2. The duration according to claim 1, wherein the component of the intermediate layer in the slow-acting granules is at least one selected from amino acids or their salts, proteins, sugars, inorganic salts, and polymeric substances. Composite granules. 3. The long-acting composite granule according to claim 1 or 2, wherein the slow-acting granules and the fast-acting granules are substantially spherical granules. 4. Any one of claims 1 to 3, wherein the pyridonecarboxylic acid antibacterial agent contained in the slow-acting granules is at least one selected from norfloxacin, ofloxacin, enoxacin, pipemic acid, and pyromidic acid.
Long-acting composite granules as described in Section 1. 5. Any one of claims 1 to 4, wherein the cephem antibiotic contained in the slow-acting granules is at least one selected from cefatridine propylene glycol, cefuroxazine, cefaclor, cefadroxil, cephalexin, and cefrazine. Long-acting composite granules as described in Section 1. 6. A slow-acting granule comprising a plurality of intermediate layers whose main constituent is a substance that prevents the migration of drugs to the outside and/or layers whose main constituent is an enteric polymer substance. The long-acting composite granule according to any one of items 1 to 5. 7. Any one of claims 1 to 6, wherein the potency ratio of the drug contained in the fast-acting granules (A) and the slow-acting granules (B) is 20:80 to 80:20. Long-acting composite granules.