JPH0420889B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing enteric-coated pharmaceutical tablets by compressing antibiotic-containing granules having an enteric coating on the surface.

Conventionally, in the field of pharmaceutical formulations, various efforts have been made to control the expression of drug efficacy, such as applying a slow-release coating, such as an enteric coating, to the surface of the formulation in order to delay the dissolution and absorption of the drug. . In particular, antibiotic preparations require frequent administration because it is necessary to maintain the blood concentration of the drug at a constant level.To avoid this, so-called long-acting preparations that maintain drug efficacy for a long time after one administration are desired. ,
For this purpose, granules that have an enteric coating on their surface and release antibiotics in a delayed manner are used in combination with granules that do not have such a coating, that is, quickly dissolving granules that release antibiotics quickly. ing.

Incidentally, tablet-type drugs are generally most commonly used for oral administration of pharmaceuticals. This seems to be because it is convenient to handle and easy to understand for users. Pharmaceutical tablets are generally manufactured by preparing granules containing the main pharmaceutical ingredient and compressing the granules together with appropriate auxiliaries. However, in the case of the above-mentioned antibiotic preparation with an enteric coating, when it is compressed into tablets, the enteric coating, which is the surface coating, breaks under pressure and the enteric effect of the coating is lost. Put it away. Therefore, it is impossible to form tablets using granules with such a surface coating, and the granules are either put into capsules as they are to make capsules, or they are used as they are in separate packages. If these coated granules can be made into tablets, enteric-coated tablets of antibiotic preparations can be obtained, and furthermore, it is possible to obtain long-acting tablets containing coated granules and uncoated granules in one tablet, It is convenient for the user.

The present inventors conducted various studies on how to tablet antibiotic-containing granules coated with such an enteric coating without damaging the coating, and found that (1) voids between granules were (2) the granules do not collide directly with each other; (3) the load is evenly distributed and the load on each granule is small; these are the necessary conditions to prevent damage to the coating. After paying attention to a certain fact and trying various methods to satisfy such conditions, we discovered that if the above granules were coated with an oily substance and a fibrous excipient and then compressed into tablets, the enteric coat would not be damaged, and the present invention was achieved. did.

That is, the present invention relates to a method for producing pharmaceutical tablets, which comprises coating antibiotic-containing granules with an enteric coating with an oily substance and a fibrous excipient, and then tabletting the granules. Furthermore, the present invention relates to a method for manufacturing a pharmaceutical tablet, which comprises compressing the coated tablet using rapidly dissolving granules having no enteric coating.

In the present invention, an oily substance is a substance that is immiscible with water or has poor miscibility (miscibility of 5% or less), exhibits viscosity at room temperature, and does not dissolve the enteric coating base material. It can be either pasty or solid, and is usually made from animal or fish oils,
Non-toxic oils and fats such as vegetable oils and fats, mineral oils, hydrogenated oils thereof, waxes such as higher fatty acid esters and higher fatty acid alcohols, triglycerides, and mineral oils are used. For example, waxes and triglycerides include animal and fish oils such as beef tallow, whale oil, spermaceti wax, squalane, white beeswax, wool fat or hydrogenated products thereof, rapeseed oil, sesame oil, soybean oil, camellia oil, Vegetable oils and fats such as coconut oil, olive oil, cacao oil, lauric fat, corn oil, peanut oil, cottonseed oil, etc. or their hydrogenated products; high-grade oils such as cetyl ricinolate, stearyl ricinolate, isopropyl myristate, butyl myristate, etc. Fatty acid esters; higher aliphatic alcohols such as cetyl alcohol and stearyl alcohol; waxes such as wood wax; triglycerides of higher fatty acids with 12 to 18 carbon atoms such as myristic acid, valmitic acid, and stearic acid; vaseline, paraffin, silicone oil, etc. Mineral oil etc. are used.
These oily substances may be used alone or as a mixture of two or more, and a water-soluble polymeric substance such as polyethylene glycol or ribinyl alcohol may be added to them. This polymeric water-soluble substance is used in a ratio of 4 parts or less to 6 parts of the oily substance. Furthermore, these oily substances may be used in the form of a solution using a soluble solvent such as methylene chloride, chloroform, acetone, methanol or ethanol. The oily substance is preferably used in an amount of 10 to 35 parts by weight per 100 parts by weight of the enteric coated antibiotic-containing granules.

Examples of fibrous excipients include cellulose or cellulose derivatives, such as microcrystalline cellulose (trade name Avicel, manufactured by Asahi Kasei Corporation), low-density hydroxypropyl cellulose (L-HPC), carboxymethyl cellulose (trade name NS-300), and carboxymethyl cellulose (trade name NS-300). Methylcellulose Ca salt, cyclic carboxymethylcellulose, etc. are used. The fibrous excipient is preferably used in an amount of 10 to 40 parts by weight per 100 parts by weight of the antibiotic-containing granules coated with an enteric coating.

The effect of the oily substance and fibrous excipient in the present invention is that they are easily peeled off from the granules by pressure during tablet compression, filling the voids between the granules, and the oily substance binds the fibrous excipients together. It is thought that this prevents the granules from directly colliding with each other. If only a fibrous excipient is used without using an oily substance, the excipient components will become non-uniform, resulting in non-uniform pressurization and granule breakage. Furthermore, when the granules are coated with a binder and an excipient without using an oily substance, the excipient does not come off even when pressure is applied, and therefore the granules are easily damaged by being directly subjected to a load.

The present invention is particularly effective when applied to the formulation of antibiotics that are absorbed near the upper part of the small intestine and are quickly excreted. Ride antibiotics are used and are particularly effective against cephalexin.

The base material for the enteric coating used in the present invention includes a copolymer of methacrylic acid and methyl methacrylate (Eudragit L: elution pH around 6, Eudragit S: elution pH around 7), acrylic ester-methacrylic acid- Bases that can be dissolved in the intestine, such as methacrylic acid ester copolymer (MPM-06) and hydroxypropyl methylcellulose phthalate (HP-55), are used. These bases are 1
The desired elution can be achieved by changing the elution PH by mixing two or more bases with different elution PH.
It can also be PH. The mixing ratio when two or more types of enteric bases are mixed is not particularly limited, since enteric bases can be obtained no matter what. It is also possible to mix a gastric soluble base, a water soluble base or an insoluble base with the enteric base.
As a stomach-soluble solvent, cellulose acetate dibutylaminohydroxypropyl ether (trade name
CABP), polyvinyl acetal-diethylaminoacetate (AEA), dimethylaminoether methacrylate-methacrylate ester copolymer (Eudragit E), etc. are used in a proportion of 4 parts by weight or less per 10 parts by weight of the enteric base. It is preferable to use Water-soluble bases include gelatin, polyvinyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, etc., and are preferably 4 parts by weight or less per 10 parts by weight of the enteric base. Examples of insoluble bases include ethyl cellulose, butyl cellulose, polyacrylic esters, polymethacrylic esters, or insoluble, pH-independent copolymers of acrylic acid, methacrylic acid, acrylic esters, and methacrylic esters (Eudragit RS, Eudragit RL), etc., and is usually used in an amount equal to or less, preferably 30% or less, based on the enteric base. The above-mentioned enteric base is usually made into a solution in a soluble solvent, and the solution is sprayed onto bare granules, which are antibiotic-containing granules, to coat them.

To produce antibiotic-containing granules for coating with an enteric coating, excipients and disintegrants are generally added to and mixed with crushed antibiotics, and a wetting agent (water,
(alcohol, etc.) or a binder solution, knead, and granulate. Lactose, sodium bicarbonate, starch, salt, sucrose, and crystalline cellulose (Avicel) are used as excipients, and starch and crystalline cellulose are used as disintegrants. The binder is 10
~20% aqueous gum arabic solution, 5~10% starch paste solution, 5~10% PVP (polyvinylpyrrolidone), 1
~2% hydroxypropylcellulose aqueous solution, etc., and an oily substance, surfactant, or buffer may also be used to modify the antibiotic release properties to some extent. The granulator is preferably an extrusion granulator.

The antibiotic-containing granules are then sprayed with an enteric coating solution using, for example, a coating pan to obtain enteric-coated antibiotic-containing granules. Furthermore, in order to coat the above-mentioned granules with an oily substance and a fibrous excipient, it is preferable to spray or sprinkle these as they are or dissolved in a solvent in a granulator.

The tableting method is usually the same as that for pharmaceutical tablets, and lubricants such as magnesium stearate (0.2 to 0.5%) are added to prevent adhesion to rods and dies.
Talc (0.5-2%), calcium stearate,
Stearic acid and the like are used.

In the present invention, the granules obtained by coating with an oily substance and a fibrous excipient are further coated with antibiotic-containing granules that do not have an enteric coating and are capable of rapidly releasing antibiotics. It is also possible to obtain long-lasting pharmaceutical tablets containing fast-dissolving granules and enteric-coated granules in one tablet by compressing into tablets. In addition, the antibiotic-containing granules that do not have an enteric coating may be those that do not have an enteric coating and quickly release the antibiotic, and are usually used for coating with an enteric coating. Granules are used,
For example, bare granules granulated and sized using antibiotics and crystalline cellulose, low-density hydroxylpropyl cellulose, lactose, starch, etc., or the production of such naked granules, especially with less than 10% oily substances and a small amount of surfactant. Examples include naked granules in which the release properties of antibiotics have been modified to some extent. Furthermore, for long-lasting pharmaceutical tablets containing fast-dissolving granules and enteric-coated granules in one tablet, the fast-dissolving granules and enteric-coated granules may be scattered throughout the tablet; Even if it is a type in which a fast-dissolving layer and an enteric-coated layer are stacked, each forming a layer, or a type in which enteric-coated granules are in the center and a layer of fast-dissolving granules exists around it. Tablets can often be made in various forms depending on the purpose. The blending ratio of these enteric-coated granules and fast-dissolving granules is generally 90:10 to 50:60, preferably 85:15 to 50:60 in terms of their potency ratio.
It is 60:40.

As mentioned earlier, the present invention makes it possible to formulate enteric-coated antibiotic-containing preparations, which have conventionally been used in granular form, into tablets, which are the most easily used dosage form as pharmaceutical preparations, and furthermore, By obtaining such enteric-coated tablets, it has also become possible to obtain tablets with specific efficacy that partially contain enteric-coated portions. The test results showing that the tablet obtained according to the present invention retains enteric properties will be explained using a graph. Figure 1 shows the tablets produced in Example 1 below (marked with ○), the enteric-coated granules used as raw materials in Example 1 that were not treated with oily substances and fibrous excipients (marked with x), and Tablets made in Example 3 (△ mark)
2 is a graph showing the relationship between elution % of each cephalexin and time. Figure 2 shows the enteric coated granules used as raw materials in Example 4 that were not treated with oily substances and fibrous excipients (marked with x), and the tablets produced in Example 4 (marked with ○) of cephalexin. It is a graph showing the relationship between elution % and time.

This test is conducted as follows.

Place 1 to 2 tablets together with 100 ml of test liquid (PH1.2) in a test tube with a stopper, set it in a dissolution test device Diftest (manufactured by Ueland, Italy), and inject 37
Rotate at 15 r/p/m at ℃. After 1 hour, replace the test solution with a PH4.5 solution and continue rotating. After another 2 hours, the solution is replaced with a solution with a pH of 6.9, rotated, and the test solution is collected at different times. (This method is an in vitro dissolution test method that simulates in vivo conditions when humans take tablets internally.) Next, the amount of antibiotic dissolved in each test solution is quantified. Find the elution rate. The test solution used for dissolution rate measurement was tested after 1 hour (PH 1.2), 2 hours (PH 4.5), and 4 hours (PH 4.5) after rotational movement.
6.9), after 6 hours (PH6.9) and after 8 hours (PH6.9)
These are each test solution.

This shows that even when tabletted, there is almost no difference in dissolution of the main drug from that of the raw material granules, indicating that the enteric coating of the raw material granules is working effectively.

Next, examples of the present invention will be shown.

Example 1 Eudragit L (manufactured by Rohm and Haas) and Eudragit RS (manufactured by Rohm and Haas)
250 g of spherical pellets (containing 500 mg of cephalexin in 1 g) with a diameter of 0.5 mm coated by spraying with a 1:1 mixture of ethyl alcohol solution (manufactured by Haas) were processed using a centrifugal fluid granulator (manufactured by Freund Sangyo). , CF360), and while rotating at 200 rpm, a solution prepared by dissolving 50 g of acetin fat (higher fatty acid triglyceride, manufactured by NOF Corporation) in methylene chloride was sprayed (Slit Air 250, spray 3 atm, 15 ml/min). While spraying, 80 g of Avicel 101 (crystalline cellulose, manufactured by Asahi Kasei Corporation) was continuously sprayed to obtain enteric-coated granules for tablet forming with a diameter of 0.7 mm.

760 mg of this granule (containing 250 mg of cephalexin titer) was mixed with 10 mg of magnesium stearate, and then tableted (manufactured by Okada Seiko Co., Ltd., KT-
2), Diameter 17.4mm, Minor axis 7.5mm, Thickness 7.5mm, Weight
Oval cephalexin enteric-coated tablets of 770 mg and potency of 250 mg were obtained.

Example 2 The mixture of tablet-molded enteric granules and magnesium stearate obtained in Example 1 was compressed into an oval shape with a diameter of 17.4 mm, a minor axis of 7.5 mm, a thickness of 6.7 mm, a weight of 770 mg, and a titer of 250 mg. Cephalexin enteric-coated tablets were obtained.

Example 3 Tablet-molded enteric granules 684 obtained in Example 1
mg (cephalexin 225 mg potency), cephalexin 27 mg (25 mg potency), Neusilin S-2 (magnesium aluminate metasilicate) 15 mg and L
-HPC (low density hydroxypropyl cellulose)
Cephalexin granules (12-20 mesh) consisting of 10mg 82mg and magnesium stearate 7.0
The components were mixed at a ratio of 1.0 mg and then tableted to obtain oval cephalexin specific tablets with a major axis of 17.4 mm, a minor axis of 7.5 mm, a thickness of 7.2 mm, a weight of 743 mg, and a potency of 250 mg.

Example 4 Diameter 1 mm, length 1 coated with a 7:3 mixture of HP-55 (hydroxypropyl cellulose phthalate, manufactured by Shin-Etsu Chemical Co., Ltd.) and Sierra Tsuk (Japanese Pharmaceutical Co., Ltd.)
~2 mm Cephalexin cylindrical granules (600 mg titer/g) 300 mg were placed in a coating pan (5 volumes,
No. 16D-S (manufactured by Kikusui Seisakusho), and while gradually adding 50 g of a 4:6 mixture of polyethylene glycol (#1000) and liquid paraffin (Japanese Pharmacy Light),
100 g of a 3:1 mixture of L-HPC and talc was sprinkled intermittently to obtain enteric granules for tabletting with a diameter of 2 mm and a length of 25 mm.

425g of this granule contains 80.2g (935mg) of cephalexin.
titer/g), Avicel 101 (crystalline cellulose) 100g
The granulated material (12 to 20 meshes) and 4.8 g of magnesium stearate were mixed and compressed into tablets (Kikusui rotary tablet press, RT-F-9-2), with a major axis of 17.4 mm and a minor axis.
An oval cephalexin specific tablet of 7.5 mm, thickness of 7.5 mm, weight of 770 mg, and potency of 250 mg was obtained.

Example 5 A mixture of enteric-coated granules for tablet forming obtained in Example 1 and magnesium stearate was compressed to form cephalexin enteric-coated tablets (cephalexin per tablet).
225mg titer), each tablet contains cephalexin
27mg (potency 25mg), Neusilin S-2 (magnesium aluminate metasilicate) 15mg, L-HPC 10mg
A proportion of cephalexin granules was layered on the above enteric-coated tablet and compressed to obtain a cephalexin sustained-release laminated tablet with a potency of 250 mg.

Example 6 In place of the mixture of Eudragit L and Eudragit RS in Example 1, a 100:25 mixture of Eudragit S and Eudragit E was used to obtain enteric granules for tablet forming in the same manner as in Example 1, and then carried out. The tablets were compressed in the same manner as in Example 1 to obtain enteric-coated tablets.

[Brief explanation of drawings]

FIGS. 1 and 2 are graphs showing the relationship between the dissolution rate of the active ingredient and time in the tablets and raw material granules of the present invention.

Claims (1)

[Scope of Claims] 1. A method for producing pharmaceutical tablets, which comprises coating antibiotic-containing granules having an enteric coating with an oily substance and a fibrous excipient, and then tableting them. 2. Antibiotic-containing granules having an enteric coating are coated with an oily substance and a fibrous excipient, and then tableted using antibiotic-containing granules not having an enteric coating. Method for manufacturing pharmaceutical tablets. 3. The manufacturing method according to claim 2, wherein granules coated with an oily substance and fibrous excipient and granules without an enteric coating are compressed into tablets in a mixed state. 4. The manufacturing method according to claim 2, wherein the granules coated with an oily substance and a fibrous excipient and the granules without an enteric coating are layered and then compressed into tablets. 5. A patent claim in which the tablet is compressed in such a state that the granules coated with an oily substance and a fibrous excipient are in the center, and the granules without an enteric coating are present as an outer layer around the granules. The manufacturing method according to scope 2.