KR20000012706A - Method of preparing enteric soluble preparations - Google Patents

Abstract

The present invention relates to a method for producing an enteric preparation, after mixing an excipient such as lactose, corn starch, crystalline cellulose to powder, and then mixing the dough with an enteric coating base to form a mixture, and then drying it as it is or constant with an extrusion molding machine. Forming and drying the shape, the method for producing an enteric preparation having a composition for coating each of the fine particles as described above, even if a part of the formulation is damaged, the rest of the function is preserved, the dissolution rate of the conventional enteric preparation Compared to 2.5 times as compared to the preparation method of enteric preparations that omit the process of coating other surfaces through the manufacturing method of the enteric preparations that can shorten the manufacturing time, reduce the manufacturing cost, and prevent the inhibition of enzyme activity during the preparation Provide a method.

Description

Method of preparing enteric soluble preparations

The present invention relates to a method for producing a preparation having an enteric function, and more particularly, to an additive having an enteric purpose, and evenly mixing and drying the binding base having an enteric purpose, after adding an excipient to the powder or fine particles. It relates to a method of preparing a formulation.

Pancreatic enzymes produced in the pancreas are secreted into the duodenum, and the pH of the duodenum is neutral or about alkaline. Under this pH condition, the enzyme is active and digestion of food by the enzyme proceeds in the upper part of the intestine. However, when pancreatic enzymes are injected from the outside of the body, gastric acid conditions in the stomach inactivate the enzymes. Thus, orally administered enzymes should be protected against inactivation of gastric acid, so that they remain intact while they pass through the stomach and into the duodenum. Once externally administered enzymes reach the duodenum, the enzymes must be released from their protectors and mixed well with food from the stomach.

In addition to pancreatic enzymes, enzymes or drugs that normally act in the intestine (1) should not be destabilized due to destabilization at a pH value below a certain level, (2) the drug should not dissolve in the stomach, and (3) The drug should not be dissolved in the stomach and the concentration of the drug in the intestines should not be diluted. Enteric preparations that meet these conditions are generally made by coating a film that is soluble in intestinal fluids. U.S. Patent No. 4,079,125 describes a composition that satisfies these conditions and a method of making the composition. Briefly, the composition comprises an enzyme, a binder such as polyvinylpyrrolidone, a stabilizer such as calcium carbonate, It describes a method of mixing with a decomposable substance such as citric acid, and coating the mixture with a nonporous, pharmacologically acceptable enteric coating polymer, and the method of making the composition is supplied with a solvent, enzymes, binders and tablets. This involves avoiding contact with water as the water inactivates some enzymes during the mixing of the degradants. The conventional method of preparing a preparation having an enteric function is to knead the binder powder such as hydroxypropyl cellulose, gelatin or polyvinylpyrrolidone, and then extruder (extruder, Alexander granulator, reverse rotation). Granules made of rod-shaped using a granulator, and then dried in a dryer (fluid-bed dryer, cabinet hot air dryer) and granulated in a coater (fluid-bed coater, fan cylindrical coater) and the surface is coated with an enteric coating material. The coating method is common, and in this method, it is common to apply the first coating on the granules, and then to the second coating on the coating, or to directly coat the surface of the granules. However, when the enteric granules are made by coating the surface of such granules, there is a problem of lowering the titer due to the heat generated during the extrusion process, and according to the morphological characteristics of the obtained granules, preparation of tablets using the same as raw materials Part of the surface damaged due to breakage of the surface coating layer in the process appears a problem that can no longer exhibit the function of enteric. In addition, since a large amount of coating material is inevitable for the surface coating of granules, there is a problem of increasing the manufacturing cost due to the use of a high titer raw material.

The present invention has been made to solve the above problems, an object of the present invention is to provide a method for producing an enteric preparation that is simple, inexpensive, fast dissolution rate, and capable of maintaining complete function in the intestine.

1 is an electron micrograph of an enteric preparation of the present invention. (a) is a photograph of the powder untreated coating, (b) is a photograph of the enteric preparation of the present invention, (c) is a photograph of the enteric preparation prepared by the method of coating the surface, which is a method of making an existing enteric preparation

Figure 2 is a figure showing the dissolution comparison test results of the enteric preparation of the present invention, P-1 represented by a thin line is an enteric preparation of the present invention, P-2 represented by a thick line is a conventional enteric preparation.

In order to achieve the above object, the present invention provides a method for preparing a formulation composition having an enteric function by combining and drying a binder base having an enteric purpose after mixing and adding an excipient to the powder or fine particles.

The preparation method of the enteric preparation of the present invention is uniformly blended excipients such as lactose, corn starch, crystalline cellulose in the powder and then put the formulation in a fluidized bed coater or granulator equipped with an upward, downward or side spray nozzle for a predetermined time, preferably For example, the enteric substrate may be spray-dried through a nozzle while mixing for about 10 to 30 minutes to obtain enteric granule particles of appropriate size.

The weight ratio% of the powder or fine particle mixture containing the coating base and the excipient used in the present invention has a lower titer as the ratio of the coating base is higher, and the coating effect is lowered when the ratio of the coating base is too low. 70 is preferable and 40:60 is the most preferable.

The concentration of the coating base solution used in the present invention is a final solid, it takes a long time to coat at 5% or less, and the viscosity becomes greater at 30% or more, so 5 to 30% is preferable.

The diameter of the particles of the powder or fine particles is preferably 30-70 um.

Hereinafter, the present invention will be described in detail through non-limiting examples and experimental examples.

Example 1

A. Preparation of Coating Liquid Composition

Eudragit L100, a methacryl polymer, is prepared by mixing 25 g, 25 g of methylene chloride, and 25 g of isopropanol. Since methylene chloride and isopropanol are evaporated during drying, the final weight ratio of Eudragit in the mixture of A and B is 25% (ie 25 g).

B. Preparation of Enzyme Mixtures

56 g of pancreatin (USP 9X) and 19 g of lactose were mixed.

After adding the enzyme mixture in the kneader and mixing it uniformly for 30 minutes, the coating solution of A was added and stirred continuously for 10 minutes and then dried in a fluidized bed dryer at 50 ℃ for 20 minutes to obtain an enteric granules.

Example 2

A. Preparation of Coating Liquid Composition

25 g of HPMCP HP-55 which is hydroxymethyl cellulose phthalate, 30 g of methylene chloride, and 45 g of isopropanol are mixed and prepared. Since methylene chloride and isopropanol are evaporated during drying, the final weight ratio of HPMCP in the mixture of A and B is 25% (ie 25 g).

B. Preparation of Enzyme Mixtures

56 g of pancreatin (USP 9X) and 19 g of corn starch were mixed.

In a high-speed granulator equipped with a stirrer, add the enzyme mixture of B and mix it uniformly for 10 minutes, add the coating solution of A, stir and knead it continuously for 10 minutes, and dry it at 50 ° C. for 20 minutes to obtain an enteric granule. Could.

Example 3

A. Preparation of Coating Liquid Composition

83.3 g (25 g of final solids) of a solid 30% suspension of Eudragit L30 D55, a methacryl polymer, was prepared.

B. Preparation of Enzyme Mixtures

56 g of pancreatin (USP 9X) and 19 g of corn starch were mixed.

In the fluidized bed granulator equipped with the top spray, enteric enzyme mixture of B was added, and the enteric granules were obtained by maintaining the internal temperature at 50 ° C. while spraying the coating liquid of A through the nozzle for 150 minutes.

Example 4

A. Preparation of Coating Liquid Composition

83.3 g (25 g as the final solid) of a 30% suspension of the Collicoat MAE30DP solid content, which is an acrylic polymer, was prepared.

B. Preparation of Enzyme Mixtures

56 g of pancreatin (USP 9X) and 19 g of corn starch were mixed.

In the fluidized bed granulator equipped with a rotary stirrer on the bottom surface, enter the enzyme mixture B and inject the coating solution of A through the nozzle for 120 minutes while performing the fluidization movement, and maintain the internal temperature at 50 ℃ to obtain the enteric granules. there was.

Example 5

A. Preparation of Coating Liquid Composition

25 g of Eudragit S100 solid content, which is an acrylic polymer, was prepared by mixing 25 g of methylene chloride and 50 g of isopropanol. Since methylene chloride and isopropanol are evaporated during drying, the final weight ratio of Eudragit in the A and B mixtures is 25% (ie 25 g).

B. Preparation of Enzyme Mixtures

56 g of pancreatin (USP 9X), 10 g of crystalline cellulose, 8 g of lactose and 1 g of Lake Yellow No. 4 pigment were mixed.

Put the enzyme mixture of B in the kneader and mix it uniformly for 30 minutes, then put the coating solution of A and continuously stir for 10 minutes, and then through the extruder 0.8 mm granule network to prepare rod-shaped granules After drying it to 50 ℃ in a fluid bed dryer it was obtained by sizing.

Example 6

A. Preparation of Coating Liquid Composition

Eudragit L-100, a methacryl polymer, was prepared by mixing 25 g, methylene chloride 25 g, and isopropane in 50 g. Since methylene chloride and isopropanol are evaporated during drying, the final weight ratio of Eudragit L-100 in the A and B mixtures is 25% (ie 25 g).

B. Preparation of Enzyme Mixtures

60 g of fungal lipase (2,000,000 U / ml) and 15 g of lactose were mixed.

After adding the enzyme mixture in the kneader and mixing the mixture evenly for 30 minutes, the coating solution of A was placed and stirred for 10 minutes continuously, which was dried at 50 ° C. in a fluidized bed dryer, and then obtained.

Example 7

A. Preparation of Coating Liquid Composition

83.3 g (25 g as final solids) of a 30% solids suspension of Eudragit L 30 D 55, a methacryl polymer, was prepared.

B. Preparation of Aspirin Mixtures

71 g of aspirin, 3 g of polyethylene glycol 6000 and 1 g of talc were mixed.

In the fluidized bed granulator equipped with a top spray, the aspirin mixture B was added, and the enteric granules were obtained by maintaining the internal temperature at 35 ° C. while spraying the coating liquid A while passing through the nozzle for 150 minutes.

Experimental Example

(Electron micrograph of the structure of the enteric preparation of the present invention)

The enteric preparation of the present invention was photographed by electron microscope. The result is shown in the photograph in FIG. (a) is a photograph of the powder untreated coating, (b) is a photograph of the enteric preparation of the present invention, (c) is a photograph of the enteric preparation prepared by the method of coating the surface, which is a method of making an existing enteric preparation. As can be seen from the photograph, the enteric preparation prepared by the method of the present invention is coated with each fine powder, whereas the enteric preparation prepared by the surface coating method of the conventional granules has a larger particle size than the present invention. In this micrograph, the existing formulation has a form in which only part of the surface is shown.

(Dissolution test)

Take 200 mg of the granules of Examples 1 to 5, and use 500 ml of macilvaine buffer solution (pH3.0) as a test solution to maintain the temperature at 37 ° C. in the vessel of the KEPCO dissolution test apparatus. According to the method (net) eluted at 100 rpm for 2 hours. Immediately, the test solution was changed to 500 ml of macilvaine buffer solution (pH 7.0) and eluted for 1 hour. 50 ml of the eluate was taken, centrifuged at 300 rpm for 15 minutes, and the supernatant was taken as a sample solution.

The dissolution comparison test results of the enteric preparation of the present invention with respect to the conventional enteric preparation are shown in FIG. 2. P-1 indicated by a thin line in FIG. 2 is an enteric preparation of the present invention, and P-2 indicated by a thick line represents a conventional enteric preparation. As can be seen in the figure, since the enteric preparation of the present invention is coated on each powder, the dissolution rate is increased by about 2.5 times or more compared with the conventional formulation.

(Protein digestion test)

1 ml of casein solution (pH 7.0) was accurately taken and allowed to stand at 40 ° C. for 5 minutes. 1 ml of the eluate sample solution obtained in Examples 1 to 5 was accurately taken, shaken, and left at 40 ° C. for 20 minutes. 2 ml of 0.4 M trichloroacetic acid was added to the mixture, followed by shaking. The mixture was left at 40 ° C. for 15 minutes and filtered. 1 ml of the filtrate was taken, and 5 ml of 0.4 M sodium carbonate solution and 1 ml of diluted polyline solution (1 → 3) were shaken, left to stand at 40 ° C. for 15 minutes, and the absorbance A _T was measured at a wavelength of 660 nm with water as a control. Separately, take 1 ml of the sample solution, add 2 ml of 0.4 M trichloroacetic acid solution and 1 ml of casein solution (pH7.0), shake the mixture, and leave it at 40 ° C. for 15 minutes, and measure absorbance A _B in the same manner as described below.

Under the above conditions, when the sample solution is operated in casein solution, the amount of enzyme that produces non-protein polyline solution colorant equivalent to 1 ug of tyrosine in 1 minute is 1 unit of protein digestibility. The experimental results are shown in [Table 1].

Protein Digestion Unit / ml = (A _T- A _B ) x F / 20 x 4

F = amount of tyrosine when the absorbance difference obtained from the tyrosine calibration curve is 1.0 (ug)

[Table 1] Protein digestibility test results

Example 1 Elution time PH of test solution Protein Digestion Power of Eluate (U / ml) 1 hours 3 1.1 2 hours 7 28.9 Example 2 Elution time PH of test solution Protein Digestion Power of Eluate (U / ml) 1 hours 3 1.0 2 hours 7 29.0 Example 3 Elution time PH of test solution Protein Digestion Power of Eluate (U / ml) 1 hours 3 1.3 2 hours 7 28.8 Example 4 Elution time PH of test solution Protein Digestion Power of Eluate (U / ml) 1 hours 3 0.9 2 hours 7 29.0 Example 5 Elution time PH of test solution Protein Digestion Power of Eluate (U / ml) 1 hours 3 1.5 2 hours 7 28.5

(Fat digestion test)

Take 5 ml of olive emulsion and 4 ml of Macilvaine buffer solution (pH 7.0), mix, and leave for 10 minutes in a constant temperature water bath at 37 ° C. Then, 1 ml of the eluate sample solution obtained in Example 6 diluted 5 times with water. The mixture was shaken every 20 minutes, reacted for exactly 60 minutes at 37 ° C, 30 ml of 90% ethanol was added to stop the enzyme reaction, and titrated with 0.05 N sodium hydroxide solution using 1% phenolphthalein solution as an indicator to obtain A ml. Separately, 30 ml of 90% ethanol was added to 1 ml of the test solution by a blank test, followed by titration to obtain B ml.

The titer was defined as 1 unit of lipase titer to enzymatically release an acid corresponding to 1 u mole as oleic acid under the above conditions.

Lipase titer (U / ml) = (A-B) x f x 50 x 5

f = nominal coefficient of sodium hydroxide solution

The experimental results are shown in [Table 2].

[Table 2] Fat digestion test results

Example 6 Elution time PH of test solution Fat Digestion Power of Eluate (U / ml) 1 hours 3 11 2 hours 7 471

(Aspirin Quantitative Test)

Dissolve 1 g of aspirin standard in 100 ml of ethanol and add 1 ml of this solution to 50 ml of water to make 200 ug / ml of aspirin standard. The absorbance is measured by diluting the eluate sample solution obtained in Example 7 with water twice and the standard solution with water at 265 nm.

Aspirin content in the sample solution (ug / ml) = A ₂₆₅ (diluent of the sample solution) / A ₂₆₅ (standard solution) x 200 x 2

The experimental results are shown in [Table 3].

Table 3 Aspirin Quantitative Results

Example 7 Elution time PH of test solution Aspirin content in eluate (ug / ml) 1 hours 3 11 2 hours 7 319

In the method for preparing an enteric preparation having a composition coated on each of the powders described above, even if a part of the preparation is damaged, the rest of the preparation is preserved, and the dissolution rate is 2.5 times higher than that of the conventional enteric preparation. By using the preparation method of the enteric preparation, the process of coating other surfaces was omitted, it was possible to obtain an enteric preparation having the effect of shortening the manufacturing time, reducing the manufacturing cost, and preventing inactivation of the enzyme during preparation.

Claims (7)

In the preparation method of an enteric preparation, a) adding and mixing excipients in the powder or particulate; b) blending the enteric binding substrate into the mixture; And c) a method for producing an enteric preparation, characterized in that it comprises the step of drying the combination. The method of claim 1, wherein the excipient is selected from lactose, corn starch and crystalline cellulose. According to claim 1, wherein the enteric bonding substrate is Eudragit L100, a metaacryl polymer, Eudragit L30 D55, a methacrylic polymer, Eudragit S100, a methacrylic polymer, HPMCP HP-55, and a collicoat of acrylic polymer. A method for producing an enteric preparation, selected from MAE30DP or polyvinylacetate phthalate. 2. The method of claim 1, wherein in step b), a fluidized bed coater or granulator equipped with upward, downward or side spray nozzles is used. The method of claim 1, wherein the diameter of the particles of the powder or fine particles is 30-70 um. The method of claim 1, wherein the powder or particulate is selected from pancreatin, lipase or aspirin. The method of claim 1, wherein the final weight ratio of the coating liquid composition comprising the enteric binder base and the powder or particulate mixture to which the excipient is added is 80:20 to 30:70.