KR0165920B1 - A process for the preparation of three layered tablets - Google Patents

Abstract

The present invention relates to a method for preparing a gastrointestinal drug in the form of a triple tablet, wherein the upper layer and the lower layer are mixed, granulated, and mixed with antacid sodium bicarbonate, magnesium metasilicate aluminate, magnesium carbonate and aldioxa (allantoin). In the middle layer, biodiastatase, lipase, and scopolyax were mixed in the middle layer and compressed into three tablets. The upper layer and the lower layer maintain the pH of the enzyme by 3.5 ~ 5.0 for gastric hashing. A novel triplet gastrointestinal drug characterized by maximizing.

Description

How to prepare triple tablets

1 is a partial cutaway cross-sectional view of a triplet gastrointestinal drug according to the present invention.

(a): upper layer (containing antacid and gastrointestinal protective agent)

(b): middle layer (enzyme)

(c): lower layer (containing antacid and gastrointestinal protective agent)

Figure 2 is a flow chart of drug efficacy in the stomach of the triple tablet gastrointestinal according to the present invention.

(a): Dissolution of the upper and lower layers after the start of dosing.

(b): The antacids in the upper and lower layers dissolve and surround the stomach wall to suppress acid secretion.

(c): enzymatic action of the middle layer begins.

The present invention relates to a method for preparing triple tablets gastrointestinal drugs, the antacid layer is dissolved first to protect the gastric mucosa, and after adjusting the acidity of the digestive enzyme layer is dissolved in a triple tablets gastrointestinal drugs that can promote digestion. More specifically, the upper and lower layers contain sodium carbonate, magnesium metasilicate aluminate, magnesium carbonate, aldioxa (allantoin), which are antacid and gastrointestinal agents, and biodiastatase and lipase, which are enzymes, in the middle layer. The present invention relates to a triple gastrointestinal medicament containing Scofolia X, which has the effect of inhibiting and secreting digestive smooth muscle.

Formulations having the same ingredients as the main medicinal ingredients of the present invention (Japan's Toda Gastrointestinal Drugs) are known, but this is known as a single dose of three tablets, in which each ingredient is homogeneously mixed in a conventional uncoated tablet form.

That is, the known gastrointestinal drugs include sodium tricarbonate 400 mg (133.3 mg in 1 tablet), magnesium metasilicate aluminate 250 mg (83.3 mg in 1 tablet), magnesium carbonate 130 mg (43.3 mg in 1 tablet), and 50 g Aldioxa. (16.6 mg in one tablet), biodiastatase 1000 30 mg (10 tablets in one tablet), lipase AP 6 10 mg (3.3 mg in one tablet) containing three tablets in a single dose not only inconvenient to take. Since pH 3.5-5.0 is not maintained, the disadvantage that the role of the enzyme may be halved.

The method of preparing the triple tablet formulation of the present invention is not only different from the uncoated tablet without a homogeneous mixed tablet layer of the whole known formulation, but the antacid layer is first dissolved to protect the gastric mucosa, and the acidity is pH 3.5∼ Maintained at 5.0 to optimize the activity of the digestive enzymes in the middle layer, and has the advantage of designing and designing a prescription so that one dose is 2 tablets (see FIGS. 1 and 2).

The triple tablet gastrointestinal agent of the present invention contains sodium bicarbonate, magnesium metasilicate aluminate, magnesium carbonate and aldioxa (allantoin) as the same component and the same amount of the antacid component in the upper and lower layers, respectively, It contains aspartase, lipase, and Scofolia X, a herbal ingredient with hardening action. More specifically, it contains 200 mg of sodium bicarbonate, 125 mg of magnesium aluminate silicate, 65 mg of magnesium carbonate, 25 mg of dioxa, squalene It is prepared to contain 5 mg of polyaex, 15 mg of biodiastatase and 5 mg of lipase AP 6, followed by first mixing and granulating sodium bicarbonate, magnesium metasilicate, magnesium carbonate and dioxa which will be contained in the upper and lower layers. To prepare an antacid granule, and separately mix the biodiastatase, lipase and scofolia extract which are contained in the intermediate layer. After preparing the first powder, to half quantity of antacid granules prescribed amount in the lower layer, other appointed after the entire amount of the supernatant an enzyme powder prescribed amount of the intermediate layer into a half quantity of antacid granules prescribed amount to prepare a triple positive.

Ordinary excipients, crystalline cellulose, polyvinylpyrrolidone, lactose and the like can be added in an acceptable amount, and flavorings such as peppermint oil can also be added.

The triple tablet according to the present invention is a digestive gastrointestinal preparation of a novel formulation, wherein the upper and lower layers containing an antacid and a gastrointestinal protective agent are first dissolved to cover the stomach wall to inhibit gastric acid secretion, and the intermediate layer containing an enzyme while maintaining a gastric pH of 3.5 to 5.0. It is designed to dissolve and increase the physiological activity of the enzyme to the maximum, and has the advantage of excellent antacid and enzyme digestion, and also has the advantage of simplifying to take two tablets once.

Hereinafter, examples and experimental examples of the present invention will be described.

Example 1

[Production of Antacid Granules]

5 g of hydroxypropyl cellulose are dissolved in 265 g of ethanol (binding solution). Separately, 200 g of sodium hydrogen carbonate, 125 g of magnesium aluminate silicate (containing 80 mg as a dried product), 65 g of magnesium carbonate, and 25 g of dioxa are passed through a No. 24 sieve and fed into a Dulida mixer (mixture). The binder is slowly added to the mixture to form particles for 20 minutes to form particles, and the raw materials having been formed are placed in a fluidized bed drier and dried (intake temperature -65 ° C, exhaust temperature 55 ° C, humidity 1.5-2%). Condition). The dried raw material was passed through a No. 16 sieve, and then, 15 g of low-substituted hydroxypropyl cellulose and 5 g of stearin magnesium were passed through No. 40 sieve. Prepare granules containing.

[Production of Enzyme Powder]

25 g of biodiastatase, 5 g of lipase AP 6, and 1 g of magnesium stearate are passed through a 40-mesh sieve and then transferred to a debulcon mixer using a powder feeder. Next, the scopolyax fold acid 79g (corresponding to 5 g of Scopolyax) is transferred to a debulcon mixer using a powder feeder and mixed for 30 minutes to prepare an enzyme powder.

[Compression with Triplet]

The rotary tableting machine is filled and tableted so that the lower antacid granules 215-220 mg per triple tablet, 110 mg of enzyme powder in the middle layer, and 215-220 mg in the upper layer. The upper layer and the lower layer were white to milky white, and the middle layer was made of round triple tablets of light brown.

Check the edges of tablets, the incorporation of enzymes into the antacid layer, the adsorption of foreign substances on the surface of tablets, and the color of enzymes.

Triple tablets prepared in this way is to take two tablets once adult, three times a day after meals or between meals.

Experimental Example

Stability tests were performed with samples of three Lot no PNTs 101, 102, 103 (manufacture date: 1990.8.30) prepared according to Example 1.

I. Main equipment used for stability test

1) Thermo-hygrostat-Constant temperature and humidity

2) UV-Spectrophotometer

3) HPLC-For content test

4) Atomic Absorption Spectrometer-for content test

II. Test Methods

1) Appearance: Observe directly with the naked eye.

2) Disintegration test: Should follow the disintegration test of the general test method of the KP.

3) Confirmation test

(1) Magnesium metasilicate

It conforms to the identification test of MBA 85-9 magnesium metasilicate, sodium hydrogencarbonate, and pancreatin tablet.

(2) sodium bicarbonate

It conforms to the identification test of MBA 85-9 magnesium metasilicate, sodium hydrogencarbonate, and pancreatin tablet.

(3) magnesium carbonate

It is tested according to the Magnesium Identification Test in (1).

(4) Aldioxa

Grind 5 tablets finely, powder it, add 10 ml of diluted hydrochloric acid, and boil for 5 minutes, and add phenyl hydrazine solution (1 100) Add 10 ml, cool, add 0.5 ml of potassium ferricyanide solution, mix well, and shake again with 1 ml of hydrochloric acid. The solution turns red.

(5) Scopolia X

About 50 mg of Scopolyaex is used as a powder, and the same procedure is followed for the identification test for Magnesium Metasilicate Aluminate, Sodium Hydrogen Carbonate, and Pancreatin Tablet.

(6) biodiastatase 1000, lipase AP6

Positive test when tested according to the Assay.

4) Antacid Test

Take about 20 tablets or more of this solution and weigh it to get the average weight of 2 tablets. Use powder as a powder to mix equally with No. 45 (350㎛), add 550mg accurately, add 100 ml of 0.1N hydrochloric acid, and stop. Shake for 1 hour at ± 2 ℃, mix, filter and cool. If necessary, filter again to accurately extract 50 ml of the filtrate, and titrate the excess hydrochloric acid with 0.1 N sodium hydroxide solution. The end point of the titration is pH 3.5. Do a blank test in the same way.

f: Regulatory coefficient coefficient of 0.1N sodium hydroxide solution

a: consumption amount of 0.1 N sodium hydroxide solution (ml)

b: Consumption of 0.1 N sodium hydroxide solution (ml)

t: weight of 6 tablets

s: amount of sample (mg)

5) Content test

(1) Silicate (SiO ₂ ), Aluminum Oxide (Al ₂ O ₃ ), Magnesium Oxide (MgO): Metabolic Aluminate in Magnesium Aluminate Magnesium Aluminate, Sodium Hydrogen Carbonate, Pancreatin Tablet Test according to Magnesium Assay.

(2) Aldioxa (Allantoin)

Take 20 tablets of Blue No. 401 and powder it. Take 1 mg of allantoin as an equivalent and add water to make exactly 100 ml. Use this solution as the sample solution. Separately, weigh 100 mg of alatoine (105 ℃, 3 hours, dry) accurately and add water to make exactly 100ml. Take 1ml of this solution and add water to make 100ml. Use this solution as standard solution. Take 5 ml of each sample and standard solution into a brown stoppered test tube, add 1 ml of 0.5 N sodium hydroxide, close the stopper, warm for 8 minutes in a water bath, cool, and add 5 ml of 0.4 N potassium dihydrogen phosphate solution. Diacetyl monooxime, acetic acid solution (1 200) and 5 ml each of the antipyrine-ferric sulfate solution prepared in a 1: 1 ratio, accurately warmed up in a water bath for about 40 minutes, ice-cooled, and left at room temperature for about 15 minutes. Separately, about 5 ml of each diluted 100-fold sample and standard solution are accurately taken, and 1 ml of 0.5 N sodium hydroxide and 5 ml of 0.4 M potassium dihydrogen phosphate are added in the same manner.

Absorbances A _T and A _S were measured at a wavelength of 460 nm with the blank test solution as a control.

◎ Diacetyl monooxime, acetic acid solution (1 200): 0.5 g of diacetyl monooxime diluted with dilute acetic acid (1 20) is added to make 100ml.

◎ Antipyrine-ferric sulfate solution: dilute sulfuric acid (1 g in antipyrine 0.4g and ferric sulfate 0.005g 5) is added to make 100ml.

(3) aluminum

① Preparation of Test Solution

Take at least 20 tablets of powder, powder it, weigh 1 g precisely, place it in a crucible of porcelain, loosen the lid, heat it, and carbonize it. After cooling, 4 ml of nitric acid and 1 ml of sulfuric acid are added and carefully heated until white smoke is not formed. When the carbide is left again, it is wetted with a small amount of nitric acid and sulfuric acid after cooling and heated again, and then carbonized by heating at 600 ° C. for 4-5 hours. After cooling, add 2 ml of aqua regia, evaporate to dryness in the water bath, and add 10 ml of boiling water and 5 drops of hydrochloric acid to the residue, and warm for 5 minutes. If necessary, filter by cold and water, wash the residue as water, add filtrate and tax solution, and add water to make exactly 100 ml. Take 5 ml of this solution accurately and add 0.5 ml of hydrochloric acid and water to make exactly 100 ml. Use this solution as the sample solution.

② Preparation of Standard Solution

Take an appropriate amount of aluminum standard stock solution and add water to make aluminum standard solution of 0.2ppm, 0.4ppm and 0.6ppm, respectively.

③ operation

For the sample solution and the standard solution, test is carried out in accordance with the KP Atomic Absorption Spectrophotometry under the following conditions, and the aluminum concentration in the sample is obtained from the calibration curve obtained from the absorbance of the standard solution.

④ Condition

Gas used: flammable gas-acetylene, delayed gas-nitrous oxide

Lamp: Aluminum Hollow Cathode Lamp

Wavelength: 309.2 nm

(4) sodium bicarbonate

Take 20 tablets of Blue No. 204 and weigh it precisely to make a powder. Take about 300mg of sodium bicarbonate and dissolve it in 30ml of water. Filter the residue by washing with 10ml of water 2 times and combine the filtrate and the tax solution. Add 3 drops and titrate with 0.1 N sulfuric acid.

0.1 N sulfuric acid 1 ml = 8.402 mg H _a HCO ₃

(5) Hiyosushiamine in scofolia extract

① Preparation of Standard Solution

Accurately take 33 mg of L-hiyosushiamine standard (in terms of dry weight loss), place it in a 100 ml volumetric flask, completely dissolve in 30 ml of methanol: water (70:30), and fill it to the mark with methanol: water (70:30). Take 10 ml of this solution into a 100 ml volumetric flask, fill it with methanol: water (70:30) to the mark, and filter with 0.45㎛ membrane filter to obtain a standard solution.

② Preparation of Test Solution

Take 20 tablets or more and calculate the average weight. Use powder to make 3.3 mg of Hiyosushiamine. Add 100 ml volumetric flask and fill with methanol: water (70:30) to the mark, stir for 30 minutes, and stir to 0.45㎛. After filtering by membrane filter, it is used as the sample solution.

③ operation

Perform the liquid chromatograph method in the pharmacopoeia general test method for 10µl of the standard solution and the sample solution under the following conditions, and then obtain the areas Q _S and Q _T of the standard solution and the sample solution.

④ Calculation: amount of hiyosushiamine (mg)

⑤ Condition

Column: Spectraphysics Spherisorb 10 Si (L: 25cm, I.D: 4.6cm)

Detector: UV Absorbance Spectrometer (210nm)

Flow rate: 1.5 ml / min

Temperature: Constant temperature around 30 ℃

Chart Speed: 0.5cm / min

Mobile phase: Methanol containing 0.1w / v% sodium lauryl sulfate, 0.33w / v% tetramethylammonium chloride, 0.05w / v% sodium perchlorate: Phosphate buffer mixture (55:45) at pH 6.8

Sensitivity: 0.01 Aufs

(6) starch sugar power (pH 5.0)

Take more than 20 tablets of Peony, weigh it, make powder, and weigh 1.0 g accurately. Add 50 ml of acetic acid and sodium acetate buffer solution (pH 5.0), shake for 10 minutes, mix, and centrifuge. Take 10 ml of this supernatant and add water to make 100 ml.

Take 10 ml of 1% solution of potato starch, leave at 37 ± 0.5 ° C for 10 minutes, and accurately add 1 ml of sample solution and shake. Leave this solution for 10 minutes at 37 ± 0.5 ℃, add 2 ml of alkaline tin salt solution of Ferring solution, shake well, add 2 ml of copper solution of Ferring solution, shake gently, place a funnel in a test tube, and heat for 15 minutes in a water bath. After cooling to below ℃ 2 ml of potassium iodide solution and diluted sulfuric acid (1 6) Add 2 ml of free iodine and titrate with 0.05 N sodium thiosulfate solution (b ml). When the end point of titration is close, add 1 ~ 2 drops of soluble starch solution. The color should be colorless.

10 ml of water instead of 10 ml of potato starch 1% solution was added and titrated as above.

f: Regulatory coefficient coefficient of 0.05N sodium thiosulfate solution

W ₁ : Average weight per tablet

W ₂ : Amount of sample taken.

Inverse assumption-When amylase acts on potato starch at 37 ° C, the amount of enzyme that leads to an increase in reducing power corresponding to 1 mg of glucose in 1 minute of the initial reaction is called 1 unit of starch saccharification capacity.

[Hours]

Acetic acid, sodium acetate (pH 5.0)-Add 13.6 g of sodium acetate to make 100 ml, and add diluted acetic acid to pH 5.0.

Potassium iodide TS-Dissolve 70 ml of water in 30 g of potassium iodide. Shade preservation, prepare when using. 1% solution of potato starch-1 g of potato starch is dried at 105 ℃ for 2 hours, and then the weight loss is measured. Accurately weigh the potato starch corresponding to 1.0 g of the dried product, add 20 ml of water, dissolve, shake, add 5.0 ml of 2N sodium hydroxide solution, heat for 3 minutes in a water bath, add 25 ml of water, cool, neutralize with 2N hydrochloric acid solution, and acetic acid and acetic acid. Add 10 ml of sodium buffer solution (pH 5.0) and add water to make 100 ml. Manufactured when used.

(7) starch purification power (PH 5.0):

Take over 20 tablets of Peony, weigh it to make powder, and weigh 2.6g accurately, add 100 ml of acetic acid and sodium acetate buffer solution (pH 5.0), shake gently for 10 minutes, mix, and centrifuge to add 5 ml of supernatant. It is taken as the test liquid. Take 10 ml of 1% solution of potato starch and leave it at 37 ± 0.5 ℃ for 10 minutes, shake 1 ml of sample solution, and shake the solution at 37 ± 0.5 ℃ for 10 minutes. Take 1 ml of this solution, add 10 ml of 0.1 N hydrochloric acid solution, and shake. Mix 0.5 ml of this solution, add 10 ml of 0.0004 N iodine solution, shake, and measure the absorbance A _T at 660 nm. Separately, add water instead of the sample solution, and operate in the same manner as the sample solution to measure the absorbance A _B.

W ₁ : average weight per tablet

W ₂ : Amount of sample taken

Inverse assumption: When amylase acts at 100 mg of potato starch and 37 ° C, the amount of enzyme that reduces the blue color of potato starch by iodine 10% in the first minute of reaction is called 1 unit of starch purification power.

(8) Protein Digestive Power (PH 6.0):

Take 20 tablets of Peanuts and weigh them to make powder. Then, weigh 2.6 g and precisely weigh, add 50 ml of cooled 0.1 N phosphate buffer in pH 6.0, shake gently for 20 minutes, mix, and filter the filtrate as a sample solution.

Take 5.0 ml of casein solution (PH 6.0) accurately, leave it at 37 ± 0.5 ° C for 10 minutes, add 1 ml of sample solution, and shake. Leave this solution at 37 ± 0.5 ℃ for 10 minutes, add 5.0ml of trichloroacetic acid solution, shake and mix, and then filter at 37 ± 0.5 ℃ for 30 minutes.

Accurately take 2.0 ml of the filtrate, 5.0 ml of 0.55 M sodium carbonate solution and diluted polyline solution (1 3) Add 1.0 ml and leave for 30 minutes at 37 ± 0.5 ℃, and measure the absorbance A _T at a wavelength of 660 nm.

Shake into the acetic acid solution, 5.0ml trichloroacetic accurately taking a sample solution separately and then 1.0ml caseinate solution into a 5.0ml allowed to stand 30 minutes at 37 ± 0.5 ℃ and measure the absorbance A _B by operating as above follows.

W ₁ : Average weight per tablet (mg)

W ₂ : Amount of sample taken (mg)

F: It is calculated | required by the tyrosine calibration curve as the quantity (microgram) of tyrosine corresponding to an absorbance difference of 1.000.

When the protease acts on casein at -37 ° C of the inverted family, the amount of enzyme that brings about an increase in the nonproteinaceous colorant corresponding to 1 μg of tyrosine in the first minute of the reaction is called 1 unit of protein digestibility.

Preparation of tyrosine calibration curve Accurately weigh 500.0 mg of tyrosine standard foam dried at -105 ° C for 3 hours, add 0.2 N hydrochloric acid solution to make 500 ml. Take 1.0 ml, 2.0 ml, 3.0 ml and 4.0 ml of this solution accurately, and add 0.2N hydrochloric acid solution to make 100.0 ml.

Take 2.0 ml of each solution accurately, 5.0 ml of 0.55 M sodium carbonate solution, and diluted polyline solution (1 3) Add 1.0 ml and leave for 30 minutes at 37 ± 0.5 ℃ and immediately measure the absorbance A ₁ , A ₂ , A ₃ and A ₄ at a wavelength of 660nm.

Separately, 2.0 ml of 0.2 N hydrochloric acid solution was operated in the same manner to measure absorbance A _B.

A calibration curve is prepared with the difference in absorbance on the vertical axis and the amount of tyrosine on the horizontal axis.

[Hours]

Trichloroacetic acid solution-Trichloroacetic acid 1.80g and anhydrous sodium acetate 1.80g, add 5.5ml of 6N acetic acid and water to make 100ml.

1 g of casein solution (PH 6.0) -emulsine casein was dried at 105 ° C. for 2 hours to calculate the weight loss. Take 1.2 g of the corresponding amount as the emulsion casein, add 160 ml of 0.05M sodium dihydrogen phosphate TS, dissolve and cool in a water bath, and cool. Add hydrochloric acid or 1N sodium hydroxide solution to adjust to PH6.0 and add water to make 200ml. Prepare when writing.

Water is added to 58.3 g of 0.55M sodium carbonate TS-sodium carbonate to dissolve to 1000 ml.

(9) Fat Digestion (PH 6.0):

Take 20 tablets of Blue No. 204 and weigh it as a powder. Accurately weigh 4.5 g, add water to dissolve it, and filter it to 50 ml. The filtrate is used as a sample solution.

5.0 ml of olive oil emulsion and 4.0 ml of 0.1M phosphate buffer solution are mixed and left to stand for 10 minutes in a constant temperature water bath at 37 ° C. Then, 1 ml of sample solution is added and shaken every 10 minutes to react for exactly 20 minutes at 37 ° C. The mixture of acetone and ethanol (1 1) Add 10 ml to stop the enzyme reaction, add 10 ml of 0.05 N sodium hydroxide solution and 10 ml of acetone-ethanol mixture (1: 1), titrate 0.05 N hydrochloric acid solution with excess sodium hydroxide (Aml)

(Indicator: 2 drops of phenolphthalein solution)

Separately, add 10 ml of acetone and ethanol mixture (1: 1) to 1 ml of the test solution, and titrate it in the same manner as above.

F: Regulatory coefficient of 0.05N hydrochloric acid

The amount of enzyme which liberates the free acid corresponding to 0.6 ml of 0.05 N sodium hydroxide solution for 30 minutes at -37 ° C of the inverse household is called 10 units of fat digestion capacity.

(The amount of enzyme that liberates an acid corresponding to 1 μeq for 1 minute under the above conditions is referred to as a 10-digestion capacity).

[Hours]

Olive oil emulsion: Take 75 ml of olive oil and 225 ml of 2% polyvinyl alcohol solution, emulsify in an ice cold bath at 3 ~ 10 ℃ for 10 minutes, and use.

2% polyvinyl alcohol solution: 5 g of polyvinyl alcohol is suspended in 250 ml of water and heated to 80 ° C with shaking.

After cooling, leave this solution until cleared and filter.

Phosphate buffer (PH 6.0): 0.1M potassium dihydrogen phosphate (KH ₂ PO ₄ ) 0.1M sodium dihydrogen phosphate (Na ₂ HPO ₄ ) is adjusted to pH 6.0.

Ⅲ, Test Result Data: (See Table 1)

Ⅳ Observation of Results

As a result of the long-term storage test results, the product was judged to be stable for 3 years of use, and could not confirm the formation of degradation products.

Ⅳ. Observation of the results

As a result of the long-term storage test results, the product was judged to be stable for 3 years of use, and the formation of degradation products could not be confirmed.

Claims (2)

In the preparation of triplet gastrointestinal drugs, the upper layer and the lower layer are mixed and granulated with sodium carbonate, magnesium metasilicate aluminate, magnesium carbonate and aldioxa (allantoin), which are antacid components, and the middle layer is biodiastat, which is an enzyme component. 1000, lipase AP6 and scopolyax is mixed, it is a triple tablets manufacturing method characterized in that the tablets are prepared. The method of claim 1, wherein the antacid component of the upper layer and the lower layer is prepared to maintain the gastric acidity at pH 3.5-5.0 when dissolving in the stomach, so that the enzyme exhibits the best enzymatic power at the optimum pH. .