KR20010067732A - The composition and preparation method of stablized enteric coated nattokinase - Google Patents

Abstract

PURPOSE: Provided is an enteric-coated preparation for oral administration that contains nattokinase having physiological activity such as a thrombolysis and requires less production cost. CONSTITUTION: The enteric-coated preparation containing nattokinase includes shellac, zein, hydroxy propylmethyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, poly(methacrylic acid and methyl methacrylate (1:1)), poly(methacrylic acid and ethylacrylate (1:1)), poly(methacrylic acid and methyl methacrylate (1:2)), ethylacrylate, poly(methyl methacrylate, trimethylammonia ethyl methacrylate chloride (1:2:0.2)), and poly(ethylacrylate, methyl methacrylate, and trimethylammonia ethyl methacrylate chloride (1:2:0.1)).

Description

Oral composition which has an anti-thrombolytic enzyme derived from natural products at pH of gastric juice (hydrogen ion concentration) and secures the stability of the enzyme by preventing inactivation of the enzyme against acid and a preparation method thereof { The composition and preparation method of stablized enteric coated nattokinase}

The present invention relates to an enteric preparation of this nattokinase and a method for producing the same to have an enteric function in an enzyme having a thrombolytic action produced by Bacillus nattokinase var, natto (hereinafter referred to as nattokinase). More specifically, it is possible to add homogeneous excipients that are acceptable for food or pharmaceutical use to the powder or fine particles of nattokinase, and then uniformly mix them, and then enteric granules, tablets, or formulations using the same, for example, capsules. It relates to a method for producing an enteric preparation of nattokinase having an enteric function by coating with an enteric coating-forming material for the purpose.

Natokinase is an enzyme that has been purified to function as a natural-derived enzyme having physiological activity of thrombolytic action derived from Bacillus subtilis using naphtha, commonly referred to as nattokinase.

This nattokinase has a neutral to weakly alkaline liquid and an optimum activity at about 55 ° C. The molecular mass measured by gel filtration is a substance having a molecular weight of about 31.5 kDa or 20,000, which is very soluble in water and highly hygroscopic. It is strong and insoluble in organic solvents, and relatively stable at temperature. The remaining activity of enzyme is 95% or more in powder state at room temperature for about 2 years, but it is very unstable in acidic condition. It is a substance having a pH dependent stability that shows a loss in activity, but remains at pH 5.0 to 11 or more at pH 5.0 to 11, as there is almost no residual activity after time.

Currently, commercially available formulations formulated using this nattokinase are mainly hard capsules, soft capsules, and liquid formulations, but all have no enteric function, and all of them have a disadvantage in that the remaining activity in the gastrointestinal tract is significantly decreased due to the influence of gastric acid. There is a situation.

Therefore, enzymes or drugs that are generally labile to gastric acid and intestinal, such as nattokinase, should not be destabilized at pH values below a certain level, and should not be decomposed. Beginning and passing through this area, the release of the drug must begin and be absorbed.

This enteric preparation of nattokinase, which satisfies the above conditions, is generally made by coating a film that can be dissolved in the intestinal fluid.

SUMMARY OF THE INVENTION The present invention has been made to solve the above problems, and an object of the present invention is to provide a composition for oral enteric preparations of nattokinase, an enzyme having a novel thrombolytic action derived from Bacillus subtilis natto, and a method for preparing the same. To provide.

In order to achieve the above-mentioned object as well as other easily expressed object in the present invention, the powder of natokinase is prepared into fine granules, and the film is directly formed by using a base having an enteric purpose for the fine granules, thereby obtaining a tablet and a hard capsule agent. In this case, enteric coatings were formed on tablets formulated with soft capsules or prepared using a mixture of nattokinase and excipients to accelerate dissolution and diffusion of nattokinase in the intestine, resulting in fast dissolution rate and complete enzymatic activity in the intestine. An enteric preparation of nattokinase that can be maintained can be prepared.

The present invention is described in more detail as follows.

In the method for preparing a composition for enteric preparation of nattokinase according to the present invention, an excipient is added to and mixed with powder (37-200 μm) or fine particles (200-590 μm) of nattokinase, followed by mixing a binder base having an enteric purpose. It is characterized by being prepared to have an enteric function by drying to prepare to have an enteric function, or to prepare tablets or capsules using conventionally acceptable excipients and to coat them with an enteric film forming agent.

In addition, the method for preparing enteric preparations of nattokinase according to the present invention includes lactose, corn starch and talc in powder or fine particles of nattokinase. After uniformly mixing the pharmaceutically acceptable excipients in edible or pharmaceutical, such as cellulose, and spray-drying the enteric coating substrate through a spray nozzle in a fluidized bed granulator to obtain fine particles or powder having an enteric function of appropriate size It is characterized by spraying a coating material having an enteric function on a conventional capsule or tablet containing nattokinase to have an enteric function.

If the powder or fine particles of the nattokinase is less than 37㎛ has a disadvantage that the coating is too excessive to exhibit the titer in the upper part of the intestine, when it exceeds 590㎛ there is a problem that the coating effect is reduced.

Excipients include lactose, corn starch and talc. Cellulose or the like may be used, but is not limited thereto, and as long as it is commonly used in the technical field to which the present invention belongs, and does not show adverse effects, any one within the range of a pharmaceutical acceptable for use in food and medicine may be used. This is possible.

The amount of the excipient is not particularly limited, but it is preferable to use 5 to 35% by weight based on the total weight of the components used in the preparation of the enteric powder or the particulate preparation, and when the amount of the excipient is less than 5% by weight, the effect of the excipient is added. There is a weak point, and if it exceeds 35% by weight, there is a disadvantage in that the dosage is relatively excessive, the amount of excipients used in the manufacture of tablets or capsules is suitable for oral administration by the human body and the acid for 2 hours Although it does not need to limit if it is the amount which can resist, Usually, an enteric coating agent can be used within about 10% with respect to a target core.

Enteric coating bases include methacrylic polymers, acrylic polymers, polyvinylacetate phthalates, shellac, zein, cellulose-based enteric film-forming materials such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and the like. The coating substrates commonly used in the technical field to which the invention belongs can be used, but in the present invention, Eudragit L100 or MAE30DP which is a metaacryl polymer, L30 which is a metaacryl polymer, L100-55, S100 which is a metaacryl polymer, HPMCP HP Commercially available ones such as -55 or polyvinylacetate phthalate were used.

The amount of the enteric coating base is not particularly limited, but in the case of powder or fine particles, it is preferable to use 20 to 50% by weight based on the total weight of the core component to be used, and when the amount of the enteric coating base is less than 20% by weight, the coating is performed. There is a disadvantage in that the effectiveness is reduced, there is a lack of enteric, and when it exceeds 50% by weight, the amount of natokinase is relatively reduced, which is not economical, and there is a disadvantage in that the coating bases are combined with each other when coating powder or fine particles, and also tablets and capsules Depending on the size of the preparation, the amount of enteric coating material required depends upon the size of the preparation, but it is usually sufficient to have a resistance for about 2 hours in gastric acid, which is the acid resistance test.

The weight ratio of the nattokinase powder or particulate mixture including the coating base and the excipient used in the present invention is lower in content 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. The ratio of nattokinase 30-60: 40-70 is suitable, and 45:55 is the most preferable.

The concentration of the coating base solution used in the present invention is a final solid content 10% or less, it takes a long time to coat, more than 20% is more preferable 10 to 15% because the viscosity increases. When coating the powder or fine particles, the mixture of the excipient and the nattokinase is added to the fluidized bed coater or the fluidized bed granulator, and then spray-dried the enteric coating material through the spray nozzle while uniformly mixing for a predetermined time, preferably 5 to 10 minutes. Fine particles or powder having an enteric function of are obtained.

That is, the enteric coating material is sprayed and dried while uniformly mixing the excipient and the nattokinase to impart an enteric function. It is preferable that the particle diameter of the finally obtained product is 30-100 micrometers. Enteric coatings of tablets or capsules can be prepared in conventional pan coaters, improved coaters such as hycota, axella coata or the like or fluidized bed coaters and are obtained by uniform coating to show resistance to gastric acid.

The following Examples and Experimental Examples illustrate the present invention in more detail, but do not limit the scope of the invention.

Example 1.

A. Preparation of Coating Liquid Composition

100 g of a solid 30% suspension (30 g as the final solid) of Eudragit L30 D55, a methacryl polymer, was prepared.

B. Preparation of Natokinase Mixtures

60 g of nattokinase and 10 g of talc were mixed.

Entering the nattokinase mixture in a fluidized bed coating machine and enteric granules was obtained by maintaining the internal temperature at 40 ℃ while spraying the spray nozzle for 100 minutes A.

Example 2

A. Preparation of Coating Liquid Composition

Eudragit S100, a methacryl polymer, is prepared in 30 g and 70 g of ethanol (30 g in the final solid content). Ethanol is sufficiently evaporated during drying, so the final weight ratio of Eudragit is 30%.

B. Preparation of Natokinase Mixtures

60 g of nattokinase and 10 g of lactose were mixed.

Enter the nattokinase mixture in a conventional mixing and coalescing machine (for example, a ribbon mixer), and uniformly mix for 10 minutes, add the coating solution of A, stir and knead it, and dry it at 50 ° C. for 30 minutes in an enteric granule. Could get

Example 3

A. Preparation of Coating Liquid Composition

30 g of HPMCP HP-55 which is hydroxypropyl methyl cellulose phthalate, 30 g of methylene chloride, and 45 g of ethanol are mixed and prepared. Since methylene chloride and ethanol are evaporated during drying, the final weight ratio of HPMCP in the mixture of A and B is 30%.

B. Preparation of Natokinase Mixtures

60 g of nattokinase and 10 g of talc were mixed.

In a high-speed granulator equipped with a rotary stirrer, add an enzyme mixture of B and mix uniformly for 10 minutes, add the coating solution of A, stir and knead continuously for 3 minutes, and then blow-dry in a fluid bed dryer at room temperature for 30 minutes and at 50 ° C. It was dried for 100 minutes to obtain an enteric granule.

Example 4

A. Preparation of Coating Liquid Composition

100 g (30 g as the final solid) of the collicoat MAE30DP solid content 30% suspension which is an acrylic polymer was prepared.

B. Preparation of Natokinase Mixtures

60 g of nattokinase and 10 g of talc were mixed.

Entering the nattokinase mixture in a fluidized bed coater equipped with a rotary stirrer at the bottom, while maintaining the internal temperature at 40 ℃ while spraying the coating liquid of A through the spray nozzle for 120 minutes was obtained enteric granules .

Example 5

A. Preparation of Coating Liquid Composition

Melt 30g of medicinal wax and use it as coating material.

B. Preparation of Natokinase Mixtures

60 g of nattokinase, 10 g of cellulose, and 10 g of talc were mixed.

Entering the natokinase mixture in a fluidized bed coating machine was mixed uniformly for 10 minutes, the molten wax coating solution was placed and sprayed continuously for 60 minutes to obtain enteric granules.

Example 6.

A. Preparation of Coating Liquid Composition

Hydroxypropylmethylcellulose Pharmacoat 606 grade 5g, methylene chloride 10g, and isopropanol 20g was mixed and prepared as a primary coating solution, 25g of ethylcellulose was prepared with 30g of methylene chloride and 40g isopropanol as a secondary coating solution.

B. Preparation of Natokinase Mixtures

60 g of nattokinase and 10 g of cellulose were mixed.

In the fluidized bed coater, the mixture of Natokinase was added, and the coating solution of A was uniformly mixed for 10 minutes, and then the first coating solution was sprayed to maintain the product temperature at 40 ° C., followed by drying for 5 minutes while idling. It was carried out under the same conditions.

Example 7.

1. Nachos: Natokinase powder 60g

20 g of microcrystalline cellulose

10 g of corn starch

Talc 0.5g

2. Coating: HPMCP 9.0%

PEG 4000 1.8%

Ethanol 45.0%

Acetone 44.2%

Enteric tablets were prepared at 315 mg per tablet by conventional pharmaceutical methods.

Example 7.

1. Nachos: Natokinase powder 60g

20 g of microcrystalline cellulose

10 g of corn starch

Talc 0.5g

2. Coating part: Shellac 20.0%

Stearic acid 2.0%

Ethanol 78.0%

Enteric tablets were prepared at 315 mg per tablet by conventional pharmaceutical methods.

Example 8.

Composition of the tablets: nattokinase powder 60 g

20 g of microcrystalline cellulose

10g corn starch

Talc 0.5g

A general tablet was prepared at 300 mg per tablet in a conventional formulation and used as a comparative formulation.

Experimental Example: Acid Resistance Test and Activity Retention Rate Test

The acid resistance test for artificial gastric juice of the preparation prepared in the above example was carried out, and the respective active residual test was performed, and the results are shown in Table 1.

As can be seen in Table 1, since the enteric preparation of the present invention is coated on each powder, the residual activity was increased by about 50% or more compared with the conventional preparation.

Experimental Example 1: Acid Resistance Test

Take 200 mg of the granules of Examples 1 to 8, and use 500 ml of macilvaine buffer solution (pH 3.0) as a test solution to maintain the temperature at 37 ± 0.3 ° C. in the container of the KEPCO dissolution test apparatus. Elution was carried out at 100 rpm for 2 hours according to the method (precipitation). Immediately, the test solution was changed to 500 ml of macilvaine buffer solution (pH 7.0) and eluted for 1 hour to perform acid resistance test. 50 ml of this eluate was centrifuged at 300 rpm for 10 minutes, and the supernatant was taken as a sample solution.

Experimental Example 2: Active Retention Rate Test

The activity persistence test checks the absorbance in the ultraviolet 275 nm wavelength region for the amount of acid-soluble low molecular degradation products that are increased by degradation of peptide bonds when acting on nattokinase on fibrin. (Reference: separate Health Life Business FOR FOOD, 1999, 2, 20; nattokinase activity method) Remaining activity of the sample after the acid resistance test of Examples 1 to 8 by setting the initial activity of the acid resistance test to 100% Is expressed in%.

Table 1. Active Retention Rate (%)

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 97% 100% 90% 95% 97% 98% 98% 45%

As described above, in the present invention, after excipients such as lactose, corn starch, talc, cellulose and the like are uniformly mixed with powders or fine particles of digestive enzymes, the mixture is placed in a fluidized bed coater or a fluidized bed granulator for a predetermined time, preferably 5 to 10 hours. Spray-drying the enteric coating base through the spray nozzle while uniformly mixing for minutes, to prepare an enteric preparation coated on each of the powders or fine particles while obtaining fine particles or powders having an appropriate size of enteric function, which is then purified or hardened. , Soft capsules, or tablets or hard capsules using nattokinase and excipients, coated with an enteric base to form a film to prevent inactivation of gastric acid in the human body. Effect of over 50% increase To have, a cost reduction of the manufacturing cost reduction, a dose reduction can be obtained the effect of the reduction of economic bokyongja.

Claims (4)

1. Oral preparations using nattokinase, an enzyme with physiological thrombolytic action produced by Bacillus subtilus var. Natto, prevent inactivation of gastric acid in the human body and from upper duodenum. Oral compositions of the preparations that can ensure stability by using a material having acid resistance to maintain the enzyme activity in the intestinal tract and a preparation method thereof 2. In case 1, acidic means pH 1.2 ~ 3.0 3. The acid resistance material according to item 1 is shellac, zein, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, poly (methacrylic acid, methyl methacrylate) 1: 1, poly ( Methacrylic acid, ethyl acrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2, poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1: 2: 0.2, poly (ethyl acrylate, methyl methacrylate, trimethylammonoethyl methacrylate chloride) 1: 2: 0.1. 4. It can be made into hard capsules, soft capsules, pellets, and enteric drugs by using powders and fine particles containing nattokinase prepared in paragraph 1 of the enteric preparation, and by using an enteric coating material on an uncoated nattokinase-containing preparation, Enteric preparations can be prepared.