KR20070012039A - Spherical digestive enzyme granules and method for preparing the same - Google Patents

Abstract

A spherical digestive enzyme granule is provided to show high sphericity and grain size uniformity, and have excellent enzymatic stability and formulating advantages by coating an aqueous dispersion of a digestive enzyme on a spherical core. The spherical digestive enzyme granule comprises a spherical core and a digestive enzyme layer coated on the core. The method for preparing the granule comprises the steps of: (a) dissolving at least one digestive enzyme selected from the group consisting of protease, lipase, amylase, cellulase, hemicellulase, xylanase, beta-glucanase, lactase, alpha-galactosidase, phytase, phospholipase, beta-glucosidase, and nattokinase and a pharmaceutically acceptable carrier in a buffer solution which is pH controlled so as to maintain the optimum activity of the digestive enzyme; (b) mixing the dissolved enzyme with an organic solvent to prepare a digestive enzyme organic solvent aqueous dispersion; and (c) spraying the aqueous dispersion into a core to be absorbed thereinto and grow particles.

Description

Spherical digestive enzyme granules and method for preparing the same

1 is a granule (A) coated with a digestive enzyme layer on a spherical core according to a preferred embodiment of the present invention, and a granule (B) having a gastric coating layer and an enteric coating layer formed on the digestive enzyme layer, respectively, and the digestive enzyme layer A cross-sectional view showing a granule (C) in which a waterborne coating layer and an enteric coating layer are formed in combination.

Figure 2 shows that the cross-section of the digestive enzyme granules prepared according to the preferred embodiment 1 of the present invention was taken with an optical microscope (magnification × 400),

Figure 3 is a graph showing the stability results of the pH at 4 ℃ and 40 ℃ to determine the optimum pH for the enzyme stability of Example 1,

4 is a photograph showing the granules (A) of the digestive enzyme prepared according to Example 1 of the present invention and the granules (B) prepared according to Comparative Example 1 according to the related art.

Figure 5 is a graph showing the ratio of the weight occupied by the particle size with respect to the total weight of the digestive enzyme granules prepared according to a preferred embodiment 1 of the present invention,

Figure 6 shows the remaining enzyme activity [protease (A) and amylase according to the change over time of the digestive enzyme granules prepared according to a preferred example 1 of the present invention and the digestive enzyme granules prepared according to Comparative Example 1 by conventional techniques (B)] is shown in the graph comparing.

The present invention relates to a spherical digestive enzyme granules and a method for manufacturing the same, and more particularly, to the spherical core for molding, the enzyme is sprayed and adsorbed onto a spherical core to form a digestive enzyme layer, thereby providing excellent enzyme stability against aging. It has a, easy to control the size of the granules in the manufacturing process, and relates to a spherical digestive enzyme granules improved high sphericity and a method for producing the same.

In general, enzyme is a biocatalyst whose protein is the main skeleton, and has a relatively good reaction specificity, and the reaction is gentle and continuous, so that it is relatively easy to control the reaction, and has many effects such as non-toxicity, low toxicity, and environmental friendliness. It has advantages. Enzymes have been widely used in the food industry such as brewing, fermentation, bakery, confectionery, and throughout the industry from leather, textile processing, and detergents.In recent years, enzymes are used for bio-conversion, biochip, and various disease diagnosis. The application is gradually expanding. Specifically, enzymes are used in fire extinguishing agents, anti-inflammatory agents, and the like, and are particularly important in the pharmaceutical industry.

However, in spite of the numerous advantages and wide application fields that come from the use of enzymes, the use of the enzymes is limited due to instability due to external conditions. In particular, unlike in the industrial field where enzymes are used in chemical reactions and processing processes, in the pharmaceutical industry, the enzyme activity prescribed at the time of manufacture must be kept constant until the patient's dose, and the stability of enzyme activity due to changes over time is more precise. More needs to be controlled.

For the above reasons, oral enzymes are limited to tablets as formulations that are more favorable for stability than other formulations, and also for cosmetic reasons, even when trying to fill the capsule with stability problems. It is limited to opaque capsules.

Many reports and efforts have been made on improving the stability of enzymes, but most of them are simple addition of stabilizers, for example, polymers such as gelatin, polyalkylene glycols (Korean Patent Application No. 10-1986-0000415), albumin ( Korean Patent Application No. 10-1986-0002879), 4-substituted-phenyl-boronic acid (Korean Patent Application No. 10-1997-7009376), polysaccharide (Korean Patent Application No. 10-2001-0084980) and many others, or encapsulation ( Korean Patent Application Nos. 10-1993-0008473; 10-2002-0073433) and immobilization (Korean Patent Application No. 10-1992-7000925) and the like are known, but the altitude and purpose of the invention to be achieved in the present invention are known. There can be different.

In addition, although the prior art related to the production of enzyme granules (Korean Patent Application No. 10-1994-0701087) is known, it is also an enzyme for the detergent industry, with the aim of low dust formation ability and stability and sustainability in application as a detergent. It can be said that the present invention is different from the purpose of the present invention and the purpose as an orally administered digestive enzyme.

In addition, as a method for producing spherical enzyme granules, a method of firstly mixing and associating respective enzyme raw materials and then extruding them through a mesh of a specific size and manufacturing them using a spheronizer is generally well known. However, it has a disadvantage of time and labor consumption, such as having to go through several stages of work process.

Recently, by using a fluidized bed process (fluidized bed process) while flowing the raw material in a certain (chamber) by spraying the binder liquid to agglomerate to a certain size and at the same time spherical through the rotation of the device, Although the method of producing granules by simplifying the process into one process is widely used for convenience of work, there is a limitation in obtaining high uniformity and sphericity of granularity in the manufacturing process.

Therefore, in the present invention, in order to achieve high particle size uniformity and sphericity on granules, a spherical core of a certain size is flowed as a nucleus and sprayed with an organic solvent aqueous dispersion in which enzymes are dissolved together with binders and stabilizers. By growing the particles, a method for producing a digestive enzyme granule having high particle size uniformity and sphericity was conceived.

In conclusion, as the oral digestive enzyme granules intended to be achieved in the present invention, there is no technology that simultaneously improves the formulation advantages such as stability, size control, sphericity, and the like with respect to the aging of the enzyme activity with time.

Accordingly, an object of the present invention is to develop oral digestive enzyme granules having a high sphericity and excellent enzyme stability and formulation advantages, and a method for preparing the same. It is to provide a digestive enzyme granules.

However, the use of an organic solvent aqueous dispersion of the enzyme by dissolving the digestive enzymes in water and an organic solvent for high sphericity results in a problem in the stability of the enzyme activity because it affects the structural denaturation of the enzyme in an aqueous solution. . This means that the enzyme has a stable pH range that shows optimum activity depending on the type, and is associated with ionizing groups in the molecule where the hydrogen ion concentration (pH) in the aqueous solution affects the three-dimensional structural characteristics of the enzyme. This is because it greatly affects the enzymatic activity and stability of [Effects of pH on Enzymes, Methods in Enzymology, 183-235].

In addition, the stability of the enzyme activity can be changed by the interaction of different enzymes. Specific examples include protease, which directly hydrolyzes another enzyme, thereby seriously lowering the stability of the enzyme being degraded.

In addition, the properties and stability of the hydrolyzate in aqueous solution according to pH are both individual and complex, so that even if the information on the individual properties of the enzyme is difficult to predict in terms of enzyme activity and stability. In addition, it is difficult to secure the activity and stability of the enzyme in the case of digestive enzymes that contain heterologous enzymes, most of which are not homogeneous. Moreover, hydrogen ion concentration is closely related to formulation stability by moisture absorption even after preparation of granules.

In addition, the activity and stability of the enzyme can be influenced by factors of temperature affecting the structural denaturation and pH change of the pore-formed enzyme.

Accordingly, the present inventors use one or at least two or more selected digestive enzymes in preparing an organic solvent aqueous dispersion of digestive enzymes, wherein the digestive enzymes exhibit a single pH range showing optimal activity at -10 ° C to 60 ° C. When the aqueous dispersion is prepared by mixing an organic solvent with an aqueous digestive enzyme solution dissolved in a controlled buffer solution (in case of one type of digestive enzyme) or in a commonly included pH range (if more than two types of digestive enzymes), Of course, the present invention was completed by proving that minimization of loss of digestive enzyme activity due to changes over time after granulation was made.

In order to achieve the above object, the present invention is a spherical core for molding; And it provides an oral spherical digestive enzyme granules comprising a digestive enzyme layer coated on the core.

In addition, in order to achieve another object, the present invention (1) protease (lipase), lipase (amylase), amylase (cellulase), hemicellulase (hemicellulase), xylanase (xylanase), beta-glu Β-glucanase, lactase, alpha-galactosidase, phytase, phospholipase, beta-glucosidase, and natto At least one digestive enzyme selected from the group consisting of nattokinase,

Solubilizing the digestive enzyme by dissolving the buffer with a pharmaceutically acceptable carrier and a controlled buffer in a pH range in which the selected digestive enzyme can maintain optimal activity;

(2) preparing an aqueous digestive enzyme organic solvent dispersion by mixing a pharmaceutically acceptable organic solvent with the accommodated digestive enzyme; And

(3) It provides a method for producing oral spherical digestive enzyme granules comprising the step of growing the particles by spraying and adsorbing the prepared digestive enzyme organic solvent aqueous dispersion of a predetermined size (core).

Furthermore, the present invention provides a digestive enzyme capsule filled with the oral spherical digestive enzyme granules described above as an active ingredient.

Hereinafter, the present invention will be described in detail.

At this time, if there is no other definition in the technical terms and scientific terms used, it has a meaning commonly understood by those of ordinary skill in the art.

In addition, repeated description of the same technical configuration and operation as in the prior art will be omitted.

The present invention relates to a single or at least two or more digestive enzymes in which a single pH range in which the digestive enzymes exhibit optimal activity at −10-60 ° C., more preferably 0-50 ° C. (if one digestive enzyme is present). Or dissolved in a controlled buffer in a pH range (in the case where two or more digestive enzymes are included in common), mixed with an organic solvent to prepare an aqueous organic solvent dispersion of the digestive enzyme, and spraying the aqueous dispersion onto a spherical core for molding. By adsorbing and growing the particles, the granules of oral spherical digestive enzymes for oral uniformity have been developed with excellent uniformity and easy size control while improving stability of the granule manufacturing process and changes over time. In this case, the lower the temperature, the more favorable the activity and stability of the enzyme in the preparation of the organic solvent aqueous dispersion of the enzyme whose pH is controlled, but the production cost such as the equipment cost due to the maintenance of low temperature increases and the organic solvent in the fluidized bed granulation and coating process The problem of prolonging the drying time due to the decrease of the volatilization rate is caused, and when the temperature is excessively increased, the particle growth and drying effect of the digestive enzyme granule are excellent, but the activity and stability of the enzyme are deteriorated due to the denaturation of the enzyme. In this invention, it is preferable to manufacture in the range which is not lower than -10 degreeC and does not exceed 60 degreeC. More preferably, the preparation of the organic solvent aqueous dispersion of the enzyme is prepared in the range of 0 ° C. to 10 ° C. where no additional costly cooling device is required, and the fluidized bed granulation and coating process is made in the temperature range of 30 ° C. to 50 ° C.

However, in the manufacturing method according to the present invention, since the temperature range is not coincident with the temperature range according to the optimum temperature of the target digestive enzyme, in some cases, the temperature range may be exceeded.

Then, the granules of the digestive enzyme according to the present invention is prepared by the following preferred process. However, in order to achieve the object of the present invention, any method may be prepared by replacing some or all of the following detailed steps as long as it is possible to form a digestive enzyme layer dispersed in an organic solvent in a spherical core for molding.

First step: preparing an aqueous solution of digestive enzyme

As shown in Figure 1, one or at least two or more types of digestive enzymes selected according to the use, the pH range of the optimal activity under the process temperature conditions for the selected digestive enzymes A common pH range of the pH range) is mixed with a buffer solution to control (maintain) and solubilized.

That is, as a specific method of determining an optimal pH range for stability in the granulation process and over time, it is possible to maintain (control) by adding a salt capable of buffering at the pH range. Determination of the pH range of can be determined simply by measuring the activity at the optimum pH of each enzyme after a certain period of pre-incubation of any digestive enzyme (s) at pH conditions at each process temperature. More specifically, as an example of determining the optimal pH range, in the case of Bacillus subtilis enzyme culture (protease and amylase), as shown in FIG. Constant temperature (within process temperature range) at an interval of 1.0 in a condition ranging from .0 to 10.0, preferably 1 to 48 hours, more preferably 4 for a predetermined time in the range of 4 to 60 ℃ After pre-incubation for ˜10 hours, the activity is measured at 7.0 and 6.0, the optimum active pH conditions for each of the Bacillus protease and amylase, to determine a pH range that maintains common maximum activity. And the control of their pH value uses a group consisting of a weak acid and its base or a weak base and the base acid, and select a salt whose pKa value is located in the center of the pH range determined above to determine the appropriate amount, preferably the concentration of the salt. It can be achieved by adding between 0.001 and 0.5 M, more preferably between 0.01 and 0.2 M on the basis of. This is because when the salt concentration is too low, the pH buffering action is not sufficiently performed. If the salt concentration is too high, it may affect the solubility and stability of the enzyme due to salting-out phenomenon. As described above, when the aqueous digestive enzyme solution is controlled to the optimum pH for stability, the digestive enzyme preparation can not only optimally bring about enzyme stability in the manufacturing process but also when moisture is absorbed with time even after being formulated into granular form or the like. It provides the effect of bringing the pH of the absorbent to an optimal stabilization condition.

In addition to the selected digestive enzymes, the digestive enzyme solution may be selected and used in a known range that can be used orally for pharmaceutically acceptable binders which are stored in pharmaceutical related procedures and food additives. Specific examples include abnormal protein series such as gelatin, albumin, gluten, polyglutamine, polylysine, cellulose, nitrocellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose such as methyl cellulose and ethyl cellulose, gum arabic. At least one carrier selected from the group consisting of vegetable gums such as agar, sodium alginate, konjac mannan, polyvinyl alcohol, starch, dextran, and Eudragit E-100 (trade name) can be used. However, the binder of the present invention is not limited to the binder described above. In addition, conventionally known for use in pharmaceuticals, sustained-release polymers, fillers, stabilizers, anti-coagulants, lubricants, lubricants, disintegrants, wetting agents, fragrances, emulsifiers, preservatives, etc. can be used to further include various additives for the purpose of additional functionality Specifically, in the case of sustained-release polymers, enteric polymers including hydroxypropyl methylcellulose phthalate, high viscosity hydroxypropyl methylcellulose, and the like are used. In order to improve the stability of the digestive enzymes, a suitable digestive enzyme substrate (substrate) and the like (substrate-like substances) can be used.

Second Process: Organic Solvents of Digestive Enzymes Water dispersion  Produce

In the above (1) process, an organic solvent is mixed with an aqueous solution of digestive enzyme having a pH controlled to prepare an aqueous digestive enzyme organic solvent dispersion.

At this time, the organic solvent used in the present invention is preferably to use a boiling point (boiling point) lower than water, can be used by mixing two or more kinds of solvents. More preferably, the organic solvent standards of the International Conference on Harmonization (ICH) are selected as those having low human toxicity, but one or two or more solvents are selected as organic solvents having a boiling point of 85 ° C. or lower. Use it. The mixing ratio of the solvent is preferably added between 0.2 and 0.8, more preferably between 0.3 and 0.6, based on the organic solvent / water. This is because when the addition ratio of the organic solvent is lower than a certain level or higher than a certain level, the effect of lowering the boiling point is small compared to the volume increase of the increased enzyme dispersion due to the addition of the organic solvent. This is because it may undermine the stability of the enzyme and the uniformity of the product. More specifically, Class 3 (class 3; ethanol, acetic acid, acetone, 1-propanol, 2-propanol, etc.) and Class 2 (acetonitrile, chloroform, methanol, Dichloromethane and the like) can be selected from among the organic solvents.

Third Process: Granulation of Digestive Enzymes

Oral spherical digestive enzyme granules are prepared by spraying and adsorbing the aqueous digestive enzyme dispersion prepared in step (2) to a spherical core having a specific or predetermined size to grow particles.

At this time, the digestive enzyme aqueous dispersion is preferably sprayed and adsorbed to the core while flowing the spherical core using a fluidized bed process, and then dried to grow the particles in monodispersion. This is because monodisperse growth of the particles can improve the sphericity while making the granules fine.

In addition, the spherical core used in the present invention can be prepared by mixing, coalescing, extruding and spheronizing together with a pharmaceutically acceptable polymer such as sugars and poly vinyl alcohol. It can be purchased and used commercially. At this time, the size of the core to be used in the pharmaceutical form is preferably between 200 ~ 1,400 ㎛ diameter, more preferably 350 ~ 1,000 ㎛ diameter core size is preferred. When the size of the core is smaller than a certain range, the cores are more likely to combine to form dimers, trimers, and polymers. This is because the fluidized bed process itself, which is not smoothly made and sprayed and adsorbed of the digestive enzyme aqueous solution, becomes impossible or there is a problem of preventing uniform particle growth.

On the other hand, in the present invention, the digestive enzyme granules prepared through the process may be prepared as a coated granule having a function on the digestive enzyme granules prepared through the process through a coating process that is additionally performed in addition to the granule manufacturing process.

4th process: coating process

By forming a coating layer of a separate polymer in the digestive enzyme layer of the granules of the digestive enzyme prepared above, the functional and stability of the digestive enzyme are further improved.

1 is a granule (A) coated with a digestive enzyme layer on a spherical core according to a preferred embodiment of the present invention and a granule (B) and a digestive enzyme layer formed on the digestive enzyme layer, respectively, a gastric coating layer and an enteric coating layer. The granules (C), in which the waterborne coating layer and the enteric coating layer are formed in combination, are briefly shown in cross-sectional view to facilitate the present invention.

And, Figure 2 is a cross-sectional view of the digestive enzyme granules prepared according to a preferred embodiment of the present invention by photographing (magnification x 400) by an optical microscope.

(1) gastric coating and gastric polymer

As shown in Figure 2 (A), in the present invention, the gas-soluble coating layer is formed by spraying an aqueous dispersion of gas-soluble polymer on the digestive enzyme layer (2) from the granules of the digestive enzyme prepared above and dried to form a coating layer. Say

In this case, the gastric soluble polymer refers to a pharmaceutically acceptable natural or synthetic polymer solubilized irrespective of pH 5.0 or less conditions or pH conditions, specifically, abnormal protein series such as gelatin, albumin, gluten, polyglutamine, polylysine, Cellulose series such as cellulose, nitrocellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, vegetable gums such as arabia gum, agar, sodium alginate, konjac mannan, polyvinyl alcohol, It is preferable to use at least one polymer selected from the group consisting of starch, dextran, Eudragit E-100 (trade name) and the like. However, in addition to the polymer described above, any polymer that can achieve the object of the present invention can be used.

(2) Enteric coatings and enteric polymers

As shown in FIG. 2 (B), the enteric coating layer in the present invention refers to a coating layer formed by spraying an aqueous dispersion of the enteric polymer on the digestive enzyme layer 2 from the granules of the digestive enzyme prepared above, and spraying the aqueous dispersion of the enteric polymer. .

In this case, the enteric polymer refers to pharmaceutically acceptable natural or synthetic polymers that are not solubilized in an environment of pH 5.0 or less, and specifically, hydroxypropylmethylcellulose phthalic acid, cellulose acetate phthalic acid, methacrylic acid-methylmethacrylic acid copolymer, Preference is given to using at least one polymer selected from the group consisting of methacrylic acid-ethylmethacrylic acid copolymer. However, in addition to the polymer described above, any polymer that can achieve the object of the present invention can be used.

 (3) plural coatings of gastric and enteric polymers

 As shown in Figure 2 (C), in the present invention, the gastric coating layer (3a) is an aqueous dispersion of gastric solvent polymer on the upper side of the digestive enzyme layer (2a) of another species newly formed on the upper side of the enteric coating layer (3b) It refers to a coating layer formed by spraying the coating and drying it.

This means that during digestion, food is transferred to the intestine via the stomach, so that the digestive enzymes that are eluted from the stomach and acting on the stomach can become active, and then the intestines can act on the intestine upon reaching the intestine. This is to allow them to elute and act.

(4) Digestive enzyme, gastric and enteric polymer

In the present invention, the digestive enzyme layer may be used by mixing with a digestive enzyme selected according to the use, a gastric polymer, an enteric polymer or a mixed polymer thereof. At this time, the mixing ratio of the components can be used as a binder or excipient by a conventionally known method according to the amount of the digestive enzyme which is an active ingredient.

 On the other hand, spherical digestive enzyme granules according to the present invention as a dosage form for the purpose of improving indigestion and digestive function in the form of capsules or tablets prepared by filling the granules in capsules in a known manner. It can be used widely.

 Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited to the following examples, and it will be apparent to those skilled in the art that various changes or modifications can be made within the spirit and scope of the present invention.

Example 1

Bacillus digestive enzyme (protease and amylase) granules

(1) pH control

1g of Bacillus subtilis enzyme culture was dissolved in 100 mL of buffer solutions of pH 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0, respectively, to prepare an enzyme solution. Each of these was measured for protease and amylase activity at pH 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0 conditions to determine the pH conditions that showed the greatest activity as follows. (Protease pH 7.0 and Amylase pH 6.0) Again, the enzyme solutions prepared at the respective pHs were allowed to stand for 8 hours in a constant temperature bath at 4 ± 0.5 ° C and 40 ± 0.5 ° C, respectively, and then the protease and amylase maximum activity determined in the above experiments. The activity was measured at pH conditions indicating In this way, an optimum pH 5.0, which is commonly satisfied, was determined (see FIG. 3).

180 g of Bacillus subtilis enzyme culture, 9 g of hydroxy propyl methyl cellulose, 10 g of talc, and 1 g of polyethylene glycol # 6000 were dissolved in 1,200 g of 20 mM acetate buffer (pH 5.0).

(2) Preparation of digestive enzyme organic solvent aqueous dispersion

600 g of ethanol and 600 g of acetone were added to the aqueous solution of digestive enzyme prepared by the process of (1), respectively, and stirred at 4 ° C. to prepare an aqueous digestive enzyme organic solvent dispersion.

(3) particle growth process

Sucrose core with 95% or more in diameter (Φ) 500 ~ 600㎛, 300g inlet temperature 40 ℃, spray rate 10 using fluidized bed granulator (Glatt GmbH, Germany) Particles were grown by spraying an aqueous dispersion of the digestive enzyme organic solvent prepared by the above process (2) under the condition of mL / min. This gave 492 g (98% yield) of Bacillus subtilis digestive enzyme spherical granules finally.

[Comparative Example 1]

180 g of Bacillus subtilis enzyme culture and 300 g of sucrose were mixed to prepare 480 g of an enzyme mixture. 9 g of hydroxy propyl methyl cellulose, 10 g of talc, and 1 g of polyethylene glycol # 6000 were purified from 500 g of purified water: ethanol. : A spray solution was prepared by mixing with acetone (w: w: w, 2: 1: 1) solution. Comparative Example 1 was used as a digestive enzyme granule obtained by spraying a spray solution while 480 g of the enzyme mixture was flowed in a fluidized bed granulator.

Example 2

Pancreatin Enteric Granules

(1) pH control

1 g each of the pancreas extract enzyme concentrate was dissolved in 100 mL of buffer solutions of pH 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0, respectively, to prepare an enzyme solution. Each of these was allowed to stand for 8 hours in a constant temperature bath at 4 ± 0.5 ° C and 40 ± 0.5 ° C, and their activities were measured according to the protease, lipase, and amylase terms of the pancreatin test of the US Pharmacopeia. In this way, the optimum pH 5.0 which was satisfied in common was determined.

Stir 235 g porcine pancreas extract enzyme concentrate, 12 g hydroxy propyl methyl cellulose, 9 g talc, and 6 g polyethylene glycol # 6000 in 1,500 g 20 mM acetate buffer (pH 5.0) Melted.

(2) Preparation of digestive enzyme organic solvent aqueous dispersion

The aqueous solution of digestive enzyme organic solvent was prepared by adding 750 g of ethanol and 750 g of acetone to the aqueous solution of digestive enzyme prepared by the above step (1) and stirring the mixture at 4 ° C.

(3) particle growth process

Sucrose core with 95% or more in diameter (Φ) 500 ~ 600㎛, 350g inlet temperature 40 ℃, spray rate 10 using a fluidized bed granulator (Glatt GmbH, Germany) Particles were grown by spraying an aqueous dispersion of the digestive enzyme organic solvent prepared by the above process (2) under the condition of mL / min. Thus, 601 g (98% yield) of the pig pancreatic extract enzyme spherical granules was finally obtained.

(4) Enteric coating process

500 g of swine pancreatic extract enzyme spherical granules obtained above were flowed in a fluidized bed coater, and 83 g of hydroxy propyl methyl cellulose pthalate, 6 g of talc, and 11 g of polyethylene glycol # 6000 were added to ethanol / acetone (1/1) 1,000. It was coated by spraying with a coating solution prepared by dissolving in g. Finally, 583 g (97% yield) of pancreatin enteric granules were obtained.

Example 3

Capsule Manufacturing

According to the preparation method of the capsule according to the Pharmacopeia General Regulations, each 500 g of the granule mixture containing the granules of Examples 1 and 2, or simultaneously (mixing ratio 1: 1), into a gelatin transparent capsule of No. 1 size The capsule was prepared by filling. Each capsule was filled with about 500 mg per capsule to obtain about 1,000 capsules each.

Experimental Example

(1) sphere

In this embodiment, the granules prepared according to Example 1 and Comparative Example 1 were observed under a microscope to determine the uniformity and sphericity of the granules visually and to measure them numerically.

The sphericality was measured by photographing and then measuring the circumferential length (Pm) and the cross-sectional area (A) of the shape of the taken granules to quantify the sphericality (Sphericity) by the following equation (see Fig. 4).

[Equation 1]

Sphericity (S) = (4 × π × A) / Pm ²

Here, A is a cross section of the cut surface of the granules, and Pm represents a perimeter of the cut surface of the granules, which means that the closer to 1, the closer the spherical shape is.

As a result, the sphericity of Example 1 prepared according to the present invention 0.967 ± 0.018 (mean ± standard deviation) was found to be very excellent compared to the sphericity of Comparative Example 1 prepared by the conventional method 0.854 ± 0.070 .

(2) Granule size distribution

Digestive enzyme granules prepared according to Example 1 were filtered through standard meshes of different sizes, and the respective weights of the filtered particles were measured to evaluate the distribution ratio and uniformity of each granule.

As a result, as shown in Figure 5, the total particle size of the total range of particles ranging from No. 30 sieve (600 ㎛) to No. 20 sieve (850 ㎛) occupy more than 98%, and defined by the General Regulations of the Pharmacopeia of the Republic of Korea The granular size of the granules passed through the '12 sieve (1,680㎛) and the remaining 14 sieve (1,410㎛) is less than 5% of the total amount, and passing through the 45 sieve (350㎛) When it is 15% or less, it is suitable. '

(3) stability

In order to measure the enzyme stability of the digestive enzyme granules prepared according to Example 1 and Comparative Example 1, respectively, with the change over time, at a temperature of 40 ° C. and a relative humidity of 75%, the protein digestibility and starch glycation power according to the change over time. Was measured to confirm the degree of stability.

As a result, as shown in Figure 6, it was found that the stability of the digestive enzyme granules according to the present invention is superior to the conventional granules.

As described above, the digestive enzyme granule of the present invention by selecting and controlling the pH range that is optimal for the stability of the digestive enzyme components to prepare an aqueous dispersion and providing a method for growing the particles by spray-drying it to a predetermined core (core), It exhibited high particle size uniformity and sphericality while having excellent enzyme stability and formulation advantages.

Claims (14)

Molding spherical cores; And Oral spherical digestive enzyme granules comprising a digestive enzyme layer coated on the core. The method of claim 1, Spherical core for molding oral spherical digestive enzyme granules, characterized in that consisting of a pharmaceutically acceptable sugar and a polymer. The method according to claim 1 or 2, Oral spherical digestive enzyme granules, characterized in that the molding spherical core has an average diameter of 200 ~ 1,400㎛. The method of claim 1, The digestive enzyme layer includes protease, lipase, amylase, amylase, cellulase, hemicellulase, xylanase, beta-glucanase, and lactase. lactase, alpha-galactosidase, phytase, phospholipase, beta-glucosidase, and nattokinase Oral spherical digestive enzyme granules comprising at least one digestive enzyme as an active ingredient. The method of claim 1, Oral spherical digestive enzyme granules, characterized in that formed on the upper side of the digestive enzyme layer (2) further comprises a gastric coating layer or enteric coating layer. The method of claim 1, The enteric coating layer 3b above the digestive enzyme layer 2b, the digestive enzyme layer 2a different from the digestive enzyme layer 2b on the enteric coating layer 3b, and the upper side of the digestive enzyme layer 2a. Oral spherical digestive enzyme granules, characterized in that the gastric coating layer (3a) is further included. The method of claim 1, The digestive enzyme layer is an oral spherical digestive enzyme granules, characterized in that the mixture is made of digestive enzymes and gastric polymers, enteric polymers or mixed polymers thereof. The method according to any one of claims 5 to 7, The above-mentioned soluble polymer is an abnormal protein series such as gelatin, albumin, gluten, polyglutamine, polylysine, cellulose, nitrocellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, etc. Oral spherical digestive enzyme granules, characterized in that gum gum, agar, agar, sodium alginate, konjac mannan and the like, polyvinyl alcohol, starch, dextran, and Eudragit E-100 (trade name). The method according to any one of claims 5 to 7, The enteric polymer is hydroxypropyl methyl cellulose phthalic acid, cellulose acetate phthalic acid, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl methacrylate copolymer, oral spherical digestive enzyme granules characterized in that. (1) Protease, lipase, amylase, cellulase, hemicellulase, xylanase, beta-glucanase, and lactase At least one selected from the group consisting of alpha-galactosidase, phytase, phospholipase, beta-glucosidase and nattokinase Abnormal digestive enzymes, Solubilizing the digestive enzyme by dissolving the buffer with a pharmaceutically acceptable carrier and a controlled buffer in a pH range in which the selected digestive enzyme can maintain optimal activity; (2) preparing an aqueous digestive enzyme organic solvent dispersion by mixing a pharmaceutically acceptable organic solvent with the accommodated digestive enzyme; And (3) A method for producing oral spherical digestive enzyme granules comprising spraying and adsorbing the prepared digestive enzyme organic solvent aqueous dispersion onto a predetermined size core to grow particles. The method of claim 10, Oral spherical digestion, characterized in that it further comprises the step of forming a coating layer by spraying a coating liquid consisting of a polymer selected from the group consisting of gastric polymers, enteric polymers and mixed polymers thereof to the formed particles of step (3) Enzyme granules. The method of claim 10, Oral spherical digestive enzyme granules, characterized in that when the digestive enzyme selected is at least heterologous, the digestive enzyme is solubilized using a buffer solution controlled to a common pH range among the respective pH ranges in which the digestive enzyme exhibits optimal activity. Manufacturing method. The method of claim 10, A method for producing oral spherical digestive enzyme granules, which is prepared at a temperature of -10 to 40 ° C. A digestive enzyme capsule filled with an oral spherical digestive enzyme granule according to claim 1 as an active ingredient.

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