WO2022092767A1

WO2022092767A1 - Method for preparing minimized oral formulation containing extract of zea mays l. unsaponifiable fraction and oral formulation prepared thereby

Info

Publication number: WO2022092767A1
Application number: PCT/KR2021/015108
Authority: WO
Inventors: 이상영; 정규호; 전준영; 김상현
Original assignee: 일동제약(주)
Priority date: 2020-10-26
Filing date: 2021-10-26
Publication date: 2022-05-05
Also published as: KR20230017814A

Abstract

Provided are a method for preparing a minimized oral formulation containing an extract of a Zea Mays L. unsaponifiable fraction as an active ingredient, and an oral formulation prepared thereby.

Description

Method for manufacturing miniaturized oral dosage form containing 　 corn unsaponifiable extract and miniaturized preparation prepared accordingly

The present invention relates to a method for preparing a miniaturized oral dosage form comprising an unsaponifiable corn extract as an active ingredient, and to a miniaturized preparation prepared accordingly.

Oral administration formulations are manufactured by adding excipients to the main ingredient to secure disintegration and dissolution rates for body action, supplement physical properties of pharmaceuticals, and increase productivity. At this time, when a large amount of excipients are added to the main component, the weight or volume of the oral dosage form is increased, and as a result, there is a problem in that the patient's takeability is deteriorated.

Corn unsaponifiable extract is effective in adjuvant treatment of gingivitis and mild/moderate periodontitis after periodontal treatment. It is sold as Jung ^TM .

[Prior art literature]

Korean Patent Registration No. 10-0361880

Insadol Tablet ^TM and Denkyu Tablet ^TM , which are representative commercial medicines containing 35 mg of corn unsaponifiable extract, contain lactose hydrate as an additive, and have a total weight of about 410 mg, a diameter of about 10.5 mm, and a thickness of 5.0 mm. It is a film-coated tablet. Many of the patients suffering from periodontal disease are elderly people, and they have to take drugs for a long time to treat periodontal disease, and they are often taken together with other health functional foods or medicines. Therefore, in order to further improve the convenience of taking the drug and to make it easier to swallow the drug when taking the drug, it is necessary to miniaturize the tablet. In addition, lactose hydrate has a problem in that it cannot be used for patients with genetic problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. However, by excluding lactose from the additives, tabletting performance was not good and a sufficient disintegration rate could not be ensured, so it was difficult to formulate it as an oral preparation.

After long research and experiments, the present inventors have developed a method for producing an oral dosage form that can be miniaturized without using lactose, has good properties, particle size and fluidity, and has excellent tabletting properties. As a result, it can be miniaturized and has excellent tabletting properties, and at the same time, it can exhibit the same disintegration rate as Insadol Tablet ^TM and Denkyu Tablet ^TM . Oral administration formulations can be provided.

In the present invention, the means for solving the problems are as follows.

(1) (a) preparing a mixture comprising 35 mg of unsaponifiable corn extract and an adsorbent;

(b) preparing an adsorbate by heating and stirring so that the temperature of the mixture becomes 40 to 55°C; and

(c) tabletting and formulating the adsorbate;

(2) In step (b), the mixture is heated for 20 to 40 minutes so that the temperature of the mixture is 40 to 55 ℃, the method for preparing an oral dosage form.

(3) The method for preparing an oral dosage form to maintain a constant temperature of the mixture heated in step (b).

(4) The step (b) is a method for producing an oral dosage form that is prepared using a high-speed mixer equipped with a heating device.

(5) In step (b), the adsorbate contains less than 0.5% of granules having a particle size of 1.4 mm, a method for preparing an oral dosage form.

(6) In step (a), the adsorbent is colloidal silicon dioxide, calcium silicate, or a mixture thereof.

(7) The mixture in step (a) further comprises an excipient selected from microcrystalline cellulose, starch, mannitol, sorbitol, carboxymethyl cellulose, calcium hydrogen phosphate, calcium carbonate, and mixtures thereof. Preparation of an oral dosage form Way.

(8) In step (a), the mixture does not contain lactose or lactose hydrate.

(9) In step (a), the mixture contains the corn unsaponifiable extract, adsorbent and excipient in a weight ratio of 1: 1-2: 1-5.

(10) In step (a), the mixture is composed of 35 mg of corn unsaponifiable extract, 50 mg of colloidal silicon dioxide and 130 mg of microcrystalline cellulose.

(11) In step (c), the adsorbate is tableted together with a disintegrant, an excipient, a binder, a lubricant, or a mixture thereof to formulate the preparation method for oral administration.

(12) A method for preparing an oral dosage form by tableting the adsorbate with sodium croscarmellose, microcrystalline cellulose, hydroxypropyl cellulose, talc, magnesium stearate, or a mixture thereof.

(13) An oral dosage form having a total weight of 200 to 300 mg prepared by the above preparation method.

(14) Orally administered formulations with a diameter of 9 mm or less when the total weight is 260 mg.

The manufacturing method according to one aspect exhibits an excellent disintegration rate without using lactose as an additive, and it is possible to miniaturize the tablet, thereby increasing the convenience of taking, and prevents raw material seepage, poor properties during tableting, and sticking. , to provide a method for preparing a formulation for oral administration containing an unsaponifiable corn extract capable of improving the productivity of the manufacturing process by increasing the fluidity.

Accordingly, it is possible to administer to lactose intolerant patients, and as the tablet can be miniaturized, it is possible to improve the convenience of administration and to provide an oral preparation containing corn unsaponifiable extract of improved quality.

Other objects and advantages of the present application will become more apparent from the claims and description of the invention. Content not described in this specification will be omitted because it can be sufficiently recognized and inferred by those skilled in the technical field or similar technical field of the present application.

In FIG. 1, the properties seen in each adsorbate prepared in Examples 1 to 4 and Comparative Examples 1 to 3 are shown along with the temperature of the mixture used to prepare each adsorbate.

In FIG. 2, the raw material oozing phenomenon seen in each of the adsorbates prepared in Examples 1 to 4 and Comparative Examples 1 to 3 is shown along with the temperature of the mixture used to prepare each adsorbate.

In FIG. 3, the tableting results of the tablets prepared in Examples 5 to 8 and Comparative Examples 4 to 6 are shown together with the temperature of the mixture used to prepare each adsorbate.

[Correction 12.01.2022 under Rule 91]
4 shows the weight and size of the coated tablet prepared in Example 10 compared to Insadol Tablet ™ and Denkyu Tablet ™ of Control Examples 1 and 2.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless otherwise defined, have the meaning as commonly understood by one of ordinary skill in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention. The contents of all publications incorporated herein by reference are hereby incorporated by reference in their entirety.

One aspect of the present invention is

(a) preparing a mixture comprising 35 mg of unsaponifiable corn extract and an adsorbent;

(c) tabletting and formulating the adsorbate; provides a method for preparing an oral dosage form comprising.

Lactose or lactose hydrate is an additive having an excellent disintegration rate and is frequently used in the manufacture of pharmaceuticals. In addition, when lactose hydrate is included in the oral formulation, there is a problem that patients with genetic problems such as galactose intolerance, Lapp lactase lactase deficiency or glucose-galactose malabsorption cannot take it. However, simply excluding lactose or lactose hydrate in the preparation of oral dosage forms reduces the disintegration rate of the preparation, and thus does not exhibit satisfactory drug efficacy during drug administration.

The manufacturing method according to an embodiment of the present invention provides a means for solving such a problem.

Corn unsaponifiable extract is an extract obtained by raw material of corn (scientific name: Zea mays L.), a plant of the Gramineae family, and is known to contain phytosterols such as β-sitosterol, campesterol, and stigmasterol.

As used herein, the term "unsaponifiable extract" refers to a substance that is not saponified as an alkali (unsaponifiable). "Unsaponifiable" refers to a substance that does not dissolve in water as a lipid component and does not react with strong alkali to form soluble soap, and may include, for example, hydrocarbons, fat-soluble pigments, and fat-soluble vitamins. The unsaponifiable corn extract may contain about 10.0 to 25.0% of total sterols (as β-sitosterol (C ₂₉ H ₅₀ O: 414.69)) and 75.0% or more of unsaponifiables when quantified.

In the manufacturing method according to one embodiment, by heating the temperature of the mixture containing 35 mg of corn unsaponifiable extract and the adsorbent to 40 to 55 ° C, the raw material is prevented from oozing out to improve the formulation quality, and to secure good fluidity and particle size. It can increase productivity in the manufacturing process and prevent tableting disorders including sticking, laminating, capping, and the like. In addition, when the mixture is out of the heating range (40 to 55° C.), the tactile test result is not good, and the occurrence of tableting failure increases, thereby reducing the quality in the manufacturing process.

As used herein, the term “sticking” refers to a phenomenon in which powder adheres to the surface of a punch in the manufacturing process to form grooves on the tablet surface.

As used herein, “laminating” refers to a phenomenon in which the tablet is peeled off in layers, and “capping” refers to a phenomenon in which the upper portion of the tablet is peeled off in a hat shape.

The manufacturing method may optionally include the following processes.

The mixture may be heated for 20 to 40 minutes so that the temperature of the mixture in step (b) is 40 to 55°C.

The temperature of the mixture heated in step (b) may be maintained constant.

As used herein, “constant” means that a value varies within ±5%. For example, the temperature of the mixture heated in step (b) may be maintained within the range of ±5% in the range of 40 to 55 ℃.

Step (b) may be prepared using a high-speed mixer equipped with a heating device.

As used herein, "high speed mixer (High Speed Mixer)" refers to a device that performs a series of processes of mixing, kneading, granulating, and sizing. The manufacturing method using the high-speed mixer according to one embodiment is to add an active ingredient (unsaponifiable corn extract) and additional pharmaceutically acceptable additives to the high-speed mixer and mix, knead, granulate, and It may be to perform the process of sizing.

The high-speed mixer equipped with the heating device may have a heating jacket attached to the high-speed mixer. The heating device can increase the temperature inside the vessel by putting hot water into the jacket through the heating water pump. For example, as the high-speed mixer equipped with the heating device, VERTICAL GRANULATOR (High speed mixer), model name: FM-VG-05P (with side jacket, manufacturer: POWREX CORPORATION, OSAKA TOKYO / JAPAN) can be used.

In order to bring the temperature of the mixture to about 40 to 55°C in the manufacturing method according to one embodiment, hot water put into the jacket through the warm water pump of the heating device may be heated to about 55 to 75°C. For example, in order to set the temperature of the mixture to about 40 ℃, 45 ℃, 50 ℃, or 55 ℃, the hot water introduced into the jacket through the warm water pump of the heating device is sequentially about 55 ℃, 65 ℃, 70 ℃, respectively. , or may be heated to 75 °C.

In the manufacturing method according to one embodiment, hot water is added through a heated water pump to raise the temperature inside the coalescing vessel, and the mixture is heated for 20 to 30 minutes until the temperature of the mixture including the excipient and the main component is about 40 to 55 ° C. After heating, an adsorption process of mixing for about 1 to 5 minutes by operating a mixer may be performed.

The manufacturing method according to one embodiment is to use the high-speed mixer to perform the adsorption process under the conditions of an agitator about 400 to 800 rpm, such as 600 rpm, and a chopper, about 1800 to 2200 rpm, for example, 2000 rpm. there is.

The manufacturing method according to an embodiment may use an additional granulator or granulator in addition to the high-speed mixer.

As used herein, the term "adsorption" (Mixture Adsorption or Adsorbed Mixture) refers to adsorption by heating and stirring a mixture containing a corn unsaponifiable extract and an adsorbent. In one embodiment, the adsorbate may be a granular material.

The adsorbate in step (b) may contain less than 0.5% of granules having a particle size of 1.4 mm.

The adsorbent in step (a) may be colloidal silicon dioxide, calcium silicate, or a mixture thereof.

The mixture in step (a) may further include an excipient selected from microcrystalline cellulose, starch, mannitol, sorbitol, carboxymethyl cellulose, calcium hydrogen phosphate, calcium carbonate, and mixtures thereof.

The mixture in step (a) may not contain lactose or lactose hydrate.

The mixture in step (a) may include the corn unsaponifiable extract, adsorbent, and excipient in a weight ratio of 1: 1-2: 1-5. For example, corn unsaponifiable extract, colloidal silicon dioxide and microcrystalline cellulose may be included in a weight ratio of 1: 1-2: 1-4. For example, the corn unsaponifiable extract, adsorbent and excipient may be included in a weight ratio of 1: 1.4 to 1.5: 3.5 to 4.5.

The mixture in step (a) may consist of 35 mg of saponified corn extract, 50 mg of colloidal silicon dioxide and 130 mg of microcrystalline cellulose.

In step (c), the adsorbate may be formulated by tableting with a disintegrant, an excipient, a binder, a lubricant, or a mixture thereof. As the disintegrant, excipient, binder, or lubricant, any additive known to be commonly used in the art may be used.

The disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrylline potassium, and any combination thereof, but is not limited thereto.

The excipient may be selected from the group consisting of starch, mannitol, sorbitol, microcrystalline cellulose, carboxymethyl cellulose, calcium hydrogen phosphate, calcium carbonate, and any combination thereof, but is not limited thereto.

The binder may be selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, copovidone, and any combination thereof, but is not limited thereto.

The lubricant may be selected from the group consisting of magnesium stearate, stearic acid, talc, light anhydrous silicic acid, sodium stearyl fumarate, colloidal silicon dioxide, calcium silicate, and any combination thereof, but is not limited thereto.

The formulation for oral administration according to one embodiment is based on 1 part by weight of the corn unsaponifiable extract, about 0.01 to 5 parts by weight of a disintegrant, about 0.5 to 15 parts by weight of an excipient, about 0 to 5 parts by weight of a binder, and about 0.01 to 1 part by weight of a lubricant parts by weight, or any combination thereof.

The excipient may be included in the mixture preparation step of step (a) and the formulation step of step (c) in the production method according to an embodiment.

In one embodiment, the adsorbate may be formulated by tableting with croscarmellose sodium, microcrystalline cellulose, hydroxypropyl cellulose, talc, magnesium stearate, or a mixture thereof.

In the manufacturing method according to an embodiment, the method may further include coating the tablet with a coating agent. The coating agent may be selected from the group consisting of cellulose derivatives dissolved or dispersed in water such as povidone, propylene glycol, polyvinyl acetate, methacrylic acid-ethyl acrylate copolymer, HPC, HPMC, CMC, and any combination thereof. , but is not limited thereto.

The coating may be a sugar coating, a film coating, an enteric coating, or a sustained release coating. As the coating method, a conventional method may be used, and examples thereof include a pan coating method, a fluidized bed coating method, or a compression coating method.

Another aspect of the present invention is

It provides an oral administration formulation prepared by the above manufacturing method.

The oral administration formulation may be selectively formulated as follows.

The oral dosage form may have a total weight of 200 to 300 mg. For example, the oral dosage form may have a total weight of 250 to 280 mg.

The oral dosage form may have a circular or oval shape. The oral dosage form may have the same or different major and minor lengths, and in other cases, in this specification, the diameter refers to the length of the major axis.

The oral dosage form may have a diameter of 10 mm or less when the total weight is 260 mg. The oral dosage form may have a diameter of 9 mm or less when the total weight is 260 mg. For example, the oral dosage form may have a diameter of 6 to 9 mm. For example, the oral dosage form may have a diameter of 7 to 9 mm.

The oral administration formulation may have a major axis and a minor axis length of 9 mm or less, respectively, when the total weight is 260 mg. For example, the oral administration formulation may have a major axis and a minor axis length of 6 to 9 mm, respectively. For example, the oral administration formulation may have a major axis and a minor axis length of 7 to 9 mm, respectively.

The oral administration formulation may further include a coating layer.

As used herein, "oral formulation" refers to a formulation made by molding or encapsulating a drug in a certain shape. The oral preparation may be formulated as tablets (including single-layered tablets, double-layered tablets, inner core tablets, etc.), granules, pellets, capsules, etc., but is not limited thereto. In one embodiment, the oral administration formulation is a tablet. When the oral dosage form is a capsule, the capsule may be in the form of including a tablet or the like therein.

The expressions and forms of the term “comprising” as used herein do not limit the present invention to the exclusion of any modifications or additions. Also, although described herein with the term “comprising”, the methods, materials, and compositions described herein may also be described as “consisting essentially of” or “consisting of.”

As used herein, the term “about” means that the referenced value may vary to some extent. For example, the value may vary by 10%, 5%, 2%, or 1%. For example, “about 5” is meant to include any value between 4.5 and 5.5, between 4.75 and 5.25, or between 4.9 and 5.1, or between 4.95 and 5.05.

As used herein, the term "to" includes the endpoints of the range and all intermediate points therebetween. Those skilled in the art will appreciate that deviations in numerical quantities are possible. Therefore, whenever a numerical value is recited in the specification or claims, it is understood that such numerical value or additional values about that numerical value are also within the scope of the present invention.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto. In addition, in the process described below, some of each step may be omitted or may be repeatedly performed, and the order of each step may be appropriately changed in some cases.

[Example]

Hereinafter, the present invention will be described in more detail by way of Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereby.

제조예 1: 옥수수불검화추출물의 제조 Preparation Example 1: Preparation of unsaponifiable corn extract

Corn oil wax (454 kg), corn oil hood (303 kg), ethanol (1157 L), potassium hydroxide (161 kg) were added, and the mixture was stirred under reflux at 81 ° C. for 4 hours, and methylene chloride (5842 L) was added to separate the layers. Purified water (1243L) was added to the lower layer, and the layer was separated to purify the product layer. Purified water (1243L) was added, and the layers were separated and purified. The obtained product layer was purified by adding purified water (1243L), followed by layer separation, and the product layer was filtered and then concentrated. After repeating the above process 3 times, ethanol was added and concentrated at 82.5° C. to obtain 370 kg of an unsaponifiable corn extract (yield: 16.3%).

The corn unsaponifiable extract contains 10.0 to 25.0% of total sterols (as β-sitosterol (C ₂₉ H ₅₀ O: 414.69)) and 75.0% or more of unsaponifiables when quantified.

실시예 1 내지 4 및 비교예 1 내지 3: 각 온도 조건 별 흡착물의 제조Examples 1 to 4 and Comparative Examples 1 to 3: Preparation of adsorbates for each temperature condition

A mixture was prepared by mixing 35 mg of the corn unsaponifiable extract obtained in Preparation Example 1, 50 mg of colloidal silicon dioxide and 130 mg of microcrystalline cellulose (weight ratio of 1: 1.43: 3.71).

Using a high speed mixer equipped with a heating device (VERTICAL GRANULATOR (High speed mixer), model name: FM-VG-05P (with side jacket), manufacturer: POWREX CORPORATION, OSAKA TOKYO / JAPAN), the mixture was stirred for 20 to 30 minutes. While heating for a while, the temperature of the mixture was increased to the target temperature shown in Table 1 below. An adsorbate was prepared by stirring the mixture under conditions of an agitator of 600 rpm and a chopper of 2000 rpm. The temperature of the mixture was kept constant while preparing the adsorbate.

The heating temperature of each mixture is shown in Table 1.

[Table 1]

실험예 1: 성상 및 촉각 검사 평가 Experimental Example 1: Appearance and tactile test evaluation

The properties of the adsorbates prepared in Examples 1 to 4 and Comparative Examples 1 to 3 were visually observed. In addition, about 1 g of each adsorbent was arbitrarily taken and pressed with the thumb and forefinger to conduct a tactile test.

As a result of the tactile test, if the raw material leaked out after pressing, it was evaluated as “poor”, and if it did not seep out, it was evaluated as “good”. The results are shown in FIGS. 1 to 2 and Table 2.

In FIG. 1, the observed properties of each adsorbate prepared in Examples 1 to 4 and Comparative Examples 1 to 3 are shown along with the temperature of the mixture used to prepare each adsorbate.

In FIG. 2, the raw material seeping phenomenon observed for each adsorbate prepared in Examples 1 to 4 and Comparative Examples 1 to 3 is shown along with the temperature of the mixture used to prepare each adsorbate.

Table 2 shows the temperature and tactile test results of the mixture used to prepare each adsorbate.

[Table 2]

As shown in Table 2, in the adsorbates of Comparative Examples 1 to 3 prepared by heating the mixture to a temperature of 25° C., 30° C., or 35° C., a raw material oozing phenomenon was observed. Therefore, it was evaluated as “poor” as a result of the tactile test.

In comparison, in the adsorbates of Examples 1 to 4 prepared by heating the mixture to a temperature of 40° C., 45° C., 50° C., or 55° C., no raw material seepage was observed. Therefore, the tactile test result was evaluated as “good”.

From the above results, it was confirmed that it is preferable to heat the mixture so that the temperature of the mixture is 40 to 55°C in order to prevent the raw material seeping out during the preparation of the adsorbate.

실험예 2: 안식각 측정 및 이에 따른 유동성 평가 Experimental Example 2: Measurement of angle of repose and evaluation of fluidity accordingly

The angle of repose of the adsorbates prepared in Examples 1 to 4 and Comparative Examples 1 to 3 was measured, and the fluidity of each adsorbate was evaluated.

When the angle of repose could not be measured as the adsorbate formed a large mass and blocked the hole of the angle of repose measurement device, it was evaluated as “not measurable”.

Table 3 shows the measurement results of the temperature and angle of repose of the mixture used to prepare each adsorbate.

[Table 3]

As shown in Table 3, the adsorbate of Comparative Examples 1 or 2 prepared by heating the mixture to a temperature of 25°C or 30°C formed a large mass, so that it was impossible to measure the angle of repose. In the case of Comparative Examples 1 or 2, it was found that the fluidity was very poor.

In comparison, the adsorbates prepared in Examples 1 to 4 and Comparative Example 3 prepared by heating the mixture to a temperature of 35 ° C., 40 ° C., 45 ° C., 50 ° C., or 55 ° C. It was confirmed that the angle of repose was shown.

From the above results, in order to secure good fluidity and increase productivity during tablet manufacturing, the temperature of the mixture should be 35° C. or higher, and when the mixture is heated to a temperature of 40 to 55° C., an angle of repose of about 35 to 38° is exhibited, and good It was confirmed that liquidity could be secured.

실험예 3: 체질에 의한 입도 평가Experimental Example 3: Evaluation of particle size by sieving

The particle sizes of the adsorbates prepared in Examples 1 to 4 and Comparative Examples 1 to 3 at each temperature were measured using a sieve network. Sieve each adsorbent using No. 14 (1.4 mm), No. 20 (0.83 mm), No. 25 (0.71 mm), No. 30 (0.6 mm), and No. 35 (0.5 mm) sieves, and sieve the No. 14 residue (~ /14), No. 20 residual fraction (14/20), No. 25 residual fraction (20/25), No. 30 residual fraction (25/30), No. 35 residual fraction (30/35), and No. 35 pass-through fraction ( 35/~).

[Table 4]

As shown in Table 4, in the adsorbates of Comparative Examples 1 to 3 prepared by heating the mixture to a temperature of 25 ° C, 30 ° C, or 35 ° C, the residual rate remaining in the No. 14 sieve net is as high as 0.5% or more, It was confirmed that the particle size was manufactured too large. The large particle size of Comparative Examples 1 to 3 may be a cause of poor properties and sticking during tableting.

In comparison, in the adsorbates of Examples 1 to 4 prepared by heating the mixture to a temperature of 40° C., 45° C., 50° C., or 55° C., the residual rate remaining in the No. 14 sieve net was less than 0.5%.

From the above results, it was confirmed that it is preferable to heat the mixture so that the temperature of the mixture is 40 to 55°C in order to secure a particle size such that the residual rate remaining in the No. 14 sieve net is less than 0.5%.

실시예 5 내지 8 및 비교예 4 내지 6: 각 온도 조건 별 흡착물을 이용한 정제의 제조 Examples 5 to 8 and Comparative Examples 4 to 6: Preparation of tablets using adsorbates for each temperature condition

Tablets were prepared from the adsorbates for each temperature condition prepared in Examples 1 to 4 and Comparative Examples 1 to 3 without a post-mixing process with other excipients for the evaluation of tabletting properties according to the temperature conditions of the mixture.

Each adsorbate prepared in Examples 1 to 4 and Comparative Examples 1 to 3 containing 35 mg of corn unsaponifiable extract, 50 mg of colloidal silicon dioxide and 130 mg (total content of about 215 mg) of microcrystalline cellulose was hydraulically operated at a pressure of 1.0 to 1.2 tons. Tablets of Examples 5 to 8 and Comparative Examples 4 to 6 were obtained by tableting using a single-shot tableting machine (round, diameter: 9.0 mm).

실험예 4: 타정 장애 및 타정성 평가 Experimental Example 4: Evaluation of tabletting disorders and tabletting properties

The tableting failure was evaluated by observing whether or not sticking occurred on the tablets prepared in Examples 5 to 8 and Comparative Examples 4 to 6, and the tabletting property was evaluated by observing whether or not the properties were defective. The results are shown in Figure 3 and Table 5. A tableting disorder occurring during the continuous tabletting process of 100 tablets was observed.

Table 5 shows the temperature of the mixture used to prepare each adsorbate and whether or not tabletting failure occurred.

[Table 5]

As shown in Table 5, the tablets prepared in Comparative Examples 4 and 5 had a sticking phenomenon, and Comparative Example 6 had poor properties.

In comparison, in the case of the tablets of Examples 5 to 8, it was confirmed that there was no tableting disorder, and the tablets had good properties.

From the above results, it was confirmed that it is preferable to heat the mixture so that the temperature of the mixture is 40 to 55° C. in order to prevent the occurrence of tableting failure and secure good properties.

실시예 9: 정제의 제조 Example 9: Preparation of tablets

Using a high speed mixer equipped with a heating device (VERTICAL GRANULATOR (High speed mixer), model name: FM-VG-05P (with side jacket), manufacturer: POWREX CORPORATION, OSAKA TOKYO / JAPAN), the mixture was stirred for 20 to 30 minutes. While warming for a while, the temperature of the mixture was increased to 40 to 55 °C. An adsorbate was prepared by stirring under the conditions of an agitator of 600 rpm and a chopper of 2000 rpm. The temperature of the mixture was kept constant while preparing the adsorbate.

The adsorbate was mixed with croscarmellose sodium 1.3 mg, microcrystalline cellulose 22.9 mg, hydroxypropyl cellulose 13 mg, talc 2.6 mg, and magnesium stearate 5.2 mg (total weight 260 mg). Using an Autotab-200TR (manufacturer: Ichihashi seki) single-shot tableting machine (round, diameter: 8.6 mm), the tablet was compressed at a pressure of 1.0 to 1.2 ton to prepare an uncoated tablet with a hardness value of about 10 kp, which was used as the tablet of Example 9.

대조예 1 및 2: 옥수수불검화추출물 함유 시판 정제 Control Examples 1 and 2: Commercially available tablets containing unsaponifiable corn extract

As Control Example 1, Insadol Tablet ^TM (including 35 mg of unsaponifiable corn extract, total weight of coated tablet about 409.5 mg) (manufacturer: Dongkuk Pharmaceutical) was obtained and used. As Control Example 2, Denkyu Tablet ^TM (including 35 mg of unsaponifiable corn extract, coated tablet total weight 410 mg, uncoated tablet total weight 392 mg) (manufacturer: Ildong Pharmaceutical) was used.

실험예 5: 붕해 시간 평가 Experimental Example 5: Evaluation of disintegration time

A disintegration tester (manufacturer: Fine scientific, model name) that reciprocates 29 to 32 times per minute, with an amplitude of 53 to 57 mm moving up and down, using 6 tablets of Control Example 2 and 6 samples of each of the tablets prepared in Example 9 : Using DIT-200) and a vibrator, when the amount of test solution is at the top of the tester, make sure that both sides of the tester fall at least 15mm below the liquid level, and when the tester goes down, both sides of the tester are at the bottom of the beaker The disintegration time was measured by setting the tester not to be completely submerged at a distance of 25 mm or more from the Water (37±2° C.) was used as the test solution, and the auxiliary plate was not used.

Table 6 shows the disintegration time and average disintegration time [minutes ('), seconds (")] of each of the six samples.

[Table 6]

The tablet of Example 9 (total weight 260 mg) showed a disintegration time equivalent to that of Control Example 2 (Denkyu Tablet ^TM , coated tablet total weight 410 mg, uncoated tablet total weight 392 mg).

From the above results, it was confirmed that the tablet of Example 9 exhibited tablet miniaturization (total weight reduction) and disintegration time equivalent to that of the commercial drug Denkyu Tablet ^TM .

실시예 10: 코팅 정제의 제조 Example 10: Preparation of coated tablets

Using a coating machine (manufacturer: Pharmatech Korea, model name: PKC-60) for the tablet of Example 9, Opadry OY-S7223 white suspension as the primary coating solution, Opadry 200 Orange 200F630014 suspension as the secondary coating solution, Opadry 200 orange 200F630014 suspension as the 3rd coating solution Closclear 97W19196 suspension was prepared and then sequentially coated to prepare coated tablets of Example 10.

실험예 6: 시판 정제와 중량 및 크기 비교 Experimental Example 6: Comparison of weight and size with commercially available tablets

[Correction 12.01.2022 under Rule 91]
The weight and size of the coated tablet prepared in Example 10 were compared with Insadol Tablet ^TM and Denkyu Tablet ^TM of Control Examples 1 and 2 and are shown in FIG. 4 .

[Correction 12.01.2022 under Rule 91]
As shown in FIG. 4, the coated tablet prepared in Example 10 was able to reduce the weight by about 34% compared to Insadol Tablet™ or Denkyu Tablet™. In addition, it was possible to reduce the thickness by about 18% and the diameter by about 15% compared to the commercially available tablets. It was confirmed that the tablet was miniaturized compared to the commercially available tablet.

[Correction 12.01.2022 under Rule 91]

So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that it may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims

(a) preparing a mixture comprising 35 mg of unsaponifiable corn extract and an adsorbent;

(b) preparing an adsorbate by heating and stirring so that the temperature of the mixture becomes 40 to 55°C; and

(c) tabletting and formulating the adsorbate;
The method according to claim 1, wherein in step (b), the mixture is heated for 20 to 40 minutes so that the temperature of the mixture is 40 to 55°C.
The method according to claim 1, wherein the temperature of the mixture heated in step (b) is constantly maintained.
The method according to claim 1, wherein step (b) is prepared using a high-speed mixer equipped with a heating device.
The method according to claim 1, wherein the adsorbate in step (b) contains less than 0.5% of granules having a particle size of 1.4 mm.
The method according to claim 1, wherein the adsorbent in step (a) is colloidal silicon dioxide, calcium silicate, or a mixture thereof.
The method according to claim 1, wherein the mixture in step (a) further comprises an excipient selected from microcrystalline cellulose, starch, mannitol, sorbitol, carboxymethyl cellulose, calcium hydrogen phosphate, calcium carbonate, and mixtures thereof, oral administration formulation manufacturing method.
The method according to claim 1, wherein the mixture in step (a) does not contain lactose or lactose hydrate.
The method according to claim 7, wherein the mixture in step (a) contains the corn unsaponifiable extract, adsorbent and excipient in a weight ratio of 1: 1-2: 1-5.
The method according to claim 6 or 7, wherein the mixture in step (a) consists of 35 mg of unsaponifiable corn extract, 50 mg of colloidal silicon dioxide and 130 mg of microcrystalline cellulose.
The method according to claim 1, wherein in step (c), the adsorbate is tableted together with a disintegrant, an excipient, a binder, a lubricant, or a mixture thereof to formulate the formulation.
The method according to claim 1, wherein the adsorbate is formulated by tableting with croscarmellose sodium, microcrystalline cellulose, hydroxypropyl cellulose, talc, magnesium stearate, or a mixture thereof.
An oral dosage form prepared by the method of claim 1, wherein the total weight is 200 to 300 mg.
The oral administration formulation according to claim 13, wherein the diameter is 9 mm or less when the total weight is 260 mg.