KR101912525B1 - Manufacturing method of oral preparation coated calcium chloride and levan - Google Patents

Abstract

The present invention relates to a manufacturing method of an oral preparation coated with calcium chloride and levan. The oral preparation coats a target material supported on an alginic acid with calcium chloride and levan. According to the present invention, probiotics such as lactobacillus in which activity is easily inhibited due to various drugs and stomach acids, which are prevented from being absorbed in a gastrointestinal, are emitted in a small intestine, thereby manufacturing the oral preparation having excellent selective drug transmissibility. The manufacturing method comprises: a first step of preparing an alginic acid solution, a calcium chloride solution and a levan solution on which the target material is supported; a second step of mixing the calcium chloride solution and the levan solution to manufacture a coating solution, and dropping the alginic acid solution on which the target material is supported to the coating solution; and a third step of collecting and drying a coating preparation generated by reacting the alginic acid solution with the coating solution through the dropping method.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oral preparation coated with calcium chloride and levan,

The present invention relates to a process for the preparation of oral preparations coated with calcium chloride and levan. More particularly, the present invention relates to a method for preparing an oral preparation coated with calcium chloride and levan on a target material carried on alginic acid.

Drugs taken into the body need to be selectively disintegrated in the oral, gastrointestinal, or small intestine depending on their use. Lactic acid bacteria and peptides that easily break down activity in gastric acid, such as lactic acid bacteria and peptides, vitamin C, antibiotics that cause gastritis, gastritis, anticancer drugs and antiinflammatory drugs that absorb or act in the stomach are essential drugs for this selective disintegration. For the selective disintegration in the small intestine, studies on delayed release agent or sustained release agent over time have been conducted variously, but the selective disintegration condition showing a great effect has not yet been established.

Alginic acid (alginate) is a type of polysaccharide contained in seaweeds and can be obtained by extracting a brown algae (Phaeophyceae, kelp, sea stew, mushroom, cornstalk, etc.) with an alkali solution and then treating with sulfuric acid. It is a complex polysaccharide mainly composed of mannuronic acid and glucuronic acid. It has a molecular weight of about 15,000 and does not dissolve in water but swells. It does not dissolve in organic solvents and does not decompose into human digestive enzymes, so it does not become a nutritional ingredient, but it acts as a plant fiber. It is mainly used as a thickening stabilizer for ice cream, confectionery, noodle, frozen food, etc., and the sodium salt of alginic acid and propylene glycol salt are designated as chemical compounds as food additives.

The chemical formula of calcium chloride is CaCl _2, and it is derived from minerals such as tachyhidite in nature and contained 0.15% in seawater. The anhydride has a rutile structure that is somewhat twisted with an opaque white crystal of an orthorhombic system. The chemical formula is 111.0, the melting point is 772 ℃, the boiling point is 1935 ℃, and the specific gravity is 2.15. The solubility in water, that is, the maximum number of grams of calcium chloride that dissolves in 100 g of water is 74.5 g (20 ° C), which is very high and it is also soluble in alcohol and acetone. Calcium chloride can be obtained by reacting calcium carbonate with diluted hydrochloric acid. &Quot; CaCO ₃ (s) + 2HCl (aq) - CaCl ₂ (s) + H ₂ O (l) + CO ₂ (g) ". When hydrochloric acid is added to calcium carbonate to evaporate the resulting solution, various hydrates can be obtained depending on the temperature. In the saturated solution, the hexahydrate of CaCl ₂ .6H ₂ O at -54.9 ° C to 29 ° C, the dihydrate of CaCl ₂ .4H ₂ O at 29 ° C to 45 ° C and the dihydrate of CaCl ₂ .2H ₂ O at 45 ° C and above And is precipitated. In 175 ℃ the CaCl ₂ · monohydrate, about 300 ℃ of H ₂ O occurs in the CaCl ₂ anhydride. Dihydrate and anhydride are highly used as a rainy season drying agent because they have strong deliquescence and absorb water well. It can absorb more than 14 times the weight of its own weight. However, it can not be used for the drying of these substances since it forms molecular compounds such as CaCl ₂ · 8NH ₃ and CaCl ₂ · 4C ₂ H ₅ OH by combining with ammonia (NH ₃ ) and alcohol (ethanol: C ₂ H ₅ OH) . A coolant (curing agent) made by mixing hexavalent (CaCl ₂ .6H ₂ O) with ice at a ratio of 1.44 to 1 can lower the temperature to -54.9 ° C. If you spray calcium chloride on your eyes in winter, it absorbs the moisture around you and melts. It is very useful as a snow remover to dissolve ice-covered roads and prevent them from freezing again because the water melted with calcium chloride can re-freeze to 54.9 ° C. As a medicinal product, it is known as Ringer's solution, which is the most easily absorbed in calcium, and is used mainly as an injectable drug because it directly injures stomach when taken directly.

Levan is a polysaccharide composed of β2 → 6-linked fructose, a kind of fructose polymer. In plants, it can be seen in leaf, stem of monocotyledonous plants, especially crests. The best-known Levan is inulin, which can be obtained from potatoes or other plants. It is a polysaccharide having a β-2,1 bond composed almost entirely of fructose only, and many glucose molecules are contained at the non-reducing end. Levan, a bacterial origin, is synthesized from sugar or raffinose as a carbon source to form macromolecules.

On the other hand, the inventors of the present invention studied various drug coating agents having small intestine disintegrability, and found that when the alginic acid-coated target material is coated with calcium chloride and levan, the composition which is not disintegrated under gastrointestinal conditions is selectively disintegrated into small intestinal conditions Thereby completing the present invention.

Korean Patent No. 10-0493354 (Lactobacillus powder having improved survival rate coated with levan and alginate beads and method for producing the same, applicant: Korea Research Institute of Bioscience and Biotechnology, Registration date: May 25, 2005) Korean Patent Laid-Open No. 10-2016-0095812 (Title of the Invention: Method for producing persistent microorganism preparation and microorganism preparation prepared by the above method, Applicant: Wonkwang University Industry & Academy Collaboration Foundation, Publication date: August 12, 2016) Korean Patent Laid-Open No. 10-2016-0115995 (entitled "Pharmaceutical or Health Functional Composition Having Resistance to Influence of Ethanol with Sustained Release Characteristics, Applicant: Ebornik K. Geheim, Publication Date: October 2016 06)

It is an object of the present invention to provide a method for producing an oral preparation coated with calcium chloride and levan. More particularly, the present invention relates to a method for producing an oral preparation in which a target material supported on alginic acid is coated with calcium chloride and levan.

The present invention is to provide a method for producing an oral preparation coated with calcium chloride and levan.

More specifically, the manufacturing method (step 1) includes: preparing an alginic acid solution, a calcium chloride solution, and a Levan solution on which a target material is supported;

(Step 2) mixing a calcium chloride solution and a Levan solution to prepare a coating solution, and dropping the alginic acid solution on which the target material is loaded into the coating solution; And

(Step 3) Collecting and drying the resulting coating formulation by reacting the alginic acid solution with the coating solution through a drip method;

. ≪ / RTI >

The target substance of the first step may be selected from the group consisting of vitamins, lactic acid bacteria, yeast, drugs, plant extracts, peptides and proteins. The drug may be selected from the group consisting of an anti-cancer agent, an antibacterial agent, an anti-inflammatory agent, an immunostimulant, an immunosuppressant, and an antiviral agent.

Accordingly, the present invention provides a method for producing an oral preparation prepared by the above method.

Hereinafter, the present invention will be described in detail.

The present invention provides a method for preparing an oral preparation coated with calcium chloride and levan. More specifically, the production method comprises the steps of (1) preparing an alginic acid solution, a calcium chloride solution, and a Levan solution ; (Step 2) mixing a calcium chloride solution and a Levan solution to prepare a coating solution, and dropping the alginic acid solution on which the target material is loaded into the coating solution; And (3) collecting the resulting coating formulation by reacting the alginic acid solution with the coating solution through a drip method, and drying the coating formulation.

In the first step, the target substance is not limited to any drug provided by oral administration, but may include various vitamins, lactic acid bacteria, yeast, various live bacteria, various drugs, various plant extracts, peptides, proteins and the like. The drug may include an anti-cancer agent, an antibacterial agent, an anti-inflammatory agent, an immunity enhancer, an immunosuppressant, an antiviral agent, and the like.

In the first step, the concentration of the alginic acid solution may be 0.5 to 2 wt%, the concentration of the calcium chloride solution may be 0.1 to 1 M, and the concentration of the Levan solution may be 0.1 to 1 wt%. At this time, the solvent of the alginic acid solution, the calcium chloride solution, and the Levan solution may be selected from the group consisting of water, saline, phosphate buffered saline, and aqueous ethanol solution.

In the second step, the calcium chloride solution and the Levans solution may be mixed in a volume ratio of 1: 0.1 to 10, preferably 1: 0.5 to 5.

When the volume of the alginate solution is 1.0 in the second step, the amount of the coating solution is preferably 0.05 to 0.15.

In the present invention, when the mixing ratios or concentrations are out of the above ranges, it may be difficult to form an oral coating agent, and drug loading may not be performed well, which is not preferable.

The present invention relates to a method for preparing an oral preparation coated with calcium chloride and levan, wherein the oral formulation is coated with alginic acid-coated target material with calcium chloride and levan. By the present invention, it is possible to produce an oral preparation excellent in selective drug delivery by producing various drugs which should be absorbed in the stomach and gastric acid, and the active agent such as lactic acid bacteria which is easily inhibited by activity due to gastric acid is released in the small intestine.

Korean Patent No. 10-0493354, Korean Patent Laid-open No. 10-2016-0095812 and Korean Patent Laid-Open No. 10-2016-0115995, alginic acid, levan, calcium chloride, etc. may be used alone or as a coating agent for a drug There has been no disclosure of a method for preparing an oral preparation which can selectively melt into a small intestine using the same method as that of the present invention.

Fig. 1 shows the result of confirming the degree of disintegration of the formulation of Example 1-10 according to the present invention for 4 hours under conditions of artificial gastric juice or artificial intestinal fluid.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.

≪ Example 1: Preparation of raw material sample >

As a target substance (drug) to be carried on the oral coating agent of the present invention, a probiotic agent was prepared, and in addition, an edible yellowish color solution was prepared in order to visually confirm the disintegrating property instead of the drug. As the probiotics, the culture broth of Lactobacillus bulgaricus, which is a lactic acid bacterium, was centrifuged and pellets of the cells were suspended in phosphate buffered saline (PBS) to adjust the optical density to 1.0.

Next, 0.1% by weight, 0.5% by weight, 1% by weight, 2% by weight and 4% by weight of alginic acid solution; 0.05 M, 0.1 M, 0.5 M, 1 M, 2 M solutions of calcium chloride; 0.05% by weight, 0.1% by weight, 0.5% by weight, 1% by weight and 2% by weight of Levan were prepared.

Phosphate buffered saline was used as a solvent for yellowish color, alginic acid solution, calcium chloride solution and Levan solution.

≪ Example 2: Preparation of an oral preparation >

Oral formulations were prepared using the raw materials of Example 1. The target substance and the alginic acid solution shown in Table 1 were mixed at a volume ratio of 1: 1 to prepare an alginic acid solution carrying the target material. Various solutions of calcium chloride and Levan were mixed at a volume ratio of 1: 1 to prepare a coating solution Respectively. Thereafter, the alginic acid solution on which the target material was supported was dropped on the coating solution, and the alginic acid solution reacted with the coating solution through the drip method, and the resulting coating agent was collected and dried. At this time, when the volume of the alginic acid solution was 1.0, the amount of the coating solution was 0.1.

Condition Target material Concentration of alginic acid solution Concentration of calcium chloride solution Concentration of Levan solution Example 1-1 Lactobacillus 0.5 wt% 0.5 M 0.5 wt% Examples 1-2 Lactobacillus 1 wt% 0.5 M 0.5 wt% Example 1-3 Lactobacillus 2 wt% 0.5 M 0.5 wt% Examples 1-4 Lactobacillus 1 wt% 0.1 M 0.5 wt% Examples 1-5 Lactobacillus 1 wt% 0.5 M 0.5 wt% Examples 1-6 Lactobacillus 1 wt% 1 M 0.5 wt% Examples 1-7 Lactobacillus 1 wt% 0.5 M 0.1 wt% Examples 1-8 Lactobacillus 1 wt% 0.5 M 0.5 wt% Examples 1-9 Lactobacillus 1 wt% 0.5 M 1 wt% Example 1-10 paint 0.5 wt% 0.5 M 0.5 wt% Example 1-11 paint 1 wt% 0.5 M 0.5 wt% Examples 1-12 paint 2 wt% 0.5 M 0.5 wt% Examples 1-13 paint 1 wt% 0.1 M 0.5 wt% Examples 1-14 paint 1 wt% 0.5 M 0.5 wt% Examples 1-15 paint 1 wt% 1 M 0.5 wt% Examples 1-16 paint 1 wt% 0.5 M 0.1 wt% Examples 1-17 paint 1 wt% 0.5 M 0.5 wt% Example 1-18 paint 1 wt% 0.5 M 1 wt%

< Comparative Example  1. Preparation of comparative oral formulations i &gt;

The oral preparations were prepared in the same manner as in Example 1 except that the kinds of the target substances contained in the oral preparations and the concentrations of the alginic acid solution / potassium carbonate solution / Levan solution were listed in Table 2 below.

Condition Target material Concentration of alginic acid solution Concentration of calcium chloride solution Concentration of Levan solution Comparative Example 1-1 Lactobacillus - 0.5 M 0.5 wt% Comparative Example 1-2 Lactobacillus 0.1 wt% 0.5 M 0.5 wt% Comparative Example 1-3 Lactobacillus 3 wt% 0.5 M 0.5 wt% Comparative Example 1-4 Lactobacillus 1 wt% - 0.5 wt% Comparative Example 1-5 Lactobacillus 1 wt% 0.05 M 0.5 wt% Comparative Example 1-6 Lactobacillus 1 wt% 2 M 0.5 wt% Comparative Example 1-7 Lactobacillus 1 wt% 0.5 M - Comparative Example 1-8 Lactobacillus 1 wt% 0.5 M 0.05 wt% Comparative Example 1-9 Lactobacillus 1 wt% 0.5 M 2 wt% Comparative Example 1-10 paint - 0.5 M 0.5 wt% Comparative Example 1-11 paint 0.1 wt% 0.5 M 0.5 wt% Comparative Example 1-12 paint 3 wt% 0.5 M 0.5 wt% Comparative Example 1-13 paint 1 wt% - 0.5 wt% Comparative Example 1-14 paint 1 wt% 0.05 M 0.5 wt% Comparative Example 1-15 paint 1 wt% 2 M 0.5 wt% Comparative Example 1-16 paint 1 wt% 0.5 M - Comparative Example 1-17 paint 1 wt% 0.5 M 0.05 wt% Comparative Example 1-18 paint 1 wt% 0.5 M 2 wt%

In Table 2, '-' indicates that phosphate buffer solution containing no alginic acid, calcium chloride and levan was used.

&Lt; Comparative Example 2 > Preparation of Comparative Oral Formulation ii &gt;

0.5% by weight solution of alginic acid, 0.5% by weight of alginic acid, 0.5% by weight of calcium chloride and 0.5% by weight of levan were used in the same manner as in Example 1-1, To prepare a drug-bearing solution. The resulting coating formulation was collected and dried using a method of dropping the solution in a 0.5 M solution of calcium chloride.

EXPERIMENTAL EXAMPLE 1: Formation of coating agent and confirmation of selective disintegration [

The results are shown in Table 3 below (Very good: Good: Good: Fair: Fair: C: Good) Bad).

In addition, 10 oral preparations were placed in a 15 mL tube containing artificial gastric juice (pH 2.0) and artificial intestinal fluid (pH 6.8). After 2 hours, 4 hours, and 6 hours, selective disintegration was confirmed under gastric and small bowel conditions (?: Completely disintegrated,?: Disintegrating,?: Not disintegrating at all, and '-' indicating no experimental group).

Condition Whether or not the coating agent is formed Disintegration in artificial gastric juice Disintegration in artificial intestinal fluid After 2 hours After 4 hours After 6 hours After 2 hours After 4 hours After 6 hours Example 1-1 ◎ × × × △ ○ ○ Examples 1-2 ○ × × × △ ○ ○ Example 1-3 ○ × × × △ △ ○ Examples 1-4 ○ × × × △ △ ○ Examples 1-5 ○ × × × △ ○ ○ Examples 1-6 ○ × × × △ ○ ○ Examples 1-7 ○ × × × △ ○ ○ Examples 1-8 ○ × × × △ ○ ○ Examples 1-9 ○ × × × △ ○ ○ Example 1-10 ◎ × × × △ ○ ○ Example 1-11 ○ × × × △ ○ ○ Examples 1-12 ○ × × × △ △ ○ Examples 1-13 ○ × × × △ △ ○ Examples 1-14 ○ × × × △ ○ ○ Examples 1-15 ○ × × × △ ○ ○ Examples 1-16 ○ × × × △ ○ ○ Examples 1-17 ○ × × × △ ○ ○ Example 1-18 ○ × × × △ ○ ○ Comparative Example 1-1 × - - - - - - Comparative Example 1-2 △ × × × × × × Comparative Example 1-3 ○ × × × × × × Comparative Example 1-4 × - - - - - - Comparative Example 1-5 × - - - - - - Comparative Example 1-6 ○ × × × × × × Comparative Example 1-7 △ × × × × × × Comparative Example 1-8 × - - - - - - Comparative Example 1-9 ○ × × × × × × Comparative Example 1-10 × - - - - - - Comparative Example 1-11 × - - - - - - Comparative Example 1-12 ○ × × × × × × Comparative Example 1-13 × - - - - - - Comparative Example 1-14 × - - - - - - Comparative Example 1-15 ○ × × × × × × Comparative Example 1-16 △ × × × × × × Comparative Example 1-17 × - - - - - - Comparative Example 1-18 ○ × × × × × × Comparative Example 2 ○ × × × × × ×

Table 3 shows that the oral preparation was well prepared under all the conditions of Example 1, but no alginic acid or calcium chloride was contained under the conditions of Comparative Example 1, no coating agent was formed. It is also found that when the concentration of alginic acid solution and calcium chloride solution is low, formation of coating agent is difficult when levan solution is not contained at all or when used at a low concentration.

It was confirmed that the disintegration degree of the oral preparation of Example 1 did not completely dissolve under the gastric condition, but disintegrated within 6 hours with a time difference in the small intestine condition. On the other hand, in the disintegration experiment using only the condition of Comparative Example 1 in which the oral preparation was formed, disintegration did not occur in both gastrointestinal and small intestinal conditions. Also in case of Comparative Example 2 in which coating agent zein levan was first loaded on alginic acid and drug, disintegration was not observed in artificial intestinal fluid.

Therefore, it is judged that only the coating agent prepared under the conditions of the present invention is excellent in selective dissolution in the field.

Claims (4)

(Step 1) preparing a 0.5 to 2 wt% solution of alginic acid on which the target substance is supported, a 0.1 to 1 M solution of calcium chloride and a 0.1 to 1 wt% solution of levan;
(Step 2) A coating solution is prepared by mixing 0.1 to 1 M of calcium chloride and 0.1 to 1% by weight of levan in a volume ratio of 1: 0.5 to 5, adding 0.5 to 2% by weight of alginic acid, Dropping the solution; And
(Step 3) Collecting the resulting coating formulation by reacting a 0.5 to 2 wt% solution of alginic acid on which the target material is supported with a coating solution through a drip method, and drying;
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Wherein the target substance of the first step is selected from the group consisting of vitamins, lactic acid bacteria, yeast, drugs, plant extracts, peptides and proteins. 3. The method of claim 2,
Wherein the drug is at least one selected from the group consisting of an anti-cancer agent, an antibacterial agent, an anti-inflammatory agent, an immunity enhancer, an immunosuppressant, and an antiviral agent. An oral preparation prepared by the method according to any one of claims 1 to 3.

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