WO2013166681A1

WO2013166681A1 - Composition for producing microcapsules and medicine made thereof

Info

Publication number: WO2013166681A1
Application number: PCT/CN2012/075283
Authority: WO
Inventors: 陈彦均; 杨艾琪; 黄汉芬
Original assignee: 聚和国际股份有限公司
Priority date: 2012-05-10
Filing date: 2012-05-10
Publication date: 2013-11-14
Also published as: CN104302279A

Abstract

Composition for producing microcapsules comprises hydrophilic polymers having carboxyl groups, hardeners, chitin and polyamines. Medicines made from the composition have excellent encapsulation efficiency and a rapid release rate and are suitable for oral administration. Medicine contains an active material encapsulated in the microcapsules made from the composition.

Description

Composition for preparing microcapsules and medicament prepared therewith

The present invention relates to a composition for preparing a microcapsule, and more particularly to a composition for preparing a microcapsule suitable for oral administration. Background technique

Oral administration is the most common and user-accepted route of administration, but this route will pass through the user's digestive system, so these drugs usually need to have a good embedding rate to protect the active substances from being digested. The liquid is destroyed. On the other hand, under the requirement of good embedding rate, the release rate of the active material is often poor, and the efficiency of the active material is lowered. Therefore, how to strike a balance between the embedding rate and the release rate has become a difficult problem that is difficult to overcome in the field.

In addition to the drugs used by the human body, the same problem also occurs in the field of vaccines for aquatic organisms. The aquaculture industry is an important industry in Taiwan. In order to solve the high infectious disease risk caused by high-density farming, the use of vaccines can effectively increase the profitability of the aquaculture industry. General aquatic vaccines can be roughly classified into three types of epidemic prevention methods: injection, immersion and oral administration. Injectable vaccines are not only time-consuming and labor-intensive, but also easy to cause fish and shrimp to be tight, and are not suitable for the prevention of fry. Although the immersion vaccine is convenient to use, not all vaccines can be used, and it cannot achieve effective epidemic prevention in large-scale breeding. Therefore, oral vaccines are the most ideal form of epidemic prevention in aquaculture.

The microcapsule vaccine used in the early aquaculture industry consisted of sodium alginate and calcium chloride, which had a good release rate, but the embedding rate was poor, so the active substance was easily damaged by gastric juice. At present, the microcapsules most commonly used in food or medicine are composed of sodium alginate, calcium chloride and chitin. By adding chitin, the embedding rate of the vaccine is increased to protect the active substance from the destruction of gastric juice. However, since aquaculture organisms usually have a shorter intestinal tract, such vaccines, despite their excellent embedding rate, sacrifice the release rate, making it impossible for the active substance to be completely released in the relatively short intestinal tract. The effect of the active substance.

In summary, vaccines currently used in aquaculture are also facing difficulties in balancing the embedding rate and release rate, which is not ideal. Summary of the invention

In order to solve the above technical problems, it is an object of the present invention to provide a composition for preparing microcapsules which has excellent embedding rate and rapid release rate.

Another object of the present invention is to provide a medicament for coating activity using microcapsules prepared by the composition The substance prevents the active substance from being damaged by the digestive juice (gastric juice) and enables the active substance to be released quickly. To achieve the above object, the present invention provides a composition for preparing a microcapsule comprising: 20-50 Wt% of a hydrophilic polymer having a carboxylic acid functional group; 30-50% by weight of a hardener; 0.5- 5 wt% of chitin; and 1-20 wt% of polyamines.

The present invention also provides a medicament comprising an active substance which is encapsulated in a microcapsule prepared by the composition.

According to a particular embodiment of the invention, preferably, the polyamine compound has a molecular weight of from 100 to 2000 g/mol o

According to a particular embodiment of the invention, preferably, the polyamine compound comprises tetraethylene pentamine > spermine, triethylene tetramine, spermidine > > triethylene tetramine, pentylene diamine, butylene diamine, propylene diamine, ethylene diamine, polyethylene Polyethyleneimine PEI or a combination thereof.

According to a particular embodiment of the invention, preferably the hydrophilic polymer having a carboxylic acid functional group is sodium alginate, gelatin, seaweed extract or a combination thereof.

According to a particular embodiment of the invention, preferably the hardener refers to calcium chloride, calcium carbonate, sodium chloride, calcium acetate, calcium gluconate, calcium sulphate, calcium citrate, sodium hydroxide or a combination thereof.

According to a particular embodiment of the invention, preferably, the drug has an embedding rate of from 85 to 100%.

According to a particular embodiment of the invention, preferably, the active substance of the drug has a release rate of 70-100% in an alkaline environment for 4 hours.

According to a particular embodiment of the invention, preferably the medicament further comprises an adjuvant.

According to a particular embodiment of the invention, the microcapsules preferably have an average particle size of from 10 to 1000 μηι, more preferably from 20 to 250 μm.

According to a particular embodiment of the invention, the medicament is an oral vaccine.

According to a particular embodiment of the invention, preferably the oral vaccine can be a first generation vaccine, a second generation vaccine or a third generation vaccine.

According to a particular embodiment of the invention, the active substance in the oral vaccine is an attenuated pathogen, a non-activated pathogen, a surface antigen of a pathogen of a dead pathogen, a recombinant protein, an immunoglobulin, an antigenic determinant or a combination thereof.

In summary, the composition of the present invention is disadvantageous in view of the fact that common drugs are difficult to achieve both the embedding rate and the release rate. The obtained microcapsules have excellent embedding rate and rapid release rate, so that the medicine prepared by using the microcapsule can not only prevent the gastric juice from damaging the active substance, but also can rapidly release the active substance in an appropriate environment, in particular Suitable for short water products in the digestive tract. DRAWINGS

1A-1F show the capsularity of each sample of Example 1; FIG. 1A is sample 1E; FIG. 1B is sample

2E; Figure 1C is a comparison sample 1E; Figure 1D is a comparison sample 2E; Figure 1E is a comparison sample 3E; Figure 1F is a comparison sample 4E;

Figure 2 shows the results of the activity test of the sample 1E-1%, the sample lE-3%, and the comparative sample 4E after the gastric acid treatment;

Figure 3 shows the results of the activity test of the sample 1S-1%, the sample lS-3%, and the comparative sample 4S after gastric acid treatment. Detailed ways

The present invention relates to a composition for preparing microcapsules which can be mixed with an active material to form a medicament in the form of a microcapsule. The medicine provided by the invention has excellent embedding rate and rapid release rate, can protect the active substance from damage of the digestive juice, and can release the active substance quickly under a suitable environment. Therefore, the medicament of the present invention is particularly suitable for oral administration, and is also particularly suitable for use in a water product having a short digestive tract.

The term "drug" as used in the present invention generally refers to a product in which a microcapsule obtained by using the composition of the present invention is coated with an active material, and the active material and an additive other than the microcapsule may be further contained therein.

The drug may be, but is not limited to, a drug, a health food, a vaccine or a combination thereof, and the active substance is an active ingredient in the drug, the health food, or the vaccine. The active substance contains a microorganism, a protein or other substance which has a disease prevention, a disease treatment, and a health promotion.

A specific example of the medicament of the present invention is a vaccine comprising an attenuating pathogen, an inactivated pathogen, a dead pathogen, a surface antigen of a pathogen, a recombinant protein, an immunoglobulin, an epitope, or a combination thereof.

The average particle diameter of the microcapsules of the present invention is preferably from 10 to 1000 μm, more preferably from 20 to 250 μm. Unless otherwise specified, the microcapsules at the time of calculating the average particle diameter may be in a state in which the active material is embedded, or may be in a state in which the active material is not embedded.

The composition for preparing a microcapsule of the present invention comprises at least the following components: sodium alginate, calcium chloride, chitin and a polyamine compound; more specifically, 20-50% by weight of a hydrophilic group having a carboxylic acid functional group Polymer; 30-50 wt% of hardener; 0.5-5 wt% of chitin; and 1-20 wt% of polyamines.

The hydrophilic polymer having a carboxylic acid functional group is used for mixing with the active material, and by virtue of it The carboxylic acid functional group produces a crosslinking reaction with the chitin. Preferably, the hydrophilic polymer having a carboxylic acid functional group is highly biocompatible, including, but not limited to, sodium alginate, gelatin, seaweed extract, or a combination thereof.

The hardener is used to provide structural stability of the medicament of the present invention. In principle, ionic compounds which generate positively charged cations after dissociation may be used, including, but not limited to, calcium chloride, calcium carbonate, sodium chloride, calcium acetate, calcium gluconate, calcium sulfate, calcium citrate, sodium hydroxide or Its combination.

In one embodiment of the invention, preferably, the hydrophilic polymer having a carboxylic acid functional group is sodium alginate, and the hardener is calcium chloride. Sodium alginate and calcium chloride are the main components commonly used in the preparation of microcapsules. However, the microcapsules prepared by these two components have poor porosity and poor embedding rate, so that the active substance is easily destroyed by gastric juice. Chitin, also known as chitosan, is a natural polymer that is highly biocompatible and is therefore widely used in biomedical materials. The addition of chitin to the present invention produces a crosslinking reaction with sodium alginate having a carboxylic acid functional group, thereby increasing the embedding rate of the microcapsules.

The embedding rate is explained by a person skilled in the art; in short, it refers to the extent to which the active substance is coated with other components of the drug without being in contact with the external environment. Further, the drug embedding rate of the present invention means the degree to which the active material is coated with the microcapsule of the present invention in the medicament of the present invention. The embedding rate of the active substance in the medicament of the present invention is 85 to 100%; among them, the components mainly providing a good embedding effect are sodium alginate, calcium chloride and chitin.

The rate of release is explained by those well known in the art; in short, it refers to the rate at which the active substance in the drug is released from the drug structure into the environment. While increasing the embedding rate, it may significantly affect the release rate of active substances in the drug. In order to provide a rapid release rate of the medicament of the present invention, the polyamine compound is added to the medicament of the present invention so that the release rate of the medicament of the present invention in the intestinal tract reaches 70-100% in 4 hours. More specifically, the polyamine compound has a property of rapidly dissolving in an alkaline environment, and therefore, it is mainly responsible for protecting the active substance from the destruction of gastric juice, and polyamine, compared with chitin, sodium alginate and calcium chloride. The compound is dissolved in the alkaline environment of the intestines, which in turn allows the active substance to be rapidly released.

The polyamine compound is a polyamine compound having a molecular weight of 100 to 2000 g/mol, which comprises: tetraethylene pentamine > spermine, triethylene tetramine , spermamine, triethylene tetramine, pentylene diamine, butylene diamine, propylene diamine, ethylene diamine Diamine), Polyethyleneimine PEI, or a combination thereof, but the selection of the polyamine compound is not limited to the above species.

The composition for preparing microcapsules of the present invention may further comprise 0.5-5% by weight of an emulsifier, and/or 40-60% by weight of an oil phase substance. The emulsifier and the oil phase material provide the function of a surfactant during the process of making the microcapsules of the compositions of the present invention. The emulsifier and the oil phase material are selected without limitation, and may be prepared according to the desired drug. The size of the material is chosen to achieve the desired HLB value (Hydrophile-Lipophile Balance Number). The emulsification includes: span20>span40>span60> span65 >span80> span85 >tween20> tween21 >tween40>tween60> tween61 > tween65 >tween80> tween81 > tween85 or a combination thereof, but not limited to the above categories. The oil phase material includes: vegetable oil such as soybean salad oil, safflower oil, sunflower oil, corn oil, olive oil, Penglai rice oil, peanut oil, animal oil such as roasted ghee, fragrant oil, refined lard or Combination, but not limited to the above categories.

In one embodiment of the invention, the drug is a vaccine. The vaccine comprises a first generation vaccine, a second generation vaccine or a third generation vaccine; and the active substance comprises: an attenuated pathogen, a dead pathogen, a surface antigen of a pathogen, an immunoglobulin, an epitope, or a combination thereof, but It is not limited to the above categories. The vaccine may further comprise an adjuvant. The adjuvant may be embedded in the microcapsules prepared by the composition as the active substance is generally, or may be formed separately from the microcapsules containing the active substance, independently of the microcapsules. A vaccine kit. The term "adjuvant" refers to an inducing substance used to enhance the immune response, which not only enhances the efficiency of the vaccine, but also reduces the amount of active substance used, and is of great value in terms of cost and safety considerations. The vaccine adjuvant of the present invention comprises: a chemical functional adjuvant and a physical functional adjuvant, for example, including an aluminum salt, an acetylated tyrosine, an acetylated saccharide, an anion-derivatized polysaccharide, or a cationic derivative. The polysaccharide is, but not limited to, the above species. One of ordinary skill in the art can select the type and amount of adjuvant as desired.

The following will describe the details of the composition for preparing microcapsules and the medicaments prepared therewith provided by the present invention in conjunction with the drawings. It should be noted that the following examples are merely illustrative of the use of the present invention. The characteristics and advantages of the composition for preparing the microcapsules and the medicaments prepared therewith are not intended to limit the scope of the invention.

Example 1: Encapsulation, embedding rate and release rate of a drug (vaccine) in the form of a microcapsule of the present invention

The capsularity and embedding rate of the drug prepared according to the spirit of the present invention was observed in this example. The medicament prepared in this embodiment is a vaccine for use in a water supply product, and the active substance is Vibrio carchariae which is treated by inactivation.

[preparation]

First, the active substance and the aqueous sodium alginate solution are uniformly mixed, and then the oil phase material (soybean salad oil) which has been uniformly mixed with the emulsifier (Span 80) is added, and all the components are quickly mixed into the first mixture at a rotation speed of 900 rpm. . Next, chitin, a polyamine compound (DETA or PEI) and calcium chloride are uniformly mixed into a second mixture. The second mixture was dropped into the first mixture and stirring was continued for 10 minutes to obtain a medicament (vaccine microcapsule) of the present example.

Composition and concentration of each sample of the present embodiment (including drugs made according to the spirit of the present invention, and comparative samples) Table 1: The components of the composition for preparing microcapsules of Example 1 and their concentrations

[Cavity and embedding rate]

The prepared drug was placed on a weighing paper and observed to be cystic by the naked eye. The results are shown in Figs. 1A - 1F; wherein the numbers in Figures 1A - 1F correspond to the English numbers listed in Table 1. In addition, the absorption values of each sample and the comparative sample were measured by OD540 and converted into the embedding rate of the drug.

The determination of the embedding rate by OD540 is based on the measurement knowledge well known in the art, and when the absorbance value is defined as 1, the number of colonies is 10 ⁹ CFU/mL. Briefly, 15 mg of the prepared drug (vaccine microcapsule) was placed in 5 mL of NaHC0 ₃ (aq), and the microcapsules were cleaved to release the active substance to become a rupture solution. The OD540 value of the rupture fluid was measured and substituted into the colony number calibration line to determine the total colony concentration: X CFU/mL (CFU; colony-forming unit). Calculate the embedding rate (EE%) by taking the value obtained into the following formula:

EE%

Wherein 'lm _S represents the amount of active ingredient contained per milligram of microcapsules.

Comparative sample 1E (Fig. 1C) showed poor cysticity, and about 50% of the drug was a sheet-shaped unformed by-product. Comparing the embedding rate of sample 1E is only 64%, presumably because the crosslinking speed of calcium ion (calcium chloride) and sodium alginate is too fast, resulting in the active substance being extruded into the microcapsule structure during the process of drug formation. outer.

Comparison of sample 2E (Fig. 1D) and comparative sample 3E (Fig. 1E) could not form a product of microcapsule type, let alone its embedding rate. Comparative sample 4E (Fig. 1F) was excellent in cysticity and its morphology was fine and consistent in powder form. Comparison The entrapment rate of sample 4E is as high as 100%, and the drug loading per gram of drug can reach 307 mg.

Sample 1E (Fig. 1A) and sample 2E (Fig. 1B) have excellent cysticity and the finished product is uniform and consistent. The entrapment rate of sample 1E and sample 2E is as high as 100%, and the drug loading per gram of drug can reach 299 mg and 287 mg, respectively.

In addition to the above samples and comparative samples, this example is based on the comparison of the ratios of the samples 1E, 4E and the sample 1E in the same manner, and changed to Vibrio alginolyticus (S4Y; I3⁄4n'o a/gm^ric∞M乍 as the active substance). The samples 1S, 4S and 1S were compared for subsequent testing. Furthermore, the average particle sizes of the samples 1E, 2E and 1S were all 70 μηι.

Example 2: Activity test of the vaccine prepared in Example 1

The oral vaccine is estimated to remain in the stomach of the fish for about 2 hours, so the vaccine must be tolerant to gastric acid for more than 2 hours. In the present example, the drug prepared in Example 1 was placed in gastric acid for 1 to 3 hours, and the remaining percentage of activity of the active substance was measured.

This activity test was designed according to the United States Pharmacopoeia. Simply put, take 150 mg of the sample or compare the sample, place it in the basket, and then wrap the 250 mesh screen on the outside of the basket and the rotating shaft to avoid sample leakage and interfere with the amount of bacteria detected. .

Next, the device was placed in 50 ml of gastric acid for 1, 2 or 3 hours, then transferred to deionized water for washing and lyophilized. The dried drug is then placed in a rupture solution and treated in a turbulent manner for 2 hours to release the active substance from the drug. Next, the active substance-containing rupture fluid was formulated into a suspension (with a bacterial concentration of 10 ⁸ cfo/ml) in a coating buffer and placed in a 96-well plate (100 μΐ/per well). The 96-well plate was then placed at 4 °C.

After overnight, 100 μM of 1% bovine serum albumin (BSA) (or 5% skim milk powder) was added to each well and allowed to react at 37 ° C for 1 hour. Next, 100 μM of rabbit antibacterial serum was added to each well and reacted at 37 ° C for 2 hours. Then, 100 μM of goat anti-rabbit serum was added to each well and reacted at 37 °C for 2 hours. Next, 100 μM of the color former was added to each well and allowed to react for 30 minutes, and the absorbance at OD 405 nm was interpreted by a spectrum analyzer. Finally, the resulting data was interpolated into the calibration curve to calculate the percent remaining activity, which is the ability of the drug to protect the active substance for each sample.

[Experiment 1]

The pure active substance (inactivated Vibrio anguillarum) was dropped into gastric acid for 1 hour, leaving only 1% of activity. Comparative sample 1E was only 3% active after 3 hours of reaction with gastric acid (not shown).

In addition, this experiment was carried out in addition to comparing samples 1E and 4E, and in addition to comparing the ratio of sample 4E (containing 10% by weight of chitin, containing no polyamines), respectively, adding 1^% or 3^ % of DETA replaces it Half of the chitin, and supplemented with sodium alginate to a total concentration of 100 Wt% (ie, containing 54 wt% sodium alginate, 40 \¥1% calcium chloride, 5 wt% chitin and 1\\% DETA , or 52 \^% sodium alginate, 40% calcium chloride, 5wt% chitin and 3wt ° / DETA), prepared samples 1E-1% and samples 1Ε-3% for testing.

Referring to Figure 2, comparing sample 4E with gastric acid, only 18% of activity remained after 2 hours. In contrast, samples 1E-1% and samples 1Ε-3% reacted with gastric acid for 2 hours, and then retained 45% and 38%, respectively.

[Experiment 2]

As in Experiment 1, a pure active substance (inactivated Vibrio alginolyticus) was dropped into gastric acid for 1 hour, leaving only 1% of activity. Comparing sample 1S after 3 hours of reaction with gastric acid, only 3% of the activity remained (not shown).

In addition, based on the comparison of the sample 4S ratio (containing 10% by weight of chitin, no polyamine compound), 1% or 3% of DETA was added to replace half of the chitin, and sodium alginate was added. Make up the total concentration to 100 wt% (BP, containing 54 wt% sodium alginate, 40 \¥1% calcium chloride, 5 wt% chitin and lwt ° / DETA, or 52 wt% sodium alginate, 40 ^ % chlorine Calcium, 5\¥1% chitin and 3\¥1% of 13⁄4 butyl), samples 1S-1% and samples 1S-3% were tested.

Referring to Figure 3, the sample 4S was compared with gastric acid for 2 hours and only 16% of the activity remained. In contrast, samples 1S-1% and samples lS-3% reacted with gastric acid for 2 hours, and then retained 22% and 64%, respectively.

[in conclusion]

Although the component mainly responsible for coating the active substance against gastric acid destruction is a polyelectrolyte membrane formed of sodium alginate, chitin and calcium chloride, and a crosslinked structure, or an egg-box structure. However, based on the results of the above two experiments, the present inventors have unexpectedly found that the addition of the polyamine compound not only increases the release rate, but more unexpectedly does not increase the extent to which the drug of the present invention is destroyed by gastric acid.

Example 3: Release rate of the vaccine prepared in Example 1

In this example, the release rate test of the simulated gastrointestinal tract was carried out using the comparative samples 1E, 1S, 4E, 4S and samples 1E, 1S, 2E of Example 1.

This gastrointestinal release test was designed according to the United States Pharmacopoeia. Simply put, take 150 mg of the sample or compare the sample, place it in the basket, and then wrap the 250 mesh screen on the outside of the basket and the rotating shaft to avoid the sample seeping out and disturb the amount of bacteria detected. .

Next, the device was placed in 50 ml of gastric acid for 2.5 hours and then transferred to deionized water for 10 minutes. After draining the water, it was transferred to 50 ml of intestinal fluid for 4 hours. At the same time, 500 μΐ of intestinal fluid was collected every hour and detected with OD540. The resulting data was converted to a calibration curve to determine its release rate in the gastrointestinal tract. Since the sample and the comparative sample are not released in the stomach acid, only the experimental results of the release rate in the intestine are summarized as follows. Listed in 2. Table 2: Experimental results of intestinal release rate of the vaccine prepared in Example 1

From the above experimental results, it was found that the samples 1E, 1S, 2E and the comparative samples 1E, IS have excellent release rates in the intestinal fluid. However, if the cysticity and embedding rate are comprehensively considered, only the drug of the present invention has excellent cyst formation, embedding rate, and intestinal release rate.

Example 4: In vivo test of the efficacy of the vaccine prepared in Example 1

This example uses a spotted grouper fry (purchased from the National Taiwan Ocean University Aquatic Animal Experimental Center, with a body length of 3 ± 2 cm;). The fish has been successfully tamed before being purchased, and can be directly fed by feeding artificial materials. The fish were purchased and returned to the test after 1 week of adaptation to the environment. The grouper was divided into three groups: control group, experimental group 1 and experimental group 2, each group containing 30 grouper.

[sample IE]

The grouper fed each of the experimental group 1 and the experimental group 2 per day was equivalent to an inactivated bacterial vaccine 1E (SP, sample 1E) containing 1.4 X 10 ⁸ CFU or 2.8 X 10 ⁷ CFU, for seven days to establish Its immunity. Next, on the eighth day (first week) and the fifteenth day (second week), each experimental grouper was injected with a pathogenic activity of 5 X 10 ⁷ CFU/ml by intraperitoneal injection. Bacteria for the challenge test. The survival rate of fish within two weeks of the record is listed in Table 3 below.

From the results listed in Table 3, Sample 1E significantly established the grouper's immunity to Vibrio anguillarum in the first week. If it was extended to the 4th week, the challenge test was carried out. The extent to which all groupers survived (data not shown). Table 3: Live test survival rate (deaths/total) of sample IE

[sample is]

Grouper feeding each experimental group 1 and experimental group 2 per day is equivalent to containing 1.4 X 10 ⁸ CFU or 2.8 X

10 ⁷ CFU bacterial inactivated bacterial vaccine 1S (SP, sample 1S) for seven days to establish its immune capacity. Then, on the eighth day (first week), the fifteenth day (second week), the twenty-ninth day (fourth week), the fifty-seventh day (eighth week) and the eighty-fifth day (Twelfth week) 5 X 10 ⁷ CFU/ml of the pathogenic Vibrio alginolyticus of each experimental grouper was injected by intraperitoneal injection for the challenge test. Record survival rates are listed in Table 4 below.

From the results listed in Table 4, compared with the test conducted by Vibrio anguillarum, the challenge test with Vibrio alginolyticus did not cause actual infection in the first week and the second week. There was no obvious death in the fish, and it was judged that this was the difference in the characteristics of Vibrio alginolyticus. The challenge test of Vibrio alginolyticus did not reach the pathogenic dose due to the challenge dose. The result was in the first week. There was no significant death from the control group in the second week. However, at the fourth week, it was clearly shown that the experimental group of fish had established immunity by taking the sample 1S, and had a survival rate of 100% and 80%, respectively. Further extension of the test time to the results of the eighth and twelfth weeks showed a clearer difference between the experimental group 1 and the experimental group 2 and the control group.

Table 4: Sample 1S in vivo test survival rate (deaths/total)

Claims

Claim

A composition for preparing microcapsules comprising:

20-50% by weight of a hydrophilic polymer having a carboxylic acid functional group;

30-50 wt% hardener;

0.5-5 wt% of chitin; and

1-20 wt% polyamine compound.

The composition according to claim 1, wherein the polyamine compound has a molecular weight of from 100 to 2000 g/mol.

3. The composition according to claim 1, wherein the polyamine compound comprises tetraethylenepentamine, spermine, triethylenetetramine, spermidine, diethylenetriamine, pentene Diamine, butenylenediamine, propylenediamine, ethylenediamine, polyethyleneimine or a combination thereof.

The composition according to claim 1, wherein the hydrophilic polymer having a carboxylic acid functional group is sodium alginate, gelatin, seaweed extract or a combination thereof.

The composition according to claim 1, wherein the hardener refers to calcium chloride, calcium carbonate, sodium chloride, calcium acetate, calcium gluconate, calcium sulfate, calcium citrate, sodium hydroxide or a combination thereof. .

A medicament comprising an active substance which is encapsulated in a microcapsule prepared by the composition of claim 1.

7. The medicament according to claim 6, which has an embedding rate of from 85 to 100%.

The drug according to claim 6 or 7, which has a release rate of 70-100% in an alkaline environment for 4 hours.

The drug according to claim 6, wherein the polyamine compound has a molecular weight of from 100 to 2000 g/mol.

The drug according to claim 6, wherein the polyamine compound comprises tetraethylenepentamine, spermine, triethylenetetramine, spermidine, diethyleneamine, pentenediamine , butenylene diamine, propylene diamine, ethylene diamine, polyethylene imine or a combination thereof.

11. The medicament of claim 6 further comprising an adjuvant.

The drug according to claim 6, wherein the microcapsules have an average particle diameter of 10 to 1000 μη.

The drug according to claim 6, wherein the microcapsules have an average particle diameter of 20 to 250 μm.

14. The medicament of claim 6 which is an oral vaccine.

15. The medicament of claim 6 which is a first generation vaccine, a second generation vaccine or a third generation vaccine.