JPH0330831A - Microcapsule - Google Patents

Abstract

PURPOSE:To obtain a capsule responsive to pH by a method wherein pectin is formed into a film having a specific thickness and the pectin which dissolves in an aq. solution having a pH of at most 3 after immersion in 1% aq. solution of polyvalent metal salt for two hours at 25 deg.C is used as wall membrane and solidified with the polyvalent metal salt. CONSTITUTION:The pectin having a specific dissolving characteristics is formed into a film of 50-150mum thickness and such film is immersed in 1% aq. solution of polyvalent metal salt for two hours at 25 deg.C. A capsule is then produced consisting of the wall membrane contg. the pectin which retains its original film shape in an aq. solution having a pH of at least 7 and its dissolution is unnoticeable but, in an aq. solution having a pH of at most 3, loses its original film shape completely collasping or dissolving. By solidifying this wall membrane with the polyvalent metal salt imparting the aforesaid dissolving characteristics, a microcapsule excellent in pH responsiveness can be obtained which does not dissolve to protect the capsulized substance stably in a neutral solution but, in an acidic solution, dissolves readily to release the capsulized substance. This capsule is useful particularly in drug applications and simple in application technique and efficient and inexpensive to produce.

Description

[Detailed description of the invention] Child! In the present invention, the wall membrane collapses and dissolves in response to pH changes,
The present invention relates to microcapsules that release their contents.

Gastric soluble microcapsules, for example, are known as I-sensitive microcapsules.

The pH value in the stomach is usually 1 to 2.5. Japanese Patent Application Publication No. 1987 =
No. 197214 discloses that in the ethyl cellulose wall of the ethyl cellulose microcapsule containing a core substance,
It has been reported that microcapsules with excellent protection of the core substance and rapid release of the core substance in the gastrointestinal tract can be obtained by coexisting with a gastric soluble polymer substance such as a polysaccharide derivative or a vinyl polymer having basic nitrogen. There is. However, these microcapsules are manufactured using an organic solvent-based phase separation method, which poses a problem in that operations are complicated and costs increase.

It is also known that microcapsules can be created using cellulose derivatives with amino groups introduced, or stomach-soluble polymers with film-forming properties such as basic heptad polymers such as vinylpyridine polymers, as coating agents. It is being

However, this method has poor productivity, high costs, and limited applications.

JP-A No. 61-15733 discloses a heat-coagulable product in which 2 edible oils and fats (core material) are coated with gelatin-gum arabic, and then coated again with heat-coagulable protein and non-thermocoagulable protein. It has been reported that microcapsules that are difficult to dissolve in water but dissolve quickly in the digestive system can be obtained by heating the protein to a temperature above the freezing point. It is also described that when coating with protein, polysaccharides such as pectin, which have a thickening effect, are used in combination.

However, this manufacturing method has poor production efficiency due to double coating, and also requires heating above the freezing point (80°C).
The scope of application is limited due to the problem of deterioration of the core substance, and furthermore, the presence of proteolytic enzymes is essential for dissolving the wall membrane, so the use is also narrow.

On the other hand, it is known that pectin is insolubilized with Ca'' ions during the production of microcapsules.
It is described in the publication No.-111440. Furthermore, the present applicant previously proposed in Japanese Patent Application No. 63-235391 that pectin be treated with Fe'' to give it a texture.

The purpose of the present invention is to provide pH-sensitive microcapsules that have excellent production efficiency and easily release their contents due to pH changes.

The microcapsules of the present invention have a wall film containing pectin, and the pectin is formed into a film with a thickness of 50 to 150 µm and soaked in a 1% polyvalent metal salt aqueous solution at 25°C for 2 hours. After immersion, in an aqueous solution with a pH of 7 or more, the film retains its original shape and no dissolution is observed, but in an aqueous solution with a pH of 3 or less, the film does not retain its original shape at all and disintegrates or dissolves. It is characterized by being hardened with metal salt.

The present invention will be explained in more detail below.

Pectin is industrially extracted from citrus fruits and apple peels, and it is also known that it can be gelled and insolubilized by Ca'' ions.However, 1. In this case, the effects of the present invention cannot be obtained.

The present invention uses pectin with specific dissolution properties, i.e., it is formed into a film with a thickness of 50 to 150 μm and is immersed in a 1% polyvalent metal salt aqueous solution at 25°C for 2 hours, and then in an aqueous solution with a pH of 7 or more. We discovered pectin that maintains its original film shape and does not dissolve, but in an aqueous solution with a pH of 3 or lower, it does not retain its original shape at all and collapses or dissolves.
By making capsules with a wall film containing this pectin and curing this wall film with a polyvalent metal salt that can impart the above-mentioned dissolution properties, the core material is stably protected without being dissolved in neutral conditions.
Under acidic conditions, the wall membrane is easily dissolved and the core substance is released.
Microcapsules with excellent pH sensitivity were obtained.

Examples of such pectin include HM pectin NL and LM pectin V manufactured by Helpstreit of West Germany.
P-U, OM, OM-D.

LM-22 manufactured by Kobembergen Pectin Factory
Examples include CG and 18CG, among which LM pectin OM and LM-22CG are preferred.

In addition, the microcapsule wall may be formed of pectin alone or as a mixed film of gelatin, which is a polycation, etc. When gelatin is used in combination, there are no particular restrictions, but acid or alkali Acid-treated gelatin having a jelly strength of 150 ml or more can be preferably used.

When used in combination with gelatin or the like, the amount of pectin used is preferably 5 parts by weight or more, particularly 10 parts by weight or more, per 100 parts by weight of gelatin. If the amount of pectin used is less than 5 parts by weight, the capsule may have insufficient PH sensitivity.

The microcapsules of the present invention can be produced by a phase separation method, an in-liquid curing method, an orifice method, a spray drying method, etc. using the above-mentioned specific pectin and, if desired, gelatin as a membrane material. They can be manufactured by various methods, such as a microencapsulation method and a soft capsule manufacturing method using a punching method. Among these manufacturing methods, the orifice method and phase separation method, which are particularly easy to control the capsule film thickness, are preferably employed in the present invention.
When manufacturing microscopic capsules of 1 or less, the phase separation method is used.
In addition, when producing coarse capsules with a particle size of 3 mm or more, it is preferable to employ the orifice method.Furthermore, when producing the microcapsules of the present invention by the phase separation method, complex coacervation of pectin and gelatin is preferred. It is more preferable to adopt the law.

Incidentally, the reaction conditions during production can be the same as those normally used.

Next, in one aspect of the present invention, microcapsules whose walls contain pectin produced by a desired method are treated with a polyvalent metal salt to harden the walls. Here, as the polyvalent metal salt, one is used that can achieve a hardening treatment that satisfies the above-mentioned solubility characteristics of pectin.

As the polyvalent metal salt, a water-soluble salt containing calcium or aluminum is suitable, such as an inorganic acid such as a hydrochloride or a sulfate, or acetic acid.

It is preferable to use an aqueous solution of a water-soluble salt of an organic acid such as lactic acid, particularly an aqueous solution of calcium lactate, calcium chloride, potassium aluminum sulfate, or the like.

The polyvalent metal salt concentration in the aqueous solution is preferably 0.05 to 1
0% by weight, more preferably 0.1 to 5% by weight.

If the polyvalent metal salt concentration is less than 0.05% by weight, the wall film may not be sufficiently cured.

Further, a sufficiently satisfactory curing reaction can be carried out with a content of 10% by weight or less, and an amount exceeding 10% by weight is economically disadvantageous and is not necessary.

The polyvalent metal salt is 0.5 to 100 parts by weight of pectin.
It is preferably used in an amount of 200 parts by weight, particularly 2 to 150 parts by weight.

Furthermore, when performing the curing reaction, an inorganic salt such as sodium sulfate that does not adversely affect pH sensitivity can be used in combination, thereby promoting densification of the water-containing film.

The microcapsules of the present invention use pectin, which is PH-sensitive through reaction with polyvalent metal ions, as the wall membrane, so that the core substance passes through the membrane and oozes out in a neutral aqueous solution. On the other hand, in an acidic aqueous solution, the membrane dissolves immediately, releasing the core substance, and exhibits excellent responsiveness to the pH environment.

Therefore, even if the microcapsules of the present invention are placed, for example, during the day, the core substance does not seep out, and the core substance can be released in the stomach, and can be widely used in the pharmaceutical field.

Furthermore, the method for producing microcapsules of the present invention is simpler than conventional PH-sensitization techniques, and can be produced efficiently and inexpensively.Furthermore, since the capsules are edible, they are not limited to pharmaceuticals. A wide range of applications are possible, such as in the food field, and even in the toiletry field.

Experimental Examples and Comparative Examples A 2% aqueous solution of 50rsQ is prepared by dissolving various pectins in water. This aqueous solution was uniformly poured onto a Teflon plate and air-dried to form a film. This film was cut into a width of 5 square meters, immersed in a 1% potassium aluminum sulfate aqueous solution or a calcium chloride aqueous solution for 2 hours, the liquid was wiped off with a piece of paper, and the thickness was measured to be 100 μm.

These various films were mixed with an aqueous solution of pH 7 and pi (2,5
The film was immersed in two types of aqueous solutions at room temperature, and the state of the film was determined.

(Left below) According to Table 1, LM pectin ○M, ○MD-D, LM-2
It can be seen that 2CG exhibits the solubility characteristics of the present invention by both Al'' and Ca2+ treatments.On the other hand, H
M-pectins NL and VP-U come to exhibit the solubility characteristics required for the present invention by Ca''+ treatment, and
M-18CG is shown by Al'+ treatment.

12. Comparison 12 Release method) Example 1 21 g of gelatin (acid treated, 250 bloom) and 4.2 g of pectin (LM pectin OM) were dissolved in 40° C. water to give a total amount of 600 g. Medium chain triglyceride (MCT) containing 30% of the medicinal ingredient was added to this aqueous solution under stirring.
0 g was added and dispersed, and the average particle size was adjusted to 2 mm. Next, 5% acetic acid aqueous solution was added to adjust the pH to 4.3, and then 2
It was cooled to 0° C. to obtain a capsule dispersion containing MCT containing a medicinal ingredient as a core material and gelatin and pectin as a wall film. The obtained capsule dispersion was filtered to separate the capsules, and after washing with water, water was added to the capsules again to bring the total volume to 80.
It was set to 0g. To this dispersion, 100 g of a 5% aqueous solution of calcium chloride was added while stirring at 20"C, and stirred for 1 hour to harden the capsule wall membrane. After separation, it was washed to obtain MC and T capsules containing medicinal ingredients. Ta.

Example 2 The procedure of Example 1 was repeated except that potassium aluminum sulfate was used instead of calcium chloride.

Comparative Example 1 The same procedure as in Example 1 was carried out except that ferric chloride was used instead of calcium chloride.

Comparative Example 2 The same procedure as in Example 1 was carried out except that potassium sulfate was used instead of calcium chloride.

Obtained microcapsules (Examples 1 and 2 Comparative Examples 1 and 2
) were immersed in an aqueous solution at 40°C, pH 7 and an aqueous solution at 40°C, pH 2.5, respectively, and the elution rate of the wall film was measured by liquid chromatography, and the time until the core substance was released was determined. Examined. The results are shown in Table 2.

Table 2 I couldn't.

From Table 2, it was confirmed that microcapsules having wall membranes using pectin, which exhibit PH sensitivity when treated with an aqueous solution containing calcium ions and aluminum ions, are PH sensitive.

34, 34 () Example 3 17 g of gelatin (acid treated, 300 Bloom) and 3.4 g of pectin (LM Pectin OM, Helpsudreit)
were dissolved in 40°C water to make a total amount of 500g.

Add and disperse 70g of peppermint oil to this aqueous solution while stirring, and adjust the average particle size of the peppermint oil to 800μ.
Adjusted to m. Next, add 5% acetic acid aqueous solution to pH 4.
.

The resulting microcapsule dispersion was filtered to separate the microcapsules, washed with water, and then water was added to the microcapsules again to make the total volume 500@a.

Add 2% potassium aluminum sulfate and 15% sodium sulfate to this microcapsule aqueous dispersion while stirring at 20°C.
200 g of an aqueous solution containing % was added and cured, and further 50 g of sodium sulfate was added and stirred for 2 hours.

Filter and separate the microcapsules from the dispersion.

It was dried to obtain the desired peppermint oil microcapsules.

Example 4 The same procedure as in Example 3 was carried out except that LM-22CG manufactured by Copenhagen Pectin Factory was used as pectin.

Comparative Example 3 The same procedure as in Example 3 was carried out except that LM-102AS manufactured by Copenhagen Pectin Factory was used as pectin.

Comparative Example 4 The same procedure as in Example 3 was performed except that HM-DD-Slow set from Copenhagen Pectin Factory was used as pectin.

The obtained microcapsules (Examples 3 and 4, Comparative Example 3,
4) were evaluated in the same manner as described above. The results are shown in Table 3.

(Margin below) I couldn't.

From Table 3, it was confirmed that the wall pectin used to impart PH sensitivity to the microcapsules was a specific one.

Example 5 Using a concentric double nozzle, a vegetable oil containing eicopentaenoic acid was poured into the inner cylinder, and an aqueous solution containing 8% gelatin and 2% pectin (LM pectin OM) was poured into the outer cylinder. sink,
Capsules with a particle size of 4 mm were prepared by dropping the mixture into vegetable oil at 10°C.

Next, the capsules were added to an aqueous solution containing 1% potassium aminium sulfate and 15% sodium sulfate,
The wall film was cured by stirring at 20° C. for 2 hours.

After separating the capsules, they were washed with a 15% aqueous sodium sulfate solution and then dried to obtain microcapsules with eicopentaenoic acid-containing vegetable oil as the core material and pectin in the wall membrane.

Comparative Example 5 The same procedure as in Example 5 was carried out except that potassium aminium sulfate was not used.

2 of the obtained microcapsules (Example 5, Comparative Example 5)
Each point was evaluated in the same manner as described above. The results are shown in Table 4.

(Margin below) Table 4 x In 30 minutes, The core material remains in the original shape of the capsule. No elution was observed.

Claims (1)

[Claims] 1. Microcapsules having a wall film containing pectin, which is formed into a film with a thickness of 50 to 150 μm and immersed in a 1% polyvalent metal salt aqueous solution at 25°C for 2 hours, and then In an aqueous solution, the film retains its original shape and no dissolution is observed, but in an aqueous solution with a pH of 3 or lower, the film does not retain its original shape at all and disintegrates or dissolves. Pectin is used, and the wall film is hardened with the polyvalent metal salt. A microcapsule characterized by the fact that