JPH07196478A - Soft capsule for highly safe food and medicine - Google Patents

Abstract

PURPOSE:To provide a soft capsule comprising an edible capsule coating film not containing an animal protein and capable of being easily dissolved, high in safety, and used for medicines and foods. CONSTITUTION:Three kinds of components comprising an edible polymeric substance (e.g. alginic acid) which can easily be dissolved in water, whose 1% aqueous solution has a viscosity of <=1000 cps at 70 deg.C, and which does not contain an animal protein as a film-forming base agent, an agar and/or a low mol. wt. agar having a jelly strength of <=300g/cm<2> a gelled filmforming base agent, and a plasticizer (e.g. glycerol) are-combined with each other to provide a soft capsule coating film-forming material. The soft capsule coating film-forming material is prepared into a soft capsule by a dropping method. By the method, a capsule content solution and the capsule coating film-forming material solution are extruded from an inside extrusion nozzle and an outside extrusion nozzle, respectively, among the nozzles of a triple or double structure into an oily liquid at a constant rate with a pump or the gravity, and the extruded solution is cut at a constant distance by some physical force such as vibration, impact or the difference between the flow rates of the capsule solution and the oily liquid, thus forming spherical soft capsules each having a diameter of 0.3-20mm by the interfacial tension between the oily liquid and the capsule coating film-forming solution.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to soft capsules for food and medicine.

[Prior art and its problems]

1. About easy-to-dissolve soft capsules that do not contain animal protein Soft capsules are solids that generally enclose non-aqueous liquid with a film that uses gelatin as a gelling and film-forming base.
Mostly used as pharmaceuticals, but recently liver oil, EPA,
It is used in the fields of health foods such as garlic oil and evening primrose oil, general processed foods such as seasoning oils, bath oil capsules, and cosmetics. There are two known manufacturing methods, a punching method (stamping method) and a dropping method (dripping method). Generally, one of the stamping methods is a liner type or Scheller type rotary die method and a dropping method. One type of liquid curing method is used.

In conventional soft capsules, gelatin derived from homeothermic animals such as cows and pigs has been used as a film base, but with the widespread use of soft capsules, the following problems have been pointed out as problems with gelatin. ing. 1) Gelatin is a protein derived from constant temperature animals such as cows and pigs, so some people cannot eat it due to vegetarianism or religious reasons. 2) Gelatin is a protein derived from homeothermic animals such as cows and pigs, but humans are the same homeothermic animals. Therefore, the disease of cows and pigs such as mad encephalopathy of cattle in the UK, or contaminating bacteria in the gelatin manufacturing process. However, pollutants have a higher risk of infection / contamination to humans than plant-derived materials.

3) Since gelatin is an animal protein, some people have allergies as a side effect after ingestion. 4) Compared with other solid agents such as tablets and hard capsules, gelatin soft capsules are inferior in heat resistance and moisture resistance and have problems in storage. On the other hand, recently, soft capsules having an agar capsule film have been reported, but agar is insoluble in water at low temperatures (below body temperature). Therefore, even if this conventional agar capsule is subjected to a disintegration test for confirming whether or not the capsule content liquid is released in the body after taking, in the artificial gastric fluid, water, and artificial intestinal fluid at body temperature (37 ° C), Even after several hours or more, the capsule film does not dissolve, and no release of the capsule content liquid as the active ingredient is observed.

If the active ingredient in the capsule content liquid is not released in the body, this is a fatal defect as a soft capsule. In addition, the conventional agar capsules have low strength, and there are problems such as capsule cracking during distribution or storage.
Therefore, almost all of the currently available soft capsules are made of gelatin, and the above problems have not been solved.

2. About carotene soft capsule containing no additive in the capsule content liquid In recent years, carotene has attracted attention as an active ingredient of health foods, pharmaceuticals and the like. Like vitamin A, carotene is one of the nutrients necessary for maintaining the health of the body, but recently it has been shown in the medical community that it has a preventive effect on cardiovascular disease and cancer, in addition to its effect as a simple nutrient. It has been reported and is attracting attention.

[0006] This carotene is also most preferably taken through a normal diet, but it is difficult to efficiently ingest a sufficient amount with food alone. Therefore, tablets, hard capsules containing a high content of carotene as a dietary supplement, Soft capsules are commercially available. Since carotene is likely to be air-oxidized like vitamin A, carotene crystals (pure products) must be stored in a cold place in a sealed container in which nitrogen is replaced. In addition, since tablets, hard capsules and other dosage forms are still unstable against oxidation by air, carotene-rich soft capsules that are dissolved or dispersed in edible oil and enclosed in a gelatin film are generally commercially available. ing.

[0007] This carotene is generally a solid (powder) at room temperature, but since soft capsules can only encapsulate oily liquids, commercially available carotene-containing health foods are made from carotene or a carotene-containing oil liquid at a predetermined amount. On the other hand, edible oil, antioxidant and the like are added to make a liquid oil having a viscosity capable of being encapsulated and then encapsulated. However, simply adding edible oil to carotene or a carotene-containing oil solution causes carotene to settle due to gravity, and to separate with time into an oil layer and a carotene settling layer in the soft capsule. For this reason, most of the commercially available products are added with a thickener such as fatty acid monoglyceride (monoglyceride) or beeswax as a food additive or a dispersant to prevent carotene from settling, so that the appearance does not change with time.

However, health foods are also used for the purpose of preventing adverse effects on health due to abuse of processed foods and food additives, and the use of such additives is not originally preferable. Therefore, a product in which the capsule content liquid is precipitated and separated without using any additive is also commercially available. However, when the capsule content liquid separates into two layers over time, the commercial value also deteriorates in appearance, and there is a demand for the development of a carotene formulation that is stable over time without the use of additives.

[0009]

[Means for solving the problem]

1. Easy-to-dissolve soft capsules containing no animal protein In the case of soft capsules, there are various physical and chemical properties that the material used as the membrane base must have in the manufacturing process, but the absolutely necessary physical properties are heat. It is a sol-gel type. Therefore, as a result of investigating and researching a natural edible gelling material, an edible polymer substance that is easily soluble in water was used as a film-forming base, and as a gelling film-forming base, agar or It has been found that the above-mentioned problems can be solved as a soft capsule film by combining three kinds of components including low molecular weight agar and a plasticizer.

As a result of further examination of agar and its related substances, agar having a jelly strength of 300 g / cm ² or less (hereinafter referred to as low molecular agar) has an appropriate gelling ability and film forming property required for capsule molding. And found to make good soft capsules. However, agar is defined by the Japanese Pharmacopoeia and the US Pharmacopoeia as follows. "1g of agar and 6 parts of water
Add 5 ml and boil for 10 minutes with constant stirring to dissolve it, and replace the evaporated water with boiling water. This liquid is clear and becomes an elastic gel when cooled to 30 to 39 ° C, and does not melt at 85 ° C or lower when heated. "

On the other hand, the low molecular weight agar is 30 to 39.
Since it does not become an elastic gel at ° C and dissolves even at 85 ° C or less, it cannot be called agar in the ordinary sense, but it is agar with a low molecular weight according to the raw material and the manufacturing method. The present invention is added to the present invention. In this soft capsule, agar used as a gelling agent for the film and a film-forming component is a cell wall component of red algae, the main component of which is agarose, and it is known as a food containing a large amount of dietary fiber that is insoluble in water. It exhibits a strong gelling ability at a low concentration, and the jelly strength is generally 400 to 500 g / cm ² or more.

However, as mentioned above, since agar is insoluble in water at 85 ° C. or lower, capsules containing only agar as the film-forming component of the film are disintegrated in the soft capsule of the Japanese Pharmacopoeia even if a plasticizer is added. It does not dissolve and does not release the capsule contents. Soft capsules for medicines and foods are supposed to be disintegrated in the body (digestive organ) after taking, to release the capsule content liquid which is the active ingredient into the body, and to be absorbed from the intestine, and not to release the content liquid in the disintegration test. Is a fatal drawback for soft capsules for medicines and foods.

Further, since agar has a high viscosity and it is difficult to increase the compounding ratio, the capsule has a thin film thickness and a low capsule strength. For this reason, the capsule is easily broken during distribution and storage, and the commercial value is significantly impaired. Therefore, as a result of investigating an edible polymer substance that compensates for these drawbacks of this agar capsule, a low-viscosity edible polymer substance (alginic acid and its salts, which is easily dissolved in water at body temperature or lower,
Carrageenan, xanthan gum, gellan gum, locust bean gum, dextrin, pullulan, etc.) and glycerin, and plasticizers such as sorbitol are added to the agar together with the agar, it is also compatible with the Japanese Pharmacopoeia disintegration test,
The capsule strength could also be increased. The polymer substance which is easily dissolved in water as used herein is not limited to the above substances, and an edible polymer substance having the following conditions can be substituted.

1) A substance containing no animal protein. 2) It is dissolved in water at 37 ° C. or lower, and the viscosity of its 1% aqueous solution is as low as 70 ° C. and 1000 cps, and when this aqueous solution is dropped into oil, it becomes spherical due to interfacial tension. 3) Must be edible. Further, the plasticizer referred to here is not limited to the above-mentioned substances, but a substance that can be used as a plasticizer for general gelatin soft capsules (plasticizer,
A non-animal protein can be substituted as long as it is a water-retaining substance).

In addition to the above components, components that can be added to the film of a normal soft capsule, such as preservatives, coloring agents, opacifying agents, flavoring agents, and corrigents, can be appropriately used if necessary. In addition, since the soft capsules cannot be manufactured by the stamping method, the soft capsules cannot be manufactured by the stamping method because the adhesiveness (heat sealing property) of each film component is small. The basic principle and equipment of the dripping method are as follows.

The capsule content liquid is discharged from the inner discharge ports of the double or triple concentric discharge ports (nozzles) and the capsule coating liquid is discharged from the outer discharge ports into the oil liquid at a constant speed. The discharge liquid is cut at regular intervals by some physical force such as vibration, shock, and a difference in flow velocity between the capsule liquid and the oil liquid, and the diameter of 0.3 ~ is obtained by the interfacial tension between the oil liquid and the capsule coating liquid (aqueous solution). This is a method of forming a 20 mm spherical soft capsule.

2. About carotene soft capsules containing no additives in the capsule content liquid We investigated and studied various substances for an oily base that is stable to carotene's air oxidation, precipitation and separation in carotene soft capsule formulations. It has been found that when carotene is dissolved or dispersed based on tocopherols (vitamin E) used as essential nutrients of the living body in health foods and the like, it is not separated in soft capsules and is stable against air oxidation.

[0018]

【The invention's effect】

1. About easily soluble soft capsule containing no animal protein The soft capsule of claim 1 of the present invention has the following actions and effects. 1. Although the gelling agent and the film base are water-insoluble agar, they comply with the Japanese Pharmacopoeia disintegration test and reliably release the capsule content liquid containing the active ingredient in the body. 2. Less allergic because it does not contain animal protein. 3. Since it is vegetable, it can be eaten by vegetarians, people who cannot eat animal-derived foods for religious reasons, and people who are allergic to gelatin. Moreover, there is no risk of diseases and pollutants derived from homeotherms.

4. Since gelatin contains an amino group and a carboxylic acid group in its molecule, it undergoes a crosslinking reaction over time and becomes insoluble in water. In particular, insolubilization tends to occur when the capsule content liquid contains aldehydes and reducing substances. On the other hand, all the coating components according to the present invention are stable, have high heat resistance, acid resistance, alkali resistance, etc., and do not extend the disintegration time with time. 5. Compared to gelatin soft capsules, the film component of the present invention softens / deforms even at high temperatures (40 ° C or higher) and high humidity
It does not adhere and is easy to store and handle.

6. Since the capsule strength is high, it is easy to handle during distribution or storage, and there is no reduction in commercial value due to capsule rupture. 7. The soft capsule according to the present invention is softer than a soft capsule made of gelatin, and is easier to chew and eat in the mouth. 8. Unlike the gelatin soft capsule, the soft capsule according to the present invention also has an effect of supplementing dietary fiber with agar.

2. About carotene soft capsule containing no additive in the capsule content liquid Vitamin E (tocopherol) used as a base of the carotene-containing soft capsule in claim 2 of the present invention is a very viscous oil liquid at room temperature and is It is known as an essential nutrient and is one of the causes of aging of the body and adult diseases.
In recent years, attention has been paid to its effects on cancer, arteriosclerosis, dementia, etc., which prevent the generation of free radicals in the body.

In the area of health foods, three vitamins, carotene, vitamin E, and vitamin C, cooperate with each other, and the effect of preventing the generation of peroxides is recognized in all metabolic systems of the living body. As a result, in the last few years, sales have been growing rapidly in Europe and America. The product forms of these products are carotene, vitamin E, and vitamin C.
Commercially available products are prepared by combining the ingredients in a single preparation, or products each containing a single ingredient. It is convenient to take when three components are combined in one drug. However, vitamin C is a water-soluble vitamin that disappears from the blood within a few hours after administration, whereas carotene and vitamin E are oil-soluble vitamins that disappear from the blood within a dozen hours after administration. In this way, it is medically unfavorable to mix the products having different pharmacokinetics and blood concentration after administration into one product and to administer them with the same usage and dose. Medically, carotene and vitamin E 1-2 times a day
It is preferable to take Vitamin C in divided doses several times a day, but it is cumbersome to take such a single preparation of three components.

Therefore, the oil-soluble vitamins carotene and vitamin E, which are taken in the same manner, are treated as one agent (soft capsule),
It is preferable to carry out the antioxidant therapy with two agents of vitamin C (generally tablets) which are taken differently. The soft capsule of carotene based on vitamin E according to the present invention has the following effects.

1. Commercially available carotene-containing soft capsules are products that use additives such as thickeners and surfactants to prevent carotene from settling / separating in the capsules, or carotene settling in the capsules without using additives.・
Although there were only separated products, the carotene-containing soft capsule according to the present invention does not contain components other than carotene, vitamin E and edible oil by dissolving and dispersing vitamin E, which is an essential nutrient of the living body, as a base, that is, In addition, it is possible to manufacture soft capsules containing no additives and having high safety and stability. The additive here means
It means that no food additives other than the active ingredient are used when formulating the content liquid of the soft capsule according to the present invention, and carotenes, carotene oil, vitamin E, which are commercially available as raw materials,
Additives already contained in Vitamin E oil and the like, that is, carryover additives are not included. Also, active ingredients other than carotene and vitamin E, such as vitamins D and D
HA, EPA, etc. are not additives and can be added.

2. The soft capsule according to the present invention is a mixture of carotene and vitamin E, which have similar absorption kinetics in the body, in the same preparation. By using a single preparation of commercially available vitamin C in combination with this preparation, it becomes easier to Moreover, you can safely take vitamins for oxidative prophylaxis. 3. Vitamin E also has the antioxidant effect of carotene, and the soft capsule according to the present invention is also safe and safe in this respect.
High stability.

[0026]

The present invention will be described in detail with reference to the following examples, but the present invention is not limited to these examples. Claim 1
An example corresponding to will be described. Comparative Example 1 The capsule coating solution and the capsule content solution shown in Table 1 were mixed and manufactured by a rotary die method, which is one of the stamping methods, to obtain spherical gelatin soft capsules having a diameter of about 8 mm.

[0027]

[Table 1]

Comparative Example 2 Using the medium-chain fatty acid triglyceride containing 1% acetaldehyde as the content liquid, spherical soft gelatin capsules having a diameter of about 8 mm were obtained in the same manner as in Comparative Example 1. Comparative Example 3 The capsule coating solution and the capsule content solution shown in Table 2 were prepared, and spherical soft capsules having a diameter of about 8 mm were obtained by the dripping method.

[0029]

[Table 2]

Example 1 The capsule coating solution and the capsule content solution shown in Table 3 were prepared, and spherical soft capsules having a diameter of about 8 mm were obtained by the dripping method.

[0031]

[Table 3]

Example 2 A capsule capsule solution and a capsule content solution shown in Table 4 were prepared and soft capsules were obtained in the same manner as in Example 1.

[0033]

[Table 4]

Example 3 A capsule capsule solution and a capsule content solution shown in Table 5 were prepared and soft capsules were obtained in the same manner as in Example 1.

[0035]

[Table 5]

Example 4 A capsule capsule solution and a capsule content solution shown in Table 6 were prepared and soft capsules were obtained in the same manner as in Example 1.

[0037]

[Table 6]

Example 5 The capsule coating solution and the capsule content solution shown in Table 7 were prepared and soft capsules were obtained in the same manner as in Example 1.

[0039]

[Table 7]

Example 6

The capsule coating solution and the capsule content solution shown in Table 8 were prepared and soft capsules were obtained in the same manner as in Example 1.

[0042]

[Table 8]

Example 7

The capsule coating liquid and the capsule content liquid shown in Table 9 were prepared and soft capsules were obtained in the same manner as in Example 1.

[0045]

[Table 9]

The capsules of Comparative Examples 1 to 3 and Examples 1 to 7 were molded by using a modified liner type rotary die automatic capsule molding machine in the stamping method during capsule molding. After molding, it is manufactured by the steps of drying, deoiling and sorting. Various evaluation tests were performed on the above capsules, and the results are shown below.

1. Capsule content liquid release test Among the Japanese Pharmacopoeia disintegration tests, the capsules of Comparative Examples 1 to 3 and Examples 1 to 7 were tested as samples according to the enteric coating test. The results are shown in Table 10.

[0048]

[Table 10]

As is clear from the results in Table 10, all the capsules of this example were compatible with the enteric disintegration test, whereas all the comparative examples were not compatible, and the following results were observed in this example. Was given.

1) Gelatin capsules react with the components (eg, aldehydes) of the capsule content liquid to insolubilize the capsule film (Comparative Example 2), but the film of this Example was stable. 2) It was confirmed that the capsule containing agar alone as a gelling / film-forming component did not release the solution in the capsule, and had the most fatal drawback as a capsule for pharmaceuticals and foods.

2. Capsule stability test A test was conducted to evaluate the stability with respect to high temperature and high humidity resistance. Comparative Example 1-Comparative Example 3, Example 1-
Take 50 capsules of the capsules up to Example 7, put them in a glass bottle, store them at 40 ° C., 75% RH for 24 hours without stopper, and after storage, change the appearance of the capsules due to heat and humidity and the same capsule or bottle. Was evaluated. The results are shown in Tables 11 and 12.

[0052]

[Table 11]

[0053]

[Table 12]

3. Strength of capsules To evaluate the strength of capsules, use a tablet hardness tester to measure 5 kg.
The load was applied for 30 seconds to test whether or not the capsule burst, and the results are shown in Table 13.

[0055]

[Table 13]

As shown in Tables 11 to 13, each of the capsules of this example has higher temperature resistance, high humidity resistance, adhesiveness, capsule strength, stability, ease of handling, etc. than conventional capsules. It was recognized that it was excellent in terms of quality.

4. Confirmation of protein For each soft capsule of the comparative example and the example, the most common "burette reaction" as a qualitative reaction (confirmation test) of protein was performed to confirm whether or not the protein was contained. The results are shown in Table 14. This example is negative,
No protein was detected.

[0058]

[Table 14]

As described above, the easily-dissolved soft capsule containing no animal protein according to the present invention is used as a soft capsule for medicines and foods, and can be safely eaten by vegetarians, people who have religious reasons or who are allergic to animal proteins. In addition, it is easy to absorb pharmaceuticals and food ingredients in the body, and has high heat resistance and high humidity resistance, which is superior to conventional capsules.

An embodiment corresponding to claim 2 will be described. Preliminary test In order to confirm the effect of vitamin E on the sedimentation and separation of oily liquid of carotene, oily liquids having the formulations shown in Tables 15 and 16 were prepared and placed in a glass test tube having a diameter of about 1.5 cm at a height of 10 cm.
cm, and allowed to stand still at room temperature, and the presence or absence of carotene precipitation was observed after 1 day and 7 days.

[0061]

[Table 15]

[0062]

[Table 16]

Each raw material was obtained as a commercial product with the same composition. In addition, a load of 3000 rpm for 15 minutes was applied to each of the samples 1 to 6 by a centrifuge to accelerate sedimentation and confirm the presence or absence of separation. The results are shown in Table 17.

[0064]

[Table 17]

In Samples 1 and 2 in which only general edible oil was used as a base without additives, clear precipitation and separation of carotene was observed, whereas additives such as thickeners and surfactants were used. As a result, Samples 3 and 4 in which carotene was prevented from settling and Samples 5 and 6 in which vitamin E was used as a base were stable without precipitation.

Example 1 An oil solution of carotene having the formulation shown in Table 18 was blended to prepare a solution in a soft capsule, and a soft capsule was produced by a rotary die type soft capsule producing machine according to a conventional method.

[0067]

[Table 18]

This soft capsule is an oval type, the capsule coating weight is 95 mg, and the coating composition is gelatin 1
It was 00 parts by weight and 25 parts by weight of glycerin. Put this capsule in a No. 6 standard glass tube, seal it tightly, and
It was stored in ° C for 2 months and its stability was confirmed.
As shown in FIG. 9, the capsule of the present invention example (capsule 3) was stable, no abnormal appearance was observed, and was stable as the conventional additive-containing capsule (capsule 2). On the other hand, the content liquid of the capsule 1 containing no additive separated into two layers.

[0069]

[Table 19]

Claims (2)

[Claims] Claims: 1. A capsule content liquid is discharged from an inner discharge port of a double or triple structure discharge port (nozzle) and a capsule coating liquid is discharged from an outer discharge port in an oil liquid or a gas at a constant speed by a pump or gravity. The discharge liquid is cut at a constant interval by some physical force such as vibration, shock, flow velocity difference between the capsule liquid and the oil liquid or gas, and the interface or surface tension between the oil liquid or gas and the capsule coating liquid is cut. This cut portion has a diameter of 0.
A soft capsule produced by a method of forming a spherical soft capsule of 3 mm to 20 mm, characterized in that the soft capsule film is composed of the following three components and is an easily soluble and edible capsule film containing no animal protein. Safe capsules for foods and pharmaceuticals with high safety. 1) An easily soluble film-forming base that is soluble in water and has a viscosity of a 1% aqueous solution of 10 at 70 ° C.
Edible high-molecular substances (alginic acid and its salts, carrageenan, dextrin, etc.) that are less than 00 cps and do not contain animal protein 2) Gelling and film-forming base Agar and / or jelly strength 300 g / cm ² or less Low molecular weight agar 3) Plasticizers such as glycerin and sorbitol 2. A soft capsule containing 1 mg or more of carotenes and 5 times more amount of vitamin E than carotenes in one bulb, and the capsule content liquid comprises carotene, vitamin E, other active ingredients and edible vegetable oil. A highly safe food and pharmaceutical soft capsule characterized by not containing so-called food additives such as a thickener and a dispersant.