JP7750505B2 - Capsules and methods for manufacturing capsules - Google Patents

Description

The present invention relates to a capsule and a method for producing the capsule.

Hard capsules and soft capsules, especially those containing liquid (content liquid), can sometimes have their capsule shells damaged, causing the contents to leak. The main cause of this is that the content liquid (solution, suspension, etc.) enclosed within the capsule shell changes volume due to environmental changes such as temperature and air pressure. Furthermore, if the capsule shell is deformed due to factors such as the capsule being dropped or being subjected to external pressure after being packaged in a supplement, large localized stresses can act on the capsule shell, causing cracks in that area and making the contents more susceptible to leakage.

In addition, leakage of the contents from the capsule shell is also affected by the ingredients contained in the contents. When soft capsules containing L-carnitine as the main ingredient are manufactured, the highly hygroscopic nature of L-carnitine can dry out the capsule shell, causing it to crack and making the contents more susceptible to leakage.

In order to solve the problem of leakage of the content liquid from the soft capsule shell, the inventors previously proposed a method for manufacturing soft capsules in which an aqueous solution containing a sugar or sugar alcohol is filled into the soft capsule shell as the content liquid, and then the sugar or sugar alcohol is supersaturated (Patent Document 1).

In recent years, 3-hydroxyisovaleric acid (β-hydroxy-β-methylbutyric acid, HMB) has attracted attention for its effectiveness in maintaining muscle mass and strength, and is used in supplements and functional foods for sports and the elderly.

JP 2013-173714 A

HMB commonly used in health foods is in the form of a salt of HMB calcium (HMB-Ca), but there is a growing need to ingest free HMB due to its rapid absorption in the body.

However, there have been no reports that have fully investigated how the inclusion of free 3-hydroxyisovaleric acid in the liquid content of a capsule affects the capsule shell. As a result of further investigations by the inventors, they discovered a new issue: when free 3-hydroxyisovaleric acid is included in the liquid content of a capsule, compatibility with the capsule shell base has a significant impact, making the capsule shell more likely to deform and potentially leading to leakage of the liquid content.

After further investigation, the inventors discovered that a completely different method from the technology described in Patent Document 1 could be used to prevent deformation of the capsule shell and leakage of the contents, leading to the completion of the present invention.

Specifically, the researchers discovered that by incorporating at least pullulan as a base in the capsule shell and adjusting the sugar alcohol composition in the capsule content liquid, they could prevent deformation of the capsule shell and leakage of the content liquid, leading to the completion of the present invention.

That is, the present invention provides the capsules shown below.

[1]
A capsule in which a capsule shell is filled with a content liquid, the capsule shell containing at least pullulan,
The inner liquid contains 3-hydroxyisovaleric acid and a sugar alcohol,
The sugar alcohol has a DE value of 40 to 80;
the sugar alcohol ratio of disaccharides contained in the sugar alcohol is 25 to 70%,
The sugar alcohols contained in the capsules have a trisaccharide sugar alcohol ratio of 8 to 40%.

[2]
The capsule according to [1], wherein the content of the sugar alcohol is 1 to 20% by mass relative to the total amount of the content liquid.

[3]
The capsule according to [1] or [2], wherein the content of the 3-hydroxyisovaleric acid is 98% by mass or less based on the total amount of the content liquid.

The present invention also provides a method for producing the capsules described below.

[4]
Contains 3-hydroxyisovaleric acid and a sugar alcohol,
The sugar alcohol has a DE value of 40 to 80;
the sugar alcohol ratio of disaccharides contained in the sugar alcohol is 25 to 70%,
preparing a content liquid in which the ratio of trisaccharide sugar alcohols contained in the sugar alcohols is 8 to 40%;
preparing a capsule shell composition containing at least pullulan;
A method for producing a capsule, comprising the step of preparing a capsule by filling the content liquid in the coating composition.

According to the present invention, by incorporating at least pullulan into the capsule shell and adjusting the sugar alcohol composition of the capsule content liquid to one that is difficult to pass through the capsule shell containing pullulan, it is possible to suppress deformation of the capsule shell and improve leakage of the content liquid.

One embodiment of the present invention is a capsule having a capsule shell filled with a content liquid, wherein the capsule shell contains at least pullulan,
The inner liquid contains 3-hydroxyisovaleric acid and a sugar alcohol,
The sugar alcohol has a DE value of 40 to 80;
the sugar alcohol ratio of disaccharides contained in the sugar alcohol is 25 to 70%,
The capsule is provided in which the sugar alcohol contains trisaccharides at a ratio of 8 to 40%.

Capsules are not particularly limited as long as they are capsules used in the food and pharmaceutical fields, and various dosage forms such as hard capsules and soft capsules (including seamless capsules) can be used.

(Liquid contained in capsules)
In the capsule of the present invention, the content liquid contains at least 3-hydroxyisovaleric acid and a sugar alcohol.

3-Hydroxyisovaleric acid (3-Hydroxy-3-Methylbutylate, β-Hydroxy-β-Methylbutyrate, hereinafter also referred to as HMB) is a compound represented by the structural formula (CH ₃ ) ₂ C(OH)CH ₂ COOH, and HMB is known to have muscle mass-enhancing effects, etc. In the present invention, HMB is a free acid and is also referred to as free HMB.

The content of 3-hydroxyisovaleric acid is not limited and may be changed as appropriate depending on the dosage form, the types and amounts of other ingredients, the intended recipient, etc., but may be, for example, 80% by mass or more, preferably 82% by mass or more, more preferably 84% by mass or more, even more preferably 86% by mass or more, and particularly preferably 88% by mass or more, relative to the total amount of the liquid content.
The content of 3-hydroxyisovaleric acid can be, for example, 98% by mass or less, 97% by mass or less, 96% by mass or less, 95% by mass or less, 94% by mass or less, etc., relative to the total amount of the content liquid.
Further, the content of 3-hydroxyisovaleric acid is, for example, 80-98% by mass, 82-98% by mass, 84-98% by mass, 86-98% by mass, 88-98% by mass, 80-97% by mass, 82-97% by mass, 84-97% by mass, 86-97% by mass, 88-97% by mass, 80-96% by mass, 8 2-96% by mass, 84-96% by mass, 86-96% by mass, 88-96% by mass, 80-95% by mass, 82-95% by mass, 84-95% by mass, 86-95 % by mass, 88-95% by mass, 80-94% by mass, 82-94% by mass, 84-94% by mass, 86-94% by mass, 88-94% by mass, etc.

The type of sugar alcohol is not particularly limited as long as it achieves the effects of the present invention. Examples of sugar alcohols include known ingredients that can be used in the food and pharmaceutical fields, such as sorbitol, xylitol, erythritol, mannitol, maltitol, lactitol, and reduced starch syrup. Among sugar alcohols, sorbitol, xylitol, erythritol, mannitol, and the like are monosaccharide alcohols composed of monosaccharides, while lactitol and the like are disaccharide alcohols composed of disaccharides.

In order to achieve the most pronounced effects of the present invention, it is preferable to use multiple types of sugar alcohols. The sugar alcohols mentioned above may be used in appropriate combination, or the material to be blended with multiple types may include, but is not limited to, reduced starch syrup. Reduced starch syrup is a general term for a mixture of monosaccharides and polysaccharide sugar alcohols produced by reducing the glucose terminals by hydrogenation, using starch syrup obtained by hydrolyzing starch with acids or enzymes as the raw material. Reduced starch syrup is also known as reduced starch hydrolysate, reduced starch saccharification product, reduced oligosaccharide, etc.

Reduced starch syrup is classified according to the sugar content of the raw material starch syrup, and includes high sugar content reduced starch syrup, medium sugar content reduced starch syrup, and low sugar content reduced starch syrup. While the reduced starch syrup is not particularly limited, medium sugar content reduced starch syrup is preferred from the perspective of significantly achieving the effects of the present invention. These reduced starch syrups may be produced by appropriately adjusting the sugar content of the raw material starch syrup, or commercially available products may be used. Commercially available high sugar content reduced starch syrup products include SE 600 (manufactured by Bussan Food Science Co., Ltd.) and PO-60 (manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.). Commercially available medium sugar content reduced starch syrup products include Sweet OL (manufactured by Bussan Food Science Co., Ltd.) and SE 57 (manufactured by Bussan Food Science Co., Ltd.). Commercially available low sugar content reduced starch syrup products include SE 30 (manufactured by Bussan Food Science Co., Ltd.) and PO-30 (manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.).

From the perspective of achieving the most pronounced effects of the present invention, the DE (Dextrose Equivalent) value of the sugar alcohol is 40 to 80, preferably 40 to 70, more preferably 40 to 65, even more preferably 40 to 60, and particularly preferably 40 to 50. The DE (Dextrose Equivalent) value is an index that indicates the purity of glucose, and the DE value of crystalline glucose is 100.

Furthermore, from the viewpoint of significantly achieving the effects of the present invention, the sugar composition of the sugar alcohol preferably contains 25-70% disaccharide alcohols and 8-40% trisaccharide alcohols. The disaccharide alcohol content is more preferably 30-65%, even more preferably 35-60%, and particularly preferably 40-55%. The trisaccharide alcohol content is more preferably 15-40%, even more preferably 20-40%, and particularly preferably 25-40%.

The sugar alcohol content may be varied as appropriate depending on the dosage form, the type and amount of other ingredients, the intended recipient, etc., and is not limited thereto. For example, it may be 1% by mass or more of the total volume of the liquid content, preferably 2% by mass or more, more preferably 4% by mass or more, even more preferably 6% by mass or more, and particularly preferably 8% by mass or more.
Furthermore, the sugar alcohol content can be, for example, 20% by mass or less, preferably 18% by mass or less, more preferably 16% by mass or less, even more preferably 14% by mass or less, and particularly preferably 12% by mass or less, relative to the total amount of the liquid content.

(Capsule shell)
The capsule shell contains at least pullulan.

Pullulan is a type of water-soluble polysaccharide, with a structure in which maltotriose units, each consisting of three glucose molecules linked together via an α1-4 bond, are linked together via an α1-6 bond. In the present invention, pullulan is included as a constituent base material for the capsule shell.

The pullulan content is not limited and may be changed as appropriate depending on the dosage form, the types and amounts of other ingredients, the intended recipient, etc. For example, in the case of a hard capsule dosage form, the pullulan content can be 85% by mass or more of the total amount of the coating composition, preferably 86% by mass or more, more preferably 87% by mass or more, and particularly preferably 88% by mass or more.
The content of pullulan can be, for example, 91% by mass or less, 90% by mass or less, 89% by mass or less, 88% by mass or less, etc. As the hard capsule containing pullulan, commercially available products can also be used, such as Plantcaps capsules (manufactured by Capsugel).

For example, in the case of a soft capsule dosage form, the pullulan content can be 20% by mass or more, preferably 26% by mass or more, more preferably 28% by mass or more, even more preferably 30% by mass or more, and particularly preferably 32% by mass or more, relative to the total amount of the coating composition.
The pullulan content can be, for example, 45% by mass or less, preferably 40% by mass or less, more preferably 38% by mass or less, even more preferably 36% by mass or less, and particularly preferably 35% by mass or less, relative to the total amount of the coating composition.

In addition to the above, the capsule shell may also contain, for example, carrageenan.

The carrageenan content may be varied as appropriate depending on the dosage form, the type and amount of other ingredients, the intended recipient, etc., and is not limited thereto. For example, in the case of a hard capsule dosage form, the content may be 0.1% by mass or more of the total amount of the coating composition, preferably 0.2% by mass or more, more preferably 0.3% by mass or more, even more preferably 0.4% by mass or more, and particularly preferably 0.5% by mass or more.
The carrageenan content can be, for example, 2% by mass or less, 1.5% by mass or less, 1% by mass or less, 0.7% by mass or less, 0.6% by mass or less, etc., relative to the total amount of the coating composition.

For example, in the case of a soft capsule dosage form, the carrageenan content can be 5% by mass or more, preferably 7% by mass or more, more preferably 9% by mass or more, even more preferably 10% by mass or more, and particularly preferably 12% by mass or more, relative to the total amount of the coating composition.
Furthermore, the carrageenan content can be, for example, 25% by mass or less, preferably 23% by mass or less, more preferably 21% by mass or less, even more preferably 19% by mass or less, and particularly preferably 17% by mass or less, relative to the total amount of the coating composition.

Capsules can be manufactured using any known method without particular limitations. In the case of hard capsule dosage forms, the contents are filled into the hard capsule shell, and a band seal is applied to the seam between the body and cap parts that make up the hard capsule, preventing the contents from leaking from the seam (band seal method).

For soft capsule dosage forms, the well-known rotary die method or seamless method can be used. With the rotary die method, for example, soft capsules can be prepared by using a rotary die to fill the space between two film sheets while molding and then punching them out. With the seamless method, seamless capsules can be prepared, for example, by a dropping method using a double nozzle.

Next, the present invention will be specifically explained using examples and test examples, but the present invention is not limited to the following examples and test examples.

Test Example 1: Effect of the type of base in HMB-containing capsules
HMB was filled into hard capsules and soft capsules with different bases, and changes over time were observed when stored at room temperature. Plantcaps capsules (manufactured by Capsugel) were used as a hard capsule film product (commercial product) manufactured from a film containing at least pullulan, Natural B/C capsules (manufactured by Capsugel) were used as a hard capsule film product manufactured from a film containing gelatin but not pullulan, and VP Natural B/C capsules (manufactured by Capsugel) were used as a hard capsule film product manufactured from a film containing HPMC but not pullulan. For soft capsules, capsule films were prepared according to the film composition shown in Table 1 using a conventional method. HMB was filled as the content liquid using these films, and hard capsules and soft capsules were produced according to a conventional method. Specifically, for hard capsule dosage forms, the content liquid was sealed in the hard capsule film to prepare hard capsules. For soft capsule dosage forms, the content liquid was encapsulated in the following coating composition using a general rotary die method to prepare soft capsules.

(Evaluation method)
The five capsules were checked for "softening" and "cracks" and evaluated based on the following criteria. The results are shown in Table 2.

(Softening criteria)
◯: No softened capsules among 5 capsules △: 2 or less softened capsules among 5 capsules ×: 3 or more softened capsules among 5 capsules

(Crack Judgment Criteria)
〇: No broken capsules among 5 capsules △: 2 or less broken capsules among 5 capsules ×: 3 or more broken capsules among 5 capsules

As shown in Table 2, when gelatin or HPMC was used as the capsule shell base, the HMB in the capsule contents affected the capsules, causing them to soften and crack more easily. On the other hand, when pullulan was used as the capsule shell base, although it was effective in preventing capsule softening, it did not have a fully satisfactory effect in preventing capsule cracking.

[Test Example 2. Effect of sugar alcohol composition in HMB-containing capsules 1]
As a simple method for evaluating soft capsule formulation, we investigated the effect of HMB-containing liquid on the hard capsule shell when it was filled into a hard capsule.
HMB content solutions were prepared so that the sugar alcohol concentrations were 40%, 25%, and 10% by mass, and filled into hard capsules containing pullulan as a base. Changes over time during storage at room temperature were observed. Specifically, Plantcaps capsules (manufactured by Capsugel) were used as a hard capsule shell product (commercially available) made from a shell containing at least pullulan, and hard capsules were produced by a conventional method based on the capsule content composition shown in Table 3. The sugar alcohol compositions used are shown in Table 4. The evaluation methods for capsule "softening" and "cracking" were the same as in Test Example 1. The results for sugar alcohol concentrations of 40%, 25%, and 10% by mass are shown in Tables 5 to 7, respectively.

As shown in Tables 5 to 7, the effect on stability over time of HMB-containing capsules using pullulan as the capsule shell base was confirmed by changing the sugar alcohol content and composition. Among the sugar alcohols, sweet OL was confirmed to have high stability against "softening" and "cracking."

[Test Example 3. Effect of sugar alcohol composition in HMB-containing capsules 2]
Based on the results of Test Example 2, a commercially available reduced starch syrup (PO-300: manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.) with a sugar alcohol composition similar to that of Sweet OL was used to confirm its stability against "softening" and "cracking."
Specifically, HMB content solutions were prepared so that the PO-300 concentrations were 40%, 25%, and 10% by mass, and these were filled into hard capsules containing pullulan as a base. Changes over time during storage at room temperature were observed. Specifically, Plantcaps capsules (manufactured by Capsugel) were used as a hard capsule shell product (commercially available) manufactured from a shell containing at least pullulan, and hard capsules were produced by a conventional method based on the capsule content composition in Table 8. Table 9 compares the sugar alcohol compositions of Sweet OL and PO-300. The methods for evaluating capsule "softening" and "cracking" were the same as in Test Example 1. The results are shown in Table 10.

As shown in Table 10, even in the case of a commercially available reduced starch syrup (PO-300), which has a similar sugar alcohol composition to Sweet OL, high stability against "softening" and "cracking" was confirmed in HMB-containing capsules that use pullulan as the capsule shell base. Sweet OL and PO-300 are particularly similar in the compositions of the disaccharide alcohols and trisaccharide alcohols contained in the sugar alcohols, and it is believed that the blending ratio of these alcohols particularly influences the effects of the present invention.

Test Example 4: Examination of the effective concentration of sugar alcohol raw materials for HMB
HMB content solutions were prepared so that the HMB concentrations were 77-82% by mass and 92-98% by mass, and the effects of filling these solutions into pullulan-derived hard capsules on "softening" and "cracking" over time were examined. Specifically, hard capsules were produced by conventional methods based on the capsule content composition shown in Table 11 using Plantcaps capsules (manufactured by Capsugel) as a hard capsule shell product (commercially available) made from a shell containing at least pullulan. The evaluation methods for capsule "softening" and "cracking" were the same as in Test Example 1. The results are shown in Tables 12 and 13.

As shown in Tables 12 and 13, it was demonstrated that in HMB-containing capsules using pullulan as the capsule shell base, stability against "softening" and "cracking" can be achieved by setting the HMB content in the capsule contents to 70% to 98% by mass.

Test Example 5: Confirmation of the effects of HMB and sugar alcohol on pullulan-based soft capsule shells
Capsule contents were prepared containing 10% by mass of each sugar alcohol to achieve an HMB concentration of 90% by mass. Specifically, 20 g of each capsule content was weighed into a 50 ml bottle, sealed with a pullulan-containing soft capsule shell according to the formulation shown in Table 14 below, and stored upside down. This confirmed the effect of contacting the HMB content solution with the pullulan-containing soft capsule shell on shell cracking. The evaluation methods for capsule "softening" and "cracking" were the same as in Test Example 1. The results are shown in Table 15.

As shown in Table 15, the test using soft capsule shells also yielded results comparable to those obtained in Example 3, which used hard capsules. These results demonstrate that by adjusting the sugar alcohol composition examined in Test Examples 2 to 4 above, HMB-containing capsules using pullulan as the capsule shell base can be made highly stable against "softening" and "cracking," not only for hard capsule shells but also for soft capsule shells with different shell compositions.

Claims (4)

A capsule in which a capsule shell is filled with a content liquid, the capsule shell containing at least pullulan,
The inner liquid contains 3-hydroxyisovaleric acid and a sugar alcohol,
The sugar alcohol has a DE value of 40 to 80;
The ratio of monosaccharide alcohol contained in the sugar alcohol is 2 to 6%,
The ratio of disaccharide alcohol contained in the sugar alcohol is 45 to 55 %,
The ratio of trisaccharide alcohol contained in the sugar alcohol is 25 to 35 % ,
The ratio of tetrasaccharide alcohol contained in the sugar alcohol is 1 to 4%,
The ratio of alcohols with five or more sugars contained in the sugar alcohol is 1 to 15%,
The content of the 3-hydroxyisovaleric acid is 82 to 92% by mass based on the total amount of the content liquid,
The capsule has a sugar alcohol content of 8 to 18% by mass based on the total amount of the content liquid . A capsule in which a capsule shell is filled with a content liquid, the capsule shell containing at least pullulan,
The inner liquid contains 3-hydroxyisovaleric acid and a sugar alcohol,
The sugar alcohol has a DE value of 40 to 80,
The ratio of monosaccharide alcohol contained in the sugar alcohol is 17 to 25%,
The ratio of disaccharide alcohol contained in the sugar alcohol is 25 to 33%,
The ratio of trisaccharide alcohol contained in the sugar alcohol is 33 to 39%,
the ratio of tetrasaccharides and pentose or higher sugar alcohols contained in the sugar alcohol is 10 to 19%;
The content of the 3-hydroxyisovaleric acid is 82 to 92% by mass relative to the total amount of the content liquid,
The capsule has a sugar alcohol content of 8 to 18% by mass based on the total amount of the content liquid. Contains 3-hydroxyisovaleric acid and a sugar alcohol,
The sugar alcohol has a DE value of 40 to 80;
The ratio of monosaccharides contained in the sugar alcohol is 2 to 6%,
the sugar alcohol contains disaccharides in an amount of 45 to 55 %;
The ratio of trisaccharides contained in the sugar alcohol is 25 to 35 % ,
the sugar alcohol contains tetrasaccharides in an amount of 1 to 4%;
the ratio of five or more sugars contained in the sugar alcohol is 1 to 15%;
The content of the 3-hydroxyisovaleric acid is 82 to 92% by mass based on the total amount,
preparing a content liquid having a sugar alcohol content of 8 to 18% by mass relative to the total amount of the content liquid ;
preparing a capsule shell composition containing at least pullulan;
A method for producing a capsule, comprising the step of preparing a capsule by filling the content liquid in the coating composition. Contains 3-hydroxyisovaleric acid and a sugar alcohol,
The sugar alcohol has a DE value of 40 to 80;
The ratio of monosaccharides contained in the sugar alcohol is 17 to 25%,
the ratio of disaccharides contained in the sugar alcohol is 25 to 33%,
the ratio of trisaccharides contained in the sugar alcohol is 33 to 39%,
the sugar alcohol contains 10 to 19% of tetrasaccharides, pentasaccharides, or more;
The content of the 3-hydroxyisovaleric acid is 82 to 92% by mass based on the total amount,
preparing a content liquid having a sugar alcohol content of 8 to 18% by mass relative to the total amount of the content liquid;
preparing a capsule shell composition containing at least pullulan;
A method for producing a capsule, comprising the step of preparing a capsule by filling the content liquid in the coating composition.