Manufacturing method of soft capsules

Abstract

To provide a method for producing a gelatin-made soft capsule containing low-methoxyl pectin with a small degree of esterification.SOLUTION: A coating stock solution is prepared that contains gelatin, low-methoxyl pectin with a degree of esterification of 3%-12% and a degree of amidation of 0%, and an alginate that is sodium alginate or potassium alginate with an aqueous solution of 1 mass% alginate having a viscosity of 100 mPa s-200 mPa s. The coating stock solution is processed with a rotary die molding device to form a soft capsule coating. The soft capsule coating is filled with contents, producing a soft capsule.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a soft capsule. [Background technology]

[0002] Gelatin is a unique substance that has both excellent film-forming ability and the property of reversibly changing from sol to gel when the temperature changes to near room temperature (gelling ability). For this reason, gelatin is often used as a coating material for soft capsules, which require heat sealing of the film during the manufacturing process using a rotary die-type molding device.

[0003] On the other hand, in some cases, it is desired to put ingredients that lose their efficacy in gastric acid or ingredients that irritate stomach tissue into soft capsules, and in such cases, the soft capsule shell is required to have the property of not disintegrating or dissolving in the stomach but disintegrating or dissolving after reaching the intestines (enteric coating). However, gelatin easily dissolves in strongly acidic gastric juice and does not have enteric coating.

[0004] Therefore, the applicant has previously proposed a technique for imparting enteric properties to a gelatin soft capsule shell by incorporating low methoxyl pectin into gelatin (see Patent Document 1). Patent Document 1 According to the technology, Since it is not necessary to add a water-insoluble salt containing a divalent or higher polyvalent metal ion to the capsule shell in advance in order to gel the low methoxyl pectin, it is possible to produce a transparent enteric soft capsule. Coating process to impart enteric properties to the soft capsule shell or a process of immersing the molded capsule in a gelling liquid containing divalent or higher polyvalent metal ions. Additional processes such as Need The enteric soft capsules can be produced without the need for a special process, which is the same as the process for producing normal gelatin soft capsules.

[0005] Here, the low methoxyl pectin is a pectin having an esterification degree of less than 50% among pectins, which are polysaccharides formed by polymerization of galacturonic acid and its methyl ester. The "esterification degree" refers to the proportion of galacturonic acid present in the form of methyl ester among all galacturonic acids. In realizing the invention of Patent Document 1, the present inventors have found that soft capsules can be made enteric by using low methoxyl pectin having an esterification degree of 20% to 40% and setting the ratio of low methoxyl pectin to gelatin within a predetermined range. In the course of the investigation, the inventors have also found that if the esterification degree of low methoxyl pectin is less than 20%, gelation proceeds rapidly and the degree of gelation is high, making it difficult to manufacture soft capsules.

[0006] While continuing to develop various soft capsules thereafter, the applicant came up with the idea of ​​producing soft capsules using low methoxyl pectin with a small degree of esterification, which had been difficult to produce in past studies, and further came up with the idea of ​​producing soft capsules with enteric properties. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 4252619 Summary of the Invention [Problem to be solved by the invention]

[0008] As described above, the first object of the present invention is to provide a method for producing soft capsules made of gelatin containing low methoxyl pectin with a small degree of esterification. The second object of the present invention is to provide a method for producing soft capsules made of gelatin having enteric properties. [Means for solving the problem]

[0009] In order to solve the above problems, the method for producing a soft capsule according to the present invention comprises the steps of: "Gelatin and Low methoxyl pectin with a degree of esterification of 3% to 12% and a degree of amidation of 0%; preparing a coating stock solution containing an alginate salt, which is sodium alginate or potassium alginate and has a viscosity of 100 mPa·s to 200 mPa·s in a 1% by mass aqueous solution; A rotary die type molding device is used to manufacture soft capsules in which the contents are filled in the soft capsule shell formed from the shell stock solution. It is something that A salt containing a divalent or higher polyvalent metal ion is not added to the shell stock solution, and the process does not include a step of immersing the formed soft capsule in a gelling solution containing the polyvalent metal ion. " It is something like that.

[0010] As mentioned above, low methoxyl pectin is a polysaccharide formed by polymerization of galacturonic acid and its methyl ester, and has a degree of esterification of less than 50%. On the other hand, pectin with a degree of esterification of 50% or more is called "high methoxyl pectin."

[0011] "Degree of esterification (DE)" refers to the proportion of galacturonic acid present in the form of methyl ester among all galacturonic acids. "Degree of amidation (DA)" refers to the proportion of galacturonic acid having an amide group among all galacturonic acids. In the present invention, low methoxyl pectin having a low degree of esterification of 3% to 12% and a degree of amidation of 0% is used. Hereinafter, this low methoxyl pectin may be referred to as "DE3-12 pectin".

[0012] The "contents" may be a target substance such as a pharmaceutical ingredient, health food ingredient, or nutritional supplement ingredient dissolved or suspended in fats or oily substances, or the target substance itself may be in an oily or paste form.

[0013] Alginic acid is a polysaccharide formed by linear polymerization of two types of uronic acid, mannuronic acid and guluronic acid, and "sodium alginate" and "potassium alginate" are salts in which the carboxyl group of alginic acid is bound to sodium ions and potassium ions, respectively. There are several types of both sodium alginate and potassium alginate, depending on differences in the degree of polymerization and the ratio of mannuronic acid to guluronic acid, but in the present invention, sodium alginate or potassium alginate is used, which has a viscosity of 100 mPa·s to 200 mPa·s in an aqueous solution with a concentration of 1% by mass. The viscosity measurement conditions are a B-type viscometer, rotor No. 2, rotation speed 30 rpm, and measurement temperature 20°C.

[0014] When DE3-12 pectin is added to a shell stock solution using gelatin as a shell base, but no alginate such as sodium alginate or potassium alginate is added, gelation occurs even at small amounts, making it difficult to form a shell. In contrast, when both DE3-12 pectin and alginate are added to the shell stock solution, gelation does not occur even when a larger amount of DE3-12 pectin is added than when it is added alone, and shell formation is possible. Therefore, it is possible to manufacture soft capsules made of gelatin, even when using low methoxyl pectin, which has a very low degree of esterification of 3% to 12%, and which has been difficult to manufacture soft capsules with in past studies. 。

[0015] In addition to the above configuration, the soft capsule manufacturing method according to the present invention further comprises: "In the film stock solution, The content of the alginate is 6 parts by weight or more and 10 parts by weight or less based on 100 parts by weight of gelatin, The sum of the contents of the low methoxyl pectin and the alginate is 10 parts by weight or more and 20 parts by weight or less per 100 parts by weight of gelatin, The weight ratio of the alginate to the low methoxyl pectin is 60% or more and 250% or less; "To produce a soft capsule having enteric properties."

[0016] As a result of the investigation, it was found that by adjusting the content of DE3-12 pectin and alginate to the above relationship, a soft capsule shell having enteric properties can be obtained, as described in detail below. Therefore, by using the above-described manufacturing method, it is possible to manufacture a soft capsule having enteric properties while containing low-methoxyl pectin with a low degree of esterification.

[0017] Suitable contents for enteric soft capsules include ingredients that are easily inactivated by gastric acid, such as lactic acid bacteria, and ingredients that are easily irritating to the cell walls of the stomach, such as iron. Effect of the Invention

[0018] As described above, according to the present invention, a method for producing soft capsules made of gelatin containing low methoxyl pectin with a small degree of esterification, and a method for producing soft capsules made of gelatin having enteric properties can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Hereinafter, a method for producing a soft capsule according to one embodiment of the present invention and a soft capsule produced by this method will be described.

[0020] The manufacturing method of soft capsules includes a shell stock solution preparation process, a molding and filling process, and a drying process. In the shell stock solution preparation process, gelatin, which is the shell base, is dissolved in water while heating, and a plasticizer, DE3-12 pectin, and alginate are added, and the mixture is stirred and mixed to prepare the shell stock solution.

[0021] The alginate used is sodium alginate or potassium alginate, whose aqueous solution with a concentration of 1% by mass has a viscosity of 100 mPa·s to 200 mPa·s. The viscosity measurement conditions are a Brookfield viscometer, rotor No. 2, rotation speed of 30 rpm, and measurement temperature of 20°C.

[0022] The forming and filling process is a process in which the soft capsule shell is formed and at the same time the contents are filled and sealed in, and is carried out using a rotary die type forming device. A rotary die type forming device generally mainly comprises a casting drum that forms the shell raw liquid into a film, a pair of die rolls with a forming mold formed on the outer surface, a wedge-shaped segment for filling the contents that is placed between the die rolls, and a pump that presses the contents into the segment and extrudes the contents from the tip of the segment.

[0023] In the forming and filling process, the shell stock solution is first cast onto the surface of a casting drum and gelled to form a sheet. Next, two of the formed sheets are fed between a pair of die rolls along the segment. As the pair of die rolls rotate in opposite directions, the two sheets are heat-sealed to form a capsule in the shape of a container that opens upward, and the contents extruded from the segment are filled into the capsule. At the same time, the two sheets are heat-sealed at the top to form a soft capsule with the contents filled in the closed internal space. In other words, the shell stock solution is turned into a film and heat-sealed to produce a soft capsule shell with a closed space inside, and at the same time, a soft capsule with the contents filled in the soft capsule shell is produced.

[0024] In this way, soft capsules manufactured using a rotary die type molding device have a "seam" which is a joining line formed during heat sealing. This seam is a structure unique to soft capsules molded using the rotary die type, and does not exist in soft capsules manufactured using the dropping method, which uses the surface tension of the shell concentrate to mold the capsules without heat sealing.

[0025] The drying process is a process in which the soft capsules after the molding and filling process are dried in a humidity-controlled dryer until the soft capsule shell reaches a specified moisture content. EXAMPLES

[0026] The basic composition of the coating solution was 100 parts by weight of gelatin, 50 parts by weight of glycerin as a plasticizer, and 150 parts by weight of water. The coating solution of the basic composition was made to contain DE3-12 pectin without sodium alginate, and the content of DE3-12 pectin relative to 100 parts by weight of gelatin was changed to prepare the coating solutions of samples P1 to P10. As the DE3-12 pectin, OF100C from the UNIPECTINE series manufactured by Cargill was used.

[0027] Furthermore, the coating solution of samples A1 to A10 were prepared by adding sodium alginate to the coating solution of the basic composition without adding DE3-12 pectin, and varying the content of sodium alginate per 100 parts by weight of gelatin. Kimica Algin I-1 manufactured by Kimica Co., Ltd. was used as the sodium alginate. Sodium alginate is a powder at room temperature, but the viscosity of a 1% by weight aqueous solution is 100 to 200 mPa s.

[0028] The viscosity of the coating solution was measured to evaluate the degree of gelation of the samples P1 to P10 and A1 to A10. The viscosity measurement conditions were a B-type viscometer, rotor No. 4, rotation speed 6 rpm, and measurement temperature 75° C. If the viscosity was too gelled to be measured, it was evaluated as “×” (poor).

[0029] For the coating solution whose viscosity was measurable, the coating formability was evaluated by casting it onto a smooth base surface. If the cast coating solution formed a film and the film had sufficient flexibility before drying, it was rated as "good", and if it had no flexibility and was brittle or cracked, it was rated as "x".

[0030] Furthermore, for samples with good film-forming properties, the enteric properties were evaluated according to the disintegration test method specified in the Japanese Pharmacopoeia. In this test, the first liquid was a test liquid of pH 1.2 for evaluating gastric juice resistance, and the soft capsule shell was moved up and down for 120 minutes in the test liquid, and in the subsequent observation, the soft capsule shell was evaluated as "○" if it remained, and as "×" if it did not remain. The second liquid was a test liquid of pH 6.8 for evaluating intestinal juice resistance, and the soft capsule shell was moved up and down for 60 minutes in the test liquid, and in the subsequent observation, the soft capsule shell was evaluated as "○" if it did not remain, and as "×" if it remained. Therefore, it can be determined that the soft capsule has enteric properties when it is "○" for both the first liquid and the second liquid.

[0031] Table 1 shows the test results for samples P1 to P10, and Table 2 shows the test results for samples A1 to A10.

[0032] [Table 1]

[0033] [Table 2]

[0034] As shown in Table 1, when DE3-12 pectin was added to a coating stock solution with a basic composition using gelatin as the coating base but no sodium alginate was added, when the content of DE3-12 pectin exceeded 4 parts by weight per 100 parts by weight of gelatin, gelation proceeded to such an extent that the viscosity could not be measured and casting was not possible. With samples containing 4 parts by weight or less of DE3-12 pectin per 100 parts by weight of gelatin, coating was possible, but in the disintegration test, they were not resistant to the first liquid and did not exhibit enteric properties.

[0035] As shown in Table 2, when the coating solution of the basic composition contained sodium alginate but did not contain DE3-12 pectin, when the sodium alginate content exceeded 10 parts by weight per 100 parts by weight of gelatin, gelation proceeded to such an extent that the viscosity could not be measured, and casting was not possible. With samples containing 10 parts by weight or less of sodium alginate per 100 parts by weight of gelatin, coating was possible, but in the disintegration test, they were not resistant to the first liquid and did not exhibit enteric properties.

[0036] In other words, when the coating solution of the basic composition contained only DE3-12 pectin or sodium alginate, gelation occurred at small amounts, making it impossible to form a coating, and even when a coating was formed, it did not exhibit enteric properties.

[0037] In contrast, when the coating solution of the basic composition contains both DE3-12 pectin and sodium alginate, as shown below, gelation does not occur even if more DE3-12 pectin is added than when it is added alone, and enteric properties are exhibited by setting the contents of the two in a specified relationship.

[0038] Samples S1-1 to S1-6, S2-1 to S2-7, S3-1 to S3-6, S4-1 to S4-6, S5-1 to S5-6, S6-1 to S6-6, S7-1 to S7-6, and S81-1 and S81-2 were prepared by adding a certain amount of DE3-12 pectin to the coating solution of the basic composition and varying the amount of sodium alginate. The content of DE3-12 pectin per 100 parts by weight of gelatin was 2 parts by weight for samples S1-1 to S1-6, 4 parts by weight for samples S2-1 to S2-7, 6 parts by weight for samples S3-1 to S3-6, 8 parts by weight for samples S4-1 to S4-6, 10 parts by weight for samples S5-1 to S5-6, 12 parts by weight for samples S6-1 to S6-6, 14 parts by weight for samples S7-1 to S7-6, and 16 parts by weight for samples S81-1 and S81-2.

[0039] For these samples, the degree of gelation based on viscosity, the film-forming ability, and the disintegration test were performed using the methods described above. The results are shown in Tables 3 to 9.

[0040] [Table 3]

[0041] [Table 4]

[0042] [Table 5]

[0043] [Table 6]

[0044] [Table 7]

[0045] [Table 8]

[0046] [Table 9]

[0047] In these tables, samples for which viscosity could be measured, the film-forming property was rated "O", and the disintegration test using both the first liquid and the second liquid was rated "O" are samples from which a soft capsule film having enteric properties was obtained.

[0048] From the results shown in Tables 1 to 9, "Condition 1, Condition 2, and Condition 3" were extracted as conditions under which enteric soft capsules can be produced. In these conditions, the ratio of DE3-12 pectin to 100 parts by weight of gelatin is abbreviated as "LP (parts by weight)," and the ratio of sodium alginate to 100 parts by weight of gelatin is abbreviated as "A (parts by weight)." Condition 1: 6≦A≦10 Condition 2: 10≦LP+A≦20 Condition 3: 60%≦A / LP≦250%

[0049] To indicate whether or not these conditions are met, "LP+A" and "A / LP (%)" are shown in the table, with each condition being indicated with "O" if it is met, "↑" if it is outside the range of the conditions, and "↓" if it is not within the range of the conditions.

[0050] The case where all of the conditions 1 to 3 are satisfied is when the amount of DE3-12 pectin and sodium alginate is neither too much nor too little, and when the amount of sodium alginate is neither excessive nor insufficient in relation to the DE3-12 pectin. For example, when the conditions 2 and 3 are satisfied but exceed the range of the condition 1 (samples S3-5, S3-6, and S4-6), that is, when the amount of sodium alginate is excessive, gelation proceeds. Also, when the conditions 1 and 2 are satisfied but do not meet the range of the condition 3 (samples S6-3 and S7-3), that is, when the amount of sodium alginate is insufficient relative to the DE3-12 pectin, gelation proceeds. When the amount of sodium alginate is excessive, gelation proceeds by the same mechanism as when only sodium alginate is included in the basic composition, and when the amount of sodium alginate is insufficient relative to the DE3-12 pectin, gelation proceeds by the same mechanism as when only DE3-12 pectin is included in the basic composition.

[0051] As described above, it was believed that by adding both DE3-12 pectin and sodium alginate to a shell stock solution using gelatin as the shell base in a manner that satisfies conditions 1 to 3, gelation, which tends to proceed when either is used alone, is suppressed and the enteric properties of pectin are exhibited. Furthermore, when only DE3-12 pectin is added to a shell stock solution of the basic composition, gelation proceeds when the content exceeds a small amount of 4 parts by weight per 100 parts by weight of gelatin, whereas it is noteworthy that by adding sodium alginate, even when 12 parts by weight of DE3-12 pectin is added per 100 parts by weight of gelatin, a soft capsule shell having enteric properties is obtained without gelation (sample S6-4).

[0052] Thus, the mechanism by which gelation is suppressed by the coexistence of DE3-12 pectin and sodium alginate is not clear; however, gelatin in aqueous solution is electrically charged, and these parts of the gelatin easily react with pectin, causing gelation to proceed. In contrast, when sodium alginate is present, it forms a complex with pectin, blocking the parts of the gelatin that react with the charged parts.

[0053] Although the above describes a sample that uses sodium alginate as the alginate, potassium alginate can also be used. Both sodium and potassium are alkali metals, and sodium alginate and potassium alginate, which both have viscosities of 1% by mass aqueous solutions of 100 mPa·s to 200 mPa·s, have very similar properties.

[0054] In fact, for the compositions of samples S2-2 to S2-4, S3-2 to S3-4, S4-3 to S4-5, S5-3 to S5-5, and S6-4, which were all good in the evaluation of the degree of gelation by viscosity, the evaluation of the film forming property, and the evaluation of the enteric property by the disintegration test, samples were prepared by replacing sodium alginate with potassium alginate. As the potassium alginate, Kimica Algin K-1 manufactured by Kimica Co., Ltd. was used. The film stock solution in which this potassium alginate was added to the standard composition shows the same viscosity as the above-mentioned film stock solution in which the same amount of sodium alginate was added to the standard composition. For example, the viscosity of the coating solution, in which 10 parts by weight of potassium alginate and 10 parts by weight of DE3-12 pectin were added to the standard composition per 100 parts by weight of gelatin, was 65,000 mPa s, which was the same as the viscosity of sample S5-5, in which the same amounts of sodium alginate and DE3-12 pectin were added to the standard composition.

[0055] For these samples, the evaluation of the degree of gelation by viscosity, the evaluation of the film-forming property, and the evaluation of the enteric property by the disintegration test were performed in the same manner as above. As a result, it was confirmed that the evaluation of the degree of gelation by viscosity, the evaluation of the film-forming property, and the evaluation of the enteric property by the disintegration test were all good for all samples in which sodium alginate was replaced with potassium alginate in the compositions of samples S2-2 to S2-4, S3-2 to S3-4, S4-3 to S4-5, S5-3 to S5-5, and S6-4. Therefore, even when the alginate is potassium alginate, soft capsules having enteric properties can be produced as long as they satisfy at least conditions 1 to 3.

[0056] The present invention has been described above with reference to preferred embodiments, but the present invention is not limited to the above embodiments, and various improvements and design changes are possible without departing from the spirit of the present invention, as described below.

[0057] For example, the soft capsule shell may contain additives such as coloring agents and flavoring agents in addition to the above-mentioned components.

Claims

[Claim 1] Gelatin and low methoxyl pectin having a degree of esterification of 3% to 12% and a degree of amidation of 0%; preparing a coating stock solution containing an alginate salt, which is sodium alginate or potassium alginate and has a viscosity of 100 mPa·s to 200 mPa·s as a 1% by mass aqueous solution; A rotary die type molding device is used to manufacture soft capsules in which the soft capsule shell formed from the shell stock solution is filled with contents, In the coating solution, The content of the alginate is 6 parts by weight or more and 10 parts by weight or less based on 100 parts by weight of gelatin, The sum of the contents of the low methoxyl pectin and the alginate is 10 parts by weight or more and 20 parts by weight or less per 100 parts by weight of gelatin, The weight ratio of the alginate to the low methoxyl pectin is 60% or more and 250% or less; A salt containing a divalent or higher polyvalent metal ion is not added to the shell stock solution, and a process of immersing the formed soft capsule in a gelling solution containing the polyvalent metal ion is not included, and a soft capsule having enteric properties is produced. A method for producing a soft capsule comprising the steps of:

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