JP2005194218A - Hard capsule and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hard capsule that has low oxygen permeability and excellent medicine release and is produced by using a conventional gelatin hard capsule production process. <P>SOLUTION: The hard capsule comprises (a) at least one kind of α-1,4-glucan and its modified substance and (b) a gelling agent. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a hard capsule composed of α-1,4-glucan and a method for producing the same.

  Among pharmaceutical dosage forms, hard capsules are widely used because they have advantages such as drug stabilization, masking of taste and odor, and ease of taking. In recent years, taking advantage of these features, it is also used for health food applications.

  Conventionally, gelatin has been widely used as a base for hard capsules. This utilizes the property that gelatin solution is in a solution state at high temperature, but gelates at low temperature. Such capsules can be manufactured by immersing the pins in a base solution containing gelatin, pulling them up, gelling the coating, peeling it off after drying, and performing treatments such as cutting as necessary. Yes (dipping method).

  However, hard capsules based on gelatin have a problem that since moisture acts as a plasticizer, cracking occurs when the moisture in the film is 10% or less, and conversely softens under high humidity conditions. In addition, when the capsule content contains an aldehyde group or a reducing sugar, it is known that the capsule reacts with gelatin to insolubilize the capsule. In addition, in recent years, the problem of bovine spongiform encephalopathy (BSE) has occurred, and movement to refrain from using animal-derived materials is spreading.

On the other hand, when the content enclosed in the capsule is a substance that is easily oxidized, the capsule film is required to be oxygen-impermeable. In general, an oxygen barrier polymer has an oxygen permeability coefficient of 0.06 × 10 ⁻¹⁰ (cm ³ · cm ² / cm ² · s · cmHg) or less. Gelatin has a lower oxygen permeability coefficient, but depending on the contents encapsulated, a membrane with even lower oxygen permeability may be required.

  In order to eliminate these drawbacks, various improvements have been made on hard capsules. Japanese Patent Laid-Open No. 3-80930 (Patent Document 1) describes a gelatin hard capsule in which polyethylene glycol is blended as a plasticizer to improve flexibility.

  Japanese translations of PCT publication No. 2003-505565 (patent document 2) describes a hard capsule using pullulan as a base and a gelling agent and a gelling aid and a manufacturing method. Pullulan films have the advantage of low oxygen permeability compared to gelatin. However, since this film has a small elongation when tension is applied, it tends to be crushed or cracked. In addition, since it is highly hygroscopic, if it is stored in a high humidity environment, adhesion between capsules or between the capsule and the packaging material occurs, and stickiness may occur during taking.

  Japanese Patent Application Laid-Open No. 3-279325 (Patent Document 3) describes a hard capsule using a water-soluble cellulose derivative such as hydroxypropylmethylcellulose as a base, and containing a gelling agent and a gelling aid, and a method for producing the same. ing. However, capsules based on water-soluble cellulose derivatives have high oxygen permeability and are difficult to use in capsules containing contents that are susceptible to oxidation. Cellulose derivatives are plant-derived materials, but are obtained by chemical modification. Furthermore, capsules based on hydroxypropylmethylcellulose also have the disadvantage of poor drug release.

  In addition, hard capsules based on starch have been developed (Takubo Norihito, Life and Medicine 10, (6) 6 (1994), Non-Patent Document 1). However, this is manufactured by an injection molding method, and has a drawback that a conventional gelatin hard capsule manufacturing apparatus cannot be used as it is.

  International Publication No. 02/102355 pamphlet (Patent Document 4) describes a hard capsule composed of poly (1,4-α-D-glucan) and starch. However, this hard capsule is a hard capsule mainly composed of starch containing starch in an amount of 50 to 95% by weight, most preferably 70 to 90% by weight, which is α-1,4-glucan according to the present invention. It is different from a hard capsule containing as a main component.

WO 02/06507 pamphlet (Patent Document 5) describes a biodegradable article obtained from enzyme-synthesized amylose, and a capsule is described as one kind of the biodegradable article. This document describes a method for producing a so-called seamless capsule by a dropping method, but on the other hand, there is no specific description about a hard capsule and no description about a method for producing a hard capsule.
Japanese Patent Laid-Open No. 3-80930 Special table 2003-505565 gazette JP-A-3-279325 International Publication No. 02/102355 Pamphlet International Publication No. 02/06507 Pamphlet Norihito Takubo, Life and Medicine 10, (6) 6 (1994)

  The present invention is intended to solve the above-mentioned problems, and the object thereof is low oxygen permeability, excellent drug release, and can be manufactured using a conventional gelatin hard capsule manufacturing process. To provide hard capsules.

  The present invention provides a hard capsule containing (a) at least one of α-1,4-glucan and a modified product thereof, and (b) a gelling agent, whereby the above object is achieved. The

  The α-1,4-glucan is preferably enzyme-synthesized α-1,4-glucan. The modification of the α-1,4-glucan modification product is preferably a chemical modification selected from the group consisting of esterification, etherification and crosslinking.

  It is preferable that the hard capsule contains (a) 60 to 99.9% by weight of at least one of α-1,4-glucan and a modified product thereof, and (b) 0.1 to 40% by weight of a gelling agent. . Moreover, it is preferable that a hard capsule contains 0.01 to 3 weight% of gelatinization adjuvant.

  The present invention also provides a method for producing the hard capsule.

  According to the present invention, a hard capsule containing (a) at least one of α-1,4-glucan and a modified product thereof and (b) a gelling agent can be produced. Since the hard capsule can be manufactured without using animal-derived gelatin, it is more safe. Furthermore, this hard capsule has the advantages of excellent stability, drug release, and low oxygen permeability. In addition, the hard capsule is easy to manufacture because it can be manufactured by using an apparatus for manufacturing gelatin hard capsules by a dipping method, which is widely used in this field.

Definition of Terms The term “dispersion degree Mw / Mn” is the ratio of the number average molecular weight Mn to the weight average molecular weight Mw (ie, Mw ÷ Mn). Except for special cases such as proteins, a high molecular compound has a molecular weight that is not single and has a certain range regardless of whether it is derived from natural or non-natural origin. Therefore, in order to show the degree of dispersion of the molecular weight of the polymer compound, the dispersion degree Mw / Mn is usually used in the field of polymer chemistry. This degree of dispersion is an indicator of the breadth of the molecular weight distribution of the polymer compound. In the case of a polymer compound having a completely single molecular weight, Mw / Mn is 1, and Mw / Mn becomes a value larger than 1 as the molecular weight distribution increases. In this specification, the term “molecular weight” refers to weight average molecular weight (Mw) unless otherwise specified.

  The term “hard capsule” as used herein refers to a capsule coating that is fitted after the cap and body parts are separately molded and filled with contents. The concept of “hard capsule” in the present specification includes a soft capsule in which the contents are filled and bonded between two films, a seamless capsule in which the contents are dropped into a coagulation liquid together with a coating solution, It does not include microcapsules that incorporate the active ingredient inside by emulsification or the like.

  The term “α-1,4-glucan”, as used herein, is a sugar having D-glucose as a constituent unit and linked only by α-1,4-glucoside bonds. Is a saccharide having at least two saccharide units. α-1,4-glucan is a linear molecule. α-1,4-glucan is also called linear glucan. The number of sugar units contained in one molecule of α-1,4-glucan is called the degree of polymerization. In this specification, the term “degree of polymerization” refers to the weight average degree of polymerization unless otherwise specified. In the case of α-1,4-glucan, the weight average degree of polymerization is calculated by dividing the weight average molecular weight by 162.

Hard capsule The hard capsule of the present invention comprises (a) at least one of α-1,4-glucan and a modified product thereof, and (b) a gelling agent. The hard capsule of the present invention may further contain a gelling aid.

  The α-1,4-glucan contained in the hard capsule of the present invention is a polymer having a structure in which glucose is linearly bonded. This can be produced from natural starch, by enzymatic methods, etc., by methods known in the art.

  As a method for obtaining α-1,4-glucan from natural starch, for example, isoamylase or pullulanase known as a debranching enzyme is used only for α-1,6-glucoside bond of amylopectin existing in natural starch. There is a method of obtaining amylose by selectively acting and decomposing amylopectin (so-called starch enzymatic decomposition method). Another example is a method in which an amylose / butanol complex is precipitated and separated from starch paste.

  In addition, α-1,4-glucan can be prepared using a known enzyme synthesis method. As an example of the enzyme synthesis method, there is a method in which amylosucrase (EC 2.4.1.4) is allowed to act using sucrose as a substrate.

  Another example of the enzyme synthesis method is a method using glucan phosphorylase (α-glucan phosphorylase, EC 2.4.1.1; usually referred to as phosphorylase). Phosphorylase is an enzyme that catalyzes a phosphorolysis reaction.

In the present invention, it is preferable to use enzyme-synthesized α-1,4-glucan, and it is particularly preferable to use α-1,4-glucan that is enzymatically synthesized using glucan phosphorylase. Enzymatic synthesis α-1,4-glucan synthesized with glucan phosphorylase has the following characteristics:
(1) Narrow molecular weight distribution (Mw / Mn is 1.1 or less);
(2) Those having an arbitrary degree of polymerization (about 60 to about 37000) can be obtained by appropriately controlling the production conditions;
(3) is completely linear and does not contain the slight branching structure found in amylose fractionated from natural starch;
(4) Like natural starch, it is composed only of glucose residues, and α-1,4-glucan, its degradation intermediates, and final degradation products are not toxic to living bodies;
(5) low oxygen permeability;
(6) Even if the moisture in the film fluctuates, physical properties such as strength hardly change;
(7) Chemical modification similar to starch is possible if necessary.

Enzymatic synthesis α-1,4-glucan synthesized by using glucan phosphorylase has the above-described characteristics, and therefore has the following advantages when used as a hard capsule base:
(A) safely decomposed and metabolized after taking;
(B) The drug release time can be controlled by controlling the molecular weight or the degree of substitution of chemical modification;
(C) protect the contents (inclusions) that are susceptible to oxidation;
(D) It is less susceptible to external humidity changes and stably protects hygroscopic drugs.

  Those obtained by modifying the above α-1,4-glucan can also be used. Examples of such modifications include esterification, etherification and crosslinking.

  Esterification, for example, reacts α-1,4-glucan with an esterification reagent (eg, acid anhydride, organic acid, acid chloride, ketene or other esterification reagent) in various solvents or without solvent. Can be done. By such esterification, for example, a modified acylated ester such as acetate ester or propionate ester can be obtained.

  Etherification can be performed, for example, by reacting α-1,4-glucan with an etherifying agent (for example, alkyl halide, dialkyl sulfate, etc.) in the presence of an alkali. By such etherification, for example, modified products of carboxymethyl ether, hydroxypropyl ether, hydroxymethyl ether, methyl ether, and ethyl ether are obtained.

  Crosslinking can be performed, for example, by reacting α-1,4-glucan with a crosslinking agent (formalin, epichlorohydrin, glutaraldehyde, various diglycidyl ethers, various esters, etc.).

  As the α-1,4-glucan, those that have not been modified or those that have been modified may be used alone or in combination. Two or more α-1,4-glucan modifications may be used in combination.

  The hard capsule of the present invention contains a gelling agent. Examples of gelling agents include polysaccharides such as carrageenan, gellan gum, locust bean gum, pectin, sodium alginate, gelatin, tragacanth, agar, xanthan, gum arabic, guar gum, tamarind gum and the like. These can be used alone or in combination. It is preferable to use the above-mentioned polysaccharide as a gelling agent because a hard capsule containing no animal-derived raw material can be produced.

  The hard capsule of the present invention may contain a gelling aid as necessary. Examples of the gelling aid include substances containing potassium ion, calcium ion, magnesium ion, ammonium ion, sodium ion, lithium ion and the like. Substances containing these ions may be used alone or in combination of two or more. By including such a gelling aid in the hard capsule of the present invention, the gelation ability at the time of producing the hard capsule can be enhanced.

  The hard capsule of the present invention contains (a) at least one of α-1,4-glucan and a modified product thereof in an amount of a lower limit of 60% by weight and an upper limit of 99.9% by weight. The lower limit is preferably 80% by weight, more preferably 90% by weight. The upper limit is preferably 99.8% by weight, more preferably 99.6% by weight. (A) When at least one of α-1,4-glucan and a modified product thereof is contained in the above range in the hard capsule, the capsule has excellent strength, stability, and drug release properties. The hard capsule of the present invention contains a gelling agent in an amount of a lower limit of 0.1% by weight and an upper limit of 40% by weight. The lower limit is preferably 0.2% by weight, and more preferably 0.3% by weight. The upper limit is preferably 15% by weight, and more preferably 5% by weight. When the amount of the gelling agent is out of the above range, it may be difficult to produce hard capsules. When the hard capsule of the present invention further contains a gelling aid, it is contained in an amount of 0.01% by weight lower limit and 3% by weight upper limit. This upper limit is preferably 1% by weight. In addition, each of these components (α-1,4-glucan, a modified product thereof, a gelling agent, and a gelling auxiliary agent) are provided on the condition that the total of each component is included in an amount not exceeding 100% by weight.

  The hard capsule of the present invention may contain a softening agent. Examples of the softening agent include glycerin, monoacetin, diacetin, triacetin, polyvinyl alcohol, polyethylene glycol, starch, dextrin, sucrose fatty acid ester, glycerin fatty acid ester and the like. By including such a softening agent, the physical properties of the resulting hard capsule can be improved.

  The hard capsule of the present invention may contain a lubricant such as a surfactant. Examples of lubricants include sodium lauryl sulfate, sucrose fatty acid ester, glycerin fatty acid ester, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester, sorbitan monostearate, lecithin, carnauba wax, shellac and the like. By using such a lubricant, the capsule can be easily opened and closed when the contents are filled, and the stickiness when taking can be improved.

  The hard capsule of the present invention may be coated on the inner surface and / or the outer surface. Examples of coating agents include zein, dextrin, pullulan, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, aminoalkylmeta Examples include acrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, shellac, and polyethylene glycol. By applying such a coating, it is possible to impart a release function such as enteric properties, and to improve gas barrier properties and administration properties.

  The hard capsule of the present invention may contain a colorant and a pigment for the purpose of imparting distinctiveness and light shielding properties. Examples of colorants and pigments include yellow ferric oxide, ferric oxide, edible red No. 2 aluminum lake, edible red No. 3, edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106, Food yellow No. 4, food yellow No. 5, food green No. 3, food blue No. 1, food blue No. 2, copper chlorofin sodium, copper chlorofin, titanium oxide and the like can be mentioned.

Method for Producing Hard Capsule As a method for producing the hard capsule of the present invention, it can be produced by a commonly used production apparatus by a method such as extrusion molding, injection molding, casting or dipping. In particular, the hard capsule of the present invention containing α-1,4-glucan and a gelling agent has an advantage that it can be produced using an apparatus generally used for producing gelatin hard capsules as it is.

The hard capsule of the present invention is preferably produced by a dipping method commonly used in the production of gelatin hard capsules. This immersion method is
A step of immersing the mold pin in a heated solution containing at least one of α-1,4-glucan and a modified product thereof and a gelling agent;
-The process of taking out the immersed mold pin from the heated solution,
A step of cooling and curing the solution adhering to the mold pin, and a step of removing the obtained cured product from the mold pin.
Is included. In FIG. 1, the schematic process drawing of manufacture of the hard capsule by a dipping method is shown.

  The above step may include a step of rotating the mold pin 180 degrees in the vertical direction before curing the solution adhering to the mold pin, if necessary. Moreover, before removing the obtained hardened | cured material from a mold pin, you may dry hardened | cured material. Further, a gelling aid may be added to the solution to be immersed to promote gelation.

  The solution used for producing the hard capsule is 5 to 50% by weight, preferably 10 to 20% by weight, and 0.05 to 5% by weight of the gelling agent, at least one of α-1,4-glucan and a modified product thereof. %, Preferably 0.1 to 1.0% by weight. Further, when a gelling aid is used, the gelling aid is contained in the range of 0.01 to 0.2% by weight, preferably 0.05 to 0.1% by weight. When at least one of α-1,4-glucan and a modified product thereof is less than 5% by weight, a hard capsule having a sufficient thickness may not be obtained. On the other hand, when it exceeds 50% by weight, the viscosity of the solution becomes high, and it may be difficult to produce a hard capsule having a uniform thickness by the dipping method. When the gelling agent is less than 0.05% by weight, there is a possibility that sufficient gelation of the solution adhering to the mold pin cannot be obtained. On the other hand, when it exceeds 5% by weight, the viscosity of the solution becomes high, and it may be difficult to produce a hard capsule having a uniform thickness by the dipping method. If the gelling aid exceeds 0.2% by weight, the viscosity of the solution may be non-uniform.

  Water is used as the medium for this solution. Examples of water that can be used include tap water, ion exchange water, distilled water, and purified water.

  The temperature of the solution in which the mold pin is immersed may be a temperature at which at least one of α-1,4-glucan and a modified product thereof and the gelling agent are dissolved satisfactorily. This temperature is preferably 40 to 70 ° C, more preferably 45 to 55 ° C. This is because the temperature within the above range is suitable for producing hard capsules having a uniform thickness. Moreover, what is necessary is just to use the conditions normally used in manufacture of the well-known hard capsule by the immersion method for the cooling time and cooling temperature of the solution adhering to the mold pin.

  The hard capsule of the present invention can be filled with powder, granule, tablet, liquid or semi-solid contents. Further, if necessary, a seal can be applied to the joint between the cap part and the body part to prevent leakage of contents and improve stability.

  Examples of the contents that can be filled in the hard capsule of the present invention include pharmaceuticals, agricultural chemicals and fertilizers, foods and food additives, fragrances, dyes, and detergents.

  EXAMPLES Hereinafter, although an Example and a test example demonstrate this invention further in detail, this invention is not limited to these Examples.

  In test examples, a method for preparing purified glucan phosphorylase derived from potato tubers, a method for preparing sucrose phosphorylase derived from Streptococcus mutans, a method for calculating the yield (%) of α-1,4-glucan, a weight average molecular weight (Mw) and a number average The measuring method of molecular weight (Mn) followed the method known by description of Unexamined-Japanese-Patent No. 2002-345458. Specifically, the molecular weight of the synthesized glucan was measured as follows. First, the synthesized glucan is completely dissolved in 1N sodium hydroxide, neutralized with an appropriate amount of hydrochloric acid, and about 300 μg of glucan is subjected to gel filtration chromatography using a differential refractometer and a multi-angle light scattering detector in combination. To determine the weight average molecular weight. Specifically, Shodex SB806M-HQ (manufactured by Showa Denko) is used as a column, and a multi-angle light scattering detector (DAWN-DSP, manufactured by Wyatt Technology) and a differential refractometer (Shodex RI-71, manufactured by Showa Denko) are used as detectors. ) Were used in this order. The column was kept at 40 ° C., and 0.1 M sodium nitrate solution was used as an eluent at a flow rate of 1 mL / min. The obtained signals were collected using data analysis software (trade name ASTRA, manufactured by Wyatt Technology), and analyzed using the same software to determine the weight average molecular weight and the number average molecular weight.

  The degree of substitution of acetylated α-1,4-glucan was measured by the following method according to the description of “Starch / Related Sugar Experimental Method” (Nakamura et al., 1986, Japan Society for the Science of Publishing). 1 g of the sample was precisely weighed into a 300 ml Erlenmeyer flask, and 50 ml of 75% ethanol was added and dispersed. To this was added 40 ml of 0.5N aqueous sodium hydroxide solution, which was sealed and shaken at room temperature for 48 hours. Excess alkali was titrated with 0.5N hydrochloric acid, and the degree of substitution (DS) was determined from the difference from the blank. The degree of substitution (DS) is the average number of substituted hydroxyl groups per anhydroglucose residue.

  The oxygen permeability test was carried out by the following method using a differential pressure method based on Japanese Industrial Standard JIS K7126 “Method for testing gas permeability of plastic films and sheets”. The apparatus includes a permeation cell for allowing oxygen to pass through the test piece, a pressure detector for detecting a pressure change due to the permeated oxygen, a test gas supplier for supplying oxygen to the permeation cell, a vacuum pump, and the like. The pressure detector was measured with the accuracy of 1 Pa using NEW Palmyl vacuum gauge PVD-9500-L21 by Sato Vacuum Co., Ltd. The diameter of the transmission surface was 30 mm, and the test piece was dried for 48 hours or more using silica gel in a desiccator. The test conditions were a room temperature of 20 ° C. and a test temperature of 25 ° C. In the test method, one side (low pressure side) separated by the test piece was kept in vacuum, oxygen was introduced to the other (high pressure side) at about 1 atm, and the pressure on the low pressure side was recorded to obtain a permeation curve. The change in pressure on the low pressure side per unit time was determined from the steady state slope of the permeation curve, and the gas permeability and gas permeation coefficient were calculated. In addition, the average value measured three places was used for the thickness of the test piece.

  The compression test of the hard capsule was performed by the following method. A hard capsule filled with pharmacopoeia lactose 200M (Gokyo Sangyo) was placed sideways on a sample stage of a rheometer (FUDOH RT-2002D · D), and sandwiched between disc-shaped adapters having a diameter of 20 mm. The sample stage was raised by 3 mm at a speed of 60 mm / min, compressed, and lowered again. After repeating this five times, the state of capsule cracks and dents was observed. Samples were stored for 1 week at a relative humidity of 60% and those dried under vacuum. Five capsules were tested per same sample.

  The hard capsule dissolution test was performed in distilled water at 37 ° C. based on the Japanese Pharmacopoeia. The content used was a mixture of acetaminophen and lactose in a weight ratio of 1: 5.

Production Example 1 : Synthesis of α-1,4-glucan Reaction solution (1) containing 15 mM phosphate buffer (pH 7.0), 106 mM sucrose, and malto-oligosaccharide mixture (Tetrap H, manufactured by Hayashibara) 5.4 mg / liter Liters), purified glucan phosphorylase derived from potato tubers (1 unit / ml) and sucrose phosphorylase derived from Streptococcus mutans (1 unit / ml) were added and incubated at 37 ° C. for 16 hours. , 4-glucan yield (%), weight average molecular weight (Mw) and molecular weight distribution (Mw / Mn) were determined. As a result, α-1,4-glucan having a weight average molecular weight of 1250 kDa and a molecular weight distribution (Mw / Mn) of 1.03 was obtained.

Production Example 2 : Synthesis of acetylated α-1,4-glucan In 80 g of dimethyl sulfoxide, the α-1,4-glucan obtained in Test Example 1 was dissolved at a concentration of 5% by weight, and 2 g of sodium carbonate was obtained. Then, 8 g of vinyl acetate was added and reacted at 40 ° C. for 60 minutes. After the reaction, ethanol was added to precipitate the product. After filtration, the product was washed several times with water and purified. The degree of substitution of the obtained acetylated α-1,4-glucan was 0.44.

Example 1
In 90 g of distilled water having a liquid temperature of 70 ° C., 0.2 g of κ-carrageenan, 0.08 g of potassium chloride and 10 g of α-1,4-glucan of Production Example 1 were dissolved with stirring. The temperature of this solution was kept at 50 ° C., and a stainless steel cylindrical pin having a diameter of 7.0 mm or 6.7 mm and having a hemispherical tip was immersed and pulled up. This was inverted 180 degrees in the vertical direction, solidified at 20 ° C., and then dried to obtain hard capsules.

Example 2
Hard capsules were obtained in the same manner as in Example 1 except that 10 g of acetylated α-1,4-glucan of Production Example 2 was used instead of 10 g of α-1,4-glucan of Production Example 1.

Comparative Example 1
Hard capsules were obtained in the same manner as in Example 1, except that 10 g of pullulan (Hayashibara, PI-20) was used instead of 10 g of α-1,4-glucan of Example 1.

Comparative Example 2
10 g of gelatin was dissolved in 90 g of distilled water having a liquid temperature of 70 ° C. while stirring. The temperature of this solution was kept at 50 ° C., and a stainless steel cylindrical pin having a diameter of 7.0 mm or 6.7 mm and having a hemispherical tip was immersed and pulled up. This was inverted 180 degrees in the vertical direction, solidified at 20 ° C., and then dried to obtain hard capsules.

Comparative Example 3
In 90 g of distilled water having a liquid temperature of 50 ° C., 0.2 g of κ-carrageenan, 0.08 g of potassium chloride and 10 g of hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., HPMC2910) were dissolved with stirring. The temperature of this solution was kept at 50 ° C., and a stainless steel cylindrical pin having a diameter of 7.0 mm or 6.7 mm and having a hemispherical tip was immersed and pulled up. This was inverted 180 degrees in the vertical direction, solidified at 20 ° C., and then dried to obtain hard capsules.

Test 1 : Film preparation and oxygen permeability test Each solution obtained in Example 1 and Comparative Examples 1 to 3 was cast into a stainless steel plate and dried with a drier kept at 30 ° C. to obtain a thickness. A film of about 30 μm was obtained. The four types of films thus obtained were subjected to an oxygen permeability test. The results are shown in Table 1.

  As shown in Table 1, a film made of α-1,4-glucan has an oxygen permeability of several tens to several thousandths compared to gelatin or hydroxypropylmethylcellulose film frequently used in hard capsules. And has an excellent oxygen barrier property.

Test 2: Hard capsule compression test The hard capsules obtained in Examples 1 and 2 and Comparative Examples 1 to 3 were subjected to a compression test. The results are shown in Table 2.

  As shown in Table 2, the samples of Examples 1 and 2 were not cracked during storage at 60% relative humidity and vacuum drying. In contrast, the sample of Comparative Example 2 based on gelatin did not crack when stored at a relative humidity of 60%, but the sample dried in vacuum cracked and the contents leaked. Further, the sample of Comparative Example 1 based on pullulan was crushed in both storage at a relative humidity of 60% and vacuum drying, and was not restored to the original shape thereafter.

Test 3: Dissolution test The dissolution test of the hard capsules obtained in Examples 1 and 2 and Comparative Example 1 was performed. The results are shown in FIG. According to FIG. 2, the hard capsules based on α-1,4-glucan of Example 1 and acetylated α-1,4-glucan of Example 2 eluted almost all drugs within 20 minutes. . The dissolution behavior was equivalent to the capsule obtained from the gelatin of Comparative Example 1, and it was confirmed that the capsules of the examples had good drug release properties.

  According to the present invention, a hard capsule containing (a) at least one of α-1,4-glucan and a modified product thereof and (b) a gelling agent can be produced. Since the hard capsule can be manufactured without using animal-derived gelatin, it is more safe. Furthermore, this hard capsule has the advantages of excellent stability, drug release, and low oxygen permeability. In addition, the hard capsule is easy to manufacture because it can be manufactured by using an apparatus for manufacturing gelatin hard capsules by a dipping method, which is widely used in this field. This hard capsule with excellent safety, stability and drug release and low oxygen permeability can encapsulate various contents, so it can be used for pharmaceuticals, agricultural chemicals and fertilizers, foods and food additives, fragrances and dyes It can be used for various purposes such as detergents.

It is a schematic process drawing of manufacture of the hard capsule by a dipping method. It is a graph which shows the result of the elution test of the hard capsule obtained by the Example and the comparative example.

Claims (8)

(A) at least one of α-1,4-glucan and a modified product thereof, and (b) a gelling agent,
Containing hard capsules.   The hard capsule according to claim 1, wherein the α-1,4-glucan is an enzymatically synthesized α-1,4-glucan.   The hard capsule according to claim 1, wherein the modification of the modified product of α-1,4-glucan is a chemical modification selected from the group consisting of esterification, etherification and crosslinking.   The hard capsule according to claim 1, wherein the gelling agent is a polysaccharide or gelatin.   Furthermore, it contains a gelling aid, and the gelling aid contains one or more ions selected from the group consisting of potassium ion, calcium ion, magnesium ion, ammonium ion, sodium ion and lithium ion. The hard capsule according to claim 1.   The (a) at least one of α-1,4-glucan and a modified product thereof is contained in an amount of 60 to 99.9% by weight, and (b) a gelling agent is contained in an amount of 0.1 to 40% by weight. Hard capsules.   Furthermore, the hard capsule of Claim 6 which contains 0.01 to 3weight% of gelatinization adjuvants, and the total of each component is contained in the quantity which does not exceed 100 weight%. A step of immersing a mold pin in a heated solution containing (a) at least one of α-1,4-glucan and a modified product thereof and (b) a gelling agent;
Removing the immersed mold pin from the heated solution;
A step of cooling and curing the solution adhering to the mold pin, and a step of removing the obtained cured product from the mold pin,
A method for producing a hard capsule, comprising:

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