JP2001170137A - Hard capsule and method for manufacturing therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a non-gelatin hard capsule capable of reliably maintaining excellent strength of a coat in a low equilibrium humidity, of filling PEG having a low molecular weight and oil and fat thereof such as a glycerol fatty acid ester or medium-chain fatty acid triglycerides without trouble, of being free from transmitting of steam or oxygen, and of being suitable for filling a water- reactive substance or an oxidizable substance. SOLUTION: The hard capsule consists of a film having a polyvinyl alcohol as a base material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a non-gelatin hard capsule used for pharmaceuticals, quasi-drugs, foods and the like.

[0002]

2. Description of the Related Art
Hard gelatin capsules are mainly used as hard capsules used for pharmaceuticals, quasi-drugs, foods, etc., but hard gelatin capsules have poor strength under low moisture, and have water-absorbing drugs and water. Such as reactive drugs,
There is a drawback that cracking is likely to occur when contents containing low moisture content are required as storage conditions or cause low moisture content.

For example, polyethylene glycol # 200
~ 600 low molecular weight polyethylene glycol (hereinafter referred to as
Abbreviated as "low molecular weight PEG") has excellent dissolving action and absorbability and is suitable as an excipient. However, this low molecular weight PEG has hygroscopicity and is filled in hard gelatin capsules. In such a case, the water content of the capsule coating is reduced, and the capsule coating is easily weakened. Similarly, PEG glycerin fatty acid esters and medium-chain fatty acid triglycerides are also known as excipients having excellent dissolution and absorption properties, but these PEG glycerin fatty acid esters and medium-chain fatty acid triglycerides weaken the gelatin film. It has the property of becoming Therefore, hard gelatin capsules filled with these excipients are more likely to crack over time. Furthermore, in the case of a hard gelatin capsule, when a drug unstable to water is filled, it is necessary to previously set the water content of the capsule shell low in order to maintain the stability of the drug. A low gelatin film is brittle and easily broken, which makes it difficult to formulate.

[0004] Hitherto, as a non-gelatin hard capsule capable of solving such a disadvantage of the hard gelatin capsule, a capsule using a water-soluble cellulose derivative as a base material has been proposed.
Capsules using PMC) have already been commercialized for some drugs.

[0005] HPMC capsules are attracting attention as hard capsules that can maintain good strength even under low moisture, do not become embrittled by the above-mentioned medium-chain fatty acid triglyceride, and can solve the disadvantages of the above hard gelatin capsules. .

However, when HPMC capsules are filled with the above-mentioned low molecular weight PEG, it is observed that the low molecular weight PEG leaks out through the capsule coating, and the low molecular weight PEG is observed.
Is difficult to apply to contents containing as an excipient or the like.

Further, the HPMC film can maintain good strength even under low moisture, and can be applied to contents having hygroscopicity and water reactivity, but the film is permeable to water vapor and oxygen, For this reason, moisture or oxygen in the outside air that has passed through the capsule coating may be absorbed by the contents, and in this case, the contents are a water-sensitive substance or an oxidizable substance that easily reacts with water or oxygen. In such a case, the contents may be deteriorated. For this reason, when such contents are filled, there is room for further improvement, such as storage under a dry atmosphere or a deoxygenated atmosphere. It should be noted that a similar problem occurs in the transmission of water vapor and oxygen even in a gelatin capsule.

[0008] The present invention has been made in view of the above circumstances, and it is possible to reliably maintain good film strength even under low moisture, and to use low molecular weight PEG and its fats and oils such as glycerin fatty acid esters and medium chain fatty acid triglycerides. It is an object of the present invention to provide a non-gelatin hard capsule which can be filled without any inconvenience and can be suitably applied to filling of a water-reactive substance or an oxidizable substance without permeation of water vapor or oxygen. .

[0009]

Means for Solving the Problems and Embodiments of the Invention In order to achieve the above object, the present inventor has proposed a method for preparing gelatin and HP.
After exploring a capsule film material to replace MC,
The film made of polyvinyl alcohol has a toughness equivalent to or surpasses that of the above-mentioned HPMC film even when the water content is low, and is permeable to fats and oils such as low molecular weight PEG and its glycerin fatty acid ester and medium-chain fatty acid triglyceride. Without being weakened by these substances, and hardly permeating water vapor or oxygen, by forming a hard capsule using this polyvinyl alcohol, good strength can be obtained even under low moisture. It can be reliably maintained, and can also be filled with fats and oils such as low molecular weight PEG and its glycerin fatty acid ester and medium-chain fatty acid triglyceride without inconvenience.
Further, they have found that a hard capsule which can be suitably applied to filling of a water-reactive substance or an oxidizable substance without permeation of water vapor or oxygen can be obtained.

Further, the present inventor has further studied a method for industrially producing hard capsules using the polyvinyl alcohol, and as a result, the preparation liquid for forming capsules containing the polyvinyl alcohol was subjected to a temperature change. By adding a gelling substance as a gelling agent,
The present inventors have found that hard capsules can be satisfactorily manufactured by a so-called immersion method in which a capsule is obtained by immersing a molding pin in a preparation liquid and pulling it up, and gelling and drying the preparation liquid attached to the periphery of the molding pin. The invention has been completed.

Accordingly, the present invention provides a hard capsule comprising a film based on polyvinyl alcohol, and a capsule forming pin immersed in a preparation liquid containing polyvinyl alcohol and a gelling agent and pulled up. The present invention also provides a method for producing a hard capsule, characterized in that the preparation liquid adhered to the molding pin is gelled, dried, peeled and recovered from the molding pin to obtain a hard capsule.

Hereinafter, the present invention will be described in more detail.
The hard capsule of the present invention is formed of a film using polyvinyl alcohol as a base material, and is obtained by gelling a preparation liquid containing polyvinyl alcohol with a gelling agent.

The polyvinyl alcohol is a polymer obtained by saponifying polyvinyl acetate, and has a saponification degree of 9
There is a completely saponified product represented by the following formula (1) at 7 mol% or more, and a partially saponified product represented by the following formula (2) having a saponification degree of 78 to 96 mol%. In the present invention, any of the above completely saponified products and partially saponified products can be used, and is not particularly limited.
Those having a content of 8 to 90 mol%, particularly about 87 to 90 mol% are preferably used.

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The degree of polymerization of the polyvinyl alcohol is not particularly limited as long as it is in a range where the film-forming ability can be exhibited, but it is usually preferably about 500 to 2,000, particularly preferably about 800 to 1500.

The hard capsule of the present invention is formed of a film based on the above-mentioned polyvinyl alcohol. In this case, when the polyvinyl alcohol is formed into a capsule-like film by an immersion method, it is usually gelled. Agent is used. That is, if the capsule is to be molded from the preparation liquid containing polyvinyl alcohol by the immersion method as it is, the preparation liquid drips from the molding pin before drying, and it is difficult to produce a good capsule without obtaining uniformity of the film. However, a gelling agent is added to a preparation solution containing polyvinyl alcohol to quickly gel the preparation solution adhered to the molding pin, thereby preventing dripping from the molding pin and forming a uniform capsule film. It can be molded.

As the above-mentioned gelling agent, a substance which gels by a change in temperature is preferably used, and specifically, carrageenan, xanthan gum, locust bean gum, gellan gum, tamarind seed polysaccharide, pectin, curdlan, gelatin, phaceleran , Agar and the like,
One or more of these can be used, and among them, carrageenan is particularly preferably used.

Further, a substance which promotes the gelling of the gelling agent can be added as a gelling aid together with the gelling agent. For example, when carrageenan is used as a gelling agent, potassium ion is used for kappa carrageenan,
Ammonium ion and calcium ion are used as gelling aids for iota carrageenan, respectively. These gelling auxiliaries can be added to the above-mentioned preparation liquid as water-soluble compounds which give the above-mentioned ions to the preparation liquid, for example, potassium chloride, ammonium chloride, calcium chloride and the like.

When the hard capsule of the present invention is obtained by the above dipping method, the concentration of polyvinyl alcohol in the above-mentioned preparation solution is 5
The concentration of the above-mentioned gelling agent is preferably 0.05 to 10% by mass, particularly 0.1 to 2% by mass, and more preferably 0.1 to 0.2% by mass. The concentration of the above-mentioned gelling aid is preferably 0.05 to 1% by mass, more preferably 0.1 to 1% by mass, as the ion amount.
Preferably it is 0.2% by mass.

In the present invention, if necessary, components other than the above-mentioned polyvinyl alcohol, a gelling agent and a gelling aid may be added. For example, together with the above-mentioned polyvinyl alcohol in order to improve the solubility of the capsule film. An appropriate amount of polyvinylpyrrolidone can be used in combination without departing from the purpose of the present invention. In this case, polyvinyl pyrrolidone having an average molecular weight of 40,000 or more is preferably used. Further, it is possible to add an appropriate amount of commonly used additives to hard capsules such as pigments and pigments.

The hard capsule of the present invention is prepared by immersing a capsule forming pin in a capsule preparation solution comprising an aqueous solution in which the above-mentioned polyvinyl alcohol, a gelling agent, a gelling aid, and other desired components are dissolved, and pulling up. It can be obtained by gelling and drying the above-mentioned preparation liquid adhering to the pin, and peeling and recovering this from the molded pin.

In this case, when the above-mentioned polyvinyl alcohol, a gelling agent, a gelling aid and other desired components are dissolved in water to obtain a capsule preparation solution, the order of dissolving each component is not limited, and polyvinyl alcohol is used first. Or the gelling agent may be dissolved first. The dissolution temperature is not particularly limited, but is usually preferably 60 ° C. or higher in view of the solubility of each component.

This capsule preparation liquid is subjected to defoaming under reduced pressure, ultrasonic defoaming or standing to remove fine bubbles.
It is preferable to provide capsules by dipping while keeping the temperature at 0 ° C. In this case, the viscosity of the preparation liquid at the time of pin immersion is 200 to 1000 Pa · s, particularly 300
Preferably, the pressure is 500 Pa · s.

Gelling after the molding pin is pulled out of the preparation solution can be carried out by heating or cooling depending on the properties of the gelling agent to be used. For example, when carrageenan is used as the gelling agent, the gel is allowed to cool. It can be quickly gelled. Then, the gelled preparation liquid is dried by air drying or the like to be completely solidified, and a hard capsule is obtained by peeling and recovering it from a molding pin. In this case, drying is performed by heating to about 50 to 80 ° C. It can also be dried. In addition, by applying edible oil or the like to the molding pin in advance as a release agent, the releasability of the obtained capsule is improved, and the release and recovery of the obtained hard capsule can be facilitated.

In this way, the hard capsule of the present invention comprising a film based on polyvinyl alcohol is obtained. In this case, although not particularly limited, the composition of the film constituting the hard capsule is as follows. It is preferred that Polyvinyl alcohol: 90% by mass or more, more preferably 95% by mass or more Gelling agent:
0.2 to 2% by mass, more preferably 0.5 to 1% by mass Gelling aid: 0.2 to 2% by mass, more preferably 0.5 to 2% by mass
1% by weight moisture: 1 to 10% by weight, more preferably 2 to 5%
mass%

The capsule according to the present invention is filled with generally known powders, granules, tablets and the like, and is applicable to medicines and foods, as well as drugs and fertilizers for animals or plants. In particular, the present invention can be applied as a drug, a container for an orally administered drug, an inhaler, or a suppository. Furthermore, the present invention is also applicable as a so-called quasi-drug for disinfecting and cleaning dentures, eyeglasses, contact lenses, and the like.

In this case, even if the capsule of the present invention is filled with low molecular weight PEG of polyethylene glycol # 200 to # 600, they do not exude, and the glycerin fatty acid ester of low molecular weight PEG and medium chain fatty acid Since the film does not become brittle even when filled with triglyceride, the film can be favorably applied to drugs containing these low-molecular-weight PEGs and their glycerin fatty acid esters and medium-chain fatty acid triglycerides as excipients. In addition, it can maintain good strength even if the moisture in the film is extremely reduced, and does not cause inconvenience such as cracking. Are also preferably used, and since water vapor and oxygen hardly pass therethrough, they are also preferably used for water-reactive substances and oxidizable substances.

Ingredients that can be filled in the hard capsule of the present invention include, in addition to the above-mentioned low molecular weight PEG and its glycerin fatty acid ester and medium chain fatty acid triglyceride, stearyl alcohol, cetanol, polyethylene glycol or alcohol as polyhydric alcohols. Its ester form is mentioned, and as fats and oils, such as sesame oil, soybean oil, peanut oil, corn oil, hardened oil, paraffin oil, salami beeswax, and others, triethyl citrate, triacetin, stearic acid, palmitic acid, myristic acid, etc. Fatty acids and derivatives thereof, and the like; liquids,
Suitable for filling semi-solid substances.

[0028]

As described above, according to the hard capsule of the present invention, good strength can be reliably maintained even under low moisture, and low molecular weight PEG and its glycerin fatty acid ester and medium chain fatty acid triglyceride can be maintained. Such fats and oils can be filled without any inconvenience, and can be suitably applied to filling of a water-reactive substance or an oxidizable substance without permeation of water vapor or oxygen.

[0029]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. Partially saponified polypinyl alcohol ("PVA1000" manufactured by Wako Pure Chemical Industries, saponification degree: 86 to 90 mol)
%, Polymerization degree of 900 to 1100), 0.3 g of kappa carrageenan and 0.2 g of potassium chloride were dissolved in 165 g of water at about 80 ° C. to obtain a capsule preparation solution. After the prepared solution was kept at 55 ° C. and defoamed, hard capsules were prepared by a dipping method. Hereinafter, this hard capsule is referred to as a PVA capsule.

After the obtained PVA capsule was dried by heating in an oven at 105 ° C. for 2 hours, a 50 g weight was naturally dropped on the capsule from a height of 10 cm using a falling weight impact tester, and the occurrence of cracks was examined. Was. The test was performed on 10 capsules, and the number of capsules in which cracks occurred was evaluated. In this case, as a control, the same test was carried out without performing the heat drying treatment.
A similar test was performed on capsules based on MC (HPMC capsules). Table 1 shows the results.

[0031]

[Table 1]

As shown in Table 1, the PV of the present invention
The A capsule was able to maintain extremely good strength even in an extremely low moisture state heated and dried at 105 ° C., and was confirmed to have excellent strength equal to or higher than the HPMC capsule.

The obtained PVA capsules were filled with about 0.3 g of silica gel, the joints of the capsules were sealed with the same preparation, and the capsules were allowed to stand at about 25 ° C. and 57% humidity for 5 days. It was taken out and the water content was measured by the Karl Fischer method. In addition, the same test was performed for a normal gelatin capsule and an HPMC capsule as a control. Table 2 shows the results. The measurement was performed on two capsules.

[0034]

[Table 2]

As shown in Table 2, the PV of the present invention
It was confirmed that the A capsule was able to reliably block the contents from the moisture in the outside air with almost no permeation of water vapor. Therefore, the PVA capsule of the present invention can be suitably applied to hygroscopic drugs and drugs that dislike water.

The obtained PVA capsules were filled with the substances shown in Table 3 and placed in a forced circulation dryer maintained at 45 ° C.
After standing for a week, the capsules were observed for liquid leakage, softening deformation and cracking. In addition, about PEG # 400 and medium chain fatty acid triglyceride, the same test was performed also with a normal gelatin capsule and HPMC capsule. The results are shown in Tables 3 and 4.

[0037]

[Table 3]

[Table 4]

As shown in Tables 3 and 4, the PVA capsules of the present invention can be applied to low molecular weight PEG and medium-chain fatty acid triglyceride without any problem, which are difficult to apply to gelatin capsules and HPMC capsules. It was confirmed that the composition can be applied to various other fats and oils.

The solubility of the obtained PVA capsule in 50 mL of purified water heated to 37 ° C. ± 1 ° C. was evaluated according to a dissolution test prescribed in the Japanese Pharmacopoeia. Table 5 shows the results
Shown in The measurement was performed on three capsules, and a similar test was performed on a normal gelatin capsule as a control.

[0040]

[Table 5]

As shown in Table 5, the PV of the present invention
A capsule is slightly inferior to gelatin capsule,
It was confirmed that the polymer had good solubility without any practical problems.

Claims (7)

[Claims] 1. A hard capsule comprising a film based on polyvinyl alcohol. 2. The hard capsule according to claim 1, wherein the film contains a gelling agent. 3. The gelling agent is one or two or more selected from carrageenan, xanthan gum, locust bean gum, gellan gum, tamarind seed polysaccharide, pectin, curdlan, gelatin, furceleran, and agar. Or the hard capsule according to 2. 4. Polyethylene glycol $ 200 to $ 6
The hard capsule according to any one of claims 1 to 3, wherein the hard capsule is filled with a content containing at least one of glycerin fatty acid ester and medium chain fatty acid triglyceride. 5. A capsule molding pin is immersed in a preparation liquid containing polyvinyl alcohol and a gelling agent, pulled up, and the preparation liquid adhered to the molding pin is gelled, dried and separated from the molding pin. And obtaining a hard capsule. 6. The method for producing a hard capsule according to claim 5, wherein a gelling aid for accelerating gelation of the gelling agent is added to the preparation liquid. 7. The gelling agent is carrageenan, and the gelling aid is one or more selected from potassium ions, calcium ions, and ammonium ions.
A method for producing the hard capsule according to the above.