JP2005137935A - Hard capsule and its production method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a non-gelatin hard capsule and its production method which do not ooze even if polyethylene glycol #200 to #600 is filled up and can produce a capsule easily without requiring strict temperature control. <P>SOLUTION: The hard capsule consists of a gel which is formulated of pullulan with one or more items chosen from xanthan gum, locust bean gum, gellan gum, and carrageenan as a gelling agent, and made into a gel. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

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

  One of solid pharmaceutical preparations is a hard capsule. This is usually made by filling a predetermined amount of powder, granule, or liquid (oily) medicine or food into a cap-like container that is open at one end and formed of a gelatin film, and then coaxially connecting the containers. Completed.

  As a non-gelatin hard capsule, a hard capsule based on a water-soluble cellulose derivative such as hydroxypropylmethylcellulose (HPMC) has been conventionally known (Patent Document 1).

  However, this hard capsule is based on a cellulose ether substituted with an alkyl group or a hydroxyalkyl group, but this type of cellulose derivative dissolves in low-temperature water, but does not dissolve at high temperature. Also, the viscosity of the cellulose derivative dissolution / dispersion solution is easily affected by temperature, and when the temperature of the cellulose derivative solution dispersed in water at a high temperature is gradually lowered, the viscosity increases rapidly at around 50 ° C.

  Therefore, when manufacturing a hard capsule using the said cellulose derivative, exact | strict temperature control of a capsule preparation liquid is required.

  Moreover, when the hard capsule shape | molded with the said cellulose derivative is filled with polyethyleneglycol # 200- # 600 (PEG # 200- # 600) in this, it has been observed that a polyethylene glycol oozes out on the capsule surface. On the other hand, as is well known, in recent years, capsules in which a liquid drug is filled into a hard capsule have been put into practical use by the development of a capsule filling machine and a sealing machine for liquids. By the way, polyethylene glycol (PEG # 200 to # 600) which is liquid at room temperature has an excellent dissolving action for hardly soluble drugs and is preferably used as an excipient. It has been observed that when the molded hard capsule is filled with the polyethylene glycol # 200 to # 600, the polyethylene glycol oozes out on the surface of the capsule film. For this reason, it is difficult to fill the hard capsules of the cellulose derivative with the contents containing polyethylene glycol # 200 to # 600.

JP-A-3-279325

  The present invention has been made in view of the above circumstances, and is a non-gelatin hard capsule that does not bleed even when filled with polyethylene glycol # 200 to # 600 and can be easily produced without requiring strict temperature control. And it aims at providing the manufacturing method.

  As a result of intensive studies to achieve the above object, the present inventors have found that it is effective to produce hard capsules based on pullulan and using a gelling agent. That is, it is known that polysaccharides such as pullulan form a good film. When these aqueous solutions are coated on a plate-like substance or a spherical substance and dried, the film is formed. However, when capsules are to be produced with these aqueous solutions by the so-called dipping method, the polymer solution drips down before drying, and the film cannot be homogenized, making it impossible to mold capsules well. . However, one or more of xanthan gum, locust bean gum, gellan gum, and carrageenan, which is a substance that easily gels due to temperature changes, is blended as a gelling agent in the polymer aqueous solution, and the polymer on the pin. It was found that capsules can be produced satisfactorily by gelling the solution. Further, it has been found that even when a hard capsule formed of the above polymer gel is filled with polyethylene glycol # 200 to # 600, no bleeding occurs.

  Accordingly, the present invention is a hard capsule characterized by comprising a gel obtained by blending pullulan with one or more selected from xanthan gum, locust bean gum, gellan gum, and carrageenan as a gelling agent. I will provide a. In this case, the hard capsule is effectively filled with a filler containing polyethylene glycol # 200 to # 600.

  Further, the present invention immerses a capsule-forming pin in a capsule preparation solution containing pullulan and one or more selected from xanthan gum, locust bean gum, gellan gum, and carrageenan as a gelling agent. There is provided a method for producing a hard capsule, characterized by pulling up a pin and gelling and drying a capsule preparation liquid adhering to the pin.

  Since the above pullulan dissolves in aqueous solutions at a wide temperature range, the relationship between temperature and viscosity is different from that of the previous cellulose derivative, and the viscosity change does not occur as rapidly as the previous cellulose in the normal temperature range. However, by adding a gelling agent to an aqueous solution of pullulan, the polymer adhering to the pin rapidly gels when cooled, so that the capsule can be easily molded. As described above, as a result of examining the moldability of the capsule and the filling property of polyethylene glycol # 200 to # 600 with respect to pullulan, it was selected from xanthan gum, locust bean gum, gellan gum, and carrageenan, which are substances that easily gel with pullulan. It has been found that by adding one or two or more kinds as a gelling agent, the moldability of the capsule is improved, and further filling with polyethylene glycol # 200 to # 600 is possible.

  According to the present invention, non-gelatin capsules can be easily produced without the need for strict temperature control or the like, and the obtained capsules can be filled with polyethylene glycol # 200 to # 600.

  The non-gelatin hard capsule of the present invention uses pullulan as a base and is obtained by gelling this pullulan with a gelling agent.

  Pullulan is a natural polysaccharide with α-1,6-linked maltotriose obtained by culturing Aureobasidium Pullulans, a kind of black yeast, using starch as a raw material. It is used for foods, pharmaceuticals, cosmetics, etc. It has been known as an additive for a long time, and a commercially available product can be used as pullulan.

  The method for producing a hard capsule based on pullulan of the present invention will be described in more detail. A capsule forming pin is immersed in a capsule preparation solution in which pullulan and a gelling agent are dissolved. The capsule preparation liquid adhered to the pin is gelled and dried.

  Here, the concentration of pullulan in the capsule preparation liquid is preferably 5 to 30% (% by weight, hereinafter the same), and particularly preferably 10 to 20%.

  In addition, as the gelling agent, a substance that easily gels due to temperature change is used. Specifically, xanthan gum, locust bean gum, gellan gum, and carrageenan are used, and two or more of these substances are mixed and used. You can also.

  These xanthan gum, locust bean gum, gellan gum, and carrageenan are all suitable as gelling agents for pullulan, and in particular, fast-dissolving capsules can be obtained by using gellan gum. The concentration of the gelling agent is preferably 0.01 to 10%, particularly 0.1 to 1.0% in the capsule preparation solution.

  When kappa carrageenan is used as the gelling agent, a water-soluble compound that gives potassium ions, ammonium ions, calcium ions, such as potassium chloride, ammonium chloride, ammonium acetate, calcium chloride, etc., may be used as the gelling aid. In the case of using iota carrageenan, a water-soluble compound that gives calcium ions such as calcium chloride can be used.

  When gellan gum is used as a gelling agent, water-soluble compounds that give sodium ions, potassium ions, calcium ions, magnesium ions, such as sodium chloride, potassium chloride, calcium chloride, magnesium sulfate, etc., are used as gelling aids. Further, organic acids and water-soluble salts thereof such as citric acid or sodium citrate can be used.

  When using the said gelatinization adjuvant, it is 0.05-0.6% in a capsule preparation liquid, and the use of 0.06-0.2% of a gelatinization adjuvant is preferable.

  In the present invention, an appropriate amount of additives usually used for hard capsules such as dyes and pigments may be added.

  In the present invention, the above-mentioned pullulan, gelling agent, and other desired components are dissolved in water to obtain a capsule preparation solution. However, there is no particular limitation on the order of dissolution of the components in water. Alternatively, the gelling agent may be dissolved. The melting temperature is not particularly limited, but it is recommended that the melting temperature be 40 to 100 ° C, more preferably 50 to 95 ° C.

  The temperature at which the capsule forming pin is immersed is also selected as appropriate, but is preferably 30 to 80 ° C, particularly 40 to 60 ° C.

  In addition, it is preferable that the viscosity of the capsule preparation liquid at the time of this pin immersion is 100-10,000 mPa * s, especially 1,000-8,000 mPa * s.

  Gelation after the pins are pulled up is preferably performed by allowing to cool, but may be dried by heating to 40 to 80 ° C. after gelation.

The hard capsule of the present invention obtained as described above is based on pullulan, and preferably has the following composition.
Pullulan: 70% or more, more preferably 80% or more,
Gelling agent: 0.01-30%, more preferably 0.1-10%,
Gelling aid: 0-30%, more preferably 5% or less,
Moisture: 1-20%, more preferably 5-15%,
Total 100%

  The capsules according to the present invention can be applied to drugs or fertilizers for animals or plants, including pharmaceuticals or foods. In particular, as a pharmaceutical, it can be applied as a container for orally administered drugs, a container for inhalation, or a suppository. Furthermore, it can also be applied as a so-called quasi-drug for the purpose of disinfecting and cleaning dentures, glasses, contact lenses and the like.

  In this case, since the capsule of the present invention does not ooze out when filled with polyethylene glycol # 200 to # 600, it is effective for filling various fillers containing polyethylene glycol # 200 to # 600.

  As other components that can be filled in the capsule of the present invention, stearyl alcohol, cetanol, polyethylene glycol, or an ester thereof can be cited as alcohol / polyhydric alcohol, in addition to generally known powders, granules, and tablets. As fats and oils, sesame oil, soybean oil, peanut oil, corn oil, hydrogenated oil, paraffin oil, salami beeswax, etc., other fatty acids such as triethyl citrate, triacetin, stearic acid, palmitic acid, myristic acid and derivatives thereof, For example, triglyceride can be mentioned, and it is suitable for filling liquid and semi-solid substances.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited to the following Example.

[Example 1]
1 g of ethyl alcohol was added to 0.3 g of xanthan gum and 0.3 g of locust bean gum, and then dispersed with 170 g of water. This was heated to 70 ° C. to dissolve 30 g of pullulan. This was kept at 60 ° C., and a capsule forming pin was put in and then taken out and dried to prepare a capsule.

  The obtained capsules were subjected to a solution test using 50 ml of purified water heated to 37 ± 2 ° C. in accordance with the solution test method stipulated by the Japanese Pharmacopoeia (3 capsules to be tested). As a result, the dissolution time was 9.19 ± 0.39 minutes.

[Example 2]
1 g of gellan gum was dissolved in 168 g of water at about 90 ° C. To this, 1 g of sodium citrate and 30 g of pullulan were dissolved. This was kept at 55 ° C., and a capsule forming pin was put in and then taken out and dried to prepare a capsule. The result of conducting the solution test in the same manner as in Example 1 was 6.41 ± 0.63 minutes.

Example 3
0.2 g of carrageenan and 0.4 g of ammonium chloride were dissolved in 170 g of water at about 70 ° C. In this, 30 g of pullulan was dissolved. This was kept at 52 ° C., a capsule forming pin was inserted, then taken out and dried to prepare a capsule. The result of the solution test as in Example 1 was 8.17 ± 0.41 minutes.

[Experimental example]
The capsules of Examples 1 to 3 were filled with PEG # 400 and stored at 60 ° C. for 3 days, and then the appearance of the capsules was visually inspected, and the results shown in Table 1 were obtained (the number of test capsules was 3). ).

＊１：ゼラチンカプセル
＊２：ＨＰＭＣカプセル
：変化なし
△：外観はほとんど変化しないが、強度が低下する
×：皮膜表面からＰＥＧ＃４００がにじみでる

* 1: Gelatin capsule * 2: HPMC capsule: No change △: Appearance hardly changes, but strength decreases ×: PEG # 400 oozes from coating surface

Claims (14)

  A hard capsule comprising a gel obtained by blending pullulan with one or more selected from xanthan gum, locust bean gum, gellan gum, and carrageenan as a gelling agent.   The hard capsule according to claim 1, comprising a gel obtained by blending xanthan gum and / or locust bean gum as a gelling agent and gelling with pullulan.   The hard capsule according to claim 1, comprising a gel obtained by blending gellan gum with gellan as a gelling agent.   The hard capsule according to claim 1, comprising a gel obtained by mixing carrageenan as a gelling agent with gelling gel.   The hard capsule according to any one of claims 1 to 4, which is filled with a filler containing polyethylene glycol # 200 to # 600.   A capsule forming pin is immersed in a capsule preparation solution containing pullulan and one or more selected from xanthan gum, locust bean gum, gellan gum, and carrageenan as a gelling agent, and then the pin is pulled up, A method for producing a hard capsule, characterized by gelling and drying a capsule preparation liquid adhering to a pin.   The manufacturing method according to claim 6, wherein the concentration of pullulan in the capsule preparation liquid is 5 to 30% by weight and the concentration of the gelling agent is 0.01 to 10% by weight.   The production method according to claim 6, wherein the capsule preparation liquid contains pullulan and xanthan gum and / or locust bean gum as a gelling agent.   The production method according to claim 6, wherein the capsule preparation liquid contains pullulan and gellan gum as a gelling agent.   The production method according to claim 6, wherein the capsule preparation liquid contains pullulan and carrageenan as a gelling agent.   The manufacturing method according to any one of claims 6 to 10, wherein the capsule preparation liquid is prepared by dissolving pullulan in water at a dissolution temperature of 40 to 100 ° C.   The manufacturing method of any one of Claims 6-11 which adjusts the temperature of the capsule preparation liquid at the time of immersing the capsule molding pin to 30-80 degreeC.   The manufacturing method of any one of Claims 6-12 which adjusts the viscosity of the capsule preparation liquid at the time of immersing the capsule molding pin to 100-10000 mPa * s. The manufacturing method according to any one of claims 6 to 13, wherein the drying temperature after gelation is 40 to 80 ° C.