Definitions

• the present invention relates to a power capsule agent having improved water stability by adjusting the water activity in the capsule in a sealed gelatin capsule.
• the stability of the capsule quality that is, the pharmacological activity of the structure and content drug, appearance, etc. is closely related to the water activity. For example, even if a gelatin capsule is produced under appropriate conditions, when it is stored in a sealed state, particularly under heating, when stored, the water in the capsule shell and the contents drug evaporates, and the inside of the capsule becomes It is known to be in a high humidity state (high water activity).
• the drug consists of an active substance that is susceptible to change due to the influence of water, or if it is difficult to separate the water from the active substance and contains impurities that are unstable to water, the free water inside the capsule and Contact with the content drug may cause destabilization with time, causing not only a change in appearance such as coloring but also a decrease in the activity of the active ingredient.
• gelatin capsules themselves may also become insolubilized, softened or deformed.
• a desiccant such as silica gel in a capsule packaging container, it is preferable to use the capsule in this method. It is difficult to control the water content in the skin properly.
• the gelatin content usually contains 12 to 16% of water.
• the water content is usually 10% or less, in particular? If it is less than 8%, it will Cracking occurs. Therefore, it is desirable to maintain the water content in the gelatin capsule properly and reduce the free water in the capsule, but it has been difficult to produce such a capsule.
• a stabilized gelatin capsule there are reported examples such as Japanese Patent Application Laid-Open Nos. Hei 3-8 0 903, 4 4 5 0 1 7, 4 1 5 9 2 s 18 etc. Also, a stabilizer is added to the inside of the gelatin coating, and no mention is made of control of the water activity in the capsule, and the above problems are not solved.
• a gelatin capsule containing polyvinyl pyrrolidone there is a report example of JP-A-53-214. However, the amount added to the gelatin capsule is small, and the purpose is to adjust the release rate of the drug. 0 0 0
• the inventors of the present invention have conducted intensive studies for the purpose of properly controlling the water activity of the capsule and for developing a capsule whose water activity is controlled.
• the present invention relates to an additive selected from the group consisting of calcium sulfate, sodium croscarmellose, partialized starch and polyvinylpolypyrrolidone in a gelatin capsule stored in a closed system.
• an additive selected from the group consisting of calcium sulfate, sodium croscarmellose, partialized starch and polyvinylpolypyrrolidone in a gelatin capsule stored in a closed system.
• Providing a water activity-controlled gelatin capsule characterized in that it is filled in the gelatin capsule at a ratio of about 50 to 150% by weight with respect to the total gelatin weight of the capsule. It is.
• FIG. 2 shows a capsule containing aspirin (AS) together with an additive (CS (corn starch); MCC (crystalline cellulose); CMC (carboxymethyl cellulose Ca); PCS (partially modified starch)) or alone.
• FIG. 7 is a graph showing the stability of aspiline in the capsule when the agent is stored with warming to 60 in a closed system.
• Figure 3 shows a closed system (25 ° C) of a mixture of gelatin beads and additives (PVPP (polyvinylpolypyrrolidon); aqueous solution; CMC-C a; PCS) in various compounding ratios. It is a graph which shows the relationship between the addition rate with respect to gelatin, and a water activity value at the time of preserve
• PVPP polyvinylpolypyrrolidon
• aqueous solution CMC-C a
• PCS PCS
• FIG. 4 is a graph showing the relationship between the addition ratio to gelatin and the water activity value when the same mixture as FIG. 3 is stored under heating (45 ° C.) in a closed system
• FIG. When the same mixture as in FIG. 3 is stored in a closed system under heating (60 ° C.), a graph showing the relationship between the addition ratio to gelatin and the water activity value is the best mode for carrying out the invention.
• the shell of the gelatin capsule of the present invention one having gelatin as a main component is suitable, but if desired, a small amount of capsule skin additives usually used in the pharmaceutical field such as polyethylene glycol etc. may be contained. Good.
• the additive as the above-mentioned water activity regulator is contained in an amount of about 50 to 150% by weight, preferably about 50 to 120% by weight, and more preferably about 50 to 100% by weight. %, More preferably about 70 to 100 times %, Especially about 75 to 90% by weight.
• the content of additives is too low, suppression of the water activity in the capsule under high temperature and high humidity conditions or long-term storage becomes insufficient, and the contents and capsules may be discolored and destabilized.
• the amount added is too large, the water activity may be excessively reduced during storage under mild conditions such as room temperature, and the capsule of the gelatin capsule may be cracked or the like.
• the water activity of each of gelatin, additives, and the whole capsule may be measured by a commercially available measuring device as described in the examples to be described later. [Example, water activity (A w) measurement system manufactured by Tronic Corporation DT type (Gunze Industrial Co., Ltd. ]] Etc. can be used for measurement.
• the water activity (Aw T ) of the whole capsule is calculated according to the following equation from the individual water activity values measured for gelatin, which is a component of the capsule shell, and an intra-muscular capsule additive. In principle, it is equivalent to the average water activity value (A ⁇ ), but if the transfer of water between the shell and the additive occurs by filling the additive in the capsule, then Aw T and ⁇ Differences will arise.
• Aw [Aw ⁇ M (gelatin) + A M (additive)] / [M (gelatin) + M (additive)]
• the gelatin capsule agent obtained by the method of the present invention has extremely high storage stability in a closed system which is usually unstable.
• the drug which is adversely affected by high water activity is stably present in the gelatin capsule even under closed heating conditions.
• the gelatin capsule shell itself is stabilized. Therefore, it may greatly contribute to maintaining the quality of the cabcel agent which has been concerned about the deterioration of quality during storage and transportation.
• the term "closed system” means a system in which the flow of ambient air is blocked as much as possible, and preferably refers to a state packaged with a breath 'through' package (PTP) or aluminum pillow etc. .
• the capsule of the present invention is produced in the usual way using usual carriers, excipients and the like, except that an appropriate amount of additive as a water activity regulator is added.
• an appropriate amount of additive as a water activity regulator is added.
• corn starch and microcrystalline cellulose, lactose, mannitol, sucrose, and other additives conventionally formulated as a standard capsule formulation it has been experimentally confirmed that the effect is the opposite in reducing the water activity. Therefore, in the capsule preparation of the present invention, it is preferable to appropriately adjust the amount used thereof (see Test Example 2 described later).
• lactose or the like may be added in a relatively small amount as an excipient within a range not to adversely affect the reduction of water activity, but such a form is also within the scope of the present invention.
• Sample 0.5-1-0 g (container: 1.7 cm in diameter, sample thickness of about 7)
• the measured value of water content was expressed by percentage of loss on drying relative to the dry weight of the measured sample.
• Test Example 1 Effect of temperature on water activity of gelatin The water activity in a closed system of gelatin used as a capsule shell was measured under the above conditions. The single result is shown in Fig.1.
• Test Example 2 Screening of additives showing the water activity reducing effect in coexistence with gelatin
• CMC-Ca carboxymethylcellulose calcium
• PC S Partially alpha mononized starch
• PVPP polyvinylpolypyrrolidone
• actisol croscarmellose sodium
• CMC-Ca carboxymethylcellulose calcium
• PCS partially starch
• Test Example 3 Stability of aspiline in a capsule stored under heating in a closed system: 1: 1 mixed powder (16 Omg) with aspirin (AS) and additives filled with gelatin hard capsule (No. 4) Then, it was placed in a closed system set using a BVK14 vial and stored warm at 60 ° C., and the change in the content of aspirin was measured. The results are shown in Fig.2.
• spirulin is significantly degraded by itself, and the addition of partially pregelatinized starch (PCS) and carboxymethylcellulose calcium (CMC) suppresses the degradation, but corn starch (CS) and crystalline cellulose (M CC) On the contrary, it is understood that the decomposition is promoted by adding.
• PCS partially pregelatinized starch
• CMC carboxymethylcellulose calcium
• CS corn starch
• M CC crystalline cellulose
• the additive exhibiting the effect of reducing the water activity under any temperature condition reduces the water activity of the whole system along with the increase of the added amount, and the addition of the deviation. It is also found that the water activity of the system increases with the increase of temperature when the agent is used.
• a indicates the value of the water activity that may cause the # 4 capsule shell (containing 4.6% PEG (polyethylene glycol) added, cap & body OP. White, manufactured by Nippon Elanco) to break. Water activity reduces the plasticity of the capsule shell and increases the probability of fracture failure during storage or transport. Therefore, it is understood from FIG. 3 that at the storage temperature of 25 ° C., the ratio of the additive to the capsule shell is preferably 150% or less.
• Carplex 67 (Shionogi) 1.5 m g
• the mixed powder of the above respective materials is filled with size 4 gelatin hard capsules (4 Omg) to obtain capsules (190.5 mg).
• the mixed powder of the above respective materials is filled with a size 4 gelatin hard capsule (4 Omg) I: to obtain a capsule (190.5 mg).
• the mixed powder of the above-mentioned respective raw materials is filled into a No. 4 size gelatin hard capsule (4 Omg) to obtain a capsule (190.5 mg).
• the gelatin capsule of the present invention has its water activity properly adjusted even under closed heating conditions, so the gelatin capsule itself is stable, and at the same time, it is susceptible to the influence of water.
• the contents containing the content drug can be maintained stably for a long period of time, which can contribute to the quality maintenance of the capsule preparation.

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