TWI554290B - Composition for enteric hard capsules, and enteric hard capsule prepared using the composition - Google Patents

Description

Composition for enteric hard capsule, enteric hard capsule prepared using the composition

The invention relates to a composition for enteric hard capsules and an enteric hard capsule prepared by using the composition, and particularly relates to an enteric hard capsule comprising a water-soluble divalent alkali and an alkaline reagent. The composition and the enteric hard capsule prepared using the composition.

Usually used as a base material using gelatin, hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose phthalate (HPMCP) as a base material for the preparation of pharmaceutical products and Capsules for health food products.

Gelatin capsules have high industrial productivity and high price competitiveness. However, if the gelatin capsule contains 10% by weight (wt%) or less of water, the gelatin capsule may lose plasticity and may exhibit a sharp deterioration in impact resistance. In addition, concerns about mad cow disease limit the use of gelatin capsules. Therefore, plant-based HPMC capsules and enteric HPMCP capsules without gelatin are noted.

However, conventional HPMCP capsules have low transparency and are brittle when they are low in water (for example, 10% by weight or less by weight). In addition, since the conventional HPMCP includes an excessive amount of a neutralizing agent such as an alkaline agent, when the conventional HPMCP is stored under severe high temperature conditions, the internal moisture may be slowly lost and hardened. Furthermore, the neutralizing agent may gradually separate from the hardened capsule, which is also known as separation of separation (separation of Salt). When HPMCP capsules are stored in a sealed package, salt separation does not occur for 12 months or longer. However, when HPMCP capsules are stored in a conventional or unpackaged manner, salt separation occurs within about 12 months.

The present invention provides a composition for an enteric hard capsule comprising a water-soluble divalent base and an alkaline agent.

The present invention also provides an enteric hard capsule prepared using the foregoing composition.

According to the concept of the present invention, there is provided a composition for an enteric hard capsule comprising: 50 parts by weight to 90 parts by weight of hydroxypropylmethylcellulose phthalate (HPMCP); 10 weight Parts to 50 parts by weight of hydroxypropylmethylcellulose (HPMC); 0.1 to 2.5 parts by weight of a water-soluble divalent base; and 3.5 parts by weight to 7.5 parts by weight of an alkaline agent. The amount of HPMCP, HPMC, water-soluble divalent base and alkaline agent is based on 100 parts by weight of the total weight of HPMCP and HPMC.

The HPMCP may include 20% to 24% by weight of a methoxy group, 6% by weight to 10% by weight of a hydroxypropoxy group, and 21% to 26% by weight of a phthalyl group. And HPMCP can have a dynamic viscosity of 48 centistokes (cSt) to 66 centistokes.

The water soluble dibasic base can be calcium hydroxide.

The alkaline reagent can be ammonia, sodium hydroxide, potassium hydroxide or Its composition.

The composition may further comprise from 1 part by weight to 15 parts by weight of the plasticizer based on 100 parts by weight based on the total weight of the HPMCP and the HPMC.

The plasticizer may include hydrogenated corn syrup, triethyl citrate (TEC), triacetin (TA), polyethylene glycol (PEG), propylene glycol (propylene). Glycol, PG) or a combination thereof.

The composition may further comprise 0.05 parts by weight to 0.5 parts by weight of an emulsifier based on 100 parts by weight of the total weight of HPMCP and HPMC.

The emulsifier may further comprise one selected from the group consisting of sodium lauryl sulfate (SLS), sugar ester (SE), and combinations thereof.

The composition may further include water, wherein the ratio of the amount of water (Ww) to the total amount (Wm) of HPMCP and HPMC (Ww/Wm) may be from 75 parts by weight to 85 parts by weight per 15 parts by weight to 25 parts by weight. Between the ranges.

According to another concept of the present invention, an enteric hard capsule prepared using the foregoing composition is provided.

According to one or more embodiments of the present invention, there is provided a composition for enteric hard capsules, the composition comprising a water-soluble divalent base and an alkaline agent.

According to one or more embodiments of the present invention, an enteric hard capsule prepared using the foregoing composition may have high mechanical strength such as impact resistance and transparency. Moreover, the enteric hard capsule can delay the occurrence of salt separation during storage.

Exemplary embodiments of the present invention will be described in detail below.

According to an embodiment of the present invention, the composition for enteric hard capsules may include: 50 parts by weight to 90 parts by weight (for example, 60 parts by weight to 80 parts by weight) of hydroxypropylmethylcellulose phthalic acid Ester (HPMCP); 10 parts by weight to 50 parts by weight (for example, 20 parts by weight to 40 parts by weight) of hydroxypropyl methylcellulose (HPMC); 0.1 to 2.5 parts by weight (for example, 1.0 parts by weight to 1.5 parts by weight) a water-soluble divalent base; and 3.5 parts by weight to 7.5 parts by weight (for example, 4.5 parts by weight to 5.5 parts by weight) of an alkaline agent. The amount of HPMCP, HPMC, water-soluble divalent base and alkaline agent is based on 100 parts by weight of the total weight of HPMCP and HPMC.

HPMCP can be maintained for 2 to 4 hours or longer at the pH of the gastric juice (a pH of about 1.2) without being decomposed, but at the pH of the intestinal fluid (a pH of about 6.8) Decompose quickly in 10 minutes. The HPMCP may include, for example, 20% by weight to 24% by weight of methoxy group, 6% by weight to 10% by weight of hydroxypropoxy group, and 21% by weight to 26% by weight of phthalic acid, and HPMCP may have 48% Dynamic viscosity of 66 cents. The weight percent of methoxy, hydroxypropoxy and phthalic acid groups is based on the weight of all HPMCP. In the specification, the words "kinetic viscosity" and "viscosity" mean the use of Anton Paar MCR 301 (heating rate: 2 ° C / min); spindle number: CC 27 8009; RPM (shear rate): 1/S; available as measured by Anton Paar). In particular, the term "dynamic viscosity of HPMCP" means a viscosity obtained by measuring an aqueous solution of 20% by weight of HPMCP by the above method. Enteric hard capsules can be prepared using a composition for enteric hard capsules containing HPMCP having the aforementioned physical characteristics. Accordingly, enteric hard capsules can have good film strength, good transparency, and good elasticity. Further, when an enteric hard capsule is prepared using a composition including HPMCP, a smaller amount of an alkaline agent can be used. This method delays salt separation, which means that alkaline components (e.g., Na ⁺ , K ^+, and Ca2 ⁺ ) are separated from the capsule membrane during storage of the enteric hard capsule. However, embodiments of the invention are not limited thereto. For example, HPMCP can have physical properties different from those listed above. When the amount of HPMCP is in the range of 50 parts by weight to 90 parts by weight based on 100 parts by weight of the total weight of HPMCP and HPMC, the aqueous solution composition may have a viscosity suitable for forming a capsule of a suitable thickness, and The capsule formed by the aforementioned aqueous solution composition has good enteric characteristics.

HPMC improves the elasticity and enteric capsule formability of the fragile enteric capsule film. HPMC can also be used to adjust the gelation onset temperature of the composition to a temperature range (eg, 20 ° C to 70 ° C) that is suitable for commercial manufacture. The HPMC may include 4% to 12% by weight (for example, 4% to 7.5% by weight) of hydroxypropoxy group and 19% to 30% by weight (for example, 27% to 30% by weight) of a methoxy group. The weight percentages of hydroxypropoxy and methoxy groups are based on the total weight of HPMC, respectively. The 2% by weight aqueous HPMC solution may have a viscosity of from 3 centipoise (cps, centipoise) to 50 centipoise (for example, from 3 centipoise to 15 centipoise). When the amount of HPMC is in the above range (i.e., 10 parts by weight to 50 parts by weight), the capsule formability is good and the prepared capsule can have good elasticity and good enteric characteristics.

The water-soluble divalent base delays salt separation. Further, by using a water-soluble divalent base, a relatively small amount of an alkaline agent and a plasticizer (which will be described later) can be used. The water soluble divalent base can include calcium hydroxide. When the amount of the water-soluble divalent base is in the range of 0.1 part by weight to 2.5 parts by weight based on 100 parts by weight based on the total weight of the HPMCP and the HPMC, the water-soluble divalent base may exhibit the same as the alkaline agent. It is a property which improves the transparency of the prepared intestinal hard capsule (making the enteric hard capsule have a good appearance) and effectively delays the occurrence of salt separation.

The alkaline agent is an alkaline agent other than a water-soluble divalent base, and it can dissolve HPMCP. The alkaline agent can be an alkaline material such as ammonia, sodium hydroxide, potassium hydroxide or a combination thereof. The alkaline reagent can affect the gelation onset temperature. As used herein, the term "gelation onset temperature" means the temperature at which the viscosity of the composition decreases as the temperature increases as the thermal energy begins to increase during the viscosity measurement. When the amount of the alkaline agent is in the range of 3.5 parts by weight to 7.5 parts by weight based on 100 parts by weight based on the total weight of the HPMCP and the HPMC, the HPMCP can be easily dissolved, and the composition containing the alkaline agent It may have an appropriate pH. Furthermore, the resulting capsules can have good enteric characteristics and can delay salt separation of the capsule film during storage.

The composition for enteric hard capsules may further comprise 1 part by weight to 15 parts by weight (for example, 5 parts by weight to 10 parts by weight) of a plasticizer based on 100 parts by weight based on the total weight of HPMCP and HPMC. A plasticizer can be used to improve the strength of the enteric hard capsule film prepared using the foregoing composition. Examples of the plasticizer include hydrogenated corn syrup, triethyl citrate (TEC), triacetin (TA), polyethylene glycol (PEG), propylene glycol (PG) or a group thereof. Compound. When the amount of the plasticizer is in the range of 1 part by weight to 15 parts by weight based on 100 parts by weight based on the total weight of the HPMCP and the HPMC, the capsule obtained by using the foregoing composition may have appropriate plasticity and have Good transparency and strength.

The composition for enteric hard capsules may further comprise 0.05 parts by weight to 0.5 parts by weight (for example, 0.1 parts by weight to 0.2 parts by weight) of an emulsifier based on 100 parts by weight of the total weight of HPMCP and HPMC. Emulsifiers improve capsule formability. Examples of emulsifiers include sodium lauryl sulfate (SLS), glycolipids (SE), and combinations thereof. In particular, SLS can greatly improve capsule formability. The composition may have good capsule formability when the amount of the emulsifier is in the range of 0.05 part by weight to 0.5 part by weight based on 100 parts by weight based on the total weight of the HPMCP and the HPMC. And when the obtained capsule is used for a gastrointestinal disease formulation, it can also have good quality and good safety.

The composition for enteric hard capsules may further comprise water. In this case, at least one of HPMCP, HPMC, a water-soluble divalent base, an alkaline agent, a plasticizer, and an emulsifier is dissolved in the water of the composition. The ratio of the amount of water (Ww) to the total amount (Wm) of HPMCP and HPMC (Ww/Wm) may range from 75 parts by weight to 85 parts by weight per 15 parts by weight to 25 parts by weight.

According to another embodiment of the present invention, an enteric hard capsule prepared using the above composition is provided.

Hereinafter, a method of preparing an enteric hard capsule using the above composition will be described in detail according to an embodiment of the present invention. Method according to the embodiment of the present invention The following steps can be included:

The first step is to prepare a composition for enteric hard capsules by adding HPMCP, HPMC, a water-soluble dibasic base, and an alkaline agent to water at room temperature (for example, 20 ° C to 30 ° C). The term "composition" as used herein denotes a composition in which at least one of HPMCP, HPMC, a water-soluble divalent base, and an alkaline agent is at least partially dissolved in water or at least partially gelatinized. In this aspect, the viscosity of the composition at room temperature may range from 1,000 centipoise to 3,000 centipoise. The composition prepared above may have a pH of from 4.5 to 6.5 and a viscosity of from 1,000 centipoise to 3,000 centipoise (e.g., from 1,500 centipoise to 2,500 centipoise) at room temperature. The gelation initiation temperature of the composition may vary depending on the mixing ratio of HPMCP, HPMC, water-soluble divalent alkali, and alkaline agent. For example, the composition may have a gelation onset temperature of 40 ° C to 60 ° C. In this case, the composition may further include at least one of titanium dioxide and/or other colorants such as mineral pigments, natural pigments, and tar pigments.

The second step is to heat the aforementioned composition to a first temperature (i.e., gelation temperature). The first temperature is higher than the gelation onset temperature of the aforementioned composition. The first temperature may be 1 ° C to 25 ° C higher than the gelation onset temperature of the composition, for example, 15 ° C to 25 ° C higher.

The third step is to cool the heated composition to a second temperature (ie, immersible temperature). The second temperature is lower than the gelation onset temperature of the composition. The second temperature may be 15 ° C to 40 ° C (eg, 15 ° C to 35 ° C) lower than the gelation onset temperature of the composition.

The fourth step is to heat the third to a temperature above the gelation initiation temperature. A temperature mold pin is immersed in the composition. The gelation initiation temperature of the third temperature structurable composition is 10 ° C to 40 ° C higher.

The fifth step is to remove the mold bar from the composition to obtain a film coated on the mold bar.

The sixth step is to maintain the film at a fourth temperature for the first period to secure the film to the mold bar. The fourth temperature is equal to or greater than the gelation onset temperature. The fourth temperature may range from 60 °C to 80 °C, and the first period may range from 1 minute to 15 minutes (eg, 8 minutes).

The seventh step is to dry the fixed film at a fifth temperature during the second period to obtain a capsule shell. The fifth temperature may be in the range of 20 ° C to 40 ° C, and the second period may be in the range of 30 minutes to 60 minutes.

One or more embodiments of the present invention are now described in more detail with reference to the following examples. These examples are provided for illustrative purposes only, and the scope of the invention is not intended to be limited thereby.

Instance

Example 1 to Example 9 and Comparative Example 1 to Comparative Example 3

(preparation of the composition)

As shown in Table 1, HPMCP, HPMC, a water-soluble divalent base, an alkaline agent, a plasticizer, an emulsifier, and water were mixed in an appropriate ratio to prepare a composition for enteric hard capsules. The composition was maintained at a temperature of 20 °C.

(Preparation of enteric capsules)

The enteric capsules were prepared using the compositions prepared above according to the manner and conditions in Table 2 below.

First, each composition is heated to its gel temperature. Next, the composition is cooled to a temperature lower than the gelation initiation temperature of the composition (soaking temperature). Next, the mold bar (available from TECHNOPHAR, bar model: #0) is preheated to a temperature (die bar temperature). The aforementioned temperature is higher than the gelation onset temperature of the corresponding composition. The mold bar is dipped into the composition such that the composition is applied to the mold bar. After the coating process, the composition applied to the mold bar is at least partially gelled. Subsequently, the mold bar coated with the composition was maintained at 70 ° C for 5 minutes. The above mold bar was then dried at 30 ° C for 45 minutes.

Evaluation example 1

The potency of the capsules prepared according to Examples 1 to 9 and Comparative Examples 1 to 3 was evaluated as described below. The results are shown in Table 3 below.

<Impact test>

A 70 gram weight was dropped in a free fall by a height of 10 cm to impact 20 capsules in each example. Next, the number of capsules broken in the 20 tested capsules was calculated. The tested capsules contained 8 ± 0.5% by weight of water.

<Salt separation test>

Five capsules from each of the examples were placed in a plastic bottle. The plastic bottle is stoppered and maintained at a temperature of 20 ° C to 30 ° C and a relative humidity of 20% to 75%. Next, the appearance of the capsule was observed once a month for 12 months. Record the month from which the test began until the month when the salt began to separate from the capsule.

<transparency>

Each dried capsule is placed under a fluorescent lamp, and the turbidity of the capsule is divided into the following three levels by visual inspection:

◎: Clear

○: Slightly unclear (if the surface of the capsule is slightly rough or undissolved impurities are found)

△:朦胧

Evaluation example 2

A disintegration test was performed according to Korean Pharmacopeia IX (Korean Pharmacopoeia IX). The capsules prepared according to Examples 1 to 9 and Comparative Examples 1 to 3 were immersed in a pH of 6.8 (similar to small The decomposition time was measured in the test solution of the pH of the intestinal juice. The results are shown in Table 3.

Referring to Table 3, the capsules of Examples 1 to 9 exhibited similar salt separation delay effects, but had higher transparency and higher impact strength than the capsules of Comparative Example 1 and Comparative Example 2. The capsules of Examples 1 to 9 exhibited higher salt separation delay effects and had similar or higher impact strength and transparency than the capsules of Example 3. The capsules of Examples 1 to 9 and Comparative Examples 1 to 3 did not decompose under at least 2 hours under the conditions of gastric juice. However, under the conditions of intestinal fluid, these capsules will decompose within 5 minutes. This case illustrates that the capsules of Examples 1 to 9 and Comparative Examples 1 to 3 all have enteric characteristics.

As described above, enteric hard capsules prepared according to one or more embodiments of the present invention have similar or higher transparency and impact strength and have similar or higher salts relative to conventional capsules. Separation delay effect.

The invention has been particularly illustrated and described with reference to the exemplary embodiments of the invention. It will be appreciated by those skilled in the art that various changes in form and detail of the invention can be made without departing from the scope of the invention as defined by the appended claims.

Claims (10)

A composition for enteric hard capsules comprising: 50 parts by weight to 90 parts by weight of hydroxypropylmethylcellulose phthalate (HPMCP); 10 parts by weight to 50 parts by weight of hydroxy group a propylmethylcellulose (HPMC); 0.1 part by weight to 2.5 parts by weight of a water-soluble divalent base; and 3.5 parts by weight to 7.5 parts by weight of an alkaline agent; wherein the HPMCP, the HPMC, the water-soluble divalent The amount of the base and the alkaline agent is based on 100 parts by weight of the total weight of the HPMCP and the HPMC. The composition for enteric hard capsules according to claim 1, wherein the HPMCP comprises 20% to 24% by weight of methoxy groups, 6% by weight to 10% by weight of hydroxypropoxy groups and 21 6% by weight to 26% by weight of phthalic acid, and the HPMCP has a dynamic viscosity of 48 centistokes (cSt) to 66 centistokes. The composition for enteric hard capsules according to claim 1, wherein the water-soluble divalent base comprises calcium hydroxide. The composition for enteric hard capsules according to claim 1, wherein the alkaline agent comprises at least one selected from the group consisting of ammonia, sodium hydroxide and potassium hydroxide. The composition for enteric hard capsules according to claim 1, further comprising 1 part by weight to 15 parts by weight of a plasticizer in an amount of 100 parts by weight based on the total weight of the HPMCP and the HPMC basis. For use in enteric hard capsules as described in claim 5 a composition, wherein the plasticizer comprises a group selected from the group consisting of hydrogenated corn syrup, triethyl citrate (TEC), triacetin (TA), polyethylene glycol (PEG), and propylene glycol (PG). At least one. The composition for enteric hard capsules according to claim 1, further comprising 0.05 parts by weight to 0.5 parts by weight of an emulsifier, the amount of which is based on 100 parts by weight of the total weight of the HPMCP and the HPMC. . The composition for enteric hard capsules according to claim 7, wherein the emulsifier comprises at least one selected from the group consisting of sodium lauryl sulfate (SLS) and glycolipid (SE). The composition for enteric hard capsules according to claim 1, further comprising water, wherein the amount of water (Ww) and the ratio of the HPMCP and the total amount of the HPMC (Wm) (Ww/Wm) It may range from 75 parts by weight to 85 parts by weight per 15 parts by weight to 25 parts by weight. An enteric hard capsule prepared by using the composition for enteric hard capsules as described in claim 1 of the patent application.