JP5820256B2 - Self-emulsifying formulation - Google Patents

Description

  The present invention relates to a hard capsule preparation having self-emulsifying ability.

  Self-emulsification is a phenomenon called natural emulsification, and refers to a phenomenon of natural emulsification by touching water or digestive fluid without requiring external force. Self-emulsifying preparations are known as preparations utilizing this phenomenon. By using this technique, it is said that a poorly water-soluble drug or the like is easily absorbed in a living body without emulsification with a bile acid. In general, physiologically active ingredients that are sparingly soluble in water are generally difficult to be absorbed even if taken orally. So far, with the aim of improving the absorbability of poorly soluble physiologically active ingredients, the physiologically active ingredients have been refined and poorly soluble physiologically by the addition of emulsifiers. Attempts have been made to improve the absorption of active ingredients.

In recent years, one or two or more emulsifiers and oils for dissolving them in the preparation of substances that have high physiological activity such as coenzyme Q10 but are difficult to be absorbed because they are poorly water-soluble substances So-called self-emulsifying preparations designed to naturally emulsify and disperse simply by contacting the digestive fluid in the stomach or intestine have been attracting attention. Such a preparation is easy to handle and suitable for ingestion when made into a capsule form made of gelatin or the like.
However, conventional self-emulsifying preparations use a large amount of emulsifier and increase the amount of liquid. This may cause gastrointestinal tract irritation. It has also been pointed out that some emulsifiers may damage hepatocytes in the liver after absorption. Furthermore, when the amount of the emulsifier used is large, relatively few physiologically active ingredients are dissolved in the oil contained in one capsule.
For example, Patent Document 1 discloses that decaglyceryl pentaoleate is used in an amount of 12.5 to 13.5 times that of coenzyme Q10 as an oily solvent (emulsifier), and diacylmonocapric acid is used as coenzyme Q10 as a stabilizer (co-surfactant). Examples of self-emulsifying soft capsules containing 0.4 to 1.6 times the amount of are disclosed. As a result, the self-emulsifying soft capsule needs 12.9 to 15.1 times as much emulsifier as Coenzyme Q10.

  On the other hand, in order to solve such problems, the present inventors have conducted intensive research. As a result, by using lysolecithin as an emulsifier and blending liquid polyhydric alcohol at a certain ratio, polyhydric alcohol and A soft capsule formulation was prepared and applied for a patent, in which an emulsified product containing a chain fatty acid triglyceride (MCT) as a main component was prepared, and coenzyme Q10, which is a poorly soluble representative example, was dispersed and dissolved in this emulsion. 2). According to this invention, the content of the emulsifier can be 0.5 to 3% by weight.

  However, since soft capsules have a thick capsule skin, the volume that can be filled is smaller than that of hard capsules, and in the case of drugs with a large dosage, It has the disadvantage that the number increases. In recent years, attempts have been made to fill a hard capsule with a self-emulsifying liquid. Patent Document 3 provides a hard capsule preparation that can maintain stable quality without causing capsule breakage even when a hard capsule made of hydroxypropylmethylcellulose (HPMC) is filled with a self-emulsifying preparation and made into a hard capsule preparation. It is disclosed that it can be done. However, this technique also requires the use of a large amount of emulsifier as described above. Moreover, the composition which reduced the emulsifier disclosed in Patent Document 2 to 0.5% to 3% could not be filled into a hard capsule because of its high viscosity even though it could be a soft capsule formulation. Until now, capsule preparations in which HPMC hard capsules are filled with a self-emulsifying solution having an emulsifier content of 5% or less have not been provided.

JP 62-0667019 A JP 2011-012003 A JP 2000-237284 A Japanese Patent Laid-Open No. 03-279325 JP 2007-289704 A JP 2006-296422 A JP 2003-238396 A

  An object of the present invention is to provide a hard HPMC capsule preparation in which the blending amount of the emulsifier is 3 to 0.5%, the self-emulsifying preparation is filled, and cracking and deformation do not occur.

The present invention is as follows.
(1) A hard capsule formulation comprising a hard hydroxypropylmethylcellulose (HPMC) capsule filled with an emulsified composition having self-emulsifying properties,
The self-emulsifying composition contains medium chain fatty acid triglyceride (MCT) (A) and glycerin or sorbitol (B), water (C), lysolecithin (D),
The weight ratio of water (C) and glycerol or sorbitol (B) (C / B) I 1/3 or less der,
Medium chain fatty acid triglyceride (MCT) is 55 wt% to 30 wt% ,
The content of glycerin or sorbitol is 30% by weight or more,
Containing only lysolecithin as an emulsifying agent, Ru der further lysolecithin 3 wt% or less hard capsule formulation.
(2) The hard capsule formulation according to (1) , wherein the medium-chain fatty acid triglyceride (MCT) in the self-emulsifiable composition contains poorly water-soluble physiologically active ingredients.
(3) The poorly water-soluble physiologically active ingredient is one or more substances selected from the group consisting of coenzyme Q10, vitamin D, vitamin E, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and saw palmetto extract (1 ) Or the hard capsule preparation according to (2) .

  Implementation of the present invention provides a hard capsule formulation filled with a self-emulsifying composition that quickly emulsifies and disperses when contacted with water or digestive fluid without using a large amount of an emulsifier, while having a high oil component ratio Is done. Since this preparation has a high oil component content, it can contain a large amount of oil-soluble components and is useful for treatment. Furthermore, the present preparation is stable without separation of the self-emulsifying composition and does not cause capsule breakage or deformation. In the preparation of the present invention, the self-emulsifying composition to be filled has a viscosity suitable for filling, and the production efficiency is improved. Furthermore, when the preparation of the present invention is brought into contact with water or digestive fluid, it is quickly emulsified and dispersed and quickly absorbed, and exhibits the intended therapeutic effect and nutritional effect.

  The present invention is a hard capsule preparation in which a hard capsule of HPMC film is filled with a self-emulsifying composition comprising a poorly water-soluble component, an oily component, a polyhydric alcohol, and an emulsifier. The HPMC capsule is prepared by adding a gelling agent such as color ginnan based on hydroxypropylmethylcellulose. A manufacturing method is described in Japanese Patent Application Laid-Open No. 03-279325, and is commercially available from Qualicaps Co., Ltd. and Capsugel Japan. The self-emulsifying composition filled in the capsule is not a conventional O / W type emulsification, but an O / D type emulsified composition called so-called D phase emulsification. That is, it is an O / D type emulsion composed of a target poorly water-soluble substance, an oil component (A), a polyhydric alcohol (B), an emulsifier (D), and water (C). The oily phase component (A) is 55% by weight or less, the polyhydric alcohol (B) is 30% by weight or more, the emulsifier (D) is 3% by weight or less, and the polyhydric alcohol (1) part by weight of water (C) ( It can achieve by mix | blending so that the content ratio of B) may become larger than three.

Oil component (A)
That is, the oil component includes animal and vegetable oils such as soybean oil, rapeseed oil, cottonseed oil, sunflower oil, safflower oil, palm oil, wheat germ oil, corn germ oil, olive oil, rice bran oil, liver oil, fish oil, whale oil, medium chain Fatty acid triglyceride (MCT) etc. are mentioned. In particular, MCT is preferable. These oil phase components may be used alone or in combination of two or more. When the polyhydric alcohol content is 30% by weight or less and the emulsifier is 3% by weight or less, if the oil component exceeds 55% by weight, it is difficult to achieve O / D type emulsification. When the oil component is 30% by weight or less, the amount of the poorly water-soluble substance is reduced. The total amount of the oil component can be appropriately selected depending on the solubility of the target poorly water-soluble component in oil or the blending amount of the poorly water-soluble component. In carrying out the present invention, it can be achieved even with a minimum amount of D-phase emulsification. For example, in Example 12 of the present invention, the oily component amount could be set to 3.83%. In the present invention, the weight of the oil component (A) is defined as the amount of the oil listed above combined with the following poorly water-soluble component.
Examples of fat-soluble substances that are poorly water-soluble and soluble in these animal and plant oils include coenzyme Q10, reduced coenzyme Q10, lipoic acid, α, β-, γ-δ-tocopherol, α, β -, Γ-δ-tocotrienol, vitamin K, α, β-, γ-δ-carotene, lycopene, lutein, zeaxanthin, astaxanthin, vitamin D, vitamin A, vitamin P, DHA, EPA, squalane, saw palmetto extract, plant sterol Etc. The fat-soluble substance that dissolves in these animal and vegetable oils can be appropriately added depending on the purpose of the preparation within a range in which the fat-soluble substance is dissolved.

Polyhydric alcohol (B)
Glycerol is suitable as the polyhydric alcohol, and concentrated glycerin is particularly desirable. In general, concentrated glycerin refers to those meeting the standard (polyhydric alcohol content 98.0 to 101.0%) listed in the Japanese Pharmacopoeia, but the standard (glycerin content 95. (0% or more) may be used. Also, sorbitol can be used instead of glycerin, or glycerin and sorbitol may be used in combination. Alternatively, a maltose or dextrin reduced product called sugar alcohol can be used. Although the compounding quantity of a polyhydric alcohol is 30 to 50 weight% as a preferable aspect, the compounding quantity of the target poorly water-soluble component can determine a compounding upper limit corresponding to the amount of oily components. In the examples of the present invention, it has been confirmed that even when the polyhydric alcohol is 85% by weight, a hard capsule containing the desired self-emulsifying composition can be obtained.

Emulsifier (D)
The amount of the emulsifier is preferably 3% by weight or less in terms of dry weight (excluding the amount of water). If it exceeds 3% by weight, the amount of the target poorly water-soluble substance must be relatively reduced, and discomfort caused by the emulsifier and stomach discomfort when ingested for a long period of time occur. If it is less than 0.5%, the self-emulsifying property is low, and the oil component is separated from the polyhydric alcohol. Also, care should be taken because the viscosity of the self-emulsifying composition may increase and the hard HPMC capsule may not be filled. As the emulsifier, lysolecithin is preferable in terms of product design, more preferably, the concentration of lysophosphatidylcholine contained in the raw material is at least 18% or more, and particularly preferably the concentration of lysophosphatidylcholine is 65% or more. Good thing.

Moisture (C)
In the present invention, it is important to control the amount of moisture in the preparation having self-emulsifying ability in order to prevent cracking and deformation of the hard capsule. In order to maintain the emulsifying ability and ensure the stabilization of the capsule, it is important that the weight ratio of water to polyhydric alcohol is 1/3 or less. If this amount is exceeded and the amount of water increases, the hard capsule will crack or deform.

Other components In the composition having self-emulsifying properties, glycine, betaine, sodium acetate, ethanol or ethanol or a viscosity modifier, if necessary, animal or vegetable wax (dispersant), silicon dioxide, starch or starch Derivatives and the like can be blended. In addition, since it contains polyhydric alcohol, water-soluble active ingredients such as water-soluble vitamins and minerals can be blended.

Method for Producing Self-Emulsifying Composition The self-emulsifying composition of the present invention is prepared using a technique called so-called D-phase emulsification. In the D phase emulsification method, instead of generating the D phase (surfactant phase), the HLB of the nonionic surfactant is adjusted by adding a water-soluble polyhydric alcohol to form the D phase, and the oil phase is added to this. Disperse to obtain a fine emulsion (O / D). A self-emulsifying preparation is obtained by filling this emulsion into a hard capsule made of HPMC. In this preparation, the capsule dissolves in the stomach or intestine and instantly becomes an O / W emulsion.
The O / D emulsion composition is in a pre-emulsified state that produces an O / W emulsion just by touching water. Therefore, by filling this into a capsule made of HPMC, a hard capsule preparation filled with the desired composition having the self-emulsifying property of the present invention can be obtained. The filling can be performed using an apparatus for filling a hard capsule with a liquid, for example, a filling apparatus provided by Capsugel Japan. The amount of liquid to be filled and the capacity of the capsule can be variously selected according to the purpose.

EXAMPLES Next, although an Example and a comparative example demonstrate this invention further in detail, this invention is not limited at all by these examples.
Examples Comparative Example 1 Self-emulsifying preparations having the compositions shown in Tables 1 to 6 were prepared. The preparation method is as follows. (1) Medium chain fatty acid triglyceride (MCT oil, product name: Coconard RK Kao Co., Ltd.) as an oil component, and Coenzyme Q10 (CoQ10) as a poorly water soluble component are weighed in a beaker, Disperser (Shinto Kagaku Co., Ltd.) The mixture was stirred and mixed under heating at 60 ° C. to dissolve completely.
(2) Emulsifier or lysolecithin (SLP-LPC70 Sakai Oil Co., Ltd.), glycerin (food additive glycerin: Kao Corporation) or sorbitol syrup (Sorbit L-70 Mitsubishi Corporation Foodtech Co., Ltd.), water is weighed into a stainless steel mug. Then, it was stirred with a disperser.
(3) While performing the operation of (2), the solution of (1) was slowly added into (2) little by little. (It was carried out while confirming that no solution separation occurred during the injection. The rotational speed was adjusted between 300 rpm and 1000 rpm as necessary.)
(4) The solution obtained in (3) was emulsified with a homomixer (manufactured by PRIMIX Corporation). The treatment was performed at 10,000 rpm for 10 minutes.
(5) The obtained solution was subjected to specific gravity measurement, viscosity measurement, and particle size distribution measurement by dynamic light scattering to confirm that it had a uniform and constant physical property. (The specific gravity was obtained by collecting the solution in a 1 mL thermosyringe and measuring the weight of the solution per mL.)

2. Each solution was then filled into hard capsules.
The solution was filled into No. 2 size HPMC hard capsules (trade name: Vcaps plus Capsugel Japan Co., Ltd.) using a liquid-filled hard capsule manufacturing machine. In addition, filling suitability was evaluated.

3. Storage Stability Test Each of the capsules obtained in 2 above was sealed and packaged with 1 g of a desiccant in an aluminum vapor-deposited bag, and allowed to stand in an environment of 40 ° C. and a relative humidity of 75% for 1 week, and changes were observed.

4). Determination After completion of the storage stability test, the aluminum vapor deposition bag was opened, and the state of the capsule was visually evaluated. Those with good filling suitability and no abnormalities in 20 capsules were evaluated as “Good”, and those in which at least one abnormality occurred were evaluated as “X”, and abnormalities were commented. Moreover, about the example with no abnormality in appearance, one capsule was put in 50 ml water, and the solubility and self-emulsification state of the capsule were evaluated. If even a single capsule had delayed solubility, abnormal self-emulsification, or a change in viscosity, it was judged as x. Tables 7 and 8 show the determination results of each example and comparative example.

As shown in Tables 7 and 8 above, all of the examples of the present invention were good self-emulsifying preparations without the occurrence of deformation and cracking of the hard HPMC capsules and abnormal appearance. On the other hand, deformation and emulsification abnormality occurred in the preparation of the comparative example. In addition, emulsions that were difficult to fill were also generated, and some of them hindered the preparation of capsule formulations. In particular, the case where the content ratio of water and polyhydric alcohol was 1/3 or less was preferable. When the content of the polyhydric alcohol was 30% by weight or more and the total amount of the oil component was 55% by weight or less, the viscosity of the composition to be filled was an appropriate viscosity for filling the capsule.
In addition, the hard capsules of the examples rapidly dissolved in water, the contents were dispersed, and appropriate self-emulsifying properties were exhibited.

Example 14
Self-emulsifying formulations were prepared with the compositions in Table 9.

(1) Weighed medium-chain fatty acid triglyceride (MCT oil, product name: Coconard RK Kao Co., Ltd.) as an oil component, and vitamin D3 (Wako Pure Chemical Industries, Ltd.) as a poorly water-soluble component in a beaker. The product was stirred and mixed under heating at 60 ° C. to completely dissolve the product.
(2) Emulsifier or lysolecithin (SLP-LPC70 Sakai Oil Co., Ltd.), glycerin (food additive glycerin: Kao Corporation) or sorbitol syrup (Sorbit L-70 Mitsubishi Corporation Foodtech Co., Ltd.), water is weighed into a stainless steel mug. Then, it was stirred with a disperser.
(3) While performing the operation of (2), the solution of (1) was slowly added into (2) little by little. (It was carried out while confirming that no solution separation occurred during the injection. The rotational speed was adjusted between 300 rpm and 1000 rpm as necessary.)
(4) The solution obtained in (3) was emulsified with a homomixer (manufactured by PRIMIX Corporation). The treatment was performed at 10,000 rpm for 10 minutes.
(5) The obtained solution was subjected to specific gravity measurement, viscosity measurement, and particle size distribution measurement by dynamic light scattering to confirm that it had a uniform and constant physical property. (The specific gravity was obtained by collecting the solution in a 1 mL thermosyringe and measuring the weight of the solution per mL.)

The solution was then filled into hard capsules as in Example 1.
The solution was filled into No. 2 size HPMC hard capsules (trade name: Vcaps plus Capsugel Japan Co., Ltd.) using a liquid-filled hard capsule manufacturing machine. In addition, filling suitability was evaluated.
Each of the obtained capsules was sealed and packaged in an aluminum vapor deposition bag together with 1 g of a desiccant, and left to stand in an environment of 40 ° C. and a relative humidity of 75% for 1 week, and the change was observed. No abnormalities were observed.
After the storage stability test, the aluminum vapor deposition bag was opened, and the state of the capsule was visually evaluated. Fillability was good and no abnormality was observed in 20 capsules. Moreover, about the example with no abnormality in appearance, one capsule was put in 50 ml water, and the solubility and self-emulsification state of the capsule were evaluated. No abnormalities were observed.

Example 15
Self-emulsifying formulations were prepared with the compositions in Table 10.

(1) EPA / DHA-containing fish oil (trade name: EPA-28, manufactured by Maruha Co., Ltd.) containing EPA and DHA as poorly water-soluble components is used as an oil component, and mixed tocopherol (trade name Emix-) is used as a poorly water-soluble component. 50L Tama Seikagaku Co., Ltd.) was weighed into a beaker and stirred and mixed using a disperser (manufactured by Shinto Kagaku Co., Ltd.) at 60 ° C. for complete dissolution.
(2) Emulsifier or lysolecithin (SLP-LPC70 Sakai Oil Co., Ltd.), glycerin (food additive glycerin: Kao Corporation) or sorbitol syrup (Sorbit L-70 Mitsubishi Corporation Foodtech Co., Ltd.), water is weighed into a stainless steel mug. Then, it was stirred with a disperser.
(3) While performing the operation of (2), the solution of (1) was slowly added into (2) little by little. (It was carried out while confirming that no solution separation occurred during the injection. The rotational speed was adjusted between 300 rpm and 1000 rpm as necessary.)
(4) The solution obtained in (3) was emulsified with a homomixer (manufactured by PRIMIX Corporation). The treatment was performed at 10,000 rpm for 10 minutes.
(5) The obtained solution was subjected to specific gravity measurement, viscosity measurement, and particle size distribution measurement by dynamic light scattering to confirm that it had a uniform and constant physical property. (The specific gravity was obtained by collecting the solution in a 1 mL thermosyringe and measuring the weight of the solution per mL.)

The solution was then filled into hard capsules as in Example 1.
The solution was filled into No. 2 size HPMC hard capsules (trade name: Vcaps plus Capsugel Japan Co., Ltd.) using a liquid-filled hard capsule manufacturing machine. In addition, filling suitability was evaluated.
Each of the obtained capsules was sealed and packaged in an aluminum vapor deposition bag together with 1 g of a desiccant, and left to stand in an environment of 40 ° C. and a relative humidity of 75% for 1 week, and the change was observed. No abnormalities were observed.
After the storage stability test, the aluminum vapor deposition bag was opened, and the state of the capsule was visually evaluated. Fillability was good and no abnormality was observed in 20 capsules. Moreover, about the example with no abnormality in appearance, one capsule was put in 50 ml water, and the solubility and self-emulsification state of the capsule were evaluated. No abnormalities were observed.

Example 15
Self-emulsifying formulations were prepared with the compositions in Table 11.

(1) Rice oil containing γ-oryzanol as a poorly water-soluble component (manufactured by Oriza Oil Chemical Co., Ltd.) is used as an oil component, and vitamin E (trade name: RIKEN E Oil 710, RIKEN Vitamin Co.) is used as a beaker The sample was weighed and stirred and mixed using a disperser (manufactured by Shinto Kagaku Co., Ltd.) at 60 ° C. for complete dissolution.
(2) Emulsifier or lysolecithin (SLP-LPC70 Sakai Oil Co., Ltd.), glycerin (food additive glycerin: Kao Corporation) or sorbitol syrup (Sorbit L-70 Mitsubishi Corporation Foodtech Co., Ltd.), water is weighed into a stainless steel mug. Then, it was stirred with a disperser.
(3) While performing the operation of (2), the solution of (1) was slowly added into (2) little by little. (It was carried out while confirming that no solution separation occurred during the injection. The rotational speed was adjusted between 300 rpm and 1000 rpm as necessary.)
(4) The solution obtained in (3) was emulsified with a homomixer (manufactured by PRIMIX Corporation). The treatment was performed at 10,000 rpm for 10 minutes.
(5) The obtained solution was subjected to specific gravity measurement, viscosity measurement, and particle size distribution measurement by dynamic light scattering to confirm that it had a uniform and constant physical property. (The specific gravity was obtained by collecting the solution in a 1 mL thermosyringe and measuring the weight of the solution per mL.)

The solution was then filled into hard capsules as in Example 1.
The solution was filled into No. 2 size HPMC hard capsules (trade name: Vcaps plus Capsugel Japan Co., Ltd.) using a liquid-filled hard capsule manufacturing machine. In addition, filling suitability was evaluated.
Each of the obtained capsules was sealed and packaged in an aluminum vapor deposition bag together with 1 g of a desiccant, and left to stand in an environment of 40 ° C. and a relative humidity of 75% for 1 week, and the change was observed. No abnormalities were observed.

Example 16
Self-emulsifying formulations were prepared with the compositions in Table 12.

(1) Oil containing a saw palmetto fruit extract as a poorly water-soluble component (trade name: Selenoa Seisei Extract, manufactured by Indena Japan Co., Ltd.) is used as an oil component, and this is stirred and mixed under heating at 60 ° C. Dissolved in.
(2) Emulsifier or lysolecithin (SLP-LPC70 Sakai Oil Co., Ltd.), glycerin (food additive glycerin: Kao Corporation) or sorbitol syrup (Sorbit L-70 Mitsubishi Corporation Foodtech Co., Ltd.), water is weighed into a stainless steel mug. Then, it was stirred with a disperser.
(3) While performing the operation of (2), the solution of (1) was slowly added into (2) little by little. (It was carried out while confirming that no solution separation occurred during the injection. The rotational speed was adjusted between 300 rpm and 1000 rpm as necessary.)
(4) The solution obtained in (3) was emulsified with a homomixer (manufactured by PRIMIX Corporation). The treatment was performed at 10,000 rpm for 10 minutes.
(5) The obtained solution was subjected to specific gravity measurement, viscosity measurement, and particle size distribution measurement by dynamic light scattering to confirm that it had a uniform and constant physical property. (The specific gravity was obtained by collecting the solution in a 1 mL thermosyringe and measuring the weight of the solution per mL.)

The solution was then filled into hard capsules as in Example 1.
The solution was filled into No. 2 size HPMC hard capsules (trade name: Vcaps plus Capsugel Japan Co., Ltd.) using a liquid-filled hard capsule manufacturing machine. In addition, filling suitability was evaluated.
Each of the obtained capsules was sealed and packaged in an aluminum vapor deposition bag together with 1 g of a desiccant, and left to stand in an environment of 40 ° C. and a relative humidity of 75% for 1 week, and the change was observed. No abnormalities were observed.

Claims (3)

A hard capsule formulation comprising a hard hydroxypropyl methylcellulose (HPMC) capsule filled with an emulsified composition having self-emulsifying properties,
The self-emulsifying composition contains medium chain fatty acid triglyceride (MCT) (A) and glycerin or sorbitol (B), water (C), lysolecithin (D),
The weight ratio of water (C) and glycerol or sorbitol (B) (C / B) I 1/3 or less der,
Medium chain fatty acid triglyceride (MCT) is 55 wt% to 30 wt% ,
The content of glycerin or sorbitol is 30% by weight or more,
Containing only lysolecithin as an emulsifying agent, Ru der further lysolecithin 3 wt% or less hard capsule formulation. The hard capsule preparation according to claim 1 , wherein hardly water-soluble physiologically active ingredients are contained in the medium-chain fatty acid triglyceride (MCT) in the self-emulsifying composition. Physiologically active ingredients are coenzyme Q10 of poorly water-soluble, vitamin D, vitamin E, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), according to claim 1 or 2 is one or more materials selected from the group consisting of saw palmetto extract Hard capsule formulation as described in 2.