JP6949670B2 - A composition for oral ingestion containing a poorly soluble substance, a method for improving the gastrointestinal absorption of the poorly soluble substance, and a method for stabilizing the emulsion of an oil-in-water emulsion containing a poorly soluble substance in the stomach. - Google Patents

Description

The present invention relates to a composition for oral ingestion containing a poorly soluble substance, a method for improving the gastrointestinal absorption of the poorly soluble substance, and a method for improving the emulsion stability of an oil-in-water emulsion containing a poorly soluble substance in the stomach. ..

Many of the components administered in the form of foods and pharmaceuticals as useful components for the human body are poorly soluble substances having low solubility in water. These substances have extremely low gastrointestinal absorption when taken orally, and even if the dose is increased, sufficient plasma concentration cannot be obtained, and the fluctuation of absorption between individuals becomes large, which causes problems in formulation. Often accompanied.
The poorly soluble substance can improve gastrointestinal absorption by solubilizing it. Emulsification is one of the methods for solubilizing poorly soluble substances.

Various surfactants are used for emulsification. Non-Patent Document 1 describes that a highly absorbent emulsion can be obtained when a highly hydrophilic surfactant such as Tween 20 or Tween 80 is used.
However, since synthetic surfactants such as Tween 20 have poor biocompatibility, it is preferable to avoid using them in applications involving administration to the human body, as they may cause serious side effects after administration. In addition, it is difficult to obtain an emulsion having an average particle size of nano (nm) scale, and the compounding raw materials deteriorate during the treatment, resulting in high cost in terms of time and price in terms of industrial production. There is a problem.

OTC drug self-medication promotion foundation 2011 research report "Search for factors that determine whether or not oral absorption can be improved by emulsification of poorly water-soluble drugs"

One of the surfactants is phospholipid. Phospholipids have high biocompatibility and have been used in fat emulsions, liposome preparations and the like. However, the fat emulsion is obtained by dissolving an oil-soluble substance in an oil phase and emulsifying it, and the poorly soluble substance cannot be solubilized. In addition, although liposomal preparations can solubilize sparingly soluble substances, they are difficult to handle due to restrictions on storage conditions and the like. In addition, according to the study of the present inventor, even if an emulsion having a nanoscale average emulsified particle size is prepared using phospholipids and ingested orally, the gastrointestinal absorption of the poorly soluble substance in the emulsion does not unexpectedly improve. I understood.

An object of the present invention is a composition for oral ingestion containing a poorly soluble substance, a method for improving the gastrointestinal absorption of the poorly soluble substance, and an improvement in the emulsion stability of an oil-in-water emulsion containing the poorly soluble substance in the stomach. It provides a method.

The present inventor has made extensive studies to achieve the above object.
As a result, it contains fats and oils, polyhydric alcohols and lysophospholipids.
By containing a sparingly soluble substance in a composition in which the content of lysophospholipid with respect to the total amount of emulsifier and the amount of fatty acid with respect to lysophospholipid are within a specific range.
After oral ingestion, contact with the digestive juice in the digestive tract produces nanoscale oil-in-water emulsion, which improves the gastrointestinal absorption of sparingly soluble substances and the stomach of oil-in-water emulsion containing sparingly soluble substances. We have found that it is possible to improve the emulsion stability within the body, and have completed the present invention.

That is, the present invention
(1) A composition for oral ingestion containing a poorly soluble substance.
Contains fats and oils, polyhydric alcohols and emulsifiers,
The lysophospholipid content with respect to the total amount of emulsifier is 15% or more,
Contains 0.01 part or more and 5 parts or less (mass ratio) of fatty acid with respect to 1 part of lysophospholipid.
Composition for oral ingestion,
(2) In the composition for oral ingestion of (1)
The average particle size (volume equivalent) of the oil-in-water emulsion obtained when the composition and the artificial gastric juice are mixed at a mass ratio of 1: 100 is 1.0 μm or less.
Composition for oral ingestion,
(3) In the composition for oral ingestion according to (1) or (2).
More than 80% of the constituent fatty acids of the lysophospholipid are saturated.
Composition for oral ingestion,
(4) In the composition for oral ingestion according to any one of (1) to (3).
The lysophospholipid content with respect to the total amount of the composition is 1% or more.
Composition for oral ingestion,
(5) In the composition for oral ingestion according to any one of (1) to (4).
The lysophospholipid is contained in 0.001 part or more and 2 parts or less (mass ratio) with respect to 1 part of the fat and oil.
Composition for oral ingestion,
(6) In the composition for oral ingestion according to any one of (1) to (5).
The content of lysophosphatidylcholine with respect to the lysophosphatid lipid is 50% or more.
Composition for oral ingestion,
(7) In the composition for oral ingestion according to any one of (1) to (6).
The lysophospholipid is derived from egg yolk,
Composition for oral ingestion,
(8) In the composition for oral ingestion according to any one of (1) to (7).
The polyhydric alcohol contains at least one of glycerin and polyethylene glycol.
Composition for oral ingestion,
(9) A method for improving the gastrointestinal absorption of poorly soluble substances.
Contains sparingly soluble substances, fats and oils, polyhydric alcohols and emulsifiers,
The lysophospholipid content with respect to the total amount of emulsifier is 15% or more,
Orally ingest a composition containing 0.01 part or more and 5 parts or less (mass ratio) of fatty acid with respect to 1 part of lysophospholipid.
How to improve gastrointestinal absorption of sparingly soluble substances,
(10) In the method of (9)
The average particle size (volume equivalent) of the oil-in-water emulsion obtained when the composition and the artificial gastric juice are mixed at a mass ratio of 1: 100 is 1.0 μm or less.
How to improve gastrointestinal absorption of sparingly soluble substances,
(11) In the method of (9) or (10)
Disperse the poorly soluble substance in fats and oils and use it for the preparation of the composition.
How to improve gastrointestinal absorption of sparingly soluble substances,
(12) A method for stabilizing the emulsification of an oil-in-water emulsion containing a poorly soluble substance in the stomach.
Contains sparingly soluble substances, fats and oils, polyhydric alcohols and emulsifiers,
The lysophospholipid content with respect to the total amount of emulsifier is 15% or more,
Orally ingest a composition containing 0.01 part or more and 5 parts or less (mass ratio) of fatty acid with respect to 1 part of lysophospholipid.
Preparing oil-in-water emulsion in the body,
A method for stabilizing the emulsion of an oil-in-water emulsion containing a sparingly soluble substance in the stomach,
(13) In the method of (12)
The average particle size (volume equivalent) of the oil-in-water emulsion obtained when the composition and the artificial gastric juice are mixed at a mass ratio of 1: 100 is 1.0 μm or less.
A method for stabilizing the emulsion of an oil-in-water emulsion containing a sparingly soluble substance in the stomach,
Is.

According to the present invention, an oil-in-water emulsion containing only a highly safe raw material for the human body, improving the gastrointestinal absorption of a poorly soluble substance and containing a poorly soluble substance in the stomach by a simple operation. Emulsification stability can be improved.

Hereinafter, the present invention will be described in detail.
In the present invention, "%" means "% by mass" and "parts" means "parts by mass".

<Composition for oral ingestion>
The composition for oral ingestion of the present invention contains a sparingly soluble substance, fats and oils, polyhydric alcohol and an emulsifier, and has a lysophospholipid content with respect to the total amount of the emulsifier and the content ratio of the lysophospholipid and the fatty acid within a specific range. .. By orally ingesting the composition for oral ingestion of the present invention, it is possible to improve the gastrointestinal absorption of the poorly soluble substance contained in the composition.
The composition for oral ingestion of the present invention is not particularly limited as long as it takes a form suitable for oral ingestion. Specifically, the composition itself may be used, and the composition itself may be filled into capsules such as hard capsules and gelatin capsules for oral ingestion. You may.

When the composition for oral ingestion of the present invention is orally ingested, it comes into contact with the digestive juice in the digestive tract to produce a nanoscale oil-in-water emulsion.
The digestive juice can be regarded as a kind of aqueous solution, but the property of producing an emulsion in which fats and oils are finely divided by contact with fresh water or an aqueous solution is called self-emulsification, and both the aqueous phase and the oil phase are continuous phases. It is characteristically found in systems in which infinite aggregates in which molecules are infinitely associated are formed, such as both continuous emulsions.
The details of the structure of the composition for oral ingestion of the present invention are not clear, but since the emulsion is produced by contact with the digestive juice, the infinite aggregate is locally formed in the whole composition or in the composition. It is presumed that the system is formed or has a similar state.

<Slightly soluble substance>
The poorly soluble substance means a substance having low solubility in water, and specifically, the solubility in the 16th revised Japanese Pharmacy Law is "slightly insoluble" (the amount of solvent required to dissolve 1 g or 1 mL of solute is 30 mL or more and less than 100 mL), "difficult to dissolve" (same solvent amount is 100 mL or more and less than 1000 mL), "extremely difficult to dissolve" (same solvent amount is 1000 mL or more and less than 10000 mL) or "almost insoluble" (same solvent amount is 10000 mL or more) Means a substance that is. In the present invention, insoluble substances are also included in the poorly soluble substances.
The composition for oral ingestion of the present invention effectively improves the absorbability of a substance that is difficult to dissolve in water and has low absorption in the body. Therefore, among the above, it is suitable to use a substance that is "extremely insoluble", a substance that is "almost insoluble", and an insoluble substance.

Examples of the poorly soluble substances include fat-soluble vitamins (eg, vitamin A, vitamin D, vitamin E, vitamin K, etc.) and carotenoids (eg, lycopene, chlorophyll, lutein, zeaxanthin, astaxanthin, fucoxanthin, etc.). , Polyphenols (eg flavonols, flavanones, flavones, isoflavones, phenolcarboxylic acids, anthocyanidins, stilbens, hydroxysilic acid derivatives, ellagic acid, etc.), coenzyme Q10, lipoic acid, prostaglandin, docetaxel , Paclitaxel, capecitabine, oxaliplatin, geftinat, doxorubicin, irinotecan, gemcitabine, pemetrexed, temozolomid, imatinib, vinorelbine, retrozol, teniposide, etopocid, podophylrotoxin, camptothecin, 10-hydroxycamptothecin, 10-hydroxycamptothecin Ethyl-10-hydroxycamptothecin, topotecan, irinotecan, vinbrastin, vincristin, bindesin, vinorelbine, vinposetin, norcantarisine, siribin, propofol, florphenicol, mitiglinide, artemicinin, dihydroartemicinin, sirolimus, ibuprinidipine, dihydroartemicinin, sylolimus , Propulsid, ferrodipine, glibenclamid, acyclovir, oleanolic acid, breviscapine, ferulic acid, paracetamol, palmitoyl lysoxin, penchromedin, tamoxyphene, navelbine, valproic acid, tachlorimus, cyclosporin A, amptothecin B, ketoconazole, donperidone, sulpylido Bezafibrato, azithromycin, itraconazole, myconazole, brimonidine, ratanoprost, cyribine, erythromycin, loxythromycin, rifaximin, cisapride, cyclosporin, diclophenac acid, ferropicin, ibprofen, indomethacin, acemetathin, nicardipine , Dipyridamole, pyroxicum, mephenamic acid, trichlorothiazide, pindolol and the like.
As the poorly soluble substance, one type may be used alone, or two or more types may be used in combination.

<Content of poorly soluble substance>
The content of the poorly soluble substance contained in the composition for oral intake of the present invention is not particularly limited, and a desired amount may be contained depending on the purpose and use thereof. The amount is preferably such that precipitation does not occur during the production of the composition for oral ingestion.

<Fat and oil>
In the present invention, the fats and oils may be triglycerides, diglycerides, fatty acid derivatives and fatty acid esters as long as they are suitable for oral ingestion.
Specifically, for example, soybean oil, rapeseed oil, sunflower oil, saflower oil, palm oil, corn oil, cottonseed oil, rice oil, perilla oil, egoma oil, olive oil, almond oil, coconut oil, flaxseed oil, grape seed oil. , Oils and fats obtained by algae and microbial culture, animal and vegetable oils such as egg yolk oil, fish oil, whale oil, liver oil or refined oils thereof (salad oil), MCT (medium chain fatty acid triglyceride), diglyceride and other chemical or enzymatic treatments. Oils and fats obtained by applying , Eikosapentaenoic acid (EPA), docosahexaenoic acid (DHA), henicosapentaenoic acid (HPA) docosapentaenoic acid (DPA), eikosatetraenoic acid (ETA), eikosatrienic acid (ETE), stearidonic acid (STA) Such as fatty acid esters such as ethyl esters of saturated and unsaturated fatty acids such as. These fats and oils may be used alone or in combination of two or more.
In the present invention, the monoglycerin fatty acid ester is not included in the fats and oils of the present invention.

<Content of fats and oils>
The content of fats and oils in the composition for oral ingestion of the present invention is not particularly limited, but the composition is composed from the viewpoint of maintaining the average particle size of the emulsion produced in the digestive tract after oral ingestion of the composition. It is preferable that it is 50% or more and 95% or less, and further 60% or more and 90% or less with respect to the total amount of the substance.

<Multivalent alcohol>
A polyhydric alcohol is an alcohol having two or more hydroxyl groups in the molecule. The polyhydric alcohol used in the present invention is not particularly limited as long as it is edible, and for example, glycerin, propylene glycol (PG), polyethylene glycol (PEG), xylitol, maltitol, pentaerythritol, sorbitol, trehalose, etc. Reduced water candy and the like can be mentioned. Among these, glycerin, propylene glycol, polyethylene glycol, and reduced water candy are preferably used from the viewpoint of producing emulsion in contact with digestive juice and maintaining stable emulsion generated in the digestive tract. It is better to use polyethylene glycol, and even better to use glycerin.
When using glycerin, concentrated glycerin that meets the standards listed in the Japanese Pharmacopoeia (glycerin content 98.0 to 101.0%) is preferable, but the standards specified in the official food additive standard (glycerin content) Those (95.0% or more) can also be used without any problem.
These polyhydric alcohols may be used alone or in combination of two or more.

<Content of polyhydric alcohol>
The content of the polyhydric alcohol in the composition for oral ingestion of the present invention is not particularly limited, but from the viewpoint of producing a nanoscale oil-in-water emulsion in contact with digestive juice, the total amount of the composition is adjusted. On the other hand, it is preferably 5% or more and 60% or less, more preferably 10% or more and 55% or less, and further preferably 15% or more and 50% or less.

<Emulsifier>
The emulsifier is not particularly limited as long as it is edible, and for example, phospholipid, lysophospholipid, cholesterol, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, palmitooleic acid, oleic acid, and erucic acid. , Linoleic acid, α-linolenic acid, γ-linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DHA), henicosapentaenoic acid (HPA) docosapentaenoic acid (DPA), eicosapentaenoic acid ( Examples include synthetic emulsifiers such as saturated and unsaturated fatty acids such as ETA), eicosapentaenoic acid (ETE) and stearidonic acid (STA), monoglycerin fatty acid esters, polyglycerin fatty acid esters and sucrose fatty acid esters.
The composition for oral ingestion of the present invention produces an emulsion in the digestive tract, and the pH of the digestive juice secreted into the digestive tract differs depending on the digestive organs. It is preferable to use phospholipids or fatty acids having high biocompatibility.

<Resoline lipid>
The emulsifier of the present invention contains a lysophospholipid. The lysophospholipid maintains the state of the composition that produces a nanoscale oil-in-water emulsion in the gastrointestinal tract, and further produces a nanoscale oil-in-water emulsion produced in contact with the digestive juice in the gastrointestinal tract after ingestion. It is essential for stable production and maintenance in the stomach.
The lysophospholipid used in the present invention is a monoacylglycerophospholipid. In general, lysophospholipid is one fatty acid of phospholipid obtained by treating phospholipid, which is a diacylglycerophospholipid extracted from egg yolk of poultry eggs such as chicken, quail and duck, and animals and plants such as soybean and rapeseed, with phosphoripase A. Is a cut phospholipid.
In addition, animal and plant raw materials such as egg yolk and rapeseed are directly enzymatically treated with phospholipase A, and then extracted by a conventional method, obtained by a synthetic method, or lysoline obtained as needed. It also includes those obtained by hydrogenating lipids.
Depending on the structure of the phosphate ester, the lysophospholipid used in the present invention may be, for example, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylinositol (LPI), lysophosphatidic acid (LPA), lysophosphatidylserine (LPS). ) Etc. can be mentioned. In the present invention, these lysophospholipids may be used alone or in combination of two or more.
The lysophospholipid added to the composition for oral intake of the present invention does not include lysophospholipid existing as a lipoprotein which is a complex with a protein such as phosphoripase A-treated egg yolk.

The composition for oral ingestion of the present invention produces nanoscale oil-in-water emulsion upon contact with the digestive juice in the digestive tract, but the pH of the digestive juice depends on the site where the digestive juice is secreted, for example. , Saliva has a pH of about 6 to 7, gastric juice has a pH of about 1 to 3, and bile and intestinal juice have a pH of about 8. From the viewpoint of improving the gastrointestinal absorption of poorly soluble substances, the emulsion generated in the digestive tract needs to maintain a stable emulsified state regardless of contact with any digestive juice having a significantly different pH.
In general, when the pH is low, emulsification is likely to occur, so maintaining an emulsified state in the stomach that comes into contact with strongly acidic gastric juice is one index, but lysophospholipids are relatively stable even under strongly acidic conditions. The emulsified state can be maintained.

<Types of constituent fatty acids of lysophospholipids>
The constituent fatty acids of phospholipids extracted from animal and plant raw materials are saturated and unsaturated.
The constituent fatty acids of the lysophospholipid used in the present invention may be either saturated or unsaturated, but they are maintained in the state of a composition that produces nanoscale oil-in-water emulsion in the digestive tract, and are further digested after oral ingestion. In order to stably produce and maintain nanoscale oil-in-water emulsion produced in contact with digestive juice in a tube, it is preferable that 80% or more of the constituent fatty acids are saturated.
Typical lysophospholipids in which 80% or more of the constituent fatty acids are saturated are egg yolk-derived lysophospholipids. However, it is preferable to use an egg yolk-derived lysophospholipid that can easily maintain an emulsified state relatively stably even under strong acidity.

<Content of lysophospholipid in emulsifier>
Maintains the state of the composition that produces a nanoscale oil-in-water emulsion in the gastrointestinal tract, and when it comes into contact with the digestive juice in the gastrointestinal tract, it produces a nanoscale oil-in-water emulsion and digests sparingly soluble substances. From the viewpoint of improving tube absorbability and emulsion stability of oil-in-water emulsion in the stomach, the content of lysophospholipid in the emulsifier is 15% or more, preferably 20% or more, and 25% of the total amount of the emulsifier. That is all right.
If the lysophospholipid content is below the above range, it is not possible to produce the state of the composition for oral ingestion of the present invention that produces a nanoscale oil-in-water emulsion in the gastrointestinal tract.
The upper limit of the lysophospholipid content is not particularly limited, but from the viewpoint of industrial productivity and cost, 95% or less is preferable, and 80% or less is more preferable.

<Fatty acid>
The composition for oral ingestion of the present invention contains fatty acids. Most of the fatty acids derived from animals and plants have 10 or more and 24 or less carbon atoms, and it is preferable to use those having the same carbon number in the present invention.

<Fatty acid content with respect to lysophospholipids>
The fatty acid content maintains the state of the composition for oral ingestion of the present invention that produces nanoscale oil-in-water emulsions in the gastrointestinal tract, and further nano-produced in contact with digestive juices in the gastrointestinal tract after oral ingestion. In order to stably produce and maintain scale oil-in-water emulsion in the stomach, the mass ratio to 1 part of lysophospholipid is 0.01 part or more and 5 part or less, and 0.05 part or more and 3 part or less. Often, it is better to have 0.1 or more and 1 or less.
When the mass ratio of the fatty acid to one part of the lysophospholipid is out of the above range, the state of the composition for oral ingestion of the present invention is maintained and the stability of the emulsion formed in the digestive tract after oral ingestion is lacking, resulting in poor solubility. Improvement of gastrointestinal absorption of substances cannot be achieved.

<Types of fatty acids>
Fatty acids derived from animals and plants are saturated and unsaturated.
The fatty acid used in the present invention may be either saturated or unsaturated, but the state of the composition for oral ingestion of the present invention that produces a nanoscale oil-in-water emulsion in the digestive tract is maintained, and further, after oral ingestion. From the viewpoint of stably producing and maintaining nanoscale oil-in-water emulsion produced in contact with digestive juice in the digestive tract in the stomach, it is preferable that 50% or more is saturated fatty acid.

<Risoline lipid content in composition for oral intake>
The lysophospholipid maintains the state of the composition for oral ingestion of the present invention that produces a nanoscale emulsion in the gastrointestinal tract, and further, a nanoscale oil-in-water type produced in contact with digestive juice in the gastrointestinal tract after oral ingestion. In order to stably produce and maintain the emulsion in the stomach, it is preferable to contain 1% or more, 1.5% or more, and further 2% or more with respect to the total amount of the composition for oral intake of the present invention. It should be contained.
The upper limit of the lysophospholipid content is not particularly limited, but from the viewpoint of cost in industrial production, it is preferably 10% or less, 8% or less is better, and further 5% or less.

<Content of lysophospholipids in fats and oils>
The composition for oral ingestion of the present invention maintains the state of the composition for oral ingestion of the present invention which produces nanoscale oil-in-water emulsion in the gastrointestinal tract, and further, after oral ingestion, contacts with digestive juice in the gastrointestinal tract. In order to stably produce and maintain the nanoscale oil-in-water emulsion produced in the stomach, it is preferable to contain 0.001 part or more and 0.5 part or less of lysophospholipid per part of fat and oil. It is better to contain 0.01 part or more and 0.2 part or less.

<Content of lysophosphatidylcholine relative to lysophosphatid lipid>
The lysophospholipid used in the composition of the present invention has a composition that produces a nanoscale oil-in-water emulsion in the digestive tract when the content of lysophosphatidylcholine (LPC) with respect to the lysophospholipid is 50% or more, further 65% or more. When the substance is maintained and comes into contact with the digestive juice in the digestive tract, nanoscale oil-in-water emulsion is produced, and the gastrointestinal absorbability of sparingly soluble substances and the oil-in-water emulsion in the stomach It is easy to improve the emulsion stability.

<Other raw materials>
In the present invention, raw materials other than poorly soluble substances, fats and oils, polyhydric alcohols and emulsifiers, which are essential raw materials of the present invention, can be appropriately selected and blended as long as the effects of the present invention are not impaired.
Specifically, for example, nutritional enhancers such as vitamins, minerals and amino acids, excipients such as lactose, crystalline cellulose, cornstarch, potato starch and pregelatinized starch, and binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose and gelatin. , Magnesium stearate, talc, lubricants such as hardened oil, base materials such as dextrin and honey wax, preservatives, preservatives and the like.

<Average particle size of emulsion obtained by contacting the composition for oral ingestion with artificial gastric juice>
The composition for oral ingestion of the present invention produces an oil-in-water emulsion in contact with digestive juice in the digestive tract, but as described above, an emulsified state in the stomach in contact with strongly acidic gastric juice is produced. It is one of the indexes related to the stability of the oil-in-water emulsion and the gastrointestinal absorption of the poorly soluble substance contained in the composition.
The average particle size (volume) of the oil-in-water emulsion obtained by contacting the composition for oral ingestion of the present invention with the artificial gastric juice described in Test Example 1 described later is 1.0 μm or less, and 850 nm or less. It is preferable that the thickness is 700 nm or less.
If the average particle size of the obtained oil-in-water emulsion is larger than the above range, it is difficult to be absorbed in the digestive tract, and it is difficult to improve the gastrointestinal absorbability of the poorly soluble substance. Deemulsification of oil-in-water emulsion produced in the digestive tract is still likely to occur.
The lower limit of the average particle size of the obtained oil-in-water emulsion is not particularly limited, but may be 100 nm or more, and may be 300 nm or more.

<Method of improving gastrointestinal absorption of poorly soluble substances>
The present invention is also a method for improving the gastrointestinal absorption of a poorly soluble substance by solubilizing the poorly soluble substance in the composition of the present invention and ingesting it orally. Specifically, the present invention contains the poorly soluble substance. The composition of the present invention is in contact with the digestive juice secreted from the digestive tract to produce nanoscale fine oil-in-water emulsion in the digestive tract. The poorly soluble substance is contained in the oil-in-water emulsion and transported to the digestive tract to improve its absorbability.

<Method for stabilizing the emulsification of oil-in-water emulsion containing a poorly soluble substance in the stomach>
The present invention is a method for further improving the emulsion stability of an oil-in-water emulsion containing a poorly soluble substance in the stomach. Specifically, the composition of the present invention containing a poorly soluble substance is orally ingested. It stabilizes the oil-in-water emulsion by producing nanoscale fine oil-in-water emulsion in the body.

In the above method, it is important to produce nanoscale oil-in-water emulsions in the gastrointestinal tract.
The oil-in-water emulsion takes an optimal emulsified state according to the conditions at the time of emulsification treatment. That is, it is stable under conditions such as salt and pH existing at the time of emulsification treatment, but when these factors change, it becomes difficult to maintain a stable emulsified state, and coalescence of emulsified particles and deemulsification are likely to occur.
When a sparingly soluble substance is orally ingested as a nanoscale oil-in-water emulsion using a high-pressure homogenizer or the like, the oil-in-water emulsion must pass through the digestive tract where there is a large difference in pH, but in water. It is presumed that coalescence of emulsified particles or partial emulsification occurs when the product comes into contact with a digestive juice having a pH significantly different from that at the time of preparing the oil-type emulsion. Therefore, it becomes difficult to maintain the particle size at the time of preparing the oil-in-water emulsion, and the gastrointestinal absorbability of the poorly soluble substance and the emulsion stability of the oil-in-water emulsion containing the poorly soluble substance in the stomach are sufficient. Cannot be improved.
On the other hand, since the method of the present invention produces an oil-in-water emulsion in the gastrointestinal tract, the emulsion state optimal for the internal environment is stably maintained, and the gastrointestinal absorbable and sparingly soluble substances of the poorly soluble substance are contained. The emulsion stability of the oil-in-water emulsion in the stomach can be improved.

<Manufacturing method of composition for oral ingestion>
The composition for oral ingestion of the present invention can be produced by mixing raw materials by a conventional method. Specifically, for example, egg yolk lysophospholipid and polyhydric alcohol are uniformly stirred and mixed, and fats and oils in which a poorly soluble substance is dissolved or dispersed are added and mixed.

Hereinafter, the present invention will be specifically described based on Examples, Comparative Examples and Test Examples. The present invention is not limited to these.

[Example 1]
Curcumin was used as a poorly soluble substance, and the composition for oral ingestion of the present invention containing curcumin was prepared so that each component had the ratio shown in Table 1.
That is, glycerin in which egg yolk lysophospholipid (lysophosphatidylcholine content 85%), mixed fatty acid (mixture of 50% oleic acid, 30% palmitic acid, and fatty acid having 14 to 18 carbon atoms) and curcumin were dissolved in a glass beaker. Was added, and the mixture was stirred and mixed with a propeller stirrer with an anchor for 5 minutes to obtain a uniform state. Then, soybean oil was gradually added over 25 minutes with continuous stirring to obtain the composition for oral ingestion of the present invention.
The ratio of lysophospholipids to the total amount of emulsifier was 67%, the ratio of lysophospholipids to fatty acids was 0.5 parts to 1 part of lysophospholipids, 2.5% to the total amount of composition, and 1 part to fats and oils. The lysophospholipid content is 0.03 parts.

[Example 2]
Curcumin was used as a poorly soluble substance, and the composition for oral ingestion of the present invention containing curcumin was prepared by the same raw materials and methods as in Example 1 according to the formulation shown in Table 2.
The ratio of lysophospholipid to the total amount of emulsifier was 67%, the ratio of lysophospholipid to fatty acid was 0.5 part of fatty acid to 1 part of lysophospholipid, 1% of lysophospholipid content to the total amount of composition, and lysophospholipid to 1 part of fat and oil. The content is 0.01 parts.

[Comparative Example 1]
Curcumin was used as a poorly soluble substance, and a curcumin-containing oil-in-water emulsion was prepared according to the formulation shown in Table 3.
That is, a mixture of soybean oil, polyethylene glycol in which curcumin is dissolved (PEG400), egg yolk lysophospholipid (lysophosphatidylcholine content 85%), mixed fatty acid (oleic acid 50%, palmitic acid 30%, and fatty acid having 14 to 18 carbon atoms). ) And the phosphate buffer were stirred with a vortex mixer, and then irradiated with ultrasonic waves for 1 minute 5 times (interval 30 seconds) with a probe-type ultrasonic homogenizer (Cycle 1.0, amplitude 40) with a tip diameter of 2.1 mm and strongly stirred. Then, it was made into an oil-in-water emulsion.
The ratio of lysophospholipids to the total amount of emulsifier is 55%, the ratio of lysophospholipids to fatty acids is 0.8 parts of fatty acids to 1 part of lysophospholipids, 1.5% of lysophospholipids to the total amount of oil-in-water emulsion, and fats and oils. The content of lysophospholipid per part is 0.09 part.

[Test Example 1] Measurement of average emulsified particle size (volume conversion) In Examples 1 and 2, the average emulsified particle size (volume conversion) of an oil-in-water emulsion generated when in contact with digestive juice was measured.
That is, 0.1 g of the compositions of Examples 1 and 2 and 9.9 g of artificial gastric juice were mixed to obtain an oil-in-water emulsion, and the average emulsified particle size (volume conversion) was measured by the following method.
In Comparative Example 1, the average emulsified particle size of the oil-in-water emulsion itself was measured.
<Preparation method of artificial gastric juice>
With reference to the formulation of the first solution of the Japanese Pharmacopoeia dissolution test, pH 1.2, 2.0 g of sodium chloride was dissolved in 7.0 mL of hydrochloric acid and water to make 1000 mL, which was used as an artificial gastric juice. The artificial gastric juice obtained is clear and colorless, and its pH is about 1.2.
<Measuring device>
Zeta Sizer nano-S (manufactured by Melvern)
<Measurement conditions and method>
The composition for oral ingestion of the present invention obtained in Examples 1 and 2 was diluted 100-fold (mass) with the prepared artificial gastric juice, and 1 mL of the obtained oil-in-water emulsion was placed in a measurement cell and used for measurement. bottom. The average particle size (volume) was measured three times in the same sample and used as the average value.

As a result of particle size measurement, the average particle size of the oil-in-water emulsion obtained by diluting the composition of Example 1 100 times with artificial gastric fluid was 678 nm, and the composition of Example 2 was diluted 100 times with artificial gastric fluid. The average particle size of the obtained oil-in-water emulsion was 1364 nm, and the average particle size of the oil-in-water emulsion of Comparative Example 1 was 357 nm.

[Test Example 2] Gastrointestinal absorption of a poorly soluble substance The gastrointestinal absorption of curcumin was measured by the following method.
<Oral administration>
Curcumin powder, the compositions of Examples 1 and 2 and the oil-in-water emulsion of Comparative Example 1 were intragastrically administered to Wistar male rats (7 to 9 weeks old) fasted for 15 hours using a gastric sonde tube. bottom. The dose of curcumin bulk powder was 100 mg / kg body weight, and that of Example 1 and Comparative Example 1 was 25 mg / kg body weight.
<Preparation of blood sample>
After anesthesia, a part of the neck of the rat fixed on the dissection table was incised to expose the jugular vein. Then, 600 μg of blood was collected over time from the administration.
<Sample preparation for HPLC measurement of blood drug concentration>
Blood collected from rats was immediately mixed with a trace amount of sodium heparin, centrifuged at 750 × g at 4 ° C. for 10 minutes, and 200 μL of the supernatant was collected and used as plasma. Since curcumin is stable, 20 μL of 1% formic acid was added to the obtained plasma and stored at −20 ° C.
To this, 200 μL of 0.1 M sodium acetate buffer (pH 5.0, containing 6000 U / mL β-glucosidase) was added, and the mixture was incubated at 37 ° C. for 2 hours. Then, 10 μL of 10 mg / mL emodin methanol solution (internal standard) and 10 μL of methanol were added and mixed vigorously with a vortex mixer for 10 seconds, 1.25 mL of ethyl acetate was added, and the mixture was vigorously mixed with a vortex mixer for 10 minutes. The mixed solution was centrifuged at 18800 × g at 4 ° C. for 10 minutes, 1 mL of the supernatant was collected, and the solvent was evaporated at 40 ° C. for 30 minutes. To the obtained residue, 100 μL of 80% acetonitrile solution was added and vigorously mixed with a vortex mixer for 60 seconds to prepare an HPLC sample.
<HPLC measurement conditions>
Column: Inertsil ODS-4 (silica gel particle size 3 μm, inner diameter 3 mm, length 150 mm, manufactured by GL Science Co., Ltd.)
Mobile phase: Acetonitrile-tetrahydrofuran-0.1% formic acid (= 35: 20: 45 (v / v / v)) mixed solution Wavelength: 425 nm
Flow rate: 0.3 mL / min
Column temperature: 40 ° C
Injection volume: 20 μL

_{The maximum curcumin blood concentration C max} when the raw curcumin powder was administered was 0.1 ± 0.1, whereas the maximum curcumin blood concentration C _max when the composition of Example 1 was administered was 0. The value was 0.8 ± 0.4 μg / mL, indicating that the gastrointestinal absorption of curcumin was significantly improved. On the other hand, when the oil-in-water emulsion of Comparative Example 1 was administered, almost no increase in the blood concentration of curcumin was observed, and the gastrointestinal absorption of curcumin was observed even though the particle size was smaller than that of Example 1. Did not improve.
Therefore, it can be seen that the gastrointestinal absorption of the poorly soluble substance contained in the composition is improved by orally administering the composition for oral ingestion of the present invention to produce an oil-in-water emulsion in the digestive tract.

The maximum blood concentration of curcumin (C _max ) when the composition of Example 2 was administered was 0.2 ± 0.1, and although the gastrointestinal absorption was improved as compared with the raw curcumin powder, Examples Compared with the case where the composition of No. 1 was administered, the curcumin gastrointestinal absorption effect was low.
Therefore, it was shown that the average particle size (volume) of the oil-in-water emulsion produced in the gastrointestinal tract is 1.0 μm or less, which easily contributes to the improvement of gastrointestinal absorption.

[Example 3]
In Example 1, the present invention contains curcumin in the same manner as in Example 1 except that the egg yolk lysophospholipid was replaced with 0.125 g and the mixed fatty acid was 0.0625 g, and the total amount was adjusted to 2.5 g with soybean oil. A composition for oral ingestion was obtained.
The ratio of lysophospholipid to the total amount of emulsifier was 67%, the ratio of lysophospholipid to fatty acid was 0.5 part of fatty acid to 1 part of lysophospholipid, 5% of lysophospholipid content to the total amount of composition, and lysophospholipid to 1 part of fat and oil. The content is 0.07 parts.

The average particle size (volume) of the oil-in-water emulsion obtained by diluting the composition for oral ingestion obtained in Example 3 with artificial gastric juice 100 times according to the method of Test Example 1 was measured. It was 573 nm.

[Example 4]
A book containing curcumin in the same manner as in Example 1 except that the egg yolk lysophospholipid was replaced with 0.25 g and the mixed fatty acid was 0.125 g, and the total amount was adjusted to 2.5 g with soybean oil. The composition for oral ingestion of the present invention was obtained.
The ratio of lysophospholipid to the total amount of emulsifier is 67%, the ratio of lysophospholipid to fatty acid is 0.5 part of fatty acid to 1 part of lysophospholipid, the content of lysophospholipid to the total amount of composition is 10%, and the ratio of lysophospholipid to 1 part of fat and oil. The content is 0.16 parts.

The average particle size (volume) of the oil-in-water emulsion obtained by diluting the composition for oral ingestion obtained in Example 4 with artificial gastric juice 100 times according to the method of Test Example 1 was measured. It was 367 nm.

[Example 5]
The composition for oral ingestion of the present invention containing curcumin was obtained in the same manner as in Example 1 except that the egg yolk lysophosphatid lipid was replaced with soybean lysophosphatidyl lipid (lysophosphatidylcholine content 40%).
The ratio of lysophospholipids to the total amount of emulsifier was 67%, the ratio of lysophospholipids to fatty acids was 0.5 parts to 1 part of lysophospholipids, 2.5% to the total amount of composition, and 1 part to fats and oils. The lysophospholipid content is 0.03 parts.

The average particle size (volume) of the oil-in-water emulsion obtained by diluting the composition for oral ingestion obtained in Example 5 with artificial gastric juice 100 times according to the method of Test Example 1 was measured. It was 1069 nm.

[Example 6]
In Example 1, after changing the egg yolk lysophosphatid lipid to one having a lysophosphatidylcholine content of 99%, the egg yolk lysophosphatid lipid amount was changed to 0.6 g, the mixed fatty acid content was changed to 0.03 g, and the total amount was changed to soybean oil. The composition for oral ingestion of the present invention containing curcumin was obtained in the same manner as in Example 1 except that the amount was adjusted to 2.5 g.
The ratio of lysophospholipid to the total amount of emulsifier was 95%, the ratio of lysophospholipid to fatty acid was 0.05 part of fatty acid to 1 part of lysophospholipid, 24% of lysophospholipid content to the total amount of composition, and lysophospholipid to 1 part of fat and oil. The content is 0.46 parts.

The average particle size (volume) of the oil-in-water emulsion obtained by diluting the composition for oral ingestion obtained in Example 6 with artificial gastric juice 100 times according to the method of Test Example 1 was measured. It was 421 nm.

[Comparative Example 2]
In Example 1, a composition for oral intake containing curcumin was obtained in the same manner as in Example 1 except that the mixed fatty acid was changed to 0.37 g and the total amount was adjusted to 2.5 g with soybean oil. rice field.
The ratio of lysophospholipids to the total amount of emulsifier was 14%, the ratio of lysophospholipids to fatty acids was 6 parts to 1 part of lysophospholipids, the content of lysophospholipids to the total amount of composition was 2.5%, and the ratio of lysophospholipids to 1 part of fats and oils. The content is 0.04 parts.

The obtained composition for oral ingestion was poorly stable and could not maintain the property of emulsifying when contacting artificial gastric juice to produce an oil-in-water emulsion. It was also suggested that if the amount of fatty acid is too large, fats and oils are separated, and when diluted 100-fold with artificial gastric juice, oil-in-water emulsion is not produced.

[Example 7]
As the poorly soluble substance, 62.5 mg of coenzyme Q10 (CoQ10) was used, and the increment of the poorly soluble substance was adjusted in the same manner as in Example 1 except that the total amount was adjusted to 2.5 g by subtracting soybean oil. A composition for oral ingestion was obtained.
The ratio of lysophospholipids to the total amount of emulsifier was 67%, the ratio of lysophospholipids to fatty acids was 0.5 parts to 1 part of lysophospholipids, 2.5% to the total amount of composition, and 1 part to fats and oils. The lysophospholipid content is 0.03 parts.
The average particle size (volume) of the oil-in-water emulsion obtained by diluting the obtained composition 100-fold with artificial gastric juice was measured by the same method as in Test Example 1, and the gastrointestinal absorbability of CoQ10 was measured by the following method. Measured by.

<Oral administration>
The CoQ10 bulk powder and the composition of Example 7 were intragastrically administered to Wistar male rats (7-9 weeks old) fasted for 15 hours using a gastric sonde tube. The dose was 100 mg / kg body weight in the case of CoQ10 bulk powder, and 25 mg / kg body weight in Example 1 and Comparative Example 1.
<Preparation of blood sample>
After anesthesia, a part of the neck of the rat fixed on the dissection table was incised to expose the jugular vein. Then, 300 μg of blood was collected over time from the administration. The collected blood was immediately mixed with a trace amount of sodium heparin, centrifuged at 750 g at 4 ° C. for 10 minutes, and 100 μL of the supernatant was collected and used as plasma.
<Sample preparation for HPLC measurement of blood drug concentration>
300 μL of blood sample collected from rats was centrifuged at 750 × g at 4 ° C. for 10 minutes, and 100 μL of plasma was collected. 400 μL of methanol was added thereto, and the mixture was vigorously mixed with a vortex mixer for 30 seconds, then 2 mL of hexane was added, and the mixture was vigorously stirred with a vortex mixer for 30 seconds. The mixed solution was centrifuged at 20 ° C. and 3000 rpm for 10 minutes, 1.8 mL of the supernatant was collected, and the solvent was evaporated at 40 ° C. for 30 minutes. To the obtained residue, 100 μL of a methanol-ethanol mixed solution (mixing ratio 35:65 (v / v)) was added, and the mixture was vigorously mixed with a vortex mixer for 10 seconds to prepare an HPLC sample.
<HPLC measurement conditions>
Column: Inertsil ODS-4 (silica gel particle size 3 μm, inner diameter 3 mm, length 150 mm, manufactured by GL Science Co., Ltd.)
Mobile phase: Methanol-ethanol (35:65 (v / v)) mixed solution Wavelength: 275 nm
Flow rate: 0.4 mL / min
Column temperature: 40 ° C
Injection volume: 40 μL

The average particle size (volume) of the oil-in-water emulsion obtained by diluting the composition for oral ingestion of Example 7 with artificial gastric juice 100-fold was 675 nm.
Further, as a result of measuring the gastrointestinal absorption, the maximum blood concentration C _max when the raw powder of CoQ10 was administered was 6.4 ± 7.1 ng / mL, whereas that of Example 7 containing CoQ10 was found. The maximum blood concentration C _max when the composition was administered was 145.0 ± 38.1 ng / mL, and the gastrointestinal absorption of CoQ10, which is a poorly soluble substance, was significantly improved.

Claims (8)

A self-emulsifying oral ingestion composition containing a sparingly soluble substance.
Contains fats and oils, polyhydric alcohols and emulsifiers,
The lysophospholipid content with respect to the total amount of emulsifier is 15% or more,
Contains 0.01 part or more and 5 parts or less (mass ratio) of fatty acid with respect to 1 part of lysophospholipid .
Contact with artificial gastric juice to produce oil-in-water emulsion,
Composition for self-emulsifying oral ingestion. In the self-emulsifying oral ingestion composition according to claim 1.
The average particle size (volume equivalent) of the oil-in-water emulsion obtained when the composition and the artificial gastric juice are mixed at a mass ratio of 1: 100 is 1.0 μm or less.
Composition for self-emulsifying oral ingestion. In the self-emulsifying oral ingestion composition according to claim 1 or 2.
More than 80% of the constituent fatty acids of the lysophospholipid are saturated.
Composition for self-emulsifying oral ingestion. In the self-emulsifying oral ingestion composition according to any one of claims 1 to 3.
The lysophospholipid content with respect to the total amount of the composition is 1% or more.
Composition for self-emulsifying oral ingestion. In the self-emulsifying oral ingestion composition according to any one of claims 1 to 4.
The lysophospholipid is contained in 0.001 part or more and 2 parts or less (mass ratio) with respect to 1 part of the fat and oil.
Composition for self-emulsifying oral ingestion. In the self-emulsifying oral ingestion composition according to any one of claims 1 to 5.
The content of lysophosphatidylcholine with respect to the lysophosphatid lipid is 50% or more.
Composition for self-emulsifying oral ingestion. In the self-emulsifying oral ingestion composition according to any one of claims 1 to 6.
The lysophospholipid is derived from egg yolk,
Composition for self-emulsifying oral ingestion. In the self-emulsifying oral ingestion composition according to any one of claims 1 to 7.
The polyhydric alcohol contains at least one of glycerin and polyethylene glycol.
Composition for self-emulsifying oral ingestion.