KR101025641B1 - Self-microemulsified mastic composition and capsule containing the composition - Google Patents

Abstract

The present invention manufactures a mastic extracted from Pistasia lentiscus exerts an excellent effect in the treatment of peptic ulcers such as a micro-emulsified emulsion composition, it is formulated by filling in soft capsules or hard capsules. That is, the present invention dissolves water solubility and stability by dissolving a very poorly water-soluble mastic in oil and a dissolving agent, adding a surfactant to exhibit excellent water dispersibility, and adding an antioxidant as an additive to ensure the stability of the preparation. This excellent mastic-containing micro self-emulsifying emulsion composition is provided.

Mastic, Helicobacter pylori, self-emulsifying emulsion, soft capsule

Description

Self-microemulsified mastic composition and capsule containing the composition

The present invention relates to a composition containing a mastic extracted from Pistasia lentiscus , which exhibits an excellent effect in the treatment of peptic ulcers, and more particularly, to a composition in which a mastic is solubilized.

Mastic is a sap extracted from Pistasia lentiscus , a pistachio tree growing on the island of Chios, Greece. It has a unique fragrance and is hardly soluble in water. . Mastic is Helicobacter pylori (Helicobactre long been known as a cause of gastritis, gastric ulcer and duodenal ulcer pyroli ) It has been found to have the effect of inhibiting or killing growth, and has been widely used in the manufacture of functional foods such as various beverages, toothpaste and cosmetics.

However, even though these mastic shows excellent antimicrobial activity, many products have not been developed because they are difficult to formulate because mastic is poorly soluble in water. In general, in order for a drug to exhibit high pharmacological activity in the human body, it must be eluted quickly. The dissolution rate of these drugs is an important factor in determining the rate of absorption of the drug in the body, and is also an important indicator of drug concentration in the blood. This dissolution rate may vary depending on the solubility of the drug, and in particular, when the drug is poorly soluble in water, solubility is poor, so it is necessary to improve the solubility to improve the dissolution rate.

The technique of solubilizing the mastic has not been introduced yet, and most of them use the oil in which the mastic is dissolved in a very small amount as a flavoring agent for toothpaste or mouthwash.

In addition, a soft capsule using a mastic has been disclosed in US Pat. No. 6,650,062, which is only dissolved in oils by mixing the mastic, adding chitin or chitosan having amphiphilic characteristics, and using ethanol as a surfactant. Although disclosed, it may be said to be an undesired configuration because it can make the gelatinous film harden and form an insoluble pellicle when manufactured as a soft capsule. In addition, because the emulsification capacity of chitin or chitosan is not so large, there is a problem that can be excreted without being absorbed upon oral administration.

Therefore, the technical problem to be achieved by the present invention is to provide a mastic containing composition with improved solubility.

Another technical problem to be achieved by the present invention is to provide a mastic-containing capsule with improved solubility.

In order to achieve the above technical problem, the present invention is 1-60% by weight of mastic ( mastic oil or mastic resin) extracted from pistachio Lanticus relative to the total weight of the composition; 5-70% by weight of one or more solubilizers selected from the group consisting of polyethylene glycol, propylene glycol, triacetin, glycerol and diethylene glycol monoethyl ether; 5-70 wt% surfactant; And 1-60% by weight of oil, and provide a mastic solubilizing composition which, when mixed with water, self-emulsification to form an emulsion.

The present invention provides a nanoemulsion concentrate comprising a mixture of a solubilizer, a surfactant and an oil to solve the water solubility of the mastic, the nanoemulsion concentrate is self-emulsified in body fluids at the time of taking to minimize the absorption of the drug by absorbing Can be increased.

The self-emulsifying composition of the present invention contains mastic oil or mastic resin as a main component, and their content is 1-60% by weight, preferably 20-60% by weight, based on the total weight of the composition. If the content of the mastic is included in excess of 60% by weight solubility is drastically lowered, such as precipitation during storage or content may be poor stability, if the active ingredient is added less than 1% by weight of the total weight Solubility and stability are increased but the disadvantage is that the dosage can be increased.

The self-emulsifying composition of the present invention comprises at least one solubilizer selected from the group consisting of polyethylene glycol, propylene glycol, triacetin, glycerol and diethylene glycol monoethyl ether, the content of which is 5-70% by weight relative to the total weight of the composition , Preferably 5-20% by weight.

The self-emulsifying composition of the present invention includes a surfactant, and the surfactant serves to stably emulsify the oil component and the co-surfactant in water to form a stable emulsion, and a pharmaceutically acceptable anionic, cationic, Various surfactants can be used, including nonionic or amphoteric surfactants.

Such surfactants include (a) the reaction product of natural or hydrogenated vegetable oils with ethylene glycol, i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils, such as polyoxyethylene glycolated natural or hydrogenated castor oil. Cremophor, HCO manufacturer: BASF, NIKKOL), (b) polyoxyethylene-sorbitan-fatty acid esters, for example esters of mono or trilauryl, palmityl, stearyl or oleyl ( Product name: Tween, make: ICI), (c) polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid ester (trade name: Myrj, make: ICI), (d) Polyoxyethylene-polyoxypropylene copolymer (trade name: Pluronic, manufacturer: BASF), (e) polyoxyethylene-polyoxypropylene block copolymer (trade name: Poloxamer, manufacturer: BASF), (f ) Dioctylsulfosuccinate or sodium lauryl sulfosate, (g) phospholipids, (h) propylene glycol mono- or di-fatty acid esters, such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol iso Stearate, propylene glycol laurate, propylene glycol ricinoleate or propylene glycol caprylic-capric acid diester sold under the tradename Miglyol 840 (manufactured by Huls), (i) natural vegetable oils Trans-esterification reaction products of triglycerides with polyalkylene polyols (trade name: Labrafil M, manufactured by Gattefosse), (j) mono-, di- or mono / di-glycerides, for example Caprylic / capric acid mono- or di-glycerides (trade name: Imwitor, manufacturer: Huls), (k) sorbitan fatty acid esters such as phase Name Span has (Span) lauryl sorbitan la available on the market, such as sorbitan or sorbitan palmityl stearyl, (l) sterol or derivative thereof, such as cholesterol, phytosterol or sitosterol can be used.

These surfactants may be used alone or in combination of two or more thereof, and may be appropriately selected depending on the type of oil component. Considering the solubilizing and self-emulsifying properties of mastic as such surfactant, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated caster oil, polysorbate, polyethylene glycol-8 glyceryl caprylate, dimethylisosorbide , Poloxamer, etc. are preferable.

The content of such surfactant is 5-70% by weight based on the total weight of the composition, more preferably 5-20% by weight. When the surfactant is used at less than 5% by weight, self-emulsification does not occur in accordance with the object of the present invention, and the particles are very large.When the amount is added in excess of 70% by weight, the size of the particles may be reduced. In case of molding, gelatin bonding is poor and the contents can be leaked in terms of adhesion during storage. Such a phenomenon is not preferable because of the expense of new equipment investment, such as additional equipment to the soft capsule molding equipment.

The present invention may also optionally include cosurfactants. As such a co-surfactant, it is preferable that the emulsion can be easily dispersed as a solvent having both hydrophilicity and lipophilicity, and the active ingredient mastic and various additives can be dissolved. Cosurfactants not only assist in formulating solubility suitable for the active ingredient, but are also dispersed in both the oil phase and the surfactant, and also aid in stabilization so that the emulsion or microemulsion can be uniformly dispersed. In addition, the present invention provides the advantage of ensuring the uniformity of the composition without changing the active ingredient over time even during the preservation of the formulation.

In particular, the co-surfactant serving this purpose is ethanol, propylene glycol (1,2-dihydroxypropane), polyethylene glycol (molecular weight 200 to 600), propylene carbonate (4-methyl-2-oxo-1,3- Dioxolane), transcutol (diethylene glycol monoethyl ether), glycofurol (glycofurol: tetrahydrofurfuryl alcohol polyethylene glycol ether), dimethyl isosorbide (1,4: 3,6- dianhydro-2, 5-dimethyl-D-glucinol) and the like can be used alone or in combination, the content of which is 1-70% by weight based on the total weight of the composition.

The mastic solubilizing composition according to the present invention comprises an oil. These oils are well mixed with co-surfactants and surfactants, can be emulsified in water to form stable microemulsions, and can dissolve the composition compounds including the active ingredient mastic. Oils can be used.

Specifically, for example, (a) fatty acid triglycerides, preferably intermediate fatty acid triglycerides, for example fractionated coconut oil (trade name: Miglyol 812N, manufactured by Huls), (b) mono-, di Or mono / di-glycerides, preferably mono- or di-glycerides of oleic acid, (c) ester compounds of fatty acids and monovalent alkanols, in particular fatty acids having 8 to 20 carbon atoms and monovalent to 3 to 3 carbon atoms Ester compounds of alkanols, for example isopropyl myristate, isopropyl palmitate, ethyl linoleate or ethyl oleate, (d) natural vegetable or animal oils such as corn oil, olive oil, soybean oil Or fish oils, (e) hydrocarbons, for example squalene or squalane, (f) free fatty acids, preferably liquid oleic acid or linoleic acid, (g) tocopherols, for example For example, dl-a-tocopheryl acetate may be used alone or in combination.

The content of such oils is 1-60% by weight, preferably 10-40% by weight relative to the total weight of the composition.

The mastic solubilizing composition of the present invention may include an antioxidant to improve the stability of the active ingredient included in the mastic.

Such antioxidants may include antioxidants such as lipophilic tocopherol, dibutylhydroxytoluene or butylhydroxyanisole, and antioxidants such as hydrophilic ascorbic acid, sodium sulfite, sodium pyrosulfite or sodium hydrogen sulfite, These may each be used alone or as a mixture of two or more.

The content of such antioxidants is 0.1-20% by weight relative to the total weight of the composition, preferably 0.1-5% by weight.

Thus, preferably, the present invention comprises 20-60% by weight of mastic extracted from pistachio lentiscus relative to the total weight of the composition; 5-20% by weight solubilizer selected from the group consisting of polyethylene glycol, propylene glycol, triacetin, glycerol and diethylene glycol monoethyl ether; 5-20% by weight of a surfactant selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated caster oil, polysorbate, polyethyleneglycol-8 glyceryl caprylate, dimethylisosorbide and poloxamer; 10-40% by weight of oil; And 0.1-5% by weight of an antioxidant, and provides a mastic solubilizing composition characterized by forming an emulsion by self-emulsification when mixed with water.

The mastic solubilizing composition of the present invention may further contain various pharmaceutically acceptable additives such as fragrances, preservatives, and the like for oral administration without departing from the object of the present invention.

The present invention also provides a soft capsule or hard capsule containing the self-emulsifying mastic containing composition, the capsule is excellent in storage stability.

The solubilizing method of mastic in the present invention is to solubilize mastic in solubilizers, surfactants, co-surfactants and oils, and to add an antioxidant to obtain a liquid content which further enhances the solubility and stability of the drug. It is prepared by soft capsules or hard capsules. The mastic solubilizing composition according to the present invention can be easily administered orally, and the mastic can be solubilized to increase the absorption rate.

The present invention provides a composition which solubilizes a very poorly soluble mastic in water, and a soft capsule or hard capsule containing the composition. The composition according to the present invention solubilizes a mastic known to be effective in the treatment of oral diseases and peptic ulcers by a micro-emulsifying emulsion method, and the solubilized mastic has improved water solubility and absorption rate compared to conventional products. It can be improved to enhance bioavailability.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Preparation of Example 1-6

Among the components shown in Table 1, the remaining components except for the main components mastic, oils and antioxidants were thoroughly mixed while warming to about 50-70 ℃ and stirred until it became transparent. Then, oils were added, and the mixture was stirred and mixed thoroughly. Subsequently, the main component mastic was slowly added to the mixed solution prepared above at about 50 ° C. to completely dissolve it, and then an emulsion solution for preparing soft capsules or hard capsules was prepared.

Ingredient Name Purpose of Mixing Example (Unit: Milligram) One 2 3 4 5 6 Mastic chief ingredient 500 500 500 500 500 500 Polyethylene glycol Dissolution Aids and Cosurfactants 100 100 50 Propylene glycol 100 50 120 Triacetin Melting aid 80 Twin 20 Surfactants 30 Twin 80 Surfactants 20 20 Poloxamer124 Surfactants 50 HCO50 Surfactants 100 Cremophor RH40 Surfactants 100 80 80 80 120 Cremophor EL Surfactants 20 Migoliol812N Oil / fatty acid 10 20 10 10 10 Medium Chain Fatty Acids (MCT) Oil / fatty acid 300 300 280 250 250 250 Soybean oil Oil / fatty acid Isopropyl myristate Oil / fatty acid 10 30 30 Tocopherol Antioxidant 10 10 10 10 10 10 Total (milligrams) 1020 1020 1020 1020 1020 1020

Hard capsules containing micro-emulsifying emulsion were commercialized by filling an amount corresponding to 50% of the total composition (510 mg / hard capsule according to the embodiment).

<Production of Soft Capsule Film>

Soft capsule coatings were prepared by a conventional coating method using soft capsule preparation components containing generally known gelatin, plasticizer, and the like. The coating composition was 118 mg of gelatin, 46.9 mg of glycerin, 0.7 mg of ethylvanillin, 0.35 mg of methyl paraoxybenzoate and 0.05 mg of paraoxybenzoate per capsule (166 mg).

The soft capsule production of the mastic-containing micro self-emulsifying composition of the present invention is formed by filling 1020 milligrams of Oblong # 16 by a conventional charging method using a rotary automatic charger which is generally used, followed by drying and sorting. It was set as the prototype.

<Production of Comparative Example 1>

500 grams of mastic, 145 grams of microcrystalline cellulose, 200 grams of lactose and 50 grams of croscarmellose sodium were mixed, and 5 grams of magnesium stearate, a lubricant, was mixed well, and tableted into a tablet of 900 milligrams using a conventional tabletting machine.

<Production of Comparative Example 2>

500 grams of mastic, 20 grams of croscarmellose sodium, and 5 grams of magnesium stearate as a lubricant were mixed well, and then filled into 525 milligrams to give hard capsules.

Experimental Example 1 Evaluation of the Soft Capsule of Example 1-6 and Comparative Example 1-2

It was confirmed that mastic was completely dissolved in the self-emulsifying emulsion composition of Examples 1-6 during the manufacturing process.

As a result of dissolving the composition of Example 1-6 and Comparative Example 1-2 in 200 ml of water, the composition of Example 1-6 solubilized the main component mastic to form an emulsion of a transparent or translucent liquid, whereas Comparative Example 1 and 2 were found to be precipitated to the bottom in the form of a sticky mass without dissolving the components contained.

Claims (8)

delete delete delete delete delete delete Of total composition weight 20-60% by weight mastic extracted from pistachio lentiscus; 5-20% by weight solubilizer selected from the group consisting of polyethylene glycol, propylene glycol, triacetin, glycerol and diethylene glycol monoethyl ether; 5-20% by weight of a surfactant selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated caster oil, polysorbate, polyethyleneglycol-8 glyceryl caprylate, dimethylisosorbide and poloxamer; Medium-chain fatty acids including coconut oil, mono- or di-glycerides of oleic acid, isopropyl myristate, isopropyl palmitate, ethyl linoleate or ethyl oleate, corn oil, olive oil, soybean oil, fish oil, 10-40% by weight of at least one oil selected from the group consisting of liquid oleic or linoleic acid and tocopheryl acetate; And 0.1-5% by weight of at least one antioxidant selected from the group consisting of tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, sodium sulfite, sodium pyrosulfite, and sodium hydrogen sulfite, Mastic solubilizing composition characterized in that the emulsion is formed by self-emulsification when mixed with water. A soft capsule or hard capsule comprising the composition of claim 7.