KR20190110312A - Solubilized liquid formation of cholecalciferol and its manufacturing method - Google Patents

Abstract

The present invention relates to a composition that increases solubilization and storage stability of cholecalciferol, a fat-soluble substance. The composition containing cholecalciferol according to the present invention can be provided in a form of a medicine or a functional food. Liquid preparations containing cholecalciferol can be provided to individuals with vitamin D shortage or deficiency in the form of pharmaceuticals, functional foods or food supplements.

Description

Solubilizing composition of cholecalciferol and its manufacturing method {SOLUBILIZED LIQUID FORMATION OF CHOLECALCIFEROL AND ITS MANUFACTURING METHOD}

The present invention relates to a composition that increases the solubilization and storage stability of cholecalciferol, a fat-soluble substance. The composition containing cholecalciferol according to the present invention may be provided in the form of a medicine or a functional food.

Lack or deficiency of vitamin D has been reported as one of the major causes of metabolic bone disease characterized by disorders of calcium and phosphate absorption. If the deficiency or deficiency of vitamin D is sustained, this leads to bone loss and related diseases.

Cholecalciferol generally refers to vitamin D ₃ and increases calcium absorption from the digestive tract or plasma, affecting the regulation of calcium levels and bone metabolism. When the body's cholecalciferol is deficient or deficient to a certain level, osteomalacia, osteoporosis, osteopenia, calcium dysregulation (e.g. hypercalcemia, hypocalcemia, etc.), rickets, bone disease, bone dystrophy (e.g. nephrotic dystrophy) Etc.), cystic fibrosis, degenerative bone disease, and extracorporeal calcification.

Therefore, in order to solve the problem of insufficient cholecalciferol, cholecalciferol is ingested in the form of medicines or functional foods. However, the cholecalciferol is a very unstable substance and accelerates decomposition in the presence of oxygen and moisture. Such instability of cholecalciferol results in a decrease in the content of cholecalciferol in products such as pharmaceuticals or functional foods. Due to the instability of cholecalciferol, products containing cholecalciferol are mostly made of solid agents.

Liquids or suspensions that are easier to take than solids are difficult to develop due to storage stability issues. In order to solve this problem, a number of studies have been conducted. As an example, the invention of increasing the storage stability of cholecalciferol by combining a specific type of tocopherol at a specific ratio and specifying a solvent condition is disclosed in Korea Patent Registration No. 10. -1785319, registered September 29, 2017.

In addition, since cholecalciferol is a fat-soluble substance, it cannot be manufactured through a simple mixing process when developing a solution or suspension based on an aqueous solution. Here, mixing process means the process of mixing a fat-soluble component and a water-soluble component and manufacturing it. Since the oil-soluble substance cholecalciferol is present in an unstable state in an aqueous solution, it is difficult to be uniformly and stably dispersed in the aqueous solution, and even if dissolved in an aqueous solution through solubilization, it causes problems such as precipitate or phase separation during storage. Accordingly, there is a need in the art for developing improved solubilization technology and securing stability in aqueous solution for cholecalciferol liquid formulations.

Korean Patent Registration No. 10-1785319 (Registration date 2017.09.29)

The present inventors have recognized the problems of the prior art and have been experimenting for a long time to develop a liquid or suspending agent containing cholecalciferol as an active ingredient.

In order to solve the above problems, the present invention provides a cholecalciferol liquid formulations that enhance the ease of taking and administering compared to solids. The liquid formulation is free from phase separation and sedimentation, and the content of the active component cholecalciferol is not lowered or lost even during long-term storage.

According to one embodiment of the invention, the composition for solubilization of cholecalciferol comprises an oil and a surfactant.

The surfactant may be a surfactant used for O / W emulsification having a HLB (hydrophile-lipophile balance) value of 8 to 20. For example, polyoxyl 35 castor oil, polyoxyl 40 hardened castor oil, polyethylene glycol 400, polysorbate 60, or caprylocaproyl macrogol-8-glyceride may be used. Preferably, polyoxyl 35 castor oil or polyoxyl 40 hardened castor oil may be used.

The oil may be, for example, propylene glycol dicaprylocaprate, propylene glycol monocaprylate, polyethylene glycol dicaprylocaprate, corn oil, oleoli polyoxyl-6 glycerides, caprylic / capric glycerides, and the like. .

According to one embodiment of the invention, the composition may further comprise an antioxidant. The antioxidant may be citric acid, ascorbic acid, butylhydroxyanisole, tocopherol acetate. Most preferably, tocopherol acetate can be used.

According to one embodiment of the present invention, a liquid preparation containing cholecalcinphenol solubilized by the composition may be used for medical purposes for treating or preventing a disease related to vitamin D deficiency or deficiency.

Diseases related to vitamin D deficiency or deficiency include, for example, osteomalacia, osteoporosis, osteopenia, calcium dysregulation (eg, hypercalcemia, hypocalcemia, etc.), rickets, Paget's bone disease, bone dystrophy (eg, nephrotic dystrophy) , Osteoarthritis (eg, cystic fibrous osteoarthritis), degenerative bone disease, extrapolation, and the like.

As used herein, the term "treatment" refers to any action in which symptoms of a vitamin D deficiency or deficiency related disease improve or be cured by administration of a pharmaceutical composition according to the invention.

As used herein, the term "prevention" refers to any action by which administration of a pharmaceutical composition according to the present invention inhibits or delays the onset of a disease related to vitamin D deficiency or deficiency.

The pharmaceutical composition according to the present invention may further contain one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Pharmaceutically acceptable carriers may be referred to those described in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995.

The pharmaceutical composition of the present invention can be administered to any mammal, including humans. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. Can be. For example, the pharmaceutical composition of the present invention may be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin injection needle, or by directly applying it to the skin.

The pharmaceutical composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.

In the case of preparations for oral administration, the compositions of the present invention are preferably in the form of liquid preparations, and may be formulated in various forms using methods known in the art, for example, in liquids, gels, syrups, slurries, suspensions, and the like. have. Alternatively, it is also possible to prepare the liquid formulation of the present invention in a solid formulation such as powders, granules, tablets, pills, dragees, capsules and the like by lyophilization. Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.

Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a prescription generally known in all pharmaceutical chemistries.

The total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose, and may be administered by a fractionated treatment protocol that is administered in multiple doses for a long time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the symptoms of vitamin D deficiency or deficiency-related diseases. Preferably the preferred total dose of the composition of the present invention may be about 0.01 μg to 1,000 mg, most preferably 0.1 μg to 100 mg per kg of patient body weight per day. However, the dosage of the pharmaceutical composition of the present invention considers the effective dosage for the patient in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate as well as the route of administration and the number of treatments. Thus, one of ordinary skill in the art will be able to determine the appropriate effective dosage. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.

In addition, the pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents. When administered in combination with other therapeutic agents, the compositions of the present invention and other therapeutic agents may be administered simultaneously, separately or sequentially. The other therapeutic agent may be a substance already known to have a therapeutic or ameliorating effect of a disease related to vitamin D deficiency or deficiency.

When the pharmaceutical composition of the present invention is administered in combination with other therapeutic agents, each may be formulated separately in a separate container, or may be formulated together in the same container.

According to another embodiment of the present invention, a liquid formulation containing cholecalcinphenol solubilized by the composition may be used as a functional food for improving or preventing a disease related to vitamin D deficiency or deficiency.

The term "improvement" used in the present invention means any action in which symptoms related to vitamin D deficiency or deficiency are reduced, improved or delayed by administration of the food composition according to the present invention.

The food may be a health functional food. The term "health functional food" means a food processed using raw materials or ingredients having functional properties useful for the human body. The term "functional" as used herein means to obtain a useful effect in health applications such as nutrient control or physiological action on the structure and function of the human body.

The food composition according to the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art.

In addition, the food composition according to the present invention may not only be used alone, but may also be used simultaneously or sequentially with the pharmaceutical composition provided by the present invention for the purpose of maximizing the vitamin D supplementation effect.

The food composition according to the present invention may further include additional ingredients in addition to cholecalciferol, oil, and surfactant to enhance the efficacy, the additional ingredients do not reduce the content of the cholecalciferol or change the properties Should be

The food composition is preferably a liquid formulation, optionally may be provided by changing the liquid formulation into a solid formulation. The kind of the food is not particularly limited and includes all foods in a general sense. The food composition of the present invention may contain various flavors or natural carbohydrates and the like used in ordinary food as additional ingredients. The natural carbohydrate may be sugar alcohols such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, xylitol, sorbitol and erythritol. As the sweetener, natural sweeteners such as tautin, stevia extract, or synthetic sweeteners such as saccharin or aspartame can be used.

According to another embodiment of the present invention, a method for preparing a composition comprising cholecalciferol as an active ingredient is provided, comprising the following steps:

a) mixing the surfactant with an oil and adding cholecalciferol to prepare an oil phase; And

b) mixing the oil phase prepared in step a) into an aqueous phase.

Preferably, an antioxidant may be further added when the oil phase is prepared in step a).

When solubilizing cholecalciferol by the solubilizing composition of the present invention, no phase separation occurs, the oil phase is present as one single phase in the aqueous phase, and the dispersion in the oil phase is easy. As such, the possibility of preparing a formulation of the active ingredient cholecalciferol as a liquid formulation may improve the discomfort in taking the drug and increase the patient's compliance with the medication. Moreover, even during long-term storage of the liquid formulation, the content of the active ingredient cholecalciferol is not lowered or lost, and since there is no change in properties, the storage stability is excellent.

As such, liquid preparations containing cholecalciferol may be provided in the form of medicines, functional foods or food supplements to individuals with vitamin D deficiency or deficiency.

The invention is illustrated in more detail by the following examples. The examples are only for illustrating the present invention, and the scope of the present invention is not limited only to the above examples.

Experimental Example  1: Surfactant and Oil Screening

In order to prepare an oil phase containing cholecalciferol, in this experiment, various types of surfactants and oils were used to confirm phase separation and precipitation.

Specifically, after mixing the oil and the surfactant in a weight ratio of 1: 1, the result of confirming the property as to whether or not phase separation occurs is described in the "primary item" in Table 1 below. Only when there was no phase separation when the oil and the surfactant were mixed, the equivalent amount of cholecalciferol 5600IU was dissolved and whether or not phase separation or precipitate occurred was described in Table 2 below.

(+: Phase separation occurs, ++: precipitate occurs,-: no change)

As shown in Table 1 above, when polyoxyl 35 castor oil or polyoxyl 40 hardened castor oil was used as the surfactant, phase separation and sedimentation did not occur when the oil and the surfactant were mixed. No phase separation and no sedimentation occurred even when cholecalciferol was dissolved in the mixture. Thus, it has been experimentally demonstrated that polyoxyl 35 castor oil or polyoxyl 40 cured castor oil as surfactant is excellent as a solvent of cholecalciferol in preparing an oily mixture.

Experimental Example  2: compounding ratio of surfactant and oil

In this experiment, the change in properties was measured by applying various blending ratios to the oil and the surfactant selected in Experimental Example 1.

Specifically, the oils used were those listed in Table 1, and the surfactants were polyoxyl 35 castor oil and polyoxyl 40 hardened castor oil selected in Experimental Example 1. Each oil and each surfactant were blended in a weight ratio of 9: 1, 7: 3, 5: 5, 3: 7, 1: 9, and 5000 IU equivalent amount of cholecalciferol was completely dissolved in the oil phase. Prepared. Subsequently, the oil phase was dispersed in 100 mL of purified water at a rate of 0.5% w / v to prepare a final product. After 24 hours, the appearance of the final product was confirmed.

As a result of confirming phase separation and precipitation, propylene glycol dicaprylocaprate, propyleneglycol monocaprylate, polyethyleneglycol dicaprylocaprate, caprylic / capric glyceride, corn oil, using polyethyleneglycol dicaprylocaprate In this case, it showed the best effect regardless of the type of surfactant. In addition, the oil and the surfactant showed the best effect when formulated in a weight ratio of 5: 5 to 3: 7.

Experimental Example  3: Antioxidant Screening

To prepare a stable emulsion composition, 8 mg of methyl paraoxybenzoate and 2 mg of paraoxybenzoic acid were completely dissolved in 100 mL of purified water, and 300 mg of sucralose and 350 mg of flavoring agent were sequentially dissolved to prepare an aqueous phase. In addition, the oil phase was prepared by dissolving cholecalciferol in a mixture of oil and surfactant according to the mixing ratios shown in Table 2, where Examples 1 to 8 added antioxidants, while Examples 9 and 10 were antioxidants. No agent was added. The oil phase thus prepared was mixed with 100 mL of an aqueous phase at a rate of 0.5% w / v to prepare a final liquid formulation.

Raw material name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Active ingredient Cholecalciferol 0.0056 0.0056 0.0056 0.0056 0.0056 0.0056 0.0056 0.0056 0.0056 0.0056 oil Polyethylene Glycol Dicaprylocaprate 0.25 0.25 0.15 0.15 0.25 0.25 0.15 0.15 0.25 0.25 Surfactants Polyoxyl 35 Castor Oil 0.25 0.35 0.25 0.35 0.25 Surfactants Polyoxyl 40 Cured Castor Oil 0.25 0.35 0.25 0.35 0.25 Antioxidant Butylhydroxyanisol 0.01 0.01 0.01 0.01 - - Antioxidant Tocopherol Acetate 0.01 0.01 0.01 0.01 - -

The present inventors centrifuged for 10 minutes at 3000 rpm for 10 minutes the composition prepared in Examples 1 to 10 under the harsh conditions (60 ℃ / RH 80%), to determine whether the precipitate is present in the container, 5 days Observation was made until this elapsed. In addition, the change in the content of cholecalciferol in the liquid formulation was observed. The results are shown in Table 3 below.

Constellation Cholecalciferol content (%) Initial 3 days 5 days Initial 3 days 5 days Example 1 ++ Example 2 ++ Example 3 ++ Example 4 ++ Example 5 - - - 103.17 100.96 101.56 Example 6 - - - 100.13 99.23 100.79 Example 7 - - - 102.01 94.44 89.79 Example 8 - - - 101.49 85.48 73.25 Example 9 - - - 100.21 76.68 52.44 Example 10 - - - 103.20 66.80 49.03

(+: Phase separation occurs, ++: precipitate occurs,-: no change)

As can be seen in Table 3, Examples 1 to 4 using butyl hydroxy anisol as the antioxidant was confirmed that the precipitate is generated when the oil phase is dispersed in the water phase, the stability is lowered.

On the other hand, Examples 5 to 8 using tocopherol acetate as antioxidant did not have phase separation and precipitate generation regardless of the composition of the oil phase. In particular, in Examples 5 and 6, no significant change was observed even after 5 days of the content of cholecalciferol in the liquid formulation composition.

Experimental Example  4: long-term storage stability test

The inventors observed changes in the content of cholecalciferol in the liquid formulation until 6 months under long-term storage conditions (25 ℃ / RH 60%) and accelerated storage conditions (40 ℃ / RH 75%).

The experimental results of the composition of Example 5 using polyoxyl 35 castor oil as the surfactant and the composition of Example 6 using polyoxyl 40 cured castor oil as the surfactant are shown in Table 4 below.

Long-term storage Long term storage condition Accelerated Storage Conditions Initial 3 months 6 months Initial 3 months 6 months Example 5 101.49 99.28 98.62 101.49 95.48 84.42 Example 6 100.13 99.23 100.79 100.13 100.01 97.79

Table 4 demonstrates that when preparing a liquid formulation containing cholecalciferol using the composition according to the present invention, the content of cholecalciferol is not lost and stable during long term storage.

Claims (11)

As a composition for solubilization of cholecalciferol,
The composition comprises an oil and a surfactant, wherein the surfactant is at least one selected from the group consisting of polyoxyl 35 castor oil and polyoxyl 40 hardened castor oil. The method of claim 1,
The oil is a composition, characterized in that at least one selected from the group consisting of polyethylene glycol dicaprylocaprate, propylene glycol dicaprylocaprate, propylene glycol monocaprylate and caprylic / capric glycerides. The method of claim 1,
The weight ratio of the oil and the surfactant is 5: 5 to 3: 7 composition. The method of claim 1,
The composition is characterized in that it further comprises an antioxidant. The method of claim 4, wherein
Wherein said antioxidant is a tocopherol acetate. A pharmaceutical composition comprising the composition according to claim 1 and cholecalcinphenol,
Pharmaceutical compositions for treating or preventing a disease associated with vitamin D deficiency or deficiency. The method of claim 6,
The vitamin D deficiency or deficiency related disease is at least one selected from the group consisting of osteomalacia, osteoporosis, osteopenia, calcium dysregulation, rickets disease, Paget's bone disease, osteotrophic disease, osteoarthritis, degenerative bone disease and extrapolation calcification . A food composition comprising the composition according to claim 1 and cholecalcinphenol,
A food composition for improving or preventing a disease related to vitamin D deficiency or deficiency. The method of claim 8,
The vitamin D deficiency or deficiency-related disease is at least one selected from the group consisting of osteomalacia, osteoporosis, osteopenia, calcium dysregulation, rickets disease, Paget's bone disease, osteotrophic disease, osteoarthritis, degenerative bone disease, and extracorporeal calcification . A method for preparing a composition comprising cholecalciferol as an active ingredient, comprising the following steps:
a) mixing an oil with at least one surfactant selected from the group consisting of polyoxyl 35 castor oil and polyoxyl 40 hardened castor oil, and adding cholecalciferol to prepare an oil phase; And
b) mixing the oil phase prepared in step a) into an aqueous phase. The method of claim 10,
The method of producing a oil phase in the step a) characterized in that further adding an antioxidant.