KR20070018008A - Composition and formulation of colloidal system comprising biocompatible aqueous-soluble polymer, and preparation method thereof - Google Patents

Abstract

The present invention relates to an emulsion or cubosome composition containing a biocompatible polymer in a three-dimensionally stabilized state, an emulsion or cubosome formulation comprising the same, and a method for preparing the same.

Description

FIELD OF THE INVENTION Colloidal compositions, formulations, and formulations comprising biocompatible hydrophilic polymers and methods for preparing the same.

The present invention relates to an emulsion or cubosome composition comprising a biocompatible polymer in a three dimensional stabilized state, a formulation comprising the same, and a method for preparing the same.

An emulsion is a system in which one liquid is dispersed in another liquid that it does not mix. For emulsions consisting of oil and water, o / w (oil) depends on whether the continuous phase is oil or water. -in-water, w / o (water-in-oil), w / o / w type emulsions, and the like. In particular, o / w type emulsions have a hydrophobic domain and have been usefully used as a delivery system for poorly soluble drugs. Since emulsions are metastable systems, effective drug delivery functions require agents to slow down the decomposition of the emulsion and stabilize it against entanglement, including coalescence.

In addition, cubosomes are those in which a stable cubic phase structure spontaneously formed when water is added to monoglyceride is dispersed in water using an emulsifier (US Pat. No. 5,531,925). Emulsifiers are required to stabilize dispersion systems such as emulsions or cubosomes. Phospholipids, nonionic surfactants, anionic surfactants, cationic surfactants and the like are mainly used as emulsifiers. Cubosomes have the advantage of easily encapsulating poorly soluble and amphoteric drugs, and are suitable for oral drug delivery because they have mucoadhesive properties.

In addition, Korean Patent Application No. 2000-12465, 2001-7123 and 2001-7125 for the invention of the present inventors composition for solubilizing a drug consisting of a monoglyceride, an emulsifier and an organic solvent Is disclosed. The solubilizing composition of the drug is characterized by effectively solubilizing a poorly soluble substance or protein, the composition is easy to disperse the dispersion of particles having an average particle size of 500 nm or less when shaken or vortex after mixing in water Form. The solubilizing composition has a degree of difference depending on the molecular weight and polarity of the drug, but most drugs are encapsulated with high efficiency. In addition, like the cubosome, the dispersion of the solubilizing composition is suitable for oral drug delivery because it has mucosal adsorption.

In order to enhance the in vivo delivery efficiency of substances such as poorly soluble drugs and / or proteins, it is of utmost importance to increase the dispersibility and stability of the fat emulsions or cubosomes useful as in vivo delivery systems of these substances. Existing body delivery systems, such as drugs, require significant amounts of separate emulsifiers in order to obtain dispersibility and solubility suitable for oral administration, which limits their preparation, use and efficacy.

1 is a photograph of a powder lyophilized cubosome formulation stabilized with an aqueous polymer solution containing insulin prepared in Example 51

FIG. 2 is a graph showing oral administration of a cubosome solution containing insulin and stabilized with an aqueous chitosan solution to a diabetic-induced rat, and then measuring relative blood glucose levels in blood collected from a tail vein at regular intervals after administration.

-●-; Phosphate buffer (PBS) 300 μL oral administration group,

-○-; 300 μL oral dose of insulin dissolved in phosphate buffer (PBS) (insulin concentration 89 IU / kg),

-■-; 300 μL of cubosome solution containing insulin and stabilized with aqueous chitosan solution (insulin concentration 89 IU / kg).

FIG. 3 is a graph showing oral administration of a cubosome solution containing paclitaxel and stabilized with an alginate aqueous solution to normal female mice, and measuring the concentration of paclitaxel absorbed into the blood at regular intervals.

-●-; Oral administration of a mixture of paclitaxel and a composition in which a low molecular weight alginate aqueous solution is emulsified in a mixed oil of tricapryline and monoolein,

-■-; Oral administration of a mixture of a composition of the low molecular weight alginate aqueous solution and paclitaxel in the mixed oil to which the emulsifier is added,

-▲-; Orally administering a mixture of paclitaxel and a composition in which chitosan is emulsified in the mixed oil to which an emulsifier is added.

Technical challenge

The present invention provides an emulsion or cubosome composition which is excellent in dispersibility and has been stericly stabilized using a biocompatible hydrophilic polymer without using an emulsifier or using only a small amount, and a formulation having excellent dispersibility and mucoadsorbent supported on the drug. It aims to provide.

Technical solution

The present invention relates to emulsions or cubosome compositions in a steric stabilized state, including biocompatible hydrophilic polymers, formulations comprising them and methods for their preparation.

As described above, in vivo delivery systems such as drugs require significant amounts of separate emulsifiers in order to obtain dispersibility and solubility suitable for oral administration, which has limited their preparation, use and efficacy. . Thus, the inventors believe that the biocompatible hydrophilic polymer acts to stabilize the fat emulsion or cubosome. That is, the present invention was completed by discovering that the hydrophilic polymer acts as an emulsifier in an emulsion or cubosome system composed of lipids. To date, nothing has been reported regarding the stabilization of fatty emulsions or cubosomes with aqueous hydrophilic polymers.

First, the present invention provides an emulsion or cubosome composition in a steric stabilized state, including a biocompatible hydrophilic polymer. More specifically, the present invention relates to an emulsion composition comprising 0.1 to 30% by weight of one or more oils, 0.01 to 5% by weight of a biocompatible hydrophilic polymer and water or an aqueous solution occupying the remainder, wherein the emulsion composition comprises a biocompatible hydrophilic polymer. Due to the emulsification and stabilization of the (sterically) is characterized in that the state is stabilized.

In addition, the present invention provides an emulsion comprising 0.1 to 30% by weight of one or more oils, 0.1 to 30% by weight of one or more monoglyceride compounds, 0.01 to 5% by weight of a biocompatible hydrophilic polymer, and water or an aqueous solution for the remainder. Regarding the composition, the emulsion composition is characterized in that the three-dimensionally stabilized state by the emulsification and stabilizing action of the biocompatible hydrophilic polymer.

In addition, the present invention relates to a cubosome composition comprising 0.1 to 30% by weight of at least one monoglyceride-based compound 0.01 to 5% by weight biocompatible hydrophilic polymer, and water or an aqueous solution occupying the remainder, It is characterized by a composition of cubosomes stericly stabilized by stabilizing action.

The present invention also relates to cubo comprising 0.1 to 6% by weight of one or more oils, 0.1 to 30% by weight of one or more monoglyceride compounds, 0.01 to 5% by weight of a biocompatible hydrophilic polymer, and water or an aqueous solution for the remainder. Some relates to the composition, wherein the cubosome composition is characterized in that the three-dimensionally stabilized state by the stabilizing action of the biocompatible hydrophilic polymer.

In addition, the present invention relates to a cubosome composition comprising 0.1 to 30% by weight of phytantriol, 0.01 to 5% by weight of a biocompatible hydrophilic polymer, and water or an aqueous solution occupying the remainder. It is characterized in that the three-dimensional stabilized state.

The present invention also relates to a cubosome composition comprising 0.1 to 6% by weight of one or more oils 0.1 to 30% by weight of pytan triol, 0.01 to 5% by weight of a biocompatible hydrophilic polymer, and water or an aqueous solution which accounts for the remainder. The cubosome composition is characterized in that it is three-dimensionally stabilized by the stabilizing action of the biocompatible hydrophilic polymer.

The composition of the steric stabilized emulsion or cubosome of the present invention may be stored in the form of an emulsion precursor or a cubosome precursor composition in which water is removed for long term storage. As a method of removing the water, conventional methods such as freeze drying and spray drying may be used. The present invention provides an emulsion precursor and a cubosome precursor composition which are dried as described above and can be stored for a long time in a stable state.

First, the present invention provides a composition of a long-term storage stereoscopically stabilized emulsion precursor comprising 0.1 to 30 parts by weight of one or more oils, and 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer.

The present invention also provides a long-term storageable steric stabilized emulsion comprising 0.1-30 parts by weight of one or more oils, 0.1-30 parts by weight of one or more monoglyceride compounds, and 0.01-5 parts by weight of a biocompatible hydrophilic polymer. It provides a precursor composition.

The present invention also provides a steric stabilized long-term storeable cubosome precursor composition comprising 0.1 to 30 parts by weight of at least one monoglyceride-based compound and 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer.

In addition, the present invention provides a long-term storage stereoscopically stabilized cubosome comprising 0.1 to 6 parts by weight of at least one oil, 0.1 to 30 parts by weight of at least one monoglyceride compound, and 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer. It provides a precursor composition.

The present invention also provides a steric stabilized long-term storage possible cubosome precursor composition comprising 0.1 to 30 parts by weight of phytantriol and 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer.

The present invention also provides a long-term storage stereoscopically stabilized cubosome precursor composition comprising 0.1 to 6 parts by weight of at least one oil, 0.1 to 30 parts by weight of phytantriol, and 0.01 to 5 parts by weight of the biocompatible hydrophilic polymer. .

It is preferable to use at least one selected from the group consisting of triglyceride, iodide oil, vegetable oil and animal oil as the oil. The triglycerides include monoglyceride compounds that are saturated or unsaturated C ₂ -C ₂₀ . For example, the triglycerides include triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, triolein, and the like. It may include. The iodide oil may include lipidodol, iodide poppy seed oil, ethiodol, and iodized soybean oil. The vegetable oil may include soybean oil, cottonseed oil, olive oil, poppy seed oil, safflower seed oil and sesame oil. The animal oil may include squalane, squalene and the like.

The monoglyceride compound preferably contains a monoglyceride compound which is saturated or unsaturated C10-C22. For example, the monoglyceride compound is monooolein (Monoolein), monopalmititolein (Monopalmitolein), monomyristoleine (Monomyristolein), monoeilaidin (Monoelaidin), monoeirucin (Monoerucin), and vegetable or A mixture of monoglycerides semi-synthesized from triglycerides of animal oil, more preferably monoolein.

The biocompatible hydrophilic polymer is selected from the group consisting of natural polymers, modified natural polymers, and synthetic polymers. The natural polymer is chitosan (chitosan), salts thereof and derivatives thereof; Dextran and its derivatives; Acacia gum; Tragacanthin; Hyaluronic acid, salts thereof and derivatives thereof; Pectin, its salts and derivatives thereof; Alginic acid, its salts and derivatives thereof; Agar; Galactomannans, salts thereof and derivatives thereof; Xanthan, salts thereof and derivatives thereof; Beta-cyclodextrin, its salts and derivatives thereof; And amylose (water soluble starch), salts thereof, derivatives thereof, and the like. Polymers modified from the natural ointment include glycol chitosan, salts thereof and derivatives thereof; Carboxymethyl cellulose (CMC), its salts and derivatives thereof; Hydroxyethyl cellulose (HEC), its salts and derivatives thereof; Hydroxypropyl cellulose (HPC), salts thereof and derivatives thereof; Hydroxypropyl methylcellulose (HMC); Methylcellulose, its salts and derivatives thereof; Cellulose acetate phthalate, salts thereof and derivatives thereof; Gelatin, salts thereof and derivatives thereof; And protamine sulfate (Protamine sulfate) and the like. The synthetic polymer may be poly (beta-hydroxyethyl methacrylate) [Poly (beta-hydroxyethyl methacrylate), PHEMA]; Polyacrylamide (PA); Polyvinyl alcohol (PVA); Polyacrylic acid (PAA), salts thereof and derivatives thereof; Polyvinylpyrrolidone (PVP); Polyethylene oxide (PEO); Polyethylene glycol (PEG); Poly (ethylene oxide-b-propylene oxide), PEO-PPO, polylysine, and the like.

The aqueous solution is preferably selected from the group consisting of an acidic aqueous solution of pH 3 to 6 that can solubilize the hydrophilic polymer, a basic aqueous solution of pH 8 to 10, a buffer solution and a salt solution of pH 5-9.

In addition, the composition may additionally contain other additives in an amount of up to 5% by weight relative to the total weight of the composition. For example, much smaller amounts of emulsifiers may be added than are commonly used for stabilizing emulsions or cubosomes. The emulsion or cubosome composition of the present invention can maintain a three-dimensionally stabilized state without including an emulsifier by emulsification and stabilizing action of the biocompatible hydrophilic polymer included therein, and an amount commonly used even when an emulsifier is included. More significantly less amount can maintain a sufficiently three-dimensionally stabilized state. In addition, the emulsion or cubosome composition of the present invention may further contain a conventionally available additive such as fatty acids, esters of fatty acids, alcohols of fatty acids and the like in an amount of 0 to 5% by weight.

The emulsifier is preferably selected from the group consisting of phospholipids, sphingolipids, nonionic surfactants, anionic surfactants, cationic surfactants and bile acids.

The phospholipid used as the emulsifier preferably includes a phosphatidyl choline derivative, a phosphatidyl ethanolamine derivative, a phosphatidyl serine derivative, and a lipid bound to a hydrophilic polymer. The sphingolipids used as the emulsifier preferably include ceramides, cerrebrosides and sphingomyelins. The nonionic surfactant used as the emulsifier is poloxamer (Poloronic; polyoxyethylene-polyoxypropylene copolymer), sorbitan esters (Span), polyoxyethylene sorbitans (Tween), And polyoxyethylene ethers (Brij). The anionic surfactant used as the emulsifier preferably includes a phosphatidylserine derivative, a phosphatitidic acid derivative, and sodium dodecyl sulfate (SDS). The cationic surfactant used as the emulsifier is 1,2-dioleyl-3-trimethylammonium propane, dimethyldioctadecylammonium chloride, N- [1 -(1,2-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride (N- [1- (1,2-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride), 1, 2-dioleyl-3-ethylphosphocholine (1,2-dioleyl-3-ethylphosphocholine), and 3β- [N-[(N ', N'-dimethylamino) ethane] carbamoyl] cholesterol (3β- [ N-[(N ', N'-dimethylamino) ethan] carbamoyl] chloresterol). Bile acids used as emulsifiers include cholic acid, salts and derivatives thereof; Deoxycholic acid, salts and derivatives thereof; Lithocholic acid, salts and derivatives thereof; And chenoholic acid, salts and derivatives thereof.

Since the biocompatible water-soluble polymers used in the present invention are mainly polymers that are present in nature or are semi-synthesized from them, not only are they easily available, but also have mucosal adsorption, which is advantageous for use as drug delivery systems. In addition, the oil composition comprising the biocompatible hydrophilic polymer is another feature that the emulsification process is very simple by the emulsifier action of the polymer. The oil composition which is stericly stabilized by the biocompatible hydrophilic polymer proposed in the present invention may be utilized to prepare a formulation capable of inducing a controlled release of the drug. In addition, many hydrophilic polymers are biodegradable, bioabsorbable, and biocompatible, thus making them safe materials.

The composition of the steric stabilized emulsion or cubosome of the present invention may be stored in a state where water is removed for long term storage. Generally, in order to dry and store the emulsion, a large amount of freeze-drying protector or creaming inhibitor should be added to increase stability during drying and redispersion. However, in the present invention, since the biocompatible hydrophilic polymer used as a stabilizer effectively prevents agglomeration of particles during freeze-drying, there is a great advantage of not having to add a separate freeze-drying protective agent. In addition, the colloidal particles are adsorbed by the dried polymer and are easily redispersed by adding an aqueous solution to redisperse.

The present invention also provides a method for preparing a composition of a steric stabilized emulsion. The manufacturing method,

1) a good mixture of one or more oils and optionally monoglycerides and / or emulsifiers into a single liquid phase;

2) preparing a solution in which the biocompatible hydrophilic polymer and an emulsifier are optionally mixed with water or an aqueous solution;

3) mixing and dispersing the single liquid phase and the solution obtained in the above steps 1) and 2) together.

At this time, the order of steps 1) and 2) may be changed. In step 1) it can be warmed or sonicated to produce a single liquid phase. Dispersion methods in step 3) include hand shaking, vortexing, sonication, and microfluidization.

The present invention also provides a method for preparing the steric stabilized cubosome composition. The manufacturing method,

1) monoglyceride, phytantriol, monoglyceride / oil mixture or phytantriol / oil mixture and optionally emulsifier well mixed into a single liquid phase;

2) preparing a solution in which the biocompatible hydrophilic polymer and an emulsifier are optionally mixed with water or an aqueous solution;

3) mixing and dispersing the single liquid phase and the solution obtained in the above steps 1) and 2) together.

At this time, the order of steps 1) and 2) may be changed. In step 1) it can be warmed or sonicated to make a single liquid phase. The method of dispersing in step 3) includes shaking by hand, vortexing, sonication, microfluidization, and the like.

Another method for producing the steric stabilized cubosome composition of the present invention,

1) L2 phase, lamellar phase or cubic phase by mixing a monoglyceride, phytantriol, monoglyceride / oil mixture or phytantriol / oil mixture and optionally an emulsifier with an aqueous solution;

2) preparing a solution in which a biocompatible hydrophilic polymer and an emulsifier are optionally added to water or an aqueous solution;

3) mixing and dispersing the L2 phase, lamellar phase or cubic phase obtained in steps 1) and 2) together with the solution.

At this time, the order of steps 1) and 2) may be changed. In step 1) it can be warmed or sonicated to make a single liquid phase. In order to form the L 2 phase, lamellar phase or cubic phase in step 1), a monoglyceride, a phytantriol, a monoglyceride / oil mixture or a phytantriol / oil mixture and an aqueous solution are mixed. At this time, the L 2 phase, lamellar phase or cubic phase is formed depending on the amount of the aqueous solution and the kind of the additive. Lipid mixer (Cheng A., Hummel B., Qiu H., Caffrey M., consisting of a syringe and three-way stop-cork) to prepare L2 phase, lamellar phase or cubic phase in step 1). Chem Phys Lipids, 1998; 95; 11-20) or a similar mixing method can be used. The method of dispersing in step 3) includes shaking by hand, vortexing, sonication, microfluidization, and the like.

The steric stabilized emulsion precursor composition of the present invention can be prepared by drying the steric stabilized emulsion composition of the present invention by a conventional method such as freeze drying or spray drying. The steric stabilized cubosome precursor composition of the present invention can be prepared by drying the steric stabilized cubosome composition of the present invention by a conventional method such as freeze drying or spray drying.

The oils, monoglycerides, biocompatible hydrophilic polymers, emulsifiers and aqueous solutions used in the emulsion or cubosome compositions and methods of preparing the emulsion precursors or cubosome precursors are as described above.

The present invention also provides a formulation comprising a drug and the steric stabilized emulsion or cubosome composition.

More specifically, the present invention provides three-dimensional stabilization comprising 0.1 to 30% by weight of one or more oils, 0.01 to 5% by weight of a biocompatible hydrophilic polymer, 0.1 to 10% by weight of one or more drugs, and water or an aqueous solution to account for the remainder. Emulsion formulations are provided.

The present invention also provides 0.1-30% by weight of one or more oils, 0.1-30% by weight of one or more monoglyceride compounds, 0.01-5% by weight biocompatible hydrophilic polymer, 0.1-10% by weight of one or more drugs, and Provided are three-dimensionally stabilized emulsion formulations comprising water or an aqueous solution to account for the remainder.

In addition, the present invention is in three dimensions comprising 0.1 to 30% by weight of one or more monoglyceride compounds, 0.01 to 5% by weight of biocompatible polymers, 0.1 to 10% by weight of one or more drugs, and water or an aqueous solution to account for the remainder. Provided are stabilized cubosome formulations.

The present invention also provides 0.1 to 6% by weight of one or more oils, 0.1 to 30% by weight of one or more monoglyceride compounds, 0.01 to 5% by weight of biocompatible hydrophilic polymers and 0.1 to 10% by weight of one or more drugs. It provides a three-dimensionally stabilized cubosome formulation comprising water or an aqueous solution occupying.

The present invention also provides steric stabilized cubo comprising 0.1-30% by weight of phytantriol, 0.01-5% by weight of the biocompatible hydrophilic polymer, 0.1-10% by weight of one or more drugs, and water or an aqueous solution occupying the remainder. Provide some formulation.

In addition, the present invention provides 0.1 to 6% by weight of one or more oils, 0.1 to 30% by weight phytantriol, 0.01 to 5% by weight biocompatible hydrophilic polymers, 0.1 to 10% by weight of one or more drugs, and water to account for the remainder. Or a steric stabilized cubosome formulation comprising an aqueous solution.

Formulations of the steric stabilized emulsions or cubosomes of the present invention can be stored with water removed, such as the following emulsion precursor formulations or cubosome precursor formulations, for long term storage. As a method of removing the water, conventional methods such as freeze drying and spray drying may be used.

In this regard, the present invention provides a long-term storage stereoscopically stabilized emulsion precursor formulation comprising 0.1 to 30 parts by weight of one or more oils, 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of one or more drugs. to provide.

The present invention also includes 0.1 to 30 parts by weight of one or more oils, 0.1 to 30 parts by weight of one or more monoglyceride compounds, 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of one or more drugs. It provides a long-term storage steric stabilized emulsion precursor formulation.

In addition, the present invention provides a long-term storage stereoscopically stabilized cubosome precursor comprising 0.1 to 30 parts by weight of at least one monoglyceride compound, 0.01 to 5 parts by weight of biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of at least one drug. Provide formulation.

The present invention also includes 0.1 to 6 parts by weight of at least one oil, 0.1 to 30 parts by weight of at least one monoglyceride compound, 0.01 to 5 parts by weight of biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of at least one water. To provide a long-term storage steric stabilized cubosome precursor formulation.

The present invention also provides a formulation of a long-term storage stereoscopically stabilized cubosome precursor comprising 0.1 to 30 parts by weight of phytantriol, 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of one or more drugs. to provide.

In addition, the present invention is capable of long-term storage containing 0.1 to 6 parts by weight of at least one oil, 0.1 to 30 parts by weight of phytantriol, 0.01 to 5 parts by weight of biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of at least one water. Provided are steric stabilized cubosome precursor formulations.

The oil is preferably selected from one or more of the group consisting of triglycerides, iodide oils, vegetable oils and animal oils. The triglyceride preferably contains a monoglyceride compound which is saturated or unsaturated C2-C20. For example, the triglycerides include triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, triolein, and the like. It may include. The iodide oil may include lipidodol, iodide poppy seed oil, ethiodol, and iodized soybean oil. The vegetable oil may include soybean oil, cottonseed oil, olive oil, poppy seed oil, safflower seed oil and sesame oil. The animal oil may include squalane, squalene and the like.

Preferably, the monoglyceride compound is selected from the group consisting of saturated or unsaturated C10-C22 monoglyceride compound. For example, the monoglyceride-based compound of the present invention is monooolein (Monoolein), monopalmititolein (Monopalmitolein), monomyristoleine (Monomyristolein), monoeilaidin (Monoelaidin), monoeirucin (Monoerucin), and It is selected from a mixture of semi-synthesized monoglycerides from triglycerides of vegetable or animal oil, more preferably monoolein.

In addition, the biocompatible hydrophilic polymer of the present invention may be selected from the group consisting of natural polymer, modified natural polymer, synthetic polymer, and the like. The natural polymer is chitosan (chitosan), salts thereof and derivatives thereof; Dextran and its derivatives; Acacia gum; Tragacanthin; Hyaluronic acid, salts thereof and derivatives thereof; Pectin, its salts and derivatives thereof; Alginic acid, its salts and derivatives thereof; Agar, Galactomannans, salts thereof and derivatives thereof; Xanthan, salts thereof and derivatives thereof; Beta-cyclodextrin, its salts and derivatives thereof; And amylose (soluble starch), salts thereof, derivatives thereof, and the like. Polymers modified from the natural ointment include glycol chitosan, salts thereof and derivatives thereof; Carboxymethyl cellulose (CMC), its salts and derivatives thereof; Hydroxyethyl cellulose (HEC), its salts and derivatives thereof; Hydroxypropyl cellulose (HPC), salts thereof and derivatives thereof; Hydroxypropyl methylcellulose (HMC); Methyl cellulose, its salts and derivatives thereof; Cellulose acetate phthalate, salts thereof and derivatives thereof; Gelatin, salts thereof and derivatives thereof; And protamine sulfate and the like. The synthetic polymer is poly (beta-hydroxyethyl methacrylate) [Poly (beta-hydroxyethyl methacrylate, PHEMA]; polyacrylamide (PA); polyvinyl alcohol (PVA); polyacrylic acid (Polyacrylic acid, PAA), salts thereof and derivatives thereof; polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); polyethylene glycol (PEG); poly (ethylene oxide-b-propylene oxide [Poly ( ethylene oxide-b-propylene oxide), PEO-PPO], and polylysine.

The drugs include proteins, antiviral agents, steroidal anti-inflammatory drugs (SAIDs), nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, antifungal agents, vitamins, hormones, prostaglandin, prostacyclin, anticancer agents, anti-metabolites, mobilizers mitotics, cholinergic drugs, adrenaline antagonists, anticonvulsants, anti-anxiety agents, thermostats, antidepressants, anesthetics, analgesics, anabolic steroids, estrogens, progesteron, glycosaminoglycans (glycosaminoglycan), polynucleotides, P-glycoprotein inhibitors, hepatic metabolism inhibitors, immunosuppressants or immunostimulants and the like.

The protein is a functional peptide (functional peptide); Adrenocorticotropic hormone (ACTH) and fragments; Angiotensin and its related peptides; Antibody fragments; Antigen and fragments thereof; Atrial natriuretic peptide; Bioadhesive peptides; Bradykinin and its related peptides; Calcitonin and its related peptides; Cell surface receptor protein fragments; Chemotactic peptides; Cyclosporins; Cytokines; Dynorphin and its related peptides; Endorphins and β-lidotropin fragments; Enkephalin and its related proteins; Enzyme inhibitors; Fibronectin fragments and related peptides; Gastrointestinal peptide; Growth hormone releasing peptides; Immunostimulating peptides; Insulin and insulin-like growth factor; Interleukins, luthenizing hormone releasing hormone (LHRH) and related peptides; Melanocyte stimulating hormone and related peptides; Nuclear localization signal related peptides; Neurotensin and related peptides; Neurotransmitter peptides; Opioid peptides; Oxytocin; Vasopressin and its related peptides; Parathyroid hormones and fragments; Protein kinase related peptides; Somatostatin and related peptides; Substrate P and its related peptides; Transforming growth factor (TGF) and related peptides thereof; Tumor necrosis factor fragments; Immunoglobulins, angiogenin, bone morphogenic protein, chemokine, colony stimulating factor (CSF) and related proteins, growth factors, Interferon, interleukin, leptin, leukemia inhibitory factor, stem cell factors and toxins or toxoids. In this case, the related peptides and related proteins refer to peptides and proteins similar in structure or function to slightly different amino acids. Among the peptides used as the drug, insulin is bovine pancreatic insulin, human recombinant insulin, porcine pancreatic insulin, arg-insulin, and insulin-biotin. ), Insulin-FITC (insulin-FITC), LisPro (Ely Lilly, USA), and polyethylene glycol-insulin (polyethylene glycol-insulin, PEG-insulin). In addition, the functional peptide may include anticancer peptides including angiostatin, antihypertension peptides, antiblood-clotting peptides, and antimicrobial peptides. Can be.

The anticancer agent may be a doxorubicin, cisplatin, carboplatin, carmustine (BCNU), dacarbazine, edoposide, fluorouracil (5-FU) or paclitaxel and derivatives thereof. The paclitaxel derivative may include paclitaxel, docetaxel, bromotaxel, taxotere, and the like. The P-glycoprotein inhibitor may include a cinchonin, a calcium channel inhibitor, a calmodulin antagonist, a vinca alcaloid, an antiarrhythmic agent, a steroid, an antihypertensive agent, an antiparasitic agent, an immunosuppressive agent, and the like. At this time, the calcium channel inhibitor may include verapamil, nifedipine, nididipine, nicardipine, dihydropyridines such as nitrendipine, and the like. The calmodulin antagonist may include trifluoroperazine and the like. The antihypertensive agent may include respine or the like. The vinca alkaloid may include vincristine, vinblastine, and the like. The steroid may include progesterone and the like. The antiarrhythmic agent may include amiodarone, quinidine, and the like. The repellent may include quinacrine, quinine, and the like. The immunosuppressive agents may include cyclosporins, staurosporine, tacrolimus, and the like. The hepatic metabolism inhibitor may include an anticancer agent such as cyclosporin A, doxorubicin, etoposide (VP-16) or cisplatin, verapamil, and tamoxifen.

In addition, the formulation may additionally contain other additives in an amount of up to 5% by weight relative to the total weight of the composition. For example, much smaller amounts of emulsifiers may be added than are commonly used for stabilizing emulsions or cubosomes. In addition, it is possible to contain 0 to 5% by weight of commonly available additives such as fatty acids, esters of fatty acids, alcohols of fatty acids and the like.

The emulsifier is preferably selected from phospholipids, sphingolipids, nonionic surfactants, anionic surfactants, cationic surfactants and bile acids.

The phospholipid used as the emulsifier is preferably selected from the group consisting of phosphatidyl choline derivatives, phosphatidyl ethanolamine derivatives, phosphatidyl serine derivatives, and polymeric lipids bound to hydrophilic polymers. Do. Sphingo lipid used as the emulsifier is preferably selected from the group consisting of ceramides (ceramides), cerebroside (cerebroside), and sphingomyelins (sphingomyelins). Nonionic surfactants used as emulsifiers include poloxamer (Poloronic; polyoxyethylene-polyoxypropylene copolymer), sorbitan esters (Span), polyoxyethylene sorbitans (Tween), And polyoxyethylene ethers (Brij). The anionic surfactant used as the emulsifier is preferably selected from the group consisting of phosphatidylserine derivatives, phosphatitidic acid derivatives, and sodium dodecyl sulfate (SDS). The cationic surfactant used as the emulsifier is 1,2-dioleyl-3-trimethylammonium propane, dimethyldioctadecylammonium chloride, N- [1 -(1,2-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride (N- [1- (1,2-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride), 1, 2-dioleyl-3-ethylphosphocholine (1,2-dioleyl-3-ethylphosphocholine), and 3β- [N-[(N ', N'-dimethylamino) ethane] carbamoyl] cholesterol (3β- [ N-[(N ', N'-dimethylamino) ethan] carbamoyl] chloresterol) is preferably selected from the group consisting of. The bile acids used as emulsifiers are cholic acid (cholic acid) and salts and derivatives thereof, deoxycholic acid and salts and derivatives thereof, lithocholic acid and salts and derivatives thereof, and chenocholic acid (Chenocholic acid) and salts and derivatives thereof are preferably selected from the group consisting of.

The aqueous solution is selected from the group consisting of an acidic aqueous solution of pH 3 to 6 capable of solubilizing the hydrophilic polymer, a basic aqueous solution of pH 8 to 10, a buffer solution of pH 5 to 9 and a salt solution.

The present invention also provides a method for preparing the steric stabilized emulsion formulation. The manufacturing method,

1) one or more oils, drugs and optionally monoglycerides and / or emulsifiers are well mixed to form a single liquid phase;

2) preparing a solution by mixing biocompatible hydrophilic polymer and emulsifier optionally in water or aqueous solution;

3) mixing and dispersing the single liquid phase obtained in steps 1) and 2) together with the solution.

At this time, the order of steps 1) and 2) may be changed. In step 1) it can be warmed or sonicated to produce a single liquid phase. Dispersion in step 3) may be performed by hand shaking, vortexing, sonication, microfluidization, or the like.

The present invention also provides a method for preparing a stereosterically stabilized cubosome formulation. The manufacturing method,

1) monoglyceride, phytantriol, monoglyceride / oil mixture or phytantriol / oil mixture, drug and optionally an emulsifier well mixed into a single liquid phase;

2) preparing a solution in which a biocompatible hydrophilic polymer and an emulsifier are optionally added to water or an aqueous solution;

3) mixing and dispersing the single liquid phase and the solution obtained in the above steps 1) and 2) together.

At this time, the order of steps 1) and 2) may be changed. In step 1) it can be warmed or sonicated to produce a single liquid phase. Dispersion in step 3) may be performed by hand shaking, vortexing, sonication, microfluidization, or the like.

Formulation of the three-dimensionally stabilized cubosome of the present invention another manufacturing method,

1) L2 phase, lamellar phase or cubic phase by mixing monoglycerides, phitantris, monoglyceride / oil mixtures or phytantriol / oil mixtures, optionally emulsifiers with aqueous solution;

2) preparing an aqueous solution in which the biocompatible hydrophilic polymer and an emulsifier are optionally added to water or an aqueous solution;

3) mixing and dispersing the L2 phase, lamellar phase or cubic phase and the liquid phase obtained in the above steps 1) and 2) together.

At this time, the order of steps 1) and 2) may be changed. In step 1), a method of preparing the L2 phase, lamellar phase or cubic phase may be performed using a lipid mixer consisting of a syringe and a three-way stop-cork, or a similar mixing method. The drug of step 1) is mixed with lipid in case of fat soluble, and with aqueous solution if water-soluble. In step 1), an aqueous solution is mixed with a monoglyceride, a phytantriol, a monoglyceride / oil mixture or a phytantriol / oil mixture to form an L 2 phase, lamellar phase or cubic phase. At this time, L2 phase, lamellar phase or cubic phase is formed according to the amount of the aqueous solution and the kind of the additive. Dispersion in step 3) may be performed by hand shaking, vortexing, sonication, microfluidization, or the like.

The formulation of the steric stabilized emulsion precursor or cubosome precursor of the present invention can be prepared using conventional methods such as freeze drying or spray drying the emulsion formulation or cubosome formulation.

The oils, monoglycerides, biocompatible hydrophilic polymers, emulsifiers and aqueous solutions used in the emulsion or cubosome compositions and methods of preparing the emulsion precursors or cubosome precursors are as described above.

The composition and formulation according to the present invention effectively form a colloidal system even when there is no emulsifier or only a small amount, and after drying the composition or formulation of the emulsion or cubosome, they help to exist as a solid rather than a liquid phase, and the water-soluble polymer It helps redistribution increases the industrial availability. In addition, biocompatible water-soluble polymers have an advantage in that they can help absorption into cells because they have excellent mucosal adsorption.

Some of the biocompatible hydrophilic polymers used in the present invention have the property of easily crosslinking. For example, chitosan may be cross-linked using biocompatible ions such as calcium ions such as sulfate ions and tripolyphosphate (TPP), alginate salts, and hyaluronic acid salts. Therefore, the composition or formulation of the present invention can be prepared by crosslinking the polymer, and when crosslinked after drying, the physical properties such as powder appear to help solidification. In addition, when diluted with excess body fluid in vivo, the crosslinking agent is diluted and returned to its original state, so that the colloidal system is dispersed again.

In the case of cubosomes, although there is an advantage of increasing the bioavailability of the drug has a critical problem that is difficult to put to practical use. That is, the cubosome is a system dispersed in an excess of aqueous solution, so in case of the oral administration of the formulations, the excess water should be administered together. Thus, in the case of drug delivery systems, the powder form prepared by removing water may be the most suitable formulation. However, the dispersion of the cubosome becomes semi-solid or liquid when water is removed, and it is difficult to disperse spontaneously by intestinal movement in the body because it is difficult to redistribute without an anti-aggregating agent, thereby reducing drug delivery efficiency. Therefore, the present invention is capable of solubilizing a drug, is biocompatible, dispersed in the intestine by several micrometers in size by the intestinal fluid, and has strong mucosal adsorption, thereby increasing the bioavailability of the drug. While providing a composition or formulation in a powder state, it can be said that the possibility of industrialization is great.

The emulsion or cubosome composition of the present invention is useful as a drug delivery system for poorly soluble and / or amphoteric drugs due to the inclusion of a biocompatible hydrophilic polymer, which is excellent in dispersibility and stability even when no emulsifier is used separately or even in very small amounts.

Hereinafter, the present invention will be described in detail by way of examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Embodiment for Invention

Experimental Example 1. Preparation of chitosan and its aqueous solution having different molecular weight

Chitosan having a molecular weight of> 100 kDa (deacetylation degree = 95%; Shinyoung Chemical, Korea) was hydrolyzed by reacting with sodium nitrite (NaNO2) in a 2% by weight acetic acid solution to prepare a low molecular weight chitosan. The molecular weight of chitosan was determined by measuring the viscosity of chitosan aqueous solution. Viscosity was measured with an Ostwald viscometer and the molecular weight of chitosan was determined by plotting the viscosity against chitosan concentration to determine the intrinsic viscosity (Zhang H .; Neau SH .; Biomaterials, 2001). 22; 1653-1658 .; Chen RH, Hwa HD ,; Carbohydr.Polym .; 1996; 29; 253.). The intrinsic viscosity and molecular weight of the chitosan thus obtained are shown in Table 1 below.

TABLE 1

The chitosan aqueous solution was prepared by putting each chitosan having a different molecular weight into an aqueous solution, followed by stirring. When the molecular weight is 20 kDa or more, the aqueous solution used sodium acetate buffer solution of pH 4.8 or less, or acetic acid solution of 2% (v / v) or less, water was used if less than 10 kDa.

Example 1 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution

100 μL of soybean oil (Sigma Chemical Company) was added to 900 μL of 3% chitosan (molecular weight 22 kDa) aqueous solution and then emulsified by sonication for 2 minutes or by vortexing for about 15 seconds 10% by weight chitosan 2.7% by weight Phosphorus fat emulsion was prepared. The particle size of the emulsion was measured by laser quasi-elastic light scattering method (Brookhaven Instruments, USA). The average diameters of the particles were 50 nm and 526 nm, respectively, when sonicated and vortexed.

Comparative Example 1. Preparation of vegetable oil emulsion composition without addition of aqueous polymer solution 1

An emulsion was prepared in the same manner as in Example 1, except that water was used instead of the aqueous chitosan solution. Both the sonication and vortexing confirmed visual and microscopic observation that phase separation occurred within minutes. The particle size was measured in the same manner as in Example 1, but the particle size could not be measured because phase separation occurred.

Example 2 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution

An emulsion was prepared in the same manner as in Example 1, except that chitosan having a molecular weight of 11 kDa and 100 kDa was used instead of the chitosan having a molecular weight of 22 kDa. As a result of measuring the particle size in the same manner as in Example 1, when vortexing, the average diameters of the particles were 526 nm and 909 nm, respectively.

Comparative Example 2 Preparation of Vegetable Oil Emulsion Composition without Adding Polymer Aqueous Solution 2

An emulsion was prepared in the same manner as in Example 2, except that water was used instead of the aqueous chitosan solution. Both the sonication and vortexing confirmed visual and microscopic observation that phase separation occurred within minutes. The particle size was measured in the same manner as in Example 1, but the particle size could not be measured because phase separation occurred.

Example 3 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution

An emulsion was prepared in the same manner as in Example 1, except that alginate (Yakuri Pure Chemicals, Japan) or polyethylene oxide (molecular weight 35 kDa; Fluka) was used instead of chitosan. In the case of vortexing, the average diameter of particles is shown in Table 2. On the other hand, when water is used instead of chitosan aqueous solution, it is not dispersed at all.

TABLE 2

Example 4 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution

Sesame oil (Sigma) or tricaproin (Sigma) is used instead of soybean oil, and chitosan with a molecular weight of 11 kDa is used instead of chitosan with a molecular weight of 22 kDa, except that the composition ratio between oil and chitosan is changed. An emulsion was prepared in the same manner as in Example 1. The average diameter of the particles in the case of vortexing is shown in Table 3. When water was used instead of aqueous chitosan solution, it was not dispersed at all.

TABLE 3

Example 5 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 5

An emulsion was prepared in the same manner as in Example 1, except that tricapryline (Sigma) was used instead of soybean oil, and chitosan having a molecular weight of 35 kDa was used instead of chitosan having a molecular weight of 22 kDa. The average diameter of the particles in the case of vortexing was 1137 nm. When water was used instead of aqueous chitosan solution, it was not dispersed at all.

Example 6 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 6

An emulsion was prepared in the same manner as in Example 1, except that alginate was used instead of chitosan, and sesame oil was used instead of soybean oil. As a result of measuring the particle size in the same manner as in Example 1, the average diameter of the particles when vortexing was 1290 nm, respectively.

Example 7 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution in the Presence of Emulsifiers

100 μL of the mixture of soybean oil and emulsifier (Tween 80 or DMTAP; 1,2-dimyristoyl-3-trimethylammonium propane, Sigma) was added to 900 μL of an aqueous 3% chitosan solution having different molecular weight and then emulsified in the same manner as in Example 1. I was. The molecular weight of the chitosan used, the type of emulsifier, the composition ratio and the average diameter of the particles obtained after vortexing are shown in Table 4. When water was used instead of aqueous chitosan solution, it was not dispersed at all.

TABLE 4

Example 8 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution in the Presence of Emulsifiers

100 μL of the mixture of soybean oil and Tween 80 was added to 900 μL of an aqueous solution of 1% or 0.11% polyethylene oxide (molecular weight 35 kDa) and emulsified in the same manner as in Example 1. Table 5 shows the average diameters of the particles obtained after vortexing. When water was used instead of aqueous polyethylene oxide solution, it was not dispersed at all.

TABLE 5

Example 9 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution in the Presence of Emulsifiers 3

100 μL of the mixture of soybean oil and Tween 80 was added to 900 μL of different types of 1% aqueous polymer solution and emulsified in the same manner as in Example 1. Table 6 shows the polymer type, composition ratio and average diameter of the particles obtained after vortexing. When water was used instead of the aqueous polymer solution, it was not dispersed at all.

TABLE 6

Example 10 Preparation of Vegetable Oil Emulsion Composition Stabilized with Aqueous Polymer Solution in the Presence of Emulsifiers 4

100 μL of the mixture of sesame oil and different emulsifiers was added to 900 μL of different aqueous polymer solutions and emulsified in the same manner as in Example 1. The types, composition ratios, and average diameters of the particles obtained after vortexing are shown in Table 7 below. When water was used instead of the aqueous polymer solution, it was not dispersed at all.

TABLE 7

Example 11 Preparation of Triglyceride Oil Emulsion Composition Stabilized with Aqueous Polymer Solution in the Presence of Emulsifiers 5

100 μL of a mixture of various triglycerides and different emulsifiers was added to 900 μL of an aqueous polymer solution of different types and concentrations, and emulsified in the same manner as in Example 1. Table 8 shows the types of oils, polymers, and emulsifiers used, the composition ratios, and the average diameter of the particles obtained after vortexing. When water was used instead of the aqueous polymer solution, it was not dispersed at all.

TABLE 8

Example 12 Preparation of Animal Oil Emulsion Composition Stabilized with Aqueous Polymer Solution in the Presence of Emulsifiers

100 μL of a mixture of animal oil, squalene or squalane and a different emulsifier, was added to 900 μL of an aqueous 3% chitosan (molecular weight 11 kDa) solution and emulsified in the same manner as in Example 1. Table 9 shows the average diameters of the particles obtained after vortexing. When water was used instead of the aqueous polymer solution, it was not dispersed at all.

TABLE 9

Example 13 Preparation of a Mixed Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 1

10 μL of the mixed oil mixed with tricaprine and monoolein in a volume ratio of 1: 2 was added to 990 μL of 0.1, 0.5, 1.5% chitosan (molecular weight 3 kDa) aqueous solution, and emulsified in the same manner as in Example 1. Table 10 shows the average diameters of the particles obtained after vortexing. When water is used instead of the aqueous polymer solution, the average particle size of 2000 nm is achieved. However, unlike dispersion in the polymer solution, phase separation occurs after 2 to 3 hours.

TABLE 10

Example 14 Preparation of a Mixed Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 2

The emulsification was carried out in the same manner as in Example 13, except that 990 µL of an aqueous solution of 0.75% and 1% chitosan (molecular weight 35 kDa) was used. Table 11 shows the average diameters of the particles obtained after vortexing. When water is used instead of the aqueous polymer solution, the average particle size is about 2000 nm. However, unlike the case of dispersion in the polymer solution, phase separation occurs after 2 to 3 hours.

TABLE 11

Example 15 Preparation of a Mixed Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 3

The emulsification was carried out in the same manner as in Example 13, except that 990 µL of 0.1% and 0.5% chitosan (molecular weight 74 kDa) aqueous solutions were used. Table 12 shows the average diameters of the particles obtained after vortexing. When water is used instead of the aqueous polymer solution, the average particle size of 2000 nm is achieved. However, unlike dispersion in the polymer solution, phase separation occurs after 2 to 3 hours.

TABLE 12

Example 16 Preparation of a Mixed Oil Emulsion Composition Stabilized with an Aqueous Polymer Solution 4

The emulsification was carried out in the same manner as in Example 13 except that tricapryline was used instead of tricaprine and 990 μL of an aqueous 3% chitosan (molecular weight 35 kDa) solution was used. A stable dispersion system with an average diameter of particles of 1527 nm was achieved. When water is used instead of the aqueous polymer solution, the average particle size is about 530 nm. However, unlike the dispersion in the polymer solution, it is unstable and phase separation occurs after 2 to 3 hours.

Example 17 Preparation of a Mixed Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 5

The emulsification was carried out in the same manner as in Example 13, except that 30 μL of tricaproin was used instead of tricaprine and 970 μL of an aqueous 3% chitosan (molecular weight 35 kDa) solution was used. A stable dispersion system with an average diameter of particles of 1790 nm was achieved. When water is used instead of the aqueous polymer solution, the average particle size is about 1600 nm. However, unlike the dispersion in the polymer solution, it is unstable and phase separation occurs after 2 to 3 hours.

Example 18 Preparation of a Mixed Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 6

The emulsification was carried out in the same manner as in Example 13, except that 990 µL of a 0.3, 0.9% chitosan (molecular weight 11 kDa) aqueous solution was used. Table 13 shows the average diameters of the particles obtained after vortexing. When water is used instead of the aqueous solution, the average particle size is about 1500 nm. However, unlike dispersion in the polymer solution, it is unstable and phase separation occurs after 2 to 3 hours.

TABLE 13

Example 19 Preparation of a Mixed Oil Emulsion Composition Stabilized with Aqueous Polymer Solution 7

The emulsification was carried out in the same manner as in Example 13, except that 990 µL of an aqueous solution of 0.033% alginate and 1% polyethylene oxide (molecular weight 35 kDa) was used. Table 14 shows the average diameters of the particles obtained after vortexing. When water is used instead of the aqueous polymer solution, the average particle size of 2000 nm is achieved. However, unlike dispersion in the polymer solution, phase separation occurs after 2 to 3 hours.

TABLE 14

Example 20. Preparation of Mixed Oil Emulsion Composition Stabilized with Aqueous Polymer Solution in the Presence of Emulsifiers

Various types and concentrations of emulsifiers were added to a mixed oil mixed with triglycerides and monoolein in a volume ratio of 1: 2 to form a single liquid phase, and then emulsified in the same manner as in Example 1 after being put in aqueous solutions of various types and concentrations. The kind and concentration of the polymer and the emulsifier used, the composition ratio and the average diameter of the particles obtained after vortexing are shown in Table 15. The average particle size when water is used instead of the aqueous polymer solution is also shown in Table 15. However, when water is used, it is unstable, unlike when dispersed in a polymer solution, and phase separation occurs after 2 to 3 hours.

TABLE 15

Example 21. Vegetable Oil Emulsion Formulation Stabilized with Aqueous Polymer Solution Containing Cyclosporin A

2 mg of cyclosporin A was dissolved in 100 μL of soybean oil, and then added to 0.33% (w / v) chitosan (molecular weight 35 kDa) aqueous solution and emulsified in the same manner as in Example 1. The particle size was measured in the same manner as in Example 1. The average diameters of the particles in the case of sonication and in the case of vortexing were 58 nm and 374 nm, respectively.

Example 22. Vegetable Oil Emulsion Formulation Stabilized with Aqueous Polymer Solution Containing Pyrene

Emulsification was carried out in the same manner as in Example 21, except that pyrene was used instead of cyclosporin A. The particle size was measured in the same manner as in Example 1. The average diameters of the particles in the case of sonication and in the case of vortexing were 83 nm and 574 nm, respectively.

Example 23. Vegetable Oil Emulsion Formulation Stabilized with Aqueous Polymer Solution Containing Cyclosporin A When Emulsifier is Present

Emulsion formulations were prepared after dissolving 2 mg of cyclosporin A in a mixture of 100 μL of soybean oil and 3 μL of Tween 80, and then adding it to 897 μL of 0.3% (w / v) chitosan (molecular weight 35 kDa) solution. The particle size was measured in the same manner as in Example 1. The average diameter of the particles in the case of vortexing was 354 nm.

Example 24. Vegetable Oil Emulsion Formulation Stabilized with Aqueous Polymer Solution Containing Talifurate, if Emulsifier is Present

Emulsification was carried out in the same manner as in Example 2 except that taliframate was used instead of cyclosporin A. The particle size was measured in the same manner as in Example 1. The average diameter of the particles in the case of vortexing was 945 nm, respectively.

Example 25. Mixed Emulsion Formulations Stabilized with Aqueous Polymer Solution Containing Cyclosporin A

Emulsion formulations were prepared in the same manner as in Example 21, except that soybean oil was mixed with triglyceride and monoglyceride in various ratios and heated at about 30 ° C. to dissolve the drug. The particle size was measured in the same manner as in Example 1. Table 16 shows the average diameter of the particles in the case of vortexing.

TABLE 16

Example 26. Mixed Emulsion Formulations Stabilized with Aqueous Polymer Solution Containing Cyclosporin A When Emulsifier is Present

An emulsion formulation was prepared in the same manner as in Example 23, except that soybean oil was mixed with tricapryline and monoglyceride in various ratios and heated at about 30 ° C. to dissolve the drug. The particle size was measured in the same manner as in Example 1. Table 17 shows the average diameter of the particles in the case of vortexing. When water is used instead of the aqueous polymer solution, the average particle size of 2000 nm is achieved. However, unlike dispersion in the polymer solution, phase separation occurs after 2 to 3 hours.

TABLE 17

Example 27. Mixed Emulsion Formulations Stabilized with Aqueous Polymer Solution Containing Pyrene

Emulsion formulations were prepared in the same manner as in Example 22, except that soybean oil was mixed with tricapryline and monoglyceride in various ratios and heated at about 30 ° C. to melt the drug. Particle size was measured in the same manner as in Example 1. Table 18 shows the average diameters of the particles in the case of vortexing.

TABLE 18

Example 28. Mixed Emulsion Formulations Stabilized with Aqueous Polymer Solution Containing Pyrene with Emulsifier

An emulsion formulation was prepared in the same manner as in Example 23 except for using mixed oil mixed with tricapryline and monoglyceride in various ratios instead of soybean oil and pyrene instead of cyclosporin A. Table 19 shows the average diameter of the particles in the case of vortexing. When water is used instead of the aqueous polymer solution, the average particle size of 2000 nm is achieved. However, unlike dispersion in the polymer solution, phase separation occurs after 2 to 3 hours.

TABLE 19

Example 29. Mixed Emulsion Formulations Stabilized with Aqueous Polymer Solution Containing Talifurate

An emulsion formulation was prepared in the same manner as in Example 27 except for using talifrumate instead of pyrene. Particle size was measured in the same manner as in Example 1. Table 20 shows the average diameters of the particles in the case of vortexing.

TABLE 20

Example 30. Mixed Emulsion Formulations Stabilized with Aqueous Polymer Solution Containing Talifurmate in the Presence of Emulsifiers

An emulsion formulation was prepared in the same manner as in Example 23, except for using mixed oil mixed with tricapryline and monoglyceride in various ratios instead of soybean oil, and using talifurate instead of cyclosporin A. The average diameter of the particles in the case of vortexing was 459 nm.

Example 31. Mixed Emulsion Formulation Stabilized with Aqueous Polymer Solution Containing Paclitaxel

An emulsion formulation was prepared in the same manner as in Example 27 except that paclitaxel was used instead of pyrene. Particle size was measured in the same manner as in Example 1. The average diameter of the particles in the case of vortexing is shown in Table 21.

TABLE 21

Example 32. Preparation of Cubosome Composition Stabilized with Aqueous Polymer Solution 1

650 μL of monoolein was placed in a 3 ml syringe, 350 μL of water was placed in another syringe, and air was removed from each syringe. Two syringes were connected by three-way stopcork and alternately pushed about 100 times to prepare a cubic phase. A cubosome was prepared by adding 500 μL of cubic phase to 10 ml of a 3% chitosan solution and vortexing. Microscopic observation of the prepared cubosome showed particles with a diameter of 20 μm, and many particles having a size of about 1 to 3 μm were observed. In addition, the clear solution of the dispersion was filtered with a syringe filter having a 450 nm hole size was 105 nm as a result of measuring the average particle size in the same manner as in Example 1. The particle size ranged from 100 nm to 20 μm and existed as a solid without phase separation after freeze-drying.

Comparative Example 3. Preparation of cubosome composition without addition of aqueous polymer solution

A cubosome was prepared in the same manner as in Example 32, except that water was used instead of the aqueous chitosan solution. The cubic phase was not distributed at all.

Example 33. Preparation of a Cubosome Composition Stabilized with an Aqueous Polymer Solution 2

A cubosome was prepared in the same manner as in Example 32 except that 5% tripolyphosphate (TPP) aqueous solution was used instead of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. Since TPP crosslinks chitosan, the solid phase showed powder-like properties. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 34. Preparation of Cubosome Composition Stabilized with an Aqueous Polymer Solution Added Emulsifier 1

An emulsion was prepared in the same manner as in Example 32, except that an aqueous solution containing 1% Pluronic F 127 (BASF, USA) as an emulsifier and 3% chitosan was used instead of the aqueous chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in an aqueous 1% Pluronic F 127 solution instead of an aqueous solution containing 1% Pluronic F 127 and 3% chitosan, the cubic phase was dispersed similarly to that using the chitosan solution, but became semisolid after freeze-drying and difficult to redisperse. .

Comparative Example 4. Preparation of cubosome composition without addition of aqueous polymer solution with emulsifier 1

An emulsion was prepared in the same manner as in Example 34, except that 1% Pluronic F 127 was used instead of an aqueous solution containing 1% Pluronic F 127 (BASF, USA) and 3% Chitosan. The cubic phase was not distributed at all.

Example 35. Preparation of Cubosome Composition Stabilized with Aqueous Polymer Solution Added Emulsifier 2

A cubosome was prepared in the same manner as in Example 34 except that a 5% tripolyphosphate (TPP) aqueous solution was used instead of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. Since TPP crosslinks chitosan, the solid phase showed powder-like properties. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 36 Preparation of a Cubosome Composition Stabilized with an Aqueous Polymer Solution 3

A cubosome was prepared in the same manner as in Example A1 except that an aqueous 3% glycol chitosan solution was used instead of the aqueous chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 37. Preparation of a Cubosome Composition Stabilized with Aqueous Polymer Solution 5

A cubosome was prepared in the same manner as in Example 32 except that an aqueous 1% alginate aqueous solution was used instead of an aqueous chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of an aqueous alginate solution, the cubic phase was not dispersed at all.

Example 38. Preparation of a Cubosome Composition Stabilized with an Aqueous Polymer Solution 6

A cubosome was prepared in the same manner as in Example 37, except that 3% aqueous calcium chloride solution was used instead of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. Calcium ion crosslinks alginate, so the solid phase showed powder-like properties. When dispersed in water instead of an aqueous alginate solution, the cubic phase was not dispersed at all.

Example 39. Preparation of a Cubosome Composition Stabilized with Aqueous Polymer Solution 7

A cubosome was prepared in the same manner as in Example 32, except that phitantriol was used instead of monoolein. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 40. Preparation of a Cubosome Composition Stabilized with Aqueous Polymer Solution 8

A cubosome was prepared in the same manner as in Example 39, except that 5% aqueous TPP solution was used instead of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. Since TPP crosslinks chitosan, the solid phase showed powder-like properties. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 41. Preparation of Cubosome Composition Stabilized with Polymeric Aqueous Solution Added Emulsifier 2

An emulsion was prepared in the same manner as in Example 40, except that an aqueous solution containing 1% Pluronic F 127 (BASF, USA) as an emulsifier and 3% chitosan was used instead of the aqueous chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in an aqueous 1% Pluronic F 127 solution instead of an aqueous solution containing 1% Pluronic F 127 and 3% chitosan, the cubic phase was dispersed similarly to that using the chitosan solution, but became semisolid after freeze-drying and difficult to redisperse. .

Comparative Example 5 Preparation of a Cubosome Composition 2 Without Adding an Aqueous Polymer Solution

An emulsion was prepared in the same manner as in Example 41, except that 1% Pluronic F 127 was used instead of an aqueous solution containing 1% Pluronic F 127 (BASF, USA) and 3% Chitosan. The cubic phase was not distributed at all. The cubic phase was dispersed similarly to the one using the chitosan solution but became semisolid after lyophilization and difficult to redisperse.

Example 42 Preparation of Cubosome Compositions Stabilized with Aqueous Polymer Solution 9

A cubosome was prepared in the same manner as in Example 35, except that an aqueous 3% glycol chitosan solution was used instead of the aqueous chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 43. Preparation of Cubosome Formulations Stable with Aqueous Polymer Solution 1

Cubosomes were prepared in the same manner as in Example 35, except that monoolein containing pyrene 1% (w / w) was used instead of monoolein. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. Since TPP crosslinks chitosan, the solid phase showed powder-like properties. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 44 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution 2

A cubosome was prepared in the same manner as in Example 43 except that a 5% tripolyphosphate (TPP) aqueous solution was used instead of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. Since TPP crosslinks chitosan, the solid phase showed powder-like properties. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 45 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Added Emulsifier 1

An emulsion was prepared in the same manner as in Example 43, except that an aqueous solution containing 1% Pluronic F 127 (BASF, USA) as an emulsifier and 3% chitosan was used instead of the aqueous chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in an aqueous 1% Pluronic F 127 solution instead of an aqueous solution containing 1% Pluronic F 127 and 3% chitosan, the cubic phase was dispersed similarly to that using the Chitosan solution, but became semisolid after freeze-drying and difficult to redisperse. .

Example 46 Preparation of Cubosome Formulation Without Adding Aqueous Polymer Solution

An emulsion was prepared in the same manner as in Example 32, except that 1% Pluronic F 127 was used instead of an aqueous solution containing 1% Pluronic F 127 (BASF, USA) and 3% Chitosan. The cubic phase was dispersed similarly to the one using the chitosan solution but became semisolid after lyophilization and difficult to redisperse.

Example 47 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Added Emulsifier 2

A cubosome was prepared in the same manner as in Example 34 except that 5% tripolyphosphate (TPP) aqueous solution was used instead of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. Since TPP crosslinks chitosan, the solid phase showed powder-like properties. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 48. Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Added Emulsifier 3

A cubosome was prepared in the same manner as in Example 45 except that phitantriol was used instead of monoolein. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 49 Preparation of Cubosome Formulations Stabilized with Aqueous Polymer Solution Containing Bovine Serum Albumin 1

A cubosome was prepared in the same manner as in Example 32 except that an aqueous 1% FITC-bovine serum albumin (FITC-BSA) solution was used instead of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 50 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing Bovine Serum Albumin 2

A cubosome was prepared in the same manner as in Example 49, except that phitantriol was used instead of monoolein. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 51 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing Insulin 1

650 μL of monoolein was placed in a 3 ml syringe and 350 μL of 5% TPP solution was placed in another syringe to remove air from each syringe. Two syringes were connected by three-way stopcork and alternately pushed about 100 times to prepare a cubic phase. Instead of the TPP solution, a 240 mg / ml insulin solution was added to prepare a cubic phase in the same manner. 250 μL of each of the two cubic phases was taken and placed in 10 ml of a 3% chitosan solution, and again connected to a three-way stopcock to alternately push about 100 times to prepare a cubic phase. The particle size of the prepared cubosome was 100 nm ~ 20 μm, the freeze-dried appearance is as shown in FIG. As can be seen in Figure 1, after lyophilization it was present as a solid without phase separation.

Example 52. Preparation of Cubosome Formulations Stabilized with Aqueous Polymer Solution Containing Insulin 2

650 μL of monoolein was placed in a 3 ml syringe, 350 μL of 5% TPP solution was placed in another syringe and air was removed from each syringe. Two syringes were connected by three-way stopcork and alternately pushed about 100 times to prepare a cubic phase. Instead of the TPP solution, a 240 mg / ml insulin solution was added to prepare a cubic phase in the same manner. 250 μL of the two cubic phases were taken, respectively, and placed in 10 ml of a 3% chitosan solution to vortex to prepare a cubic phase. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying.

Example 53 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing an Emulsifier Containing Insulin 1

Cubosomes were prepared in the same manner as in Example 51, except that an aqueous solution containing 1% Pluronic F 127 and 3% chitosan was used instead of the 3% chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 54 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing Bovine Serum Albumin 3

950 μL of monoolein was placed in a 3 ml syringe and 50 μL of 1% FITC-BSA solution was placed in another syringe and air was removed from each syringe. Two syringes were connected by three-way stopcork and alternately pushed about 100 times to prepare L2 phase. 500 μL of L2 phase was taken and placed in 10 ml of a 3% chitosan solution to vortex to prepare a cubic phase. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying.

Example 55 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing an Emulsifier Containing Bovine Serum Albumin 1

Cubosomes were prepared in the same manner as in Example 54, except that an aqueous solution containing 1% Pluronic F 127 and 3% chitosan was used instead of the 3% chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 56 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing Bovine Serum Albumin 4

850 μL of monoolein was placed in a 3 ml syringe and 150 μL of 1% FITC-BSA solution was placed in another syringe to remove air from each syringe. Two syringes were connected by three-way stopcork and alternately pushed about 100 times to prepare a lamellar liquid crystal phase. 500 μL of a lamellar liquid crystal phase was taken and placed in 10 ml of a 3% chitosan solution to vortex to prepare a cubic phase. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying.

Example 57 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing an Emulsifier Containing Bovine Serum Albumin 2

A cubosome was prepared in the same manner as in Example 56, except that an aqueous solution containing 1% Pluronic F 127 and 3% chitosan was used instead of the 3% chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 58. Preparation of a Cubosome Composition Stabilized with an Aqueous Polymer Solution 10

300 μL of monoolein was added to 10 ml of a 3% chitosan solution and vortexed to prepare a cubosome. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 59. Preparation of a Cubosome Composition Stabilized with an Aqueous Polymer Solution 11

950 μL of monoolein was placed in a 3 ml syringe and 50 μL of water was placed in another syringe to remove air from each syringe. Two syringes were connected by three-way stopcork and alternately pushed about 100 times to prepare L2 phase. A cubosome was prepared by vortexing 500 L of L2 phase in 10 ml of a 3% chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 60. Preparation of a Cubosome Composition Stabilized with an Aqueous Polymer Solution 12

850 μL of monoolein was placed in a 3 ml syringe and 150 μL of water was placed in another syringe to remove air from each syringe. Two syringes were connected by three-way stopcork and alternately pushed about 100 times to prepare a lamellar liquid crystal phase. A cubosome was prepared by vortexing 500 µL of the lamellar liquid crystal phase into 10 ml of a 3% chitosan solution. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 61 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing Bovine Serum Albumin 5

Cubosomes were prepared in the same manner as in Example 59, except that 50 μL of an aqueous 3% FITC-BSA solution was used instead of 50 μL of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Example 62 Preparation of a Cubosome Formulation Stabilized with an Aqueous Polymer Solution Containing Bovine Serum Albumin 6

Cubosomes were prepared in the same manner as in Example 60, except that 150 μL of an aqueous 3% FITC-BSA solution was used instead of 150 μL of water. The particle size of the prepared cubosome was 100 nm-20 μm, and the particles exist as solid without undergoing phase separation after freeze-drying. When dispersed in water instead of aqueous chitosan solution, the cubic phase was not dispersed at all.

Test Example 1. In vivo oral administration experiment-insulin

Animal experiments were performed with the cubosome prepared in Example 51.

1-1. Diabetes induction

Fasting 6-week-old male rats for 8-10 hours and then intraperitoneally with 100 mg / kg of normal saline solution in which streptozotocin and alloxan monohydrate were dissolved Three injections were repeated at two-day intervals. One week later, blood was collected from the rats treated as described above, and blood glucose levels were measured. Among the rats, the blood glucose level in the non-fasted state was 400 mg / dL or higher, and the following experiment was performed.

1-2. Oral Administration of Cubosomes Stabilized with Aqueous Polymer Solution Containing Insulin

300 μL of the cubosome solution stabilized with an aqueous polymer solution containing insulin was fasted for 6 hours in normal rats aged 6-7 weeks and the diabetic-induced rats selected in Test Example 1-1, and blood was collected from the tail vein. The blood glucose level was measured, and the value was used as an initial value before drug administration. 300 μL of the liquid formulation of cubosomes stabilized with an aqueous polymer solution containing insulin prepared in Example 51 was orally administered with Sonde. The dose of insulin for each experimental animal is 89 IU / kg. Comparative groups were orally administered in the same manner using PBS and insulin / PBS solutions. At 1, 2, 3, 4 and 6 hours after drug administration, blood was collected from the tail vein to measure blood glucose levels. The blood glucose level of each time slot was converted to the initial value before administration to 100%, and the result is shown in FIG.

As shown in FIG. 2, in the diabetic rat-induced rat group administered with the cubosome stabilized with the aqueous polymer solution containing insulin of the present invention, the blood glucose level was reduced by about 50% after 1 hour compared to the initial blood glucose level, and the low blood sugar level was about While it lasted up to 3 hours, the group treated with PBS and the aqueous solution of insulin showed no significant results.

Example 63 Preparation of Low Molecular Weight Alginate and Its Aqueous Solution

The high molecular weight alginate (Yakuri Pure Chemicals, Japan) was hydrolyzed in 85 wt% phosphoric acid solution (Sigma) and freeze-dried to prepare a low molecular weight alginate. The molecular weight of the alginate salt was determined by measuring the viscosity of the aqueous solution. Viscosity was measured with an Ostwald viscometer and the intrinsic viscosity values were plotted against the alginate concentration to determine the molecular weight of the alginate (Ikeda A .; Takemura A .; Ono H). .; Carbohydr.Polym .; 2000; 42; 421.). The intrinsic viscosity and molecular weight of the alginate thus obtained are shown in Table 22 below.

Table 22

Example 64 Preparation of a Mixed Oil Emulsion Composition Stabilized with an Alginate Aqueous Solution in the Presence of Emulsifiers

To a mixed oil containing paclitaxel prepared by mixing tricapryline, monoolein and paclitaxel in a weight ratio of 33: 66: 1, an emulsifier (Tween 80) was added to 20% of the total volume to prepare a single liquid phase. 10 ml of the low molecular weight alginate aqueous solution prepared in Example 63 was added to 1 ml of the prepared single liquid phase to emulsify in the same manner as in Example 1 to prepare a mixed oil emulsion composition. In the case of vortexing, the average diameter of the particles was 396 nm. However, when water is used, it is unstable, unlike in the case of dispersing in an alginate aqueous solution, and phase separation occurs after 2 to 3 hours.

Test Example 2: In vivo oral administration experiment-paclitaxel

Animal experiments were performed using the mixed oil emulsion composition prepared in Example 64 above. After 8-week-old Balb / c female mice were fasted for 8 hours, the mixed oil emulsion composition containing paclitaxel stabilized with a low molecular weight alginate aqueous solution was orally administered to the mice so that the paclitaxel dose was 50 mg / kg. . Orally administered time intervals were 1, 2 and 4 hours, and blood was collected from the capillaries of the eye using micro glass tubes at each time, and the concentration of paclitaxel absorbed by high performance liquid chromatography was quantified.

The experimental results thus obtained are shown in FIG. 3. In FIG. 3, MT-Alginate, indicated by a black circle, is a result obtained from a group in which a mixture of paclitaxel and a composition obtained by emulsifying a low molecular weight aqueous solution of alginate in a mixed oil of tricapryline and monoolein is obtained. MTT-Alginate is the result obtained from the group of emulsified low oil solution of alginate and the mixture of paclitaxel. The results obtained from the group administered with the mixture of the composition emulsified chitosan aqueous solution and paclitaxel are shown. As shown in FIG. 3, it can be seen that the low molecular weight alginate aqueous solution assists the paclitaxel absorption more effectively than the chitosan aqueous solution, and it can be seen that the addition of the emulsifier affects the initial absorption of paclitaxel.

Claims (95)

A stericly stabilized emulsion composition comprising from 0.1 to 30% by weight of one or more oils, from 0.01 to 5% by weight of a biocompatible hydrophilic polymer and water or an aqueous solution occupying the remainder. The composition of claim 1 further comprising at least one monoglyceride compound in an amount of 0.1 to 30% by weight. A steric stabilized cubosome composition comprising from 0.1 to 30% by weight of at least one monoglyceride-based compound, from 0.01 to 5% by weight of a biocompatible hydrophilic polymer, and water or an aqueous solution occupying the remainder. The composition of claim 3 further comprising at least one oil in an amount of 0.1 to 6% by weight. A steric stabilized cubosome composition comprising 0.1 to 30% by weight of phytantriol, 0.01 to 5% by weight of a biocompatible hydrophilic polymer, and water or an aqueous solution to account for the remainder. The composition of claim 5 further comprising at least one oil in an amount of 0.1 to 6% by weight. A composition of long-term storage stereoscopically stabilized emulsion precursor comprising 0.1 to 30 parts by weight of one or more oils, and 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer. The emulsion precursor composition of claim 7 further comprising 0.1 to 30 parts by weight of at least one monoglyceride compound. A stereoscopically stabilized long-term storeable cubosome precursor composition comprising 0.1 to 30 parts by weight of at least one monoglyceride-based compound and 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer. 10. The cubosome precursor composition according to claim 9, further comprising 0.1 to 6 parts by weight of one or more oils. A steric stabilized long-term storeable cubosome precursor composition comprising 0.1-30 parts by weight of phytantriol and 0.01-5 parts by weight of a biocompatible hydrophilic polymer. The composition of claim 11 further comprising 0.1 to 6 parts by weight of one or more oils. The composition of claim 1, wherein the oil is one or more oils selected from the group consisting of triglycerides, iodide oils, vegetable oils and animal oils. The composition of claim 13, wherein said triglyceride is a saturated or unsaturated C 2 -C 20 monoglyceride-based compound. The method of claim 13, wherein the triglyceride is triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein ( triolein) is selected from the group consisting of. 14. The composition of claim 13, wherein said iodide oil is selected from the group consisting of Lipiodol, iodized poppy seed oil, ethiodol, and iodized soybean oil. The composition of claim 13, wherein the vegetable oil is selected from the group consisting of soybean oil, cottonseed oil, olive oil, poppy seed oil, safflower seed oil and sesame oil. The composition of claim 13, wherein said animal oil is squalane or squalene. The composition according to any one of claims 2 to 4 and 8 to 10, wherein the monoglyceride compound comprises a monoglyceride compound which is C10-C22 saturated or unsaturated. 20. The method of claim 19, wherein the monoglyceride-based compound is monooolein (Monoolein), monopalmititolein (Monopalmitolein), mono myristolein (Monomyristolein), monoeilaidin (Monoelaidin), monoirucine (Monoerucin) And a mixture of monoglycerides semi-synthesized from triglycerides of vegetable or animal oils. The composition of claim 20, wherein the monoglyceride compound is monoolein. The method according to any one of claims 1 to 12, wherein the biocompatible hydrophilic polymer is selected from the group consisting of natural polymers, modified natural polymers, and synthetic polymers. Composition. The method of claim 22, wherein the natural polymer is chitosan (chitosan), salts thereof and derivatives thereof; Dextran and its derivatives; Acacia gum; Tragacanthin; Hyaluronic acid, salts thereof and derivatives thereof; Pectin, its salts and derivatives thereof; Alginic acid, its salts and derivatives thereof; Agar; Galactomannans, salts thereof and derivatives thereof; Xanthan, salts thereof and derivatives thereof; Beta-cyclodextrin, its salts and derivatives thereof; And amylose (water soluble starch), salts thereof and derivatives thereof. The method of claim 22, wherein the polymer modified from the natural polymer is glycol chitosan (Glycol chitosan), salts thereof and derivatives thereof; Carboxymethyl cellulose (CMC), its salts and derivatives thereof; Hydroxyethyl cellulose (HEC), its salts and derivatives thereof; Hydroxypropyl cellulose (HPC), salts thereof and derivatives thereof; Hydroxypropyl methylcellulose (HMC); Methylcellulose, its salts and derivatives thereof; Cellulose acetate phthalate, salts thereof and derivatives thereof; Gelatin, salts thereof and derivatives thereof; And protamine sulfate. The method of claim 22, wherein the synthetic polymer is selected from the group consisting of poly (beta-hydroxyethyl methacrylate) [Poly (beta-hydroxyethyl methacrylate), PHEMA]; Polyacrylamide (PA); Polyvinyl alcohol (PVA); Polyacrylic acid (PAA), salts thereof and derivatives thereof; Polyvinylpyrrolidone (PVP); Polyethylene oxide (PEO); Polyethylene glycol (PEG); Poly (ethylene oxide-b-propylene oxide), PEO-PPO) and polylysine (Polylysine) composition. The composition according to any one of claims 1 to 12, wherein the aqueous solution is selected from the group consisting of an acidic aqueous solution, a basic aqueous solution, a buffered solution, a salt solution, and the like, which can solubilize the hydrophilic polymer. The composition according to any one of claims 1 to 12, further comprising an additive selected from the group consisting of emulsifiers, fatty acids, esters of fatty acids, and alcohols of fatty acids in an amount of 5% by weight or less. The composition of claim 27 wherein the emulsifier is selected from the group consisting of phospholipids, sphingolipids, nonionic surfactants, anionic surfactants, cationic surfactants and bile acids. The method of claim 28, wherein the phospholipid is selected from the group consisting of phosphatidyl choline derivatives, phosphatidyl ethanolamine derivatives, phosphatidyl serine derivatives, and lipids to which hydrophilic polymers are bound. Phosphorus composition. The composition of claim 28, wherein the sphingolipid is selected from the group consisting of ceramides, cerebrosides and sphingomyelins. 29. The method of claim 28, wherein the nonionic surfactant is selected from the group consisting of poloxamer (Pluronic; polyoxyethylene-polyoxypropylene copolymer), sorbitan esters (Span), polyoxyethylene sorbitans (Tween) ), And polyoxyethylene ethers (Brij). 29. The composition of claim 28, wherein the anionic surfactant is selected from the group consisting of phosphatidylserine derivatives, phosphatitidic acid derivatives and sodium dodecyl sulfate (SDS). The method of claim 28, wherein the cationic surfactant is 1,2-dioleyl-3-trimethylammonium propane, dimethyldioctadecylammonium chloride, N- [1- (1,2-Dioleyloxy) propyl] -N, N, N-trimethylammonium chloride (N- [1- (1,2-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride), 1,2-dioleyl-3-ethylphosphocholine (1,2-dioleyl-3-ethylphosphocholine) And 3β- [N-[(N ', N'-dimethylamino) ethane] carbamoyl] cholesterol (3β- [N-[(N', N'-dimethylamino) ethan] carbamoyl] chloresterol) The composition selected. 29. The method of claim 28, wherein the bile acid is selected from the group consisting of cholic acid, salts and derivatives thereof; Deoxycholic acid, salts and derivatives thereof; Lithocholic acid, salts and derivatives thereof; And chenoholic acid (Chenocholic acid), salts and derivatives thereof. Mixing well one or more oils and optionally monoglycerides and / or emulsifiers into a single liquid phase, and preparing a solution by mixing biocompatible hydrophilic polymers and optionally emulsifiers in water or an aqueous solution; Method for producing an emulsion composition comprising the step of mixing together and dispersing the single liquid phase and the solution obtained above. 36. The method of claim 35, wherein the preparation of the single liquid phase is carried out by warming or sonicating. 36. The method of claim 35, wherein the dispersion is performed by hand shaking, vortexing, sonication, or microfluidization. Monoglycerides, phytantriols, monoglycerides / oil mixtures or phytantriols / oil mixtures are optionally mixed with emulsifiers to form a single liquid phase, and biocompatible hydrophilic polymers and optionally emulsifiers are mixed with water or an aqueous solution. To prepare a solution; Method for producing a cubosome composition comprising the step of mixing and dispersing together the obtained single liquid phase and the solution. The method of claim 38, wherein the preparation of the single liquid phase is carried out by warming or sonicating. The method of claim 38, wherein the dispersion is performed by hand shaking, vortexing, sonication, or microfluidization. Monoglycerides, phytantriols, monoglycerides / oil mixtures or phytantriols / oil mixtures and optionally emulsifiers are mixed with aqueous solutions to form L2, lamellar or cubic phases, and biocompatible hydrophilic in water or aqueous solutions. A solution is prepared by mixing the polymer and an emulsifier optionally; Method for producing a cubosome composition comprising the step of dispersing after mixing the L2 phase, lamellar phase or cubic phase obtained with the solution. 42. The method of claim 41, wherein the preparation of the L2, lamellar or cubic phase is carried out using a lipid mixer consisting of a syringe and three-way stop-cork. 42. The method of claim 41 wherein the dispersion is performed by hand shaking, vortexing, sonication, or microfluidization. Three-dimensionally stabilized emulsion formulations comprising 0.1-30% by weight of one or more oils, 0.01-5% by weight of biocompatible hydrophilic polymers, 0.1-10% by weight of one or more drugs, and water or an aqueous solution occupying the remainder. 45. The emulsion formulation of claim 44, further comprising at least one monoglyceride-based compound in an amount of 0.1 to 30% by weight. Stereoscopically stabilized cubosome formulations comprising from 0.1 to 30% by weight of at least one monoglyceride-based compound, from 0.01 to 5% by weight of biocompatible polymer, from 0.1 to 10% by weight of at least one drug, and water or aqueous solution for the remainder . 47. The cubosome formulation according to claim 46 further comprising at least one oil in an amount of 0.1 to 6% by weight. A steric stabilized cubosome formulation comprising from 0.1 to 30% by weight of phytantriol, from 0.01 to 5% by weight of a biocompatible hydrophilic polymer, from 0.1 to 10% by weight of one or more drugs, and water or an aqueous solution occupying the remainder. 49. The cubosome formulation according to claim 48 further comprising at least one oil in an amount of 0.1 to 6% by weight. A long-term storage stereoscopically stabilized emulsion precursor formulation comprising 0.1-30 parts by weight of one or more oils, 0.01-5 parts by weight of a biocompatible hydrophilic polymer, and 0.1-10 parts by weight of one or more drugs. 51. The emulsion precursor formulation of claim 50, further comprising 0.1 to 30 parts by weight of one or more monoglyceride compounds. A long-term storage stereoscopically stabilized cubosome precursor formulation comprising 0.1 to 30 parts by weight of at least one monoglyceride-based compound, 0.01 to 5 parts by weight of biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of at least one drug. The cubosome precursor formulation according to claim 49 further comprising 0.1 to 6 parts by weight of one or more oils. A long-term storage stereoscopically stabilized cubosome precursor formulation comprising 0.1 to 30 parts by weight of phytantriol, 0.01 to 5 parts by weight of a biocompatible hydrophilic polymer, and 0.1 to 10 parts by weight of one or more drugs. 55. The cubosome precursor formulation according to claim 54 further comprising 0.1 to 6 parts by weight of one or more oils. The formulation of claim 44, wherein the oil is one or more selected from the group consisting of triglycerides, iodide oils, vegetable oils, and animal oils. The formulation of claim 56, wherein the triglyceride is a monoglyceride-based compound that is saturated or unsaturated C 2 -C 20. 58. The method of claim 57, wherein the triglycerides are triacetin, tributyrin, tricaproin, tricaprylin, tricaprin, and triolein. triolein). 57. The formulation of claim 56, wherein said iodide oil is selected from the group consisting of Lipiodol, iodized poppy seed oil, ethiodol, and iodized soybean oil. The formulation of claim 56, wherein the vegetable oil is selected from the group consisting of soybean oil, cottonseed oil, olive oil, poppy seed oil, safflower seed oil and sesame oil. The formulation of claim 56, wherein said animal oil is squalane or squalene. 55. The formulation of any one of claims 45-47 and 51-53, wherein said monoglyceride compound comprises a saturated or unsaturated C10-C22 monoglyceride compound. 63. The method of claim 62, wherein the monoglyceride-based compound is monooolein (Monoolein), monopalmititolein (Monopalmitolein), mono myristoleine (Monomyristolein), monoeilaidin (Monoelaidin), monoirucine (Monoerucin) And a mixture of monoglycerides semi-synthesized from triglycerides of vegetable or animal oils. 64. The formulation of claim 63, wherein said monoglyceride compound is monoolein. 56. The group of any of claims 44-55, wherein the biocompatible hydrophilic polymer is comprised of a natural polymer, a modified natural polymer, and a synthetic polymer. Formulations selected from. 66. The method of claim 65, wherein the natural polymer is chitosan (chitosan), salts thereof and derivatives thereof; Dextran and its derivatives; Acacia gum; Tragacanthin; Hyaluronic acid, salts thereof and derivatives thereof; Pectin, its salts and derivatives thereof; Alginic acid, its salts and derivatives thereof; Agar, Galactomannans, salts thereof and derivatives thereof; Xanthan, salts thereof and derivatives thereof; Beta-cyclodextrin, its salts and derivatives thereof; And amylose (soluble starch), salts thereof and derivatives thereof. 66. The method of claim 65, wherein the polymer modified from natural polymers comprises glycol chitosan, salts thereof and derivatives thereof; Carboxymethyl cellulose (CMC), its salts and derivatives thereof; Hydroxyethyl cellulose (HEC), its salts and derivatives thereof; Hydroxypropyl cellulose (HPC), salts thereof and derivatives thereof; Hydroxypropyl methylcellulose (HMC); Methyl cellulose, its salts and derivatives thereof; Cellulose acetate phthalate, salts thereof and derivatives thereof; Gelatin, salts thereof and derivatives thereof; And protamine sulfate. 66. The method of claim 65, wherein the synthetic polymer is poly (beta-hydroxyethyl methacrylate) [Poly (beta-hydroxyethyl methacrylate, PHEMA]; polyacrylamide (PA); polyvinyl alcohol (PVA) Polyacrylic acid (PAA), salts thereof and derivatives thereof; polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); polyethylene glycol (PEG); poly (ethylene oxide-b- Formulation selected from the group consisting of propylene oxide [Poly (ethylene oxide-b-propylene oxide), PEO-PPO]; and polylysine. The method of claim 44, wherein the drug is a protein, an antiviral agent, a steroidal anti-inflammatory agent (SAID), a nonsteroidal anti-inflammatory agent (NSAID), an antibiotic, an antifungal agent, a vitamin, a hormone, a prostaglandin, Prostacyclin, anticancer, anti-metabolic, mitotics, cholinergic, adrenaline antagonist, anticonvulsant, anti-anxiety, thermostatic, antidepressant, anesthetic, analgesic, anabolic steroid, estrogen (estrogen), progesteron, glycosaminoglycan, polynucleotide, polynucleotide, P-glycoprotein inhibitor, hepatic metabolism inhibitor, immunosuppressant and immunostimulator. 65. The method of claim 64, wherein the protein comprises a functional peptide; Adrenocorticotropic hormone (ACTH) and fragments; Angiotensin and its related peptides; Antibody fragments; Antigen and fragments thereof; Atrial natriuretic peptide; Bioadhesive peptides; Bradykinin and its related peptides; Calcitonin and its related peptides; Cell surface receptor protein fragments; Chemotactic peptides; Cyclosporins; Cytokines; Dynorphin and its related peptides; Endorphins and β-lidotropin fragments; Enkephalin and its related proteins; Enzyme inhibitors; Fibronectin fragments and related peptides; Gastrointestinal peptide; Growth hormone releasing peptides; Immunostimulating peptides; Insulin and insulin-like growth factor; Interleukins, luthenizing hormone releasing hormone (LHRH) and related peptides; Melanocyte stimulating hormone and related peptides; Nuclear localization signal related peptides; Neurotensin and related peptides; Neurotransmitter peptides; Opioid peptides; Oxytocin; Vasopressin and its related peptides; Parathyroid hormones and fragments; Protein kinase related peptides; Somatostatin and related peptides; Substrate P and its related peptides; Transforming growth factor (TGF) and related peptides; Tumor necrosis factor fragments; Immunoglobulins, angiogenins, bone morphogenic proteins, chemokines, colony stimulating factors (CSFs) and related proteins, growth factors, The formulation is selected from the group consisting of interferon, interleukin, leptin, polio inhibitory factor, stem cell factors and toxin or toxoid . 71. The method of claim 70, wherein said insulin is bovine pancreatic insulin, human recombinant insulin, porcine pancreatic insulin, arg-insulin, insulin-biotin. ), Insulin-FITC (insulin-FITC), LysPro (Ely Lilly, USA), and polyethylene glycol-insulin (polyethylene glycol-insulin, PEG-insulin). 71. The method of claim 70, wherein the functional peptide is an anticancer peptide comprising angiostatin, an antihypertension peptide, an antiblood-clotting peptide, and an antimicrobial. Formulations selected from the group consisting of peptides. 70. The method of claim 69, wherein the anticancer agent is selected from the group consisting of doxorubicin, cisplatin, carboplatin, carmustine (BCNU), dacarbazine, edoposide, fluorouracil (5-FU), and paclitaxel and derivatives thereof. Formulation. 75. The formulation of claim 73, wherein said paclitaxel derivative is selected from the group consisting of paclitaxel, docetaxel, bromotaxel and taxotere. 70. The method of claim 69, wherein the P-glycoprotein inhibitor consists of cinchonin, calcium channel inhibitors, calmodulin antagonists, Vinca alcaloids, antiarrhythmics, steroids, antihypertensives, antiparasitic agents, and immunosuppressants. Formulations selected from the group. 77. The cal module according to claim 75, wherein the calcium channel inhibitor is dihydropyridines selected from the group consisting of verapamil, nifedipine, nicardipine, and nitrendipine. The lean antagonist is trifluoroperazine, the antihypertensive agent is respine, the vinca alkaloid is selected from the group consisting of vincristine, and vinblastine, The steroid is progesterone and the antiarrhythmic agent is selected from the group consisting of amiodarone and quinidine. The antiparasitic agent is selected from the group consisting of quinacrine and quinine, and the immunosuppressive agent is selected from the group consisting of cyclosporins, staurosporine, and tacrolimus. . 70. The method of claim 69, wherein said liver metabolism inhibitor is selected from the group consisting of cyclosporin A, doxorubicin, etoposide (VP-16), cisplatin, verapamil, and tamoxifen. The formulation selected. The formulation according to any one of claims 44 to 55, further comprising an additive selected from the group consisting of emulsifiers, fatty acids, esters of fatty acids, and alcohols of fatty acids in an amount of up to 5% by weight. 79. The formulation of claim 78, wherein said emulsifier is selected from the group consisting of phospholipids, sphingolipids, nonionic surfactants, anionic surfactants, cationic surfactants, and bile acids. The phospholipid of claim 79, wherein the phospholipid is selected from the group consisting of phosphatidyl choline derivatives, phosphatidyl ethanolamine derivatives, phosphatidyl serine derivatives, and lipids bound to hydrophilic polymers. Formulation. 80. The formulation of claim 79, wherein the sphingolipids are selected from the group consisting of ceramides, cerebrosides, and sphingomyelins. 80. The method of claim 79, wherein the nonionic surfactant is a poloxamer (Pluronic; polyoxyethylene-polyoxypropylene copolymer), sorbitan esters (Span), polyoxyethylene sorbitans (Tween) ), And polyoxy ethylene ethers (Brij). 80. The formulation of claim 79, wherein the anionic surfactant used as an emulsifier is selected from the group consisting of phosphatidylserine derivatives, phosphatitidic acid derivatives, and sodium dodecyl sulfate (SDS). 80. The method of claim 79, wherein the cationic surfactant is 1,2-dioleyl-3-trimethylammonium propane, dimethyldioctadecylammonium chloride, N- [1- (1,2-Dioleyloxy) propyl] -N, N, N-trimethylammonium chloride (N- [1- (1,2-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride), 1,2-dioleyl-3-ethylphosphocholine (1,2-dioleyl-3-ethylphosphocholine), and 3β- [N-[(N ', N'-dimethylamino) ethane] carbamoyl] cholesterol (3β -[N-[(N ', N'-dimethylamino) ethan] carbamoyl] chloresterol). 80. The method of claim 79, wherein the bile acid is cholic acid (cholic acid) and salts and derivatives thereof, deoxycholic acid and salts and derivatives thereof, lithocholic acid and salts and derivatives thereof, and cheno Formulation selected from the group consisting of Cholincholic acid, salts and derivatives thereof. The formulation according to any one of claims 44 to 55, wherein the aqueous solution is selected from the group consisting of an acidic aqueous solution, a basic aqueous solution, a buffer solution, a salt solution, and the like, which can solubilize the hydrophilic polymer. Mixing one or more oils, drugs, optionally monoglycerides, and emulsifiers into a single liquid phase to prepare an aqueous solution containing a biocompatible hydrophilic polymer and an emulsifier optionally; Method for producing a three-dimensional stabilized emulsion formulation comprising the step of mixing and dispersing together the obtained single liquid and aqueous solution. 88. The method of claim 87, wherein the preparation of said single liquid phase is carried out by warming or sonicating. 88. The method of claim 87, wherein the dispersion is performed by hand shaking, vortexing, sonication, or microfluidization. Monoglycerides, phytantriols, monoglycerides / oil mixtures or phytantriols / oil mixtures, drugs and optionally emulsifiers are mixed well into a single liquid phase, and biocompatible hydrophilic polymers and aqueous solutions containing emulsifiers are optionally prepared. and; Method for producing a three-dimensional stabilized cubosome formulation comprising the step of mixing and dispersing together the obtained single liquid and aqueous solution. 91. The method of claim 90, wherein the preparation of the single liquid phase is carried out by warming or sonicating. 91. The method of claim 90, wherein the dispersion is performed by hand shaking, vortexing, sonication, or microfluidization. Monoglycerides, phitantriols, monoglycerides / oil mixtures or phytantriols / oil mixtures, optionally with an emulsifier, are mixed with an aqueous solution to form L2 phase, lamellar phase or cubic phase, optionally with biocompatible hydrophilic polymers Preparing an aqueous solution containing an emulsifier; Method for producing a three-dimensionally stabilized cubosome formulation comprising the step of mixing and then dispersing the L2 phase, lamellar phase or cubic phase and the aqueous solution obtained above. 94. The method of claim 93, wherein the preparation of the L2, lamella or cubic phase is carried out using a lipid mixer consisting of a syringe and a three-way stop-cork. 94. The method of claim 93, wherein the dispersion is performed by hand shaking, vortexing, sonication, or microfluidization.

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