KR20220000849A - The cyclodextrin-based composite composition for oral administration and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a composite composition which solves the problem of the release of an active material of a conventional cyclodextrin-based metal-organic framework and harm to the human body, and is stabilized and has enteric properties while effectively controlling the absorption and release of the active material by introducing a release-controlling polymer such as Eudragit for efficient mass transfer when administered orally.

Description

Composite composition for oral administration using cyclodextrin and manufacturing method thereof {The cyclodextrin-based composite composition for oral administration and manufacturing method thereof}

The present invention relates to a composite composition comprising a cyclodextrin (CD)-based metal-organic frameworks (MOF) and a release-controlling polymer such as Eudragit, and a method for preparing the same.

Metal-organic frameworks (MOF) are crystalline nanoporous structures in which metal ions and organic linkers or organic ligands are linked by coordination bonds to form a three-dimensional structure. . As a porous material, MOF has a large surface area, so chemical reactions occur actively, and the pore size, pore shape, and structure can be adjusted depending on the type of metal ion and organic linker used in the MOF, so the pore size and shape as well as the internal structure are elaborated. It has the advantage that it can be easily synthesized.

Research results on the structure of MOF were published from the late 1950s to the early 1960s, but after R. Robson of the University of Melbourne published a polymer skeleton infinitely connected in a 3-D structure in 1989, Arizona University's The Omar H. Yaghi group (now the University of California, Berkeley campus) rediscovered MOF in 1995, and the release of MOF-5 in 1999 led to rapid growth. Currently, MOFs are being studied in many fields due to their high surface area, inner surface and size controllable properties, and are particularly applied in the fields of medicine, carbon storage, semiconductors, adsorbents, electronics, sensors, and catalysts. In this regard, Korean Patent Registration No. 10-1846085 relates to a method of stabilizing a cosmetic component using a metal-organic framework, and discloses that a functional material can be supported on the MOF.

However, in the field of medicine and drug delivery, MOF was difficult to apply in practice in that it comes from non-renewable or toxic substances.

Cyclodextrin (CD) is a representative biodegradable and biodegradable material, has low toxicity, and has the characteristics of increasing drug safety, bioavailability and solubility in water-soluble substances. Therefore, MOF using cyclodextrin has been studied.

Cyclodextrin-based MOF has excellent properties compared to conventional porous crystals such as zeolite or porous carbon by combining the porous characteristics of MOF with the encapsulation ability of cyclodextrin by placing cyclodextrin as a ligand. Also, studies have been reported that CD-MOF can overcome the physicochemical and biochemical limitations of drugs.

As a related patent, US Patent Publication No. 2017-0028383 discloses a cyclodextrin-based metalloorganic framework and a method of using the same, and US Patent Publication No. 2017-0274097 discloses a composition comprising a cyclodextrin-based metalorganic framework It is effective in releasing the active substance as, and it is disclosed that it can be used for cosmetic or therapeutic purposes. In addition, European Patent Publication No. 3374402 discloses that the cyclodextrin-based metal-organic framework is water-soluble and non-toxic, so it can be used in oral pharmaceutical preparations.

However, due to the hydrophilicity of the outer surface of CD-MOF, it has the property of being easily released in a hydrophilic environment at an early stage, which has a problem in that it is difficult to utilize in fields where the substance must be released continuously or through control, and it has a significant impact on the overall pharmacological effect of biomedical medicine. There are problems that can cause problems.

In general, oral dosage forms are preferred due to portability and ease of administration, but they often fail to release drugs effectively due to difficulty in controlling drug release, dosage form collapse, chemical degradation due to rapid intestinal pH change, hydrolysis, etc. becomes In this regard, the prior art attempts to solve the problem through a mixture of a swellable polymer or a hydrophilic excipient. There is an attempt to utilize oral administration through glyceryl monooleate, glyceryl monolaurate, methacrylic acid polymer, methacrylic acid-acrylic acid copolymer, etc. as a swellable polymer or hydrophilic excipient, Republic of Korea Patent Publication No. 10-2019-0096387 An oral formulation of a glucokinase activator comprising a copolymer polymer carrier containing butyl methacrylate is disclosed in the above publication, and Korean Patent No. 10-1859200 discloses an oral formulation of a monoacetyldiacylglycerol compound containing a hydrophilic sustained-release polymer. Solid formulations are disclosed.

However, although various research results on coating, encapsulation, carrier and drug control through the polymer are known, there is no technology used in combination with MOF, and there is no known about combinability, combination method, etc. In addition, it is not known in detail whether MOF is released to the active material.

Accordingly, as a result of the present inventors' efforts to prepare a composition for oral administration, by applying a release-controlling polymer to CD-MOF, the release of the active material of CD-MOF is controlled and stability is improved, thereby preparing a composite composition that can be administered orally By revealing that it can be done, the present invention has been completed.

Korean Patent No. 10-1846085 US Patent Publication No. 2017-0028383 US Patent Publication No. 2017-0274097 European Patent Publication No. 3,374,402 Korean Patent Publication No. 10-2019-0096387 Korean Patent Publication No. 10-1859200

Chonbuk National University Graduate School Master's Thesis, pp. 1-9, 2016, Jibong Choi Polydopamine-polycaprolactone composite coating to improve the corrosion resistance of biodegradable magesium, Pharmaceutics 2018, 10, 271, Yaoyao Han et al., Cyclodextrin-Based Metal-Organic Frameworks (CD-MOFs) in Pharmaceutics and Biomedicine

In the present invention, the conventional cyclodextrin (CD)-based metal-organic frameworks (MOF) do not control the release rate of the active material, are decomposed in an aqueous environment, and may be harmful to the human body. To solve this problem, it is to provide a stabilized composite composition while effectively controlling the absorption and release of the active material by applying a release-controlling polymer such as Eudragit to the CD-MOF.

In order to achieve the above object, the present invention includes a metal organic framework (MOF), wherein the metal organic framework is composed of a coordination bond of a repeating unit comprising a cyclodextrin (CD) and a metal. And, the active material is supported on the inside of the framework, and the outside of the framework is coated with a release-controlling polymer, providing a composite composition.

In one embodiment of the present invention, the cyclodextrin is γ-cyclodextrin.

In one aspect of the present invention, the release-controlling polymer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, shellac, methacrylic acid ethylacrylic acid copolymer, methacrylic acid methylmethacrylate copolymer, polyvinylacetyl phthalate , and may be selected from the group consisting of Eudragit.

In one aspect of the present invention, the release-controlling polymer is Eudragit, and the Eudragit is Eudragit E, Eudragit S, Eudragit L, Eudragit RS, Eudragit RL and Eudragit. Dragit NE is selected from the group consisting of.

In one aspect of the present invention, the active material is an organic acid, drug, metal ion, oxide, omega-3, omega-6, DHA, EPA, vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12 and amino acids.

In a specific aspect of the present invention, the active material is at least one selected from the group consisting of lactic acid, omega-3, vitamin C and resorufin.

In one embodiment of the present invention, the metal-organic framework has a molar ratio of cyclodextrin (CD) and metal of 1: 5 to 15.

In one aspect of the present invention, the supported active material has a weight ratio of 0.05 to 0.5:1 with respect to the total weight of the composite composition.

In one aspect of the present invention, the composite composition is capable of releasing the active substance at a pH of 6 to 8.

In one embodiment of the present invention, the release amount of the active substance is 50 to 90%.

In addition, the present invention comprises the steps of: 1) mixing cyclodextrin (CD), a metal compound, and an active material to prepare metal-organic frameworks (MOF) on which an active material is supported; And 2) mixing the metal-organic framework on which the active material of step 1) is supported and the release-controlling polymer to obtain a composite composition; provides a method for producing a composite composition comprising a.

In the method for preparing the composite composition of the present invention, the cyclodextrin, the metal of the metal compound, the active material, and the release-controlling polymer are as described above.

In one aspect of the present invention, in step 2), the metal-organic framework and the release-controlling polymer on which the active material of step 1) is supported are dissolved in a solvent, and then mixed by ball milling.

In a specific embodiment of the present invention, when step 2) is to obtain a composite composition by ball milling, the weight ratio of the metal-organic framework on which the active material is supported to the release-controlling polymer is 1:1 to 5.

In one aspect of the present invention, step 2) comprises a mixed solution (A) in which 2)-1 is mixed with a metal-organic framework on which an active material is supported and a release-controlling polymer; and preparing an emulsifying solution (B); and 2)-2 dripping the mixed solution (A) of step 2)-1 into the emulsifying solution (B) to prepare a composite composition;

In a specific embodiment of the present invention, when the composite composition is obtained by emulsification in step 2), the weight ratio of the metal-organic framework on which the active material is supported and the release-controlling polymer is 1: 0.01 to 0.5.

In a specific aspect of the present invention, step 2)-1 includes a plasticizer and a dispersant.

In a specific embodiment of the present invention, the emulsifying solution (B) of step 2)-1 includes a non-polar solvent and a surfactant.

In addition, the present invention provides an oral formulation comprising the composite composition.

The present invention relates to a composite composition prepared by mixing cyclodextrin (CD)-based metal-organic frameworks (MOF) with a release-controlling polymer such as Eudragit, and a method for preparing the same. , The composition of the present invention has the advantage that the release of the active material can be controlled by the release-controlling polymer, the release of the active material is possible at a specific pH, and it is stabilized by preventing hydrolysis of cyclodextrin and is harmless to the human body.

1 is a view confirming the CD-MOF through SEM.
2 is a diagram confirming the crystallinity of CD-MOF through PXRD.
3 is a diagram showing the amount of release according to the conditions of lactic acid.
4 is a diagram showing the amount of vitamin C released according to the conditions.
5 is a diagram showing the form of CD-MOF loaded with omega-3.
6 is a view confirming the release pattern according to the condition of omega-3.
7 is a diagram showing the form of CD-MOF loaded with resorufin.
8 is a view confirming the release pattern according to the conditions of resorufin.

Hereinafter, the present invention will be described in detail.

Throughout the specification of the present invention, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.

As used throughout the specification of the present invention, the term “step of (to)” or “step of” does not mean “step for”.

The present invention includes a metal organic framework (MOF), wherein the metal organic framework is composed of a coordination bond of a repeating unit containing cyclodextrin (CD) and a metal, and is active inside the framework It relates to a composite composition that supports a material, and the outside of the framework is coated with a release-controlling polymer.

In addition, the present invention comprises the steps of: 1) mixing cyclodextrin (CD), a metal compound, and an active material to prepare metal-organic frameworks (MOF) on which an active material is supported; and 2) mixing the metal-organic framework on which the active material of step 1) is supported and the release-controlling polymer to obtain a composite composition; it relates to a method for producing a composite composition comprising a.

In the present invention, the metal-organic framework is a crystalline material of a framework structure formed by connecting a metal (ion) and an organic linker, wherein the metal includes not only a single metal (ion) but also a metal cluster, and various organic linkers are metals. It serves to increase the distance between metals while connecting them, and these organic linkers periodically form a network structure to connect the metals.

Therefore, selective absorption and release of the active material is possible by controlling the size of micropores present in the metal-organic framework through various combinations between metals (ions) and organic linkers. In addition, macroscopically, by changing the absorption and release distance of the active material through the control of the particle size of the metal-organic framework having micropores, the active material of the metal-organic framework can be changed.

In the present invention, the organic linker used basically means a cyclodextrin composed of several glucose, and the cyclodextrin refers to α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. In addition, the organic linker includes cross-linking of other organic molecules to the cyclodextrin, and may form empty regions, that is, pores in the resulting structure by forming a gap between metals (ions), and adjust their size.

In the present invention, an active material may be supported inside the framework, and a plurality of metal clusters and a plurality of cyclodextrins are combined to form a skeletal structure of the metal-organic framework, and the cyclodextrin is between the metal cluster and the metal cluster. A space is created in the space, and an active material can be loaded in the space.

In the present invention, the fact that the release amount and release rate can be controlled by coating the outside of the framework with a release-controlling polymer does not mean that a high release amount and release rate is excellent, and the release amount and release rate according to the field to which the present invention is applied This means that the speed can be adjusted high or low.

In the present invention, the cyclodextrin may be selected from α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

In the present invention, the metal compound is selected from the group consisting of metal acetate, metal acrylate, metal carboxylate, metal sulfate, metal hydroxide, metal nitrate, metal oxynitrate, metal oxide, metal oxychloride and metal chloride. can be The metal moiety of the metal compound may form a repeating unit with the cyclodextrin.

In addition, metal compounds include Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Cd, La, W, Os, Ir consisting of , Pt, Au, Hg, Sm, Eu, Gd, Tb, Dy, Ho, Al, Ga, In, Ge, Sn, Pb, Li, Na, K, Rb, Cs, Mg, Ca, Sr and Ba It may include one or more metal elements or ions selected from the group.

In one aspect of the present invention, the metal compound may be potassium hydroxide (KOH) or sodium hydroxide (sodium hydroxide, NaOH).

In the present invention, the release-controlling polymer is a biocompatible polymer, and may be a cellulose-based polymer or a polyvinyl alcohol-based polymer. Cellulose-based polymers include, for example, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, stearyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, and the like, and polyvinyl cellulose. Alcohol-based polymers include, for example, polyvinylacetyl phthalate and polyvinyl alcohol.

In one aspect of the present invention, the release-controlling polymer is hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, shellac, methacrylic acid ethyl acrylic acid copolymer, methacrylic acid methyl methacrylate copolymer, poly It may be at least one selected from the group consisting of vinylacetyl phthalate, polyvinyl alcohol, and eudragit.

In addition, in one aspect of the present invention, the release-controlling polymer may be Eudragit.

The Eudragit includes Eudragit E, Eudragit S, Eudragit L, Eudragit RS, Eudragit RL, and Eudragit NE, and Eudragit corresponds to a copolymer polymer composition as known and , for example, Eudragit E is a poly(dimethylaminoethyl methacrylate-methacrylate) copolymer, Eudragit L is a poly(methacrylic acid-methylmethacrylate) copolymer, and Eudragit S is poly(methacrylic acid-methylmethacrylate) copolymer.

In one aspect of the present invention, the active material is an organic acid, drug, metal ion, oxide, omega-3, omega-6, DHA, EPA, vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, vitamin B2, It may be at least one selected from the group consisting of vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, and amino acids.

In a specific aspect of the present invention, the active material is lactic acid, citric acid, malic acid, tartaric acid, maleic acid, acetic acid, omega-3, omega-6, DHA, EPA, vitamin A, vitamin C, vitamin D, vitamin E, It is at least one selected from the group consisting of vitamin K, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, and vitamin B12.

In a specific aspect of the present invention, the active material is at least one selected from the group consisting of lactic acid, omega-3, vitamin C and resorufin.

Also, in the present invention, the active material may be a dye. As a dye, for example, coumarin, umbeliferone, aminocoumarin, fluorescene, propidium iodide, tetramethylrhodamine, carboxy rhodamine, rhodamine, naphthalimide, cyanine, luciferin, naphthofluorescein, resorufin.

Vitamin A, organic acid, omega-3, omega-6, etc. may be commercially available for the active material, synthesized by a method known in the art, or obtained by processing after collecting from nature, The present invention is not limited thereto.

In one aspect of the present invention, the supported active material has a weight ratio of 0.05 to 0.5:1 with respect to the total weight of the composite composition. Specifically, the supported active material may have a weight ratio of 0.05 to 0.4:1, 0.05 to 0.3:1, 0.06 to 0.2:1, and 0.075 to 0.2:1.

In one aspect of the present invention, the composite composition may release the active substance at a pH of 6 to 8.

In one embodiment of the present invention, the composite composition has an active substance release amount of 50 to 90%. Specifically, the release amount of the active material may be 55 to 85%, 60 to 80%, 65 to 80%.

The composite composition of the present invention is capable of releasing a large amount of the active substance in a specific pH range, and thus has a high bioabsorption rate.

The present invention comprises the steps of 1) mixing cyclodextrin (CD), a metal compound, and an active material to prepare metal-organic frameworks (MOF) on which an active material is supported; and 2) mixing the metal-organic framework on which the active material of step 1) is supported and the release-controlling polymer to obtain a composite composition; it relates to a method for producing a composite composition comprising a.

In the method for preparing the composite composition of the present invention, the cyclodextrin, the metal compound, the active material, and the release-controlling polymer are as described above.

In the present invention, in the step 1) or 2), the metal-organic framework, the active material and the release-controlling polymer may be dissolved and mixed in a solvent, and any solvent may be used as long as the solvent can dissolve the material, For example, distilled water, methanol, ethanol, acetone, or a mixed solvent thereof may be used.

In the present invention, in step 1), after preparing a cyclodextrin-based metal-organic framework, it is mixed with an active material to prepare a metal-organic framework on which the active material is supported. Here, in the step of preparing the metal-organic framework, it may be prepared by additionally mixing cetyl trimethyl ammonium bromide (CTAB).

In the present invention, the release-controlled polymer can be coated on the metal-organic framework on which the active material is supported through step 2).

In one aspect of the present invention, in step 2), the metal-organic framework on which the active material is supported and the release-controlling polymer are dissolved in a solvent, and then mixed by ball milling.

In the present invention, ball milling may be performed by a conventional method by adjusting the size, strength, weight, rotational speed, milling time, loading amount, etc. of the ball in consideration of the materials to be mixed.

In one aspect of the present invention, when the composite composition is obtained through ball milling, the weight ratio of the metal-organic framework on which the active material is supported to the release-controlling polymer is 1:1 to 5. Specifically, the weight ratio may be 1:1 to 4, more specifically 1:1 to 3.

In another aspect of the present invention, step 2) comprises a mixed solution (A) in which 2)-1 is mixed with a metal-organic framework on which an active material is supported and a release-controlling polymer; and preparing an emulsifying solution (B); and 2)-2 dripping the mixed solution (A) of step 2)-1 into the emulsifying solution (B) to prepare a composite composition.

In another aspect of the present invention, the step 2) comprises the steps of preparing a 2)-1 emulsifying solution (B); and 2)-2 preparing a composite composition by dropping the metal-organic framework powder on which the active material obtained in step (1) is supported to the emulsifying solution (B).

In the present invention, emulsification is to create a state in which a liquid immiscible with the liquid is dispersed in fine droplets, and can be carried out by a conventional method such as a dispersion method, mechanical stirring, spraying, or dripping.

In the present invention, the mixed solution (A) in which the metal-organic framework and the release-controlling polymer are mixed may further include a plasticizer and a dispersing agent for emulsification.

Emulsification can be performed more smoothly by adding a plasticizer, and the plasticizer is, for example, triethyl citrate, polyethylene glycol, propylene glycol, sorbitol, dia. Cetin (Diacetin), triacetin (Triacetin), etc. can be used.

In one aspect of the present invention, the plasticizer may use triethyl citrate. In addition, in one aspect of the present invention, the plasticizer may be used in an amount of 1 to 20 wt% compared to the release-controlling polymer in consideration of emulsification. More specifically, 5 to 15 wt% of the release-controlling polymer may be used.

Dispersants can be used to form emulsions, for example, zinc stearate, aluminum stearate, calcium stearate, aluminum hydroxide, polyoxy Ethylene stearate (Polyoxyethylene stearate), gelatin, casein, methacrylic acid, methacrylate, etc. may be used.

In one aspect of the present invention, the dispersant may use aluminum stearate. In addition, in one aspect of the present invention, the dispersant may be used in an amount of 10 to 50 wt% compared to the release-controlling polymer in consideration of emulsification. More specifically, 20 to 45 wt% of the release-controlling polymer may be used.

In the present invention, the emulsifying solution is a solution having a different polarity from that of the metal-organic framework and the release-controlling polymer, and specifically, a non-polar solvent may be used. More specifically, hydrocarbon-based oil, ester-based oil, vegetable oil, animal oil, etc. may be used, for example, squalene, paraffin, caprylic triglyceride, hexyllaurate, octyldodecanol, olive oil, lanolin etc. can be used.

In addition, the emulsifying solution may include a surfactant, and the surfactant is, for example, polyoxyethylene glycols, polyoxyethylene-polyoxypropylene copolymers, poloxamers, fatty acid esters, cholesterols, polyalkylenes. glycol ethers, more specifically, glyceryl stearate, sorbitan oleate, sorbitan stearate, sorbitan sesquioleate (span 83), etc. can be used

In one embodiment of the present invention, the surfactant may be sorbitan sesquioleate (span 83). In addition, surfactants may be used in a concentration range of 0.1 to 5 w/v% for emulsification control. More specifically, it may be used in a concentration range of 0.5 to 2 w/v%.

In addition, the method for preparing a composite composition through emulsification is a mixed solution (A) in which an active material-supported metal-organic framework and a release-controlling polymer are mixed, or an emulsifying solution (B) of a metal-organic framework powder on which an active material is supported. ) to prepare a composite composition, and a pump can be used for dropping, and the properties of the composite composition can be changed by adjusting the rpm of the pump.

In one aspect of the present invention, the rpm of the pump may be 1 to 30 rpm.

In one embodiment of the present invention, when the composite composition is obtained through emulsification, the weight ratio of the metal-organic framework on which the active material is supported and the release-controlling polymer is 1: 0.01 to 0.5. Specifically, the weight ratio may be 1:0.05 to 0.4, more specifically 1:0.1 to 0.2.

In addition, the present invention provides an oral formulation comprising the composite composition.

The oral preparation according to the present invention may be formulated in the form of tablets, powders, granules, capsules, syrups, and the like, by a conventional method.

Formulations for oral administration may include tablets, patients, powders, granules, capsules, troches, and the like, and such preparations include at least one excipient, for example, starch, calcium carbonate, It may be prepared by mixing sucrose or lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc may also be used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used. However, it is not necessarily included as an excipient that may be additionally included.

The composition according to the present invention may be administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to prevent/treat/ameliorate a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level depends on the type and severity of the patient's disease. , drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, an amount capable of obtaining the maximum effect with a minimum amount without side effects can be administered, which can be easily determined by a person skilled in the art.

Specifically, the effective amount of the compound according to the present invention may vary depending on the age, sex, and weight of the patient, and generally 0.1 mg to 100 mg per kg body weight, more specifically 1 mg to 15 mg per kg body weight, is administered daily or every other day Or it can be administered in divided doses 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.

In addition, the composite composition of the present invention using a dye as an active material, it can be used for sensors, biosensors, external environment evaluation, and the like.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

<Example 1> Preparation of cyclodextrin-based metal-organic framework

<Example 1-1> Preparation of metal-organic framework based on cyclodextrin

Potassium hydroxide, methanol and γ-cyclodextrin were prepared from Wako Chemicals. 56.11 mg (1 mmol) of potassium hydroxide and 162 mg (0.125 mmol) of γ-cyclodextrin were placed in a 10 ml vial and dissolved in 5.0 ml of distilled water. Thereafter, a solution of potassium hydroxide and γ-cyclodextrin was added to a 135 ml wide-mouth bottle containing 20 ml of methanol, and the mixture was reacted in an oven at 50° C. for 18 to 24 hours without closing the lid.

<Example 1-2> Preparation of metal-organic framework based on cyclodextrin

Cetyl Trimethyl Ammonium Bromide (CTAB) was prepared from Wako Chemicals. The solution reacted in <Example 1-1> was put into a 20 ml vial containing 0.5 ml of ethanol and 8 mg (0.022 mmol) of CTAB, and then reacted at room temperature for 3 hours. Then, it was washed with isopropyl alcohol and dried under vacuum to obtain a cyclodextrin-based metal-organic framework (CD-MOF).

<Example 2> Preparation of cyclodextrin-based metal-organic framework containing active material

<Example 2-1> Preparation of cyclodextrin-based metal-organic framework containing lactic acid

7 μL of lactic acid and 1 ml of ethanol were placed in a 20 ml vial, and then mixed. Thereafter, 100 mg of the CD-MOF prepared in <Example 1> was additionally added, and the mixture was loaded in an oven at 37° C. for 2 hours, centrifuged to remove the supernatant, and washed with ethanol. After that, it was vacuum dried to prepare a CD-MOF (LA-CD-MOF) containing lactic acid.

<Example 2-2> Preparation of cyclodextrin-based metal-organic framework containing vitamin C (Vitamin C)

17.61 mg of vitamin C, and 1 ml of ethanol were placed in a 20 ml vial and then mixed. After that, 100 mg of the CD-MOF prepared in <Example 1> was additionally added, and the mixture was loaded in an oven at 37° C. for 2 hours, centrifuged to remove the supernatant, and washed with ethanol. Thereafter, by vacuum drying, a CD-MOF containing vitamin C (Vit.C-CD-MOF) was prepared.

<Example 2-3> Preparation of cyclodextrin-based metal-organic framework containing omega-3

38.5 mg of omega-3 and 1 ml of ethanol were placed in a 20 ml vial and then mixed. After that, 100 mg of the CD-MOF prepared in <Example 1> was additionally added, and the CD-MOF containing omega-3 was loaded in an oven at 37° C. for 2 hours, concentrated under reduced pressure, and dried under vacuum. (Omega3-CD-MOF) was prepared.

<Example 2-4> Preparation of cyclodextrin-based metal-organic framework containing resorufin

50 mg of resorufin and 1 ml of ethanol were placed in a 20 ml vial and then mixed. Thereafter, 100 mg of the CD-MOF prepared in <Example 1> was additionally added, and the mixture was loaded in an oven at 37° C. for 2 hours, centrifuged to remove the supernatant, and washed with ethanol. Then, it was vacuum dried to prepare a CD-MOF (RS-CD-MOF) containing resorufin.

<Example 3> Eudragit coating of cyclodextrin-based metal-organic framework by ball milling

<Example 3-1> Eudragit coating by ball milling (lactic acid)

1.5 g of Eudragit S was dissolved in ethanol to prepare a 30 wt% mixed solution (solution 1). Separately, 1 g of LA-CD-MOF prepared in <Example 2-1> was dissolved in ethanol to prepare a 30 wt% mixed solution (Solution 2). Thereafter, solution 1 and solution 2 were loaded into a grinding vessel and coated by a ball milling method of milling in the presence of balls, and LA-CD-MOF coated with Eudragit (ES-LA-CD -MOF) was obtained.

<Example 3-2> Eudragit coating by ball milling (vitamin C)

Eudragit S 2 g, Vit.C-CD-MOF 1 g prepared in <Example 2-2> In the same manner as in <Example 3-1>, Vit coated with Eudragit .C-CD-MOF (ES-Vit.C-CD-MOF) was obtained.

<Example 3-3> Eudragit coating by ball milling (omega-3)

Eudragit S 2 g, Omega3-CD coated with Eudragit by the same method as in <Example 3-1> using 1 g of Omega3-CD-MOF prepared in <Example 2-3> -MOF (ES-Omega3-CD-MOF) was obtained.

<Example 3-4> Eudragit coating by ball milling (resorufin)

Eudragit S 2 g and Eudragit-coated LA-CD by the same method as in <Example 3-1> using 1 g of RS-CD-MOF prepared in <Example 2-4> -MOF (ES-LA-CD-MOF) was obtained.

<Example 4> Eudragit coating of cyclodextrin-based metal-organic framework by emulsion

<Example 4-1> Eudragit coating by emulsion (lactic acid)

0.1 g of Eudragit S was dissolved in ethanol to prepare a mixed solution. Then, 0.5 g of LA-CD-MOF prepared in <Example 2-1> (5 times the weight of Eudragit S), 0.01 g (10 wt%) of triethyl citrate, and aluminum stearate (aluminium stearate) 0.035 g (35 wt%) was added to the solution, followed by stirring to prepare a mixed solution (solution a).

Separately, 99 ml of paraffin and 1 ml of sorbitan sesquioleate (span 83) were mixed and stirred to prepare a 100 ml mixed solution of 1% w/v solution, and then LA-CD-MOF was A mixed solution (solution b) dissolved in ethanol was prepared.

Using a tubing pump (peristaltic pump), the solution a was dropped toward the solution b (dropping). At this time, the coating degree was changed by adjusting the rpm of the tubing pump. Then, after all of the solution a was added, stirred overnight, filtered, and washed with petroleum ether to obtain Eudragit-coated LA-CD-MOF (ES-LA-CD-MOF). .

In addition, LA-CD-MOF was added dropwise to the solution a in powder form, and thereafter, Eudragit-coated LA-CD-MOF (ES-LA-CD-MOF) was obtained in the same manner.

<Example 4-2> Eudragit coating by emulsion

Eudragit S 0.1 g and Vit.C-CD-MOF 0.5 g prepared in <Example 2-2> were used in Vit. C-CD-MOF (ES-Vit.C-CD-MOF) was obtained.

<Example 4-3> Eudragit coating by emulsion (omega-3)

Eudragit S 0.1 g and Omega3-CD-MOF prepared in <Example 2-3> were used in the same manner as in <Example 4-1>, with Eudragit coated Omega3-CD- MOF (ES-Omega3-CD-MOF) was obtained.

<Example 4-4> Eudragit coating by emulsion (resorufin)

Eudragit S 0.1 g and Eudragit-coated LA-CD- by the same method as in <Example 4-1> using 0.5 g of RS-CD-MOF prepared in <Example 2-4> MOF (ES-LA-CD-MOF) was obtained.

<Experimental Example 1> Enteric release of cyclodextrin-based metal-organic framework coated by ball milling (lactic acid)

<Experimental Example 1-1> Release confirmation at pH 1.2

After loading 100 mg of the ES-LA-CD-MOF prepared in <Example 3-1> in 20 ml of a solution adjusted to pH 1.2, 1 ml was sampled immediately. Thereafter, after soaking for 2 hours at pH 1.2, 1 mL was sampled.

<Experimental Example 1-2> Release confirmation at pH 6.8

_{0.2 M monosodium phosphate (NaH 2} PO ₄ ) and 1 N sodium hydroxide (NaOH) were added to the solution loaded with ES-LA-CD-MOF adjusted to pH 1.2 in <Experimental Example 1-1> to pH 6.8 was adjusted with After soaking for 2 hours at pH 6.8, 1 mL was sampled.

<Experimental Example 1-3> Release confirmation at pH 7.4

In <Experimental Example 1-2>, the ES-LA-CD-MOF-supported solution adjusted to pH 6.8 was adjusted to pH 7.4 by adding 1 N sodium hydroxide (NaOH). After soaking for 2 hours at pH 7.4, 1 mL was sampled.

Thereafter, the solutions sampled in <Experimental Example 1-1> to <Experimental Example 1-3> were quantitatively analyzed using HPCL. For HPLC, an Agilent 1200 model was used, a column for Phenomenex Luna C18 HPLC was used, and an aqueous solution of phosphoric acid (H ₃ PO ₄ , pH ~2) and acetonitrile were used as the mobile phase, and the flow rate was 0.6 ml/min. and UV 210 nm.

As a result of the analysis, the content of lactic acid in LA-CD-MOF was 109.78 mg _(LA) /g _(LA-CD-MOF) , and the release results are shown in Table 1 and FIG. 3 below.

Eudragit S :
LA-CD-MOF h pH at sampling Lactic acid release (mg/g) Lactic acid release (%) 2:1 0 1.2 15.557 0 2 1.2 27.583 9.09 4 6.8 94.877 76.43 6 7.4 93.531 78.61

As a result of the analysis, it was confirmed that the release of lactic acid was not controlled in the case of the uncoated LA-CD-MOF, but the release rate of the ES-LA-CD-MOF was different depending on the pH condition to release lactic acid.

<Experimental Example 2> Enteric release (vitamin C) of a cyclodextrin-based metalorganic framework coated by ball milling

Enteric release was tested for the ES-Vit.C-CD-MOF prepared in <Example 3-2> in the same manner as in <Experimental Example 1>.

However, the Agilent 1200 model was used for HPLC, the column for Phenomenex Luna C18 HPLC was used, and potassium phosphate aqueous solution (KH ₂ PO ₄ , pH 2.5) was used as the mobile phase, flow rate 1 ml/min and UV Analysis was performed using 254 nm.

As a result of the analysis, the content of vitamin C in Vit.C-CD-MOF was 119.30 mg _(Vit.C) /g _{(Vit.C-CD-MOF)} , and the release results are shown in Table 2 and FIG. 4 below.

Eudragit S :
Vit.C-CD-MOF h pH at sampling Vitamin C release (mg/g) Vitamin C release (%) 1.5:1 0 1.2 4.071 0 2 1.2 8.988 6.038 4 6.8 53.694 64.236 6 7.4 58.772 74.695

As a result of the analysis, the release of vitamin C was not controlled in the case of uncoated Vit.C-CD-MOF, but it was confirmed that ES-Vit.C-CD-MOF released vitamin C by varying the release rate according to pH conditions. did

<Experimental Example 3> Enteric release (omega-3) of a cyclodextrin-based metal-organic framework coated by ball milling

Enteric release of the ES-Omega3-CD-MOF prepared in <Example 3-3> was tested in the same manner as in <Experimental Example 1>.

As a result of the analysis, the content of Omega3 in Omega3-CD-MOF was 277.9 mg _(omega3) /g _{(omega3-CD-MOF)} , and the experimental results are as shown in FIGS. 5 and 6 .

As shown in FIG. 5 , it was confirmed that uncoated Omega3-CD-MOF was suspended at pH 1.2, but ES-Omega3-CD-MOF was not suspended at pH 1.2, but was suspended from pH 6.8. . This is due to swelling according to the pH change of Eudragit, confirming that omega-3 is protected by Eudragit and then released by changes in pH conditions.

<Experimental Example 4> Enteric release of cyclodextrin-based metalorganic framework coated by ball milling (resorufin)

The ES-RS-CD-MOF prepared in <Example 3-4> was sampled in the same manner as in <Experimental Example 1>. Thereafter, the change was confirmed by irradiating ultraviolet rays (320 nm), and the experimental results are as shown in FIGS. 7 and 8 .

As shown in FIG. 7 , in the case of ES-RS-CD-MOF, the luminescence phenomenon was not confirmed under the condition of pH 1.2, but the luminescence phenomenon was confirmed from the condition of pH 6.8. This is due to the swelling caused by the pH change of Eudragit, confirming that resorufin is protected by Eudragit and then released by the change in pH conditions.

<Experimental Example 5> Enteric release of cyclodextrin-based metal-organic framework coated by emulsion (lactic acid)

Enteric release of the ES-LA-CD-MOF prepared in <Example 4> was confirmed by the same method as in <Experimental Example 1>.

In the case of ES-LA-CD-MOF prepared by adding a solution of LA-CD-MOF dissolved in ethanol, the analysis results are shown in Tables 3 to 6, and the ES prepared by adding LA-CD-MOF powder In the case of -LA-CD-MOF, the analysis results are shown in Tables 7 to 11.

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (5 rpm) 0 1.2 5.01 2 1.2 9.88 4 6.8 10.05 6 7.4 11.51 8 7.4 10.89 24 7.4 10.48

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (10 rpm) 0 1.2 5.11 2 1.2 9.82 4 6.8 21.11 6 7.4 20.85 8 7.4 20.46 24 7.4 20.11

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (15 rpm) 0 1.2 4.82 2 1.2 8.87 4 6.8 17.58 6 7.4 17.11 8 7.4 16.48 24 7.4 16.75

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (20 rpm) 0 1.2 6.52 2 1.2 8.68 4 6.8 13.25 6 7.4 13.11 8 7.4 12.96 24 7.4 12.75

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (1 rpm) 0 1.2 20.11 2 1.2 35.11 4 6.8 78.52 6 7.4 79.58 8 7.4 78.88

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (3 rpm) 0 1.2 15.22 2 1.2 28.11 4 6.8 50.12 6 7.4 50.85 8 7.4 49.72

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (5 rpm) 0 1.2 10.21 2 1.2 19.52 4 6.8 25.11 6 7.4 26.15 8 7.4 25.81

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (7 rpm) 0 1.2 2.51 2 1.2 5.23 4 6.8 5.03 6 7.4 5.85 8 7.4 5.51

Eudragit S :
LA-CD-MOF
and rpm h pH at sampling Lactic acid (LA) release (mg/g) 1:0.2 (9 rpm) 0 1.2 1.70 2 1.2 3.58 4 6.8 4.01 6 7.4 4.21 8 7.4 3.98

As a result of the analysis, as shown in Tables 3 to 11, it was confirmed that the ES-LA-CD-MOF released the active material by varying the release amount and release rate according to the change of rpm and the change of pH conditions, respectively.

<Experimental Example 6> Enteric release of cyclodextrin-based metal-organic framework coated by emulsion (vitamin C)

Enteric release of the ES-Vit.C-CD-MOF prepared in <Example 4> was confirmed by the same method as in <Experimental Example 1>. In the case of ES-Vit.C-CD-MOF prepared by adding a solution of Vit.C-CD-MOF dissolved in ethanol, the analysis results are shown in Tables 12 to 15, and Vit.C-CD-MOF powder In the case of ES-Vit.C-CD-MOF prepared by adding , the analysis results are shown in Tables 16 to 20.

Eudragit S :
VitC-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (5 rpm) 0 1.2 3.03 2 1.2 6.11 4 6.8 6.20 6 7.4 6.01 8 7.4 6.02 24 7.4 5.88

Eudragit S :
VitC-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (10 rpm) 0 1.2 2.55 2 1.2 5.02 4 6.8 15.01 6 7.4 15.11 8 7.4 16.01 24 7.4 15.88

Eudragit S :
VitC-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (15 rpm) 0 1.2 2.88 2 1.2 5.01 4 6.8 16.01 6 7.4 15.55 8 7.4 15.85 24 7.4 14.98

Eudragit S :
VitC-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (20 rpm) 0 1.2 3.12 2 1.2 6.01 4 6.8 17.01 6 7.4 16.88 8 7.4 16.75 24 7.4 15.89

Eudragit S :
VitC-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (1 rpm) 0 1.2 10.25 2 1.2 25.55 4 6.8 60.11 6 7.4 61.12 8 7.4 60.18

Eudragit S :
VitC-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (3 rpm) 0 1.2 10.11 2 1.2 22.05 4 6.8 45.22 6 7.4 42.55 8 7.4 41.48

Eudragit S :
VitC-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (5 rpm) 0 1.2 7.08 2 1.2 15.55 4 6.8 20.11 6 7.4 19.45 8 7.4 19.75

Eudragit S :
VitB-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (7 rpm) 0 1.2 0.90 2 1.2 7.55 4 6.8 4.93 6 7.4 4.60 8 7.4 4.20

Eudragit S :
VitB-CD-MOF
and rpm h pH at sampling Vitamin C release (mg/g) 1:0.2 (9 rpm) 0 1.2 0.70 2 1.2 3.21 4 6.8 2.55 6 7.4 2.38 8 7.4 2.27

As a result of the analysis, as shown in Tables 12 to 20, it was confirmed that the ES-Vit.C-CD-MOF released the active material by varying the release amount and release rate according to the change in rpm and change in pH conditions, respectively.

<Experimental Example 7> Enteric release of cyclodextrin-based metal-organic framework coated by emulsion (omega-3)

Enteric release of the ES-Omega3-CD-MOF prepared in <Example 4> was confirmed in the same manner as in <Experimental Example 1>.

As a result of the experiment, ES-Omega3-CD-MOF prepared by adding a solution of Omega3-CD-MOF dissolved in ethanol and ES-Omega3-CD-MOF prepared by adding Omega3-CD-MOF powder were both pH 1.2 conditions. It was confirmed that it was not suspended at pH 6.8, but became suspended from pH 6.8. This is due to swelling according to the pH change of Eudragit, confirming that omega-3 is protected by Eudragit and then released by changes in pH conditions.

<Experimental Example 8> Enteric release of cyclodextrin-based metal-organic framework coated by emulsion (resorufin)

Enteric release of the ES-RS-CD-MOF prepared in <Example 4> was confirmed by the same method as in <Experimental Example 1>.

As a result of the experiment, both ES-RS-CD-MOF prepared by adding a solution dissolved in ethanol and ES-RS-CD-MOF prepared by adding Omega3-CD-MOF powder showed light emission under the condition of pH 1.2. However, luminescence was confirmed from pH 6.8 conditions. This is due to the swelling phenomenon according to the pH change of Eudragit, confirming that resorufin is protected by Eudragit and then released by the change in pH conditions.

Claims (24)

comprising a metal organic framework (MOF);
The metal-organic framework is composed of a coordination bond of a repeating unit containing a cyclodextrin (CD) and a metal,
The active material is loaded inside the skeleton,
The outside of the framework is coated with a release-controlling polymer, the composite composition.
According to claim 1,
The cyclodextrin is γ-cyclodextrin, the composite composition.
According to claim 1,
The release-controlling polymer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, shellac, methacrylic acid ethylacrylic acid copolymer, methacrylic acid methylmethacrylate copolymer, polyvinylacetyl phthalate, and Eudragit. At least one selected from the group consisting of, a composite composition.
According to claim 1,
The release-controlling polymer is Eudragit,
Wherein the Eudragit is selected from the group consisting of Eudragit E, Eudragit S, Eudragit L, Eudragit RS, Eudragit RL and Eudragit NE.
According to claim 1,
The active substances include organic acids, drugs, metal ions, oxides, omega-3, omega-6, DHA, EPA, vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, vitamin B2, vitamin B3, vitamin B5, vitamins At least one selected from the group consisting of B6, vitamin B7, vitamin B9, vitamin B12 and amino acids, a complex composition.
According to claim 1,
The active material is at least one selected from the group consisting of lactic acid, omega-3, vitamin C and resorufin, a complex composition.
According to claim 1,
The metal-organic framework has a molar ratio of cyclodextrin (CD) and metal of 1: 5 to 15, the composite composition.
According to claim 1,
The supported active material has a weight ratio of 0.05 to 0.5: 1 compared to the total weight of the composite composition, the composite composition.
According to claim 1,
wherein the composite composition releases the active substance at a pH of 6 to 8.
According to claim 1,
wherein the composite composition has a release amount of 50 to 90% of the active substance.
1) preparing metal-organic frameworks (MOF) on which an active material is supported by mixing cyclodextrin (CD), a metal compound, and an active material; and
2) mixing the metal-organic framework on which the active material of step 1) is supported and a release-controlling polymer to obtain a composite composition;
12. The method of claim 11,
The active material of step 1) is organic acid, drug, metal ion, oxide, omega-3, omega-6, DHA, EPA, vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, vitamin B2, vitamin B3, At least one selected from the group consisting of vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12 and amino acids, a complex composition.
12. The method of claim 11,
The active material of step 1) is at least one selected from the group consisting of lactic acid, omega-3, vitamin C and resorufin, a method for producing a complex composition
12. The method of claim 11,
The release-controlling polymer of step 2) is Eudragit, the release-controlling polymer is Eudragit,
Wherein the Eudragit is selected from the group consisting of Eudragit E, Eudragit S, Eudragit L, Eudragit RS, Eudragit RL and Eudragit NE.
12. The method of claim 11,
In step 2), the metal-organic framework on which the active material of step 1) is supported and the release-controlling polymer are dissolved in a solvent and then mixed by ball milling.
16. The method of claim 15,
The weight ratio of the metal-organic framework on which the active material of step 2) is supported and the release-controlling polymer is 1:1 to 5, the method for producing a composite composition.
12. The method of claim 11,
Step 2) is
2)-1 A mixed solution (A) in which an active material-supported metal-organic framework and a release-controlling polymer are mixed; and preparing an emulsifying solution (B); and
2)-2 Dropping the mixed solution (A) of step 2)-1 into the emulsifying solution (B) to prepare a composite composition;
18. The method of claim 17,
The method for producing a composite composition, wherein the weight ratio of the metal-organic framework on which the active material of step 2)-1 is supported and the release-controlling polymer is 1: 0.01 to 0.5.
18. The method of claim 17,
The mixed solution (A) of step 2)-1 comprises a plasticizer and a dispersant, the method for producing a composite composition.
20. The method of claim 19,
The plasticizer is 1 to 20 wt% of the release-controlling polymer, the method for producing a composite composition.
20. The method of claim 19,
The dispersant is 10 to 50 wt% of the release-controlling polymer, the method for producing a composite composition.
18. The method of claim 17,
The emulsifying solution (B) of step 2)-1 is a method for producing a composite composition comprising a non-polar solvent and a surfactant.
23. The method of claim 22,
The surfactant is in a concentration range of 0.1 to 5 w/v% compared to the emulsifying solution (B), the method for producing a composite composition.
An oral formulation comprising the composite composition according to any one of claims 1 to 10.

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