KR102690574B1 - Enteric composition for protection and delivery of vitamin B1 - Google Patents

Abstract

The present invention is a stabilized enteric composition that effectively controls the absorption and release of vitamin B1 by introducing a release-controlling polymer such as Eudragit to solve the problems of controlled release and human toxicity of conventional cyclodextrin-based metal-organic frameworks. It's about.

Description

Enteric composition for protection and delivery of vitamin B1 {Enteric composition for protection and delivery of vitamin B1}

The present invention provides an enteric composition comprising cyclodextrin (CD)-based metal-organic frameworks (MOF) and release-controlling polymers such as Eudragit for the protection and delivery of vitamin B1. and its manufacturing method.

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. . MOF is a porous material and has a large surface area, allowing active chemical reactions to occur. 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 not only the pore size and shape but also the internal structure can be elaborated. It has the advantage of being easily synthesized.

Research results on the structure of MOF were published from the late 1950s to the early 1960s, but following the publication of a polymer skeleton infinitely connected in a 3-D structure in 1989 by R. Robson and others at the University of Melbourne, the University of Arizona Omar H. Yaghi's group (now at the University of California, Berkeley) rediscovered MOF in 1995 and achieved rapid growth with the release of MOF-5 in 1999. Currently, MOFs are being studied in many fields due to their high surface area, internal surface, and size-tunable properties, and are especially applied in fields such as medicine, carbon storage, semiconductors, adsorbents, electronics, sensors, and catalysts. In this regard, Republic of Korea Patent No. 10-1846085 relates to a method for stabilizing cosmetic ingredients using a metal-organic framework, and discloses that functional materials can be supported on MOF.

However, in the fields of medicine and drug delivery, MOFs have had difficulties in practical application in that they come from non-renewable or toxic substances. To solve this problem, selection of metal ions and organic molecules used in MOFs was necessary.

Cyclodextrin (CD) is a representative naturally degradable and biodegradable material that has low toxicity and has properties that increase drug safety, bioavailability, and solubility in water-soluble substances. Therefore, MOFs using cyclodextrin have been studied.

Cyclodextrin-based MOF uses cyclodextrin as a ligand, and research results show that the porous characteristics of MOF and the encapsulation ability of cyclodextrin are combined to have superior properties compared to existing porous crystals such as zeolite or porous carbon. In addition, studies have reported that CD-MOF can overcome the physicochemical and biochemical limitations of drugs.

As related patents, U.S. Patent Publication No. 2017-0028383 discloses a cyclodextrin-based metal-organic framework and a method of using the same, and U.S. Patent Publication No. 2017-0274097 discloses a composition containing a cyclodextrin-based metal-organic framework. It is disclosed that it is effective in releasing active substances and can be used for cosmetic or therapeutic purposes. In addition, European Patent Publication No. 3374402 discloses that a cyclodextrin-based metal-organic framework is water-soluble and non-toxic, so it can be used in oral drug preparations.

However, due to the hydrophilic nature of the external surface of CD-MOF, it is prone to early release in a hydrophilic environment, which makes it difficult to utilize in fields where substances must be released continuously or through control, and is not effective in biomedical and overall pharmacological effects. There is a problem that can cause problems.

In general, oral dosage forms are preferred due to portability and ease of administration, but there are many problems with the inability to effectively release the drug due to difficulty in drug release control, dosage form collapse, chemical decomposition due to rapid pH changes in the intestines, and hydrolysis. It becomes. In relation to this, prior art attempts are being made to solve the problem through tablets mixed with swellable polymers or hydrophilic excipients. There are attempts to utilize oral administration through swellable polymers or hydrophilic excipients such as glyceryl monooleate, glyceryl monolaurate, methacrylic acid polymer, methacrylic acid-acrylic acid copolymer, etc., Republic of Korea Patent Publication No. 10-2019-0096387 An oral formulation of a glucokinase activator containing a copolymer polymer carrier containing butyl methacrylate is disclosed, and an oral formulation of a monoacetyldiacylglycerol compound containing a hydrophilic sustained-release polymer is disclosed in Korean Patent No. 10-1859200. A solid formulation is disclosed.

However, although various research results on coating, encapsulation, carrier, and drug control through polymers are known, there is no technology used in combination with MOF, and nothing is known about the possibility of combination, combination method, etc. In addition, there is nothing specifically known about whether MOF releases vitamin B1.

Accordingly, the present inventors tried to prepare a composition for oral administration to protect and deliver vitamin B1, and as a result, by applying a release-controlling polymer to CD-MOF, the release of the active substance of CD-MOF was controlled and stability was improved. The present invention was completed by demonstrating that an enteric composition capable of oral administration can be prepared.

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, Ji-bong 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 problem of conventional cyclodextrin (CD)-based metal-organic frameworks (MOF) is that the release rate of the active material cannot be controlled, decomposes in an aqueous environment, and may be harmful to the human body. In order to solve this problem, the purpose is to provide a stabilized enteric composition while effectively controlling the absorption and release of the active substance, vitamin B1, by applying a release-controlling polymer such as Eudragit to CD-MOF.

In order to achieve the above object, the present invention is a complex composition containing vitamin B1 as an active material, comprising a metal organic framework (MOF), and the metal organic framework is cyclodextrin (CD). and a coordination bond of a repeating unit containing a metal, vitamin B1 is supported inside the skeleton, and the outside of the skeleton is coated with a release-controlling polymer.

In one aspect 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, ethyl methacrylic acid copolymer, methyl methacrylate methacrylate copolymer, and polyvinylacetyl phthalate. , and may be selected from the group consisting of Yudrajit.

In one aspect of the present invention, the release-controlling polymer is Eudragit,

The Eudragit is selected from the group consisting of Eudragit E, Eudragit S, Eudragit L, Eudragit RS, Eudragit RL and Eudragit NE.

In one aspect 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 loaded vitamin B1 has a weight ratio of 0.05 to 0.5:1 relative to the entire complex composition.

In one aspect of the invention, the complex composition is capable of releasing vitamin B1 at pH 6 to 8.

In addition, the present invention includes the following steps: 1) mixing cyclodextrin (CD), a metal compound, and vitamin B1 as an active material to prepare metal-organic frameworks (MOF) loaded with vitamin B1; and 2) mixing the metal-organic framework carrying vitamin B1 of step 1) with the release-controlling polymer to obtain a composite composition.

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

In one aspect of the present invention, step 2) may involve dissolving the vitamin B1-supported metal organic framework and the release-controlling polymer in a solvent and then mixing them by ball milling.

In a specific aspect of the present invention, when step 2) is to obtain a composite composition by ball milling, the weight ratio of the metal-organic framework carrying vitamin B1 and the release-controlling polymer is 1:1 to 5.

In one aspect of the present invention, step 2) includes 2)-1 a mixed solution (A) in which a metal-organic framework carrying vitamin B1 and a release-controlling polymer are mixed; and preparing an emulsification solution (B); and 2)-2 dropping the mixed solution (A) of step 2)-1 into the emulsification solution (B) to prepare a composite composition.

In one specific aspect of the present invention, when step 2) obtains a composite composition by emulsification, the weight ratio of the metal-organic framework carrying vitamin B1 and the release-controlling polymer is 1:0.01 to 0.5.

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

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

Additionally, the present invention provides an oral formulation containing the above composite composition.

The present invention is an enteric composition for protecting and delivering vitamin B1. The composition of the present invention has the advantage that the release of the active ingredient, vitamin B1, can be controlled by a release-controlling polymer, is stabilized, and is harmless to the human body.

Figure 1 is a diagram confirming CD-MOF through SEM.
Figure 2 is a diagram confirming the crystallinity of CD-MOF through PXRD.
Figure 3 is a diagram confirming the CD-MOF loaded with vitamin B1 through SEM.
Figure 4 is a diagram confirming the crystallinity of the CD-MOF loaded with vitamin B1 through PXRD.
Figures 5 to 7 are diagrams confirming the CD-MOF loaded with vitamin B1 and coated with Eudragit through SEM.
Figure 8 is a diagram confirming the amount of vitamin B1 released through HPLC.
Figure 9 is a diagram confirming the amount of vitamin B1 released from CD-MOF manufactured by ball milling.
Figures 10 and 11 are diagrams confirming the amount of vitamin B1 released from CD-MOF prepared by emulsification.

Hereinafter, the present invention will be described in detail.

Throughout the specification of the present invention, when a part is said to “include” a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary.

The term “step of” or “step of” used throughout the specification of the present invention does not mean “step for.”

The present invention relates to a complex composition containing vitamin B1 as an active ingredient, and more specifically, to a complex composition comprising a metal organic framework (MOF), wherein the metal organic framework includes cyclodextrin (CD) and It relates to a composite composition composed of a coordination bond of repeating units containing a metal, carrying vitamin B1 inside the skeleton, and coating the outside of the skeleton with a release-controlling polymer.

In addition, the present invention includes the steps of 1) mixing cyclodextrin (CD), a metal compound, and vitamin B1 to prepare metal-organic frameworks (MOF) carrying vitamin B1; and 2) mixing the metal-organic framework carrying vitamin B1 of step 1) with the release-controlling polymer to obtain a composite composition.

In the present invention, the metal-organic framework is a crystalline material with a skeletal structure formed by connecting a metal (ion) and an organic linker, where the metal includes not only a single metal (ion) but also a metal cluster, and various organic linkers are metal. It plays a role in increasing the distance between metals by linking them together, and these organic linkers periodically form a network structure to connect metals.

Therefore, selective absorption and release of active substances is possible by controlling the size of the micropores present in the metal-organic framework through various combinations between metal (ions) and organic linkers.

The organic linker used in the present invention basically refers to a cyclodextrin composed of several glucoses. Cyclodextrins include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. In addition, the organic linker involves cross-linking other organic molecules to cyclodextrin, and by forming gaps between metals (ions), empty areas, or pores, can be formed inside the resulting structure, and their size can be adjusted.

In the present invention, the active material can be supported inside the framework, where a plurality of metal clusters and a plurality of cyclodextrins are combined to form a skeletal structure of a metal-organic framework, and the cyclodextrin is used to form a skeletal structure between the metal clusters and the metal cluster. A space is created, and the active material can be stored 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 skeleton with a biodegradable polymer does not mean that the release amount and release rate are superior, and the release amount and release rate depend on 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 may be 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. You can. The metal portion of the metal compound can form a repeating unit with cyclodextrin.

Additionally, 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. , 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 contain one or more metal elements or ions selected from the group, and more specifically, the metal compound may be potassium hydroxide (KOH) or 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, methylcellulose, ethylcellulose, carboxymethyl cellulose, stearyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, and polyvinyl Alcohol-based polymers include, for example, polyvinylacetyl phthalate and polyvinyl alcohol.

In one aspect of the present invention, the release-controlling polymer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, shellac, methacrylic acid ethyl acrylic acid copolymer, methacrylic acid methyl methacrylate copolymer, polyvinyl It may be one or more selected from the group consisting of acetyl phthalate, polyvinyl alcohol, and Eudragit. In a more specific aspect of the present invention, Eudragit may be used as the release-controlling polymer.

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. For example, Eudragit E is a poly(dimethylaminoethyl methacrylate-methacrylate) copolymer, Eudragit L is a poly(methacrylic acid-methyl methacrylate) copolymer, and Eudragit S is It refers to poly(methacrylic acid-methyl methacrylate) copolymer. However, it is not limited to Yudrajit listed above.

In the present invention, the hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and cellulose acetape phthalate are cellulose-based release-controlling polymers, and may further include cellulose-based polymers other than the above polymers, polyvinylacetyl phthalate, Polyvinyl alcohol is a polyvinyl alcohol-based polymer, and may further include polyvinyl alcohol-based polymers other than the above polymers.

In one aspect of the invention, the active substance is vitamin B1.

The vitamin B1 can be used commercially, synthesized by a method known in the art, or collected from nature and then processed, but is not limited thereto.

In one aspect of the present invention, the loaded vitamin B1 has a weight ratio of 0.05 to 0.5:1 relative to the entire complex composition. Specifically, the loaded vitamin B1 may have a weight ratio of 0.05 to 0.4:1, 0.05 to 0.3:1, 0.06 to 0.2:1, or 0.075 to 0.2:1.

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

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

The present invention includes the steps of 1) mixing cyclodextrin (CD), a metal compound, and vitamin B1 to prepare metal-organic frameworks (MOF) carrying vitamin B1; and 2) mixing the metal-organic framework carrying vitamin B1 of step 1) with the release-controlling polymer to obtain a composite composition.

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

In the present invention, in step 1) or 2), the metal-organic framework, vitamin B1, and release-controlling polymer can be mixed by dissolving them in a solvent, and any solvent that can dissolve the materials can be used, e.g. For example, distilled water, methanol, ethanol, acetone, or a mixed solvent thereof can be used.

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

In the present invention, in step 1), a cyclodextrin-based metal-organic framework can be prepared and then mixed with vitamin B1 to produce a metal-organic framework loaded with vitamin B1. Here, in the step of manufacturing the metal-organic framework, it can be manufactured by additionally mixing cetyl trimethyl ammonium bromide (CTAB).

In one aspect of the present invention, in step 1), the metal organic framework and vitamin B1 may be mixed at a mixing ratio of 1:0.2 to 0.7.

In the present invention, through step 2), the release-controlling polymer can be coated on the metal-organic framework carrying vitamin B1.

In one aspect of the present invention, step 2) may involve dissolving the vitamin B1-supported metal organic framework and the release-controlling polymer in a solvent and then mixing them by ball milling.

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

In one aspect of the present invention, when the composite composition is obtained through ball milling, the weight ratio of the metal-organic framework carrying vitamin B1 and 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 one aspect of the present invention, step 2) includes 2)-1 a mixed solution (A) in which a metal-organic framework carrying vitamin B1 and a release-controlling polymer are dissolved in a solvent; and preparing an emulsification solution (B); and 2)-2 dropping the mixed solution (A) of step 2)1- into the emulsification solution (B) to prepare a composite composition.

In one aspect of the present invention, step 2) includes preparing 2)-1 emulsification solution (B); and 2)-2 dropping the metal-organic framework powder carrying vitamin B1 into the emulsification solution (B) to prepare a composite composition.

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

In the present invention, the mixed solution obtained by dissolving the metal-organic framework carrying vitamin B1 and the release-controlling polymer in a solvent may further include a plasticizer and a dispersant for emulsification.

Mechanical properties can be improved through plasticizers, and plasticizers such as triethyl citrate, polyethylene glycol, propylene glycol, and sorbitol can be used.

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

The dispersant can be dispersed and placed inside, and for example, zinc stearate, aluminum stearate, calcium stearate, aluminum hydroxide, etc. can be used as the dispersant.

In one aspect of the present invention, the dispersant may use aluminum stearate. Additionally, considering emulsification, the dispersant can be used in an amount of 10 to 50 wt% compared to the release-controlling polymer.

In the present invention, the emulsifying solution is a solution that has a different polarity from the metal-organic framework and the release-controlling polymer, and specifically, a non-polar solvent can be used. More specifically, hydrocarbon oils, ester oils, vegetable oils, animal oils, etc. can be used, such as squalene, paraffin, caprylic triglyceride, hexyl laurate, octyldodecanol, olive oil, lanolin, etc. can be used.

Additionally, the emulsifying solution may contain a surfactant, and the surfactant may be, for example, glyceryl stearate, sorbitan olivate, sorbitan stearate, sorbitan sesquioleate (span 83), etc. . In one aspect of the present invention, the surfactant may be sorbitan sesquioleate (span 83). Additionally, to control emulsification, the surfactant may be used in an amount of 0.1 to 5 wt% based on the emulsification solution. More specifically, it can be used in a concentration range of 0.5 to 2 w/v%.

Additionally, the emulsification solution may include a solution containing a metal-organic framework carrying vitamin B1 or a powder of a metal-organic framework carrying vitamin B1.

In addition, the method of manufacturing a composite composition through emulsification involves mixing a mixed solution (A) of a metal-organic framework carrying vitamin B1 and a release-controlling polymer, or an emulsification solution (B) of a powder of a metal-organic framework carrying vitamin B1. ) to prepare a composite composition by dropping the solution, a pump can be used when dropping, and the characteristics 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 aspect of the present invention, when the composite composition is obtained through emulsification, the weight ratio of the metal-organic framework carrying vitamin B1 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.

Additionally, the present invention provides an oral formulation containing the above composite composition.

The oral preparation according to the present invention can be formulated in the form of tablets, powders, granules, capsules, syrup, etc. by conventional methods.

The dosage of the oral formulation of the composite composition according to the present invention can be adjusted depending on the age, gender, health status, etc. of the user.

Hereinafter, the present invention will be described in detail through examples and experimental examples.

However, the following examples and experimental examples only illustrate 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 added to a 10 ml vial and dissolved in 5.0 ml of distilled water. Afterwards, a mixed solution of potassium hydroxide and γ-cyclodextrin was added to a 135 ml wide-mouth bottle containing 20 ml of methanol, and 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 added to 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. Afterwards, it was washed with isopropyl alcohol and dried in vacuum to obtain a cyclodextrin-based metal-organic framework (CD-MOF).

<Example 2> Preparation of cyclodextrin-based metal-organic framework containing vitamin B1

39.77 mg of vitamin B1, 0.2 ml of distilled water, and 1 ml of ethanol were added to a 20 ml vial and mixed. Afterwards, 100 g of CD-MOF prepared in <Example 1> was additionally added, kept in an oven at 37° C. for 2 hours, centrifuged, the supernatant was removed, and washed with ethanol. Afterwards, it was vacuum dried to prepare a CD-MOF containing vitamin B1 (Vit.B1-CD-MOF).

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

<Example 3-1> Eudragit coating by ball milling

A 30 wt% mixed solution (solution 1) was prepared by dissolving 0.5 g of Eudragit S in ethanol. Separately, 0.25 g of Vit.B1-CD-MOF prepared in <Example 2> was dissolved in ethanol to prepare a 30 wt% mixed solution (solution 2). Afterwards, the solution 1 and solution 2 were loaded into a grinding container and coated by a ball milling method in the presence of balls to produce Eudragit-coated Vit.B1-CD-MOF (ES- Vit.B1-CD-MOF) was obtained.

<Example 3-1> Eudragit coating by emulsion

A mixed solution was prepared by dissolving 0.1 g of Eudragit S in ethanol. Afterwards, 0.5 g of Vit.B1-CD-MOF prepared in <Example 2>, 0.01 g of triethyl citrate, and 0.035 g of aluminum stearate were added to the solution and stirred. A mixed solution (solution a) was prepared.

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, then Vit.B1-CD- A mixed solution (solution b) was prepared by adding a solution of MOF dissolved in ethanol.

Using a tubing pump (peristaltic pump), solution a was dropped toward solution b. At this time, the degree of coating was changed by adjusting the rpm of the tubing pump. After adding all of solution a, stirring overnight, filtering, and washing with petroleum ether to produce Eudragit-coated Vit.B1-CD-MOF (ES-Vit.B1-CD-MOF) was obtained.

In addition, Vit.B1-CD-MOF powder was added dropwise to solution a, and Eudragit-coated Vit.B1-CD-MOF (ES-Vit.B1-CD-MOF) was obtained in the same manner. did.

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

<Experimental Example 1-1> Confirmation of release at pH 1.2

100 mg of ES-Vit.B1-CD-MOF prepared in <Example 3> was placed in 20 ml of a solution adjusted to pH 1.2 and then immediately sampled at 1 ml. Afterwards, it was stored for 2 hours under pH 1.2 conditions and then 1 mL was sampled.

<Experimental Example 1-2> Confirmation of release at pH 6.8

In <Experimental Example 1-1>, 0.2 M monosodium phosphate (NaH ₂ PO ₄ ) and 1 N sodium hydroxide (NaOH) were added to the solution carrying the ES-Vit.B1-CD-MOF adjusted to pH 1.2. The pH was adjusted to 6.8. After soaking for 2 hours at pH 6.8, 1 mL was sampled.

<Experimental Example 1-3> Confirmation of release at pH 7.4

The solution carrying ES-Vit.B1-CD-MOF, which was adjusted to pH 6.8 in <Experimental Example 1-2>, was adjusted to pH 7.4 by adding 1 N sodium hydroxide (NaOH). After being held for 2 hours under pH 7.4 conditions, 1 mL was sampled.

Thereafter, the solutions sampled in <Experimental Example 1-1> to <Experimental Example 1-3> were quantitatively analyzed using HPCL. The Agilent 1200 model was used for HPLC, the Phenomenex Luna C18 HPLC column was used, the mobile phase was an aqueous potassium phosphate solution (KH ₂ PO ₄ , pH 2.5), and the flow rate was 1 ml/min and UV 220 ㎚. and analyzed.

As a result of the analysis, the content of vitamin B1 in Vit.B1-CD-MOF was 129.4 mg _(Vit.B1) / g _{(Vit.B1-CD-MOF)} , and the release results were shown in Table 1 and Figures 8 to 9. same.

Yudrajit S:
VitB-CD-MOF h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 2:1 0 1.2 3.433 0 2 1.2 24.957 18.0 4 6.8 96.632 64.92 6 7.4 94.967 74.31

As a result of the analysis, it was confirmed that uncoated ViT.B1-CD-MOF did not release vitamin B1 slowly, but ES-Vit.B1-CD-MOF released vitamin B1 at different release rates depending on pH conditions.

<Experimental Example 2> Confirmation of enteric release of cyclodextrin-based metal-organic framework coated by emulsion

<Experimental Example 2-1> Release of CD-MOF coated by emulsion (1)

ES-Vit.B1-CD-MOF prepared by dropping solution a into solution b prepared by adding a portion of the solution of Vit.B1-CD-MOF dissolved in ethanol in <Example 3-1> above. Enteric release of ES-Vit.B1-CD-MOF was confirmed by the same method as Experimental Example 1>.

As a result of the analysis, the content of vitamin B1 in Vit.B1-CD-MOF is 129.4 mg _(Vit.B1) /g _{(Vit.B1-CD-MOF)} , and the release results are shown in Tables 2 to 5 and Figure 10. It's like a bar.

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (5 rpm) 0 1.2 2.99 2.31 2 1.2 6.18 4.78 4 6.8 6.20 4.79 6 7.4 5.94 4.59 8 7.4 5.86 4.53 24 7.4 5.38 4.16

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (10 rpm) 0 1.2 2.18 1.68 2 1.2 4.12 3.18 4 6.8 19.78 15.29 6 7.4 18.87 14.58 8 7.4 18.27 14.12 24 7.4 17.44 13.48

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (15 rpm) 0 1.2 2.05 1.58 2 1.2 3.32 2.57 4 6.8 15.13 11.69 6 7.4 14.75 11.4 8 7.4 14.18 10.96 24 7.4 13.23 10.22

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (20 rpm) 0 1.2 3.12 2.41 2 1.2 5.89 4.55 4 6.8 16.95 13.1 6 7.4 16.19 12.51 8 7.4 15.11 11.68 24 7.4 14.73 11.38

As shown in Tables 2 to 5 and Figure 10, ES-Vit.B1-CD-MOF was confirmed to release vitamin B1 with different release amounts and release rates depending on changes in rpm and pH conditions.

<Experimental Example 2-3> Release of CD-MOF coated by emulsion (2)

ES-Vit.B1-CD-MOF prepared by dropping solution a into solution b prepared by adding a portion of the Vit.B1-CD-MOF powder in <Example 3-1> was prepared in the same manner as <Experimental Example 1>. Enteric release of ES-Vit.B1-CD-MOF was confirmed by the same method.

As a result of the analysis, the content of vitamin B1 in Vit.B1-CD-MOF is 129.4 mg _(Vit.B1) /g _{(Vit.B1-CD-MOF)} , and the release results are shown in Tables 6 to 10 and Figure 11. It's like a bar.

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (1 rpm) 0 1.2 14.37 11.11 2 1.2 29.25 22.6 4 6.8 52.78 40.79 6 7.4 50.50 39.03 8 7.4 50.71 39.19

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (3 rpm) 0 1.2 12.21 9.44 2 1.2 23.19 17.92 4 6.8 32.34 25.0 6 7.4 31.11 24.04 8 7.4 29.75 22.99

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (5 rpm) 0 1.2 5.67 4.38 2 1.2 13.53 10.45 4 6.8 11.42 8.82 6 7.4 10.85 8.38 8 7.4 10.52 8.12

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (7 rpm) 0 1.2 0.80 0.62 2 1.2 6.95 5.37 4 6.8 5.93 4.58 6 7.4 5.70 4.4 8 7.4 5.50 4.25

Yudrajit S:
VitB-CD-MOF
and rpm h pH at sampling Vitamin B1 release amount (mg/g) Vitamin B1 release amount (%) 1:0.2 (9 rpm) 0 1.2 0.79 0.61 2 1.2 3.28 2.53 4 6.8 3.05 2.35 6 7.4 2.98 2.3 8 7.4 2.97 2.29

As shown in Tables 6 to 10 and Figure 11, ES-Vit.B1-CD-MOF was confirmed to release vitamin B1 at different release amounts and release rates depending on changes in rpm and pH conditions.

Claims (19)

Contains a metal organic framework (MOF),
The metal-organic framework is a coordination bond of a repeating unit containing cyclodextrin (CD) and one or more metals selected from the group consisting of Li, Na, K, Rb, Cs, Mg, Ca, Sr, and Ba. It is composed,
Vitamin B1 is supported inside the skeleton at a weight ratio of 0.05 to 0.5:1 compared to the entire complex composition,
The outside of the skeleton is poly(dimethylaminoethyl methacrylate-methacrylate) copolymer, poly(methacrylic acid-methyl methacrylate) copolymer, poly(methacrylic acid-methyl methacrylate) copolymer, poly( Coated with one or more release-controlling polymers selected from the group consisting of ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride) copolymer, and poly(ethyl acrylate-methyl methacrylate) copolymer. A composite composition.
According to paragraph 1,
The composite composition, wherein the cyclodextrin is γ-cyclodextrin.
delete delete According to paragraph 1,
The metal-organic framework is a composite composition in which the molar ratio of cyclodextrin (CD) and metal is 1:5 to 15.
delete According to paragraph 1,
The composite composition is one in which the active substance is released at pH 6 to 8.
1) Cyclodextrin (CD); A metal compound containing one or more metal elements or ions selected from the group consisting of Li, Na, K, Rb, Cs, Mg, Ca, Sr, and Ba; and mixing vitamin B1 to prepare metal-organic frameworks (MOF) loaded with vitamin B1; and
2) The metal-organic framework carrying vitamin B1 of step 1) and poly(dimethylaminoethyl methacrylate-methacrylate) copolymer, poly(methacrylic acid-methyl methacrylate) copolymer, poly(methacrylate) acrylic acid-methyl methacrylate) copolymer, poly(ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride) copolymer, and poly(ethyl acrylate-methyl methacrylate) copolymer. Mixing one or more release-controlling polymers selected from the group consisting of a weight ratio of 1:0.01 to 5 to obtain a composite composition in which the outside of the metal-organic framework is coated with the release-controlling polymer.
delete According to clause 8,
In step 2), the metal-organic framework and release-controlling polymer carrying vitamin B1 of step 1) are dissolved in a solvent and then mixed by ball milling.
According to clause 10,
The weight ratio of the metal-organic framework carrying vitamin B1 and the release-controlling polymer in step 2) is 1:1 to 5.
According to clause 8,
Step 2) is
2)-1 Mixed solution (A) mixing a metal-organic framework loaded with vitamin B1 and a release-controlling polymer; and preparing an emulsification solution (B); and
2)-2 Preparing a composite composition by dropping the mixed solution (A) of step 2)-1 into the emulsification solution (B).
According to clause 12,
A method for producing a composite composition, wherein the metal-organic framework carrying vitamin B1 and the release-controlling polymer in step 2)-1 have a weight ratio of 1:0.01 to 0.5.
According to clause 12,
A method for producing a composite composition, wherein the mixed solution (A) of step 2)-1 includes a plasticizer and a dispersant.
According to clause 14,
A method for producing a composite composition, wherein the plasticizer is used in an amount of 1 to 20 wt% relative to the release-controlling polymer.
According to clause 14,
A method for producing a composite composition, wherein the dispersant is 10 to 50 wt% relative to the release-controlling polymer.
According to clause 12,
The emulsifying solution (B) of step 2)-1 includes a non-polar solvent and a surfactant.
According to clause 17,
A method for producing a composite composition, wherein the surfactant is in a concentration range of 0.1 to 5 w/v% compared to the emulsification solution (B).
A preparation comprising the composite composition according to any one of claims 1, 2, 5 and 7.