KR20030014182A - Hybrid Materials For Stabilization And Delivery Of Drugs And Processes For Preparing The Same - Google Patents

Abstract

PURPOSE: A process of preparing a hybrid material containing 3-benzoyl-α -methylbenzene acetic acid, 4-biphenyl acetic acid, minocycline, etc. is provided. Whereby, the new hybrid material is useful in stabilization and delivery of specified drugs, low in adverse effects and excellent in stability and can be used in the form of an ointment, patch, oral administration, injection or the like. CONSTITUTION: The hybrid material is prepared by coprecipitation or ion exchange reaction of: a drug selected from the group consisting of 3-benzoyl-α-methylbenzene acetic acid, 4-biphenyl acetic acid and minocycline; and a layered inorganic material selected from the group consisting of layered silicate, layered aluminosilicate, layered phosphate and layered metal oxide.

Description

Hybrid Materials for Stabilization and Delivery of Drugs and Methods for Manufacturing the Same {Hybrid Materials For Stabilization And Delivery Of Drugs And Processes For Preparing The Same}

The present invention relates to hybrid materials for the stabilization and delivery of certain drugs and methods of making the same. More specifically, the present invention provides a drug delivery system having excellent stability, sustained release, and low side effects, comprising: a hybrid material including a drug such as 3-benzoyl-α-methylbenzeneacetic acid, 4-biphenylacetic acid, minocycline, and the like. The manufacturing method is related.

3-benzoyl-α-methylbenzeneacetic acid (C ₁₆ H ₁₄ O ₃ , Ketoprofen) and 4-biphenylacetic acid (C ₁₄ H ₂ O ₂ , Felbinac) are nonsteroidal anti-inflammatory and As antirheumatic agents, Minocycline (C ₂₃ H ₂₇ N ₃ O ₇ ) is also well known as an anti-inflammatory agent, in particular anti-inflammatory agents for the treatment of periodontitis.

However, the drugs are limited in use due to the problems of efficacy such as gastrointestinal disorders, decrease of drug concentration by liver metabolism, and consequent decrease in drug efficacy or lack of stability of the drug itself. 3-Benzoyl-α-methylbenzeneacetic acid and 4-biphenylacetic acid have excellent stability of the drug itself. Development of the formulation is necessary. On the other hand, since the drug itself is very unstable in the external environment, such as light, air, heat, browning phenomenon occurs when the drug itself is a method of stabilizing the drug is required first. In addition, when minocycline is prescribed by injection directly into the periodontal sac, sustained drug sustainability is also required to alleviate pain of patients due to frequent injections.

Thus, there has been much research on sustained and effective drug delivery systems to stabilize the drugs and to prevent transient overdoses or side effects on normal cells. In the related arts, in the case of 3-benzoyl-α-methylbenzeneacetic acid and 4-biphenylacetic acid, a transdermal administration method using a patch is generally used to overcome the problems of gastrointestinal disorders caused by oral administration as mentioned above. It is adopted. In this case, the drug is dispersed and fixed in the drug carrier containing the polymer as a main component and percutaneously absorbed by the diffusion of the drug to act on the affected part. Therefore, in the case of drugs for this purpose, sustained release is required to improve the sustainability of the drug. Minocycline for the treatment of periodontitis has been used a lot of capping method mainly using a polymer to ensure the stability of the drug itself. Korean Patent Publication No. 199-0019209 describes a sustained release formulation using a cellulose-minocycline blend polymer, and Korean Patent Publication No. 1998-0084302 discloses a minocy in a microsphere made of a biodegradable polymer such as PLA. It describes a method of containing clean to improve stability and sustained release. In addition, U.S. Patent No. 5,599,553 describes a method using a minocycline and polycaprolactone hybrid, U.S. Patent 4,933,192 uses a fine particle composed of a polymer, U.S. Patent 4,175,326 uses a cellulose acetate, Japanese Patent Publication No. 61-130228 describes a method using ethylene glycol or glycerin, and EP 0 418 565 A2 describes a method for stabilizing and releasing sustained release of minocycline using hydroxypropylmethylcellulose phthalate.

However, these prior arts have further improvements in drug stability and sustained release, and side effects due to the delivery material itself remain a problem.

Accordingly, an object of the present invention is to provide a novel hybrid material of the drugs as a drug delivery system having excellent stability, sustained release, and low side effects.

Another object of the present invention is to provide a method for economically and effectively producing the hybrid material.

Another object of the present invention is to provide a pharmaceutical composition comprising the hybrid material.

1: Field emission scanning electron micrograph of a hybrid of hydrogincite and 3-benzoyl-α-methylbenzeneacetic acid prepared by coprecipitation.

FIG. 2: Powder X-ray diffraction diagram of hybrids of mica and minocycline prepared by ion exchange method

FIG. 3: Field emission scanning electron micrograph of powder of hybrid material of mica and minocycline prepared by ion exchange method

Figure 4: Field emission scanning electron micrograph of a hybrid of mica and minocycline coated with silica

Figure 5: Minocycline release rate of 0.8% NaCl aqueous solution of mica and minocycline prepared by ion exchange method

As a result of research efforts to achieve the above object, the inventors have found that the hybrid material of the drug and the layered inorganic material has excellent stability and sustained release property and has few side effects.

The "layered inorganic material" used in the present invention includes layered metal hydroxides, layered silicates, layered aluminosilicates, layered phosphates, and layered metal oxides, and different layered inorganic materials are used depending on the properties of the drugs.

In one embodiment according to the present invention there is provided a hybrid of anionic drugs 3-benzoyl-α-methylbenzeneacetic acid and 4-biphenylacetic acid with a layered metal hydroxide. "Layered metal hydroxide" is a weakly basic or neutral inorganic compound, the crystal structure is layered and exhibits an unusual interlaminar reactivity, and has an anion exchange ability, so that it can be effectively utilized for stabilization of anionic drugs.

The layered metal hydroxides used in the present invention are preferably metal double hydroxides (HDS) or layered doublehydroxides (LDH). Metal double oxalate during dihydro binary sites ^{_{(. Zn 5 (OH) 6}} (CO 3) 2 nH 2 O) or zinc basic salt ^{_{(Zinc basic salts;. Zn 5}} (OH) 8 Cl 2 nH 2 O) in the form of crystal structure More preferably. As the metal component, besides Zn ²⁺ , for example, Mg ²⁺ , Ca ²⁺ , Ni ²⁺ , Fe ²⁺ , Cu ²⁺ or a mixture of two or more different metal components among these metal components may be used. Meanwhile, the layered bilayer metal hydroxide may be represented by the chemical formula of [M (II) _1-x M (III) _x (OH) ₂ ] ^{x +} (A ^n- _{x / n} ) .mH ₂ O. Here, M (II) represents a divalent metal cation such as Zn (II), Mg (II), Ca (II), Ni (II), Fe (II), Cu (II), and M (III) is Trivalent metal cations such as Al (III), Fe (III), Cr (III), Co (III), and the like, A represents an anion, and x is a number of 0 <x <1. Hydrotalcite is a typical example of a double layer metal hydroxide. In the case of these compounds, the cause is different, but in general, the hydroxide layer has a positive charge, so that an interlayer anion exists to compensate for this, and the interlayer anion may be replaced with another anionic species. Thus, these compounds exhibit the property of stabilizing negatively charged inorganic ions, organic ions or biomolecules between layers.

In another embodiment according to the present invention, there is provided a hybrid of a cationic drug, minoxyclin, and a layered inorganic material selected from the group consisting of layered silicates, layered aluminosilicates, layered phosphates, and layered metal oxides. Natural and synthetic clay compounds, such as montmorillonite, saponite, swellable mica, etc., contain ion-exchangeable cations (usually Na ⁺ or Ca ²⁺ ) between layers to facilitate the substitution of positively charged organics, inorganics and biomolecules. It is a layered inorganic compound which can be characterized. In addition, there is a layered compound in which the skeleton of the layer is composed only of SiO ₄ tetrahedron, which is typically silicic acid (H ₂ SiO ₅ ), which is substituted with other cationic materials with protons (H ⁺ ) present between the layers. Cation exchange layered compound which may be used. In addition, metal phosphates such as Ti (PO ₄ ) (H ₂ PO ₄ ) · 2H ₂ O, and layered metal oxides such as K ₂ Ti ₄ O ₉ are also typical layered compounds with cation exchange ability and are fully utilized as inorganic capsule materials for certain drugs. Can be. In consideration of safety to the human body, ease of manufacture and economy, it is most preferable to use aluminosilicate as the cationic layered inorganic material.

The present invention also provides a method for producing a hybrid of the aforementioned drug and layered inorganic material.

The first production method is coprecipitation, which is characterized by a precipitation reaction between the metal starting material of the layered inorganic material and the drug. This coprecipitation method is a preferred method when the drug has a negative charge, such as 3-benzoyl-α-methylbenzeneacetic acid and 4-biphenylacetic acid.

In the case of the layered metal hydroxide, it is more preferable that the metal starting material has high solubility in the solvent used, and when the base is added, it can effectively produce a precipitate in the form of the layered metal hydroxide. More preferably, metal salts such as metal carbonates, metal chlorides, metal nitrates, and organic metal salts such as acetates, oxalates and citrates are used. Examples of such metal salts are ZnCl ₂ , Zn (NO ₃ ) ₃ , Zn (CH ₃ COO) ₂ , MgCl ₂ , AlCl ₃ , CaCl ₂ or their hydrates.

The solvent used in the coprecipitation method is water, alcohol, or a mixture thereof. As alcohol, ethanol is preferable. In the coprecipitation method, the concentration of metal ions is, for example, 0.01 mol to 5 mol, and the amount of drug component is used, for example, by a molar ratio of, for example, 0.1 to 10 times based on the total moles of the metal component. In the precipitation reaction, precipitation may be induced by adding a base if necessary. Suitable bases include, for example, alkali metal hydroxides or amines. The pH of the reaction solution is 4 to 11, preferably about 6 to 8, and the reaction temperature is 0 ° C to 50 ° C, preferably 0 ° C to 10 ° C. The reaction time is preferably 30 minutes or more. In addition, during the reaction, it is preferable to continuously add nitrogen and other inert gas, and to shield the reaction.

Another method of preparing the hybrid material of the drug and the layered inorganic material according to the present invention is an ion exchange method, characterized in that the method includes an ion exchange reaction between the previously obtained or prepared layered inorganic material and the drug.

In the coprecipitation method, a layered hybrid material is obtained through precipitation reaction of a starting inorganic material with a drug, while the ion exchange method obtains or prepares a layered inorganic material in advance, and then obtains the hybrid material through an ion exchange reaction between the layered inorganic material and a drug. There is a difference in getting Therefore, the ion exchange method has a disadvantage in that the manufacturing process is more complicated than the coprecipitation method, but it is the case of a hybrid material of a clay compound and a cationic drug which cannot be prepared by the coprecipitation method or a drug by a chemical used in the coprecipitation reaction. It is a manufacturing method that can be applied as an alternative in the case of problems such as destruction of.

In the case of the layered metal hydroxide, the above-described starting material of the layered metal hydroxide can be reacted in a basic solution to prepare a layered inorganic material used for the ion exchange reaction. The conditions of the ion exchange reaction between the layered inorganic substance and the drug are almost similar to those of the coprecipitation reaction described above, but in order to obtain a product free of impurities, a repeated reaction may be required.

In the present invention, "hybrid material" refers to a material that is based on chemical bonding force between components rather than a simple mixture. For example, in the case of cationic layered inorganic materials and anionic drugs, electrostatic interactions between components with opposite charges act as the main chemical bonding force. The coprecipitation method and the ion exchange method can be said to be a manufacturing method based on this.

As described above, the hybrid material of the drug and the layered inorganic material prepared as described above is composed of inorganic materials, so that agglomeration occurs during the manufacturing process or drying process through coprecipitation in a solution, so that the homogeneity, blendability, dispersion and dispersion of the hybrid material particles It may cause deterioration of stability. As one of the methods for solving such a problem, there is a method of coating the surface of the prepared hybrid material with a surface coating material, for example, an inorganic material, an organic material, a polymer material and the like that are harmless to the human body.

Inorganic coating materials include silica (SiO ₂ ), titania (TiO ₂ ), alumina (Al ₂ O ₃ ), and the like, but silica is most preferred in consideration of surface property modification performance, manufacturing process, and raw material price. As the raw material of the inorganic coating material, metal salts such as SiCl ₄ , TiCl ₄ , Si (OC ₂ H ₅ ) ₄ , Si (OCH ₃ ) ₄ , Ti (OC ₃ H ₇ ) ₄ , Al (OC ₃ H ₇ ) and the like. Preferably, alkoxides such as Si (OC ₂ H ₅ ) ₄ , Si (OCH ₃ ) ₄ , Ti (OC ₃ H ₇ ) ₄ , and Al (OC ₃ H ₇ ) ₃ are used as raw materials. Surface coating using the inorganic coating material is characterized by the hydrolysis reaction between the hybrid material and the coating raw material. If necessary, a base or acid catalyst may be added.

In addition to the inorganic coating material, various neutral surfactants having hydrophilic or lipophilic properties, such as polyvinyl alcohol, polyethylene glycol, cellulose, polymethyl methacrylate, or the like, may be coated alone or in combination, or the silane compound and the polymer material may be coated simultaneously. The coating may also be used.

The present invention also provides a pharmaceutical composition comprising a hybrid of a drug as described above and a layered inorganic material. The pharmaceutical composition may comprise pharmaceutically acceptable carriers and / or additives conventionally used in conventional pharmaceutical formulations of the drug.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are merely illustrative and are in no way intended to limit the invention.

Example

Example 1

155 g of Zn (NO ₃ ) ₂ .6H ₂ O was completely dissolved in 1 liter of distilled water, and then 20 g of 3-benzoyl-α-methylbenzeneacetic acid (C ₁₆ H ₁₄ O ₃ , molecular weight = 254.29 g / mol) was added. It was dissolved and mixed. 500 ml of 0.5 N NaOH solution was slowly added to the mixed solution and the precipitation reaction was induced with stirring for 24 hours. After the reaction was completed, the precipitate and the filtrate were separated by centrifugation, and the precipitate was washed with distilled water five times or more to remove impurities. After washing with water, the slurry-like precipitate was dried at room temperature to obtain a drug-inorganic hybrid material as a fine particulate powder. From the X-ray diffraction pattern analysis, it was confirmed that the hybrid material was a layered hybrid material in the form of hydrozincite in which 3-benzoyl-α-methylbenzeneacetic acid was present between the layers. It can be seen that the material consists of fine particles of 100-200 nm.

Example 2

31 g of Zn (NO ₃ ) ₂ 6H ₂ O and 13 g of Al (NO ₃ ) ₃ 9H ₂ O were completely dissolved in 500 ml of distilled water, followed by 4-biphenylacetic acid (C ₁₄ H ₁₂ O ₂ , molecular weight = 212.25 g / mol) 11 g were added and mixed uniformly. 2N NaOH solution was slowly added to the mixed solution to bring the pH of the solution to 8 and stirred for 12 hours to induce a precipitation reaction. After the reaction was completed, the precipitate and the filtrate were separated by centrifugation, and the precipitate was washed with distilled water five times or more to remove impurities. After washing with water, the slurry-like precipitate was freeze-dried to obtain a hybrid material as a fine particulate powder. X-ray diffractogram analysis of the hybrid material of ZnAl-LDH and 4-biphenylacetic acid prepared as described above showed that the hybrid material was a hydrotalcite-type layered double layer metal hydroxide in which 4-biphenylacetic anion was present between the layers. Could.

Example 3

Hybrid using swellable layered silicate Na-tetrasilic fluoric mica (Na _0.65 (Mg _2.65 Si ₄ ) O ₁₀ F ₂ ) and minocycline (C ₂₃ H ₂₇ N ₃ O ₇ , molecular weight = 457.48 g / mol) The material was prepared. First, 1 g of mica was sufficiently swollen in 100 ml aqueous solution for 12 hours, and 0.5 g of minocycline was added thereto, followed by an ion exchange reaction at room temperature for 24 hours. After the reaction was completed, the resultant was centrifuged, washed with an aqueous solution and dried to obtain a mixed material of minocycline and mica. Figure 2 is an X-ray diffraction pattern of the minocycline-mica hybrids thus prepared. From the interlayer distance (d ₀₀₁ = 21.5 kPa) of the (001) plane, it can be seen that the minocycline molecule is stabilized between the layers of the silicate. 3 is a scanning electron micrograph of the hybrid material, it can be seen that the layered particles of 1 ~ 2 ㎛ size.

Example 4

The Minocycline-Mica hybrid material synthesized in Example 3 was subjected to surface coating using silica (SiO ₂ ). First, a solution of 1 g of minocycline-mica mixture was dispersed in 10 ml of distilled water by stirring for 1 hour, and 5 g of tetraethoxysilicate (Si (OC ₂ H ₅ ) ₄ , TEOS) was dissolved in 10 ml of ethanol solution. The reaction was performed dropwise for 12 hours. At this time, ammonia water was used as a hydrolysis catalyst of TEOS. FIG. 4 is a scanning electron micrograph of the silica coated minocycline- mica hybrid material, showing that silica is uniformly coated on the surface of the plate-shaped particle.

Example 5

The sustained release of the minocycline, which was stabilized between the layers, was measured for the minocycline-mica hybrid material prepared in Example 3. In this case, the measurement conditions were obtained by dispersing 500 mg of the mixed material in 10 ml of 0.8% -NaCl aqueous solution and stirring the amount of minoxylin over time with the absorbance intensity of the ultraviolet absorption spectrum (λ _max = 380, 243 nm: 0.1N NaOH). Measured through change. FIG. 5 is a graph showing the release rate of the minocycline thus measured, and it can be seen that the release of the minocycline cation stabilized between layers by Na ⁺ ions in the saline solution is gradually released by ion exchange.

Drug components stabilized through the hybrid material according to the present invention can be released at an appropriate rate in the desired tissue, organ or skin to express its own effects or functions. In addition, most of the layered inorganic materials used in the present invention have neutral and weakly basic properties, and the inorganic capsule material and the drug have opposite charges and are coupled by electrostatic interaction. In the case of encapsulation using a conventional polymer, the drug is eluted by the diffusion of the useful drug, while the hybrid material developed in the present invention has the characteristic that the drug contained in the inorganic capsule is eluted by ion exchange. That is, when the inorganic capsule-drug hybrid material designed in accordance with the present invention is orally administered, various anions or cations in gastric juice and drugs in the inorganic capsule are eluted in a controlled manner through ion exchange. In addition, when prescribed through percutaneous transfusion or injection in a specific affected area, ion exchange with various ionic species in the body fluid may occur. In particular, when the layered metal hydroxide is used as the inorganic capsule material, not only the ion exchange method but also drug release due to dissolution of the inorganic capsule may occur simultaneously. This exhibits sustained release by a mechanism different from the sustained release formulation using a conventional polymer in principle.

In addition, the hybrid material according to the present invention exhibits several properties that distinguish it from conventional stabilizing products. First, the hybrid material obtained through the present invention is a fine particle powder whose surface is coated with an inorganic material, the particle size is several tens of nm to several micrometers and is generally spherical. If necessary, it is possible to prepare a suspension, colloid or slurry by omission of the drying process in the manufacturing process, it is also easy to manufacture in the form of granules, various formulations are possible to satisfy the conditions required during the process. Second, since the capsule is composed of an inorganic material, the stability of the capsule is superior to that of the conventional organic capsule, and also excellent in blocking heat, light, moisture, oxygen, and the like. In particular, it exhibits a characteristic of drastically improving the deterioration of drugs caused by heat or light. Third, the content of the drug per unit mass is very high compared to the organic capsule stabilizer. Fourth, as a bio-friendly inorganic material, there are fewer problems of toxicity, irritation, and side effects than stabilizing substances such as organic materials and polymers, and when applied to the human body, it is possible to simultaneously supply inorganic nutrients essential for metabolism of the living body. Fifth, the manufacturing method is relatively simple and economic advantages.

Since the hybrid material according to the present invention has the characteristics as described above, it can be usefully used in the pharmaceutical, pharmaceutical and quasi-drug fields, depending on the use of the drug ointment, patch, oral administration, injection, etc. It can be used in various formulations.

Claims (18)

A hybrid of a layered inorganic material with a drug selected from the group consisting of 3-benzoyl-α-methylbenzeneacetic acid, 4-biphenylacetic acid, and minocycline. The hybrid material of claim 1, wherein the drug is selected from the group consisting of 3-benzoyl-α-methylbenzeneacetic acid and 4-biphenylacetic acid, and the layered inorganic material is a layered metal hydroxide. 3. The hybrid material of claim 2, wherein the layered metal hydroxide is a metal double hydroxide or a double layer metal hydroxide. The hybrid material of claim 1, wherein the drug is minoxylin and the layered inorganic material is selected from the group consisting of layered silicates, layered aluminosilicates, layered phosphates, and layered metal oxides. The hybrid material of claim 4 wherein the layered inorganic material is a swellable mica. 6. The hybrid material of any one of claims 1 to 5, wherein the surface is coated. The hybrid material of claim 6 wherein the surface is coated with silica. The hybrid material of claim 6, wherein the surface is coated with at least one selected from the group consisting of polyvinyl alcohol, polyethylene glycol, cellulose, polymethyl methacrylate, and silane. A method for producing a hybrid material according to any one of claims 1 to 8, characterized in that it comprises a precipitation reaction between the metal starting material of the layered inorganic material and the drug. 10. The method of claim 9, wherein the drug is selected from the group consisting of 3-benzoyl-α-methylbenzeneacetic acid and 4-biphenylacetic acid, and the layered inorganic material is a layered metal hydroxide. The method of claim 10, wherein the layered metal hydroxide is a metal double hydroxide or a double layer metal hydroxide. A method for producing a hybrid material according to any one of claims 1 to 8, comprising an ion exchange reaction between the previously obtained or prepared layered inorganic material and the drug. 13. The method of claim 12, wherein the drug is minocycline and the layered inorganic material is selected from the group consisting of layered silicates, layered aluminosilicates, layered phosphates and layered metal oxides. The method of claim 13 wherein the layered inorganic material is a swellable mica. The method of claim 9, further comprising coating the surface of the hybrid material. The method of claim 15, wherein the coating material is silica. The method of claim 15, wherein the coating material is at least one selected from the group consisting of polyvinyl alcohol, polyethylene glycol, cellulose, polymethyl methacrylate, and silane. A pharmaceutical composition comprising the hybrid material of claim 1.