KR20070070061A - A complex material using caprolacton and glycolide for drug delivery system and method for preparing the same - Google Patents

Abstract

A complex material for drug delivery system by using caprolactone and glycolide and a method for preparing the same complex material are provided to simplify the preparation process by physically mixing biodegradable polymer with active materials, and inhibit environmental pollution by using no organic catalyst in a copolymerization process. The method for preparing the biodegradable film type complex material for drug delivery system using caprolactone and glycolide comprises the steps of: mixing caprolactone with glycolide in 1,2-dichloroethane solvent in a weight ratio of 70-90 : 10-30, and copolymerizing the mixture in the absence of ethylene glycol initiator and catalyst to prepare oligomer; adding triethylamine and metacryloyl chloride into the oligomer in tetrahydrofuran solvent to prepare macromer, wherein OH group of the oligomer is modified by metacrylate group; increasing the temperature of 90-98 wt.% of macromer to 60-70 deg.C, and mixing the dissolved macromer with 2-10 wt.% of solid phase micro particle active materials; and forming a film by spreading the mixture on the surface of a frame, irradiating ultraviolet(UV) rays to the film, and drying it at room temperature.

Description

Compound complex using caprolacton and glycolide for drug delivery system and method for preparing the same

1 is a SEM (Scanning Electron Microscopy) photograph of a macromer mixed with methylene blue 10% according to an embodiment of the present invention.

FIG. 2 is a simplified illustration of a reaction mechanism for preparing a composite material of a drug delivery system by preparing a macromer, which is a standard polymer, from caprolactone and glycolide according to the present invention.

3 is an NMR analysis graph for measuring the absolute molecular weight of diol copolymerized with caprolactone and glycolide according to Example 1) of the present invention.

4 is a graph analyzed by DSC method to determine the thermal properties of polyester diol copolymerized with caprolactone and glycolide according to Example 1) according to the present invention.

5 is a dissolution test of methylene blue through hydrolysis in the experimental example, first is a graph measuring the weight of the film (S) that does not contain the active material and the film (SM) containing 10% methylene blue, respectively.

The present invention relates to a composite material for a drug delivery system through physical coupling of an active substance and a method for preparing the same, to prepare an oligomer using caprolactone and glycolide as starting materials, and to obtain a macromer by methacrylation of the oligomer. Then, the present invention relates to a composite material in the form of a film which is biodegradable and effective in drug delivery by physically mixing an active substance which shows a medicinal effect when the drug is administered, with the macromer.

In general, as biodegradable and biocompatible polymer materials, aliphatic polyester polycaprolactone, polylactide, and polyglycolide and copolymers thereof are known. Poly (lactide-co-glycolide) (hereinafter referred to as PLGA), which is a copolymer of polylactide and polyglycolide, is applied as a substrate of drug release system, scaffold and suture for cell culture, have. In addition, polyether is known to exhibit excellent biocompatibility due to the inhibition of protein adsorption through hydrophilic properties. Therefore, when a block copolymer is formed by copolymerizing an aliphatic polyester having hydrophobic properties and a polyether having hydrophilic properties, it exhibits amphipathicity, inhibits the adsorption of proteins in the blood, and maintains the form in the body of a human or animal for a long time. Various functions such as release can be performed.

PLGA, which has been widely used in the past, has been used as a medium in which decomposition is completed within one to two months due to its rapid decomposition rate. However, PLGA is not easy to manufacture in the form of a film requiring excellent mechanical strength, and is difficult to use for long-term applications requiring several months of decomposition, and due to the rapid drop in pH, the application of poorly stable drugs such as proteins due to the severe drop in pH in the substrate. There is difficulty. On the other hand, the use of single polymers, polycaprolactone and polylactide, has excellent mechanical properties and takes a long time to decompose.However, due to high crystallinity, decomposition products have crystallinity and damage to surrounding cells. Has the disadvantage of giving.

On the other hand, when polycaprolactone is used as a biodegradable delivery medium, the strength and controlled release period of the active substance may be long, but the flexibility may be problematic, whereas the use of polyglycolide as a material may increase flexibility. As the rate of decomposition is shortened and the emission control period is shortened, a copolymer having flexibility while maintaining the properties of polycaprolactone as a biodegradable delivery medium is required.

In addition, in the related art, the physical combination (mixing) of the active substance (also called an active substance, meaning a component that exhibits efficacy when the drug is administered) and the biodegradable delivery medium is impossible or fine depending on the kind of active substance. Only the amounts can be mixed so that the production itself is impossible. In addition, the chemical combination of the active material and the biodegradable delivery medium is not only limited in its manufacture but also unnecessarily complicated process has become a disadvantage in terms of economics. In addition, conventionally, when synthesizing polyester, which is a biodegradable polymer transfer medium, was synthesized using a highly toxic catalyst, so that the catalyst had to be removed again after synthesis.

For example, Korean Patent No. 515035 discloses that hydrophobic blocks include amorphous poly (d, l-lactide), poly (d, l-lactide-co-glycolide), poly (d, l-lactide-co -ε-caprolactone), poly (l-lactide-co-glycolide), poly (l-lactide-co-ε-caprolactone), poly (ε-caprolactone-co-glycolide), poly ( ε-caprolactone-co-glycolide-co-d, l-lactide), poly (ε-caprolactone-co-glycolide-co-l-lactide), and a hydrophilic block as poly Thermally sensitive star block copolymers are described that have biodegradability with (ethylene oxide) and exhibit sol / gel transition with temperature in aqueous solution.

In addition, Korean Patent No. 527292 includes a cationic polymer micelle type A (hydrophilic polymer block) -B (hydrophobic biodegradable polymer block) block copolymer having one cation group at the end of the hydrophobic biodegradable polymer block. Drug carriers are described and are characterized in that the cationic biodegradable block copolymers form complexes with anionic drugs by electrostatic interaction. In addition, Korean Patent No. 527408 describes a method for preparing biodegradable block copolymers using random copolymers of caprolactone and lactide and polyethers, and Korean Patent No. 348717 discloses glycols using trivalent or higher polyhydric alcohols. The method of polymerizing a lide and ε-caprolactone to obtain a high molecular weight glycolide / ε-caprolactone copolymer in high yield, and a biodegradable glycolide / ε-caprolactone copolymer having a star molecular structure prepared therefrom Korean Patent No. 408458 describes a porous support for tissue engineering prepared from a biodegradable glycolide / ε-caprolactone copolymer having a weight average molecular weight of 10,000 or more and mechanical properties and moderate hydrolyzability.

However, there is a continuous demand for efficient development in the method for producing a complex material for an environmentally friendly drug delivery system.

Accordingly, the present inventors simplified the manufacturing method by preparing the active material in a natural combination with a biodegradable polymer material capable of naturally degrading, and developed and completed a manufacturing method of a composite material for an environmentally friendly drug delivery system without using a toxic organic catalyst. .

An object of the present invention is to synthesize a biodegradable delivery medium from the caprolactone and glycolide in the form of oligomers and obtain a macromer in which the OH group of the oligomer is modified with a methacrylate group, and then physically bonds the macromer with the active substance. The present invention provides an environment-friendly drug delivery system composite material and a method for manufacturing the same, which are manufactured in a film form through UV curing and room temperature drying.

Method for producing a composite material for drug delivery system through the physical combination of the active material according to the present invention for achieving the above object, 70 to 90: 10 to 30 weight ratio of caprolactone and glycolide in 1,2-dichloroethane solvent A first step of polymerizing an oligomer having a weight average molecular weight of 1,000 to 10,000 by mixing with an ethylene glycol initiator and copolymerizing in the absence of an ethylene glycol initiator; A second step of obtaining a macromer in which triethylamine and methacryloyl chloride are added in a molar ratio of 1: 1 in the solvent of tetrahydrofuran to transform the OH group of the oligomer into a methacrylate group to the oligomer; A third step of mixing the macromer 90 to 98% by weight to 60 to 70 ° C and melting and mixing the same with 2 to 10% by weight of the solid particulate active material having a melting point of 60 ° C or more; And spreading the mixture thinly on the desired frame to form a film. And irradiating and drying at room temperature to form a film.

In addition, the present invention using the above-described method is mixed with caprolactone and glycolide in a 1,2-dichloroethane solvent in a weight ratio of 70 to 90: 10 to 30, and copolymerized in an ethylene glycol initiator and a non-catalyst, tetrahydrofuran Triethylamine and methacryloyl chloride were added in a predetermined molar ratio in a solvent of and mixed with 90 to 98% by weight of the macromer in which the OH group of the oligomer was modified with a methacrylate group and 2 to 10% by weight of the solid particulate active material. It provides a composite material for drug delivery system through the physical combination of the active material, characterized in that the filmed after.

Hereinafter, the present invention will be described in more detail.

As described above, the present invention provides an ideal form of drug delivery system by physically combining an active substance, which was conventionally complicated with a biodegradable delivery medium, and a step by step of the preparation method, caprolactone and glycolide are first described. The mixture is mixed at a weight ratio of 70 to 90:10 to 30 in a solvent of 1,2-dichloroethane and copolymerized under an ethylene glycol initiator and a non-catalyst to polymerize an oligomer having a weight average molecular weight of 1,000 to 10,000. The reaction mechanism of this method is described in Scheme 1 below.

As can be seen in Scheme 1, when the caprolactone and the glycolide are copolymerized with ethylene glycol as an initiator without a catalyst, the oligo [(ε-caprolactone) -co-glycolide] diol is polymerized. It is preferable that the polymerization degree of this oligomer has a weight average molecular weight of 1,000-10,000. The degree of polymerization can be obtained in an appropriate yield and speed without using a toxic organic catalyst, it is suitable for the composite material according to the present invention.

Tetrahydrofuran was used as a solvent in the oligomer obtained in Scheme 1, and triethylamine and methacryloyl chloride were added in a molar ratio of 1: 1 to obtain a macromer in which the OH group of the oligomer was modified with a methacrylate group. The reaction mechanism of is shown in Scheme 2 below.

Thus, the relative molecular weight and molecular weight distribution of the synthesized macromers (Polydispersity) is then bonded acetyl groups at both ends of a polymer analyzed by (Gel Permeation Chromatography) GPC and through the absolute molecular weight and functional group reactions such as in Scheme 3 ¹ H Analyze with -NMR-Spectroskopy. In addition, the thermal properties can be analyzed by differential scanning calorimetry (DSC).

On the other hand, after heating 90-98 weight% of said macromers to 60-70 degreeC, and melting it, it mixes with 2-10 weight% of solid-state particulate active materials whose melting point is 60 degreeC or more.

The solid particulate active material may be at least one dye selected from the group consisting of methylene blue, tar pigment, potassium or sodium salt of chlorophyllin, riboflavin and its derivatives, water soluble anato, copper sulfate, caramel, curcumin and kochina. .

Alternatively, the solid particulate active material is selected from the group consisting of an inorganic coagulant of aluminum sulfate, an anionic polymer coagulant of acrylic acid and sulfonic acid, a cationic polymer coagulant of methacrylate and an acrylate, and a nonionic polymer coagulant. May be at least one flocculant.

Alternatively, the solid particulate active material may be at least one selected from the group consisting of inorganic pesticides of copper, inorganic emulsifiers and arsenic agents, natural organic pesticides of nicotine and pyrethrin, and organic synthetic pesticides of organophosphorus, organochlorine and carbamate. May be a pesticide.

Depending on the nature of the active material described above, the final composite material obtained in the present invention can be used in various applications.

Mixing of the macromer and the active substance is carried out by applying a physical treatment such as conventional physical stirring or stirring.

The obtained mixture was thinly spread on a desired frame and filmed in U.V. Irradiation and room temperature drying form a film to prepare the composite material for drug delivery system according to the present invention.

The thickness of the film is not particularly limited, and may be prepared by setting the desired frame and thickness according to the desired use.

2 illustrates a reaction mechanism for preparing a macromer which is a standard polymer from caprolactone and glycolide according to the present invention to prepare a composite material of a drug delivery system.

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto.

Example

1) Synthesis of Polyester Diol by Caprolactone, Glycolide and Ethylene Glycol

In a 500 ml round flask equipped with nitrogen gas, 14.47 g (0.125 mol) glycolide and 161.40 g (1.414 mol) caprolactone were dissolved in 150 ml 1,2-dichloroethane and 3.73 g (60.1 mmol) ethylene glycol was added. . The reactants were reacted at 130 ° C. for 14 days under nitrogen gas and then cooled to 65 ° C.

The viscous solution in the flask was dissolved in 150 ml 1,2-dichloroethane at 65 ° C. Immediately, the solution was stirred well at 0 ° C. nucleic acid and slowly dropped to precipitate. The nucleic acid was poured off and the waxy product was concentrated well in a rotary concentrator and dried in high vacuum for one day to obtain oligomers.

2) Synthesis of Polyester Dimethacrylate by Triethylamine and Methacryloyl Chloride

In a 500 ml eggplant flask, 0.01 mol copolyesterdiol was dissolved in 200 ml of dried tetrahydrofuran in the presence of nitrogen gas. Then 5.3 ml (0.038 mol) triethylamine and 3.7 ml (0.038 mmol) methacryloylchloride were slowly added under ice cooling. After 2 hours the ice bath was removed and the reaction mixture was stirred at room temperature for 3 days. The white product in the flask was filtered through filter paper and the filtrate was dried with a rotary concentrator. The remaining material was dissolved in triethylamine (10 times the weight of the first reacted copolyesterdiol) to remove small molecular weight oligomers. And the undissolved material was filtered out. This standard polymer was then stirred vigorously and precipitated by dropping a mixture of nucleic acid, methanol and diethyl ether (18: 1: 1). Finally, the product was washed with nucleic acid and dried in high vacuum for one day.

3) Mixing copolyester dimethacrylate and methylene blue (active substance)

The standard polymer was melted by heating to 70 ° C. in a 5 ml beaker, well mixed with methylene blue at a ratio of 9: 1, and cooled to room temperature to make a 0.4 g sample.

1 shows a photograph of a macromer mixed with methylene blue 10% by SEM (Scanning Electron Microscopy).

4) Film forming through UV curing

The sample was heat treated at 70 ° C. in an oven for 1 hour. The samples are then melted and no bubbles formed therein. When this melt is poured into a glass plate without stirring, it solidifies at room temperature after about 1 minute. The sample was again heated to 70 ° C. in an oven for 5 minutes. Then a Teflon 1mm frame was attached to the corners and covered with a second glass plate. The lower and upper glass plates were fixed with tongs, taking care not to let the sample flow out. The sample can now be cured in an ultraviolet irradiator.

The sample was placed on a hotplate and heated to 70 ° C. until it melted. This sample polymer should be in a liquid state during the irradiation of ultraviolet light. The sample was exposed from the light source at 40 cm distance for 20 minutes. After the sample had sufficiently cooled down, the film was removed from the glass plate.

Experimental Example 1

Gel Permeation Chromatography (GPC) Analysis of Polyester Diols

In order to determine the relative molecular weight of polyester diol copolymerized with caprolactone and glycolide of Example 1, it was analyzed by GPC method. GPC analysis was measured with a machine from Polymer Laboratories. RI Detector ERC-7515A was used as a detector. Columns were calibrated with polystyrene standards. The concentration of the sample was adjusted to 8-10 mg / ml using chloroform solvent. 100 μl of this solution was inserted into the machine by syringe. Acetone was used as an internal standard. Data measurement and numerical analysis were performed using JANUS (Marsch Software 1995), a GPC specialist program. As a result, the number average molecular weight (Mn) of the synthesized polyester diol was 7,000 g / mol and the molecular weight distribution was 1.5.

Experimental Example 2

Acetylation of Polyesterdiol for 1H-NMR (Nuclear Magnetic Resonance Spectroscopy) Analysis

1 mmol polyesterdiol synthesized in the presence of nitrogen gas in a branched 50 ml flask was dissolved in 2.5 ml 1,2-dichloroethane. The flask was then cooled with ice and slowly 0.36 ml (4.5 mmol) pyridine and 0.215 ml (3.0 mmol) acetylchloride were added. At this time, a severe exothermic reaction occurs to form a salt and the color of the solution changes from light yellow to white. This was stirred for 2 hours while cooling with ice and then stirred at room temperature for 12 hours.

The white powder (polyester diacetylate) produced in the reaction was filtered with filter paper and precipitated again in distilled water. The product was then filtered again and washed with water five times. Finally, the resultant was washed with nucleic acid cooled by ice 5 times and dried using a rotary concentrator and a high vacuum device to obtain polyester diacetylate.

Experimental Example 3

1 H-NMR Analysis of Polyester Diacetylate

In order to determine the absolute molecular weight of the polyester diol copolymerized with caprolactone and glycolide, the polyester diacetylate was analyzed by 1 H-NMR, and the spectrum thereof is shown in FIG. 3. The 1 H-NMR spectrum was measured using a 400 MHz spectrum machine from INOVA. Samples for measurement were dissolved in D6-dimethylsulfoxide (D6-DMSO) or chloroform (CDCl ₃ ) substituted with deuterium. In addition, a standard solution was used for chemical conversion of the solvent (D6-DMSO: 2.50 ppm, CDCl ₃ : 7.26 ppm). Software FELIX (BIOSYM Technologies, 1993) was used in part for numerical analysis of the spectrum. The molecular weight of the synthesized polyesterdiol (oligomer) was 3700.

Experimental Example 4

DSC (Differential Scanning Calorimetry) Analysis of Polyester Diol

In order to determine the thermal properties of the polyester diol copolymerized with caprolactone and glycolide of the above example, the results were analyzed by DSC. DSC analysis was performed using a Perkin-Elmer DSC7 machine. For this purpose 7-15 mg of the sample was placed in a small aluminum container. The sample was first heated at a heating rate of 30 ° C./min and cooled at a rate of 10 ° C./min. Subsequently, the heating rate was measured at a temperature range of -75 to 80 ° C at a heating rate of 10 ° C / min. As a result, the glass transition temperature (Tg) was -60 ° C, the melting point was 45-55 ° C, and the melting enthalpy was 65.08 J / g.

Experimental Example 5

Dissolution test of methylene blue through hydrolysis

First, weigh the film (S) and 10% methylene blue (SM) film containing no active substance, and put them together with 40 ml phosphate buffer (pH = 7) in a 100 ml polyethylene container. Stored at ° C. After a certain decomposition period, the solution was discarded, the film was dried, the weight thereof was measured, and the results are shown in FIG. 5. As a result, only 4% of the film (S) without active material was decomposed for 7 weeks. Films containing methylene blue as an active material (SM) exhibited a resolution of about 9% during this period.

The composite material for drug delivery system prepared according to the present invention is simply biodegradable and effective in drug delivery just by physically mixing the biodegradable polymer and the active material, and the manufacturing step is simple, and the organic catalyst is used during copolymerization. It is eco-friendly because it is not used.

Claims (9)

A first step in which caprolactone and glycolide are mixed in a 1,2-dichloroethane solvent in a 70 to 90:10 to 30 weight ratio and copolymerized under an ethylene glycol initiator and a catalyst to polymerize the oligomer; A second step of adding triethylamine and methacryloyl chloride in a predetermined molar ratio to the oligomer under a solvent of tetrahydrofuran to obtain a macromer in which the OH group of the oligomer is modified with a methacrylate group; A third step of heating the macromer to 90 to 98% by weight to a predetermined temperature to melt and then mixing the same to 2 to 10% by weight of the solid particulate active material; And The mixture is thinned and filmed on the desired frame and U.V. Irradiating and drying at room temperature to form a film; Method for producing a composite material for drug delivery system through the physical combination of the active material comprising a. The method of claim 1, Method of producing a composite material for drug delivery system through the physical combination of the active material, characterized in that the polymerization degree of the oligomer in the first step has a weight average molecular weight of 1,000 ~ 10,000. The method of claim 1, The triethylamine and methacryloyl chloride in the second step is added in a molar ratio of 1: 1. The method of claim 1, In the third step The macromer is characterized in that the melting at 60 ~ 70 ℃ The method of claim 1, Solid particulate active material is characterized in that the melting point of 60 ℃ or more selected The method of claim 5, The solid particulate active material in the third step is; At least one dye selected from the group consisting of methylene blue, tar pigments, potassium or sodium salts of chlorophyllin, riboflavin and derivatives thereof, water soluble anato, copper sulfate, caramel, curcumin and kochina The method of claim 5, The solid particulate active material in the third step is; At least one flocculant selected from the group consisting of inorganic coagulants of aluminum sulfate, anionic polymer coagulants of acrylic acid and sulfonic acid, cationic polymer coagulants of methacrylate and acrylate, and nonionic polymer coagulants. doing The method of claim 5, The solid particulate active material in the third step is; Active substance characterized in that the inorganic pesticides of copper, inorganic emulsifiers and arsenic agents and at least one pesticide selected from the group consisting of natural organic pesticides of nicotine and pyrethrin and organic synthetic pesticides of organophosphorus, organochlorine and carbamate Method for producing a composite material for drug delivery system through the physical combination of. Caprolactone and glycolide were mixed in a 1,2-dichloroethane solvent in a 70-90: 10 to 30-30 weight ratio, and copolymerized in an ethylene glycol initiator and a non-catalyst, triethylamine and methacryl in a solvent of tetrahydrofuran. Active material characterized in that the film is mixed with 90 to 98% by weight of the macromer transformed OH group of the oligomer into methacrylate group and 2 to 10% by weight of the solid particulate active material by adding monochloride in a predetermined molar ratio. Compounds for drug delivery systems through physical combinations.

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