KR20000026767A - Star type polymer of poly-l-lactide and polyethylene oxide - Google Patents

Abstract

PURPOSE: A copolymer useful as drug release controlling agent is prepared by copolymerization of poly-L-lactide and polyethylene. CONSTITUTION: A copolymer of formula 1 is provided: wherein R is alcohol initiator; m is polymerization degree of polyethylene(10-4,500); n is polymerization degree of poly-L-lactide(10-3,000). Thus, dicyclohexyl carbodiimide, dimethyl aminopyridine, poly-L-lactide and polyethylene oxide in the ratio of 6: 1: 4: 8 are reacted in dichloromethane, and dried for 24 hours to give the copolymer.

Description

Star copolymer of polyelactide and polyethylene oxide

According to the present invention, a polyelactide having excellent biocompatibility (poly-L-lactic acid, hereinafter referred to as PLLA) is combined with polyethylene oxide (hereinafter referred to as PEO) to form a star polyelactide-polyethylene having the following structural formula. It relates to an oxide copolymer (hereinafter referred to as PLE).

Structural Formula 1. Copolymer of Polyelactide-Polyethylene Oxide

Here, R represents the alcohol initiator used in the ring-opening polymerization of the elactide, m represents the degree of polymerization of polyethylene oxide, has a value of 10 to 4,500, n represents the degree of polymerization of polyelactide and has a value of 10 to 30,00.

Polyelactide is a polymer in which ester bonds are decomposed by hydrolysis and esterases in vivo and has been used for various surgical treatments such as sutures since the 1960s. As development of drug delivery agents for drugs, interest and research have begun to increase, and many studies on block copolymers with polyethylene have been reported to make polyelactide into emulsion-type nanoparticles and increase half-life in the blood. It is becoming.

Studies on star polymers have been published as a method for increasing the degradation in vivo and half-life in the blood while maintaining the properties of polyelactide. In 1989, Yang Shilin reported the study of synthesizing polyelactide using polyethylene glycol having several strands as an initiator (Journal of polymer Science: Part A: polymer chemistry, 27, 2151-2159, In 1989, P. Vit synthesized star- and comb-shaped polylactide copolymers using polyhydric alcohols such as glucose with six hydroxy group (OH) groups (Journal of controlled release). , 16, 27-42, 1991), 1992 Young Ha Kim reported a study on the synthesis of copolymers of star polyelactide and alcohol using pentaerythritol as an initiator (Makromol chem. 193, 1623-1631, 1992).

In 1994, MIT's Langer reported a study on the synthesis of dumbbell-type block copolymers in which multiple strands of polyelactide were bonded on both ends of polyethylene oxide (Science, 263 (18), 1600-1603, 1994). And at the 1997 Controlled Release Society (CRS) Symposium, Kissel of Philip University, Germany, presented a star copolymer polymerized by lactide in polyethylene.

The present invention is a biodegradable medical polymer having excellent biocompatibility and widely used as a support for drug release control agent and tissue regeneration, but the copolymer is synthesized with polyethylene oxide on polyelactide with weak mechanical properties, slow decomposition rate and no elasticity. To solve the disadvantages of the polyelactide listed above to develop a drug release control agent.

Figure 1 (a) is a schematic diagram showing a linear polyelactide-polyethylene oxide copolymer having one end group of polyelactide

(b) is a schematic diagram showing a star polyelactide-polyethylene oxide copolymer having four terminal groups of polyelactide;

(c) is a schematic diagram showing a star polyelactide-polyethylene oxide copolymer having 8 end groups of tetravalent polyelactide and then 8 PEOs bonded thereto;

(d) is a schematic diagram showing a star polyelactide-polyethylene oxide copolymer having 8 terminal groups of polyelactide.

FIG. 2 is a block diagram showing a ring-opening reaction mechanism of L-lactide using 1-dodecanol (denoted as R-OH) and sternus octane (Sn (Oct) ₂ ) as an alcohol initiator ( a) is the first step of the reaction, indicating the association of stenos octane with initiator and elactide.

In order to synthesize the biodegradable star-type polyelactide-polyethylene oxide copolymer (PLE) of the present invention, ring-opening polymerization of elactide is first performed using an alcohol initiator such as 1-dodecanol, pentaerythritol, and tripentaerythritol. Should. 2 shows the ring-opening polymerization reaction mechanism of lactide using 1-dodecanol, which is an alcohol initiator, and stern's octate (Sn (Oct) ₂ ). The reaction begins with the formation of the complex of the elactide with the stern octate in section (a), followed by the formation of the monomer electide with the sensation octane complex. It is a reaction mechanism that indicates ring opening.

The polyelactide polymerized as described above and represented by the following structural formula is confirmed by nuclear magnetic resonance analysis (H-NMR) to determine whether it is synthesized, and their molecular weight and other properties are measured by the viscometer and differential scanning calorimetry method (Differential). Check using scanning calorimetry (hereinafter named DSC).

Structural Formula 2. Structural Formula of Polyelactide

R represents an alcohol initiator used in ring-opening polymerization of ellactide, n represents the degree of polymerization of polyelactide and has a value of 10 to 3,000.

Then, a copolymer is synthesized by attaching a polyethylene oxide having the following structural formula to a polyelactide end using dicyclohexylcarbodiimide (hereinafter referred to as DCC).

Structural Formula 3. Structural Formula of Polyethylene Oxide

H- (O-CH ₂ -CH _2- ) _m O-CH ₃

Where m represents the degree of polymerization of polyethylene oxide and has a value from 10 to 4,500.

Hereinafter, the present invention will be described by the following examples and test examples. However, these are provided only to facilitate the description of the present invention, but the technical scope of the present invention is not limited thereto.

<Example 1>

Place 5,000 mg of ellactide in a glass reactor and dissolve 41.2 mg of 1-dodecanol and 80 mg of saneous octate (Sn (Oct) ₂ ) in 1-2 ml of toluene. It was used as a reaction and injected into the reactor using a syringe. After adding the reactants, the water and toluene contained in the reactants were removed for 3 hours using a vacuum pump, the reactor was sealed in a vacuum state using a torch, soaked in silicon oil at 120 ° C., and stirred for 5 hours. After 2 hours, the white polymer begins to form in the colorless liquid. After 5 hours, the reactants turn into white polymer products. After the reaction, the reactor was taken out of the silicon oil, the sealed portion was removed, and the produced polymer was dissolved using dichloromethane and then precipitated in methanol. The remaining 1-dodecanol and SnOct ₂ are dissolved in methanol, filtered using a polymer membrane filter paper to obtain a reaction product, and then dried in vacuo for one day to obtain polyelactide.

<Example 2>

1 mole of polyelactide (PLLA) synthesized in Example 1 was prepared using 1.5 moles of dimethylaminopyridine (hereinafter referred to as DMAP) and 1.5 moles of succinic anhydride (hereinafter referred to as SA). After carboxylating the end of the elactide, polyethylene oxide (PEO) and polyelactide (PLLA) were prepared using DCC: DMAP: PLLA: PEO = 6: 1: 4 using dicyclohexylcarbodiimide (DCC) and DMAP. : React at a molar ratio of 8. The solvent used was dichloromethane. To remove unreacted material after the reaction, the mixture was poured into a mixture of methanol and ether having a mixing ratio of 4: 1 (v / v) to precipitate the reactant, followed by filtration and mixing at a ratio of 2: 1 (v / v). ) Was purified by precipitation in normal heptane (n-heptane) and ethyl acetate (ethylacetate), filtered and dried at room temperature in vacuo for 24 hours.

<Example 3>

The terminal is carboxylated, and 1 g of tetravalent polyelactide having a molecular weight of 49,200 and 0.5 g of polyethylene oxide having a molecular weight of 5,000 substituted with a methyl group on one side are dried at 80 ° C. for 30 minutes using a vacuum pump, and then argon (Argon In the air stream, the two polymers are dissolved in 20 ml of solvent dichloromethane and put into the reactor. DCC and DMAP are also dissolved in dichloromethane and put into the reactor, and the reaction is stirred slowly for 24 hours. At this time, the molar ratio of the used material was DCC: DMAP: PLLA: PEO = 1: 0.25: 1: 5 and the mixture was mixed with methanol and ether in a mixture of 4: 1 (v / v) to remove unreacted material after the reaction. The precipitate was poured into precipitates, filtered and filtered again. The mixture was purified by precipitation in normal heptane and ethyl acetate having a mixing ratio of 2: 1 (v / v), and then filtered and dried at room temperature in a vacuum for 24 hours.

<Example 4>

1 g of polyelactide having 1,3,5-cyclohexanetricarboxylic acid (CTA), each having two carboxyl groups at the ends of the tetravalent polyelactide and having a molecular weight of 49,200. 0.5 g of polyethylene oxide having a molecular weight of 2,000 substituted with a methyl group, and dried at 80 ° C. for 30 minutes using a vacuum pump, dissolved in 20 ml of solvent dichloromethane under argon, and then put into a reactor. It is dissolved in dichloromethane and put into the reactor to react with stirring slowly for 24 hours. At this time, the molar ratio of the used material was DCC: DMAP: PLLA: PEO = 1: 0.25: 1: 5 The precipitate was poured into precipitates, filtered, filtered, and then precipitated and purified in normal heptane and ethyl acetate in a mixing ratio of 2: 1 (v / v), followed by filtration and drying at room temperature in vacuo for 24 hours.

<Test Example 1>

The polymerized elrak Tide Tide elrak and poly-nuclear magnetic resonance ⁽¹ H -NMR) to confirm the polyethylene oxide copolymer that is synthesized and correctly confirm that a certain amount of binding was used. The synthesized polyelactide showed a peak represented by CH- at 5.2 ppm and a peak represented by CH ₃ -at 1.6 ppm, and in the case of the polyelactide-polyethylene oxide block copolymer, _{The 2} -CH ₂ -peak appeared at 3.7 ppm indicating that the copolymer was successfully obtained.

On the other hand, in order to determine the degree of copolymerization (coupling) of the polyethylene oxide with a molecular weight of 2,000 and polyelactide with a molecular weight of 2,000, and then quantitative analysis using nuclear magnetic resonance method. As a result, it was found that 98% of polyethylene oxide was combined with polyelactide. Thus, by using the degree of binding obtained by binding the tetravalent and monovalent polyelactide with polyethylene oxide having a molecular weight of 2,000, H-NMR analysis was performed, which is shown in Table 1 below.

<Test Example 2>

Gel permeation chromatography (hereinafter referred to as GPC) was used to know the molecular weight of the synthesized polymer. Tetrahydrofuran (THF) was used as the solvent, and measured using polystyrene as a reference sample at 40 ° C. Through this synthesis of the copolymer was found that the low molecular weight polyelactide is more reactive than the high molecular weight polyelactide, and Table 1 below shows the molecular weight of the polyelactide and polyelactide-polyethylene oxide block copolymer. .

Table 1.Molecular weights of polyelactide and polyelactide-polyethylene oxide block copolymers

division rescue Mn _G Mw _G Mn ¹⁾ Mn ²⁾ MWD 1-PLLA Linear polylactide with 1 -OH 44,100 65,400 46,700 34,300 1.48 4-PLLA Star polylactide with 4 -OH 49,200 78,200 52,400 110,900 1.59 8-PLLA Star polylactide with 8 -OH 45,300 76,600 39,562 276,700 1.69 1-PLE Linear dicopolymers with one PEO 48,500 60,000 - 50,300 1.24 4-PLE Dual copolymer with four PEOs 65,800 83,500 - 130,900 1.27 4-PLE-2 Double Copolymers with Eight PEOs in Tetravalent PLL 56,900 76,700 - 125,000 1.35 8-PLE Double copolymer with 8 PEOs in an octavalent PLL 47,500 76,000 - 292,700 1.60

Mn _G : Number average molecular weight measured by GPC

Mw _G : Weight average molecular weight measured by GPC

Mn ¹⁾ : [η] = 2.21 x 10 ^-4 Mn ^0.770 Number average molecular weight obtained by

Mn ²⁾ : calculated by H-NMR after bonding with polyethylene oxide with a molecular weight of 2,000

Number average molecular weight

MWD: Abbreviation for Molecular weight distribution, showing molecular weight distribution.

<Test Example 3>

The solution characteristics of the polyelactide-polyethylene oxide copolymer and the number of branches of the polyelactide were measured at 25 ° C. using a viscometer Ubbelohde with solvent chloroform to obtain intrinsic viscosity as shown in Table 2 below. Since is affected by the number of branches of the polymer it can be used to guess the number of branches of the polyelactide.

This value is the g value, which indicates the effect of the number of branches and the shape of the branch on the three-dimensional structure of the molecule. g _exp = [η] _s / [η] _l And theoretical g _{theo, 1} = (3f-2) / f ₂ Wow g _{theo, 2} = 6f / (f + 1) (f + 2) Etc. The value of g _{theo, 1} is the theoretical value of star polymers in θ condition, and the value of g _{theo, 2} is the theoretical value that can be applied to star polymers with the most common molecular weight distribution. Since tetravalent polyelactide is close to the value of g _{theo, 2} , it can be seen that the application of this value can have a value closer to the actual value. It can be seen that the tetravalent polyelactide has four branches because the theoretical value and the experimental value are almost identical for the tetravalent polyelactide.

Table 2. Intrinsic viscosity and g value of polyelactide and polyelactide-polyethylene oxide block copolymer

division Intrinsic viscosity [η] g ' _exp g ' _{theo, 1} g ' _{theo, 2} 1-PLLA 0.870 1.000 1.000 1.000 4-PLLA 0.780 0.896 0.791 0.894 8-PLLA 0.761 0.874 0.586 0.730 1-PLE 0.902 1.000 1.000 1.000 4-PLE 0.881 0.976 0.791 0.894 4-PLE-2 0.781 0.865 0.586 0.730 8-PLE 0.879 0.974 0.586 0.730

g '= g ^1/2

g ′ _exp = [η] _s / [η] _l

g _{theo, 1} = (3f-2) / f ₂ : Theoretical value applied to star polymer in θ condition

g _{theo, 2} = 6f / (f + 1) (f + 2) : The star polymer having the most common molecular weight distribution

Applied theory

<Test Example 4>

Thermal properties such as melting point (Tm), glass transition temperature (Tg), and enthalpy change (ΔH) of the polyelactide polymer synthesized using the differential scanning calorimetry (DSC) were observed and shown in Table 3. As shown in Table 3, the melting point of star polyelactide was lower than that of linear polyelactide, and the melting point and glass transition temperature of polyelactide-polyethylene oxide block copolymer were lower than those of polyelactide.

Table 3. Thermal Properties of Polyelactide and Polyelactide-Polyethylene Oxide Copolymers

division Tm (℃) Tg (℃) ΔH (J / g) 1-PLLA 174.93 55.31 40.61 4-PLLA 169.73 56.02 26.96 8-PLLA 173.67 53.84 41.55 1-PLE 176.28 47.71 43.07 4-PLE 171.28 40.00 47.06 4-PLE-2 173.03 34.81 41.95 8-PLE 171.79 32.93 45.62

The star polyelactide-polyethylene oxide block copolymer made by the present invention can synthesize materials having different mechanical and thermal properties according to the molecular weight and content of polyelactide and polyethylene oxide, Nanoparticles and microparticles that are drug delivery agents for human insertion, sublingual and transdermal absorbents, sutures, supports for tissue regeneration, carriers for protein transport, film-type drug delivery agents, and the like.

Claims (4)

A star copolymer of polyelactide and polyethylene oxide, which forms a structural formula by combining polyethylene oxide at the end of a star polyelactide. Here, R represents an alcohol initiator used in ring-opening polymerization of elactide, m represents a degree of polymerization of polyethylene oxide, has a value of 10 to 4,500, n represents a degree of polymerization of polyelactide, and has a value of 10 to 3,000. The star copolymer of polyelactide and polyethylene oxide according to claim 1, wherein the star polyelactide has 1 to 16 terminal groups. 2. The star copolymer of polyelactide and polyethylene oxide according to claim 1, wherein the polyelactide has a molecular weight of 1,000 to 200,000. The star copolymer of polyelactide and polyethylene oxide according to claim 1, wherein the polyethylene oxide has a molecular weight of 500 to 200,000.