The present invention relates to a block copolymer formed by coupling the following components with each other, as well as a hydrogel composition comprising the block copolymer and a hydrogel formed from the composition: (a) a copolymer of a polyethylene glycol (PEG)-based compound with a biodegradable polymer; and (b) a sulfonamide-based oligomer. The inventive block copolymer shows the sol-gel transition behavior sensitive to changes in not only temperature but also pH. Thus, the inventive block copolymer overcomes the shortcomings of temperature-sensitive copolymers, form a more strong and stable hydrogel, and is stable in vivo. Accordingly, the inventive block copolymer can be used in various applications in the medical and drug delivery fields.

Description of the Invention

TECHNICAL FIELD

The present invention relates to a pH- and temperature-sensitive block copolymer, a hydrogel composition containing the block copolymer, and a hydrogel prepared from the composition. More particularly, the present invention relates to a block copolymer formed by coupling the following components with each other, as well as a hydrogel composition containing the block copolymer and a hydrogel prepared from the composition: (a) a copolymer of a polyethylene glycol-based compound with a biodegradable polymer; and (b) a sulfonamide-based oligomer.

BACKGROUND ART

Amphiphilic polymers having both hydrophobicity and hydrophilicity have been of interest. Particularly, amphiphilic polymers that exhibit a temperature-sensitive sol-gel behavior are now studied intensively in the drug delivery system and medical fields, and studies on their use are also actively conducted. Particularly, copolymers composed of polyethylene oxide and polypropylene oxide are commercially available under the trade names Pluronic and Poloxamer and used in various applications.

However, the Pluronic- and Poloxamer-based polymers encountered problems upon use in medical applications due to non-biodegradability. For this reason, copolymers composed of biodegradable polylactide (PLA) (or polyglycolide (PGA), polycaprolactone (PCL) and a copolymer thereof) and polyethylene glycol (PEG) have been studied and used.

U.S. Pat. Nos. 4,882,168 and 4,716,203 disclose copolymers of hydrophilic polyalkylene glycol with polyglycolic acid, trimethylene carbonate and the like.

Furthermore, U.S. Pat. No. 4,942,035 discloses a pharmaceutical composition comprising a block copolymer of polyethylene glycol (PEG) with polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), hydrophobic polypeptide or polyacetal.

Moreover, U.S. Pat. No. 5,476,909 discloses a biodegradable triblock (A-B-A) copolymer consisting of: hydrophobic blocks (A) comprising polylactide (PLA), polyglycolide (PGA) or derivatives thereof, and a hydrophilic block (B) comprising polyethylene glycol (PEG) or its derivatives.

And, U.S. Pat. No. 5,548,035 discloses a biodegradable multi-block copolymer with thermoplasticity comprising a hydrophobic block selected from polylactide, polyglycolic acid, a copolymer thereof, and polycaprolactone.

Meanwhile, Korean Patent Laid-Open Publication No. 2000-0012970 (Mar. 6, 2000) discloses a pH-sensitive polymer comprising sulfonamide groups, and a preparation method thereof. This patent relates mainly to either a change in the solubility of linear polymers formed by the random copolymerization of sulfonamide monomers with DMAAm or NiPAAm, or the swelling index of crosslinked polymers thereof.

The above-described prior arts were so designed that a sol-gel transition phenomenon is shown by the use of the block copolymer of the hydrophobic biodegradable polymer with the hydrophilic polymer. The block copolymer when injected in vivo in an aqueous solution form, a sol state, is changed into a gel state. Thus, the block copolymer was used as a sustained-release drug delivery system which carries and slowly releases drugs in vivo.

However, block copolymers that exhibit a temperature sensitive sol-gel transition phenomenon cause problems, such as the clogging phenomenon of injection needles occurring during injection before in vivo injection, since in vivo temperature and the temperature of the injection needles are adjusted to the same temperature by thermal equilibrium. In addition, hydrophobic moieties comprised of PLA, PLGA or PCL are reported to exhibit pH sensitivity. However, such moieties are not so sensitive that they can be applied to in vivo pH, and thus, they are not suitable for practical use in the drug delivery field.

DISCLOSURE OF THE INVENTION

The present invention has been made to solve the above-described problems occurring in the prior art, and it is an object of the present invention to provide a novel pH- and temperature-sensitive block copolymer which shows a sol-gel transition behavior sensitive to not only temperature but also pH, and thus becomes gel around pH 7-7.4 similar to in vivo pH and sol at a higher pH than this pH range, so that, when the block copolymer is dissolved at high pH and injected in vivo, it can show a gel state in vivo.

To achieve the above object, the present invention provides a block copolymer formed by coupling the following components with each other, as well as hydrogels containing the block copolymer, and a hydrogel formed from the components: (a) a copolymer of a polyethylene glycol-based compound with a biodegradable polymer; and (b) a sulfonamide-based oligomer.

Hereinafter, the present invention will be described in detail.

The present invention is characterized in that a sulfonamide-based oligomer showing a change in ionization degree with a change in pH (pH sensitivity) is coupled to a copolymer of a hydrophilic PEG-based compound with a biodegradable polymer, thus forming a novel block copolymer which can be used in actual drug delivery.

Because of the characteristic as described above, the inventive block copolymer shows a sol-gel transition behavior sensitive to not only temperature but also pH.

Namely, the prior block copolymer composed of a hydrophobic biodegradable polymer and a hydrophilic polymer showed a sol-gel transition behavior caused by a change in the physical properties of each of the hydrophobic block and the hydrophilic block with a change in temperature. However, due to the in vivo incompatibility of the block copolymer caused by the thermal equilibrium of a delivery medium, it was difficult to apply the block copolymer in actual drug delivery.

However, according to the present invention, the sulfonamide-based oligomer that shows a change in ionization degree with a change in pH is coupled to the copolymer composed of the hydrophobic biodegradable polymer and the hydrophilic polymer so as to impart pH sensitivity in addition to temperature sensitivity to the copolymer. This can solve the above-described problem with the temperature-sensitive hydrogels. Also, the temperature- and pH-sensitive block copolymer according to the present invention forms a more stable hydrogel and is stable in vivo, and thus, it can be applied in the medical and drug delivery fields, particularly as sustained-release drug delivery systems which carry and release drugs.

One component of the temperature- and pH-sensitive block copolymer according to the present invention is the copolymer (a) of the PEG-based compound with the biodegradable polymer. The copolymer (a) has not only the hydrophilicity of the PEG-based compound but also the hydrophobicity of the biodegradable polymer, so that it can show sol-gel transition by a change in temperature.

As the PEG-based compound contained in the copolymer (a), any conventional PEG-based compound known in the art may be used. Particularly, a PEG-based compound represented by the following formula 1, such as PEG or methoxy PEG, is preferred -- see Original Patent.

The molecular weight of the polyethylene glycol-based compound is preferably 500-2,000. Particularly, the molecular weight of polyethylene glycol (PEG) where R in the formula 1 represents hydrogen is preferably 1,000-2,000, and the molecular weight of methoxy polyethylene glycol where R represents a methyl group is preferably 500-2,000. If the molecular weight is less than 500 or more than 2,000, there will be problems in that gel formation does not occur well, or otherwise, even if gel is formed, gel formation under in vivo conditions (37.degree. C.) does not occur.

As the biodegradable polymer contained in the copolymer (a), any conventional biodegradable polymer known in the art may be used and examples thereof include, but are not limited to, caprolactone (CL), glycolide (GA), lactide (LA) and copolymers thereof.

Examples of the copolymer (a) formed by the polymerization of the polyethylene glycol-based compound with the biodegradable polymer include, but are not limited to, polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), poly(caprolactone-lactide) random copolymer (PCLA), poly(caprolactone-glycolide) random copolymer (PCGA) or poly(lactide-glycolide) random copolymer (PLGA).

The molecular weight ratio of the PEG-based compound to the biodegradable polymer in the copolymer (a) is not limited to any special range, but is preferably in a range of 1:1-3. If the molecular weight ratio is less than 1:1, the block copolymer will not form gel, and if it is more than 1:3, the magnitude of hydrophobicity of the block copolymer will be increased such that the block copolymer cannot be dissolved.

Moreover, in the case where the biodegradable polymer in the copolymer is PCLA. PCGA or PLGA, its molar ratio can be suitably controlled so as to increase the temperature- and pH-sensitivity effect of the block copolymer.

As another component of the temperature- and pH-sensitive block copolymer according to the present invention, a compound that shows a change in ionization degree with a change in pH may be used. Particularly, the oligomer (b) formed from a sulfonamide-based compound is preferably used. The sulfonamide-based oligomer preferably contains functional groups, such as hydroxyl groups (--OH), carboxyl groups (--COOH) or amine groups (--NH.sub.2). This makes it easy to prepare the inventive block copolymer by polymerization reaction.

Examples of the sulfonamide-based compound for use in forming the oligomer (b) include, but are not limited to, sulfamethisole, sulfamethazine, sulfasetamide, sulfisomidine, sulfafenasole, sulfamethoxasole, sulfadiazine, sulfamethoxydiazine, sulfamethoxypyridazine, sulfadoxine, sulfapyridine, sulfabenzamide, sulfisoxazole or derivatives thereof.

The molecular weight of the oligomer formed from the sulfonamide-based compound is not specifically limited, but is preferably 500-2,000. If the molecular weight is less than 500, the block copolymer will not show a sol-gel transition behavior caused by a change in pH, and if it is more than 2,000, the block copolymer will be difficult to exhibit temperature sensitivity as well.

The inventive copolymer formed by coupling the above-described components (i.e., the copolymer of the PEG-based compound with the biodegradable polymer (a) and the sulfonamide-based oligomer (b)) to each other is preferably in the form of a triblock or higher order multiblock copolymer, particularly a triblock or pentablock copolymer. Specific examples of the triblock or pentablock copolymer include a compound represented by the following formula 2 (OSM-PCLA-PEG-PCLA-OSM), a compound represented by the following formula 3 (MPEG-PCLA-OSM), and a compound represented by the following formula 4 (OSM-PCGA-PEG-PCGA-OSM) -- see Original Patent.

The block copolymer represented by the formula 3 has a block structure with a sulfamethazine oligomer coupled to only one side thereof, because there is a hydroxyl group at only one end of the copolymer of the PEG-based compound with the biodegradable polymer (MPEG-PCLA).

The temperature- and pH-sensitive block copolymer according to the present invention may contain, in addition to the above-described components, other components or additives which are conventionally used in the art.

To prepare the temperature- and pH-sensitive block copolymer from the copolymer (a) of the PEG-based compound with the biodegradable polymer; and the sulfonamide-based oligomer (b), any polymerization method known in the art, such as radical polymerization, cationic polymerization, anionic polymerization, condensation polymerization or the like, may be used.

One embodiment of a method for preparing the temperature- and pH-sensitive block copolymer according to the present invention comprises the steps of: a) polymerizing a PEG-based compound with a biodegradable polymer so as to prepare a copolymer; b) preparing a sulfonamide-based oligomer from a sulfonamide-based compound; and c) coupling the copolymer of the step a) with the oligomer of the step b).

First, 1) the PEG-based compound is polymerized with the biodegradable polymer so as to form a copolymer. This polymerization reaction can be illustrated by, for example, the following reaction scheme 1 -- see Original Patent.

Ring opening polymerization is preferably used, in which case the polymerization temperature and time are not specifically limited, but are 130-150.degree. C. and 12-48 hours, respectively. Moreover, a catalyst may also be used in the polymerization reaction, and examples thereof include stannous octoate, stannous chloride, metal oxide (GeO.sub.2, Sb.sub.3O.sub.2, SnO.sub.2, etc), aluminum triisopropoxide, CaH.sub.2, Zn, lithium chloride, tris(2,6-di-tert-butylphenolate), and the like. Also, in order to make the magnitude of hydrophobicity wide, the molecular weight or kind of the above-described biodegradable polymer can be suitably controlled.

2) The oligomer is prepared from the sulfonamide-based compound. This reaction can be illustrated by, for example, the following reaction scheme 2 -- see Original Patent.

Examples of a chain transfer agent (CTA) which can be used in the preparation of the sulfonamide-based oligomer include C8-C18 alkyl mercaptans, organic halogen compounds, .alpha.-methylstyrene dimers, terpinolene, .alpha.-terpinene, and the like. The chain transfer agents may be selected depending on purpose. Particularly, mercaptans are preferred because they have high chain transfer constant and chain transfer efficiency.

Any initiator known in the art may be used and examples thereof include, but are not limited to, 2,2'-azobisisobutyronitrile (AIBN), 2,2'-azobis-(2,4-dimethylvaleronitrile), 2,2'-azobis-(4-methoxy-2,4-dimethylvaleronitrile), benzoylperoxide, lauroylperoxide, t-butylperoxypivalate, 1,1'-bis-(bis-t-butylperoxy)cyclohexane, and the like.

For coupling to the copolymer of the PEG-based compound with the biodegradable polymer, the sulfonamide-based oligomer preferably contains, in a molecule, hydrophilic functional groups, for example, hydroxyl, carboxyl or amine groups.

3) The temperature- and pH-sensitive block copolymer according to the present invention can be prepared by the coupling between the copolymer (a) of the PEG-based compound with the biodegradable polymer; and the sulfonamide-based oligomer (b). This coupling reaction can be illustrated by the following reaction scheme 3 -- see Original Patent.

The reaction temperature and time in the step 3) are not specifically limited, and the coupling reaction may be performed by any method known in the art.

The block copolymer prepared by the above-described method can show sensitivity to not only temperature but also pH, because it is in a form where the hydrophilic block, the hydrophobic block, and the sulfonamide-based oligomer which shows a change in ionization degree with a change in pH, are coupled with each other as described above. Actually, in a sulfamethazine-polycaprolactone/lactide-polyethylene glycol-polycaprolactone/lactide-sulfamethazine (OSM-PCLA-PEG-PCLA-OSM) block copolymer prepared by the above-described method, the introduction of functional groups and the reaction of terminal groups could be confirmed by FT-IR and .sup.1H-NMR. Also, it could be confirmed by gel permeation chromatography (GPC) that the molecular weight of the block copolymer was increased, indicating that the copolymer of the PEG-based compound with the biodegradable polymer and the sulfonamide-based compound were coupled with each other.

Also, in order to determine if the block copolymer has pH sensitivity, a change in sol-gel transition behavior was measured while changing pH with temperature, and the measurement results demonstrated that the inventive block copolymer has pH-sensitive characteristics.

In another aspect, the present invention provides a hydrogel composition comprising the inventive block copolymer. This composition may additionally contain other additives and solvent known in the art.

In addition, the present invention provides a new hydrogel formed from the hydrogel composition by changes in temperature and pH. The hydrogel may be applied in various applications in the medical and drug delivery fields.
 

Claim 1 of 15 Claims

1. A block copolymer formed of: (a) a copolymer of a polyethylene glycol (PEG)-based compound and a biodegradable polymer; and (b) a sulfonamide-based oligomer, wherein the sulfonamide-based oligomer (b) contains a hydrophilic functional group selected from the group consisting of hydroxyl and carboxyl groups at a terminal end thereof; wherein the sulfonamide-based oligomer (b) is coupled to only the biodegradable polymer in the copolymer (a) by a direct bond at the hydrophilic functional group; and wherein the block copolymer forms hydrogel by sol-gel transition in accordance with a change in temperature and pH.
 

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