JP3135340B2 - Drug carrier - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug carrier capable of continuously releasing a drug in a living body or a lumen of a living body. More specifically, the present invention relates to a drug carrier that can be easily administered because it is liquid at the administration temperature and that can continuously release a drug because it gels in a living body or a lumen of a living body.

[0002]

2. Description of the Related Art In recent years, a drug delivery system is a drug administration method that supplies a required amount of a drug to a required diseased area for a required time, thereby maximizing the efficacy and minimizing side effects. (Drug Delivery System, DDS)
Is actively being developed. The most typical example is
In vivo implant systems have been developed in which a drug is complexed with various types of matrices and placed in organs, organs, subcutaneous tissues, lumens of a living body, or the like to release the drug slowly.

As an in vivo implant system, an implant in which an anticancer drug is composited with a polymer carrier is directly placed in a cancer lesion, and sustained release of the anticancer drug is expected to reduce tumor size, prolong life, and alleviate cancer pain. Have been developed and have a number of clinical applications. In addition to anticancer drugs, various hormonal drugs, immunostimulants such as interferon and interleukin, narcotic antagonists, anesthetics, and the like are applied to this system.
The in-vivo implant performs sustained release by dispersing a drug in a polymer matrix mainly by physical means and diffusing the drug from the inside of the matrix. Since it is easy to form a complex between a drug and a matrix, there are advantages that the range of the target drug is wide and that the pharmacological activity of the drug is hardly deactivated in the manufacturing process.

In order to clinically apply these in vivo implants, implants having a shape such as a needle, rod, film, or pellet corresponding to the application site must be embedded in the living body by a surgical operation or the like. No.
A dosage form in which such a surgical operation is inevitable is undesirable for clinical application in terms of patient pain, infection, and traces of operation.

[0005] Further, since the implant placed in the living body has various shapes as described above, the action of the released drug is likely to be limited only to the portion in contact with the implant, and the drug concentration distribution at the lesion is not sufficient. Tends to be uniform.

[0006] As described above, the conventional in vivo implant system has various serious problems, and a drug carrier which is easy to administer and which satisfies a sufficient sustained release property has not yet been provided.

[0007]

Accordingly, an object of the present invention is to provide a drug carrier which can be easily administered and can maintain a drug concentration in a living body or a lumen of a living body for a long time.

[0008]

The above object can be attained by a drug carrier characterized in that it is formed of a polymer compound which gels at a temperature lower than the body temperature and is water-soluble at a temperature lower than the gelation temperature. it can.

The polymer compound used in the drug carrier of the present invention may be any substance having the above properties and not harmful in a living body. Preferred as such a polymer compound is a polymer compound in which a temperature-sensitive polymer compound having an LCST and a water-soluble polymer compound are combined.

A temperature-sensitive polymer compound having an LCST is a polymer compound having a negative temperature coefficient of solubility in water, and a hydration dependent on hydrogen bonding between the polymer compound formed at a low temperature and water molecules. (Oxonium hydroxide) is decomposed at a high temperature, and polymer compounds aggregate and precipitate by dehydration. LCST (Lower Critic
al Solution Temperature) refers to a transition temperature of hydration and dehydration of such temperature-sensitive polymer compound (e.g., F Skins (M. H e skins) and Gyuretto (JE
Guillet) , J. Macromol, Sci.-Chem., A2 (8), 1
441 ( 1968 )). That is, the temperature-sensitive polymer compound of the present invention is hydrophilic and soluble in water at a temperature lower than LCST, but becomes hydrophobic and precipitates at a temperature higher than LCST, and this change is reversible. In the present invention, it is necessary that the LCST of the temperature-sensitive polymer compound is lower than the body temperature.

The temperature-sensitive polymer compound used in the present invention includes poly N-substituted acrylamide derivatives, poly N
Substituted methacrylamide derivatives and copolymers thereof, polyvinyl methyl ether, partially acetylated polyvinyl alcohol, and the like can be mentioned. Preferred temperature-sensitive polymer compounds are listed below in ascending order of LCST.

Poly-N-acryloylpiperidine; Poly-N-n-propylmethacrylamide; Poly-N-isopropylacrylamide; Poly-N, N-diethylacrylamide; Poly-N-isopropylmethacrylamide; Poly-N-cyclopropylacrylamide; Acryloylpyrrolidine; poly-N, N-ethylmethylacrylamide; poly-N-cyclopropylmethacrylamide; poly-N-ethylacrylamide The above-mentioned polymer compound may be obtained by polymerizing a single monomer or other monomer. It may be copolymerized with a monomer.
As the monomer to be copolymerized, either a hydrophilic monomer or a hydrophobic monomer can be used. In general, copolymerization with a hydrophilic monomer will increase the LCST of the product, and copolymerization with a hydrophobic monomer will lower the LCST of the product. Therefore, a desired L can be obtained by appropriately selecting these.
A polymer compound having CST can be obtained.

Examples of the hydrophilic monomer include N-vinylpyrrolidone, vinylpyridine, acrylamide, methacrylamide, N-methylacrylamide, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxymethyl methacrylate, hydroxymethyl acrylate, and acidic groups. Acrylic acid, methacrylic acid and salts thereof, vinyl sulfonic acid, styrene sulfonic acid, etc., and basic N, N-dimethylaminoethyl methacrylate, N, N-diethylaminoethyl methacrylate, N, N-dimethylaminopropyl Acrylamide and their salts and the like,
It is not limited to these.

On the other hand, examples of the hydrophobic monomer include acrylate derivatives and methacrylate derivatives such as ethyl acrylate, methyl methacrylate and glycidyl methacrylate, N-substituted alkyl methacrylamide derivatives such as Nn-butyl methacrylamide, vinyl chloride, acrylonitrile, and the like. Examples include, but are not limited to, styrene and vinyl acetate.

On the other hand, the water-soluble polymer compound used in the present invention is not particularly limited as long as it is a water-soluble polymer compound. For example, polyethylene oxide, polyvinyl alcohol, poly-N-vinylpyrrolidone, polyvinylpyridine , Polyacrylamide, polymethacrylamide, poly-N-methylacrylamide, polyhydroxyethyl methacrylate, polyhydroxyethyl acrylate, polyhydroxymethyl methacrylate, polyhydroxymethyl acrylate, polyacrylic acid, polymethacrylic acid, polyvinyl sulfonic acid, polystyrene Sulfonic acid and salts thereof, poly-N, N-dimethylaminoethyl methacrylate, poly-N, N-diethylaminoethyl methacrylate, poly-N, N-dimethylaminopropyl acrylamide And thereof, and the like salts.

The bond between the temperature-sensitive polymer compound having an LCST and the water-soluble polymer compound is obtained by introducing a polymerizable functional group into one of the polymer compounds and forming a monomer that gives the other polymer compound. It can be carried out by copolymerization. For example, a monomer that gives a temperature-sensitive polymer compound having an LCST after reacting acrylic acid chloride at both terminal hydroxyl groups of polyethylene oxide, which is a water-soluble polymer compound, and introducing a polymerizable functional group and an acrylic group, For example, by copolymerizing N-isopropylacrylamide, a conjugate of a temperature-sensitive polymer compound having an LCST at about 30 ° C. and a water-soluble polymer compound can be obtained. In addition, the conjugate of the temperature-sensitive polymer compound having the LCST and the water-soluble polymer compound is a block copolymer of the monomer that gives the temperature-sensitive polymer compound and the monomer that gives the water-soluble polymer compound. It can also be obtained by polymerization. Also, L
The binding between the temperature-sensitive polymer compound having CST and the water-soluble polymer compound can also be carried out by introducing a reactive group into both of them in advance and bonding them by a chemical reaction. At this time, it is necessary to introduce a plurality of reactive groups into the water-soluble polymer compound. For example, N-isopropylacrylamide and N-acryloxysuccinimide are copolymerized to synthesize a temperature-sensitive polymer compound into which a group that easily reacts with a primary amine is introduced, and a primary amino group is added to both ends of the polymer. About 30 ° C. by the reaction of polyethylene oxide, which is a water-soluble polymer compound having
A conjugate of a temperature-sensitive polymer compound having an LCST and a water-soluble polymer compound can be obtained.

The combination of the temperature-sensitive polymer compound and the water-soluble polymer compound is the same as the LCST of the temperature-sensitive polymer compound.
At the following temperatures, the temperature-sensitive polymer compound portion and the water-soluble polymer compound portion are both water-soluble, and are completely dissolved in water. However, when the temperature of the aqueous solution is heated to a temperature equal to or higher than the LCST of the temperature-sensitive polymer compound, the temperature-sensitive polymer compound portion becomes hydrophobic,
It associates between distinct molecules by hydrophobic interactions. On the other hand, since the water-soluble polymer compound portion is still water-soluble at this time, the conjugate has a three-dimensional network structure in water, in which a hydrophobic association portion between the temperature-sensitive polymer compound portions is a crosslinking point. Produces a hydrogel. Since the conjugate has such properties, the drug carrier of the present invention can encapsulate a drug in a living body inside a gel as described below. At this time, the water-soluble polymer compound portion prevents the drug carrier from precipitating and insolubilizing because the hydrophobic bond between the temperature-sensitive polymer compound portions is too strong, so that the drug and the drug carrier are not completely separated. Working. In addition, the temperature of the gelled compound is
When cooled to a temperature lower than the LCST of the temperature-sensitive polymer compound, the temperature-sensitive polymer compound portion becomes water-soluble, the crosslinking points due to hydrophobic association are released, and the hydrogel structure disappears. Thus, the conjugate becomes a complete aqueous solution again.

The drug carrier of the present invention can be complexed with various drugs. As the complexing method, a method in which a uniform aqueous solution of the drug carrier of the present invention is prepared at a temperature equal to or lower than the LCST and mixed with a desired drug is most generally used. The conjugation method is the simplest and has the advantage that the pharmacological activity of the drug is hardly lost during the conjugation process. A plurality of drugs having different medicinal effects can be simultaneously conjugated to the drug carrier of the present invention.

The drug carrier of the present invention complexed with a drug is prepared by injecting or injecting a mixed solution of the drug and the drug carrier of the present invention, which is uniformly mixed at a temperature lower than LCST, into a living body or a lumen of a living body. Can be administered. It is an important feature of the present invention that administration can be performed by such a simple method. As soon as the temperature (body temperature) becomes equal to or higher than the LCST of the temperature-sensitive polymer compound after being administered into a living body or a lumen of a living body, the drug carrier of the present invention gels, and the drug is sealed in the gel. For this reason, the retention property of the drug in the living body or the lumen of the living body is remarkably improved, and at the same time, the drug inside the gel is gradually released by the diffusion phenomenon.

Since the drug carrier of the present invention is liquid at the time of administration, unlike conventional in vivo implants, it can be injected without performing surgery or the like, and after injection, the drug can reach every corner of the trunk. It is possible. Further, the gel in the living body or in the lumen of the living body is flexible unlike the conventional implant material in the living body, and the mechanical damage to living tissues and organs is remarkably reduced.

[0021]

【Example】

(1) Synthesis of poly (N-isopropylacrylamide-co-N-acryloxysuccinimide) as a temperature-sensitive polymer compound 10.2 g of N-isopropylacrylamide, 1.71 g of N-acryloxysuccinimide and chloroform 40
After dissolving in 0 ml and purging with nitrogen, 0.135 g of N, N'-azobisinbutyronitrile was added and polymerized at 60 ° C for 6 hours. After concentration, the precipitate was reprecipitated in diethyl ether. Agglomerated, vacuum dried and 8.8 g of poly (N-isopropylacrylamide-co-N-acryloxysuccinimide)
I got (2) The poly (N-isopropylacrylamide-co-
Coupling of N-acryloxysuccinimide) and polyethylene oxide at both ends as a water-soluble polymer compound 1.0 g of poly (N-isopropylacrylamide-co-N-acryloxysuccinimide), polyethylene oxide at both ends with a molecular weight of 6 0.5 g of Kawaken Fine Chemical Co., Ltd.) was dissolved in 100 ml of chloroform and reacted at 50 ° C. for 3 hours. After cooling to room temperature,
0.1 g of isopropylamine was added and left for 1 hour.
After concentration, it was precipitated in diethyl ether. Agglomeration and vacuum drying gave 1.5 g of the drug carrier of the present invention.

0.5 g of the drug carrier was dissolved in 10 ml of distilled water under ice cooling. When this aqueous solution was gradually heated, it lost its fluidity at about 30 ° C. or higher and gelled. When the gel is cooled, it regains its fluidity below about 30 ° C,
It returned to the aqueous solution again. This change was observed reversibly and repeatedly.

(3) Combination of the drug carrier and 5-florouracil (hereinafter abbreviated as 5-FU) having anti-pyrimidine metabolic activity as an anticancer drug in a glass test tube having a capacity of about 10 ml (inner diameter: 7 mm) After dissolving 0.2 g of the drug carrier in 1 ml of physiological saline at room temperature, about 1 mg of 5-FU (Kyowa Hakko Co., Ltd.) is added to the solution and completely dissolved by shaking.
The test tube containing the solution was transferred to a bath at about 37 ° C., and allowed to stand for 5 minutes to form a gel containing 5-FU. Next, 5-F
In order to simulate the in vivo release of 5-FU from the U-containing gel, about 5 ml of pre-warmed 37 ° C. serum from home immunity was added to a test tube maintained at 37 ° C. and shaken. The amount of 5-FU migrating into the serum was quantified by the method described below, and the amount of 5-FU remaining in the gel was estimated.

To 1 ml of the serum collected at each time, 0.1 ml of 60% perchloric acid was added and shaken for 2 minutes.
After high-speed centrifugation at 10 rpm for 10 minutes, 0.2 ml of the upper layer was collected, added with 0.2 ml of ethyl acetate, and centrifuged at 3000 rpm for 10 minutes. 20 to 60 μl of the lower layer was collected, and 5-FU was quantified by high performance liquid chromatography (HPLC). HPLC calibration curve is 5-FU
A known amount of (Kyowa Hakko Co., Ltd.) was dissolved in serum and prepared in the same manner as described above. HPLC measurement was carried out using a Shimadzu high-performance liquid chromatography apparatus as a stationary phase with a strongly acidic cation exchange resin (Shimadzu, 4 mm inside diameter × 15 cm length)
And using a 0.02 M aqueous solution of monosodium phosphate as a mobile phase.

As a result of measuring the residual ratio of 5-FU in the gel by the above method, it was found that the residual amount of 5-FU in the gel was 50% of the initial value.
Was about 25 hours.

The residual behavior of 5-FU in a living body was examined by administering 5-FU to a vein of a home immune system and then measuring the residual of 5-FU in serum or living tissue by HPLC. As a result, the residual ratio in serum decreased to about 50% in 10 to 20 minutes, the residual ratio in tissues decreased to 50% in 20 to 30 minutes, and the disappearance of 5-FU in the living body was very short. (Ikuo Katsumata, Dentistry)
70 (5) , 869, 1983).

Therefore, the residence time of 5-FU in a living body can be significantly prolonged by using the gel of the present invention.

[0028]

Since the drug carrier of the present invention is liquid at the administration temperature, it can be easily administered orally, injected, or injected by catheter. In addition, since the gel is instantaneously formed in the lumen of the living body or in the living body, the release control of the drug and the bioavailability can be increased. For this reason, it is possible to maintain a continuous effective concentration, maximize the efficacy of the drug, and reduce side effects.

Continuation of front page (56) References JP-A-3-83914 (JP, A) JP-A-59-219217 (JP, A) JP-A-5-16114 (JP, A) WO 91/19481 (WO, A1) WO 87/6152 (WO, A1) Controlled Release, Vol. 4 (1986), p. 213-222 Controlled Release, Vol. 6 (1987), p. 297 -305 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/00-9/72 A61K 47/00-47/48 CA (STN) MEDLINE (STN) WPI (DIALOG)

Claims (6)

(57) [Claims] 1. A temperature-sensitive polymeric moiety <br/> having LCST, a polymer compound composed of a water soluble polymer moiety; temperature-sensitive polymeric moiety having the LCST is one molecule Of multiple blocks or grafts in the polymer
Consists compound, gelled below body temperature, in the gelation temperature below the temperature shows a water-soluble, and, at higher than the LCST temperature
A drug carrier which produces a hydrogel . 2. A temperature-sensitive polymer having the LCST.
One of the polymer part and the water-soluble polymer part
More than one monomer to give the other polymer part
The compound according to claim 1, which is copolymerized with the above repeating unit.
Rug carrier. 3. The temperature-sensitive polymer having the LCST
Two or more repeating units of the monomer giving the moiety, and
Two or more repeating units of a monomer that gives a polymer moiety
The drug carrier according to claim 1, comprising: 4. Two or more repetitions having said LCST
Unit of temperature-sensitive polymer part and two or more repeating units
Of water-soluble polymer by chemical reaction
The drug carrier according to claim 1 . 5. It is substantially insoluble in rabbit serum at 37 ° C.
The drug carrier according to any one of claims 1 to 4.
- 6. A temperature sensitive device having said plurality of LCSTs.
Water-soluble polymer part is placed between polymer parts
The drug carrier according to claim 1.