KR100482650B1 - Locallly implantable anticancer agent using self-microemulsion system - Google Patents

Abstract

The present invention relates to a topical implantable anticancer agent using a self-emulsifying emulsion system, and more specifically, to a pharmaceutical composition composed of a biodegradable polymer capable of sustaining the release of nitrosourea-based anticancer agents and anticancer agents. And is formulated in the form of a disc with the addition of a surfactant, and when exposed to an aqueous phase (water, blood) in biological tissues, the oil and the contrast agent spontaneously form a protective layer that inhibits the hydrolysis of the anticancer agent. The present invention relates to a topical implantable anticancer agent which has an effect of enhancing the stability of an anticancer agent by an emulsion system.

Description

Locally implantable anticancer agent using self-microemulsion system

The present invention relates to a topical implantable anticancer agent using a self-emulsifying emulsion system, and more specifically, to a pharmaceutical composition composed of a biodegradable polymer capable of sustaining the release of nitrosourea-based anticancer agents and anticancer agents. And is formulated in the form of a disc with the addition of a surfactant, and when exposed to an aqueous phase (water, blood) in biological tissues, the oil and the contrast agent spontaneously form a protective layer that inhibits the hydrolysis of the anticancer agent. The present invention relates to a topical implantable anticancer agent which has an effect of enhancing the stability of an anticancer agent by an emulsion system. In addition, the anticancer agent of the present invention has a sustained release property by using a biodegradable polymer for the purpose of sustained release of a self-emulsifying system.

Nitrosourea-based anticancer agent, which is the most widely used brain chemotherapeutic agent, especially BCNU (1,3-bis (2-chloroethyl) -1-nitrosourea), known as carmustine, Due to its lipid solubility and low molecular weight, it is thought to be able to penetrate the vascular-brain membrane to some extent during systemic administration, and thus the drug transition from the circulatory system to the brain is possible. This is known to be very low. In addition, depending on the dosage, it causes serious side effects such as bone marrow suppression, pulmonary fibrolysis and kidney toxicity. To remedy these shortcomings, sustained-release brain tumor treatments using biodegradable polymers have been developed and based on biodegradable polymers, polyanhydrides, such as Taxol, Camptothecin, or Carmustine. Formulations containing are disclosed in US Pat. No. 5,626,862. This is a formulation that can overcome the problem of conventional non-degradable polymer remaining in the body. Among these drugs, polyanhydride formulations containing carmustine are commercialized and marketed under the trade name Gliadel ^?? . However, Gliadel also does not provide stability of anticancer drugs against water and blood, and the released anticancer drugs are decomposed and do not exhibit drug effects, and they also show a limited penetration into tissues.

Meanwhile, it has been reported that covalent compounds of drugs and drug carriers can enhance brain tissue permeability and anticancer stability [Dang, WB, Covalent coupling of methotrexate to dextran enhances the penetration of cytotoxicity into a tissue-like matrix. Cancer Research, 54, 1729-1735. 1994]. In addition, reports of measuring the rate of loss of carmustine and immunoglobulin G (immunoglobulin G, IgG) into the bloodstream according to the molecular weight [Chi-Hwa Wang, The delivery of BCNU to brain tumors, journal of controlled release, 61, 21-41. 1999] has a low molecular weight (MW = 214) and a short half-life, whereas the immunoglobulin G has a very high molecular weight (MW = 146,000) and a molecular weight of 10 ⁶ times smaller than that of carmustine. Small carmustines have been reported to have a high rate of loss in the bloodstream, resulting in reduced tissue permeation.

Therefore, the present invention aims to develop a new anticancer agent that can enhance the stability of carmustine by enhancing the brain tissue permeability of the anticancer agent and reducing the hydrolysis of carmustine in the blood.

Therefore, the present inventors formulated a pharmaceutical composition comprising a biodegradable polymer capable of sustaining the release of a nitrosourea anticancer agent and an anticancer agent, and formulating an osmotic agent, a contrast agent, and a drug carrier, an oil and a surfactant, as a disk-shaped solid phase preparation, and transplanting the body. When the agent comes into contact with water (blood, blood) in the tissues of the body, the nitrosourea-based anticancer agent is equipped with a self-emulsifying emulsion system in which oils and contrast agents form a protective layer that inhibits the hydrolysis of the anticancer agent. It was found that stability in water phase (water, blood) is enhanced, thus completing the present invention.

In addition, the present invention can enhance the cytotoxic effect of the anticancer agent by increasing the osmotic pressure around the tumor cells using the contrast agent as an osmotic agent, and by using a specific oil as a drug carrier to inhibit the hydrolysis of the anticancer agent to improve the safety of the anticancer agent The purpose of the present invention is to provide a topical transplantable anticancer agent using a self-emulsifying emulsion system.

The present invention provides a pharmaceutical composition comprising a nitrosourea-based anticancer agent and a biodegradable polymer, containing 1-10 wt% of a contrast agent, 1-10 wt% of an oil selected from a fatty acid derivative having 4 to 18 carbon atoms, and 0-3 wt% of a surfactant. It is characterized by a topical implantable anticancer agent using a self-emulsifying emulsion system, which is formulated into a solid phase preparation in the form of a disc.

The present invention is a biodegradable topical type anticancer agent which improves the stability of drugs by preventing the nitrosourea anticancer agent from being hydrolyzed by blood or water by a self-emulsifying emulsion system composed of an implantable oil and a contrast agent. The present invention relates to an improved invention of the topical anti-cancer agent added with osmotic inducer of Korean Patent Application No. 2002-49074, filed by the present inventors, which has the greatest characteristics in securing the stability of a nitrosourea-based anticancer agent. Have

Hereinafter, the present invention will be described in detail.

First, the contrast agent used as an osmotic induction agent in the anticancer agent of the present invention is as follows.

In general, the contrast agent is used for the purpose of contrasting various blood vessels such as cerebrovascular and cardiovascular vessels, and as a condition of the contrast agent, stability to the human body is an absolute condition. The contrast agent names mono and di iodine contrast agents as the first generation contrast agents, ionic triiode contrast agents are classified as second generation contrast agents, and nonionic triiode contrast agents are classified as third generation contrast agents. The second generation contrast agent is typically used iotalamet (trade name: Conlay), amidotorizoate (eurographine, etc.), yodamido (Konra Kissing), metrizoade (isopec), etc. Since these second-generation contrast agents are ionic, the osmotic pressure is high (usually 3 to 5 times the plasma osmotic pressure in the range of use concentration), and it is possible to use the second-generation contrast agent as the osmotic pressure-inducing agent. The third generation of contrast agents include water-soluble contrast agents, such as iohexel (omnipaque), iofamido (iopamiron), oki saguret (hexabrix), and ioversor (opti-ray), and iodide keji oil (lipiodol). It is classified as a fat-soluble contrast agent, and can be used as a substance for enhancing stability in drugs that are unstable to hydrolysis such as carmustine.

Among these contrast agents, water-soluble contrast agents and fat-soluble contrast agents may be used in the anticancer agent of the present invention. For example, as the water-soluble contrast agents, iocarmic acid, iocetamic acid, iodixanol, and i-dodohydroxide sodium (o-iodohippurate sodium), iodopyracet, ioglycamic acid, iohexol, iopamidol, iopentol, iotrolan, ioversol, i Oxylan (ioxilan) can be used, and fat-soluble contrast agents such as iobenzamic acid (iobenzamic acid), iodipamide (iodipamide), iodized oil (lipiodol), iodoalphionic acid (iodoalphionic acid), Talein sodium (iodophthalein sodium), iomeglamic acid, iopanoic acid, iophendylate, ipodate, iodide, iophenoxic acid), iopromide, Ofonic acid (iopronic acid), iopydol (iopydol), iopydone (iopydone), iothalamic acid (iothalamic acid), ioxaglic acid (ioxaglic acid) can be used, one selected from the above water-soluble and fat-soluble contrast agents The above can be used.

The contrast agent is preferably added in an amount of 1 to 10% by weight to the anticancer agent of the present invention. If the amount is less than 1% by weight, there is a problem in securing the stability of the anticancer agent. The problem is that the contrast agent falls into the sedimentation, causing side effects in the tissue or in the blood.

In the anticancer agent of the present invention, the oil capable of forming the protective layer of the anticancer agent may be a low molecule, a medium molecule, or a polymer derived from mono, di, or triglycerides. Preferably, fatty acid derivatives derived from triglycerides may be those having 4 to 18 carbon atoms, and tributyline, tricafline, and the like may be used, and vegetable oils or derivatives thereof, animal oils or derivatives thereof, and transplanted into tissues Alternatively, synthetic oils that can be injected can be used. The oil is preferably added in an amount of 1 to 10% by weight to the anticancer agent of the present invention. If the amount is less than 1% by weight, the effect of coating and stabilizing the anticancer agent is weak and there is a problem in that the stability of the anticancer agent cannot be secured. If it exceeds 10% by weight, the fluidity of the formulation is increased, there is a problem that can not be solidified.

In addition, since the addition of a surfactant to the anticancer agent of the present invention may facilitate the formation of a self-emulsifying emulsion, the anticancer agent may be added in an amount of 0 to 3% by weight, and the surfactant may be a polyethylene glycol derivative (CRE). Morpho), polysorbitan-based (Tween 20, 25, 60, 80, 85), sorbitan-based (span 60, 80), polypropylene glycol aliphatic derivatives, and the like. If the amount of the surfactant exceeds 3% by weight, the surfactant may exhibit side effects that may cause toxicity problems in the tissue.

Anticancer agents that can be applied to the present invention include Nimustine, Carmustine, Lomustine, Chlorozoticin, Streptozoticin, MeCCNU (methyl chloroethyl cyclohexyl nitrosourea) and PCNU One or more nitrosourea anticancer agents selected from (piperidyl chloroethyl nitrosurea) and derivatives thereof may be used. The nitrosourea-based anticancer agent is preferably contained in the anticancer agent of the present invention in an amount of 0.01 to 50% by weight. Sufficient amount of anticancer agent is hard to be released, and if it exceeds 50% by weight, the fluidity of the mixture is increased due to the increase in the amount of oil required to form the stabilizing coating layer of the anticancer agent, making it impossible to formulate a disk.

Biodegradable polymeric inclusions for inclusion and sustained release implants include polylactide, polyglycolide, lactide-glycolide copolymers, polyhydroxybutyric acid, polycaprolactone, polyanhydrides, polyalkyls Cyanoacrylate, polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer or polysaccharide may be used, and the polymer is a biodegradable polymer, which is decomposed by moisture and enzymes in the body to produce a low molecular substance that is harmless to the human body. Because. In addition, the biodegradable polymer preferably has a weight average molecular weight of 5,000 to 100,000, and the polymer having a molecular weight of less than 5,000 has a short decomposition period and does not have an effect as a sustained release preparation. When the molecular weight exceeds 100,000, the decomposition period of the polymer is too long. There is a problem in that it is difficult to release an effective concentration of drug for a desired period of time. The biodegradable polymer is preferably added to the anticancer agent of the present invention in an amount of 30 to 97.99% by weight, and if the addition amount is less than 30% by weight, the initial release of the anticancer agent may cause the slow release of the anticancer agent of the present invention. There is a problem, and when the content exceeds 97.99% by weight, the content of the effective anticancer agent is so low that it is difficult to prepare a formulation capable of releasing the anticancer agent above the concentration effective for treatment.

The anticancer agent according to the present invention using the above components ensures the stability of the drug by inhibiting hydrolysis of the anticancer agent using a self-emulsifying emulsion system. Topical implantable anticancer drugs using existing biodegradable polymers, in particular, anticancer agents that are rapidly decomposed by moisture in vivo, such as carmustine, are formulated by mixing with biodegradable polymers. The released anticancer drug is decomposed before exposure to body fluids and sufficient effect, and therefore the transition to cancer tissue is limited. A self-emulsifying emulsion system is a homogeneous mixture of liquid or solid state in which an aqueous phase (water) has been removed from existing emulsion components, which meets the aqueous phase and easily forms a microemulsion by weak force. The system consisting of the anticancer agent, oil, contrast agent and biodegradable polymer of the present invention spontaneously forms an emulsion in the aqueous phase of the tissue while forming a lipid coating layer that protects the anticancer agent released from the agent when the agent is administered by implantation. It is characterized by a system to achieve the effect of improving the stability by the lipid coating layer.

In addition, the manufacturing method of the disc containing the self-emulsifying emulsion system using the above-mentioned components can be administered by transplantation to the tumor site or the site from which the tumor is removed at the time of the procedure by the direct compression method known to those skilled in the art. It is preferable to formulate in the form of a disc having a diameter of 1 to 20 mm and a thickness of 0.1 to 5.0 mm, because the implantable sustained release preparation should have sufficient durability in the transplanted tissue and take into account the size of the lesion site. That is, it is necessary to determine and use a disk of appropriate size according to the size of the tumor and the tumor removal site.

In addition, the anticancer agent may be administered by transplantation to the tumor or the site from which the tumor is usually removed, and a single dose may range from 10 to 2,000 μg / kg body weight, preferably 100 to 1,000 μg / kg body weight. It is preferable to determine the number of agents to be administered in consideration of conditions such as the size of the tumor or the size of the tumor removal site to adjust the dosage once. However, it should be understood that the actual dosage of the active ingredient should be determined in light of several relevant factors such as the disease to be treated, the patient's age, sex and weight, and the severity of the disease, and therefore the dosage can be viewed in any way. It is not intended to limit the scope of the invention.

Hereinafter, the present invention will be described in more detail based on Examples, but the present invention is not limited to the Examples.

First, in order to confirm the stability of the anticancer agent of the present invention, the contrast agent, the oil, the surfactant and the anticancer agent were mixed as in Examples 1 to 5 and Comparative Example 1, and then the stability of the anticancer agent was measured under certain conditions.

Example 1

Lipiodol (contrast): Tricaplin (oil) is mixed at a weight ratio of 1: 9, and the ratio of carmustine (anticancer agent) and the mixture is mixed at a ratio of 1:10 by weight to form a phosphate buffer solution (PBS) of pH 7.4. Into a vial containing 20 ml of light, and after stirring for a certain period of time at 37 ℃ and 60 rpm, take a certain amount and add acetonitrile to measure stability using HPLC. It was.

Example 2

Iopanoic acid (contrast): Tricaplin (oil) is mixed in a 1: 9 weight ratio, and then the mixture of carmustine and the mixture is remixed in a 1:10 weight ratio to form a phosphate buffer solution (PBS) at pH 7.4 20 After putting in a vial containing the light containing ml and stirring at a speed of 37 ° C. and 60 rpm, a certain amount was taken, and then a certain amount was added to acetonitrile, and stability was measured using HPLC. .

Example 3

Lipiodol (contrast agent): Iopanoic acid (contrast agent): tricaplin (oil) is mixed in a 1: 1: 8 weight ratio, and the ratio of carmustine and the mixture is remixed in a 1:10 weight ratio to obtain a pH 7.4 phosphate buffer solution ( phosphate buffer solution (PBS) was added to a vial containing 20 ml of light, and then stirred at 37 ° C and 60 rpm for a certain period of time. Stability was measured using.

Example 4

Lauroglycol 90 (Surfactant): Iopanic acid (contrast agent): Tricaplin (oil) was mixed in a 0.5: 1: 7.5 weight ratio, and the ratio of carmustine and the mixture was remixed in a 1:10 weight ratio to pH 7.4. Put in a vial containing 20 ml of phosphate buffer solution (PBS) and then block it at 37 ° C and 60 rpm. Stability was measured using HPLC by adding thereto.

Example 5

Cremophor RH 40 (Surfactant): Iopanic acid (contrast agent): Tricaplin (oil) were mixed in a 1.5: 1: 7.5 weight ratio, respectively, and the ratio of carmustine and the mixture was remixed in a 1:10 weight ratio. Into a light-blocked vial containing 20 ml of 7.4 phosphate buffer solution (PBS), stirred at 37 ° C and 60 rpm. Nitrile was added to measure stability using HPLC.

Comparative Example 1

Carmustine alone was added to a light-blocked vial containing 20 ml of phosphate buffer solution (PBS) at pH 7.4, followed by stirring at 37 ° C and 60 rpm. After taking a certain amount of acetonitrile was added to measure the stability using HPLC.

The results of Examples 1 to 5 and Comparative Example 1 are shown in FIG. 1. As shown in FIG. 1, the self-microemulsifying system including carmustine according to the present invention has a half-life of carmustine as compared to 45 minutes (comparative example 1). It was effective in improving the stability of Stine. In particular, the use of iopanoic acid as a contrast agent was more effective in improving the stability of carmustine.

Experimental Example 1

Lactide glycolide copolymer (hereinafter referred to as PLGA5050-8K) having a molar ratio of lactic acid and glycolic acid of 50:50 in Example 1 (hereinafter referred to as PLGA5050-8K), 3.85 wt% of carmustine, 0.77 wt% of contrast agent (lipiodol) %, 6.93% by weight of oil (tricaplin) was vortex-mixed to prepare an anticancer composition having a uniform content of carmustine. 25 mg of the anticancer agent composition was stipulated using a mesh of 425 μm, put into a mold, and molded using a compactor to prepare a disc having a diameter of 5 mm and a thickness of 1 mm. At this time, all the experimental conditions were made in the state of blocking the light. Drug release experiments were conducted over time from the prepared formulations. At this time, since carmustine is easily decomposed in an aqueous solution, after a predetermined time, the amount of carmustine remaining on the disk was measured to convert the amount of drug released. First, the disk prepared above was immersed in a pH 7.4 phosphate buffer solution (PBS) and stirred at a speed of 37 ° C. and 60 rpm, and then the disk was extracted from the release test solution and lyophilized. . A dry disk was added to methylene chloride to dissolve the biodegradable polymer and drug, and methanol was slowly added to precipitate the biodegradable polymer, which was then removed by centrifugation. The supernatant containing the drug was taken and analyzed at UV wavelength 248 nm using HPLC. It was.

Experimental Examples 2 to 5 and Comparative Example 2

In Experimental Examples 2 to 5, the nitrosourea anticancer agent (disc) was prepared in the same manner as in Experimental Example 1 with the composition and content shown in Table 1 below, and the release amount of the anticancer agent was measured by the same method as in Experimental Example 1. .

The results of Experimental Examples 1 to 5 and Comparative Example 2 are shown in FIG. 2. As shown in FIG. 2, the release pattern of the disc containing the self-emulsifying emulsion system including carmustine was the same as that of the disc containing only carmustine, and the release rate was improved.

As described above, the anticancer agent according to the present invention introduces the concept of a self-emulsifying emulsion system in which an oil, a contrast agent and a surfactant spontaneously in an aqueous solution (water, blood) form a protective layer to inhibit the hydrolysis of the anticancer agent. It is possible to improve the permeability of brain tissue by securing the safety of anticancer drugs and the transition to blood flow, and by increasing the osmotic pressure around tumor cells by using a contrast agent as an osmotic inducer, it can enhance the cytotoxic effect of anticancer drugs. A topical transplant anticancer agent capable of controlling the release of carmustine contained in a biodegradable polymer can be provided.

Figure 1 shows the stability test results of the anticancer agent according to the embodiment of the present invention.

Figure 2 shows the release trend of the anticancer agent according to the experimental example of the present invention.

Claims (6)

A pharmaceutical composition comprising a nitrosourea-based anticancer agent and a biodegradable polymer contains 1-10 wt% of contrast agent, 1-10 wt% of oil selected from fatty acid derivatives having 4 to 18 carbon atoms, and 0-3 wt% of surfactant. Topical anticancer agent using a self-emulsifying emulsion system, characterized in that it is formulated as a solid phase preparation. The method of claim 1, wherein the nitrosourea-based anticancer agent is nimustine, carmustine, lomustine, chlorozoticin, streptozothycin, methylchloroethylcyclohexyl nitrosourea, piperidylchloroethylnitrosourea A topical transplant type anticancer agent using a self-emulsifying emulsion system, characterized in that at least one selected from and derivatives thereof. The method of claim 1, wherein the contrast agent is iocamic acid, iocetamic acid, yoddixanol, o- iodohypurate sodium, iodopyracet, ioglycamic acid, iohexol, iopamidol, iotrolan, ioversol, ioxane, Iobenzamic acid, Iodipamide, Iodidide Oil, Iodoalfionic Acid, Iodophthalein Sodium, Iomeglymic Acid, Iopanoic Acid, Iopenedylate, Ipodate, Iodide, Iofenoxic Acid, Iopromide Local transplantation type anticancer agent using automicroemulsion type emulsion system, characterized in that at least one selected from, iopronic acid, iopidodol, iopidone, iotalamic acid and dioxaglinic acid. According to claim 1, wherein the oil is a fatty acid derivative derived from triglycerides having 4 to 18 carbon atoms, tributyl, tricaplin, vegetable oils and derivatives thereof, animal oils and derivatives thereof, synthetic oils that can be orally administered Local transplantation type anticancer agent using an auto-microemulsion emulsion system, characterized in that at least one selected from. The method of claim 1, wherein the surfactant is a polyethylene glycol derivative (cremopore, polysorbitan-based (Tween 20, 25, 60, 80, 85), sorbitan (span 60, 80) and a grafted anticancer agent using a self-emulsifying emulsion system, characterized in that at least one selected from propylene glycol aliphatic derivatives. The method of claim 1, wherein the biodegradable polymer is selected from polylactide, polyglycolide, lactide-glycolide copolymer, polyhydroxybutyric acid, polycaprolactone, polyanhydride and polyalkylcyanoacrylate A topical transplant anticancer agent using an auto-emulsifying emulsion system, characterized in that the average molecular weight of 5,000 to 100,000.