KR20090115269A - Sustained released polymer nanoparticle formulation containing water-insoluble drugs - Google Patents

Abstract

PURPOSE: A controlled-release polymer nanoparticle formulation and an agent containing the same for oral administration and injection are provided to improve elution rate of biphenyl-dimethyl-dicarboxylate(BDD) which is water-insoluble drug and effectively treats liver diseases. CONSTITUTION: A controlled-release polymer nanoparticle formulation comprises a polymer nanoparticle in which biphenyl dimethyl dicarboxylate(BDD) is dipped to biodegradable polymer and poly-D-lactic acid-co-glycolic acid(PLGA). The ratio of BDD and PLGA is 0.5-5:10-100 weight parts. The polymer nanoparticle further comprises an emulsifier coating layer.

Description

 Sustained released polymer nanoparticle formulation containing water-insoluble drugs

The present invention relates to a sustained release polymer nanoparticle formulation containing biphenyl-dimethyl-dicarboxylate (BDD), a poorly soluble drug.

Chronic diseases should be taken for a long time for the prevention and treatment. In this case, even a small amount of a single dose of the drug causes side effects due to long-term accumulation in the body. In the case of poorly soluble drugs, the dissolution rate is low, so that a large dose is administered in a single dose, and the administration of poorly soluble drugs in chronic diseases is an important problem to prevent side effects. In addition, since it is necessary to take a long time to administer several times a day is inconvenient to the user, it is effective to develop a sustained release formulation to reduce the frequency of administration and to maintain a constant concentration of the drug in the blood for a long time.

For example, Biphenyl-Dimethyl-Dicarboxylate (hereinafter referred to as "BDD") drugs can treat hepatitis and protect the liver, and are clinically known as serum transaminase, especially serum glutamine. It has a function of lowering the activity of pyruvate transaminase (Serum glutamic pyruvic transaminase; SGPT) (Lee Hyo-seok et al., Journal of the Korean Society of Internal Medicine, Vol. In addition, animal experiments have shown that there is a protective action against liver damage caused by carbon tetrachloride or thioacetamide toxicity, and cytochrome P ₄₅₀ 2B1 mRNA and benzyloxy resorphin-O-dialkylase (benzyloxyresorufin- It has been shown to increase O-dealkylase activity and to have free radical removal.

However, it is known that the compound is very poorly soluble in water (2.0-4.0 [mu] g / ml), has a very low dissolution rate, and has a bioavailability of only 20-30% when taken in tablet form (Kim HJ et. al ., J Kor Pharm Sci Vol. 30, No. 2: 119-125, 2000). The BDD-based liver disease treatment agent has a drawback in that the amount of elution in the body is so low that the bioavailability is extremely low.

On the other hand, researches to increase the solubility through physical or chemical modification in order to improve the absorption rate of poorly soluble drugs have been extensively carried out, in particular to enable oral administration of poorly soluble drugs through physical modification to nano-crystallize the crystal of the drug. Research is underway (Khang KS et al . , Polymer Science and Technology 13 (3) 342-359, 2002). In addition, various experiments have been reported for supporting drugs in biodegradable polymers to increase bioavailability of drugs and to sustain long-term effects.

For example, Korean Patent Laid-Open Publication No. 2005-0038224 discloses poorly soluble drugs in "oral microemulsion compositions containing biphenyldimethylcarboxylate and cardios marianus extract or silybin purified therefrom, which are useful for treating liver disease. The addition of additives (cosurfactants, surfactants and oils) to the dissolution rate was increased, indicating that the treatment effect of liver disease (chronic disease) is increased with increasing bioavailability.

In addition, Korean Patent Laid-Open Publication No. 1997-0058726 improves the initial release of large amounts of water-soluble drugs by uniformly distributing water-soluble protein drugs to biodegradable polymers and recoating the drug particles or biodegradable polymer matrix with biocompatible hydrophobic materials. One sustained release formulation is described.

However, the increased dissolution effects, sustained release effects, etc. of these formulations still do not meet expectations.

Accordingly, the present inventors prepared a BDD-based poorly soluble liver disease therapeutic drug in an oil- or crystalline-type formulation impregnated again inside an oil-based polymer dispersed in an aqueous solution having a uniform particle size distribution of nanoparticle size. By improving the dissolution rate by increasing the surface area and providing a sustained release formulation that can be continuously released for a long time, the problem of having to continuously take an excessive dose due to the low amount of the dissolution of the conventional BDD-based poorly soluble drugs in the body and consequently lowered the bioavailability By finding out that the amount of drug can be reduced by completing the present invention.

An object of the present invention is to provide a sustained release polymer nanoparticle formulation containing biphenyl-dimethyl-dicarboxylate (BDD), a poorly soluble drug for treating liver disease.

In order to achieve the above object, the present invention provides a sustained-release polymer nanoparticle formulation of a narrow and uniform particle size distribution impregnated in the poorly water-soluble drug BDD biodegradable polymer nanoparticles and coated with an emulsifier on the surface.

The BDD-containing sustained-release polymer nanoparticle formulation of the poorly soluble drug for treating liver disease according to the present invention improves the dissolution rate of the poorly soluble drug, BDD, increases the bioavailability, and gradually releases the drug to a constant concentration in the blood. By long-term maintenance, it can be effectively used for the treatment of liver disease, and it is possible to reduce the excessive amount of BDD due to the decrease in the body dissolution and bioavailability of the conventional BDD-containing formulation.

Hereinafter, the present invention will be described in detail.

The present invention provides a biodegradable polymer nanoparticle formulation containing biphenyl-dimethyl-dicarboxylate (hereinafter referred to as "BDD"), a poorly soluble drug for treating liver disease.

The BDD-containing biodegradable polymer nanoparticle formulation according to the present invention may further comprise a layer of amphipathic (having both hydrophilic and lipophilic groups) emulsifier on the surface.

Biodegradable polymer nanoparticle formulations containing BDD, a poorly soluble drug of the present invention, have a particle size variation of 0 to 30 nm, more preferably, particle size variation of 5 to 25 nm, and an average of 200 nm or less. Have a particle size (see FIGS. 1-3). As a result, the dissolution rate can be increased by increasing the surface area of the poorly soluble drug contained in the nanoparticle formulation. In addition, an amphiphilic emulsifier layer is added to the surface of the biodegradable polymer nanoparticles in which oil-soluble drugs are dissolved, so that they may be uniformly dispersed in an aqueous solution, and thus prepared in a very small size. It enables redispersion into particles and provides the advantage of ensuring uniformity in size of the biodegradable polymer impregnated with BDD during storage.

Biodegradable polymer nanoparticle formulation of the present invention can be prepared by the following method.

Biodegradable polymer nanoparticle formulation according to the present invention uses the form of oil-in-water (o / w) as an emulsion method, specifically in the oil phase or crystals inside the oil phase polymer dispersed in an aqueous solution Impregnation of BDD, a poorly soluble drug in the stomach. This will be described in detail as follows. First, the biodegradable polymer is dissolved in a nonvolatile polar organic solvent (step 1), and then a dispersion is prepared by adding BDD, a poorly soluble drug, to water in oil or crystalline water (step 2), and then Under a stirring condition, the dispersion is added to an aqueous solution of an emulsifier (step 3) to prepare a dispersion in which nano-sized polymer particles containing BDD are dispersed. Filtration of this dispersion quickly removes the emulsifier and organic solvent through the membrane and separates the polymer nanoparticles. The separated nanoparticles are lyophilized to obtain nanoparticle powders. The low mechanical energy level of agitation conditions is preferably 50 to 5000 rpm.

The polymer nanoparticle formulation containing the poorly soluble drug according to the present invention will be described in detail.

(1) poorly soluble drugs

The poorly soluble drug may be used without particular limitation as long as the drug is eluted due to low solubility and becomes a rate controlling step of bioavailability. Preferably, BDD (Biphenyl-Dimethyl-Dicarboxylate), DDB (Dimethyl Dimethoxy Biphenyl Dicarboxylate, dimethyldimethoxybiphenyldicarboxylate), etc., which are agents for treating liver disease, may be used. (Griseofulvin), Digoxin, Dipyridamole, Spironolactone, Cyclosporin, Amphotericin B, Fluorouracil, Etoposide Etoposide, 6-mercaptopurine, dexamethasone, and perphenasine do not exclude drugs that are poorly soluble in water.

The poorly soluble drug of the present invention can be used as long as it is mixed with the biodegradable polymer and mixed in the organic solvent. It is preferable that the organic solvent is a nonvolatile polar organic solvent. In particular, the polarity is similar to water and is a pharmaceutically acceptable solvent having a high affinity with water. For example, dimethyl sulfoxide (DMSO), dimethyl foramide (DMF), dimethylacetamide (Dimethyl) acetamide; DMAc), N-methyl-2-pyrrolidone (NMP), pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro- Non-volatile solvents such as 2 (1H) -pyrimidinone [1,3-Dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU), Hexamethylphosphoramide (HMPA) May be used alone or in combination, but is not limited thereto. Among these, dimethylacetamide (DMAc) is more preferable. If the solvent is a non-volatile, polar, and particularly similar to water and has a high affinity with water, then when the polymer dispersion impregnated with the drug is redispersed in an aqueous solution of an emulsifier, the mechanical dispersion medium of the polymer dispersion is low. Easily transferred to the water layer even under stirring conditions of energy, the drug may be impregnated again in the oily polymer inside the oily polymer dispersed in an aqueous solution having a uniform particle size distribution of nanoparticle size by reacting with the emulsifier.

(2) biodegradable polymer

In addition, the biodegradable polymer according to the present invention is a biocompatible polymer that can be degraded in vivo, specifically, poly-L-lactic acid (hereinafter referred to as "PLA"), poly-glycolic acid (poly glycolic acid, "PGA"), poly-D-lactic acid-co-glycolic acid (hereinafter "PLGA"), poly-L-lactic acid-co-glycolic acid ( poly-L-lactic acid-co-glycolic acid), poly-D, L-lactic acid-co-glycolic acid (poly-D, L-lactic acid-co-glycolic acid), poly-caprolactone , Polyester-based polymers such as poly-valerolacton, poly-hydroxy butyrate, poly-hydroxy valerate, etc. alone or in combination It can be used, but is not limited thereto. In particular, it is more preferable to use PLGA in view of biodegradability and biocompatibility. The PLGA is a polymer material approved for medical use by the US Food and Drug Administration, and thus has no toxicity problem, and thus, direct application of the PLGA is more readily available for medical use such as drug carriers or biomaterials compared to other polymers. In addition, there is a characteristic that can control the release behavior of the drug by changing the decomposition rate of the polymer according to the control of the fraction or molecular weight of glycolide (glycolide) and lactide (Lactide) during copolymerization (Anderson JM et. al . , Advanced Drug Delivery Reviews 28: 5-24, 1997).

In the present invention, the content ratio of the poorly soluble drug and the biodegradable polymer is 0.5 to 5: 10 to 100 parts by weight.

(3) emulsifier

The emulsifier is an amphiphilic (having both hydrophilic and lipophilic groups) solvent, as long as it can easily disperse the oily dispersed phase in an aqueous solution. Emulsifiers of the present invention include propylene glycol (i.e. 1,2-dihydroxypropane), polyethylene glycol (especially polyethylene glycols having a molecular weight of 200 to 600; hereafter "PEG"), propylene carbonate (i.e. 4-methyl-2 Oxo-1,3-dioxolane), polyvinyl alcohol (hereinafter referred to as "PVA"), and polyvinylpyrrolidone (hereinafter referred to as "PVP"), each of which is two or more It can be used as a mixture of the above, but is not limited thereto. The emulsifier aqueous solution used in the present invention is prepared by dissolving the emulsifier in tertiary distilled water, and it is particularly preferable to use a PVA solution or a PVP solution.

Nanoparticles according to the invention can be used to make sustained release injectables by dispersing in solution for injections. As a solution for injection, a buffered or aqueous solution containing a dispersant or preservative in a buffered solution, or edible oil, mineral oil, squalene, squaanan, cod liver oil, mono-, di- and triglycerides or mixtures thereof may be used. As edible oil, jade oil, olive oil, soybean oil or a mixture thereof can be used.

In the case of oral administration of the polymer nanoparticles of the present invention, pharmaceutically acceptable additives such as viscosity modifiers, antioxidants, fragrances or preservatives may be further added within the scope of not impairing the effects of the present invention. have. The oral microemulsion composition of the present invention may be formulated in tablets, powders, or filled with hard capsules or soft capsules according to conventional pharmaceutical methods.

In addition, the biodegradable polymer nanoparticles of the present invention has a drug efficacy duration of 2 weeks or more in vivo administration, the dissolution rate is improved 5 to 10 times or more. Thus, the biodegradable polymer nanoparticles are sustained for a longer period of time even at a smaller dose than when administered with BDD alone.

As a result of comparing the therapeutic effect of carbon tetrachloride-induced liver damage in the case of oral administration of the nanoparticles of the present invention to oral administration of the active ingredient alone, the nanoparticle and the active ingredient of the present invention were continuously orally administered for 4 weeks. In the hepatic protective effect of the nanoparticle administration group was slightly lower than the active ingredient administration group, but was similar. However, in the case of orally administering the nanoparticles and the active ingredient only for two weeks and continuously causing liver damage, the liver protective effect of the nanoparticles was maintained for four weeks (see Tables 1 and 2). Hepatoprotective effect of the slowly decreased after 4 weeks was confirmed to be surely reduced (see Figs. 4 and 5). In other words, the nanoparticles of the present invention are sustained by the sustained release effect of the active ingredient for more than two weeks.

In addition, as shown in Tables 1 and 2, the carbon tetrachloride-induced ALT and AST concentration-increasing inhibitory effect of the polymer nanoparticle-administered group containing BDD and BDD of Example 1 was about 2 times or more compared to the control group. The effect of the BDD-containing polymer nanoparticle group was slightly lower than that of the BDD group, but similar. However, the polymer nanoparticles of Example 1 had a dose of 25 mg of the whole polymer nanoparticles containing BDD, and their drug content was 1/10, that is 2.5 mg, compared to the second group to which 25 mg of BDD itself was administered. do. Thus, looking at the results of the third group for Example 1, administering 1/10 of the drug of the second group, the effect of about 56% compared to the second group in Table 1, about 91 in Table 2 Since the effect of%, the dissolution of the actual drug is 5.6 times and 9.1 times improved, respectively.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, these are provided to facilitate the understanding of the present invention, and the technical scope of the present invention is not limited thereto.

Example 1 Preparation of PLGA - BDD Nanoparticles

10 g of PLGA (poly-D-lactic acid-co-glycolic acid; Boehringer Ingelheim, Germany) was dissolved in 300 ml of DMSO (dimethyl sulfoxide), and then 1 g of BDD (Biphenyl-Dimethyl-Dicarboxylate) was dissolved. To prepare a dispersion. The PLGA-BDD dispersion was added to 3 L of 4% PVA (Polyvinyl alcohol; Sigma-Aldrich, USA) emulsifier solution in one batch and stirred for 3 hours at low stirring condition of 500 rpm.

Subsequently, when the solution is circulated through the separation tube by a circulation pump while stirring the nanoparticle solution in the vessel using a pump-type membrane filtration device (Labscale ™ TFF System, Millipore, USA), the emulsifier, organic solvent and distilled water in the membrane Was quickly removed through a membrane filter (Pellicon® XL Filter, 500K, Millipore, USA) and the nanoparticles were continuously concentrated in circulation.

Separated and concentrated nanoparticles were obtained by lyophilization (EYELA, Japan) to obtain nanoparticle powder and stored at 4 ℃. The final nanoparticles were observed by SEM (Scanning Electron Microscope, Scanion Microscope; Sirion, Japan), TEM (Transmission Electron Microscope; JEOL, Japan) and particle size analyzer (OTSUKA ELECTRONICS, Japan). Uniform PLGA-BDD nanoparticles containing an active material having a narrow particle size distribution and an average particle size of 152 nm were identified (FIGS. 1 to 3).

< Experimental Example  1> Therapeutic Effect on Carbon Tetrachloride-Induced Liver Injury

The therapeutic effect of carbon tetrachloride-induced liver damage of the polymer nanoparticles of the present invention containing BDD prepared in Example 1 was confirmed through animal experiments.

<1-1> Carbon Tetrachloride-Induced Liver Damage

Sprague Dawley rats were weighed by 20 male 6-week-old rats (Oriental Bio, Korea), and their average weight and variance were uniformly divided into four groups and divided into five rats. 50% (v / v) solution of carbon tetrachloride (CCl ₄ ), a hepatotoxic substance mixed with corn oil, in a laboratory animal room set at a temperature of 23 ± 2 ° C. and a relative humidity of 55 ± 5% (Sigma-Aldrich, USA) was intraperitoneally administered at a dose of 0.75 ml / kg twice a week (Mon, Fri) for a total of 4 weeks.

<1-2> compound treatment

1. The first group (control) was administered with a compound of 0.74 ml / kg of carbon tetrachloride twice a week (Mon, Fri) for 4 weeks after intraperitoneal administration.

2. In the second group, rats were dosed with 0.75 ml / kg of carbon tetrachloride twice weekly (Mon, Fri) for 4 weeks, and rats received 25 mg of BDD per kg of body weight (1% (w / v)) of CMC (Carboxyl). Methyl cellulose sodium salt, Sigma-Aldrich, USA) solution was orally administered for 4 weeks once a day, six times a week.

3. In the third group, the polymer of the present invention containing BDD prepared in Example 1 per kg of body weight to rats with intraperitoneal administration twice a week (Mon, Fri) for 4 weeks at a dose of 0.75 ml / kg of carbon tetrachloride. 25 mg of each nanoparticle was suspended in 1% (w / v) CMC solution and administered orally once a day, six times a week for a total of four weeks.

4. The fourth group (non-treated group) did not receive carbon tetrachloride and the compound.

<1-3> Confirmation of treatment effect

After 4 weeks to obtain a serum, the therapeutic effect of the PLGA-BDD nanoparticles of Example 1 according to the present invention was confirmed by measuring the concentration of ALT (Alanine aminotransferase, GPT) and AST (Aspartate aminotransferase, GOT).

Specifically, animals were anesthetized by injecting 4 ml of 4% chloral hydrate (BDH Laboratory Supplies, UK) solution intraperitoneally after 4 weeks, and blood was drawn from the heart and left at room temperature for 1 hour. After spin down for 20 minutes at 16000 rpm to obtain a serum, the ALT and AST using a reagent (TA-Test Wako; WAKO Pure Chemical, Japan) to measure the ALT and AST concentrations automatic blood biochemical equipment ( HITACHI 7080, HITACHI, Japan).

As a result, as shown in Table 1 and Table 2, the carbon tetrachloride-induced ALT and AST concentration increase inhibitory effect of the polymer nanoparticle-administered group containing BDD and BDD of Example 1 was about 2 times or more compared to the control group. The effect of the BDD-containing polymer nanoparticle-administered group of Example 1 was slightly lower than that of the BDD-administered group, but was similar. However, the polymer nanoparticles of Example 1 had a dose of 25 mg of the whole polymer nanoparticles containing BDD, and their drug content was 1/10, that is, 2.5 mg compared to the second group to which 25 mg of BDD itself was administered. . Thus, looking at the results of the third group for Example 1, administering 1/10 of the drug of the second group, the effect of about 56% compared to the second group in Table 1, about 91 in Table 2 Since the effect of%, the dissolution of the actual drug is 5.6 times and 9.1 times improved, respectively.

Fauna ALT ^* (SF IU / ℓ) Number of rats (horses) % Of ALT concentration relative to the control First group (control group) 547.9 ± 26.8 5 100 Second group (BDD) 229.6 ± 99.7 5 42 Third group (Example 1) 367.7 ± 45.5 5 67.1 4th group (non-treated group) 54.6 ± 15.4 5 - *: Mean ± standard deviation of ALT concentration; SF: Sigma-Frankel, activity of enzyme per unit volume

Fauna AST ^* (SF IU / ℓ) Number of rats (horses) Percentage of AST concentration relative to the control First group (control group) 906.6 ± 92.0 5 100 Second group (BDD) 479.7 ± 144.8 5 52.9 Third group (Example 1) 516.1 ± 37.0 5 56.9 4th group (non-treated group) 194.3 ± 14.5 5 - *: Mean ± standard deviation of AST concentration; SF: Sigma-Frankel, activity of enzyme per unit volume

Experimental Example 2 Continuous Treatment Effect on Carbon Tetrachloride-Induced Liver Injury

Animal experiments confirmed the sustained treatment effect of carbon tetrachloride-induced liver damage of the polymer nanoparticles of the present invention containing BDD prepared in Example 1. That is, the polymer nanoparticles of the present invention containing BDD and BDD of Example 1 were each administered only for 2 weeks, and continuously treated with carbon tetrachloride to confirm the therapeutic effect according to time change.

<2-1> Carbon Tetrachloride-Induced Liver Injury

Carbon tetrachloride-induced liver damage was given to eight groups of rats in the same manner as in Experimental Example 1-1.

<2-2> compound treatment

1. The first group (control) was not administered any compound after intraperitoneal administration for 4 weeks twice a month (Mon, Fri) at a dose of 0.75 ml / kg of carbon tetrachloride.

2. In the second group, intraperitoneally administered twice a week (Mon, Fri) at a dose of 0.75 ml / kg of carbon tetrachloride, 25 mg of BDD per kg of body weight was suspended in 1% (w / v) CMC solution. Once a day, six times a week, orally administered for two weeks.

3. In group 3, BDD 25 mg per kg of body weight was suspended in 1% (w / v) CMC solution with intraperitoneal administration twice a week (Mon, Fri) for 3 weeks at a dose of 0.75 ml / kg of carbon tetrachloride. Once a day, six times a week, orally administered for two weeks.

4. In group 4, BDD 25 mg per kg of body weight was suspended in 1% (w / v) CMC solution with intraperitoneal administration twice a week for 4 weeks at a dose of 0.75 ml / kg of carbon tetrachloride. Once a day, six times a week, orally administered for two weeks.

5. In the fifth group, 1 mg of 25 mg of polymer nanoparticles containing BDD of Example 1 per kg of body weight per 1 kg of body weight was administered intraperitoneally with twice a week (Mon, Fri) at a dose of 0.75 ml / kg of carbon tetrachloride. It was suspended in (w / v) CMC solution and administered orally once a day, six times a week, and two weeks.

6. In Group 6, 1 mg of 25 mg of polymer nanoparticles containing BDD of Example 1 per kg of body weight per 1 kg of body weight was administered intraperitoneally with three doses of carbon tetrachloride 0.75 ml / kg twice a week for three weeks. It was suspended in (w / v) CMC solution and administered orally once a day, six times a week, and two weeks.

7. In Group 7, 1% of 25 mg of polymer nanoparticles containing BDD of Example 1 per kg of body weight per 1 kg of body weight was administered intraperitoneally with four doses of 0.75 ml / kg of carbon tetrachloride twice a week for four weeks. It was suspended in (w / v) CMC solution and administered orally once a day, six times a week, and two weeks.

8. Group 8 (untreated) was not administered carbon tetrachloride and the compound.

<2-3> Confirmation of treatment effect

After two weeks, the animals were killed by a weekly unit to obtain serum by the method of Experimental Example 1-3, and then the ALT and AST concentrations were measured to thereby maintain the therapeutic effect of the PLGA-BDD nanoparticles of Example 1 according to the present invention. It was confirmed.

As a result, as shown in Fig. 4 and 5, the PLGA-BDD nanoparticles of Example 1 is very excellent in inhibiting the increase in liver ALT and AST concentration in carbon tetrachloride-induced fatty liver even after 3 and 4 weeks However, in the case of BDD, the concentration of ALT and AST in the liver increased after 4 weeks. It was found that the PLGA-BDD nanoparticle form of Example 1 according to the present invention can be used more effectively than the direct administration of BDD in the treatment of liver disease since the drug is slowly released continuously.

< Experimental Example  3> Acute Toxicity  Experiment

Acute toxicity following administration was investigated for each of BDD and PLGA-BDD nanoparticles of Example 1 according to the present invention.

Specifically, the amount of 0.005 g, 0.1 g, 0.25 g, 0.5 g, 1 g of BDD and PLGA-BDD nanoparticles of Example 1 to each of 2 groups of 20 Ig-based mice weighing 20-25 g per kg of body weight Mortality was measured by counting the number of mice that died one week after oral administration.

As a result, as shown in Table 3, even when administered PLGA-BDD nanoparticles of Example 1 was confirmed to be very safe and non-toxic.

0.005g 0.1g 0.25g 0.5g 1 g LD ₅₀ (g / kg) Death (Mari) Lethality (%) Death (Mari) Lethality (%) Death (Mari) Lethality (%) Death (Mari) Lethality (%) Death (Mari) Lethality (%) > 2 BDD 0 0 0 0 0 0 0 0 0 0 > 2 Example 1 PLGA - BDD Nanoparticles 0 0 0 0 0 0 0 0 0 0 > 2

< Formulation example  1> Powder  Produce

2 g of biodegradable polymer nanoparticles impregnated with the poorly soluble drug of the present invention

1 g lactose

The above ingredients were mixed and filled in airtight cloth to prepare a powder.

< Formulation example  2> Preparation of Tablet

100 mg of biodegradable polymer nanoparticles impregnated with the poorly soluble drug of the present invention

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

< Formulation example  3> Preparation of capsule

100 mg of biodegradable polymer nanoparticles impregnated with the poorly soluble drug of the present invention

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

< Formulation example  4> Preparation of capsule

After dissolving 100 mg of the biodegradable polymer nanoparticles impregnated with the poorly soluble drug of the present invention in an aqueous solution, the capsules were prepared by filling into gelatin capsules according to a conventional method for preparing capsules.

< Formulation example  5> Preparation of Injection Solution

100 mg of biodegradable polymer nanoparticles impregnated with the poorly soluble drug of the present invention

Injectable sodium chloride BP up to 4 ml

The gammalinolenic acid complex of the present invention was dissolved in an appropriate volume of sodium chloride BP for injection, and the volume was adjusted using a sodium chloride BP for injection and thoroughly mixed. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

As described above in detail a specific part of the content of the present invention, for those skilled in the art, such a specific description is only a preferred embodiment, which is not limited by the scope of the present invention Will be obvious. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

1 shows an SEM image of nanoparticles containing poorly soluble BDD.

Figure 2 shows a TEM picture of the nanoparticles containing poorly soluble BDD.

Figure 3 shows a particle size analysis picture of the nanoparticles containing poorly soluble BDD.

4 and 5 are graphs showing the continuous therapeutic effect of the biodegradable polymer nanoparticles containing BDD of Example 1 according to the present invention for carbon tetrachloride-induced liver damage.

Claims (10)

A poorly soluble drug, Biphenyl-Dimethyl-Dicarboxylate (BDD), is a biodegradable polymer, poly-D-lactic acid-co-glycolic. or sustained release polymer nanoparticle formulation consisting of polymer nanoparticles impregnated in " PLGA " The sustained release polymer nanoparticle formulation of claim 1, wherein the BDD and the PLGA are contained in an amount of 0.5 to 5: 10 to 100 parts by weight. The sustained-release polymer nanoparticle formulation of claim 1, wherein the polymer nanoparticle further has an emulsifier coating layer on its outer shell. The sustained release polymer nanoparticle formulation of claim 3, wherein the emulsifier is amphiphilic. The method of claim 3, wherein the emulsifier is propylene glycol (ie 1,2-dihydroxypropane), polyethylene glycol (particularly polyethylene glycol having a molecular weight of 200 to 600; hereinafter “PEG”), propylene carbonate (ie, 4 -Methyl-2-oxo-1,3-dioxolane), polyvinyl alcohol (hereinafter "PVA") and polyvinylpyrrolidone (hereinafter "PVP"). Sustained release polymer nanoparticle formulation, characterized in that. The sustained-release polymer nanoparticle formulation of claim 1, wherein the polymer nanoparticle formulation has a narrow and uniform particle size distribution having a particle size variation of 0 to 30 nm. 8. The sustained release polymer nanoparticle formulation of claim 7, wherein the sustained release polymer nanoparticle formulation lasts longer with a smaller dose than when administered with BDD alone. A formulation for oral administration containing the sustained release polymer nanoparticle formulation of claim 1. The preparation for oral administration according to claim 8, wherein the oral preparation is a tablet, powder or capsule. An injection comprising the sustained release polymer nanoparticle formulation of claim 1 dispersed in a solution for injection.

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