KR101441450B1 - Eprosartan solid dispersant improved bioavailability, its fabrication method and the use - Google Patents

Abstract

The present invention relates to a fibrinolytic solid dispersion having improved bioavailability, a method for producing the same, and a method for producing the fibrinolytic solid dispersion. The fibrinolytic solid dispersion comprises amorphous fructan comprising fructan, a hydrophilic polymer and a surfactant, And a production method and use thereof.
The above-mentioned fructosan solid dispersion is prepared so as to have an amorphous crystal structure of fructan, and the solubility and dissolution rate of the fructan is increased. Thus, it is possible to provide a pharmaceutical composition for preventing or treating hypertension, preventing congestive heart failure, It is possible to improve the bioavailability of the rosats.

Description

[0001] The present invention relates to a solid dispersion of fructosan having improved bioavailability and a method for producing the same,

TECHNICAL FIELD The present invention relates to an fructosan solid dispersion having improved bioavailability, a method for producing the same and a use thereof.

In the pharmaceutical industry, the most important consideration when formulating a drug that has been proven to be stable and effective is oral. However, the most important factors for drug efficacy are drug permeability and drug solubility , Which is very useful for predicting bioavailability.

Representative methods for improving the solubility of poorly soluble drugs include crystal form conversion of active materials, inclusion compounds, solid dispersions, microemulsions, micelles and nanoparticles using amphiphilic copolymers, and the like.

Among these, solid dispersion is a typical method widely used to improve the solubility, dissolution rate and bioavailability of a poorly soluble drug, and an extremely low solubility drug may increase the solubility and dissolution in the range of several hundred to several thousand.

The solid dispersion which is very effective for the solubilization of the drug has a problem of stability in which the elution is changed during storage from an amorphous to a low energy crystalline form. Therefore, the amorphous solid dispersion has lower thermodynamic stability than the crystalline form, and attempts have been made to suppress recrystallization by using a polymer having a high phase transition temperature to overcome this problem [G. Van den Mooter et al. , Evaluation of Inutec SP1 as a new carrier in the formulation of solid dispersions for poorly soluble drugs, International journal of pharmaceutics, 316 (1-2), 1 (2006); SR Vippagunta et al. , Factors affecting the formation of eutectic solid dispersions and their dissolution behavior, J. Pharm. Sci., 96 , 294 (2007); K. Sekiguchi and N. Obi, Chem. Pharm. Bull., 9 (1), 866 (1961)].

Due to the change of the solubilization effect due to the change of the amorphous form into the crystalline form which is more thermodynamically stable due to the surrounding temperature, humidity and physical stress during the process of producing the solid dispersion and the stability problem accompanying the change of the dissolution to be. In particular, the stability of the amorphous drug increases the fluidity of the drug by absorbing the surrounding water, thereby causing the crystallization of the drug, which is particularly accelerated by the hygroscopic effect due to the hydrophilicity of the polymer used as the carrier.

Such changes may result in a change in the performance of the initially made formulation as the drug promotes changes in solubilization and dissolution patterns, eventually reducing the release of drug in the gastrointestinal tract of the formulation and ultimately lowering the bioavailability. Therefore, it is very important to suppress the recrystallization of the drug dispersed in the solid dispersion to ensure the stability of the solid dispersion. For this purpose, polymers and surfactants should be selected according to the physical and chemical properties of the drug, and research on optimal composition and manufacturing methods is required.

Korean Patent Laid-Open Publication No. 2008-0076306 discloses a method for producing a solid dispersion containing an effective amount of re flunomide, which is an anti-rheumatic agent, together with hydroxypropyl methylcellulose, using a polar solvent and a non-polar solvent appropriately Korean Patent Laid-Open Publication No. 2008-0090057 discloses an itraconazole-containing solid dispersion using a hydrophilic polymer and an acidifying agent, which is widely known as an antifungal agent, and Korea Patent Publication No. 2008-0089817 discloses an anti- Celecoxib solid dispersions using polyvinylpyrrolidone-polyvinylacetate copolymer and sodium lauryl sulfate surfactant are disclosed.

So far, studies for solubilization of poorly soluble drugs have focused on the selection of polymers and the combination of suitable surfactants to change the drug into amorphous state. However, the number of polymers and surfactants that can be used in the human body is not really large.

The preparation of the solid dispersion by the spray drying method can produce particles having a small particle size and porous properties, but the weight of the particles is light and bulky, and the flowability of the particles is not good.

Eprosartan, on the other hand, was found to be a mixture of (E) -α - [[2-butyl-1 - [(4-carboxyphenyl) methyl] -1H-imidazol-5-yl] methyl-ene] -2-thiophenepropanoic acid monomethanesulfonate It is an angiotensin II receptor blocker, a blood pressure-increasing hormone.

The angiotensin II receptor blocker is mainly used as a tablet for oral administration and can treat or manage hypertension very effectively. The mechanism of action of this drug, angiotensin I receptor activation, vasoconstriction, antidiuretic hormone secretion, blood vessels and heart muscle growth is promoted. One of the angiotensin II receptor blocker drugs, fructosan, blocks all the action mechanisms associated with it.

The market for treatment and management of hypertension, which is one of the chronic diseases, is very high. In Korea, hypertension treatment market is very large, about 1.4 trillion won in 2010, and the annual growth rate is 9%. Among them, the market for angiotensin receptor blocker The annual growth rate is more than 23%.

However, frovartan has a bioavailability of about 13% in bioavailability of angiotensin II receptors. This means that the amount of medication that should be taken to produce the same medicinal effect as the other medicines is increased, and the dose of medicines to be taken once a day is 600 mg, which is an important factor that makes it difficult to take the medicines. This is because fffalathan is an insoluble drug that is almost insoluble in water. To improve patient convenience and compete in the market with other angiotensin II receptor blockers, drug studies that increase solubility and decrease capacity through solid dispersion are needed .

Korean Patent Laid-Open Publication No. 2011-0009753 discloses a method in which the solubility and the dissolution rate of a drug can be greatly improved under an acidic condition corresponding to an absorption part of the drug in the body, and in order to greatly improve the bioavailability of the drug, And an ionic polymer having an amine-based repeating unit such as a copolymer of acrylate, acrylate, and dimethylaminoethyl methacrylate, dissolving it in an aqueous solvent, and spray-drying it to prepare a solid dispersion.

Currently, the flazatan preparation marketed in Korea is Tabbeten (600 mg / tab.), Which is sold by Handok Pharmaceutical. However, the tablet has a definite weight of about 1000 mg including the drug, so it has a disadvantage that the convenience of taking the patient is significantly lower than other drugs having the same drug efficacy. For this reason, various studies have been conducted to reduce the drug dose through solubilization of the drug.

More specifically, Vitamin E TPGS or polyvinylpyrrolidone (PVP K29) as a base for the solubilization of fructosan was subjected to thermal melting to prepare a solid dispersion, the degree of solubilization of the drug was evaluated, and then oral administration to SD rats Respectively. The purpose of this study was to analyze drug concentration in blood and to compare pharmacokinetics parameters to achieve drug dose reduction.

Recent research trends have shown that a combination of hydrochlorothiazide and a compound that is classified as a diuretic has been developed to develop a combination agent that expects a better hypertensive effect. However, as described above, the amount of fructan to be taken to show the therapeutic effect of hypertension is not so small, so research for solubilizing to minimize it is urgently required.

Korean Patent Publication No. 2008-0076306 Korean Patent Publication No. 2008-0090057 Korean Patent Publication No. 2012-0089817

G. Van den Mooter et al., Evaluation of Inutec SP1 as a new carrier in the formulation of solid dispersions for poorly soluble drugs, International journal of pharmaceutics, 316 (1-2), 1 (2006) S. R. Vippagunta et al., Factors affecting the formation of eutectic solid dispersions and their dissolution behavior, J. Pharm. Sci., 96, 294 (2007) K. Sekiguchi and N. Obi, Chem. Pharm. Bull., 9 (1), 866 (1961)

In order to solve the above-mentioned problems, the present invention aims to provide an fructan solid dispersion capable of improving the bioavailability by maintaining an amorphous crystal structure and high solubility and dissolution rate, and a method for producing the same.

It is another object of the present invention to provide a pharmaceutical composition comprising the above fructosan solid dispersion as an active ingredient.

In order to achieve the above object, the present invention provides an ephrosatan solid dispersion having an amorphous crystal structure, comprising 1.0 to 10.0 g of a hydrophilic polymer and 1.0 to 7.0 g of a poloxamer surfactant, based on 1 g of fructosan.

In addition, the present invention relates to a method for producing a crystalline form of flavanone, which comprises spray-drying a solution of 1.0 to 10.0 g of a hydrophilic polymer, 1.0 to 7.0 g of a poloxamer surfactant and 10 to 1000 ml of a solvent, The present invention also provides a method for producing an epsilon solid dispersion.

The present invention also provides a pharmaceutical composition comprising the above-mentioned fructosan solid dispersion or a pharmaceutically acceptable carrier.

The fructosan solid dispersion according to the present invention is prepared to have an amorphous crystal structure of fructan, and the solubility and dissolution rate of the fructan is increased, and thus it is possible to prevent or treat hypertension, prevent or cure congestive heart failure, The bioavailability of fructan as an agent can be improved.

Figure 1 is a DSC thermogram of polyvinylpyrrolidone and the fructan solid dispersions prepared in Examples 1-3.
Fig. 2 is a DSC thermogram of hydroxypropyl cellulose and the fructan solid dispersions prepared in Examples 4 to 6. Fig.
3 is an X-ray diffraction pattern of fructan, polyvinylpyrrolidone and the solid dispersion of fructan produced in Examples 1 to 3. Fig.
Fig. 4 is an X-ray diffraction pattern of fructan, hydroxypropylcellulose, and the fructan solid dispersions prepared in Examples 4 to 6. Fig.
5 is an X-ray diffraction pattern of fructosan, polyethylene glycol and the fructan solid dispersions prepared in Comparative Examples 1 and 2. Fig.
FIG. 6 is a scanning electron microscope image of ffalathan and the fursosan solid dispersions prepared in Examples 1 to 6, (a) ffalathan, (b) the solid dispersion of Example 1, (c) (D) the solid dispersion of Example 3, (e) the solid dispersion of Example 4, (f) the solid dispersion of Example 5, and (g) the solid dispersion of Example 6.
FIG. 7 is a graph showing dissolution rates of fructan and the fructosan solid dispersions prepared in Examples 1 to 3. FIG.
FIG. 8 is a graph showing dissolution rates of fructan and the fructosan solid dispersions prepared in Examples 4 to 6. FIG.

Hereinafter, the present invention will be described in more detail.

In the present invention, a hydrophilic polymer having excellent compatibility with frovartan is selected, and a solid dispersion is prepared by using a surfactant capable of enhancing compatibility of the hydrophilic polymer with frovartan. At this time, a method of improving the solubility of the solid dispersion and the dissolution rate of fructan through not only the composition constituting the solid dispersion but also the method suggestion is suggested.

The hydrophilic polymer is used to improve the thermodynamic stability of the drug when the solid dispersion is prepared, thereby suppressing the formation of recrystallization and improving the elution property. Such a hydrophilic polymer may be a hydrophilic polymer having excellent compatibility with fructosan, and a polymer suitable for an oral preparation can be used because of its low toxicity when considering the use of frovartan as a preparation.

Examples of the hydrophilic polymer that can be used include one or more selected from the group consisting of polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, cellulose, hydroxypropylcellulose, hydroxymethylcellulose, and combinations thereof. Among them, polyvinylpyrrolidone Showed the best results in terms of solubility and dissolution rate. At this time, the polyethylene glycol has a number average molecular weight of 500 to 15000 daltons, preferably 3000 to 8000 daltons.

The hydrophilic polymer is used in an amount of 1.0 to 10.0 g, preferably 1.0 to 7.0 g, per g of furathanthane for the production of the fructan solid dispersion. If the content is less than the above range, it is difficult to effectively collapse the fatsartan to be granulated, and if it exceeds the above range, the content of the polymer is increased more than necessary and the release of the drug is relatively hindered. As appropriate.

The poloxamer surfactant improves the compatibility between the fructose and the hydrophilic polymer and not only improves the solubility of the solid dispersion but also lowers the crystallinity of the fructan.

In the present invention, a polyoxyethylene-based poloxamer surfactant is used as a surfactant, and a polyoxyethylene-polyoxypropylene copolymer (e.g., Poloxamer 188 ™, Poloxamer 237 ™, Poloxamer 338 ™), polyethylene glycol- Polypropylene glycol-polyethylene glycol copolymer (e.g., Poloxamer 407 ™), and a combination thereof. Preferably, a polyethylene glycol-polypropylene glycol-polyethylene glycol copolymer (eg, poloxamer 407 ™).

As a result of previous experiments of the present invention, the degree of crystallinity of fffalactan varies depending on the presence of a surfactant, and even when an amorphous fructan solid dispersion is prepared, the amorphous crystal structure is maintained for a long period of time. Surfactants of known solid dispersions include sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycolated natural or hydrogenated castor oil, da-tocopheryl polyethylene glycol 1000 succinate and fatty acid macrogol glycerides , And these surfactants did not effectively maintain the amorphous crystal structure of frosatan.

Specifically, according to Experimental Example 2 of the present invention, it was confirmed that the use of Poloxamer 407 ™ as a surfactant influences the degree of crystallization of frosatan to maintain amorphousness of the furathanthane.

According to Experimental Example 3, the solid dispersion was prepared using poloxamer. As a result, it was confirmed that the solubility of frosatan was increased by at least 7 times when poloxamer was used.

In the present invention, the surfactant is used in an amount of 0.5 to 7.0 g, preferably 0.5 to 5.0 g, per g of frosato. If the content is less than the above range, the above-mentioned effect can not be ensured. On the other hand, if the content exceeds the above range, the content of the surfactant is increased more than necessary and the release of the drug is relatively hindered. do.

The solvent is required for uniform spraying in the spraying process, and a solvent such as dichloromethane, trichloromethane, tetrachloromethane, toluene, dimethylacetamide, N-methylpyrrolidone, Dimethyl sulfoxide, xylene, benzene, n-butyl acetate, methylcyclohexane, dimethylcyclohexane, and mixed solvents thereof. Preferably, ethanol or a co-solvent containing it is used, and they are used in an amount of 10 to 1000 ml per 1 g of fructosan.

In order to prepare the solid dispersion of fructan using the above-mentioned composition, a solvent, fructan, a hydrophilic polymer, and a surfactant are put into a mixer and the solution is uniformly prepared.

At this time, the mixer may be equipped with a stirrer equipped with a stirring blade, an ultrasonic vibrator, a microfluidizer, a high pressure homogenizer, propeller-containing mixers, a homogenizer, Can be performed. In addition, a sufficiently homogeneous suspension can be prepared even with a stirrer equipped with a stirring wing, and even homogenization or microfluidizer can be more evenly dispersed.

Next, the obtained solution is injected into a spraying device, followed by spray drying to obtain a solid dispersion.

The spray drying can be performed in a conventional manner using a fluidized bed granulator or a spray dryer, and preferably the chamber temperature is in the range of 30 to 120 캜. Spray drying is a process in which a spraying process and a drying process are performed in a single process. Since the spraying process is performed simultaneously with the spraying process, the amorphous solid dispersion can not be obtained because the crystals can not be rearranged due to rapid drying . Preferably, in the embodiment of the present invention, an injection temperature of 60 to 80 占 폚 and a chamber temperature of 30 to 65 占 폚 were set so that an fructan solid dispersion was prepared.

The solid dispersion thus obtained may be obtained in the form of a powder or granules having a particle size of 0.1 to 1000 μm.

The solid dispersion of fructan according to the present invention prepared by this method can further increase the solubility and the dissolution rate of fructan due to the hydrophilic polymer and the surfactant. It has been known that frapalsatan has a crystalline molecular structure composed of a large number of aromatic structures and is a representative poorly soluble drug exhibiting low bioavailability due to incomplete absorption due to low solubility during oral administration. As amorphous (amorphous) exists in the sieve, the solubility of fffalathane, which was conventionally poorly soluble, increases, bioavailability increases, and the bioavailability increases.

As a result of analyzing the characteristics of the solid dispersion of fructan according to Experimental Examples 1 to 3 of the present invention, it was found that in order to maximize the solubilization effect of the solid dispersion of fructan, the polyvinylpyrrolidone among the various polymers was used as the polymer base And selecting the spray drying method as the production method showed the best solubilization effect. The solubility of the fructan solid dispersion was improved about 2 ~ 4 times and the dissolution rate was 3 ~ 7 times higher than that of the conventional drug. As a result, it can be seen that, in the case of the solid dispersion of fructosan, the solid dispersion is prepared by spray-drying based on polyvinylpyrrolidone, which is the most effective method for solubilizing the drug.

Accordingly, the present invention provides a pharmaceutical composition comprising the above fructosan solid dispersion as an active ingredient. Such a pharmaceutical composition maintains the activity of frapalastan even when it is used as a therapeutic agent for hypertension due to the water-soluble blocking effect of angiotensin II, which is a blood pressure-increasing hormone possessed by fructosan.

As a result, the fructan solid dispersion according to the present invention can be preferably used as a pharmaceutical composition for the prevention or treatment of hypertension, prevention or treatment of congestive heart failure and renal failure.

Such an fructan solid dispersion can be obtained in the form of granules through the spray drying method described above and can be used as a pharmaceutical composition without any additional pharmaceutical treatment. In addition, the granular fructan solid dispersion can be formulated into an oral solid form according to a conventional method.

The formulations of the oral solid preparations may be in various forms, but include solid preparations such as granules, tablets, capsules, dry syrups, or powders, more preferably granules, tablets, or capsules. These formulations may be prepared according to methods commonly used in pharmacy, including pharmaceutically acceptable carriers. For example, the tablet may be prepared by mixing the surface-modified solid dispersion with an excipient, a disintegrant, a lubricant or the like, or adding an excipient or the like to the surface-modified solid dispersion to prepare a granule, mixing the excipient with a disintegrant, And the capsules can be prepared by filling the capsules with the above mixture. In addition, film-coating or enteric-coating may be performed for the purpose of improving stability, convenience of taking, and appearance.

Examples of excipients include lactose, xylitol, maltitol, cellulose, microcrystalline cellulose, saccharose, lactose, silicon dioxide, dextrin, dextrates, calcium dihydrogenphosphate, xanthan gum, polyvinylpyrrolidone, carboxymethylcellulose, cellulose, Starch, starch, corn starch, prosolve ^TM , microcell ^TM , hydroxypropylcellulose, hydroxypropylmethylcellulose and mixtures thereof, and examples of such disintegrants include croscarmellose sodium, crospovidone, Low-substituted hydroxypropylmethylcellulose, and the like. Examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, magnesium trisilicate, talc, and the like. In addition, the composition of the present invention may contain additives such as sodium hydrogencarbonate, sodium starch glyconate, and sucrose fatty acid ester. The pharmaceutically acceptable carrier may be suitably selected and used by those skilled in the art according to the finally obtained formulation.

The content of the falasilane contained as the active ingredient in the solid dispersion of the present invention depends on the unit dosage form administered to achieve therapeutic purposes such as hypertension. For example, the agent is subdivided into unit dosage forms containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation containing a discrete amount of the preparation, for example, a packaged tablet, capsule or powder in a vial or ampoule. More preferably in the form of tablets and capsules, and the effective dose may contain 10 to 800 mg, preferably 100 to 600 mg per day.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

<Reagents and Samples>

The insoluble drug eprosartan mesylate used in this Example and Comparative Example was purchased from Unichem Laboratorie (India), PEG 6000 was purchased from Sanyo Chemical Industries, Inc. (Japan), PVP K30 and Poloxamer 407 ^TM P407) were purchased from BASF (Germany). Water was used in the third distilled water, and all of the raw materials used in the other studies were above the level of pharmacopoeia. The HPLC grade was used for the analysis of solvents and other reagents without further purification. The 99.8% ethanol used in the preparation of the solid dispersion was a product of Fluka (Switzerland). Acetonitrile, a reagent used in the preparation of HPLC mobile phase, was purchased from Burdick & Jackson (USA), and triethylamine and phosphoric acid was purchased from Fluka.

Example 1: Preparation of fructan solid dispersion by spray drying

Hydrophilic polymers and Poloxamer 407 ^™ were first dissolved in ethanol, which is the most widely used organic solvent in the pharmaceutical field. Ephthalathane was added thereto and stirred. When the solution became completely transparent, the solution was dispersed using Mini-Glatt (Glatt Co., Germany) Followed by spray drying to prepare an fructan solid dispersion. At this time, the spray drying process was performed by increasing the internal temperature of the chamber to about 30 to 65 ° C.

Comparative Examples 1 and 2: Preparation of fructan solid dispersion using solvent evaporation method (SE)

A minimum amount of ethanol was added until the mixture having the composition corresponding to each composition was transparent. When the mixture became transparent, most of the solvent was evaporated at 40 ° C using a rotary evaporator (EYELA N-1000, Sunilia, Korea) Followed by vacuum drying at room temperature. The resulting solid dispersion was pulverized using a mortar bowl and sieved through a 200 mu m sieve.

Comparative Examples 3 to 4: Preparation of fructan solid dispersion using thermal melting (HM)

After the hydrophilic polymer was melted by heating to a temperature higher than the melting point, folsatan and Poloxamer 407 ^TM corresponding to the composition ratios were added and stirred for 30 minutes or more, dispersed evenly, cooled at room temperature and vacuum dried for 24 hours or more. The dried solid dispersion was pulverized using a mortar and sieved with a sieve of 200 mu m.

Comparative Examples 5 to 6: Preparation of fructan solid dispersion using physical mixing (PM)

Hydrophilic polymer, and Poloxamer 407 ^™ were shaken in a plastic bag, followed by pulverization in a mortar and then sieved with a 200 μm sieve to prepare an epsilon solid dispersion.

Comparative Examples 7 to 12: Preparation of fructan solid dispersion using dry spray (SD)

The procedure of Example 1 was repeated except that the composition was changed as shown in Table 1, to thereby prepare a solid dispersion of fructan.

content
Way
Efrosatan
(g) The hydrophilic polymer (g) Surfactant (g) Each composition ratio (w / w / w) PVP HPC PEG Poloxamer 407 ^TM SLS Example 1 SD 2.50 2.50 - - 2.50 - 1: 1: 1 Example 2 SD 1.25 3.75 - - 1.25 - 1: 3: 1 Example 3 SD 0.83 4.17 - - 0.83 - 1: 5: 1 Example 4 SD 2.5 - 2.50 - 2.50 - 1: 1: 1 Example 5 SD 1.25 - 3.75 - 1.25 - 1: 3: 1 Example 6 SD 0.83 - 4.17 - 0.83 - 1: 5: 1 Comparative Example 1 SE 2.50 - - 2.50 - - 1: 1: 0 Comparative Example 2 SE 0.71 - - 3.57 0.71 - 1: 5: 1 Comparative Example 3 HM 2.50 - - 2.50 - - 1: 1: 0 Comparative Example 4 HM 1.25 3.75 - - 1.25 - 1: 3: 1 Comparative Example 5 PM 2.50 - - 2.50 - - 1: 1: 0 Comparative Example 6 PM 1.25 3.75 - - 1.25 - 1: 3: 1 Comparative Example 7 SD 3.13 1.87 - - 3.13 - 1: 0.6: 1 Comparative Example 8 SD 0.30 4.70 - - 0.30 - 1: 15: 1 Comparative Example 9 SD 1.25 3.75 - - - - 1: 3: 0 Comparative Example 10 SD 1.25 3.75 - - - 2.50 1: 3: 1 Comparative Example 11 SD 1.25 3.75 - - 0.625 - 1: 3: 0.5 Comparative Example 12 SD 1.25 3.75 - - 10.0 - 1: 3: 8

Experimental Example 1: Crystallographic analysis of solid dispersion of fructan

Differential scanning calorimetry (DSC), differential scanning calorimetry (S-650, Shinko, Korea, hereinafter DSC) and powder X-ray diffractometry were used to determine the crystalline state of the fructan solid dispersion prepared in the above Examples. TOPAS 4.2 was used as a program. The measurement conditions of the DSC were measured in a temperature range of 20 to 300 占 폚 at a temperature raising rate of 20 占 폚 / min under a nitrogen stream. The measurement conditions of PXRD generated Cu K-α radiation (1.5406 Å) at 40 mA and 40 kV for X-ray. The scan range was from 5 to 80 ° and measured at a rate of 0.4 ° / min. PSD-Lynxeye detector (1-D) was used as the measuring device and EVA was used as software.

(1) Differential scanning calorimetry (DSC) analysis

FIG. 1 is a DSC thermogram of polyvinylpyrrolidone and the fructan solid dispersions prepared in Examples 1 to 3, and FIG. 2 is a graph showing the DSC thermograms of hydroxypropylcellulose and the fructan solid dispersions prepared in Examples 4 to 6 DSC Thermogram.

The melting temperature of fffalatan appears at about 230 캜. From the thermograms of Fig. 1 and Fig. 2, it is not possible to confirm a specific melting peak in the above-mentioned temperature range in the fructan solid dispersion of the examples. In addition, as the content of PVP as a hydrophilic polymer increases, the melting peak is greatly decreased. From these results, it can be understood that the content of the hydrophilic polymer affects the crystallization degree of the solid dispersion.

(2) X-ray diffraction analysis

3 is an X-ray diffraction pattern of fructosan, polyvinylpyrrolidone and the solid dispersion of fructosan prepared in Examples 1 to 3, Fig. 4 is a graph showing the X-ray diffraction pattern of frosatan, hydroxypropylcellulose, FIG. 5 is an X-ray diffraction pattern of fructosan solid dispersion prepared from fructosan, polyethylene glycol and Comparative Examples 1 and 2. FIG.

As shown in FIG. 3 and FIG. 4, peaks were not observed in the above range in the case of the solid dispersion of furathanthane prepared in the examples, and peaks were observed in the case of the solid dispersion of frosatan in the comparative example of FIG. 5, The fructan in the solid dispersion is amorphous.

In the case of the solid dispersion of fructan according to Examples 1, 4 and 5, some melting point peaks were observed in the DSC thermogram of (1), but the X-ray diffraction Through the analysis, the diffraction peak disappeared. From these results, it can be seen that the fructan in the fructan solid dispersion of Examples 1 to 5 is amorphous without crystallinity.

Experimental Example 2: Morphological analysis of solid dispersion of fructan

Scanning Electron Microscopy (JSM-7000F, JEOL, Japan) was used to confirm the particle state of the solid dispersion of fructan produced in the above example. The conditions for measuring the form of the solid dispersion of fructan were as follows. Each particle was fixed on a carbon tape, coated with 10.0 kV pt for 30 seconds, and the particle surface was observed at 10.0 kV by changing the electron microscope magnification.

FIG. 6 is a scanning electron microscope image of ffalathan and the fursosan solid dispersions prepared in Examples 1 to 6, (a) ffalathan, (b) the solid dispersion of Example 1, (c) (D) the solid dispersion of Example 3, (e) the solid dispersion of Example 4, (f) the solid dispersion of Example 5, and (g) the solid dispersion of Example 6.

Referring to FIG. 6, the fructan in the fructosan solid dispersion according to the present invention has a plate-like crystal, a particle size is not constant but a relatively large particle size is observed. As the content of the hydrophilic polymer increases, It can be seen that the dispersion has a spherical particle shape.

Experimental Example 3: Solubility and dissolution behavior of the solid dispersion of fructanthan

The solubility and dissolution behavior of the solid dispersions prepared in Examples and Comparative Examples were analyzed.

(1) Solubility measurement

The solubility was measured by weighing the solid dispersion to 10 mg of furathan so that the drug could be saturated with 10 mL of distilled water, stirring the mixture at 100 rpm for 24 hours in a thermostatic chamber at room temperature, then centrifuging at 4000 rpm for 10 The separated solution was filtered with a 0.2 占 퐉 PVDF filter, and the solubility was analyzed using HPLC. The obtained results are shown in Table 2 below.

Way Each composition ratio (w / w / w) Solubility (/ / ml) Efrosatan - - 30 Example 1 SD 1: 1: 1 125.1 Example 2 SD 1: 3: 1 135.8 Example 3 SD 1: 5: 1 144.7 Example 4 SD 1: 1: 1 103.3 Example 5 SD 1: 3: 1 114.2 Example 6 SD 1: 5: 1 134.5 Comparative Example 1 SE 1: 1: 0 55.1 Comparative Example 2 SE 1: 5: 1 78.5 Comparative Example 3 HM 1: 1: 0 61.3 Comparative Example 4 HM 1: 3: 1 71.1 Comparative Example 5 PM 1: 1: 0 45.5 Comparative Example 6 PM 1: 3: 1 54.9 Comparative Example 7 SD 1: 0.6: 1 87.5 Comparative Example 8 SD 1: 15: 1 134.9 Comparative Example 9 SD 1: 3: 0 77.6. Comparative Example 10 SD 1: 3: 1 54.6 Comparative Example 11 SD 1: 3: 0.5 87.9 Comparative Example 12 SD 1: 3: 8 63.7

Referring to the above Table 2, the solubility was different according to the production method of the solid dispersion even when the same composition was used, and the solubility was also different depending on the kind and content of the hydrophilic polymer and the kind and content of the surfactant.

Specifically, the solubility of the solid dispersion of Example 3 was about 4.5 times higher than that of flazatan, and the solubility was increased when spray drying was used compared to other processes of the comparative example. In addition, as in Comparative Examples 7 to 9 and Comparative Examples 11 and 12, the solubility was also different depending on the content of the hydrophilic polymer and the surfactant. Also, when the sodium dowryyl sulfite known as a surfactant was used as in Comparative Example 10, the solubility difference was about 2 to 3 times.

(2) Elution test

The dissolution test was carried out using the paddle method of the USP second corporation. DST-610 (Lab Fine Inc., Korea) was used for the elution test and 5 mL of Tween 80 was added to 500 mL of the third distilled water to completely dissolve the eluate. The amount of the solid dispersion used was weighed to 50 mg with furathan. The temperature was 37 ± 0.5 ° C and the paddle speed was 100 rpm. Samples were taken at 0, 5, 10, 15, 20, 30, 60 min, 2 mL each, filtered through 0.45 μm PTFE filter, and analyzed for drug content in solution using HPLC.

FIG. 7 is a graph showing dissolution rates of fructan and the fructosan solid dispersions prepared in Examples 1 to 3. FIG. FIG. 8 is a graph showing dissolution rates of fructan and the fructosan solid dispersions prepared in Examples 4 to 6. FIG.

The maximum dissolution rate of flazatan was 11.5%, and the maximum dissolution rate of the flazalan solid dispersion prepared in the Example was increased to about 77.5% in Example 3 by about 7-fold, It is understood that the dissolution rate of the fatsolsatan is effectively improved.

Formulation example

The formulation examples of the composition are described below, but the present invention is not intended to be limited thereto but is specifically described.

Formulation Example 1: Preparation of an epsilon solid dispersion tablet

The fructan solid dispersion of Example 1 100 mg

Corn starch ............................... 68 mg

Lactose .................................. 90 mg

Crospovidone .............................. 40 mg

Magnesium stearate ..................... 2 mg

According to the conventional preparation method of tablets, the above ingredients were added in the prescribed amounts, uniformly mixed, stirred, and then granulated. After drying, the tablets were used to prepare the desired tablets containing 100 mg of the fructan solid dispersion as an active ingredient per one tablet.

Formulation Example 2: Preparation of capsule of fructan solid dispersion

The fructan solid dispersion of Example 1 100 mg

Corn starch ................................ 68 mg

Lactose ................................... 90 mg

Microcrystalline cellulose ........................ 40 mg

Magnesium stearate ...................... 2 mg

According to a conventional method for preparing a capsule, the above ingredients were added in the prescribed amounts, uniformly mixed, and filled in an appropriate size gelatin capsule so as to contain a 100 mg of fructan solid dispersion per capsule to prepare a desired capsule .

Claims (10)

delete delete delete delete delete 1.0 g to 10.0 g of polyvinylpyrrolidone or hydroxypropylcellulose as a hydrophilic polymer and 1.0 g to 10.0 g of a polyethylene glycol-polypropylene glycol-polyethylene glycol copolymer (Poloxamer 407 ™) as a poloxamer surfactant, g, and 10 to 1000 ml of ethanol was prepared,
The solution thus prepared was spray-dried at 30 to 65 캜
Wherein the particle size is 10 to 1000 mu m and the solubility is 103.3 to 144.7 mu g / mL, and has an amorphous crystal structure. delete delete delete delete

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