KR101121589B1 - Amorphous adefovir dipivoxil solid dispersion having enhanced stability and preparation method thereof - Google Patents

Abstract

The present invention relates to an amorphous adefovir difficile solid dispersion having improved stability and a method for preparing the same, and more particularly, to an adefovir difficile solid dispersion containing adefovir difficile and a hydrophilic polymer as an active ingredient. . The amorphous adefovir difficile solid dispersion containing crystalline or amorphous adefovir difficile and a hydrophilic polymer as the active ingredient according to the present invention is thermodynamically stable under high temperature and humidity conditions and has excellent solubility. In addition, the formulation containing the amorphous adefovir difficile solid dispersion has a high dissolution rate and can be usefully used for the prevention or treatment of chronic hepatitis B.

Adefovir difficile, AD, crystal, amorphous, hepcera, hepatitis B, solid dispersion

Description

Amorphous adefovir dipivoxil solid dispersion having enhanced stability and preparation method

The present invention relates to an amorphous adefovir difficile solid dispersion having improved stability and a method for preparing the same.

Adefovir dipivoxil (AD) is 9- [2-[[{bis (pivaloyloxy) -methoxy} phosphinyl] methoxy] ethyl] adenine (9- [2-[[ {bis (pivaloyloxy) -methoxy} phosphinyl] methoxy] ethyl] adenine) and is known for treating chronic hepatitis B by having antiviral activity in animals and humans.

Conventional techniques for the adefovir difficile are disclosed in US Pat. Nos. 4,724,233, 4,808,716, European Patent No. 481214, etc. Amorphous or amorphous adefovir difficile, the preparation method thereof is described in Starrett at al. J. Med. Chem. (1994), 19: 1857-1864. However, the amorphous adefovir difficile has a problem in that it cannot be easily used because of its low stability.

The crystalline compound contains a small amount of residual solvent in the final drug in any form such as dissolved state, and further purification can be obtained by crystallization. In addition, it exhibits a high stability in the manufacture of the drug, there is an advantage that it is easy to handle in the manufacturing plant.

Such crystalline compounds can generally exhibit their properties by X-ray diffraction (XRD), differential scanning calorimetry (DSC) thermograms, and the like. A commonly used method to characterize or evaluate the properties of crystalline compositions is XRD. The XRD is a very useful means to clarify the internal microstructure of a material. Crystals in which atoms are arranged regularly scatter strongly in a specific direction as a result of scattering X-rays caused by atoms, and the crystal structure can be detected by measuring them. . At this time, the XRD peak is detected at 2θ value, and when a wide XRD peak at any given position is detected at any 2θ value, it means that the peak is at 2θ value ± 0.3.

In addition, differential scanning calorimetry (DSC), melting point measurement, and infrared absorption spectroscopy (IR) can optionally be used as additional diagnostic techniques for determining crystalline compounds.

DSC measures the thermal transition temperature at which the crystal absorbs or releases heat when its crystal structure changes or melts and, in the case of other crystal forms, their transition temperature profile can be detected based on another.

IR measures the absorption of infrared light caused by a unique chemical bond that links molecular functional groups with tremor (vibration) in response to light.

Thus, DSC or IR can provide physicochemical information that can be used to describe crystalline compounds.

Thus, research has been conducted to prepare adefovir difficile in crystalline form, and WO 1999/04774 discloses a crystalline adefovir difficile compound. Specifically, the crystalline adefovir difficile disclosed in WO 1999/04774 has X-ray diffraction (XRD) spectra with 2θ of about 6.9, about 11.8, about 12.7, about 20.7, about 21.5, about 22.5, and about 23.3 in Cu-Kα radiation. Form 1 (anhydrous crystalline form) having; Crystalline forms with X-ray diffraction spectra with 2θ of about 8.7-8.9, about 9.6, about 16.3, about 18.3, about 18.9, about 19.7, about 21.0, about 21.4, about 22.0, about 24.3, about 27.9, about 30.8, and about 32.8 2 (hydration type); Form 3 (methanol solvate) having an X-ray diffraction spectrum with 2θ of about 8.1, about 8.7, about 14.1, about 16.5, about 17.0, about 19.4, about 21.1, about 22.6, about 23.4, about 24.2, about 25.4 and about 30.9 brother); And Form 4 (fumarate type) having an X-ray diffraction spectrum with 2θ of about 9.8, about 15.2, about 15.7, about 18.1, about 18.3, about 21.0, about 26.3, and about 31.7. In nature, there is a tendency to return to Form 1 (anhydrous form) or to Form 2 (hydration form). These crystalline compounds are prepared by dissolving amorphous or amorphous solids in crystallization solvents such as methanol and forming crystals. Among them, adefovir difficile of Form 1 is a chronic hepatitis B treatment approved by the US Food and Drug Administration (FDA). It is used as a raw material of "hepsera".

In addition, WO 2004/043972 discloses a new crystalline form of adefovir difficile, a composition comprising the new crystalline form, and a method for preparing the crystalline, specifically, the novel crystalline powder X-ray diffraction pattern is represented by 2θ. And, at about 3.60, about 7.28, about 15.08, about 17.24, about 17.96, about 20.12, and about 22.24. The new crystalline form of the adefovir difficile was prepared by dissolving the raw adefovir difficile in ethanol followed by spray drying.

In addition, in relation to the new crystalline form of adefovir difficile, Chinese Patent Publication No. 1470517 discloses a crystalline adefovir difficile having an X-ray diffraction spectrum with 2θ of about 7.1, about 15.8, about 17.36, about 17.5 and about 20.9. , Chinese Patent Application Publication No. 1498890, which has an X-ray diffraction spectrum with 2θ of about 7.3, about 7.8, about 10.1, about 12.3, about 15.1, about 16.3, about 17.2, about 18.0, about 20.1, about 21.3 and about 22.2. Crystalline adefovir difficiles are disclosed.

However, when the adefovir difficile of the crystalline form was exposed to high humidity conditions, crystalline conversion was observed as shown in FIGS . 1 and 2 , and when it was dried again, an additional crystalline conversion was observed.

Drug compounds of different crystal forms are known to have different melting points, solubilities and densities. In addition, the flowability and elastic deformation of such a compound crystal and the dissolution rate, stability and effectiveness of the crystal in a pharmaceutical formulation may also be different. This difference may change the absorption rate of the drug when administered in vivo, and the change in the absorption rate of the drug causes a change in the concentration of the drug in the blood, which may cause difficulty in showing the same therapeutic effect.

Therefore, it is necessary to select adefovir difficile which has stability in which crystalline conversion does not occur even at high temperature and humidity conditions during manufacture and storage. In addition, in the preparation of compounds having enhanced stability, a production method having reproducibility and in situ is important.

Thus, the inventors of the present invention while researching to produce a new adefovir difficile with high stability even under high temperature and humidity conditions, the amorphous adefovir difficile solid dispersion having high stability under high temperature and humidity conditions through the solid dispersion production method And the present invention was completed.

An object of the present invention is to provide an amorphous adefovir difficile solid dispersion with improved stability even under high temperature and humidity conditions.

Another object of the present invention is to provide a method for preparing the amorphous adefovir difficile solid dispersion.

Still another object of the present invention is to provide an agent for treating chronic hepatitis B containing the amorphous adefovir difficile solid dispersion as an active ingredient.

In order to achieve the above object, the present invention provides an amorphous adefovir difficile solid dispersion having improved stability containing adefovir difficile and a hydrophilic polymer as an active ingredient.

In addition, the present invention comprises the steps of completely dissolving adefovir difficile and hydrophilic polymer as an active ingredient (step 1); And

After drying the solution prepared in step 1, the formulation provides a method for producing an amorphous adefovir difficile solid dispersion comprising the step of preparing a solid dispersion (step 2).

Furthermore, the present invention comprises the steps of mixing and melting adefovir difficile and a hydrophilic polymer as an active ingredient (step 1); And

It provides a method for producing the adefovir difficile solid dispersion comprising the step (step 2) to prepare a solid dispersion by cooling the molten blend prepared in step 1, and then.

The present invention also provides a preparation for treating chronic hepatitis B containing the amorphous adefovir difficile solid dispersion as an active ingredient.

The amorphous adefovir difficile solid dispersion containing crystalline or amorphous adefovir difficile and a hydrophilic polymer as the active ingredient according to the present invention is thermodynamically stable under high temperature and humidity conditions and has excellent solubility. In addition, the formulation containing the amorphous adefovir difficile solid dispersion has a high dissolution rate and can be usefully used for the prevention or treatment of chronic hepatitis B.

Hereinafter, the present invention will be described in detail.

The present invention provides an improved amorphous adefovir difficile solid dispersion containing adefovir difficile and a hydrophilic polymer as an active ingredient.

A solid dispersion is one in which a large amount (dispersion medium) is contained in a small amount (dispersion medium). The dispersion medium is a solid.

The adefovir difficile used in the present invention may use an amorphous or conventional crystalline adefovir difficile compound, which may be prepared or commercially available by the method of the prior art.

The hydrophilic polymer used in the present invention is essential for the adefovir difficile to form a complete amorphous solid dispersion. That is, the hydrophilic polymer improves solubility while forming a uniform distribution with adefovir difficile as a water-soluble carrier, and also secures stability of the amorphous form by minimizing thermodynamic deformation of adefovir difficile due to external temperature and moisture. The hydrophilic polymer thus forms a complete solid dispersion with adefovir difficile, which does not characterize the diffraction peaks in the X-ray powder diffraction analysis, contributing to maintaining the amorphous state.

When the particles obtained by grinding and the solid dispersion are compared, the particles obtained by grinding are difficult to be crushed to several micrometers or less, whereas the solid dispersion is dispersed in molecular units, so that the solubility of the solid dispersion is generally It is much greater than solubility. Adefovir difficile is a drug with high solubility based on BCS (Biopharmaceutics Classificaton System, FDA) in pH 2.0 solution. Therefore, since the solid dispersion is used to increase the solubility of the drug with low solubility, there was no need to make adefovir difficile having high solubility as a solid dispersion as in the present invention, and actually produced an adefovir difficile solid dispersion. Was not yet. However, the present inventors found that the crystalline adefovir difficile has a problem with stability due to the crystalline conversion at high temperature and humidity conditions, and to solve this problem, the amorphous or crystalline adefovir difficile and the hydrophilic polymer, which are water-soluble active ingredients, have been studied. It was found that the solid dispersion prepared by dissolving and drying together was stable without changing the crystal form even at high temperature and humidity conditions. The solid dispersion is that adefovir difficile is dispersed in the hydrophilic polymer matrix, the adefovir difficile was found to be amorphous and unchanged in the crystal form to complete the present invention.

At this time, the hydrophilic polymer is methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, chitosan, alginic acid, carrageenan, methacrylate copolymer, polyethylene oxide, povidone and mixtures thereof It may be selected from the group consisting of, but not limited to both hydrophilic polymer cotton is possible.

In the solid dispersion according to the present invention, the adefovir difficile and the hydrophilic polymer may be mixed in various ratios, and preferably, the adefovir difficile: hydrophilic polymer = 1: 0.1 to 1:10.

In addition,

Completely dissolving adefovir difficile and the hydrophilic polymer as an active ingredient in a solvent (step 1); And

After drying the solution prepared in step 1, the formulation provides a method for producing the adefovir difficile solid dispersion comprising the step of preparing a solid dispersion (step 2).

Further,

Mixing and melting adefovir difficile and a hydrophilic polymer as the active ingredient (step 1); And

It provides a method for producing the adefovir difficile solid dispersion comprising the step (step 2) to prepare a solid dispersion by cooling the molten blend prepared in step 1, and then.

The method of preparing a solid dispersion includes a hot melt method and a spray drying method. A melting method is a method of mixing a main component and a polymer while applying heat to cool the mixture to make a eutectic mixture, and a spray drying method. Is to dissolve the main component and the polymer in a solvent and then spray-dry to obtain a eutectic mixture.

In the preparation method according to the present invention, the adefovir difficile compound may be an amorphous or conventional crystalline adefovir difficile compound, which may be prepared or marketed by the method of the prior art.

In the preparation method according to the invention, the hydrophilic polymer is methyl cellulose, hydroxy methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, chitosan, alginic acid, carrageenan, methacrylate copolymer, polyethylene But may be selected from the group consisting of oxides, povidones and mixtures thereof.

In the preparation method according to the present invention, the adefovir difficile and the hydrophilic polymer may be mixed in various ratios, preferably, the adefovir difficile: hydrophilic polymer = 1: 0.1 to 1:10.

In the manufacturing method according to the present invention, the solvent may be used as the solvent when prepared by the spray drying method, but is not limited thereto.

In the production method according to the present invention, the adefovir difficile solid dispersion can be prepared by removing a solvent from a solution in which adefovir difficile and a hydrophilic polymer are dissolved according to a conventional method. In this case, spray drying or reduced pressure evaporation is preferable as the method of removing the solvent.

The prepared adefovir difficile solid dispersion can be used by sizing using a sieve.

Furthermore, the present invention provides a preparation for preventing or treating chronic hepatitis B comprising the adefovir difficile solid dispersion.

Adefovir difficile in the adefovir difficile solid dispersion prepared according to the present invention was observed to be amorphous by X-ray diffraction analysis (see FIGS . 3 and 5 ), and the adefovir difficile solid dispersion was 40 ° C, relative It was found to be stable by maintaining the amorphous even after storage for 2 months at 75% humidity (see Fig. 6 ). Therefore, the adefovir difficile solid dispersion according to the present invention can be usefully used for the prevention or treatment of chronic hepatitis B.

The composition according to the present invention may be prepared by additionally containing one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration. The pharmaceutically acceptable carrier is an organic or inorganic carrier which can be administered with an active ingredient, for solid pharmaceutical preparations such as excipients, lubricants, binders and disintegrants, and pharmaceutically acceptable additives, eg For example, a coloring agent, a sweetener, etc. are contained.

In the present invention, preferred excipients are lactose, sugar, D-mannitol, D-sorbitol, starch, α-starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, amylopectin, Hard silicic anhydrides, synthetic aluminum silicates, aluminum-magnesium silicates and the like.

In the present invention, preferred lubricants are magnesium stearate, calcium stearate, talcum powder, silica gel and the like.

In the present invention, preferred binders include α-starch, sucrose, glutin, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sugar, D-mannitol, trehalose, dextrin, Amylopectin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pyrrolidone and the like.

In the present invention, preferred disintegrating agents include lactose, sugar, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hard anhydrous silica acid, low-substituted hydroxypropyl cellulose and the like.

In the present invention, preferred colorants include utility red No. 2, edible yellow No. 4, edible blue No. 1 and No. 2, water insoluble dyes, beta-carotene, chlorophyll, iron red and the like.

In the present invention, preferred sweetening agents include saccharin sodium, potassium glycyrrhetinate dibasic, aspartame, stevioside and the like.

The composition according to the present invention can conveniently use any route suitable for administration, for example, oral administration, topical administration, parenteral administration, inhalation administration, and the like, preferably orally. Suitable formulations of the composition are tablets, granules or capsules, and the drug can be compressed into solid unit dosage forms such as pills, tablets, or mixed with a pharmaceutically acceptable carrier and then processed into capsules. The formulation for the treatment of chronic hepatitis B of the composition comprises crystalline adefovir difficile according to the invention in an amount of 1 to 80 mg / unit, preferably 5 to 20 mg / unit. Dosage varies depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion and severity of disease. The daily dose of the composition according to the invention is 500 ± 200 μg / kg, preferably 400 ± 100 μg / kg, preferably administered once to three times a day.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the invention.

< Example  1> Adefovir Difference Room Solid dispersion  Preparation of tablets containing 1

After 200 g of crystalline adefovir difficile and 20 g of hydroxypropylmethylcellulose were completely dissolved in 200 g of ethanol solution, 160 g of crospovidone was added and mixed. The mixture was dried in a drier at 60 ° C. until the loss of drying was 2.0% or less, and then sieved using a 20 mesh sieve. 4 g of magnesium stearate was added to the sieved material, mixed and tableted.

< Example  2> Adefovir Difference Room Solid dispersion  Preparation of tablets containing 2

Tablets were prepared in the same manner as in Example 1, except that 20 g of povidone was used instead of hydroxypropylmethylcellulose.

< Comparative example  1> Adefovir Definitely  Preparation of conventional tablets containing 1

All components were weighed with the same ingredients as in Example 1 and then apologies were used using a 20 mesh sieve. The apple water was mixed and then compressed.

< Comparative example  2> Adefovir Definitely  Preparation of existing tablets containing 2

All components were weighed with the same ingredients as in Example 2, and then apples were used using a 20 mesh sieve. The apple water was mixed and then compressed.

The composition of the components used for the said Examples 1-2 and Comparative Examples 1-2 was put together in Table 1, and was shown.

Ingredient Content (mg / 1 tablet) Example 1 Example 2 Comparative Example 1 Comparative Example 2 Adefovir Difficile 10 10 10 10 Hydroxypropyl Methyl Cellulose 10 - 10 - Povidone - 10 - 10 Crospovidone 80 80 80 80 Magnesium stearate 2 2 2 2 ethanol 100 100 - -

<Analysis>

As a result of X-ray diffraction analysis on the prepared tablets, Examples 1 and 2 showed amorphous adefovir difficile as shown in FIG . 3 , while Comparative Examples 1 and 2 showed crystalline adefovir diffi as shown in FIG . 4 . Compounds were observed.

< Example  3 ~ 12> Adefovir Difference Room Solid dispersion  Preparation of Tablets Containing

As shown in Tables 2 and 3, only the hydrophilic polymer was changed to prepare tablets containing adefovir difficile solid dispersion in the same manner as in Example 1.

Ingredient Content (mg / 1 tablet) Example 3 Example 4 Example 5 Example 6 Example 7 Adefovir Difficile 10 10 10 10 10 Methyl Cellulose 10 - - - - Hydroxymethyl Cellulose - 10 - - - Hydroxyethyl Cellulose - - 10 - - Hydroxypropylcellulose - - - 10 - Carboxymethyl Cellulose - - - - 10 Crospovidone 80 80 80 80 80 Magnesium stearate 2 2 2 2 2 ethanol 100 100 100 100 100

Ingredient Content (mg / 1 tablet) Example 8 Example 9 Example 10 Example 11 Example 12 Adefovir Difficile 10 10 10 10 10 Chitosan 10 - - - - Alginic acid - 10 - - - Carrageenan - - 10 - - Methacrylate copolymer - - - 10 - Polyethylene oxide - - - - 10 Crospovidone 80 80 80 80 80 Magnesium stearate 2 2 2 2 2 ethanol 100 100 100 100 100

One exemplary X-ray diffraction test of the manufactured tablet results, Examples 3 to 12 was observed adefovir Diffie Fifi amorphous as shown in Fig.

< Example  13-16> Adefovir Difference Room Solid dispersion  Preparation of Tablets Containing

As shown in Table 4, only the amount of hydroxypropyl methyl cellulose was changed to prepare a tablet containing adefovir difficile solid dispersion in the same manner as in Example 1.

Ingredient Content (mg / 1 tablet) Example 13 Example 14 Example 15 Example 16 Adefovir Difficile 10 10 10 10 Hydroxypropyl Methyl Cellulose 2.5 5 7.5 20 Crospovidone 80 80 80 80 Magnesium stearate 2 2 2 2 ethanol 100 100 100 100

< Example  17-20 Adefovir Difference Room Solid dispersion  Preparation of Tablets Containing

As shown in Table 5, only the amount of povidone was changed to prepare a tablet containing adefovir difficile solid dispersion in the same manner as in Example 1.

Ingredient Content (mg / 1 tablet) Example 17 Example 18 Example 19 Example 20 Adefovir Difficile 10 10 10 10 Povidone 2.5 5 7.5 20 Crospovidone 80 80 80 80 Magnesium stearate 2 2 2 2 ethanol 100 100 100 100

< Experimental Example  1> crystalline Adefovir Difficile  Crystalline Conversion Test

(One) Commercially available  Crystalline transition

A commercial "hepsera" formulation with adefovir difficile of Form 1 was stored at 40 ° C. and 75% relative humidity for 3 days and then subjected to X-ray diffraction analysis. Thereafter, the preparation was dried at 60 ° C. and then subjected to X-ray diffraction analysis.

The test results are shown in Fig.

In FIG. 1 , (a) shows the X-ray diffraction spectrum of a commercial formulation, (b) shows the X-ray diffraction spectrum when the commercial preparation is left at high humidity, and (c) the dry commercially produced product left at the high humidity again. The X-ray diffraction spectrum in the case of making it appear.

As shown in FIG . 1 , when the commercial preparation is left at high humidity, it can be seen that the 6.9 degrees peak, which is the X-ray diffraction peak of Form 1, disappears, and 24.3 degrees, which is the X-ray diffraction peak of Form 2, is generated. In addition, it can be seen that when the commercially available product left at the high humidity is dried again, a 6.9 ° peak, which is the X-ray diffraction peak of Form 1, is generated, and a 32.8 ° peak, which is the X-ray diffraction peak of Crystal Form 2, disappears. Therefore, it can be seen that adefovir difficile in commercially available formulations converts the crystal form depending on the storage conditions.

(2) New Crystallinity Adefovir Difficile  Crystalline transition

Adefovir difficile (hereinafter referred to as crystalline adefovir difficile) having a crystalline form different from that of a commercially available formulation was stored in the same manner as in (1) at 40 ° C. and a relative humidity of 75% for 3 days, followed by X-ray diffraction analysis. . Thereafter, the novel crystalline adefovir difficile was dried at 60 ° C. and subjected to X-ray diffraction analysis again.

The test results is shown in Fig.

In FIG. 2 , (a) shows the X-ray diffraction spectrum of the novel crystalline adefovir difficile, (b) shows the X-ray diffraction spectrum when the novel crystalline adefovir difficile was left at high humidity, and (c) the high humidity. The X-ray diffraction spectrum at the time of drying again the crystalline adefovir difficile which was left to stand is shown.

As shown in FIG . 2 , when the commercially available product was left at high humidity, the 6.4 and 13.5 ° peaks of the new crystalline X-ray diffraction peaks disappeared, and the X-ray diffraction peaks of crystalline Form 2 16.3 and 24.3 ° were produced. Can be. In addition, when the commercially available product left at the high humidity was dried again, 6.4, 13.5 ° peaks of the new crystalline form and 6.9 ° peaks, the X-ray diffraction peak of Crystal Form 1 were generated. Therefore, even in the case of adefovir difficile having a different crystal form, it can be seen that the crystal form is converted according to the storage conditions.

< Experimental Example  2> stability test

In order to determine the stability of the tablet containing the amorphous adefovir difficile solid dispersion prepared according to the present invention was carried out the following test.

Tablets containing amorphous adefovir difficile solid dispersions prepared in Examples 1, 2 and 13 to 20 were stored at 40 ° C. and 75% relative humidity for 2 months, and then subjected to X-ray diffraction analysis.

The analysis results are shown in FIG. 6 .

As shown in Figure 6 , even after two months of storage at high humidity it can be seen that the adefovir difficile of the tablet containing the amorphous adefovir difficile solid dispersion according to the present invention remains amorphous.

Therefore, it can be seen that the amorphous adefovir difficile solid dispersion according to the present invention does not convert into a crystalline form even when stored for a long period of time at high humidity, thereby having stability.

< Experimental Example  3> Solubility Test

In order to determine the solubility of the amorphous adefovir difficile solid dispersion according to the present invention was carried out the following test.

(1) Standard Solution Preparation

50 mg of adefovir difficile standard was accurately taken into a 50 ml volumetric flask, dissolved in a pH 3.0 phosphate buffer (9 tablets): acetonitrile (1: 4) mixture, and labeled.

(2) sample preparation

Accurately take 1 g of adefovir difficile solid dispersion prepared in the commercially available formulation (hepsera) or Examples 1, 2, 13-20, and place in a 10 ml flask, and mark with pH 7.2 phosphate buffer (30 tablets). It was left to stand on a water bath for 12 hours. It was diluted 10-fold with the first solution of disintegration test method (9 tablets).

(3) Quantitative Analysis

The solubility was calculated by quantitative analysis under the following conditions using high performance liquid chromatography (HPLC) for the standard solution and the sample solution prepared in (1) and (2).

Detector: ultraviolet absorbance photometer (wavelength: 260 nm)

Column: Altech Mixed Mode Anion Exchange C8, 7 μm, 250 mm × 4.6 mm

Mobile phase: phosphate buffer (pH 6.0) and acetonitrile mixture (6: 4)

Flow rate: 1.2 ml / min

The analysis results are shown in Table 6.

division Solubility (mg / ml) Commercially available 0.37 Example 1 1.18 Example 2 0.75 Example 13 1.31 Example 14 1.24 Example 15 1.05 Example 16 1.88 Example 17 0.75 Example 18 0.68 Example 19 0.86 Example 20 0.82

As shown in Table 6, it can be seen that the adefovir difficile solid dispersion according to the present invention has a solubility two times higher than that of a commercially available formulation.

On the other hand, the amorphous adefovir difficile solid dispersion according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the amorphous adefovir difficile solid dispersion according to the present invention as an active ingredient, but the present invention is not limited thereto.

Preparation Example 1 Preparation of Pharmaceutical Formulation

1. Preparation of tablets

100 mg of adefovir difficile solid dispersion according to the present invention

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

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

2. Preparation of Capsule

100 mg of adefovir difficile solid dispersion according to the present invention

100 mg corn starch

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.

1 is an X-ray diffraction graph showing the crystalline conversion of a commercially available formulation when stored at high humidity ((a) adefovir difficile agent of a commercially available formulation, (b) when stored at high humidity, and (c) when dried).

FIG. 2 is an X-ray diffraction graph showing the crystalline transformation of another crystalline adefovir difficile when stored at high humidity ((a) another crystalline adefovir difficile, (b) stored at high humidity, (c) dry) .

3 is an X-ray diffraction graph of adefovir difficile solid dispersions according to Examples 1 and 2 of the present invention.

4 is an X-ray diffraction graph of adefovir difficile solid dispersions according to Examples 1 and 2 and Comparative Examples 1 and 2. FIG.

5 is an X-ray diffraction graph of adefovir difficile solid dispersions according to Examples 3 to 12 of the present invention.

6 is an X-ray diffraction graph after storage at high humidity of the adefovir difficile solid dispersion according to an embodiment of the present invention.

Claims (13)

delete delete delete Completely dissolving adefovir difficile and the hydrophilic polymer as an active ingredient in a solvent (step 1); And After drying the solution prepared in step 1, sizing to prepare a solid dispersion (step 2) comprising the improved stability of adefovir difficile solid dispersion comprising the step. The method of claim 4, wherein the solvent is ethanol. Mixing and melting adefovir difficile and a hydrophilic polymer as the active ingredient (step 1); And Cooling the melt blend prepared in step 1, and then sizing to prepare a solid dispersion (step 2) comprising the improved stability of adefovir difficile solid dispersion comprising the step. The method of claim 4 or 6, wherein the adefovir difficile of step 1 is amorphous or crystalline, characterized in that the improved stability of adefovir difficile solid dispersion. 8. The stable adefovir difficile solid according to claim 7, wherein the crystalline form is Form 1 (anhydrous form), Form 2 (hydrate form), Form 3 (methanol solvate form) or Form 4 (fumarate form). Method for preparing a dispersion. The method according to claim 4 or 6, wherein the hydrophilic polymer is hydroxypropylmethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, chitosan, alginic acid, carrageenan, meta A method for preparing stability improved adefovir difficile solid dispersion, characterized in that it is selected from the group consisting of acrylate copolymer, polyethylene oxide, povidone and mixtures thereof. 9. The method of claim 8, wherein the hydrophilic polymer is hydroxypropylmethylcellulose or povidone. An oral solid preparation comprising adefovir difficile solid dispersion prepared by the method of claim 4 or 6. Oral solids for the treatment of chronic hepatitis B comprising adefovir difficile solid dispersion prepared by the method of claim 4 or 6. 13. The oral solid according to claim 11 or 12, wherein the oral solid agent is a granule or a tablet.

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