KR20170075090A - Oral pharmaceutical composition and manufacturing method thereof - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition comprising a water-soluble polymer and a solid dispersion containing an amorphous active pharmaceutical ingredient (API) dispersed in the water-soluble polymer, and a preparation method thereof. Since the oral pharmaceutical composition according to the present invention contains a solid dispersion containing an amorphous API, it exhibits high solubility and excellent bioavailability, and since the oral pharmaceutical composition is prepared through the spray drying method, It is possible to provide a method for producing an oral pharmaceutical composition which does not affect stability.

Description

TECHNICAL FIELD [0001] The present invention relates to an oral pharmaceutical composition and a manufacturing method thereof,

The present invention relates to an oral pharmaceutical composition and a preparation method thereof, and more particularly, to an oral pharmaceutical composition having excellent bioavailability by containing a solid dispersion containing an active pharmaceutical ingredient (API) And a manufacturing method thereof.

The drug is not administered to the human body as it is in the chemical state, but is formulated into a formulation easy for the patient to take or use, or a formulation capable of effectively and effectively expressing the pharmacological effect, and administered via various routes. The administered drug moves to the appropriate place or is absorbed, is distributed to each organ in the bloodstream, is metabolized, excreted through the urine, sometimes through the respiratory tract, and disappears from the human body. High bioavailability should be ensured to effectively treat the drug.

Bioavailability refers to the degree of drug used at the site of interest after administration. When administered orally to a poorly water soluble drug, the bioavailability is negatively impacted It is pointed out. For example, in the case of an oral pharmaceutical composition containing an active pharmaceutical ingredient (API) having a low solubility in water, it is difficult to develop a formulation when it is prepared in a liquid form and it is prepared in the form of tablets or capsules, , The solubility and dissolution rate in the digestive juices are low in the process of being absorbed in vivo, so that it is difficult to exert proper therapeutic effects by eliminating and excretion in the gastrointestinal tract before transition to the systemic circulation.

Techniques for improving the solubility in water by reducing the size of the API particles have been used as a method for solving the problem.

In this conventional method, a technique for producing fine particles using wet grinding is disclosed in Patent Document 1 (US 5,145,684). In this patent, a pharmaceutical material is added to a liquid medium that is hardly dissolved, a surface modifier is added to make a premix, and then a ball mill, an art mill, a vibratory mill, a sand mill and a bead mill, Lt; RTI ID = 0.0 > 400nm. ≪ / RTI > Since this dispersion is present as a suspension, it is subjected to a drying process to obtain solid fine particles. However, according to Patent Document 1, the milling process time is long and the risk of drug contamination arising from the milling medium may occur.

One of the techniques for producing fine particles using a high-pressure homogenizer is disclosed in Patent Document 2 (US 5,858,410). According to Patent Document 2, a suspension obtained by suspending a pure active ingredient or a mixture of active ingredients insoluble or hardly soluble at room temperature in water or an aqueous medium is subjected to high pressure homogenization treatment in a piston gap homogeniser, Thereby forming particles having an average diameter of 10 nm to 1000 nm as measured by an analytical method. However, when the method of reducing the particle size using the high-pressure homogenizer as described above is used, high energy and a large number of process steps are required, there is a risk of damaging the drug due to heat energy generated in the process, Drug contamination may occur due to metal debris generated from machine wear.

In addition, the manufacturing method according to the prior art has a disadvantage in that the production yield is low due to a low production yield, and even if the particle size is small, there is a limit to improve its solubility as long as it has a crystalline structure.

US 5145684 B US 5858410 B

The object of the present invention is to provide an oral pharmaceutical composition having high solubility and improved bioavailability by including a solid dispersion containing an amorphous API.

Another problem to be solved by the present invention is to provide a method for producing an oral pharmaceutical composition which has high production efficiency and does not affect the stability of a drug by using a spray drying method.

In order to solve the above problems, the present invention provides an oral pharmaceutical composition comprising a water-soluble polymer and a solid dispersion containing an amorphous active pharmaceutical ingredient (API) dispersed in the water-soluble polymer to provide.

The amorphous API dispersed in the water-soluble polymer may be formed through spray drying.

The solid dispersion may further contain a surfactant.

The API may include any one selected from the group consisting of ezetimibe, simvastatin, and a mixture thereof.

The content of the water-soluble polymer is preferably 50 to 300 parts by weight based on 100 parts by weight of the API.

The content of the surfactant is preferably 10 to 100 parts by weight based on 100 parts by weight of the API.

The solid dispersion may further contain 1 to 10 parts by weight of a stabilizer based on 100 parts by weight of the API.

In addition, the oral pharmaceutical composition according to the present invention may further comprise one or two or more additives selected from the group consisting of excipients, disintegrants, and glidants, wherein the oral pharmaceutical composition contains the solid dispersion 15 to 50 By weight and 50 to 85% by weight of the additive.

The present invention also relates to a pharmaceutical composition comprising an active pharmaceutical ingredient (API) dissolved in an organic solvent; Adding a water-soluble polymer to the solution in which the API is dissolved to prepare a mixed solution; And spray drying the mixed solution to prepare a solid dispersion in which an amorphous API is dispersed in the water-soluble polymer.

In the step of preparing the mixed solution, a surfactant may be further added.

The organic solvent may be any one or more selected from the group consisting of ethanol, methanol, acetone, and dichloromethane, and the concentration of the mixed solution is preferably 2 to 10% (w / w).

The spray drying may be performed by using any one of a disk type spray dryer and a nozzle type spray dryer or a combination thereof and is carried out under conditions of an air inlet temperature of 85 to 100 ° C and a chamber temperature of 70 to 75 ° C .

The present invention also provides an oral medicament containing the aforementioned medicinal composition for oral administration. The oral medicines may be tableted by direct tabletting.

According to the present invention, it is possible to improve the solubility of the API by dissolving a crystalline API having a low solubility in water in an organic solvent, followed by spray drying and solid-dispersing the product in an amorphous form. Accordingly, the oral pharmaceutical composition comprising the solid dispersion containing the amorphous API according to the present invention exhibits a high bioavailability and can be useful for preventing or treating diseases.

In addition, since the pharmaceutical composition for oral use according to the present invention is produced by using the spray drying method, not only the production efficiency is high but also the method of reducing the particle size and increasing the solubility of the API, It is possible to solve the contamination problem of the drug that has been generated, and thus the stability of the drug can be secured.

FIG. 1 schematically shows a solid dispersion in which an amorphous API is dispersed among water-soluble polymers according to an embodiment of the present invention.
Fig. 2 is a photograph of a spray dryer used in Example 1 and a spray drying section. Fig.
3 is a graph comparing solubilities of ezetimibe in the solid dispersion prepared according to Examples 1 to 3 and pH of the ezetimibe in the mixed powder according to the comparative example.
4 is a graph comparing the solubilities of simvastatin in the solid dispersion prepared according to Examples 1 to 3 and simvastatin in the mixed powder according to the comparative example by pH.
5 is a SEM photograph of the solid dispersion prepared according to Example 1. Fig.
FIG. 6 shows XRD analysis results of the solid dispersion prepared according to Examples 1 and 2, the mixed powder according to the comparative example, and hydroxypropyl methylcellulose (trade name: AnyCoat AN6).

The present invention relates to an oral pharmaceutical composition comprising a water-soluble polymer and a solid dispersion containing an amorphous active pharmaceutical ingredient (API) dispersed in the water-soluble polymer, and a preparation method thereof.

The amorphous API dispersed in the water-soluble polymer may be formed through spray drying.

The API refers to a raw material drug just before the production of a drug that is easy to administer to humans. It is estimated that approximately 40% of the existing API and a much higher proportion of all newly developed drugs are water insoluble or insoluble . This can be found in a crystal structure of the API, and when a drug prepared from a pharmaceutical composition containing a crystalline API is orally administered, the drug elution characteristics are poor and the bioavailability may be lowered.

The present inventors have found that when an insoluble API having a low solubility in water is dissolved in an organic solvent and then mixed with a water-soluble polymer and solid-dispersed by a spray drying method, the structure of the API is converted to an amorphous form, And the oral pharmaceutical composition prepared using the same has a high dissolution rate and a high dissolution rate, and thus has excellent bioavailability. Thus, the present invention has been completed.

 Examples of the insoluble API having a low solubility in water are xanthan, tadalafil, phenobibrate, cholecalciferol (vitamin D), simvastatin, ezetimibe, ketoprofen, celecoxib, candesartan, NSAIDs such as statins, sirolimus, naproxen and ibuprofen, megestrol acetate, retinavir (HIV protease inhibitor) or cyclosporin.

Among these APIs, the poorly soluble API preferably used in the present invention is ezetimibe, simvastatin, fenofibrate, sirolimus, ketoprofen, celecoxib wherein the API is any one or more selected from the group consisting of celecoxib, candesartan and atorvastatin, more preferably the API is selected from the group consisting of ezetimibe, simvastatin and mixtures thereof And may include any one of them.

The above ezetimibe is an azetidinone-based drug, and its chemical name is [1- (4-fluorophenyl) - (3R) - [3- (4- fluorophenyl) - (3S) -hydroxypropyl] - (4S) - (4-hydroxyphenyl) -2-azetidinone). Ezetimibe acts on Niemann-Pick C1 Like 1 protein in the apical membrane of the small intestinal epithelium to inhibit the absorption of cholesterol in food and bile Concomitant use of simvastatin as a depressant can significantly improve the effect of LDL-C reduction. Particularly, since the above-mentioned ezetimibe and simvastatin have different mechanisms of action, a complementary effect can be expected when they are used together.

However, the above-mentioned agents such as ezetimibe and simvastatin are BCS (Biopharmaceutical Classification System) Class II drugs, which have a low solubility and thus have a low dissolution rate in the digestive juices. As a result, they are excreted before they are absorbed into the living body. Accordingly, as an example of a method for improving the absorption rate of drugs by improving solubility of the above-mentioned ezetimibe and simvastatin, the present invention proposes a method of dissolving them in an organic solvent and then dispersing them in a water-soluble polymer to convert them into an amorphous structure have. When the amorphous structure is converted into the amorphous structure as described above, the solubility of ezetimibe and simvastatin is further increased, and a superior drug absorption rate can be exhibited. Such ezetimibe and simvastain can improve the bioavailability in the body and, as a result, can exert an excellent effect for prevention and treatment of hyperlipemia.

The water-soluble polymer serves as a base for dispersing the API in the solid dispersion. FIG. 1 schematically shows a solid dispersion including an amorphous API uniformly dispersed between water-soluble polymers. The water-soluble polymer also affects the solubility of the API. For example, referring to FIGS. 3 and 4 which show solubilities of ezetimibe and simvastatin corresponding to the API in the solid dispersion prepared according to Examples 1 to 3 of the present invention The higher the content of the water-soluble polymer, the higher the solubility of the API. However, if the content of the water-soluble polymer is excessive, the content of the API may be relatively low to lower the therapeutic effect. Therefore, the content of the water-soluble polymer is preferably 50 to 300 parts by weight based on 100 parts by weight of the API desirable.

Examples of the water-soluble polymer include hydroxypropylmethyl cellulose, hydroxypropylbutyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Hydroxybutyl cellulose, hydroxypentyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol may be included in the composition of the present invention, , And more preferably hydroxypropylmethylcellulose.

The solid dispersion may further contain a surfactant. The surfactant helps the API and the water-soluble polymer to be effectively solubilized in the process of preparing the medicinal composition for oral use according to the present invention, and thus helps the API to be uniformly dispersed in the water-soluble polymer. The content of the surfactant may be 10 to 100 parts by weight based on 100 parts by weight of the API. When the content is less than 10 parts by weight, it is difficult to effectively solubilize the API. When the content exceeds 100 parts by weight, It may cause adverse effects on the user. Examples of the surfactant include, but are not limited to, polyoxyethylene (POE) -20-sorbitan monooleate, Tween 80, Crillet 4, and the like, as long as they do not affect the drug efficacy of the oral pharmaceutical composition. 4), polyoxyethylene (POE) -20-sorbitan monolaurate, Tween 60, Tween 40, Tween 20, Crillet 1, Poloxamer 188 Polyoxyethylene (POE) -10-oleyl ether and oleyl ether or Breeze < RTI ID = 0.0 > 96V < / RTI > (Poloxamer 188), Pluronic / Lutrol F 68, (Brij 96 V) may be used.

In addition, the solid dispersion according to the present invention may further include a stabilizer for securing the stability of the drug such as oxidation inhibition. The content of the stabilizer may be 1 to 10 parts by weight based on 100 parts by weight of the API. When the content is less than 1 part by weight, the stability of the drug is insufficient. On the other hand, It may cause adverse effects on the user. As the stabilizer, any stabilizers may be used without limitation as long as they do not affect the efficacy of the pharmaceutical composition for oral administration. Examples of the stabilizer include butylhydroxyanisole, butylhydroxytoluene, carotene, retinol, ascorbic acid, tocopherol, tocopherol polyethylene glycol succinic acid, A cyclic compound of a saccharide such as cyclodextrin, carboxyethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutyl ether or cyclodextrin, an antioxidant such as an antioxidant such as lactose, Organic acids such as acid, propionic acid, gluconic acid or glucuronic acid, and the like can be used.

The oral pharmaceutical composition according to the present invention may further comprise any one or two or more additives selected from the group consisting of excipients, disintegrants, and glidants.

The excipient serves as a substance that improves the ease of tableting and maintains the tablet form. Such excipients include starch (e.g., potato starch, corn starch, wheat starch, pregelatinized starch), microcrystalline cellulose (e.g., low hydrated microcrystalline cellulose), lactose (e.g., lactose monohydrate, Anhydrous calcium carbonate, calcium phosphate anhydrous or sprayed lactose, glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salts, clay, polyethylene glycol and dicalcium phosphate, anhydrous calcium hydrogen phosphate or silicon dioxide may be used alone or in combination It is not.

The disintegant is added to facilitate disintegration or disintegration of the solid dosage form after vital administration. Examples of the disintegrant include starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clays such as bentonite, montmorillonite, and veegum; Cellulose such as microcrystalline cellulose, hydroxypropylcellulose or carboxymethylcellulose; Alginic acid such as sodium alginate or alginic acid, and cross-linked cellulose such as croscarmellose sodium; Guar gum, xanthan gum and the like, crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone) and the like; Sodium bicarbonate, citric acid and the like may be used alone or in combination, but the present invention is not limited thereto.

The glidant improves the fluidity of the powder and increases the filling of the die, which is the lower part of the tablet machine, and the gap between the powder and the punch-die, which is the upper part of the powder and the tablet, Thereby reducing friction and facilitating compression and release of the tablet. Examples of such lubricants include silicon dioxide, talc, stearic acid, metal salts of stearic acid (such as magnesium or calcium salts), sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monostearate Or polyethylene glycol may be used alone or in combination, but the present invention is not limited thereto.

The oral pharmaceutical composition may contain 15 to 50% by weight of the solid dispersion and 50 to 85% by weight of the additive. When the content of the pharmaceutical composition is within the above range, the oral bioavailability of the API is high and an oral pharmaceutical agent capable of providing an excellent therapeutic effect can be obtained.

According to another aspect of the present invention, there is provided a method for preparing an oral pharmaceutical composition comprising dissolving an active pharmaceutical ingredient (API) in an organic solvent; Adding a water-soluble polymer to the solution in which the API is dissolved to prepare a mixed solution; And spray drying the mixed solution to prepare a solid dispersion in which an amorphous API is dispersed in the water-soluble polymer.

Examples of the API that can be used in the above production method are as described above. Particularly preferably, the API may include any one selected from the group consisting of ezetimibe, simvastatin and a mixture thereof.

The poorly soluble API is usually a substance having a crystal structure, and the crystal structure may be converted to an amorphous state during the spray drying process according to the production method of the present invention. The API converted to amorphous has a much higher solubility and a faster dissolution rate than the crystalline form. The advantages of this crystal-to-amorphous API have been particularly evident in the case of substances with low solubility in water, such as ezetimibe and simvastatin, and this crystal structure contributes greatly to the elution properties and bioavailability of the drug .

The organic solvent is used to dissolve API having low solubility in water, and any one or two or more selected from the group consisting of ethanol, methanol, acetone, and dichloromethane can be used. The concentration of the mixed solution may be in the range of 2 to 10% (w / w), more preferably in the range of 2.5 to 3 (w / w) % (w / w). In this case, the unit% (w / w) of the concentration represents the number of solutes contained in 100 g of the mixed solution.

The content of the water-soluble polymer added to the solution in which the API is dissolved in the organic solvent may be 50-300 parts by weight based on 100 parts by weight of the API as described above. Examples of the water-soluble polymer include hydroxypropylmethyl cellulose cellulose, hydroxypropylbutyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, Hydroxypentyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol. The solvent may be used alone or in admixture of two or more selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol.

According to the method for producing an oral pharmaceutical composition of the present invention, a surfactant may be further added in the step of preparing the mixed solution. The amount of the surfactant added is preferably 10 to 100 parts by weight based on 100 parts by weight of the API. When the added amount of the surfactant is within the above range, the API is preferable in terms of effective solubilization and therapeutic effect. The surfactant may be added together with the water-soluble polymer to the step of preparing the mixed solution, or may be added to the solution after the water-soluble polymer is dissolved in the solution in which the API is dissolved to prepare a mixed solution. The kind of the surfactant used at this time is as described above.

The stabilizing agent may be added to the step of preparing the mixed solution, and the stabilizing agent may be added together with the water-soluble polymer to the step of preparing the mixed solution like the surfactant, or the API May be added to the solution after the water-soluble polymer is dissolved in the solution. The amount of the stabilizer added may be 1 to 10 parts by weight based on 100 parts by weight of the API. When the added amount of the stabilizer is within the above range, stability of the API in the solid dispersion or therapeutic effect is preferable. The kind of the stabilizer used at this time is as described above.

In the present invention, it is preferable that the spray drying is performed under conditions of an air inlet temperature of 85-100 ° C. and a chamber temperature of 70-75 ° C. Through this spray drying method, a crystalline API having a low solubility in water It is converted into an amorphous structure and is uniformly dispersed in the water-soluble polymer. In addition, the spray drying can be performed using a conventional spray dryer well known in the art, and can be preferably performed by using any one or a combination of a disk type spray dryer and a nozzle type spray dryer. For example, when a disk type spray dryer is used, the spray drying can be carried out at a disk rotation speed of 7,000 to 10,000 rpm / min and a flow rate of 16 to 20 kg / h.

The amorphous API prepared through this process has excellent solubility in water, and therefore, the solid dispersion in which the API is dispersed in the water-soluble polymer also has a high solubility. Therefore, the oral pharmaceutical composition containing the solid dispersion exhibits high dissolution characteristics and thus has excellent bioavailability.

The present invention also provides an oral medicament containing the above-mentioned medicinal composition for oral administration. The oral pharmaceutical preparation may be in the form of one selected from tablets, capsules and liquid preparations.

As the preparation method of the oral pharmaceutical preparation, any conventional method known in the art can be used without limitation. In the case of the tablet type, it can be directly tableted or wet-pressed using a tableting method. Preferably, the present invention provides a method for the manufacture of an oral medicament comprising the step of titrating by direct tabletting. When direct compression is used, the solid dispersion and the additive may be homogeneously mixed and compressed with a tablet-molding compressor to produce an oral drug.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these embodiments.

Example  One

20 g of powdered simvastatin (Teva Pharmaceuticals) and 10 g of Teva Pharmaceuticals were mixed, and the mixed powder was dissolved in 2000 g of a mixed solvent of ethanol and dichloromethane mixed at a volume ratio of 1.5: 8.5.

15 g of hydroxypropylmethylcellulose (HPMC 2910, manufactured by Samsung Fine Chemicals Co., Ltd.) as a water-soluble polymer was added to a solution of simvastatin and agemative dissolved therein, and 5 g of Poloxamer 188 (BASF Corp.) To prepare a mixed solution having a concentration of 2.46% (w / w). At this time, the viscosity of the hydroxypropylmethylcellulose is 6 cps.

Then, 0.55 g of a stabilizer was added to the mixed solution and dissolved. (Sigma-Aldrich Co., LLC.), 0.04 g of butylhydroxyanisole (Merck & Co., Inc.) and 0.04 g of propyl gallate (Merck & Co., Were mixed and used.

The mixed solution in which the surfactant and the stabilizer were dissolved was put into a disk type spray drier and spray-dried to prepare a solid dispersion in which amorphous simvastatin and ezetimibe were dispersed in hydroxypropyl methylcellulose. The spray drying was carried out at an air inlet temperature of 95 캜, a chamber temperature of 70 to 75 캜, a disk rotation rate of 7,500 rpm / min, and a flow rate of 17 kg / h. Referring to FIG. 2, there is shown a photograph showing a state in which the mixed solution is sprayed through the disk type spray dryer, and a schematic view of the spray dryer.

Example  2

Except that 30 g of hydroxypropylmethylcellulose was added to prepare a mixed solution and the concentration of the mixed solution was adjusted to 2.75% (w / w) to prepare a solid dispersion Respectively.

Example  3

A solid dispersion was prepared in the same manner as in Example 1 except that 60 g of hydroxypropylmethylcellulose was added to prepare a mixed solution and the concentration of the mixed solution was adjusted to 3.0% (w / w) .

Comparative Example

20 g of simvastatin in powder form and 10 g of ezetimibe used as raw materials in the above examples were mixed to prepare a mixed powder.

<Evaluation method>

1. Solubility

The solubilities of the solid dispersions prepared according to Examples 1 to 3 and the mixed powders of the comparative examples were compared and measured. Specifically, the solid dispersion and the mixed powder were weighed to give 1 g of the simvastatin and the ezetimibe mixture, and the mixture was added to 250 ml of hydrochloric acid buffer solution (pH 1.2) and 250 ml of water (pH 7), followed by stirring at 25 ° C for 2 hours And then sonicated for 2 hours. Next, the ultrasonic pulverization step was performed by filtering the solution with a 0.45 μm PVDF syringe filter, and analyzing the filtrate using HPLC (high performance liquid chromatography). The results are shown in FIGS. 3 and 4 4.

3 and 4, the solubilities of ezetimibe and simvastatin contained in the solid dispersion prepared according to Examples 1 to 3 were at least three times as high as those of ezetimibe and simvastatin in the pure raw material state (comparative example) And more than ten times more. This demonstrates that the solidly dispersed API through the spray drying method provides a much better solubility than the API in the pure raw material state (comparative example). According to the present invention, solubility of the poorly soluble API can be increased, By using the API, an oral pharmaceutical composition having excellent bioavailability can be provided.

2. SEM analysis

A scanning electron microscope (SEM) photograph was taken to analyze the morphological characteristics of the solid dispersion prepared according to Example 1, and a SEM photograph thereof is shown in FIG. Referring to FIG. 5, the amorphous raw material form in the solid dispersion can be confirmed.

3. XRD (X-ray diffraction) analysis

In order to confirm the crystallographic structure of the solid dispersion prepared according to Examples 1 and 2 and the mixed powder prepared according to the comparative example, the analysis was performed using an X-ray diffractometer, and the results are shown in FIG. At this time, the analytical equipment was an X-ray diffractometer (Rigaku, SmartLab).

Referring to FIG. 6, the XRD analysis of the mixed powder of the comparative example shows that the crystal peaks of simvastatin and ezetimibe, which are raw materials, are very high and clear, and thus the crystallinity is very high. On the other hand, the solid dispersions prepared according to Examples 1 and 2 of the present invention show that the crystal peaks of simvastatin and ezetimibe are very low or almost not appear.

In FIG. 6, AnyCoat AN6 is a material having an amorphous structure which does not exhibit a crystal peak as a result of XRD analysis under the trade name of hydroxypropyl methylcellulose (manufactured by Samsung Fine Chemicals Co., Ltd.). 6, it can be seen that the XRD patterns of the AnyCoat AN6 and the XRD patterns of the solid dispersions of Examples 1 and 2 are similar to each other. From these results, it can be seen that, in the case of simvastatin and ezetimibe dispersed in the water-soluble polymer by the spray drying method according to the present invention, the raw material having a crystalline structure was converted into a substance having an amorphous form.

3 and 4, it can be seen that as the crystal peak height decreases considerably, that is, the solubility increases in Examples 1 and 2 in comparison with the comparative example, The dissolution rate and the water absorption rate of the API are increased proportionally, so that the bioavailability of the oral pharmaceutical composition containing the solid dispersion prepared according to the present invention can be improved.

While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Should be construed as being included in the scope of the present invention.

Claims (21)

Water-soluble polymers; And
And a solid dispersion containing an amorphous active pharmaceutical ingredient (API) dispersed in the water-soluble polymer. The method according to claim 1,
Wherein the amorphous API dispersed in the water-soluble polymer is formed through a spray drying method. The method according to claim 1,
Wherein the solid dispersion further comprises a surfactant. The method according to claim 1,
Wherein the API comprises any one selected from the group consisting of ezetimibe, simvastatin, and a mixture thereof. The method according to claim 1,
Wherein the content of the water-soluble polymer is 50 to 300 parts by weight based on 100 parts by weight of the API. The method according to claim 1,
The water-soluble polymer may be selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropylbutyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, , Hydroxybutyl cellulose, hydroxypentyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol. In the present invention, it is preferable that the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose, polyvinyl pyrrolidone, Oral pharmaceutical composition. The method of claim 3,
Wherein the content of the surfactant is 10 to 100 parts by weight based on 100 parts by weight of the API. The method according to claim 1,
Wherein the solid dispersion further comprises 1 to 10 parts by weight of a stabilizer based on 100 parts by weight of the API. The method according to claim 1,
Wherein the oral pharmaceutical composition further comprises one or more additives selected from the group consisting of an excipient, a disintegrant, and a glidant. 10. The method of claim 9,
Wherein the oral pharmaceutical composition comprises 15 to 50% by weight of the solid dispersion and 50 to 85% by weight of the additive. Dissolving an active pharmaceutical ingredient (API) in an organic solvent;
Adding a water-soluble polymer to the solution in which the API is dissolved to prepare a mixed solution; And
And spray drying the mixed solution to prepare a solid dispersion in which an amorphous API is dispersed in the water-soluble polymer. 12. The method of claim 11,
Wherein the surfactant is further added in the step of preparing the mixed solution. 12. The method of claim 11,
Wherein the API comprises any one selected from the group consisting of ezetimibe, simvastatin, and a mixture thereof. 12. The method of claim 11,
Wherein the organic solvent is one or more selected from the group consisting of ethanol, methanol, acetone, and dichloromethane. 12. The method of claim 11,
Wherein the concentration of the mixed solution is 2 to 10% (w / w). 12. The method of claim 11,
Wherein the water-soluble polymer is added in an amount of 50 to 300 parts by weight based on 100 parts by weight of the API. 12. The method of claim 11,
The water-soluble polymer may be selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropylbutyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, , Hydroxybutyl cellulose, hydroxypentyl cellulose, polyvinyl pyrrolidone, and polyvinyl alcohol. In the present invention, it is preferable that the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose, polyvinyl pyrrolidone, A method for producing an oral pharmaceutical composition. 13. The method of claim 12,
Wherein the chelating agent is added in an amount of 10 to 100 parts by weight based on 100 parts by weight of the API. 12. The method of claim 11,
Wherein the stabilizer is added in an amount of 1 to 10 parts by weight based on 100 parts by weight of the API and mixed in the step of preparing the mixed solution. 12. The method of claim 11,
The spray drying is performed by using any one of a disk-type spray dryer and a nozzle-type spray dryer or a combination thereof, and the spray drying is performed under conditions of an air inlet temperature of 85 to 100 ° C and a chamber temperature of 70 to 75 ° C Wherein the pharmaceutical composition is an oral pharmaceutical composition. An oral pharmaceutical preparation comprising the oral pharmaceutical composition according to any one of claims 1 to 10.

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