KR102485766B1 - Pharmaceutical Composition Comprising Pioglitazone with Enhanced Bioavailability - Google Patents

Abstract

The pharmaceutical composition for oral administration of pioglitazone according to the present invention is an improved version of the conventional formulation containing pioglitazone, which has low bioavailability in a high pH environment, and is characterized by high bioavailability and low variation in bioavailability depending on the patient's constitution.

Description

Pharmaceutical composition containing pioglitazone with improved bioavailability {Pharmaceutical Composition Comprising Pioglitazone with Enhanced Bioavailability}

The present invention relates to an orally administered pharmaceutical composition comprising pioglitazone or a pharmaceutically acceptable salt thereof as an active ingredient, and more specifically, to a pharmaceutical composition containing pioglitazone that improves bioavailability by inhibiting precipitation of active ingredients due to pH changes. .

Type 2 diabetes is caused by insulin resistance and intrinsic beta cell dysfunction. When insulin resistance occurs, the antilipolytic effect of insulin decreases in adipose tissue, increasing the serum free fatty acid concentration, and in liver and skeletal muscle, glucose uptake decreases and gluconeogenesis increases. In addition, dysfunction of adipocytes secretes a large amount of various cytokines (TNF-α, IL-6, resistin), further aggravating insulin resistance, causing inflammation or atherosclerosis, and inhibiting the insulin-sensitive cytokine adiponectin. secretion is reduced

Pioglitazone belongs to the thiazolidinedione class. As an agonist of the cell's peroxisome proliferator-activated receptor-gamma (PPAR-γ), the agent regulates the expression of various genes by binding to PPAR-γ in various types of cells. In particular, it reduces the production of free fatty acids in adipocytes. It is known to increase adiponectin secretion and directly or indirectly affect adenosine monophosphate dependent protein kinase. This relieves the burden on the pancreas and improves pancreatic function and insulin secretion. In addition, it prevents fat accumulation in tissues that have a large effect on blood sugar rise, such as visceral fat, liver, muscle, and beta cells of the pancreas, induces fat accumulation in subcutaneous fat, and generates nitric oxide in the pancreas and destroys beta cells due to accumulated free fatty acids. acts to prevent it from happening. In addition to the effect of improving insulin resistance, it has also been found to improve the function of pancreatic beta cells, and the preventive effect of type 2 diabetes is also attracting attention.

The currently known bioavailability of pioglitazone is about 83%, which is high, but does not appear to be completely absorbed in the body. When looking at the pharmacokinetic properties of pioglitazone, it can be seen that the absorption and biomembrane permeability of the drug are high and the solubility is low. In particular, pioglitazone is a weakly basic drug and shows lower solubility under basic conditions than under acidic conditions. According to the literature written by Y.Tanaka et al. (Eur J Pharm Sci. 2017 Aug 30; 106:431-438), one of the important reasons for the reduced bioavailability of pioglitazone is that the drug changes from acidic conditions in the stomach to basic conditions in the duodenum. It was found to be a precipitation phenomenon that occurred while moving. That is, pioglitazone dissolved in the stomach moves in a saturated state and is mostly absorbed in the duodenum, but part of the process is precipitated due to basic conditions and is excreted out of the body without being absorbed.

Pioglitazone formulations, including the reference drug currently on the market (Actos Tab., Korea Takeda Pharmaceutical), are on the market without improvement in relation to the above, and show high bioavailability, but as mentioned above, compared to high permeability. Complete absorption of the drug in vivo is not achieved, and since the drug dissolution is very sensitive depending on the pH conditions in vivo between individuals, it can be expected that the variation in bioavailability will appear at a considerable level.

Korean Patent Publication No. 2014-0081826 Korean Patent Publication No. 2009-0109115

In the oral preparation containing pioglitazone or a pharmaceutically acceptable salt thereof of the present invention, oral pioglitazone has better bioavailability and reduced side effects by improving the problem of lower bioavailability of conventional preparations and variation according to patient's constitution. Its object is to provide a formulation for use.

In order to achieve the above object, the present invention is a tablet having improved dissolution rate and bioavailability compared to conventional pioglitazone-containing pharmaceutical preparations by improving the solubility of active ingredients and maintaining a stable dissolution state in basic conditions to prevent precipitation of active ingredients. It provides a pharmaceutical composition in the form of.

Specifically, the pharmaceutical composition of the present invention may include a solid dispersion containing pioglitazone and a pharmaceutically acceptable salt thereof, an adsorbent and a solubilizing agent.

The adsorbent is an excipient included for preparing the solid dispersion into tablets, and is preferably 200 to 700% by weight, more preferably 250 to 650% by weight, and most preferably 250 to 350% by weight based on the total weight of the active ingredient. % by weight. The adsorbent is used to powder the solid dispersion into a form that can be used in formulations. If it is less than the above range, the powder is not well formed. can As the adsorbent, one or two or more selected from the group consisting of calcium silicate, magnesium aluminate silicate, silicon dioxide, microcrystalline cellulose, bentonite, pectin, anhydrous calcium hydrogen phosphate, and tricalcium phosphate may be used.

In addition, the solubilizing agent is a hydrophilic polymer and serves to increase the solubility of pioglitazone, and is preferably 50 to 400% by weight, more preferably 100 to 300% by weight, and most preferably 100 to 400% by weight based on the total weight of the active ingredient. 200% by weight may be included. characterized by inclusion. If the solubilizing agent is less than the above range, the bioavailability of pioglitazone may decrease, and even if the solubilizing agent is included in the above range, significant bioavailability is not improved, which is not preferable. The solubilizing agent is selected from the group consisting of polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, dimethylaminoethyl methacrylate/methyl methacrylate copolymer, polyvinylpyrrolidone, polyethylene glycol, sodium alginate, and carbomer 1 type or 2 or more types can be used.

On the other hand, the solubilizing agent has different effects depending on the viscosity range, preferably 20 to 100 mPa·s, more preferably 30 to 80 mPa·s, and most preferably 40 to 60 mPa·s.

In addition, the pharmaceutical composition is one selected from the group consisting of cyclodextrin, sodium lauryl sulfate, polysorbate, poloxamer, macrogol, polyethylene glycol, polyoxyglyceride, sorbitan monooleate, cremophor, and transcutol or two or more solubilizing agents may be further included, wherein the solubilizing agent is preferably 100 to 300% by weight, more preferably 150 to 250% by weight, and most preferably 170% by weight based on the total weight of pioglitazone as an active ingredient. to 200% by weight.

The pharmaceutical composition according to the present invention further comprises one or more acidifying agents selected from the group consisting of hydrochloric acid, phosphoric acid, fumaric acid, citric acid, propionic acid, acetic acid, ascorbic acid, sorbic acid, succinic acid, ammonium hydrochloride, lactic acid, sulfuric acid, and tartaric acid can do. The acidifying agent serves to adjust the pH around the active ingredient so that pioglitazone can be smoothly dissolved in a high pH environment. In this case, the acidifying agent may be included in an amount of preferably 20 to 100% by weight, more preferably 30 to 70% by weight, and most preferably 40 to 60% by weight, based on the total weight of pioglitazone.

The pharmaceutical composition of the present invention shows excellent dissolution rate and bioavailability compared to conventional pioglitazone preparations, and according to the second dissolution method (paddle method) according to the Korean Pharmacopoeia, pH 6.8 at 37 ° C. After eluted for 30 minutes, it is characterized in that 15% or more of the total active ingredient is eluted.

The pharmaceutical composition of the present invention has excellent solubility of the active ingredient of pioglitazone, and maintains stability even when the surrounding pH environment changes after the active ingredient is dissolved, so that the amount of active ingredient precipitated is low. Therefore, it has an improved dissolution rate and bioavailability compared to conventional pioglitazone-containing pharmaceutical preparations.

1 is a graph showing the results of a comparative dissolution test in 900mL of pH 6.8 dissolution solution between Examples 6 to 13 and a control drug (Actos tablet).
Figure 2 is a graph showing the results of the comparative dissolution test in Examples 14 to 17 and the control drug (Actos tablet) in pH 6.8 eluate 900mL.
Figure 3 is a graph showing the results of the comparative dissolution test in 900mL of pH 6.8 dissolution between Examples 17 to 20 and the control drug (Actos tablet).
4 is a graph showing the results of a comparative dissolution test performed continuously between Example 18 and a control drug (Actos tablet) under acidic conditions (pH 1.2) and basic conditions (pH 6.8).

In order to achieve the above object, the present invention provides an oral tablet with improved dissolution rate compared to conventional formulations and containing pioglitazone or a pharmaceutically acceptable salt thereof as an active ingredient.

The tablet includes a solid dispersion containing a hydrophilic polymer capable of forming a hydrophilic polymer matrix and pioglitazone or a pharmaceutically acceptable salt thereof, and may contain a solubilizing agent such as cyclodextrin. Specific techniques for producing solid dispersions as needed, e.g. solvent-controlled precipitation, solvent evaporation method, spray-drying, hot-melt extrusion extrusion), freeze-drying, and the like can be used.

Hereinafter, the present invention will be described in detail.

Solid dispersion is one of the technologies widely used to increase drug solubility, and is a technology for generating particles in the form of dispersing an amorphous drug in a hydrophilic polymer matrix. Here, the hydrophilic polymer matrix functions as a transporter to deliver the drug in an amorphous state of small particles. The advantages of the solid dispersion in terms of improving the solubility of the drug are as follows. First, it has the effect of inducing the drug to dissolve well in the solvent by increasing the surface area by minimizing the particle size of the drug. Second, the hydrophilic polymer increases the wettability of the drug so that the dissolution rate of the drug can occur quickly, and the hydrophobic interaction between the drug and the polymer, hydrogen bonding, and electrostatic interaction are possible, and the fine viscous effect gives the drug crystallization to have a stable dissolved state. Thirdly, the crystal form of the drug is changed to an amorphous form so that the free volume is large and the molecular mobility is high, so that the energy required to dissolve the drug is reduced so that the dissolution process occurs more smoothly.

In the present invention, a pioglitazone formulation having improved solubility and dissolution rate was invented by preparing and utilizing a solid dispersion in which pioglitazone or a pharmaceutically acceptable salt thereof is dispersed in a hydrophilic polymer matrix. In particular, in the case of producing a solid dispersion, productivity and stability problems are likely to occur depending on the manufacturing process, such as low yield and denaturation due to instability of the drug due to heating. As a result of repeated research in the present invention, the solid dispersion manufacturing process It was possible to secure high productivity and stability by greatly simplifying the adsorption process based on the solvent evaporation method.

Specifically, a hydrophilic polymer is mixed with an organic solvent solution in which pioglitazone or a pharmaceutically acceptable salt thereof is dissolved, and then uniformly dispersed, and then mixed with warm water at about 50° C. to swell and gelate the hydrophilic polymer to obtain a hydrophilic property. to form a polymer matrix. The formed polymer matrix is in a highly viscous gel state, which is adsorbed using an adsorbent to be powdered so that it can be used pharmaceutically. When the powder formed through the process is sufficiently dried, a solid dispersion having high yield and stability is produced.

Hereinafter, the present invention will be described in more detail through Examples and Comparative Examples. The following Examples and Comparative Examples are intended to explain the present invention in more detail, but the scope of the present invention is not limited thereto.

<Examples 1 to 5 and Comparative Example 1: Preparation of powder for pioglitazone hydrophilic polymer screening test>

For the purpose of screening substances that can be used as dissolution aids as polymeric substances capable of increasing the solubility of pioglitazone in basic conditions, all raw materials were added according to the components and contents shown in Table 1 below, and 60% ethanol (water: ethanol = 2:3) The solution was prepared by adding an appropriate amount and mixing uniformly. For the prepared solution, all solvents are dried using an oven dryer, and then powdered through a pulverization process.

(Unit: mg) combination
purpose ingredient name Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 note active ingredient pioglitazone
hydrochloride 16.53 16.53 16.53 16.53 16.53 16.53 15 mg as pioglitazone Dissolution
supplements polyvinyl alcohol - 63.47 - - - - Dissolution
supplements hypromelo 2910 - - 63.47 - - - Dissolution
supplements Hydroxypropyl Cellulose - - - 63.47 - - Dissolution
supplements Dimethyl methacrylate Aminoethylㆍmethyl methacrylate
copolymer - - - - 63.47 - Eudragit ® EPO Dissolution
supplements Povidone K30 - - - - - 63.47 acidifier citric acid 10.00 10.00 10.00 10.00 10.00 10.00 Sum 26.53 90.00 90.00 90.00 90.00 90.00

<Test Example 1> Measurement of solubility in a pH 6.8 environment according to the type of hydrophilic polymer (solubilizer)

In order to check the solubility improvement in basic conditions for each powder prepared in Examples 1 to 5 and Comparative Example 1, pH 6.8 solution (Korean Pharmacopoeia 11th edition Dissolution test method 2nd liquid) Excess powder in 100mL After being added, it was dissolved at 37°C for 24 hours using a shaking constant temperature water bath. Then, the solubility in the pH 6.8 solution of Examples 1 to 5 and Comparative Example 1 was measured using HPLC, and the results are shown in Table 2 below.

division Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Solubility (μg/ml) 0.2 22.06 6.95 0.88 11.16 0.62

As shown in Table 2, when the hydrophilic polymer was included, the solubility was increased compared to the case where the hydrophilic polymer was not included. Therefore, all of the hydrophilic polymers used in the above examples can be used as dissolving aids, and the degree of increase varies greatly depending on the type of polymer. Among the hydrophilic polymers, it was confirmed that the polyvinyl alcohol used in Example 1 showed the highest solubility improving effect.

<Examples 6 to 13: Preparation of pioglitazone solid dispersion powder>

According to the ingredients and contents shown in Table 3 below, after mixing the active ingredient and the acidifying agent, a mixed solution was prepared by adding a mixed solution obtained by mixing water and ethanol at a volume ratio of 1:9. The mixed solution was added to the hydrophilic polymer (solubilizer) and mixed, and then the hydrophilic polymer was appropriately dispersed in the mixed solution, and purified water at about 50° C. was additionally added and kneaded to form a hydrophilic polymer matrix gel. An adsorbent was added to the formed polymer matrix gel, powdered, and sufficiently dried to prepare a solid dispersion powder. In the case of Examples 6 and 10, after drying the polymer matrix gel as it is, the dried film-type film was finely crushed using a mixer or the like to prepare a solid dispersion powder.

(Unit: mg) Blending purpose ingredient name Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 note active ingredient Pioglitazone Hydrochloride 16.53 16.53 16.53 16.53 16.53 16.53 16.53 16.53 15 mg as pioglitazone high viscosity solubilizer polyvinyl alcohol 45 45 45 45 - - - - Viscosity: 43 mPa s low-viscosity solubilizer polyvinyl alcohol - - - - 45 45 45 45 Viscosity: 5.3 mPa s acidifier citric acid 13.47 13.47 13.47 13.47 13.47 13.47 13.47 13.47 absorbent calcium silicate - 100 - - - 100 - - FLORITE PS-200 absorbent Magnesium Silicate Aluminate - - 100 - - - 100 - Neusilin®US2 absorbent silicon dioxide - - - 100 - - - 100 Sylisia®350 Sum 75 175 175 175 75 175 175 175

<Test Example 2>

In order to confirm the degree of solubility improvement of the pioglitazone solid dispersion powder prepared in Examples 6 to 13 in basic conditions, a currently marketed product (Actos tablet, Korea Takeda Pharmaceutical) was used as a control drug, and a pH 6.8 solution (Korean Pharmacopoeia No. 11 A comparative dissolution test was conducted for 1 hour using 900mL of the revised dissolution test method second solution) as an elution solution. The dissolution test was applied with a paddle method of 50 rotations per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2), and the test results are shown in FIG.

As shown in Figure 1, it was confirmed that most of Examples 6 to 13 showed improved dissolution rates and final dissolution rates under basic conditions. In addition, the degree of solubility improvement of the prepared solid dispersion was found to be affected by the viscosity of the hydrophilic polymer used. When comparing Example 6 and Example 10, it was confirmed that Example 6 showed a higher dissolution rate and final dissolution rate. In other words, the higher the viscosity, the higher the solubility of the drug. This means that the higher the viscosity of the hydrophilic polymer, the stronger the hydrophobic interaction, hydrogen bonding, and electrostatic interaction between the drug and the hydrophilic polymer, and the stronger the microviscous effect. It can be assumed from the test results that the crystallization inhibitory effect of the drug is increased and it has a more stable dissolved state.

Therefore, the viscosity of the hydrophilic polymer as a solubilizing agent is preferably at least 20 mPa·s or more. However, when the viscosity exceeds 100 mPa·s, problems such as dissolution of the active ingredient may occur in a sustained release form due to the high viscosity of the polymer are not preferable. More specifically, the solubilizing agent may have a viscosity of 30 to 80 mPa·s, most preferably 40 to 60 mPa·s.

In addition, it was confirmed that there was a difference in dissolution rate depending on whether or not the adsorbent was added to the dissolution results of Examples 6 to 9 using a dissolution aid having a high viscosity and Examples 10 to 13 using a dissolution aid having a low viscosity.

Overall, when the adsorbent was used, a significant level of dissolution rate was reduced compared to when no adsorbent was used. However, powderization of the solid dispersion is absolutely necessary to manufacture into tablets, and since an adsorbent is required for powderization, an adsorbent must be used, but an adsorbent with low dissolution rate inhibition must be selected to prepare the solid dispersion powder. According to the above results, when comparing the degree of decrease in dissolution rate between the adsorbents, the degree of decrease in the dissolution rate in Examples 9 and 13 using silicon dioxide was relatively low compared to Examples 6 and 10, respectively, in which no adsorbent was used. was able to confirm On the other hand, it was confirmed that the effect appeared when the content of the adsorbent was about 600% by weight based on the total weight of pioglitazone. However, as a result of repeated experiments, it was confirmed that the same effect was obtained even when the content of the adsorbent having suitable physical properties was reduced by half. Therefore, silicon dioxide was used as an adsorbent in the final tablet composition including the solid dispersion, and at this time, 50 mg of the adsorbent, which is about 300% by weight based on the total weight of pioglitazone, was included.

<Examples 14 to 20: Preparation of pioglitazone tablets having improved solubility and stable dissolution state>

Pioglitazone tablets were prepared according to the ingredients and contents shown in Table 4 below. First, the active ingredient and the acidifying agent were mixed, and then a mixed solution was prepared by adding a mixture of water and ethanol at a volume ratio of 1:9. The solution was added to polyvinyl alcohol, which is a hydrophilic polymer among dissolution aids, and mixed so that the hydrophilic polymer was properly dispersed in the solution, and purified water at about 50 ° C. was additionally added and kneaded to form a hydrophilic polymer matrix gel. Silicon dioxide as an adsorbent and the rest of the solubilizing agent were added to the formed polymer matrix gel, mixed and powdered, and dried sufficiently to prepare a solid dispersion powder. The remaining components were mixed with the prepared solid dispersion powder, and the mixture was tableted using a rotary tablet press to prepare tablets.

(Unit: mg) Blending purpose ingredient name Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 note active ingredient Pioglitazone Hydrochloride 16.53 16.53 16.53 16.53 16.53 16.53 16.53 15 mg as pioglitazone solubility aid polyvinyl alcohol 50 40 30 20 20 20 20 Viscosity: 43 mPa s solubilizing agent betadex - - - - 30 - - solubilizing agent sodium lauryl sulfate - - - - - 30 - solubilizing agent Polysorbate 80 - - - - - - 30 absorbent silicon dioxide 50 50 50 50 50 50 50 Sylisia®350 excipient lactose hydrate 22 32 42 52 22 22 22 acidifier citric acid 8.47 8.47 8.47 8.47 8.47 8.47 8.47 disintegrant crospovidone 20 20 20 20 20 20 20 glidant Sodium stearyl fumarate 3 3 3 3 3 3 3 PRUV ® Total (mg/tablet) 170 170 170 170 170 170 170

<Test Example 3>

For the pioglitazone tablets prepared in Examples 14 to 17, to confirm the change in dissolution rate according to the content ratio of pioglitazone hydrochloride used as an active ingredient in the solid dispersion and polyvinyl alcohol, a hydrophilic polymer used as a dissolution aid . A comparative dissolution test was conducted for 2 hours using 900mL of a pH 6.8 solution (the second liquid in the 11th edition of the Korean Pharmacopoeia) as an elution solution, using a currently marketed product (Actos Tablet, Takeda Pharmaceutical Korea) as a reference drug. The dissolution test applied a paddle method of 50 rotations per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2), and the test results are shown in FIG. 2.

As a result of the test, it was confirmed that the final dissolution rate and the dissolution rate were improved from Example 16 in which the content of polyvinyl alcohol, a hydrophilic polymer, was reduced to about 200% by weight based on the weight of pioglitazone hydrochloride, an active ingredient. However, even in the case of Examples 14 and 15, the dissolution rate slightly increased until 1 hour, the final dissolution time, so it was expected that the dissolution could continue for a certain period of time even after the final dissolution time. Therefore, even when the hydrophilic polymer content is 300% by weight or more based on the weight of pioglitazone hydrochloride, the pharmacological effect is slightly delayed compared to Example 16, but the same effect is expected to be finally obtained. However, if it exceeds 400% by weight, the expression of the pharmacological effect will be too late, which is not preferable.

<Test Example 4>

For the pioglitazone tablets prepared in Examples 14 to 17, in order to confirm the degree of solubility improvement according to the ratio between the drug and the hydrophilic polymer polyvinyl alcohol in the pioglitazone solid dispersion used for tablet manufacturing, The tablets were added to 200 mL of a pH 6.8 solution (the second liquid of the 11th revision of the Korean Pharmacopoeia), and then dissolved at 37° C. for 24 hours using a shaking water bath, and then the solubility was measured using HPLC.

As a result of the test, as shown in Table 5 below, it was confirmed that the solubility of the tablet prepared in Example 14 was the highest, and the solubility gradually decreased in the order of Examples 15, 16, and 17. That is, when the drug was dissolved over a sufficient period of time, it was confirmed that the tablet containing the solid dispersion having a high ratio of polyvinyl alcohol showed a higher solubility.

division Example 14 Example 15 Example 16 Example 17 Solubility (μg/ml) 15.84 14.72 13.34 13.07

In view of the above test results, it can be seen that the results shown in <Test Example 3> also show that the dissolution is delayed due to the increase in viscosity due to the increase in the content of polyvinyl alcohol, a hydrophilic polymer, rather than the decrease in the dissolution rate due to the decrease in solubility. That is, when the dissolution test is performed with more time than the test time conducted in <Test Example 3>, it suggests that the final dissolution rate may appear highest in Example 14. However, it is difficult to simply define a tablet with high solubility as a tablet that produces the optimal drug effect because the tablet is an immediate-release tablet, so the dissolution should appear in a short time to give a quick effect. That is, considering the dissolution rate and the expression time of the pharmacological effect, it would be appropriate to finally determine the dissolution rate between Example 14 and Example 17 at 1 hour to 2 hours, and as a result, the tablet prepared in Example 16 or 17 It can be evaluated as showing optimal dissolution. However, in the case of Examples 14 and 15, the pharmacological effect onset time is slightly delayed, but it is expected to be equivalent in terms of the final pharmacological effect.

<Test Example 5>

For the pioglitazone tablets prepared in Examples 17 to 20, products currently on the market (Actos tablets, Takeda Korea Pharmaceuticals) as a control drug, a comparative dissolution test was conducted for 2 hours using 900mL of a pH 6.8 solution (the second liquid of the dissolution test method of the 11th revision of the Korean Pharmacopoeia) as an eluent. In the case of Example 18, an inclusion complex was used, and in Examples 19 and 20, a surfactant was used as a solubilizing agent.

The dissolution test applied a paddle method of 50 revolutions per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2), and the test results are shown in FIG. 3.

As a result of the test, it was confirmed that Examples 19 and 20 showed a lower or similar dissolution rate and final dissolution rate compared to Example 17, and Example 18 showed a higher dissolution rate and final dissolution rate than Example 17. That is, it can be confirmed that the solubility improvement of pioglitazone does not occur well through mixing with a surfactant, and the effect of improving the dissolution rate is significantly shown when a part of pioglitazone is included with a material capable of forming an inclusion complex such as cyclodextrin.

<Test Example 6>

For the pioglitazone tablets prepared in Example 18, a comparative dissolution test was conducted using a currently marketed product (Actos tablet, Takeda Pharmaceutical Korea) as a control drug. The dissolution test method is as follows.

Acidic conditions: Using 750 mL of 0.1 mol/L hydrochloric acid solution as the eluent, the paddle method at 75 revolutions per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2) is performed for 1 hour.

Basic condition: 250 mL of 0.2 mol/L sodium phosphate solution was added after the dissolution test under acidic conditions, and the dissolution test was conducted for 2 hours by the paddle method at 50 revolutions per minute (Korean Pharmacopoeia 11th revision, Dissolution test method 2). Conduct.

As a result of the test, both Example 18 and the reference drug showed a dissolution rate approaching 100% under acidic conditions. After that, as the dissolution conditions were changed to basic conditions, the final dissolution rate of the control drug was reduced to about 50%, whereas in Example 18, it was confirmed that the dissolution rate did not decrease at all. That is, when the elution conditions are changed from acidic conditions to basic conditions, in Example 18, unlike the reference drug, precipitation of pioglitazone does not occur. Judging from the results, it can be expected that the bioavailability of the pioglitazone tablet prepared in Example 18 will not decrease due to precipitation that may occur in the duodenum and small intestine during the absorption process.

Claims (9)

pioglitazone and its pharmaceutically acceptable salts; a solid dispersion containing an adsorbent and a solubilizing agent; acidifying agent; And a pharmaceutical composition comprising a solubilizing agent,
With respect to 100 parts by weight of the pioglitazone,
200 to 700 parts by weight of the adsorbent
The solubilizing agent is included in 100 to 300 parts by weight,
The solubilizing agent is selected from the group consisting of polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, dimethylaminoethyl methacrylate/methyl methacrylate copolymer, polyvinylpyrrolidone, polyethylene glycol, sodium alginate, and carbomer 1 type or 2 or more types,
The solubilizing agent is a hydrophilic polymer having a viscosity of 40 to 60 mPa s,
The acidifying agent is one or two or more selected from the group consisting of hydrochloric acid, phosphoric acid, fumaric acid, citric acid, propionic acid, acetic acid, ascorbic acid, sorbic acid, succinic acid, ammonium hydrochloride, lactic acid, sulfuric acid, and tartaric acid,
The acidifying agent is included in 20 to 100 parts by weight,
The solubilizing agent is a pharmaceutical composition that is an inclusion complex.
According to claim 1,
The adsorbent is one or two or more selected from the group consisting of calcium silicate, magnesium aluminate silicate, silicon dioxide, microcrystalline cellulose, bentonite, pectin, anhydrous calcium hydrogen phosphate, and tricalcium phosphate.
delete delete delete According to claim 1,
The solubilizing agent is based on 100 parts by weight of pioglitazone
A pharmaceutical composition that is contained in 100 to 300 parts by weight.
According to claim 1,
The pharmaceutical composition was eluted for 30 minutes in a pH 6.8 elution solution (Korean Pharmacopoeia 11th revision dissolution test method 2nd solution) according to the dissolution method 2 (paddle method) according to the Korean Pharmacopoeia, and then 15% or more of the total active ingredients A pharmaceutical composition, characterized in that eluted. delete delete

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