KR102308227B1 - Oral tablet composition containing sunitinib - Google Patents

Abstract

The present invention relates to an oral tablet composition containing sunitinib and a method for preparing the same, and more particularly, to a sunitinib formulation prepared as a hard capsule, which has the same physicochemical and pharmacological effects as the sunitinib formulation, and is convenient for taking. , handleability, safety, etc. are further improved, to a composition in tablet form and a method for preparing the same.

Description

Oral tablet composition containing sunitinib

The present invention relates to an oral tablet composition containing sunitinib and a method for preparing the same, and more particularly, to a sunitinib formulation prepared as a hard capsule, which has the same physicochemical and pharmacological effects as the sunitinib formulation, and is convenient for taking. , handleability, safety, etc. are further improved, to a composition in tablet form and a method for preparing the same.

Sunitinib, a vascular endothelial growth factor (VEGF) inhibitor, is a compound (SU11248) of an oxoindol structure synthesized and discovered by Sugen, a biotech company, and is involved in cancer growth, proliferation and metastasis. It is a multi-target tyrosine kinase inhibitor that selectively blocks molecular targets (VEGFR1, VEGFR2, VEGFR3, PDGFRa, PDGFRb, KIT, FLT3, CSF1R).

A commercially available formulation of sunitinib, Suten ^® capsules, contains sunitinib malate as an active ingredient, a yellow to orange powder with a pKa of 8.95, well soluble in dimethylsulfoxide (DMSO) but poorly soluble in ethanol and water. , and it is known to show a solubility of about 25 mg/mL or more in an acidic aqueous medium due to the nature of the weak base. The molecular weight of sunitinib is 398.4 (532.6 as sunitinib malate) and the maximum plasma concentration (Cmax) is usually observed between 6 and 12 hours (Tmax) after oral administration. Dietary intake does not affect the bioavailability (BA) of sunitinib, and in vitro binding between human plasma protein and sunitinib and its primary metabolite is 95% and 90%, respectively, and 25 to 100 mg It is known that the area under the plasma concentration-time curve (AUC) and Cmax increase in proportion to the dose over the dose range. In this regard, Korean Patent Application Laid-Open No. 2007-0119745 also discloses a cancer treatment formulation using sunitinib malate. However, while sunitinib malate as an active ingredient accounts for the largest proportion of the composition of the entire composition, it has a bulky feeling and poor flowability. There is a problem that the same additional processes are required.

Suten ^® capsule is a hard capsule formulation containing excipients of mannitol, croscarmellose sodium, povidone, and magnesium stearate in addition to the active ingredient, sunitinib malate, and has been developed in three dosages: 12.5 mg, 25 mg and 50 mg. . These contain 16.7 mg, 33.4 mg, and 66.8 mg of sunitinib malate, respectively, and are filled in gelatin capsules of size No. 4, No. 3, and No. 2, and are packaged in plastic bottles in units of 28 capsules.

In general, in the case of capsules, due to the nature of gelatin, it is vulnerable to moisture, so it is often necessary to pay attention to the production and storage process. In particular, when several formulations are bottled at once rather than individually packaged, gelatin capsules may stick to each other due to storage conditions such as temperature and humidity, so a countermeasure should be taken. In terms of dosage, the capsule may stick to the throat or esophagus in the process of swallowing by a patient, and the drug may be exposed or accompanied by pain, so there is a need to change the capsule to a tablet form to compensate for this. In addition, due to the characteristics of anticancer drugs, it is necessary to reliably shield the external exposure of the drug during distribution and handling. There is a risk that the capsule may break when taken out, exposing the drug. Therefore, when changing the capsule to a tablet, it is necessary to perform sufficient coating using a coating base with proven stability to secure a shielding effect equivalent to or higher than that of the gelatin capsule membrane and safety within the packaging material.

In addition, the Suten ^® capsule formulation has a different ratio of excipients to active ingredient depending on the unit weight, and the 12.5 mg formulation, which is the lowest unit, contains a relatively high ratio of excipients. This difference in composition ratio may affect the release rate of the drug in the body, so caution is required when prescribing the dosage adjustment. In addition, since the volume of the capsule is also not reduced in proportion to the content, when a prescription combining several dosage forms is required, the patient may experience inconvenience in taking it.

An object of the present invention is to prepare a sunitinib tablet composition using sunitinib free base or a pharmaceutically acceptable salt thereof in changing the dosage form of a sunitinib formulation marketed as a hard capsule into a tablet. It is to provide a tablet composition that increases the stability and dissolution deviation of the nib tablet to equal or greater than that of a commercially available capsule formulation containing sunitinib malate, and has excellent pharmacological efficacy and improved productivity.

One aspect of the present invention for solving the above problems relates to an oral tablet composition comprising sunitinib free base or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant and a lubricant as an active ingredient.

According to one embodiment of the present invention, when the oral tablet composition includes sunitinib free base as an active ingredient, an organic acid may be further included.

According to one embodiment of the present invention, the organic acid is selected from fumaric acid, malic acid, tartaric acid, maleic acid, carboxylic acid, acrylic acid, tartaric acid, citric acid, acetic acid, succinic acid, lactic acid, succinic acid, malonic acid, glutaric acid, and combinations thereof. and may be selected from, for example, fumaric acid, maleic acid, and combinations thereof.

According to one embodiment of the present invention, the oral tablet composition may contain 5% to 30% by weight of the active ingredient based on the total weight of the tablet.

According to one embodiment of the present invention, when the oral tablet composition includes sunitinib free base as an active ingredient, it may contain 0.01 to 5 parts by weight of an organic acid based on 1 part by weight of sunitinib free base.

According to one embodiment of the present invention, the content of the diluent included in the oral tablet composition is 1 to 30 parts by weight based on 1 part by weight of the active ingredient, and the content of the disintegrant is 1 to 10 parts by weight based on 100 parts by weight of the total composition. parts by weight, and the amount of the lubricant may be 0.1 to 5 parts by weight based on 100 parts by weight of the total composition.

According to one embodiment of the present invention, the oral tablet composition may further include a binder. The content of the binder may be 0.5 to 10 parts by weight based on 100 parts by weight of the total composition.

According to one embodiment of the present invention, the oral tablet composition may further include a coating layer, wherein the content of the coating layer may be 1 to 30 parts by weight based on 100 parts by weight of the tablet (uncoated tablet) before coating.

According to one embodiment of the present invention, the content ratio of each component may be constant regardless of the content of the active ingredient in the oral tablet composition.

According to one embodiment of the present invention, in the oral tablet composition, the volume of the tablet may be proportional to the content of the active ingredient.

Another aspect of the present invention is a step of mixing sunitinib or a pharmaceutically acceptable salt thereof, an excipient, a binder, a disintegrant, a lubricant and optionally an organic acid, and tabletting the mixture to tablet before coating (uncoated tablet) It relates to a method for producing an oral tablet according to the present invention, comprising the steps of preparing a tablet, and coating the surface of the uncoated tablet with a coating base.

The oral tablet composition containing sunitinib according to the present invention reduces the volume of the formulation compared to the capsule formulation, thereby increasing the convenience of patients in taking it, as well as easy handling in the production process, and stability in the packaging and storage process. The problem also has the advantage that it can be improved.

In addition, the oral tablet composition containing sunitinib according to the present invention is effective because the drug release deviation is small compared to the existing hard capsule formulation, and pharmacological equivalence to that of the hard capsule formulation was confirmed in a non-clinical test. A therapeutic effect can be expected. Moreover, compared to the commercial formulation, the same effect can be obtained even with a small amount of active ingredient, and not only the application of the formulation process is advantageous due to the low active ingredient content, but also the production yield can be improved.

Moreover, when a tablet composition is prepared using the salt-removed sunitinib free base, the molecular weight of the free base is relatively small and the specific gravity of the active ingredient in the composition is low, so it has the advantage of having less effect on the tablet manufacturing process, and most Since the active ingredient of

1 is a graph showing the dissolution pattern in a pH 1.2 solution of oral tablet compositions prepared according to Examples and Comparative Examples of the present invention.
2 is a graph showing the dissolution pattern in the pH 4.0 solution of the oral tablet composition prepared according to the Examples and Comparative Examples of the present invention.
3 is a graph showing the dissolution pattern in water of oral tablet compositions prepared according to Examples and Comparative Examples of the present invention.

Definition of Terms

Unless explicitly stated otherwise, some terms used throughout this specification may be defined as follows.

Throughout this specification, unless otherwise specified, "included" or "containing" refers to including any component (or component) without particular limitation, and excludes the addition of other components (or components). not to be construed as

In order to solve the above problems, the present invention provides an oral tablet composition comprising sunitinib free base or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant and a lubricant as an active ingredient.

In this case, "sunitinib" may be sunitinib free base or an isomer thereof, or a mixture thereof. It may also be one which in each case forms various hydrates, and in each case various crystalline forms. For example, it may be various hydrates or various solvates, such as sunitinib anhydride, monohydrate, dihydrate, trihydrate, or mixtures thereof. Alternatively, “sunitinib” may be a pharmaceutically acceptable salt. In this case, the pharmaceutically acceptable salt is an organic acid selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid, or an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. It may be in the form of an acid addition salt.

The oral tablet composition containing sunitinib can be used for the treatment of cancer diseases such as liver cancer, renal cell cancer, breast cancer, colorectal cancer, lung cancer, endocrine tumor, thyroid cancer, leukemia, prostate cancer, lymphoma and pancreatic cancer, in particular It can be effectively used for the treatment of renal cell carcinoma.

In the present invention, sunitinib may be used in a finely divided form, and in this case, the average particle size (X50) of the finely divided sunitinib may be less than 100 μm, for example, less than 50 μm, for example, less than 30 μm. may be, for example, less than 20 μm. In addition, the average particle size (X50) of the finely divided sunitinib may be 0.1 μm or more, for example, 1 μm or more. When using sunitinib in a range outside the above-mentioned average particle size, there may be a decrease in the dissolution rate or an obstacle in the process. The average particle size (X50) may mean an average particle size of particles of the lower 50% of all particles. The average particle size may be measured using, for example, an optical diffraction particle size meter. As used herein, the expression “pulverized” means powdered to a very small size, for example, an average diameter of the order of micrometers or nanometers.

For example, sunitinib or a pharmaceutically acceptable salt thereof as an active ingredient may be included in an amount of from about 5% to about 30% by weight or from about 10% to about 20% by weight based on the total weight of the tablet composition. factors including, but not limited to, the severity of the disease to be treated, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the route of administration, the rate of excretion, the duration of treatment, and the drug used in combination with or concurrently with sunitinib; It may be appropriately determined according to factors well-known in other medical fields.

When the salt-removed sunitinib free base is used, the molecular weight is smaller than that of sunitinib malate and the like, so the specific gravity of the active ingredient in the composition is low, so it has the advantage of having a relatively less effect on the tablet manufacturing process, which is Considering that the active ingredient is expensive, it may be advantageous in terms of productivity. Thus, the use of sunitinib free base may contain less active ingredient compared to conventional sunitinib formulations.

"Organic acid" is a generic term for organic compounds exhibiting acidity, specifically, fumaric acid, malic acid, tartaric acid, maleic acid, carboxylic acid, acrylic acid, tartaric acid, citric acid, acetic acid, succinic acid, lactic acid, succinic acid, malonic acid, glutaric acid, or these It may be a mixture of, but may not be limited thereto. The above organic acid may be used to improve solubility of sunitinib free base in an aqueous solvent and lower dissolution deviation when sunitinib organic base is used as an active ingredient.

In an embodiment of the present invention, the organic acid includes an organic acid having a carboxylic acid and may be, for example, a dibasic acid having two carboxyl functional groups, but is not limited thereto. For example, the organic acid may be malic acid, maleic acid, tartaric acid, citric acid, fumaric acid, tartaric acid or a mixture thereof, for example fumaric acid, maleic acid or a mixture thereof, for example fumaric acid. For example, the organic acid is an organic acid other than malic acid.

The organic acid may be used in an appropriate amount according to physical properties such as pKa and stability of each component, for example, 0.01 to 5 parts by weight, for example, 0.05 to 3 parts by weight, based on 1 part by weight of sunitinib, for example, It can be used in an amount of 0.1 to 1 part by weight. If the organic acid is less than the above-mentioned lower limit range, there is a lack of effect of reducing the dissolution deviation, and if it is outside the above-mentioned upper limit range, the stability of the tablet composition may be affected due to the characteristics of the highly reactive material.

The diluent may be, for example, lactose (anhydrous or hydrated, for example monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, Magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dec. It may be one or more selected from the group consisting of straw, maltose, sucrose, glucose, fructose, maltodextrin, dextrate, dextrin, and mixtures thereof, but is not limited thereto. For example, the diluent may be selected from mannitol, microcrystalline cellulose, or a mixture thereof. For example, microcrystalline cellulose may be selected as the diluent.

In this case, the diluent may be used in an amount of, for example, 1 to 30 parts by weight, for example, 2 to 20 parts by weight, more, for example, 3 to 15 parts by weight, based on 1 part by weight of sunitinib. If the diluent is less than the above lower limit range, it may be difficult to manufacture a tablet, and if the diluent is out of the above upper limit range, the weight of the formulation becomes excessively large, making it difficult to formulate and difficult to take.

The binder may be used in the preparation of granules and may be included in the preparation of simple mixtures. In this case, the binder is any material that does not affect the action of the active ingredient. In one embodiment, the binder may be a hydrophilic binder. For example, the binder may be selected from the group consisting of povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, calcium hydrogen phosphate, calcium carbonate, and any combination thereof. However, the present invention is not limited thereto. In one embodiment of the present invention, the binder is povidone.

In this case, the binder may be used in an amount of, for example, 0.5 to 10 parts by weight, for example, 1 to 5 parts by weight, based on 100 parts by weight of the total tablet composition. If the binder is less than the above-mentioned lower limit, the binding force of the mixture is lowered, making it difficult to compress the tablet.

The disintegrant is, for example, croscarmellose sodium (CrosCMC-Na), carboxymethylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), It may be one or more selected from the group consisting of starch (wheat, rice, corn or potato starch), sodium carboxymethyl starch, sodium starch glycolate, partially hydrolyzed starch, and mixtures thereof, but is not limited thereto. For example, the disintegrant may be sodium starch glycolate.

In this case, the disintegrant may be used in an amount of, for example, 1 to 10 parts by weight, for example, 2 to 5 parts by weight, based on 100 parts by weight of the total composition. If the disintegrant is less than the above-mentioned lower limit range, there may be a problem with the dissolution rate delay due to the disintegration rate delay.

The lubricant is, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed type (colloidal type) ) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof may be at least one selected from the group consisting of, but limited thereto no. For example, the lubricant may be magnesium stearate.

In this case, the lubricant may be used in an amount of, for example, 0.1 to 5.0 parts by weight, 0.3 to 2.0 parts by weight, or 0.5 to 1.5 parts by weight based on 100 parts by weight of the total tablet weight. If the amount of the lubricant used is excessively less than the above range, there may be problems in productivity such as tableting disorder, and on the contrary, if it is excessively larger than the above range, there may be problems in dissolution delay or productivity.

Although it is known that the free base of sunitinib has lower water solubility than sunitinib malate, the water solubility can be increased to that of sunitinib malate or higher by adjusting the pH in the tablet composition by adding an organic acid, and the dissolution deviation is also can be reduced In addition, desired physical properties can be obtained even by using a relatively small amount of organic acid compared to the amount of malic acid bound to sunitinib malate, so the content of the active ingredient is lowered to secure the advantages of process application and yield improvement of various oral tablet compositions can do.

In an embodiment of the present invention, the oral tablet composition is a tablet comprising sunitinib free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

The tablet may be prepared in the order of granulation (optional), mixing, tableting, and coating after weighing the active ingredient and additives. The granulation may be prepared by a method of dry granulation, wet granulation, or the like. If granulation is not performed, the process is simplified because it is mixed and tableted immediately after weighing. In addition, since the exposure of the worker to the drug is minimized, the direct hit method may be the most preferable.

In the case of the direct pressing method, which is tableted immediately after mixing without granulation, it is very important to ensure the uniformity and fluidity of the mixture. Therefore, care may be required to ensure uniformity and fluidity from the mixing stage. Mixing uniformity of the mixture may be improved if the drug, diluent, disintegrant, lubricant, etc. are not added at once and dispersed in stages.

For example, after adding and mixing a part of the diluent and the drug, the remaining amount of the diluent is added and mixed again, and a disintegrant, a binder, and/or a lubricant are added and mixed in stages to the first mixture, respectively, and then optionally an organic acid is added. It is possible to prepare a semi-finished product for tableting by adding and final mixing.

For example, in another method, the binder is first mixed with the drug, then a diluent is added to further mix, and a disintegrant and a lubricant are added thereto in this order, and optionally an organic acid is finally mixed in the last step after mixing to obtain a semi-finished product for tableting. can be prepared

The above tablets may be uncoated tablets, dragees, or film-coated tablets, for example, film-coated tablets capable of shielding and moisture-proofing the drug. The coating layer of the film-coated tablet may be a single layer or a multilayer, for example, may be a single layer.

The coating base for manufacturing the film-coated tablet is a hydrophilic polymer, for example, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methyl Cellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinylacetate public It may be at least one member selected from the group consisting of coal (eg, Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof. However, the present invention is not limited thereto. for example polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC).

In this case, the coating base agent is, for example, in an amount of 1 to 30 parts by weight, for example, in an amount of 2 to 20 parts by weight, even more, for example, 3 to 10 parts by weight based on 100 parts by weight of the tablet (uncoated tablet) before coating. It can be used in negative amounts. If the coating amount is less than the above-mentioned lower limit range, there may be a problem that the entire uncoated tablet is not covered with the coating base, and if it is outside the above-mentioned upper limit range, there may be a problem of excessive delay of the dissolution rate.

The tablet composition of the present invention may contain an active ingredient, a diluent, a disintegrant and a lubricant; Alternatively, when a coating layer is included, each content ratio of the active ingredient, diluent, disintegrant, lubricant, and coating layer may be constant, and the volume of the tablet may be proportional to the content of the active ingredient.

In the tablet, various additives may be mixed in order to improve the physical properties, manufacturability, compressibility, appearance, taste, stability of the drug, and the like of the tablet. Such additives include, for example, stabilizers, solubilizers, sweeteners, flavoring agents, pigments, wetting agents, fillers, stabilizers, surfactants, solubilizers, buffers, adsorbents, suspending agents, curing agents, antioxidants, brightening agents, flavoring agents , flavoring agent, wetting agent, antifoaming agent, refreshing agent, chewing agent, antistatic agent, colorant, dragee, isotonic agent, emollient, emulsifier, adhesive, thickener, foaming agent, pH regulator, dispersant, waterproofing agent, preservative, preservative, solubilizing agent , a solvent, a fluidizing agent, etc., but is not limited thereto, and any pharmaceutically acceptable one may be used.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of sunitinib tablets using sunitinib free base and fumaric acid 1

After sieving and mixing 2.5 g of sunitinib free base and 10.31 g of microcrystalline cellulose, 0.6 g of povidone and 0.72 g of sodium starch glycolate were sieved and mixed, and 0.15 g of magnesium stearate was additionally mixed, followed by fumaric acid. A final mixture was prepared by mixing 0.73 g through a sieve. This mixture was tableted with a rectangular punch at a weight of 300 mg per tablet. The hardness of uncoated tablets was 70 N. With respect to the prepared tablet (uncooked tablet), a film coating corresponding to a total of 3% (w/w) of the total weight of the uncooked tablet 100% (w/w) with an Opadry base containing hydroxypropylmethylcellulose (HPMC) as a main component carried out.

Example 2: Preparation of sunitinib tablets using sunitinib free base and maleic acid 1

After sieving 2.5 g of sunitinib free base and 10.31 g of microcrystalline cellulose, 0.6 g of povidone and 0.72 g of sodium starch glycolate were sieved and mixed, and 0.15 g of magnesium stearate was additionally mixed, followed by maleic acid. A final mixture was prepared by mixing 0.73 g through a sieve. This mixture was tableted with a rectangular punch at a weight of 300 mg per tablet. The hardness of uncoated tablets was 70 N. Film coating corresponding to a total of 3% (w/w) compared to 100% (w/w) of the total weight of the raw tablet was performed on the prepared tablet (uncooked tablet) with an Opadry base containing HPMC as a main component.

Example 3: Preparation of sunitinib tablets using sunitinib free base and fumaric acid 2

After sifting and mixing 2.5 g of sunitinib free base and 9.53 g of microcrystalline cellulose, 0.6 g of povidone and 0.72 g of sodium starch glycolate were sieved and mixed, and 0.15 g of magnesium stearate was additionally mixed, followed by fumaric acid. The final mixture was prepared by mixing 1.5 g through a sieve. This mixture was tableted with a rectangular punch at a weight of 300 mg per tablet. The hardness of uncoated tablets was 70 N. Film coating corresponding to a total of 3% (w/w) compared to 100% (w/w) of the total weight of the raw tablet was performed on the prepared tablet (uncooked tablet) with an Opadry base containing HPMC as a main component.

Example 4: Preparation of sunitinib tablets using sunitinib free base and maleic acid 2

After sieving 2.5 g of sunitinib free base and 9.53 g of microcrystalline cellulose, 0.6 g of povidone and 0.72 g of sodium starch glycolate were sieved and mixed, and 0.15 g of magnesium stearate was additionally mixed, followed by maleic acid. The final mixture was prepared by mixing 1.5 g through a sieve. This mixture was tableted with a rectangular punch at a weight of 300 mg per tablet. The hardness of uncoated tablets was 70 N. Film coating corresponding to a total of 3% (w/w) compared to 100% (w/w) of the total weight of the raw tablet was performed on the prepared tablet (uncooked tablet) with an Opadry base containing HPMC as a main component.

Example 5: Preparation of sunitinib tablets using sunitinib free base and fumaric acid 3

After sieving 2.5 g of sunitinib free base and 10.31 g of mannitol, 0.6 g of povidone and 0.72 g of sodium starch glycolate were sieved and mixed, and 0.15 g of magnesium stearate was additionally mixed, followed by 0.73 g of fumaric acid The final mixture was prepared by sieving and mixing. This mixture was tableted with a rectangular punch at a weight of 300 mg per tablet. The hardness of uncoated tablets was 70 N. Film coating corresponding to a total of 3% (w/w) compared to 100% (w/w) of the total weight of the raw tablet was performed on the prepared tablet (uncooked tablet) with an Opadry base containing HPMC as a main component.

Example 6: Preparation of sunitinib tablets using sunitinib free base and maleic acid 3

2.5 g of sunitinib free base and 10.31 g of mannitol were sieved and mixed, and then 0.6 g of povidone and 0.72 g of sodium starch glycolate were sieved and mixed, and 0.15 g of magnesium stearate was additionally mixed, followed by 0.73 g of maleic acid The final mixture was prepared by sieving and mixing. This mixture was tableted with a rectangular punch at a weight of 300 mg per tablet. The hardness of uncoated tablets was 70 N. Film coating corresponding to a total of 3% (w/w) compared to 100% (w/w) of the total weight of the raw tablet was performed on the prepared tablet (uncooked tablet) with an Opadry base containing HPMC as a main component.

Comparative Example 1: Sunitinib Hard Capsule Containing Sunitinib Malate

As a comparative example using sunitinib malate, commercially available Suten ^® (sunitinib 50 mg) capsules were used.

comparative example 2: Sunitinib free base only used Sunitinib tablet manufacturing

2.5 g of sunitinib free base and 11.03 g of mannitol were sieved and mixed, and 0.6 g of povidone and 0.72 g of sodium starch glycolate were sieved and mixed, followed by mixing 0.15 g of magnesium stearate to prepare a final mixture. This mixture was tableted with a rectangular punch at a weight of 300 mg per tablet. The hardness of uncoated tablets was 70 N. Film coating corresponding to a total of 3% (w/w) compared to 100% (w/w) of the total weight of the raw tablet was performed on the prepared tablet (uncooked tablet) with an Opadry base containing HPMC as a main component.

The contents of each component of the sunitinib tablets prepared in Examples 1 to 6 and Comparative Example 2 are shown in Table 1 below.

test example 1: Analysis of purification properties

After preparing the tablets according to Examples 1 to 6, the content of each tablet and the total amount of related substances were measured, and comparative analysis was performed with the capsule of Comparative Example 1, and the results are shown in Table 2 below.

As a result of the analysis, it was confirmed that the total amount of related substances in the tablets of Examples 1 to 6 was significantly lower than that of the capsule of Comparative Example 1.

Test Example 2: Sunitinib dissolution test

For Examples 1 to 6 and Comparative Example 1, a dissolution test was performed under the following conditions with n=6.

Test Methods: Export of pharmaceuticals to Korea test method paddle method

Eluent: 0.1 M HCl solution

Rotational speed: 50 rpm

Temperature: 37℃

Dissolution reference time: 30 minutes

Analytical method: HPLC method

Table 3 below shows the sunitinib dissolution rates from the tablets of Examples 1 to 6 and the capsules of Comparative Example 1 measured as a result of the test.

The dissolution rate was used to judge the equivalence, and when 85% or more was achieved, it was considered as the equivalent range. As a result, it was confirmed that all examples had dissolution rates in the same range.

Test Example 3: Comparative dissolution experiment of sunitinib

Using the tablets of Examples 1, 2, 3 and 4, and Comparative Example 1 (Suten ^® capsule formulation) and Comparative Example 2, the dissolution rate with time was measured at pH 1.2, pH 4.0 and DW, respectively, and the results were 1 to 3 are shown. As a result of the dissolution test in solutions of various pHs, most of the drugs were released at low pH due to the nature of the main component having the characteristics of a weak base, and the final dissolution rate showed similar results in Examples and Comparative Examples, but the initial value of 5 to 10 minutes was It was confirmed that the Example was higher. In addition, it was confirmed that when the pH of the solution gradually increased, the dissolution rate of the drug was somewhat decreased, and it was confirmed that the dissolution rate difference due to this change in solution pH was smaller in Examples than Comparative Examples. In particular, in Comparative Example 1, the dissolution rate deviation was measured to be large. The dissolution conditions for measuring the dissolution rate were as follows:

Dissolution test apparatus: Paddle method of dissolution test method of the Korean Pharmacopoeia

Test solution: pH 1.2, pH 4.0, DW

Rotational speed: 50 rpm

Temperature: 37℃

Dissolution reference time: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min

Analytical method: HPLC method

test example 4. beagle dog used of sunitinib Pharmacokinetics (PK) test

For comparison of the 50 mg sunitinib tablet according to Examples 3 and 4 and Comparative Example 2 with the Suten ^® capsule of Comparative Example 1, a pharmacokinetic test was performed as a non-clinical test using a beagle dog as an experimental animal. The number of 20 beagle dogs was divided into 4 groups, the first group was Comparative Example 1, the second group was Comparative Example 2, the third group was Test Group 3 (Example 3), and the fourth group was Test Group 4 (Example 3). Example 4) was named. After taking the drug along with 20 mL of water in a fasting state, the animals were bled at fixed time intervals up to 48 hours. Blood samples were stored frozen after separation of plasma, and the concentration was analyzed with LC/MS/MS equipment to measure the blood concentration over time, and from the data, AUC (plasma concentration-area under the time curve) and C _max (highest blood concentration) was obtained. The experimental results are shown in Table 4 below.

As a result of the pharmacokinetic experiment, the oral tablet composition containing sunitinib according to the present invention showed higher AUC and C _max than that of the commercially available sunitinib hard capsule formulation. As a result, conventional sunitinib containing sunitinib malate It was confirmed to have superior pharmacokinetic properties compared to the hard capsule formulation.

Claims (18)

As an active ingredient, it contains sunitinib free base, an organic acid, a diluent, a disintegrant, a lubricant, a binder and a coating layer,
wherein the organic acid is selected from fumaric acid, maleic acid, and combinations thereof,
wherein the diluent is selected from microcrystalline cellulose, mannitol, and combinations thereof,
The disintegrant is sodium starch glycolate,
The lubricant is magnesium stearate,
the binder is povidone,
The content of the organic acid is 0.1 to 1 part by weight based on 1 part by weight of sunitinib free base,
The content of the coating layer is 1 to 30 parts by weight based on 100 parts by weight of the tablet before coating,
Oral tablet composition. The oral tablet composition according to claim 1, wherein the active ingredient is contained in an amount of 5% to 30% by weight based on the total weight of the tablet. According to claim 1,
The diluent content is 1 to 30 parts by weight based on 1 part by weight of the active ingredient,
The disintegrant content is 1 to 10 parts by weight based on 100 parts by weight of the total composition,
The lubricant content is 0.1 to 5 parts by weight based on 100 parts by weight of the total composition,
The binder content is 0.5 to 10 parts by weight based on 100 parts by weight of the total composition,
Oral tablet composition. The oral tablet composition according to claim 1, wherein the content ratio of each component is constant regardless of the content of the active ingredient. The oral tablet composition according to claim 4, wherein the volume of the tablet is proportional to the content of the active ingredient. The method of claim 1, wherein the coating base of the coating layer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose sodium salt, carboxymethylcellulose calcium salt, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethyl Cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginates, At least one selected from the group consisting of xanthan and mixtures thereof, oral tablet composition. delete delete delete delete delete delete delete delete delete delete delete delete

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