KR20180002977A - Pharmaceutical Composition For Oral Administration, Comprising Sorafenib Tosylate Having Improved Drug Release Properties and Bioavailability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration, which comprises, as an active ingredient, Sorafenib tosylate to have improved drug release properties and bioavailability, to a pharmaceutical preparation comprising the same, and to a manufacturing method thereof.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a pharmaceutical composition for oral administration comprising sorapenib tosylate having improved release properties and bioavailability,

The present invention relates to a novel pharmaceutical composition for oral administration, which comprises sorapenib tosylate as an active ingredient, and which has improved release characteristics and bioavailability, a pharmaceutical preparation containing the same, and a preparation method thereof.

Sorafenib tosylate has the structure represented by the formula (1), and is currently marketed worldwide under the trade name Nexavar.

[Chemical Formula 1]

Sorapenib is a class of serine-threonine kinase inhibitors and kinase inhibitors in the art (Smith et al., Bioorg. Med. Chem. Lett. 2001, 11, 2775-2778, Lowinger et al., Clin. Cancer Res. 2000 Cancer 2001, 8, 219-225, Lowinger et al., Curr. Pharm Design 2002, 8, 99-110). Omega-carboxyaryl diphenylurea is disclosed in International Patent Publication No. 2000/42012 and International Patent Publication No. 2000/41698. In particular, "BAY 43-9006" or 4- {4- [({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) -amino] phenoxy} -Carboxamide, is known to be a potent inhibitor of raf, VEGFR-2, p38, and PDGFR kinase, and the like.

All of these enzymes are molecular targets of interest for the treatment of hyperproliferative diseases, including cancer. Accordingly, sorapenib tosylate has been used for the treatment of various cancers including kidney cancer, liver cancer, thyroid cancer, and desmoid cancer.

However, sorapenib tosylate is a poorly soluble drug and has very low solubility and is known to have extremely poor drug release properties and bioavailability. Thus, there is a growing need for formulations comprising a novel form of sorapenib tosylate, which has better release properties and bioavailability, as an active ingredient.

Korean Patent No. 1,335,932 discloses a tablet containing sorapenib tosylate as an active ingredient, which uses hydroquinone alone as a binding agent, but does not show satisfactory release characteristics and bioavailability .

Under these technical backgrounds, the inventors of the present application have been studying to improve the release properties and bioavailability of sorapenib tosylate. When povidone and hypromellose are used together as a binder, The solubility, release characteristics and bioavailability of tosylate can be remarkably improved, and the present invention has been completed.

The present invention relates to a novel pharmaceutical composition for oral administration, which comprises sorapenib tosylate as an active ingredient, and which has improved release characteristics and bioavailability, a pharmaceutical preparation containing the same, and a preparation method thereof.

More specifically, the pharmaceutical composition according to the present invention comprises sorafenip tisylate as an active ingredient, povidone and hypromellose as binders, a disintegrant, a diluent and a solubilizing agent .

In addition, the pharmaceutical preparation according to the present invention is preferably a tablet, but the present invention is not limited thereto. The pharmaceutical composition and preparation according to the present invention are preferably prepared by the wet granulation method, It is not.

The pharmaceutical composition comprising sorapenib tosylate according to the present invention as an active ingredient comprises sorapenib tosylate, povidone and hypromellose as binders, a disintegrant, a diluent, a solubilizing agent and additionally a lubricant .

The pharmaceutical composition provided in the present invention may be formulated in an oral dosage form such as tablets, capsules and the like.

In addition, the pharmaceutical compositions and formulations comprising sorapenib tosylate according to the present invention as an active ingredient can be prepared through a wet granulation process,

a) dissolving the binder and the solubilizing agent in a volatile solvent to prepare a solution;

b) mixing sorapenib tosylate, a diluent and a binder; And

c) combining the solution obtained in step a) with the mixture obtained in step b) to obtain a wet granulation mixture and drying.

The pharmaceutical compositions and preparations containing sorapenib tosylate according to the present invention as an active ingredient are characterized in that the solubility, release characteristics and bioavailability of sorapenib tosylate, an insoluble drug, are improved by oral pharmaceutical preparations, As a result, an excellent therapeutic effect can be expected compared with other conventional formulations.

1 is a view showing a dissolution test result of a tablet formulation according to the content of polyethylene glycol (PEG) as a binder in the composition.
2 is a graph showing the dissolution test results of the tablet formulation according to the content of the binder hydroxypropyl cellulose (HPC) in the composition.
FIG. 3 is a view showing a dissolution test result of the tablet formulation according to the content of the binder povidone in the composition. FIG.
Fig. 4 is a graph showing a dissolution test result of a tablet formulation according to the content of sodium lauryl sulfate as a solubilizing agent, using a hydrogel as a binding agent.
FIG. 5 is a graph showing the results of pharmacokinetic parameter analysis of tablets using povidone and hydromellose together as a binding agent and tablet formulations using only hypromellose. FIG.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

In one aspect, the present invention is directed to a pharmaceutical composition comprising sorapenib tosylate as an active ingredient and having improved release properties and bioavailability of sorapenib tosylate.

The pharmaceutical composition comprising sorapenib tosylate according to the present invention as an active ingredient comprises sorapenib tosylate, povidone and hypromellose as binders, a disintegrant, a diluent, a solubilizing agent, . ≪ / RTI > It has been found that release characteristics and bioavailability (dissolution rate and AUC effect, etc.) are further improved when further binders are used in combination with hypromellose as compared to tablets (comparative examples) which have been previously used alone as a binding agent with hypromellose In particular, when povidone was used as a binding agent together with hypromellose, the release characteristics and bioavailability were remarkably improved.

Based on this, in one embodiment the binder may be hypromellose and povidone. In this case, povidone, which is a binder in the pharmaceutical composition, may be contained in an amount of 0.5 to 15% by weight, preferably 1 to 10% by weight, and the hydromelose is contained in an amount of 0.5 to 10% by weight, preferably 1 to 5% . The weight ratio of hypromellose and povidone may be, for example, 0.5: 1 to 1: 5, preferably 1: 1 to 1: 3.

The pharmaceutical composition according to the present invention may contain 50 to 90% by weight, preferably 70 to 85% by weight, and most preferably 75 to 80% by weight of the active ingredient sorapenib tosylate.

Suitable disintegrants for the pharmaceutical compositions according to the present invention may be one selected from the group consisting of croscarmellose sodium, starch glycollate sodium and crospovidone, preferably croscarmellose sodium.

The disintegrant may be included in the pharmaceutical composition according to the present invention in an amount of 3 to 20% by weight, preferably 5 to 10% by weight.

The diluent suitable for the pharmaceutical composition according to the present invention may be at least one selected from the group consisting of microcrystalline cellulose, powdered cellulose, pregelatinized starch, hydrated lactose, compressed sugar and calcium monohydrogen phosphate, preferably microcrystalline cellulose (Avicel PH1010).

The diluent may be included in the pharmaceutical composition according to the present invention in an amount of 0.5 to 10% by weight, preferably 2 to 7% by weight.

Suitable solubilizing agents for the pharmaceutical compositions according to the invention can be used to assist in the dissolution of the drug and include, for example, sodium lauryl sulfate (SLS), sodium dioctyl sulfosuccinate, glycerol monostearate, sorbitan monolaurate Polyoxyethylene fatty acid esters, ethylene oxide-propylene oxide block copolymers (Pluronic), polyoxyethylene sorbitan monolaurate, monostearate, monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ), Ethoxylated triglycerides, and mixtures thereof, and may preferably be sodium lauryl sulfate (SLS).

The solubilizing agent may be contained in the pharmaceutical composition according to the present invention in an amount of 0.1 to 5% by weight, preferably 0.2 to 2% by weight.

Suitable lubricants for pharmaceutical compositions according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol. Magnesium stearate is preferred.

The lubricant may be included in the pharmaceutical composition according to the present invention in an amount of 0.05 to 5% by weight, preferably 0.1 to 2% by weight.

In one embodiment, the pharmaceutical composition comprises 50 to 90% by weight, preferably 70 to 85% by weight of sorapenib tosylate, 0.5 to 15% by weight of the binder povidone, 0.5 to 10% by weight of hyporomelose, 3 to 20% by weight of disintegrant croscarmellose sodium, 0.5 to 10% by weight of microcrystalline cellulose as a diluent, 0.1 to 5% by weight of sodium laurylsulfate as a solubilizer, and 0.05 to 5% by weight of magnesium stearate as a lubricant .

The pharmaceutical preparations containing the pharmaceutical composition according to the present invention are preferably used in the form of tablets or capsules for oral administration, particularly tablets.

The tablet formulations according to the present invention may be in film-coated form, including a film coating layer. The film coating layer may contain a film forming agent (coating material), a plasticizer and / or a coloring agent.

Examples of the film forming agent include liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose (hydroxypropyl methylcellulose), methyl cellulose, ethyl cellulose, cellulose acetate phthalate, shellac, polyvinyl pyrrolidone, And copolymers of vinyl acetate such as Kollidon, VA64BASF, copolymers of acrylic acid and / or methacrylic acid esters with trimethylammonium methyl acrylate, copolymers of dimethylaminomethacrylic acid and natural methacrylic acid esters, But are not limited to, a polymer of methacrylic acid or methacrylic acid ester, a copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester, and a copolymer of acrylic acid and methyl acrylate. , Preferably a hypromellose is used There.

As the plasticizer, at least one selected from the group consisting of polyethylene glycol (PEG), diethyl phthalate and glycerol may be used, but not limited thereto, preferably polyethylene glycol may be used.

Examples of the colorant include pigments, inorganic pigments, FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No. 2, D & C Green No. 5, D & C Orange No. 5, D & C Red No. 8, caramel, Ferric yellow and titanium dioxide may be used, but not limited thereto, preferably ferric oxide red, ferric yellow oxide or titanium dioxide may be used.

In yet another aspect, the present invention is directed to a pharmaceutical composition and formulation having improved bioavailability and improved release characteristics of sorapenib tosylate, characterized by the use of a wet granulation process.

Specifically, the production method according to the present invention comprises:

a) dissolving the binder and the solubilizing agent in a volatile solvent to prepare a solution;

b) mixing sorapenib tosylate, a diluent and a binder; And

c) combining the solution obtained in step a) with the mixture obtained in step b) to obtain a wet granulation mixture and drying.

The binder of step a) may be one or more substances selected from the group consisting of polyethylene glycol (PEG), hydroxypropylcellulose (HPC) and povidone, preferably povidone, and the binder of step b) Melose is preferable.

Preferably, after step c)

(d) obtaining a final blend with the disintegrant and glidant;

(e) forming a tablet on a suitable tablet press.

The wet granulation method according to the present invention is not limited as long as the solvent is a process for producing granules by contacting the active ingredient, for example, i) mixing the active ingredient with a pharmaceutically acceptable excipient And then drying the kneaded dough after shaping the dough into an appropriate sized granule, followed by drying to form an active ingredient-containing granule, or ii) using a fluidized bed granulator while using the same components, , And drying and crushing the agglomerated mixed components to prepare granules, or iii) drying the same components while preparing the wet granules with a high-speed mixer.

The combination of the mixture obtained in the step b) and the solution obtained in the step a) can be carried out so as to be sufficiently wetted in the wet granulation process. This can increase the porosity of the granules and shorten the disintegration time.

As the volatile solvent used in the production method according to the present invention, a solvent for granulating liquid which does not remain in the final product may be used, and methanol, ethanol, isopropyl alcohols or purified water may be used, For this purpose, purified water can be used as a solvent.

Except for the volatile components that are volatilized and disappear in the wet granulation mixture, for example, based on the final formulation

70 to 85% by weight, and most preferably 75 to 80% by weight of sorapenib tosylate;

0.5 to 10% by weight, preferably 2 to 7% by weight, of a diluent;

3 to 20% by weight, preferably 5 to 10% by weight of a disintegrant;

0.5 to 15% by weight, preferably 1 to 10% by weight, of the binder povidone;

From 0.5 to 10% by weight, preferably from 1 to 5% by weight, of the binding agent hepomelose;

And 0.1 to 5% by weight, preferably 0.2 to 2% by weight, of a solubilizing agent.

Based on the final formulation as an additional ingredient,

0.05 to 5% by weight, preferably 0.1 to 2% by weight, of a lubricant; And / or

0.5 to 5% by weight, preferably 1 to 3% by weight, of a coloring agent.

The volatile component may be included in the manufacturing process, for example, in a range of 50 to 200 parts by weight, preferably 50 to 100 parts by weight, based on 100 parts by weight of sorapenib tosylate, of the solvent for the granulating liquid.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are for illustrating the present invention only and that the scope of the present invention is not construed as being limited by these embodiments.

Example 1. Preparation of sorapenib tosylate tablets prepared from wet granules

Tablets containing sorapenib tosylate were prepared by wet granulation according to the compositions of Tables 1 to 3. Specifically, purified water is prepared by dissolving a binder (PEG, hydroxypropylcellulose or povidone) and a solubilizing agent (sodium lauryl sulfate) to prepare a solution. Separately, sorapenib tosylate (Qilu, China) A mixture was prepared by mixing cellulose and a binder (heptromelose), and the solution was then mixed with the mixture for 5 minutes to obtain a premixture with a No. 20 sieve, followed by drying at 60 캜. The dried granular mixture (Croscarmellose sodium) and magnesium stearate as a lubricant to obtain a final blend, followed by compression on a suitable tablet press to prepare tablets.

Table 1. Preparation of sorapenib tosylate tablets containing PEG and hypromellose as binding agents

Table 2. Preparation of sorapenib tosylate tablets containing HPC and hypromellose as binding agents

Table 3. Preparation of sorapenib tosylate tablets containing povidone and hypromellose as binding agents

Comparative Example 1. Sorapenip tosylate tablets prepared by wet granulation Comparative Example

A comparative example was prepared as in Example 1 with the respective contents of the components listed in Table 4.

Table 4. Preparation of sorapenib tosylate tablets containing < RTI ID = 0.0 > hypromellose < / RTI >

Experimental Example 1: Evaluation of elution properties of the tablets prepared in Examples 1 to 9 and Comparative Examples 1 to 3

The pharmaceutical preparations for oral use according to the present invention were prepared, and the tablets of Examples 1 to 9 containing hypromellose and an additional binder and the tablets of Comparative Examples 1 to 3 using hemiromellose as a binder were subjected to a dissolution experiment Respectively. As the eluent, 900 mL of pH 4.0 acetate buffer solution was used, and the tablet 9T was tested at 50 rpm to prepare a supersaturated state in consideration of the poorly soluble drug.

The analysis was carried out on 10 μL of the above test solution by the liquid chromatography method under the following conditions, and the liquid chromatography (HPLC) measurement conditions were as follows.

- Detector: ultraviolet absorption spectrophotometer (measuring wavelength: 280 nm)

- Column: column packed with octadecylsilylated silica gel (15 cm x 4.6 mm, 5 um) or similar column

- Flow rate: 1.5 mL / min

- Column temperature: 40 ° C

- mobile phase: mobile phase A ^* : mobile phase B ^* = 65: 35 v / v%

- * Mobile phase A: Dissolve 1.0 g of potassium dihydrogenphosphate in 1000 ml of water, then add phosphoric acid to adjust the pH to 2.4.

- * mobile phase B: acetonitrile: ethanol = 60: 40

As shown in FIGS. 1 to 4, when povidone, polyethylene glycol (PEG) or hydroxypropylcellulose (HPC) was additionally used in combination with hypromellose as a binder, It was confirmed that the elution property was improved as compared with the case where Melose was used alone as a binding agent,

Particularly, the tablets of Example 7 (Fig. 3) using povidone in addition to hypromellose as a binder showed remarkably improved elution properties as compared with the tablets of Comparative Example 1 (in the case of using hypromellose as a binder, Fig. 4) Respectively.

Experimental Example 2: Comparison of pharmacokinetics of tablets containing sorapenib tosylate

The beagle dogs (n = 12) were divided into two groups, and the tablets of Comparative Example 1 were administered to the first group and the tablets of Example 7 were administered to the second group by the double blind method. After analyzing the drug concentration in the blood, the pharmacokinetic parameter results using the drug concentration with time are shown in Table 5 and FIG. 5, respectively.

Table 5. Comparison of pharmacokinetic properties of tablets according to Example 7 and Comparative Example 1

As can be seen in Table 5 and FIG. 5, the wet granulation tablets obtained by further using povidone as the binding agent were found to have an AUC of about 1.35 times higher than those of the wet granulated tablets using the hypromellose as the binder Respectively.

Therefore, it has been confirmed that the wet granulation using the povidone as a binding agent in the hydromellose can improve the solubility and maximize the concentration of the drug in a specific organ to increase the bioavailability of the drug, Can be maximized.

Claims (9)

Characterized in that it comprises sorapenib tosylate as an active ingredient, povidone and hypromellose as binders, disintegrant, diluent and solubilizing agent.
The pharmaceutical composition according to claim 1, further comprising a lubricant.
3. The pharmaceutical composition according to claim 2, wherein the disintegrant is croscarmellose sodium, the diluent is microcrystalline cellulose, the solubilizing agent is sodium lauryl sulfate, and the lubricant is magnesium stearate.
The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises 50 to 90% by weight of sorapenib tosylate, 0.5 to 15% by weight of povidone as a binder, 0.5 to 10% by weight of heptamelose, croscarmellose sodium as a disintegrant 3 to 20% by weight, microcrystalline cellulose as a diluent in an amount of 0.5 to 10% by weight, sodium lauryl sulfate as a solubilizer in an amount of 0.1 to 5% by weight, and magnesium stearate as a lubricant in an amount of 0.05 to 5% by weight.
A tablet comprising a pharmaceutical composition according to any one of claims 1 to 4.
6. The film coated tablet of claim 5,
a) dissolving the binder and the solubilizing agent in a volatile solvent to prepare a solution;
b) mixing sorapenib tosylate, a diluent and a binder; And
c) combining the solution obtained in the step a) with the mixture obtained in the step b) to obtain a wet granulation mixture and drying the tablet. Way.
8. The method of claim 7, wherein after step c)
(d) obtaining a final blend with the disintegrant and glidant;
(e) forming a tablet on a suitable tablet press. < RTI ID = 0.0 > 11. < / RTI >
9. The method of claim 8,
The binder in step a) is povidone, the binder in step b) is hypromellose, the diluent is microcrystalline cellulose, the solubilizing agent is sodium lauryl sulfate, and the lubricant is magnesium stearate. Characterized in that the tablet contains sorapenib tosylate as an active ingredient.

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