KR20190048867A - Composition of Sorafenib nanoparticles for oral administration with enhanced solubility and bioavailability and method for preparation thereof - Google Patents

Abstract

Disclosed are a composition for oral administration with improved water solubility and bioavailability, comprising nanoparticles of sorafenib, and a method of preparing the same. Improved water solubility and bioavailability of sorafenib allow a drug to achieve the same effects in a body as a commercially available drug even with a relatively smaller amount, thus bringing economic advantages due to reduced usage of costly drugs.

Description

TECHNICAL FIELD The present invention relates to a composition for oral administration of sorafenib nanoparticles improved in water solubility and bioavailability and a method for preparing the same,

The present invention relates to an oral composition comprising sorafenib nanoparticles with improved water solubility and bioavailability, and a method of producing the same.

(4-chloro-3-trifluoromethylphenyl) -ureido] -phenoxy} -pyridine-2-carboxylic acid methylamide) is useful for the treatment of renal cell carcinoma, hepatocellular carcinoma, TKI (Tyrosine Kinase Inhibitor) is a targeted anticancer drug used for thyroid cancer. It is marketed as an oral tablet both at home and abroad.

Korean Patent No. 1335932 discloses a pharmaceutical composition for treating hyperproliferative disorders including cancer, which is a tablet containing 55% or more of p-toluenesulfonic acid salt of sorapenib to the weight of the composition, 3 to 20% of microcrystalline cellulose as a filler, 5 to 12% of croscarmellose sodium as a disintegrant, 0.5 to 8% of heptromelose as a binder, 0.2 to 0.8% of magnesium stearate as a lubricant, And 0.1 to 2% sodium lauryl sulfate as an active agent.

However, sorapenib has very low solubility in water (0.00171 mg / ml) and absolute bioavailability is not known in humans. Relative bioavailability of oral tablets compared to oral solutions is 38-49% to be.

Various studies have been conducted to improve the water solubility and bioavailability of sorafenib.

It is an object of the present invention to provide an oral composition comprising sorafenib nanoparticles with improved water solubility and bioavailability.

Another object of the present invention is to provide a method for producing an oral composition having improved water solubility and bioavailability by using Sorapemib nanoparticles.

An aspect of the present invention relates to an oral composition having improved water solubility and bioavailability, comprising sorafenib nanoparticles comprising sorafenib or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for preparing a pharmaceutical composition comprising: (1) nanopartizing sorapenib or a pharmaceutically acceptable salt thereof; And (2) forming an oral preparation containing the nanoparticles obtained in the step (1). The present invention also relates to a method for producing an oral composition having improved water solubility and bioavailability.

The oral composition comprising sorapenib nanoparticles according to the present invention can exert the same effect as a commercial formulation in the body even if a relatively small amount of drug is used because of the improved water solubility and bioavailability of sorafenib. In addition, such a composition may be beneficial to a patient because it may be less affected by dietary intake, may have a relatively low side effect due to low individual differences in absorption, and may be economically beneficial due to the use of less expensive drugs have. That is, by using the nanoparticles of sorafenib, the water solubility and bioavailability of sorapenib are remarkably improved, so that a drug having the same bioavailability can be developed even if the drug is reduced in volume, so that the side effects are reduced And the preparation cost can be reduced.

Definition of Terms

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

The word " comprising " or " containing ", unless the context clearly dictates otherwise throughout the specification, refers to any element (or component), including without limitation, the addition of another component .

&Quot; Sorapenib " includes sorapenib base (a free salt free prebasin drug), its isomers, or a mixture thereof. &Quot; Pharmaceutically acceptable salts of < RTI ID = 0.0 > sorapenib " includes < / RTI > all pharmaceutically acceptable salts or forms of salts which contain sorapenib as an active ingredient. In each case forming various hydrates, or various crystalline forms. For example, " pharmaceutically acceptable salts of sorapenib " may be sorapenib tosylate and may be amorphous, crystalline forms 1, 2, 3 or mixtures thereof of sorapenib tosylate .

The term " nano " in nanoparticles or nanoparticles means that 90% or more of the nanoparticles have a diameter of 5 μm or less, preferably 2 μm or less, more preferably 1 μm or less, even more preferably 0.8 μm or less, The average particle size of the nanoparticles is not particularly limited. For example, the average particle size of the nanoparticles is 1 nm or less Or more, or 10 nm or more, or 50 nm or more, or 80 nm or more, but is not limited thereto.

As used herein, the term " sorafenip nanoparticles " is used in a context encompassing nanoparticles of drugs containing sorapanib as the active ingredient, including sorafenib and its pharmaceutically acceptable salts, depending on the context.

&Quot; Supercritical fluid " refers to a gas or liquid that is inert but inert, such as carbon dioxide or nitrogen, and can be a supercritical fluid at a certain temperature and pressure, i.e., supercritical temperature and supercritical pressure .

"Supercritical pressure" refers to the specific pressure at which the supercritical fluid gas can become a supercritical fluid under pressure above that pressure.

Discovery of solution

Various methods have been used to improve water solubility and bioavailability of water-soluble drugs. Such as the preparation of salts, crystals, and prodrugs, microspheres or nanoemulsions, the preparation of solid dispersions, undrawn or nanoized through the reduction of particle size of the drug, and micelle formation. However, because the characteristics of drugs such as solubility, pH, pKa, melting point, molecular weight, functional group, stereostructure, crystallinity, permeability, absorption site, degradation degree and effective drug capacity are different for each drug, It can not be commonly applied to drugs, but it must be found through a lot of efforts to find a way that works well for a particular drug. However, the nanoparticles of the drug particles may increase the surface area of the drug while using a small amount of the additive, thereby rapidly increasing the dissolution rate of the drug, which may lead to a drastic increase in the bioavailability. Methods for preparing such nanoparticles are known in the literature and are commercially available by several companies. However, the nanoparticles thus obtained exist in the form of a mixture using a stabilizing material for holding the nanoparticles in an aqueous solution. In many cases, the nanoparticle stabilizing material is a surfactant or a water-soluble polymer. Such water-soluble polymers and surfactants may greatly affect the weight, manufacturability, physical properties, dissolution characteristics and disintegration characteristics of the finished product. Therefore, it is very important to make a preparation that is excellent in physical properties, smooth in manufacture, and low in weight, without disrupting the disintegration and dissolution characteristics of the nanoized drug.

The present inventors have made extensive efforts to evaluate the effect of various substances on the water solubility of sorapenib, and found that the method of nanoparticles of drug particles having excellent effect for improving the water solubility and bioavailability of sorapenib and the finished composition thereof The present invention has been accomplished based on the discovery that a formulation capable of producing a drug having excellent physical properties, smooth preparation and low weight without any disruption to the disintegration and dissolution characteristics of the nanoized drug.

details

The present invention provides an oral composition having improved water solubility and bioavailability by using Sorapemib nanoparticles and a method for producing the same.

Sorafenip nanoparticles

In embodiments of the present invention, sorafenip nanoparticles can be obtained through the following steps:

(a) providing a mixture comprising sorafenib or a pharmaceutically acceptable salt thereof, and a lipid as a lubricant;

(b) pulverizing the result of step (a) using a roll mill; And

(c) removing lipid from the result of step (b) using a supercritical fluid.

The method for producing nanoparticles used in the present invention may be as disclosed in Korean Patent Application No. 2017-0051600, which Korean Patent Application is incorporated herein by reference in its entirety.

In the embodiment of the present invention, the step (a) comprises the steps of (a-1) mixing sorapenib and lipid as a lubricant, and (a-2) adding biopolymer and / Or adding and mixing a surfactant.

In the embodiment of the present invention, the step (a-1) can be carried out by physically simply mixing the sorapenib powder and the lipid powder as a lubricant.

In another embodiment of the present invention, in the step (a-1), the solution obtained by dissolving sorapenib and lipid, which is a lubricant, in an organic solvent having water-miscibility (water-miscible property) is poured into water to solidify the resulting solids Followed by filtration and drying.

In the embodiment of the present invention, the step (a-2) may be performed by adding the biocompatible polymer and / or the surfactant to the resultant product of step (a-1) in powder form and mixing.

In another embodiment of the present invention, the step (a-2) may be carried out by adding the biocompatible polymer and / or the surfactant to the resultant product of step (a-1) in the form of an aqueous solution and mixing.

In the embodiment of the present invention, in addition to the biocompatible polymer and / or the surfactant, an anti-aggregation agent may be added to the result of the step (a-1) in the step (a-2).

In the embodiment of the present invention, the roll milling in the step (b) may be carried out continuously using rolls (for example, 2-roll mill or 3-roll mill) rotating in opposite directions.

In an embodiment of the present invention, the lipid removal in step (c) can be performed by continuously injecting and discharging supercritical fluid into the reactor containing the product of step (b).

In the embodiment of the present invention, the lipid removal using the supercritical fluid in the step (c) may be performed under a pressure condition of 50 atm or higher and a temperature condition of 10 to 50 ° C.

In the present invention, there is no particular limitation on the properties of the lipid used as a lubricant, and a liquid or solid phase can be used at room temperature. In one embodiment, lipids having a good solubility in supercritical fluids can be used. Examples of such lipids include saturated fatty acids having 10 to 22 carbon atoms, saturated fatty acid esters having 10 to 22 carbon atoms, Saturated or unsaturated fatty alcohols, saturated fatty alcohols, mono-, di- or tri-glycerides having saturated fatty acid groups of 10 to 22 carbon atoms, hydrocarbons of 14 or more carbon atoms (such as 14 to 24), and combinations thereof. It is not.

According to a particular embodiment of the invention, the lipid is selected from the group consisting of fatty alcohols such as, for example, myristyl alcohol, cetyl alcohol, stearyl alcohol and lauryl alcohol fatty alcohol, stearic acid, palmitic acid, myristic acid, lauric acid and their esters such as methyl, ethyl, propyl and butyl alcohol, Fatty acid monoglycerides such as monostearyl glyceride, monopalmityl glyceride, monomyristyl glyceride, monolauryl glyceride and the like, distearyl glyceride, dipalmityl glyceride, dimyristyl glyceride, Hexadecane, heptadecane, octadecane, and octadecane, such as fatty acid diglycerides such as glycerides, glycerides and the like, But are not limited to, hydrocarbons such as nonadecane, icosane, heneicosane, docosane, tricosane, tetracosane, and the like, and combinations thereof. And any lipid that can act as a lubricant in the milling process and can be removed by the supercritical fluid can be used according to the method of the present invention.

In the present invention, the lipid may be used in an amount of 0.1 parts by weight or more, or 0.3 parts by weight or more, or 0.5 parts by weight or more, based on 1 part by weight of sorapenib. The lipid may be used in an amount of 5 parts by weight or less, 4 parts by weight or less, or 3 parts by weight or less, based on 1 part by weight of sorapenib. If the amount of the lipid used is too small as compared with that of sorapenib, it may be difficult to perform smooth milling because of a heavy load on the subsequent roll milling process, or sorafenib may be amorphous or deformed into another crystal form, resulting in poor stability of nanoparticles. On the contrary, if the amount of lipid used is too large as compared with sorapenib, the economical efficiency of the subsequent lipid removing process can be significantly lowered. When the lipid to be used is a liquid at room temperature, the amount of the lipid to be used may be 3 parts by weight or less with respect to 1 part by weight of sorapenib. If the amount of the lipid used is too large, the properties of the mixture may become atherosclerotic and the milling may not be performed properly.

The water-miscible organic solvent which can be used in the present invention can dissolve the lipid used as sorapenib and lubricant well and can mix well with water, so that a mixture in which the active material and the lipid used as the lubricant are homogeneously mixed There is no particular limitation as long as it is a solvent which can be produced.

Specific examples of the water-miscible organic solvent include mono- or polyhydric alcohols having 8 or less carbon atoms (for example, 1 to 8 carbon atoms), ketones such as amine and acetone, dimethyl sulfoxide (DMSO), dimethylformamide But are not limited to, tetrahydrofuran (THF), pyridine, and combinations thereof.

In the present invention, when the water-miscible organic solvent is used, it may be used in an amount of 0.1 parts by weight or more, or 0.5 parts by weight or more, or 1 part by weight or more, based on 1 part by weight of sorapenib. The water-miscible organic solvent may be used in an amount of 10 parts by weight or less, or 6 parts by weight or less, or 3 parts by weight or less, based on 1 part by weight of sorapenib. If the amount of the water-miscible organic solvent used is too small as compared with that of sorapenib, it may be difficult to dissolve sorapenib and lipid as a lubricant at a low temperature (for example, 100 ° C or less). On the other hand, when the amount of the water-miscible organic solvent used is too high as compared with sorapenib, a considerable amount of sorapenib can not be solidified when solidified in water, resulting in a problem of lowering the production yield.

The biocompatible polymers and / or surfactants usable in the present invention are used in pharmaceuticals, foods and / or cosmetics. There is no particular limitation on their electrical properties (for example, ionic properties, nonionic properties) (For example, liquid phase, wax, solid phase, etc.). Any of the known biocompatible polymers and / or surfactants known to be usable for nanoparticle formation of sorafenib, or anything that can be used for the nanoparticle formation of sorapenib, even new ones, can be applied to the present invention.

Specific examples of the biocompatible polymer include gelatin, casein, dextran, gum acacia, tragacanth, polyethylene glycols, carboxymethylcellulose ( carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, Hydroxypropyl methylcellulose acetate succinate, methylcellulose noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, poloxamers, and polyvinylpyrrolidone. Eudragit (R), lysozyme, But are not limited to, albumin, and combinations thereof.

In the present invention, when the biocompatible polymer is used, it may be used in an amount of 0.001 parts by weight or more, or 0.005 parts by weight or more, or 0.01 parts by weight or more, based on 1 part by weight of sorapenib. The biocompatible polymer may be used in an amount of 5 parts by weight or less, 3 parts by weight or less, 2 parts by weight or less, 1 part by weight or 0.6 parts by weight or less based on 1 part by weight of sorapenib . If the biocompatible polymer is used in an excessively small amount relative to sorapenib, the aggregation of the nanoparticles produced in the nanoparticle formation of sorapenib can not be sufficiently prevented, which may make it difficult to produce uniform nanoparticles. On the other hand, if the amount of the biocompatible polymer is too high as compared with that of sorapenib, the volume of the final dosage form becomes large, which may impair convenience for the patient to take.

Specific examples of the surfactant include cetyl pyridinium chloride, phospholipids, fatty acid, benzalkonium chloride, calcium stearate, glycerin esters, of fatty acids, fatty alcohols, cetomacrogol, polyoxyethylene alkyl ethers, sorbitan esters, polyoxyethylene castor oil derivatives, Polyoxyethylene sorbitan fatty acid esters, dodecyl trimethyl ammonium bromide, polyoxyethylene stearate, sodium lauryl sulfate, sucrose fatty acid esters, Sucrose fatty acid ester, PEG-cholesterol (PEG- cholesterol), PEG-vitamin E (PEG-vitamin E), and combinations thereof.

In the present invention, when the surfactant is used, it may be used in an amount of 0.001 parts by weight or more, or 0.005 parts by weight or more, or 0.01 parts by weight or more, based on 1 part by weight of sorapenib. The surfactant may be used in an amount of 5 parts by weight or less, or 3 parts by weight or less, or 2 parts by weight or less, or 1 part by weight or less, or 0.5 parts by weight or less, based on 1 part by weight of sorapenib. If the amount of the surfactant is too small as compared with sorapenib, dispersion and dissolution of the prepared nanoparticles may be slow or low. On the other hand, if the amount of the surfactant used is too large as compared with sorapenib, the volume of the final formulation may become large, which may cause problems in convenience of taking.

The anti-aggregation agent usable in the present invention is used for the purpose of preventing agglomeration of the produced nanoparticles. As such an anti-aggregation agent, generally, a sugar compound selected from a sugar compound, for example, a monosaccharide compound, a disaccharide compound, a polysaccharide compound, a sugar alcohol and a combination thereof may be used. More specifically, glucose, lactose, mannitol, Clot, xylitol, chitosan, starch fiber, and combinations thereof, but is not limited thereto.

In the present invention, when the anti-aggregation agent is used, it may be used in an amount of not more than 5 parts by weight (for example, 0.0001 part by weight to 5 parts by weight), or 3 parts by weight or less, or 2 parts by weight or less based on 1 part by weight of sorapenib , Or 1 part by weight or less, or 0.5 parts by weight or less, 2 parts by weight or less, 1 part by weight or less, or 0.5 parts by weight or less. If the amount of the anti-aggregation agent used is too high as compared to sorapenib, the size of the final formulation may become large, which may be inconvenient for taking.

In an embodiment of the nanoparticle manufacturing method of the present invention, in the step (a), a mixture comprising sorapanib and the lipid as a lubricant is provided, and in one embodiment, the step (a) 1) mixing Sorapanib with a lipid as a lubricant, and (a-2) adding a biocompatible polymer and / or a surfactant to the resultant product of step (a-1) and mixing. In another embodiment, the step (a-1) may be performed by physically simply mixing the sorapenib powder and the lipid as a lubricant. In another embodiment, the step (a-1) A solution obtained by dissolving lipid in a water-miscible organic solvent is poured into water to solidify it, and the resultant solid is filtered and dried.

When the crystallinity of sorapenib is to be maintained, or when sorapenib is sensitive to heat, sorapanib and lipid may be added to the mixer in powder form and mixed uniformly.

When it is necessary to more uniformly mix the sorapenib and the lipid, the sorapenib and the lipid are placed in the reactor, the water-miscible organic solvent is added thereto, and the mixture is heated to dissolve the mixture in a transparent state. Preferably 30 占 폚 or less, more preferably 25 占 폚 or less, and even more preferably 20 占 폚 or less to solidify the obtained solid, filtrate the resulting solid and dry it under reduced pressure to obtain a mixture of sorafenib and lipid Powder can be obtained.

In one embodiment, the step (a-2) may be performed by adding a biocompatible polymer and / or a surfactant in powder form to the resultant product of step (a-1) The step (a-2) may be carried out by adding the biocompatible polymer and / or the surfactant in the form of an aqueous solution to the resultant product of step (a-1) and mixing. In addition to the biocompatible polymer and / or surfactant, an anti-aggregation agent may be further added to the result of step (a-2) in step (a-2).

The biocompatible polymer, surfactant or anti-aggregation agent may be added in powder form or optionally in the form of an aqueous solution. When the biocompatible polymer, surfactant or coagulation inhibitor is added in the form of an aqueous solution, the amount of water (for example, distilled water) used in the preparation of the aqueous solution is, for example, from 0.1 part by weight to 5 parts by weight Preferably not more than 3 parts by weight, more preferably not more than 2 parts by weight, and even more preferably not more than 1 part by weight is preferable for smooth roll milling. If the amount of water used is too large, the shear force is lowered and the production of fine nanoparticles is difficult and the number of milling is increased, resulting in poor economical efficiency.

In the embodiment of the nanoparticle production method of the present invention, in the step (b), the product of step (a) (i.e., sorapenib, a lipid as a lubricant, a biocompatible polymer and / or a surfactant, A mixture containing an anti-aggregation agent) is pulverized using a roll mill. The pulverization can be carried out continuously using, for example, 2-roll mill or 3-roll mill.

The roll mill is a device for crushing two or more rolls (for example, two roll mills or three roll mills) rotating in opposite directions to each other by applying compression and shearing force to the mixture to be fed. In the present invention, Any type of roll mill capable of pulverizing by applying a shearing force can be used.

The inter-roller clearance during the roll-milling process may be, for example, 200 μm or less, preferably 100 μm or less, more preferably 50 μm or less, and still more preferably 30 μm or less. If the clearance between the rollers is too wide, the pressing and shearing force is lowered, so that it is difficult to obtain a sufficient pulverizing effect. If the gap is too narrow, the feeding speed may be slowed down.

In a roll milling process, the temperature of the roll mill may be suitably adjusted according to the lubricant used, i.e., the melting point of the lipid and the amount used. In one embodiment, when the amount of lipid used is at least 1 part by weight relative to 1 part by weight of sorapenib, it may be desirable to maintain the temperature of the roll mill below the melting point of the lipid used. In another embodiment, when the amount of lipid used is less than 1 part by weight with respect to 1 part by weight of sorapenib, the temperature of the roll mill may be near the melting point of the lipid used (melting point +/- 5 ° C) or higher . Alternatively, when using lipids that are liquid at room temperature, such as lauryl alcohol (melting point: 22 ° C), the amount of lipid added may be controlled rather than the temperature of the roll mill (eg, 0.1-1 Or 0.2 to 0.8 part by weight, or 0.3 to 0.5 part by weight) may be advantageous for a roll milling process.

In the embodiment of the nanoparticle production method of the present invention, in the step (c), the lipid used as a lubricant is removed from the resultant of the step (b) by using a supercritical fluid. In one embodiment, the lipid removal can be carried out by continuously introducing and discharging a supercritical fluid into the reactor containing the product of step (b), which can be carried out, for example, under pressure conditions of at least 50 atmospheres and at a temperature of from 10 to 50 & Under conditions.

In one embodiment, the solid mixture obtained in step (b) is placed in a high-pressure reactor, and the inside of the reactor is maintained at a temperature at which lipid used as a lubricant does not flow down, for example, 10 to 60 ° C, more specifically 15 to 40 ° C. The supercritical fluid inlet valve and the outlet valve are controlled by applying a supercritical fluid gas (for example, carbon dioxide) to the reactor and pressurizing the inside of the reactor at 60 to 400 atm, more specifically 70 to 200 atm, The supercritical fluid is continually introduced into the reactor and out of the reactor, whereby the lipid used as the lubricant is sent out of the reactor together with the supercritical fluid to be removed. At this time, if the temperature inside the high-pressure reactor is too high, the lipid used as a lubricant may act as a solvent for sorapenib, and as a result, crystals of sorapenib, which has been produced in nanoparticle size, may grow. Therefore, it is preferable to maintain the temperature of the reactor at a temperature that can minimize the fluidity of the lipid present in the solid mixture powder obtained in the step (b), preferably the temperature of the melting point of the lipid, , It is preferable to maintain the temperature at 15 to 40 占 폚.

In addition, the time required to remove lipid as supercritical fluid depends on the type and amount of lipid used. In order to obtain sorafenib particles of higher purity, lipid is removed for a sufficient time to minimize the amount of residual lipid . Since the lipids preferably used in the present invention are harmless to the human body, it is not necessary to limit the residual amount to a specific range. However, considering the purity of the obtained sorapenib, it is preferable that the lipids remain at less than 1 wt% Do. Of course, when a lipid used as a surfactant such as a mono-, di- or tri-glyceride-based compound is used, the residual amount may exceed 10% by weight.

The lipids removed from the solid mixture powder as described above can be collected in a separate reactor and continuously used in the next production process.

Completed using nanoparticles

The oral compositions of the present invention may preferably be in the form of solid oral preparations, especially tablets or capsules. When preparing the finished product using sorafenip nanoparticles, it is very important to keep the properties of the sorafenib nanoparticles in the form of the final formulation while preserving their properties. Particularly, disintegration characteristics, dispersion characteristics, dissolution characteristics, and maintenance characteristics of nanoparticles in an aqueous solution should be maintained in the finished product. However, the biocompatible polymers used in the nanofiber are highly viscous and have a strong binding force, which can serve to retard the disintegration, dispersion and dissolution of the finished product. In particular, hypromellose and povidone are hydrophilic polymers and have the property of absorbing water well. When a tablet made of a hydrophilic polymer and a drug or other excipient meets water, the polymer hydrates to form a swollen surface, and a glassy layer is formed in a tablet having a dry core state. Over time, this layer becomes a gel layer to form a diffusion layer, and through this diffusion layer, drug molecules are slowly released to the external medium. After a further period of time, the tablet will form an erosion surface where erosion occurs on the tablet surface due to external stimuli, such as peristalsis of the intestines. This process results in delayed release of the drug. The higher the viscosity grade, such as 2280 and 2910, the greater the delay effect.

However, the main ingredient, sorafenib, rapidly disintegrates in the body and must reach a final dissolution rate in a short time. The higher the pH, the lower the solubility of the drug due to the nature of the top of the gastrointestinal tract can maintain the highest concentration can promote absorption. Therefore, the use of polymers for nanoparticle production can be a deterrent to absorption improvement by delayed drug release.

In particular, when making the preparation in the form of tablets, the disintegration of the tablet formed by tableting may be delayed by the biocompatible polymer. Even if disintegration occurs, dispersion or dissolution in the form of granules or lumps can be delayed by the biocompatible polymer.

The formulation designed to maximize the disintegration and dispersion or dissolution of tablets allows the properties of sorafenib nanoparticles to be retained even after production of the finished product.

A tablet containing a hydrophilic polymer with a high viscosity, such as hypromellose, hydrates the surface of the polymer when it is in contact with water, forming a film to prevent moisture from penetrating into the inside. In order to prevent such a phenomenon, it is possible to use a disintegrant, a large amount of excipients, and the like.

When a disintegrant is used, the disintegration and dispersion and dissolution of the formulation can be promoted by the action of wetting through capillary action or swelling of the disintegrant itself by drawing water into the tablet.

Also, when a large amount of diluent is used, biodegradable polymers can be separated from each other to prevent disintegration delay.

However, when the disintegrant is used in a large amount, the final formulation may be susceptible to moisture, resulting in deterioration of stability. If the diluent is used in a large amount, the final formulation is disadvantageously increased.

As a result, the refining composition of the design which promotes the disintegration by devising gel layer by the spacing between polymer particles by physical force at the moment of contact with water was devised. It has been proposed to use a foamable material for this purpose.

In one embodiment, the sodium bicarbonate used as a pH adjusting agent and an antacid produces CO ₂ gas in an acidic solution, which rapidly expands the volume of the tablet by the pressure change that occurs, resulting in the penetration of water into the tablet and the disintegration . ≪ / RTI >

In one embodiment, the chemical formula of the tablet surface with NaHCO ₃ in gastric conditions is as follows:

_{NaHCO 3 (s) + HCl (} aq) → NaCl (aq) + H 2 O (l) + CO 2 (g)

As the additive showing foamability, the agent of the present invention may contain a foaming agent or an acidifying agent.

The foaming agent may be an alkali metal carbonate, preferably sodium carbonate, sodium bicarbonate (sodium bicarbonate), potassium carbonate or potassium hydrogencarbonate, either alone or in combination. Most preferably, sodium bicarbonate may be used have.

The composition of the present invention preferably contains 10 to 200 parts by weight of the blowing agent relative to 100 parts by weight of the polymer. If the foaming agent is contained in an amount less than 10 parts by weight, the foaming performance may be deteriorated. If the foaming agent is contained in an amount exceeding 200 parts by weight, the preparation of the preparation may become difficult due to a decrease in the content of other components. Air bubbles are generated even when exposed to water, resulting in a decrease in stability. The foaming agent may be used in an amount of preferably 20 to 170 parts by weight, more preferably 30 to 150 parts by weight, and most preferably 50 to 120 parts by weight, based on 100 parts by weight of the polymer.

As the acidifying agent, citric acid, succinic acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, acetylsalicylic acid and nicotinic acid may be used singly or in combination, and most preferably, citric acid or tartaric acid may be used. The composition of the present invention may contain 0 to 200 parts by weight, more preferably 0 to 150 parts by weight, and most preferably 0 to 100 parts by weight of the acidifying agent relative to 100 parts by weight of the foaming agent. When the acidifying agent is not added, gastric acid plays a role. If the acidifying agent is contained in an amount exceeding 200 parts by weight, the content of the other ingredients may be lowered and the hardness of the preparation may be lowered.

When the acidifying agent is included in the formulations together, the formulations may react with each other even when moisture is drawn in the air during manufacture or during storage, so that it is necessary to block moisture during the process or during storage.

However, in the case of an oral preparation, since the tablet is directly exposed to the gastric juice which is strongly acidic after taking it, it is more preferable to use only the foaming agent (for example, sodium hydrogencarbonate) as an additive without separately using an acidifying agent.

The composition of the present invention may comprise other additional components in addition to the sorafenib nanoparticles. Examples of other additional constituents include solubilizers, diluents, disintegrants, lubricants and coaters.

As the dissolution aid, a polymer or a surfactant may be used. Preferably, a polymethacrylate copolymer can be used. The polymethacrylate copolymer is preferably a cationic polymer with dimethylaminoethyl methacrylate as a functional group as a functional group, more preferably poly (butyl methacrylate-co - (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate).

The polymethacrylate copolymer may have a weight average molecular weight of 3,000 to 200,000, preferably 5,000 to 150,000, more preferably 10,000 to 100,000, and even more preferably 20,000 to 80,000 g / mole. If the weight average molecular weight is less than 3,000 g / mole, the water solubility improvement effect may be low. If the weight average molecular weight is more than 200,000 g / mole, the disintegration may be delayed.

There is no particular limitation on the state of the polymethacrylate copolymer, but it may be granular or powdered.

As a specific example, the polymethacrylate copolymer may be Eudragit E PO (Ebonic, Germany) or Eudragit E 100 (Ebonic, Germany). As a specific example, the weight average molecular weight of the polymethacrylate copolymer may be about 47,000 g / mole.

The polymethacrylate copolymer is used in an amount of 0.05 to 5 parts by weight, preferably 0.1 to 4 parts by weight, more preferably 0.2 part by weight, based on 1 part by weight of sorapenib or a pharmaceutically acceptable salt thereof, To 3 parts by weight. When the polymethacrylate copolymer is used in an amount less than the lower limit of the above range, the water solubility and bioavailability of sorapenib may not be improved, Which may cause discomfort when the patient is taking the medicine.

The diluent may be, for example, lactose (anhydride or hydrate, such as monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol But is not limited to, at least one selected from the group consisting of maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin and mixtures thereof. Preferably, lactose, microcrystalline cellulose or mixtures thereof may be selected. Most preferably, starch, a mixture of lactose and microcrystalline cellulose may be selected. The diluent may also act as a binder.

The diluent may be used in an amount of, for example, 0.1 to 80 parts by weight, preferably 1 to 65 parts by weight, more preferably 2 to 50 parts by weight, based on 100 parts by weight of the whole preparation (e.g. tablet) . If the diluent is less than the lower limit of the range described above, the preparation may be difficult to prepare, for example, the stability may be lowered. If the diluent is out of the upper limit range described above, the preparation may become excessively large, have.

The disintegrant may be, for example, croscarmellose sodium (CrosCMC-Na), carboxymethyl cellulose, crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low substituted hydroxypropyl cellulose) , Starch (wheat, rice, corn or potato starch), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolyzed starch, and mixtures thereof. It is not. Preferably, it may be croscarmellose sodium (CrosCMC-Na) or L-HPC (low-substituted hydroxypropylcellulose) or a mixture thereof.

The disintegrant may be used in an amount of, for example, 1 to 30 parts by weight, preferably 2 to 20 parts by weight, based on 100 parts by weight of the whole preparation (e.g. tablet). If the disintegration is less than the above-mentioned lower limit range, there may be a problem of delayed dissolution rate due to the delay of the disintegration rate, and if the disintegration exceeds the above-mentioned upper limit range, there may be a problem in productivity such as a disability.

The lubricant may be, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, But is not limited to, at least one selected from the group consisting of silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof . It may preferably be magnesium stearate.

The lubricant may be present in an amount of, for example, 0.1 to 3 parts by weight, preferably 0.2 to 3 parts by weight, more preferably 0.5 to 2 parts by weight, based on 100 parts by weight of the total formulation (e.g. tablet) . If the lubricant is less than the above-mentioned lower limit range, there may be a problem in productivity such as a maltreating disorder. If the lubricant is out of the above-mentioned upper limit range, there may be a problem of delayed dissolution and productivity.

Examples of the coating agent include hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (sodium salt and calcium salt), ethyl cellulose Hydroxypropylcellulose (HPC), L-HPC (HPC of low degree of substitution), polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl Acetate copolymer (e.g., Kollidon 占 VA64, BASF), Polycoat IR, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof , But the present invention is not limited thereto. Preferably polyvinyl acetate (PVA), hydroxypropylmethyl cellulose (HPMC), polycoat IR (Polycoat IR).

The coating agent may be used in an amount of, for example, 0.2 to 15 parts by weight, preferably 0.5 to 10 parts by weight, more preferably 1 to 7 parts by weight, based on 100 parts by weight of the pre-coating tablet . If the coating agent is less than the above lower limit range, there may be a problem that some of the entire surface of the lozenge is not covered with the coating agent, and there may be an excessive delay in the dissolution rate if the above-mentioned upper limit range is exceeded.

As described above, various additional biologically inert ingredients may be added for the purpose of improving coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance improvement, Can be used.

According to one embodiment, the biologically inert ingredients which may additionally be included in the coating layer include plasticizers, lubricants, colorants, flavors, surfactants, stabilizers, antioxidants, foaming agents, defoamers, And the like.

For example, the plasticizer is used in an amount of not more than 100% by weight (for example, 0.1 to 100% by weight), specifically not more than 50% by weight (for example, about 0.1 to 50% by weight) 30% by weight or less (for example, 0.1 to 30% by weight).

For example, the plasticizer is selected from the group consisting of triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, acetyl triethyl citrate, acetyl triethyl citrate, propylene glycol, triacetin , Polyethylene glycol, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol, but the present invention is not limited thereto.

For example, the lubricant may be contained in an amount of 100% by weight or less (for example, 0.1 to 100% by weight) based on the dry weight of the whole polymer used in each coating layer.

For example, the lubricant may be selected from the group consisting of magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed colloidal silica, But is not limited to, at least one selected from the group consisting of magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof.

Various additives may be mixed in the tablets or capsules in order to improve the physical properties of the tablets or capsules, the composition, the compressibility, the appearance, the taste, the stability of the drug, and the like. Such additives include, for example, stabilizers, solubilizers, sweeteners, mating agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, An antioxidant, a brightener, a flavoring agent, a flavoring agent, a pigment, a coating agent, a wetting agent, a wetting agent, a filler, an antifoaming agent, a chelating agent, a chelating agent, an antistatic agent, a colorant, a sugar, an isotonic agent, a softening agent, A preservative, a solubilizer, a solvent, a fluidizing agent, and the like. However, any of pharmaceutically acceptable ones may be used, for example, .

Manufacturing method of finished product

In the preparation of the oral composition, the finished product using Sorapemib nanoparticles can be formulated in various ways.

In one embodiment, the finished product utilizing sorafenib nanoparticles can be formulated by simple mixing. Such a mixture may be mixed with other additional components and tableted or tableted in a direct tablet system, or encapsulated in a capsule.

In other embodiments, Sorapemib nanoparticles and other additional components may be granulated in a variety of ways and then lubricated with a lubricant, etc., and tableted or tabletted, or encapsulated in capsules. Examples of various methods of granulation include wet granules, dry granules, and the like. The wet granulation can be a high speed mixer or a fluidized bed granulator, and the dry granule can be a roller compactor, an extruder or the like.

Best Mode for Carrying Out the Invention Hereinafter, preferred embodiments are described to facilitate understanding of the present invention. However, the following examples are intended to illustrate the invention and are not intended to limit the invention in any way.

[ Example ]

Manufacturing example  One. Sorapanib  Manufacture of nanoparticles

3 g of sorapenib tosylate crystal type III powder was mixed well with 9 g of myristyl alcohol powder as a lubricant and 0.75 g of hydroxypropylmethylcellulose (HPMC; 5 cp), povidone (PVP) ) And 0.06 g of Poloxamer 407 were dissolved in 3 ml of demineralized distilled water and mixed well. The mixture was stirred at a roller speed (RS) of 60 rpm and a roller temperature (RT) of 15 to 19 ° C Followed by continuous roll milling. After the roll milling, the remaining water was removed by vacuum drying.

The solid dispersion type mixture obtained by the above method was put into a high pressure reactor and carbon dioxide as a supercritical fluid was continuously flowed at 15 to 25 ° C under 70 to 100 atmospheric pressure to remove the lipid used as a lubricant and the sorafenib, HPMC, PVP and A poloxamer mixed powder was obtained.

The obtained powder was dispersed in desalted distilled water at a concentration of 1 mg / ml (based on sorapenib), and then the particle size was measured by Otsuka ELSZ-1000 of dynamic light scattering (DLS) method to confirm that the average particle size was 496.8 nm . In addition, pXRD analysis confirmed that the crystalline form of sorapenib tosylate III was retained. As a result of pXRD analysis of the nanoparticles prepared in Example 1, it was confirmed that the original crystal form was maintained.

Example  One

10.0 g of sorafenib nano particles (7.2 g of sorapenib tosylate III, 1.8 g of hypromellose (= hydroxypropyl methylcellulose), 0.7 g of povidone and 0.2 g of poloxamer), 2.9 g of Eudragit E, , 0.8 g of sodium starch glycolate, and 1.3 g of sodium hydrogencarbonate were mixed together and mixed with 0.1 g of magnesium stearate, followed by final mixing. The mixture was compressed into 11 mm circular punches based on the weight of 350.0 mg per tablet.

Example  2

10.0 g of sorafenib nano particles (7.2 g of sorapenib tosylate III, 1.8 g of hypromellose, 0.7 g of povidone, 0.2 g of poloxamer), 2.9 g of Eudragit E, 2.0 g of mannitol, 0.8 g of starch glycolate 0.8 g and sodium bicarbonate (2.6 g) were mixed together and mixed with 0.1 g of magnesium stearate, followed by final mixing. The mixture was compressed into 11 mm circular punches based on the weight of 350.0 mg per tablet.

Example  3

10.0 g of sorafenib nano particles (7.2 g of sorapenib tosylate III, 1.8 g of hypromellose, 0.7 g of povidone and 0.2 g of poloxamer), 2.9 g of Eudragit E, 1.5 g of mannitol, 0.8 g of starch glycolate 0.8 g and 3.2 g of sodium hydrogencarbonate were mixed and mixed with 0.1 g of magnesium stearate, followed by final mixing. The mixture was compressed into 11 mm circular punches based on the weight of 350.0 mg per tablet.

Example  4

10.0 g of sorafenib nano particles (7.2 g of sorapenib tosylate III type, 1.8 g of hypromellose, 0.7 g of povidone and 0.2 g of poloxamer), 2.9 g of Eudragit E, 1.0 g of mannitol, 0.8 g of starch glycolic acid 0.8 g, and sodium bicarbonate (3.7 g) were mixed and mixed. Then, 0.1 g of magnesium stearate was added thereto, followed by final mixing. The mixture was compressed into 11 mm circular punches based on the weight of 350.0 mg per tablet.

The composition of the examples according to the sodium hydrogencarbonate ratio is shown in Table 1 below.

[Table 1] (Unit: mg)

Test Example  1: Measurement of physical properties of tablets

[Measuring the degree of wear]

Masodo was measured using a lapine friability tester for 10 tablets by the method described in USP 1216 Tablet Friability, and the results are shown in Table 2 below (measurement time = 4 minutes ).

[Table 2]

[Disintegration test]

According to the disintegration test method of the Korean Pharmacopoeia 10th edition, the disintegration test was carried out in the pH 1.2 solution at n = 3 for each example, and the results are shown in Table 3 below.

[Table 3]

Example  5

≪ Manufacture of noodles &

10.0 g of sorafenib nano particles (7.2 g of sorapenib tosylate III type, 1.8 g of hypromellose, 0.7 g of povidone and 0.2 g of poloxamer), 2.9 g of Eudragit E, 1.9 g of mannitol, 0.8 g of starch glycolate 0.8 g, and sodium bicarbonate (2.8 g) were mixed and compacted using a roller compactor, followed by granulation in a 710 체 sieve. Then, 0.1 g of magnesium stearate was sieved and finally mixed. The mixture was compressed into 11 mm circular punches based on 350.9 mg weight per tablet. At this time, the hardness of the bottom is about 15 ~ 30N.

≪ Coating <

A film coating corresponding to a total of 3.0% (w / w) based on the total weight of the nonwoven fabric was applied to the thus prepared foil. The coating agent was prepared by preparing a coating liquid having an organic solvent composition as an opaque base agent containing HPMC as a main component. The primary coating operating conditions are shown in Table 4 below.

[Table 4]

The composition of Example 5 is shown in Table 5 below.

[Table 5] (Unit: mg)

Claims (10)

A composition for oral administration having improved water solubility and bioavailability, which comprises sorapenib nanoparticles comprising sorafenib or a pharmaceutically acceptable salt thereof. The composition of claim 1, further comprising a foaming component. 3. The composition of claim 2, further comprising a solubility aid. The composition according to claim 2, wherein the foaming component comprises a foaming agent and an acidifying agent. 3. The composition of claim 2, wherein the foamable component comprises only a blowing agent and does not comprise an acidifying agent. 4. The composition of claim 3 comprising a polymethacrylate copolymer as a solubility aid. 7. The composition according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt of sorapenib is sorapenib tosylate. 7. The composition according to any one of claims 1 to 6, in the form of a solid oral preparation. (1) nanoparticles of sorafenib or a pharmaceutically acceptable salt thereof; And
(2) forming an oral preparation containing the nanoparticles obtained in the step (1).
A method for preparing an oral composition having improved water solubility and bioavailability. 10. The method of claim 9, wherein step (1)
(a) providing a mixture comprising sorafenib or a pharmaceutically acceptable salt thereof and a lipid as a lubricant;
(b) pulverizing the product of step (a) using a roll mill; And
(c) removing lipid from the result of step (b) using a supercritical fluid.
Way.