WO2015147366A1 - Celecoxib solid dispersion and method for preparing same - Google Patents

Celecoxib solid dispersion and method for preparing same Download PDF

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Publication number
WO2015147366A1
WO2015147366A1 PCT/KR2014/003020 KR2014003020W WO2015147366A1 WO 2015147366 A1 WO2015147366 A1 WO 2015147366A1 KR 2014003020 W KR2014003020 W KR 2014003020W WO 2015147366 A1 WO2015147366 A1 WO 2015147366A1
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celecoxib
solid dispersion
weight
parts
adsorbent
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French (fr)
Korean (ko)
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이성균
박용덕
장재원
소남우
남기원
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주식회사 일화
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to a celecoxib solid dispersion and a method for preparing the same, and more particularly, to a celecoxib solid dispersion having improved dissolution rate of a poorly soluble drug, celecoxib.
  • Celecoxib represented by the chemical name 4- [5 [(4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, is cyclooxygenase (COX) As a selective inhibitor for -2, it has the effect of treating and preventing arthritis without side effects on the gastrointestinal tract. It is currently marketed under the brand name Celebrex Capsule (Pfizer). Celecoxib and its manufacturing method are disclosed in detail in Korean Patent Nos. 10-0229343 and 10-0261669.
  • celecoxib drugs such as rofecoxib (Biox) have been marketed, but after their withdrawal from the market due to severe cardiovascular side effects, celecoxib now has the largest market share in the arthritis treatment market without gastrointestinal disorders. It is shown. Recent studies have shown that celecoxib is also very effective in preventing lung cancer in smokers. Despite these excellent effects, celecoxib is a needle-like crystalline compound that is extremely poorly soluble in water and has very low bioavailability due to little absorption into the body upon oral administration. Therefore, there are various problems such as a high dose required to exhibit an effective effect, a high risk of side effects due to high dose intake, and low convenience of taking a patient according to an increase in the size of the preparation. In particular, celecoxib has been reported to significantly increase the risk of cardiovascular side effects as the dose is increased, there is a need for a method that can improve the bioavailability to achieve the desired pharmacological effect in the smallest dose possible.
  • Biox rofecoxib
  • US Pat. No. 6,589,557 discloses a porous matrix form comprising celecoxib with enhanced drug dissolution rate upon contact with an aqueous medium.
  • the disclosed porous matrix rapidly produces celecoxib nanoparticles upon contact with an aqueous medium, thereby increasing the dissolution rate of celecoxib.
  • the manufacturing method is complicated and difficult, such as celecoxib is dissolved in a volatile solvent and mixed with a pore-forming solution such as ammonium bicarbonate to form an emulsion, and then these solvents and pore-forming agents are removed to form a dry pore matrix.
  • U.S. Patent Application Publication No. 2007/0059356 discloses that celecoxib and nicotinamide are dissolved in acetone, respectively, and then mixed, and the mixture is gradually evaporated to acetone overnight to obtain a precipitate, which is redissolved in acetone and dried to co-crystal with celecoxib and nicotinamide.
  • a method of obtaining is disclosed.
  • the obtained celecoxib-nicotinamide cocrystal has improved elution rate and hygroscopicity, but has a problem in that it requires a long time for production, including a low safety using a toxic solvent such as acetone, and a process of slowly evaporating overnight.
  • Korean Patent Laid-Open Publication No. 2013-0069484 discloses a celecoxib-containing solid dispersion and a method for producing the same, wherein the celecoxib, the water-soluble polymer carrier and the surfactant are dissolved in a solvent and then spray dried to improve the water solubility and bioavailability.
  • the spray drying method the use of celecoxib, which is a relatively large particle having a particle size (D90) of 200 ⁇ m or more, is difficult to prepare and the dissolution rate is significantly lower than that of the pharmaceutical composition using the celecoxib having a small particle size. There is.
  • the present invention has been made to solve the above problems, while using a celecoxib raw material of a wide particle size range, a celecoxib solid dispersion which can stably improve the dissolution rate of the celecoxib drug and a pharmaceutical using the same It is intended to provide tablets.
  • the present invention is to provide a method for easily preparing a celecoxib solid dispersion having improved dissolution rate without employing a conventional spray drying method.
  • the present invention provides a celecoxib solid dispersion comprising a celecoxib, a water-soluble polymer carrier, a solubilizer and an adsorbent.
  • the water-soluble polymer carrier provides a celecoxib solid dispersion, characterized in that the polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • solubilizer provides a celecoxib solid dispersion, characterized in that sodium lauryl sulfate.
  • the adsorbent provides a celecoxib solid dispersion, characterized in that the magnesium metasilicate aluminate.
  • the celecoxib solid dispersion is composed of 3 to 20 parts by weight of the water-soluble polymer carrier, 3 to 20 parts by weight of the solubilizer and 50 to 100 parts by weight of the adsorbent based on 100 parts by weight of the celecoxib.
  • a celecoxib solid dispersion is provided.
  • celecoxib solid dispersion characterized in that it further comprises 5 to 25 parts by weight of croscarmellose sodium disintegrant and 3 to 20 parts by weight of sodium stearyl fumarate lubricant based on 100 parts by weight of the celecoxib. .
  • the present invention to solve the above another problem, provides a pharmaceutical tablet containing the celecoxib solid dispersion as an active ingredient.
  • the present invention to solve the above another problem, (a) dissolving a celecoxib, a water-soluble polymer carrier and a solubilizer in a solvent to form a solid dispersion solution; (b) mixing the adsorbent with the solid dispersion solution to form a mixed liquid; (c) naturally drying and pulverizing the mixed liquid to form a mixed solid; And (d) mixing an excipient with the mixed solid agent.
  • the method for preparing celecoxib solid dispersion comprising a;
  • the celecoxib provides a method for producing a celecoxib solid dispersion, characterized in that the particle size (D 90 ) is 200 ⁇ 500 ⁇ m.
  • the solvent provides a method for producing a celecoxib solid dispersion, characterized in that consisting of 20 to 40% by volume of ethanol and 60 to 80% by volume of dichloromethane.
  • the adsorbent in the celecoxib by including the adsorbent in the celecoxib, the water-soluble polymer carrier and the solubilizing agent, even when using a celecoxib raw material having a relatively large particle size, drug dissolution rate is improved and bioavailability is improved during oral administration Sieve solid dispersions can be provided.
  • a celecoxib solid dispersion having celecoxib, a water-soluble polymer carrier, and a solubilizing agent in a solid dispersion solution in which an adsorbent is mixed and manufactured by simply drying and pulverizing the celecoxib solid dispersion having an improved dissolution rate It can provide a way to mass production in a simple way.
  • the present invention discloses a celecoxib solid dispersion comprising a celecoxib, a water soluble polymer carrier, a solubilizer and an adsorbent.
  • the celecoxib is contained in the form of particles.
  • Celecoxib particles are prepared by grinding or precipitation from solution, which can aggregate to form aggregated particles.
  • the celecoxib that can be used in the present invention has a wide range of particle sizes, and in particular, a celecoxib having a relatively large particle size can be advantageously applied.
  • the celecoxib particle size means the largest dimension
  • D 90 is preferably 200 to 500 ⁇ m as the largest dimension, and 300 to 400 ⁇ m may be most preferably applied.
  • the 'solid dispersion' refers to a form in which the intermolecular bonds of the water-soluble polymer carrier and the solubilizing agent and celecoxib are adsorbed and dried on the adsorbent, and the wettability of the celecoxib is increased by the adsorption to the sere. The solubility and dissolution rate of the coxib are further increased.
  • celecoxib is present in amorphous form in the solid dispersion. Since celecoxib is a poorly water-soluble drug, it is not absorbed in the gastrointestinal tract when precipitated as crystals, so the bioavailability is significantly reduced.
  • the solubility of the celecoxib may be remarkably increased, thereby improving bioavailability.
  • amorphous celecoxib in the solid dispersion maintains the amorphous form as it is, it has excellent storage stability.
  • the water-soluble polymer carrier is a material used to maintain the amorphous form of celecoxib, hydroxypropyl methyl cellulose (HPMC), polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), Hydroxypropyl cellulose (HPC), cellulose polymer, poly (meth) acrylate and the like can be used, preferably polyvinylpyrrolidone (PVP) can be used.
  • HPMC hydroxypropyl methyl cellulose
  • PEG polyethylene glycol
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • HPC Hydroxypropyl cellulose
  • cellulose polymer poly (meth) acrylate and the like
  • PVP polyvinylpyrrolidone
  • PVP K25 and PVP K30 preferably PVP K30, are well soluble in relatively harmless solvents such as water and ethanol, and due to their relatively small molecular weight, the viscosity of the solution is not high so that they are suitable for use as a carrier in the solid dispersion according to the present invention. Do.
  • the preferred content of the water-soluble polymer carrier in the present invention can be determined from the dissolution rate test results described below. It is preferably 3 to 20 parts by weight, more preferably 5 to 15 parts by weight, and most preferably 5 to 10 parts by weight based on 100 parts by weight of the celecoxib raw material.
  • the solubilizer is a material that serves to effectively combine the water-soluble polymer carrier and celecoxib in the preparation of celecoxib solid dispersion, solubility of celecoxib, sodium lauryl sulfate, polyoxyethylene glycolation Natural or hydrogenated castor oil, sorbitan esters and polyoxyethylene sorbitan fatty acid esters, polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymers, synthetic vitamin E derivatives, fatty acid macrogol glycerides, poly Glyceryl fatty acid esters, glyceryl fatty acid esters, stearic acid polyethylene glycol and the like can be used, preferably sodium lauryl sulfate or castor oil can be used.
  • sodium lauryl is effective in improving the dissolution and solubility of celecoxib having a particularly large particle size by binding the hydrophilic portion of the solubilizer to the outside of the celecoxib dissolved in the solvent when preparing the celecoxib solid dispersion.
  • sulfate is used.
  • the preferred content of the solubilizer in the present invention can be determined from the dissolution rate test results described below. It is preferably 3 to 20 parts by weight, more preferably 5 to 15 parts by weight, and most preferably 5 to 10 parts by weight based on 100 parts by weight of the celecoxib raw material.
  • the adsorbent is a material used to prevent recrystallization caused by interaction with other components on the surface of the celecoxib particle in the preparation of celecoxib solid dispersion according to the present invention. That is, in the process of applying an excipient to a solid dispersion solution containing a celecoxib, a water-soluble polymer carrier and a solubilizing agent, the solid dispersion in the excipient as in the prior art by using a celecoxib having relatively large particles as a raw material Rather than spray-drying the solution by spraying, a simple general mixing method is used again to recrystallize to a larger particle size (bound particles of celecoxib and water-soluble polymer carrier).
  • the binding particles of the celecoxib and the water-soluble polymer carrier are quickly adsorbed and dried on the adsorbent particles, thereby binding particles of the celecoxib and the water-soluble polymer carrier having a large particle size. Will not be generated.
  • the adsorbent is porous fine particles, the particle diameter is preferably 1 to 500 ⁇ m, more preferably 10 to 250 ⁇ m, most preferably 50 to 200 ⁇ m.
  • examples of such an adsorbent include magnesium metasilicate aluminate, lactose, anhydrous dibasic calcium phosphate, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, soybean hull fiber, corn starch, fluorite and the like.
  • magnesium metasilicate aluminate is sold in various forms, for example, under noisin (trade name, Fuji Chemical Industry Co., Ltd.).
  • the preferred content of the adsorbent in the present invention can be determined from the dissolution rate test results described below. It is preferably 50 to 100 parts by weight, more preferably 60 to 95 parts by weight, and most preferably 80 to 90 parts by weight based on 100 parts by weight of the celecoxib raw material.
  • the celecoxib solid dispersion according to the present invention may be mixed with a pharmaceutically acceptable disintegrant, lubricant and the like in the preparation of a pharmaceutical formulation using the same.
  • disintegrant examples include starch, sodium starch glycolate, croscarmellose sodium, cellulose, alginate, and the like.
  • the starch glycon may be used to improve the dissolution rate of celecoxib in the celecoxib solid dispersion according to the present invention.
  • Sodium acid or croscarmellose sodium is suitable, and croscarmellose sodium is most suitable.
  • the preferred content may be determined from the dissolution rate test results described below, and may be included in an amount of preferably 5 to 25 parts by weight, more preferably 10 to 20 parts by weight, based on 100 parts by weight of the celecoxib raw material. Can be.
  • the lubricant examples include magnesium stearate, sodium stearyl fumarate, sodium acetate, sodium fumarate, sodium chloride, polyethylene glycol, sodium oleate, and the like. Magnesium stearate or sodium stearyl fumarate is suitable, with sodium stearyl fumarate being most suitable. If the lubricant is contained, the preferred content can be determined from the dissolution rate test results described below, preferably 3 to 20 parts by weight, more preferably 5 to 15 parts by weight, most preferably 100 parts by weight of celecoxib raw material. 5 to 10 parts by weight may be included.
  • the present invention also discloses a pharmaceutical formulation containing the celecoxib solid dispersion as an active ingredient.
  • Such pharmaceutical preparations are used as oral preparations, and the active ingredient celecoxib may be included in an amount of 5-100 mg, preferably 10-80 mg, most preferably 20-50 mg.
  • This low content of celecoxib is a characteristic of the celecoxib solid dispersion according to the present invention, it is possible to lower the drug content of the celecoxib contained in the formulation by improving the solubility and bioavailability of the celecoxib.
  • Oral preparations are in the form of tablets or dry syrups such as powders, granules, capsules, uncoated tablets, film coated tablets, and fast disintegrating tablets. These formulations may be prepared according to methods commonly used in the pharmaceutical art.
  • the celecoxib solid dispersion according to the present invention may be prepared as a powder, granules, capsules, tablets, etc. by adding a pharmaceutically acceptable disintegrant, a lubricant, and the like, as described above. Or a film-forming agent, a plasticizer, or the like in order to obtain a film-coated tablet.
  • the method for producing a celecoxib solid dispersion comprises the steps of: (a) dissolving a celecoxib, a water-soluble polymer carrier and a solubilizer in a solvent to form a solid dispersion solution; (b) mixing the adsorbent with the solid dispersion solution to form a mixed liquid; (c) naturally drying and pulverizing the mixed liquid to form a mixed solid; And (d) mixing an excipient with the mixed solid agent.
  • the adsorbent is mixed with the solid dispersion solution, thereby allowing the combined particles of the celecoxib and the water-soluble polymer carrier to be rapidly adsorbed and dried on the adsorbent particles, thereby allowing the celecoxib and the water-soluble polymer to have a large particle size.
  • the binding particles of the carrier are not produced.
  • the celecoxib in the form of particles used in step (a) may be advantageously applied to a celecoxib having a relatively large particle size, and that D 90 is 200 to 500 ⁇ m as the largest dimension.
  • D 90 is 200 to 500 ⁇ m as the largest dimension.
  • 300 ⁇ 400 ⁇ m may be most preferably applied.
  • the solvent used in step (a) may be pharmaceutically usable and may be water, methanol, ethanol, C1-C4 lower alcohols such as isopropanol, ethyl ether, acetone, dichloromethane or a mixed solvent thereof.
  • ethanol and dichloromethane mixed solvents may be used.
  • the amount of the solvent used is not particularly limited as long as it can sufficiently dissolve the celecoxib raw material, the water-soluble polymer carrier, and the solubilizing agent. However, if the above-mentioned preferred ethanol and dichloromethane mixed solvents are used, the amount of the celecoxib may be reduced.
  • a mixed solvent composed of 20 to 40% by volume of ethanol and 60 to 80% by volume of dichloromethane, and to use a mixed solvent composed of 25 to 35% by volume of ethanol and 65 to 75% of dichloromethane. More preferred.
  • the adsorbent is further mixed with the formed solid dispersion solution to form a mixed liquid. Thereafter, instead of spray-drying the mixed liquid, (c) the mixed liquid is naturally dried and pulverized to form a mixed solid, and (d) a simple mixing of an excipient such as a disintegrant and a lubricant into the mixed solid can be performed simply.
  • Coxy solid dispersions can be prepared.
  • solubilizing agent (about 30 to 50% by weight) may be prepared by (a) solid dispersion solution forming step, the remainder may be prepared by mixing with excipients in step (d), In some cases (about 70-90% by weight) may be prepared by (b) mixing the liquid mixture forming step, the remainder is mixed with the excipient in step (d).
  • the celecoxib solid dispersion prepared as described above may be prepared in oral formulations of various formulations, for example, as tablets in a circular shape and may be prepared by tableting to a total weight of 450 mg and a hardness of 6 to 7 Kp.
  • Test Example 1 Check the dissolution rate according to the type and content of the water-soluble polymer carrier
  • PVP polyvinylpyrrolidone
  • PVP K90 the hardening (hardness) during the manufacturing process was so severe that it was not possible to check the dissolution rate by filling the actual capsule.
  • celecoxib and PVP were dissolved in a mixed solvent of ethanol and dichloromethane to form a solid dispersion solution, and lactose was mixed with the solid dispersion solution to form a mixed solution.
  • the mixed solution was completely dried in a dryer, and then pulverized (30mesh) using a pulverizer, followed by mixing sodium lauryl sulfate (SLS) and sodium starch glycolate, and filling the capsule No. 0 to prepare a celecoxib solid dispersion. .
  • the celecoxib and PVP were dissolved in a mixed solvent of ethanol and dichloromethane in the content of Table 4 to form a solid dispersion solution, and lactose (or magnesium metasilicate aluminate) was mixed with the solid dispersion solution to form a mixed solution. It was.
  • the mixed solution is completely dried in a drier, and then pulverized (30mesh) using a grinder, followed by mixing sodium lauryl sulfate, sodium starch glycolate and magnesium stearate, and filling into capsule No. 1 for a capsule sample and about tablets.
  • Cerecoxib solid dispersion was prepared by tableting with uncoated tablet to have a hardness of 7 Kp.
  • a tablet prepared using magnesium metasilicate aluminate as an adsorbent has a higher dissolution rate than a capsule prepared using lactose.
  • Celecoxib solid dispersions were prepared according to the following preparation examples in order to compare the dissolution rate according to the use of various adsorbents when prepared in tablet form as in Test Example 2.
  • celecoxib and PVP were dissolved in a mixed solvent of ethanol and dichloromethane to form a solid dispersion solution, and the respective adsorbents were mixed with the solid dispersion solution to form a mixed solution.
  • the mixed liquid is completely dried in a drier, and then pulverized (30mesh) using a grinder, followed by mixing sodium lauryl sulfate, sodium starch glycolate, and magnesium stearate, and tableting to a hardness of about 7 Kp to celecoxib solid dispersion.
  • Table 5 celecoxib and PVP were dissolved in a mixed solvent of ethanol and dichloromethane to form a solid dispersion solution, and the respective adsorbents were mixed with the solid dispersion solution to form a mixed solution.
  • the mixed liquid is completely dried in a drier, and then pulverized (30mesh) using a grinder, followed by mixing sodium lauryl sulfate, sodium starch glycolate, and magnesium ste
  • celecoxib is used to form a solid dispersion solution. 80% by weight was added and the remaining 20% by weight was added with the final excipient.
  • magnesium metasilicate aluminate is used as the adsorbent (Example 9)
  • the initial five-minute dissolution rate is decreased and the highest dissolution rate is generally observed.
  • lactose it may be impossible to produce during production as prepared in the solvent state as in Test Example 2, when using a mixture of magnesium aluminate silicate and lactose (Example 7) It can be seen that the dissolution rate was relatively low.
  • Test Example 4 Check the dissolution rate according to the composition of the adsorbent and the carrier
  • the dissolution rate is the best at the level of 7.5 parts by weight (Example 11) PVP based on 100 parts by weight of celecoxib.
  • Test Example 5 Check the dissolution rate according to the excipient content
  • Test Example 6 Check the dissolution rate according to the adsorbent content
  • the celecoxib solid dispersion was prepared in the same manner as in Test Example 3 in the composition of Table 8 below.
  • the dissolution test was carried out in the same manner as in Test Example 1 for the cerebrex capsule (200 mg, Pfizer Pharmaceuticals) commercially available as the celecoxib solid dispersion and the control formulation of Examples 18 and 19 of Table 8, and the results are shown in FIG. And FIG. 7. (In the case of the control formulation in FIGS. 6 and 7, there was a slight error in the dissolution rate measurement value due to the separate dissolution test corresponding to Examples 18 and 19, respectively.)
  • the celecoxib solid dispersion prepared according to Example 18 it can be seen that the dissolution rate is lower than the control formulation as a whole. Therefore, when the adsorbent content is increased to the optimum level, and the disintegrant and the lubricant are replaced with croscarmellose sodium and sodium stearyl fumarate, respectively, and the content is increased to the optimum level (Example 19), it is similar to that of the control formulation. It can be seen that the level of dissolution rate is shown (see FIG. 7).
  • the dissolution rate in the pH 4.0 eluate was slightly lower than that of the celecoxib solid dispersion prepared according to the present invention compared to the control formulation, but the dissolution rate in the pH 1.2 eluate was higher than that of the control formulation. It can be seen that better.
  • the dissolution rate in the pH 1.2 eluate is more important in evaluating the bioavailability of poorly soluble drugs, so it can be seen that the celecoxib solid dispersion prepared according to the present invention showed an excellent dissolution rate compared to the control formulation. .

Abstract

Disclosed is a celecoxib solid dispersion capable of stably improving the release rate of celecoxib drug while using a celecoxib raw material having a wide range of particle sizes. The present invention provides a celecoxib solid dispersion containing celecoxib, a water-soluble polymer carrier, a solubilizer, and an absorbent.

Description

세레콕시브 고체분산체 및 그 제조방법Celecoxib solid dispersion and preparation method thereof
본 발명은 세레콕시브 고체분산체 및 그 제조방법에 관한 것으로, 보다 상세하게는 난용성 약물인 세레콕시브의 용출률이 향상된 세레콕시브 고체분산체 및 그 제조방법에 관한 것이다.The present invention relates to a celecoxib solid dispersion and a method for preparing the same, and more particularly, to a celecoxib solid dispersion having improved dissolution rate of a poorly soluble drug, celecoxib.
화학명 4-[5[(4-메틸페닐)-3-(트리플루오로메틸)-1H-피라졸-1-일]벤젠설폰아미드로 표시되는 세레콕시브(Celecoxib)는 사이클로옥시게나제(COX)-2에 대한 선택적 억제제로서, 위장관에 대한 부작용 없이 관절염을 치료 및 예방하는 효과를 나타낸다. 현재, 쎄레브렉스 캡슐(화이자)이라는 상품명으로 시판되고 있다. 세레콕시브 및 그 제조방법은 대한민국 특허 제10-0229343호 및 제10-0261669호에 상세히 개시되어 있다.Celecoxib, represented by the chemical name 4- [5 [(4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, is cyclooxygenase (COX) As a selective inhibitor for -2, it has the effect of treating and preventing arthritis without side effects on the gastrointestinal tract. It is currently marketed under the brand name Celebrex Capsule (Pfizer). Celecoxib and its manufacturing method are disclosed in detail in Korean Patent Nos. 10-0229343 and 10-0261669.
종래에는 로페콕시브(rofecoxib, 상품명: 바이옥스) 등 다양한 콕시브 약물들이 시판되었으나, 심각한 심혈관계 부작용으로 인해 이들이 시장에서 철수된 후, 세레콕시브는 현재 위장장애 없는 관절염 치료제 시장에서 가장 큰 점유율을 나타내고 있다. 최근 연구에 따르면, 세레콕시브는 흡연 경험자에서의 폐암 예방에도 매우 효과적인 것으로 나타났다. 이와 같은 우수한 효과에도 불구하고, 세레콕시브는 침상형의 결정형 화합물로서, 물에 극히 난용성이며, 경구 투여시 체내로의 흡수가 거의 되지 않아 생체이용율이 매우 낮다. 따라서, 유효한 효과를 나타내는데 필요한 복용량이 높고, 높은 복용량 섭취에 따른 부작용 발현의 우려가 크며, 제제 크기 증가에 따른 환자의 복용 편리성이 낮은 등 여러 가지 문제가 있다. 특히, 세레콕시브는 투여량이 증가될수록 심혈관계 부작용 발생 위험이 현저히 증가되는 것으로 보고되어, 가능한 적은 복용량으로 원하는 약리 효과를 나타낼 수 있도록 생체이용율을 향상시킬 수 있는 방안이 요망된다.Conventionally, various coxib drugs such as rofecoxib (Biox) have been marketed, but after their withdrawal from the market due to severe cardiovascular side effects, celecoxib now has the largest market share in the arthritis treatment market without gastrointestinal disorders. It is shown. Recent studies have shown that celecoxib is also very effective in preventing lung cancer in smokers. Despite these excellent effects, celecoxib is a needle-like crystalline compound that is extremely poorly soluble in water and has very low bioavailability due to little absorption into the body upon oral administration. Therefore, there are various problems such as a high dose required to exhibit an effective effect, a high risk of side effects due to high dose intake, and low convenience of taking a patient according to an increase in the size of the preparation. In particular, celecoxib has been reported to significantly increase the risk of cardiovascular side effects as the dose is increased, there is a need for a method that can improve the bioavailability to achieve the desired pharmacological effect in the smallest dose possible.
세레콕시브의 난용성 및 낮은 생체이용율을 개선하기 위해 다양한 방법들이 연구되어 왔다.Various methods have been studied to improve the poor solubility and low bioavailability of celecoxib.
예컨대, 미국 등록특허 제6,589,557호는 수성 매질에 접촉 시 약물 용출속도가 증강된 세레콕시브를 포함하는 다공성 매트릭스 형태를 개시하고 있다. 개시된 다공성 매트릭스는 수성 매질과 접촉 시 신속하게 세레콕시브 나노입자를 생성함으로써, 세레콕시브의 용출속도를 증가시킨다. 그러나, 세레콕시브를 휘발성 용매에 녹이고 암모늄 바이카보네이트와 같은 기공형성제 용액과 혼합하여 에멀젼을 만든 후 이들 용매와 기공형성제를 제거시켜 건조 기공 매트릭스를 형성하는 등 제조방법이 복잡하고 까다롭다. For example, US Pat. No. 6,589,557 discloses a porous matrix form comprising celecoxib with enhanced drug dissolution rate upon contact with an aqueous medium. The disclosed porous matrix rapidly produces celecoxib nanoparticles upon contact with an aqueous medium, thereby increasing the dissolution rate of celecoxib. However, the manufacturing method is complicated and difficult, such as celecoxib is dissolved in a volatile solvent and mixed with a pore-forming solution such as ammonium bicarbonate to form an emulsion, and then these solvents and pore-forming agents are removed to form a dry pore matrix.
미국 공개특허 제2007/0059356호는 세레콕시브와 니코틴아미드를 각각 아세톤에 녹인 후 이들을 혼합하고 밤새 서서히 아세톤을 증발시켜 침전을 얻고 이를 아세톤에 재용해시킨 후 건조하여 세레콕시브와 니코틴아미드 공결정을 얻는 방법을 개시하고 있다. 수득된 세레콕시브-니코틴아미드 공결정은 용출속도 및 흡습성은 개선되나, 아세톤과 같은 유독성 용매를 사용하여 안전성이 낮고, 밤새 서서히 증발시키는 공정을 포함하는 등 제조에 장시간이 요구되는 문제가 있다.U.S. Patent Application Publication No. 2007/0059356 discloses that celecoxib and nicotinamide are dissolved in acetone, respectively, and then mixed, and the mixture is gradually evaporated to acetone overnight to obtain a precipitate, which is redissolved in acetone and dried to co-crystal with celecoxib and nicotinamide. A method of obtaining is disclosed. The obtained celecoxib-nicotinamide cocrystal has improved elution rate and hygroscopicity, but has a problem in that it requires a long time for production, including a low safety using a toxic solvent such as acetone, and a process of slowly evaporating overnight.
공개특허공보 제2013-0069484호는 세레콕시브, 수용성 고분자 담체 및 계면활성제를 용매에 용해시킨 후 이를 분무 건조하여 수용해성 및 생체이용율을 개선시킨 세레콕시브 함유 고체분산체 및 그 제조방법을 개시하고 있으나, 분무 건조 방식을 채용하여 입자 크기(D90)가 200㎛ 이상의 상대적으로 큰 입자인 세레콕시브를 이용할 경우 제조가 어렵고 입자 크기가 작은 세레콕시브를 이용한 약학 조성물에 비해 용출률이 현저히 떨어지는 문제가 있다.Korean Patent Laid-Open Publication No. 2013-0069484 discloses a celecoxib-containing solid dispersion and a method for producing the same, wherein the celecoxib, the water-soluble polymer carrier and the surfactant are dissolved in a solvent and then spray dried to improve the water solubility and bioavailability. However, by using the spray drying method, the use of celecoxib, which is a relatively large particle having a particle size (D90) of 200 μm or more, is difficult to prepare and the dissolution rate is significantly lower than that of the pharmaceutical composition using the celecoxib having a small particle size. There is.
따라서, 본 발명은 상기 문제점을 해결하고자 안출된 것으로, 넓은 입자 크기 범위의 세레콕시브 원료를 이용하면서도 세레콕시브 약물의 용출률을 안정적으로 향상시킬 수 있는 세레콕시브 고체분산체와 이를 이용한 약제학적 정제를 제공하고자 한다.Accordingly, the present invention has been made to solve the above problems, while using a celecoxib raw material of a wide particle size range, a celecoxib solid dispersion which can stably improve the dissolution rate of the celecoxib drug and a pharmaceutical using the same It is intended to provide tablets.
또한, 종래 분무 건조 방식의 채용 없이도 향상된 용출률을 갖는 세레콕시브 고체분산체를 용이하게 제조할 수 있는 방법을 제공하고자 한다.In addition, the present invention is to provide a method for easily preparing a celecoxib solid dispersion having improved dissolution rate without employing a conventional spray drying method.
상기 과제를 해결하기 위하여 본 발명은, 세레콕시브, 수용성 고분자 담체, 가용화제 및 흡착제를 포함하는 세레콕시브 고체분산체를 제공한다.In order to solve the above problems, the present invention provides a celecoxib solid dispersion comprising a celecoxib, a water-soluble polymer carrier, a solubilizer and an adsorbent.
또한, 상기 수용성 고분자 담체는 폴리비닐피롤리돈(PVP)인 것을 특징으로 하는 세레콕시브 고체분산체를 제공한다.In addition, the water-soluble polymer carrier provides a celecoxib solid dispersion, characterized in that the polyvinylpyrrolidone (PVP).
또한, 상기 가용화제는 소디움라우릴설페이트인 것을 특징으로 하는 세레콕시브 고체분산체를 제공한다.In addition, the solubilizer provides a celecoxib solid dispersion, characterized in that sodium lauryl sulfate.
또한, 상기 흡착제는 메타규산알루민산마그네슘인 것을 특징으로 하는 세레콕시브 고체분산체를 제공한다.In addition, the adsorbent provides a celecoxib solid dispersion, characterized in that the magnesium metasilicate aluminate.
또한, 상기 세레콕시브 고체분산체는 상기 세레콕시브 100중량부에 대하여 상기 수용성 고분자 담체 3~20중량부, 상기 가용화제 3~20중량부 및 상기 흡착제 50~100중량부 함량으로 구성된 것을 특징으로 하는 세레콕시브 고체분산체를 제공한다.In addition, the celecoxib solid dispersion is composed of 3 to 20 parts by weight of the water-soluble polymer carrier, 3 to 20 parts by weight of the solubilizer and 50 to 100 parts by weight of the adsorbent based on 100 parts by weight of the celecoxib. There is provided a celecoxib solid dispersion.
또한, 상기 세레콕시브 100중량부에 대하여 크로스카멜로오스나트륨 붕해제 5~25중량부 및 스테아릴푸마르산나트륨 활택제 3~20중량부를 더 포함하는 것을 특징으로 하는 세레콕시브 고체분산체를 제공한다.In addition, it provides a celecoxib solid dispersion characterized in that it further comprises 5 to 25 parts by weight of croscarmellose sodium disintegrant and 3 to 20 parts by weight of sodium stearyl fumarate lubricant based on 100 parts by weight of the celecoxib. .
상기 다른 과제 해결을 위하여 본 발명은, 상기 세레콕시브 고체분산체를 유효성분으로 함유하는 약제학적 정제를 제공한다.The present invention to solve the above another problem, provides a pharmaceutical tablet containing the celecoxib solid dispersion as an active ingredient.
상기 또 다른 과제 해결을 위하여 본 발명은, (a) 세레콕시브, 수용성 고분자 담체 및 가용화제를 용매에 용해시켜 고체분산체 용액을 형성하는 단계; (b) 상기 고체분산체 용액에 흡착제를 혼합하여 혼합 액제를 형성하는 단계; (c) 상기 혼합 액제를 자연 건조 및 분쇄하여 혼합 고체제를 형성하는 단계; 및 (d) 상기 혼합 고체제에 부형제를 혼합하는 단계;를 포함하는 세레콕시브 고체분산체 제조방법을 제공한다.The present invention to solve the above another problem, (a) dissolving a celecoxib, a water-soluble polymer carrier and a solubilizer in a solvent to form a solid dispersion solution; (b) mixing the adsorbent with the solid dispersion solution to form a mixed liquid; (c) naturally drying and pulverizing the mixed liquid to form a mixed solid; And (d) mixing an excipient with the mixed solid agent. The method for preparing celecoxib solid dispersion comprising a;
또한, 상기 (a) 단계에서 상기 세레콕시브는 입자 크기(D90)가 200~500㎛인 것을 특징으로 하는 세레콕시브 고체분산체 제조방법을 제공한다.In addition, in the step (a), the celecoxib provides a method for producing a celecoxib solid dispersion, characterized in that the particle size (D 90 ) is 200 ~ 500㎛.
또한, 상기 용매는 에탄올 20~40부피% 및 디클로로메탄 60~80부피%로 구성된 것을 특징으로 하는 세레콕시브 고체분산체 제조방법을 제공한다.In addition, the solvent provides a method for producing a celecoxib solid dispersion, characterized in that consisting of 20 to 40% by volume of ethanol and 60 to 80% by volume of dichloromethane.
이러한 본 발명에 따르면, 세레콕시브, 수용성 고분자 담체 및 가용화제에 흡착제를 포함함으로써 상대적으로 큰 입자 크기를 갖는 세레콕시브 원료를 이용할 경우에도 약물 용출률이 개선되어 경구 투여 시 생체이용율이 향상된 세레콕시브 고체분산체를 제공할 수 있다.According to the present invention, by including the adsorbent in the celecoxib, the water-soluble polymer carrier and the solubilizing agent, even when using a celecoxib raw material having a relatively large particle size, drug dissolution rate is improved and bioavailability is improved during oral administration Sieve solid dispersions can be provided.
또한, 세레콕시브 고체분산체를 세레콕시브, 수용성 고분자 담체 및 가용화제가 용해된 고체분산체 용액에 흡착제를 혼합하여 이를 단순 자연 건조 및 분쇄하여 제조함으로써 향상된 용출률을 갖는 세레콕시브 고체분산체를 간단한 방법으로 대량 생산할 수 있는 방법을 제공할 수 있다.In addition, a celecoxib solid dispersion having celecoxib, a water-soluble polymer carrier, and a solubilizing agent in a solid dispersion solution in which an adsorbent is mixed and manufactured by simply drying and pulverizing the celecoxib solid dispersion having an improved dissolution rate It can provide a way to mass production in a simple way.
도 1은 본 발명의 시험예 1에 따른 용출시험 결과를 나타낸 그래프,1 is a graph showing the dissolution test results according to Test Example 1 of the present invention,
도 2는 본 발명의 시험예 2에 따른 용출시험 결과를 나타낸 그래프,2 is a graph showing the dissolution test results according to Test Example 2 of the present invention,
도 3은 본 발명의 시험예 3에 따른 용출시험 결과를 나타낸 그래프,3 is a graph showing the dissolution test results according to Test Example 3 of the present invention,
도 4는 본 발명의 시험예 4에 따른 용출시험 결과를 나타낸 그래프,4 is a graph showing the dissolution test results according to Test Example 4 of the present invention,
도 5는 본 발명의 시험예 5에 따른 용출시험 결과를 나타낸 그래프,5 is a graph showing the dissolution test results according to Test Example 5 of the present invention,
도 6 및 도 7은 본 발명의 시험예 6에 따른 용출시험 결과를 나타낸 그래프,6 and 7 are graphs showing the dissolution test results according to Test Example 6 of the present invention,
도 8 내지 도 11은 본 발명의 시험예 7에 따른 용출시험 결과를 나타낸 그래프.8 to 11 are graphs showing the dissolution test results according to Test Example 7 of the present invention.
이하에서는 본 발명의 바람직한 실시예를 상세하게 설명한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐리게 할 수 있다고 판단되는 경우 그 상세한 설명을 생략하기로 한다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한, 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있음을 의미한다.Hereinafter, a preferred embodiment of the present invention will be described in detail. In the following description of the present invention, if it is determined that the detailed description of the related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted. Throughout the specification, when a part is said to "include" a certain component, it means that it may further include other components, not to exclude other components, unless otherwise stated.
본 발명은 세레콕시브, 수용성 고분자 담체, 가용화제 및 흡착제를 포함하는 세레콕시브 고체분산체를 개시한다.The present invention discloses a celecoxib solid dispersion comprising a celecoxib, a water soluble polymer carrier, a solubilizer and an adsorbent.
상기 세레콕시브는 입자 형태로 함유된다. 세레콕시브 입자는 분쇄 또는 용액으로부터 침전시켜 제조되는데, 이는 응집되어 응집 입자를 형성할 수 있다. 본 발명에서 사용될 수 있는 세레콕시브는 입자 크기의 범위가 넓으며, 특히, 기존 대비 상대적으로 큰 입자 크기를 갖는 세레콕시브가 유리하게 적용될 수 있다. 본 발명에서 세레콕시브 입자 크기는 최대 치수를 의미하며, D90이 최대 치수로서 200~500㎛인 것이 바람직하며, 300~400㎛인 것이 가장 바람직하게 적용될 수 있다.The celecoxib is contained in the form of particles. Celecoxib particles are prepared by grinding or precipitation from solution, which can aggregate to form aggregated particles. The celecoxib that can be used in the present invention has a wide range of particle sizes, and in particular, a celecoxib having a relatively large particle size can be advantageously applied. In the present invention, the celecoxib particle size means the largest dimension, D 90 is preferably 200 to 500 µm as the largest dimension, and 300 to 400 µm may be most preferably applied.
본 발명에서 '고체분산체'란 수용성 고분자 담체 및 가용화제와 세레콕시브의 분자간 결합이 흡착제에 흡착되어 건조된 형태를 의미하며, 흡착에 의해 세레콕시브의 적심성(wettability)이 증가되어 세레콕시브의 용해성 및 용출률을 더욱 증가시키도록 한다. 이때, 세레콕시브는 고체분산체 내에서 무정형 형태로 존재한다. 세레콕시브는 난용성 약물이기 때문에 결정으로 석출될 경우 위장관 등에서 흡수되지 않아 생체이용율이 현저히 떨어진다. 본 발명에서는 세레콕시브가 고체분산체 내에서 무정형으로 존재하기 때문에 세레콕시브의 용해성이 현저히 높아지고 이에 따라 생체이용율이 개선될 수 있다. 또한, 고체분산체 내에 존재하는 무정형의 세레콕시브가 무정형의 형태를 그대로 유지하기 때문에 우수한 저장 안정성을 갖도록 한다.In the present invention, the 'solid dispersion' refers to a form in which the intermolecular bonds of the water-soluble polymer carrier and the solubilizing agent and celecoxib are adsorbed and dried on the adsorbent, and the wettability of the celecoxib is increased by the adsorption to the sere. The solubility and dissolution rate of the coxib are further increased. Here, celecoxib is present in amorphous form in the solid dispersion. Since celecoxib is a poorly water-soluble drug, it is not absorbed in the gastrointestinal tract when precipitated as crystals, so the bioavailability is significantly reduced. In the present invention, since the celecoxib is amorphous in the solid dispersion, the solubility of the celecoxib may be remarkably increased, thereby improving bioavailability. In addition, since amorphous celecoxib in the solid dispersion maintains the amorphous form as it is, it has excellent storage stability.
상기 수용성 고분자 담체는 세레콕시브의 무정형을 유지하기 위해 사용되는 물질로서, 히드록시프로필메틸셀룰로오스(HPMC), 폴리에틸렌글리콜(PEG), 폴리비닐피롤리돈(PVP), 폴리비닐알콜(PVA), 히드록시프로필셀룰로오스(HPC), 셀룰로오스 폴리머, 폴리(메트)아크릴레이트 등이 사용될 수 있고, 바람직하게는 폴리비닐피롤리돈(PVP)이 사용될 수 있다.The water-soluble polymer carrier is a material used to maintain the amorphous form of celecoxib, hydroxypropyl methyl cellulose (HPMC), polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), Hydroxypropyl cellulose (HPC), cellulose polymer, poly (meth) acrylate and the like can be used, preferably polyvinylpyrrolidone (PVP) can be used.
폴리비닐피롤리돈(PVP)은 분자량에 따라 PVP F17(Mw=10,000), PVP K25(Mw=30,000), PVP K30(Mw=50,000), PVP K90(Mw=1,100,000) 등으로 나뉘어지며, HPMC, HPC, PVA와 더불어 생체 친화적인 고분자이다. 특히, PVP K25와 PVP K30, 바람직하게 PVP K30은 물과 에탄올 같은 비교적 인체에 무해한 용매에 잘 녹고 비교적 작은 분자량으로 인해 용액의 점도가 크지 않아 본 발명에 따른 고체분산체에서 담체로 사용하기에 적합하다.Polyvinylpyrrolidone (PVP) is divided into PVP F17 (Mw = 10,000), PVP K25 (Mw = 30,000), PVP K30 (Mw = 50,000), PVP K90 (Mw = 1,100,000), etc. In addition to HPC and PVA, it is a biocompatible polymer. In particular, PVP K25 and PVP K30, preferably PVP K30, are well soluble in relatively harmless solvents such as water and ethanol, and due to their relatively small molecular weight, the viscosity of the solution is not high so that they are suitable for use as a carrier in the solid dispersion according to the present invention. Do.
본 발명에서 수용성 고분자 담체의 바람직한 함량은 후술하는 용출률 시험 결과로부터 정해질 수 있다. 세레콕시브 원료 100중량부에 대하여 바람직하게는 3~20중량부, 더욱 바람직하게는 5~15중량부, 가장 바람직하게는 5~10중량부 함량으로 포함될 수 있다.The preferred content of the water-soluble polymer carrier in the present invention can be determined from the dissolution rate test results described below. It is preferably 3 to 20 parts by weight, more preferably 5 to 15 parts by weight, and most preferably 5 to 10 parts by weight based on 100 parts by weight of the celecoxib raw material.
상기 가용화제는 세레콕시브 고체분산체 제조 시 수용성 고분자 담체와 세레콕시브가 효과적으로 결합될 수 있도록 하여 세레콕시브의 용해도를 향상시키는 역할을 하는 물질로서, 소디움라우릴설페이트, 폴리옥시에틸렌 글리콜화 천연 또는 수소화 피마자유, 솔비탄 에스테르 및 폴리옥시에틸렌 솔비탄 지방산 에스테르, 폴리에틸렌 글리콜-15-히드록시스테아레이트, 폴리옥시에틸렌-폴리옥시프로필렌 공중합체, 합성 비타민 E 유도체, 지방산 마크로골 글리세라이드, 폴리글리세릴 지방산 에스테르, 글리세릴 지방산 에스테르, 스테아린산 폴리에틸렌 글리콜 등이 사용될 수 있고, 바람직하게는 소디움라우릴설페이트 또는 피마자유가 사용될 수 있다. 이때, 세레콕시브 고체분산체 제조 시 용매에 용해된 세레콕시브에 가용화제의 친수성 부분이 바깥쪽을 향하도록 결합하여 특히 큰 입자 크기를 갖는 세레콕시브의 분산과 용해도 향상에 효과적인 소디움라우릴설페이트를 사용하는 것이 가장 바람직하다.The solubilizer is a material that serves to effectively combine the water-soluble polymer carrier and celecoxib in the preparation of celecoxib solid dispersion, solubility of celecoxib, sodium lauryl sulfate, polyoxyethylene glycolation Natural or hydrogenated castor oil, sorbitan esters and polyoxyethylene sorbitan fatty acid esters, polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymers, synthetic vitamin E derivatives, fatty acid macrogol glycerides, poly Glyceryl fatty acid esters, glyceryl fatty acid esters, stearic acid polyethylene glycol and the like can be used, preferably sodium lauryl sulfate or castor oil can be used. At this time, sodium lauryl is effective in improving the dissolution and solubility of celecoxib having a particularly large particle size by binding the hydrophilic portion of the solubilizer to the outside of the celecoxib dissolved in the solvent when preparing the celecoxib solid dispersion. Most preferably, sulfate is used.
본 발명에서 가용화제의 바람직한 함량은 후술하는 용출률 시험 결과로부터 정해질 수 있다. 세레콕시브 원료 100중량부에 대하여 바람직하게는 3~20중량부, 더욱 바람직하게는 5~15중량부, 가장 바람직하게는 5~10중량부 함량으로 포함될 수 있다.The preferred content of the solubilizer in the present invention can be determined from the dissolution rate test results described below. It is preferably 3 to 20 parts by weight, more preferably 5 to 15 parts by weight, and most preferably 5 to 10 parts by weight based on 100 parts by weight of the celecoxib raw material.
상기 흡착제는 본 발명에 따른 세레콕시브 고체분산체 제조 시 세레콕시브 입자 표면에서 다른 성분과의 상호작용에 의해 발생하는 재결정화를 방지하기 위해 사용되는 물질이다. 즉, 세레콕시브, 수용성 고분자 담체 및 가용화제를 포함한 고체분산체 용액에 부형제를 적용하는 공정에 있어, 상대적으로 큰 입자를 갖는 세레콕시브를 원료 사용으로 인해, 종래와 같이 부형제에 고체분산체 용액을 스프레이 방식으로 분무 건조하지 않고, 단순 일반혼합 방식을 적용하게 되면 다시 입도(세레콕시브와 수용성 고분자 담체의 결합 입자) 크기가 큰 형태로 재결정화된다. 이때, 고체분산체 용액에 흡착제를 혼합하는 단계를 거치게 되면, 흡착제 입자에 세레콕시브와 수용성 고분자 담체의 결합 입자가 빠르게 흡착되어 건조되기 때문에 큰 입도를 갖는 세레콕시브와 수용성 고분자 담체의 결합 입자가 생성되지 않도록 하게 된다.The adsorbent is a material used to prevent recrystallization caused by interaction with other components on the surface of the celecoxib particle in the preparation of celecoxib solid dispersion according to the present invention. That is, in the process of applying an excipient to a solid dispersion solution containing a celecoxib, a water-soluble polymer carrier and a solubilizing agent, the solid dispersion in the excipient as in the prior art by using a celecoxib having relatively large particles as a raw material Rather than spray-drying the solution by spraying, a simple general mixing method is used again to recrystallize to a larger particle size (bound particles of celecoxib and water-soluble polymer carrier). At this time, when the adsorbent is mixed with the solid dispersion solution, the binding particles of the celecoxib and the water-soluble polymer carrier are quickly adsorbed and dried on the adsorbent particles, thereby binding particles of the celecoxib and the water-soluble polymer carrier having a large particle size. Will not be generated.
상기 흡착제는 다공질의 미립자로서 입경이 바람직하게는 1~500㎛, 더욱 바람직하게는 10~250㎛, 가장 바람직하게는 50~200㎛일 수 있다. 이러한 흡착제로 예를 들면, 메타규산알루민산마그네슘, 유당, 무수 제2인산 칼슘, 미결정성 셀룰로오스, 가교 카르복실메틸 셀룰로오스 나트륨, 대두 외피 섬유, 옥수수전분, 플로라이트 등을 들 수 있으며, 본 발명에 따른 세레콕시브 고체분산체에서 세레콕시브의 용출률 향상에 있어서는 메타규산알루민산마그네슘을 선택하는 것이 가장 적합하다. 상기 메타규산알루민산마그네슘은 예컨대, 노이시린(상표명, 후지화학공업주식회사)으로 다양한 형태가 판매되고 있다. The adsorbent is porous fine particles, the particle diameter is preferably 1 to 500㎛, more preferably 10 to 250㎛, most preferably 50 to 200㎛. Examples of such an adsorbent include magnesium metasilicate aluminate, lactose, anhydrous dibasic calcium phosphate, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, soybean hull fiber, corn starch, fluorite and the like. In the improvement of the dissolution rate of celecoxib in a celecoxib solid dispersion, it is most suitable to select magnesium metasilicate aluminate. The magnesium metasilicate aluminate is sold in various forms, for example, under noisin (trade name, Fuji Chemical Industry Co., Ltd.).
본 발명에서 흡착제의 바람직한 함량은 후술하는 용출률 시험 결과로부터 정해질 수 있다. 세레콕시브 원료 100중량부에 대하여 바람직하게는 50~100중량부, 더욱 바람직하게는 60~95중량부, 가장 바람직하게는 80~90중량부 함량으로 포함될 수 있다.The preferred content of the adsorbent in the present invention can be determined from the dissolution rate test results described below. It is preferably 50 to 100 parts by weight, more preferably 60 to 95 parts by weight, and most preferably 80 to 90 parts by weight based on 100 parts by weight of the celecoxib raw material.
본 발명에 따른 세레콕시브 고체분산체는 이를 이용한 약제학적 제제 제조에 있어 약학적으로 허용되는 붕해제, 활택제 등이 혼합될 수 있다.The celecoxib solid dispersion according to the present invention may be mixed with a pharmaceutically acceptable disintegrant, lubricant and the like in the preparation of a pharmaceutical formulation using the same.
상기 붕해제로는 전분, 전분글리콘산나트륨, 크로스카멜로오스나트륨, 셀룰로오스, 알긴산염 등을 들 수 있으며, 본 발명에 따른 세레콕시브 고체분산체에서 세레콕시브의 용출률 향상에 있어서는 전분글리콘산나트륨 또는 크로스카멜로오스나트륨이 적합하며, 크로스카멜로오스나트륨이 가장 적합하다. 붕해제가 함유될 경우 바람직한 함량은 후술하는 용출률 시험 결과로부터 정해질 수 있으며, 세레콕시브 원료 100중량부에 대하여 바람직하게는 5~25중량부, 더욱 바람직하게는 10~20중량부 함량으로 포함될 수 있다.Examples of the disintegrant include starch, sodium starch glycolate, croscarmellose sodium, cellulose, alginate, and the like. The starch glycon may be used to improve the dissolution rate of celecoxib in the celecoxib solid dispersion according to the present invention. Sodium acid or croscarmellose sodium is suitable, and croscarmellose sodium is most suitable. When the disintegrant is contained, the preferred content may be determined from the dissolution rate test results described below, and may be included in an amount of preferably 5 to 25 parts by weight, more preferably 10 to 20 parts by weight, based on 100 parts by weight of the celecoxib raw material. Can be.
상기 활택제로는 스테아린산마그네슘, 스테아릴푸마르산나트륨, 아세트산나트륨, 푸마르산나트륨, 염화나트륨, 폴리에틸렌글리콜, 올레산나트륨 등을 들 수 있으며, 본 발명에 따른 세레콕시브 고체분산체에서 세레콕시브의 용출률 향상에 있어서는 스테아린산마그네슘 또는 스테아릴푸마르산나트륨이 적합하며, 스테아릴푸마르산나트륨이 가장 적합하다. 활택제가 함유될 경우 바람직한 함량은 후술하는 용출률 시험 결과로부터 정해질 수 있으며, 세레콕시브 원료 100중량부에 대하여 바람직하게는 3~20중량부, 더욱 바람직하게는 5~15중량부, 가장 바람직하게는 5~10중량부 함량으로 포함될 수 있다.Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sodium acetate, sodium fumarate, sodium chloride, polyethylene glycol, sodium oleate, and the like. Magnesium stearate or sodium stearyl fumarate is suitable, with sodium stearyl fumarate being most suitable. If the lubricant is contained, the preferred content can be determined from the dissolution rate test results described below, preferably 3 to 20 parts by weight, more preferably 5 to 15 parts by weight, most preferably 100 parts by weight of celecoxib raw material. 5 to 10 parts by weight may be included.
본 발명은 또한 상기 세레콕시브 고체분산체를 유효성분으로 함유하는 약제학적 제제를 개시한다. 이러한 약제학적 제제는 경구 제제로 사용되며, 활성성분인 세레콕시브는 5~100㎎, 바람직하게는 10~80㎎, 가장 바람직하게는 20~50㎎ 함량으로 포함될 수 있다. 이러한 세레콕시브의 낮은 함량은 본 발명에 따른 세레콕시브 고체분산체의 특징으로, 세레콕시브의 용해도 및 생체이용율을 향상시켜 제제내에 포함된 세레콕시브의 약물 함량을 낮출 수 있게 된다.The present invention also discloses a pharmaceutical formulation containing the celecoxib solid dispersion as an active ingredient. Such pharmaceutical preparations are used as oral preparations, and the active ingredient celecoxib may be included in an amount of 5-100 mg, preferably 10-80 mg, most preferably 20-50 mg. This low content of celecoxib is a characteristic of the celecoxib solid dispersion according to the present invention, it is possible to lower the drug content of the celecoxib contained in the formulation by improving the solubility and bioavailability of the celecoxib.
경구 제제로는 산제, 과립제, 캡슐제, 나정, 필름코팅정, 속붕해정 등의 정제 또는 건조시럽제 형태이다. 이들 제형은 약제학 분야에 통상적으로 사용되는 방법에 따라 제조될 수 있다. 본 발명에 따른 세레콕시브 고체분산체는 전술한 바와 같이 제약상 허용되는 붕해제, 활택제 등을 첨가하여 산제, 과립제, 캡슐제, 정제 등으로 제조될 수 있고, 정제의 형태를 속붕해정으로 하거나, 필름코팅정으로 하기 위하여 제피제 및 가소제 등을 함유할 수 있다.Oral preparations are in the form of tablets or dry syrups such as powders, granules, capsules, uncoated tablets, film coated tablets, and fast disintegrating tablets. These formulations may be prepared according to methods commonly used in the pharmaceutical art. The celecoxib solid dispersion according to the present invention may be prepared as a powder, granules, capsules, tablets, etc. by adding a pharmaceutically acceptable disintegrant, a lubricant, and the like, as described above. Or a film-forming agent, a plasticizer, or the like in order to obtain a film-coated tablet.
이하, 본 발명에 따른 세레콕시브 고체분산체 제조방법에 관하여 상세히 설명한다.Hereinafter, a method for producing a celecoxib solid dispersion according to the present invention will be described in detail.
본 발명에 따른 세레콕시브 고체분산체 제조방법은 (a) 세레콕시브, 수용성 고분자 담체 및 가용화제를 용매에 용해시켜 고체분산체 용액을 형성하는 단계; (b) 상기 고체분산체 용액에 흡착제를 혼합하여 혼합 액제를 형성하는 단계; (c) 상기 혼합 액제를 자연 건조 및 분쇄하여 혼합 고체제를 형성하는 단계; 및 (d) 상기 혼합 고체제에 부형제를 혼합하는 단계;를 포함한다.The method for producing a celecoxib solid dispersion according to the present invention comprises the steps of: (a) dissolving a celecoxib, a water-soluble polymer carrier and a solubilizer in a solvent to form a solid dispersion solution; (b) mixing the adsorbent with the solid dispersion solution to form a mixed liquid; (c) naturally drying and pulverizing the mixed liquid to form a mixed solid; And (d) mixing an excipient with the mixed solid agent.
전술한 바와 같이, 기존 대비 상대적으로 큰 입자를 갖는 세레콕시브 원료를 선택할 경우에는 종래와 같이 부형제에 고체분산체 용액을 스프레이 방식으로 분무 건조할 경우 균일한 입자를 얻기 어려운 점 등 공정상 문제로 인해, 단순 일반혼합 방식을 적용을 고려할 수 있는데, 단순 일반혼합 시 다시 입도(세레콕시브와 수용성 고분자 담체의 결합 입자) 크기가 큰 형태로 재결정화되는 문제가 있다. 이에, 본 발명에서는 고체분산체 용액에 흡착제를 혼합하는 단계를 거치도록 하여, 흡착제 입자에 세레콕시브와 수용성 고분자 담체의 결합 입자가 빠르게 흡착되어 건조되도록 함으로써 큰 입도를 갖는 세레콕시브와 수용성 고분자 담체의 결합 입자가 생성되지 않도록 한다.As described above, when selecting a celecoxib raw material having a relatively large particle compared to the conventional process, it is difficult to obtain uniform particles when spray-drying the solid dispersion solution in the excipient by spraying as in the prior art. For this reason, the application of the simple general mixing method may be considered, but when the simple general mixing, there is a problem of recrystallization in the form of large particle size (combined particles of celecoxib and the water-soluble polymer carrier). Therefore, in the present invention, the adsorbent is mixed with the solid dispersion solution, thereby allowing the combined particles of the celecoxib and the water-soluble polymer carrier to be rapidly adsorbed and dried on the adsorbent particles, thereby allowing the celecoxib and the water-soluble polymer to have a large particle size. The binding particles of the carrier are not produced.
따라서, 본 발명에서는 (a) 단계에 사용되는 입자 형태의 세레콕시브는 기존 대비 상대적으로 큰 입자 크기를 갖는 세레콕시브가 유리하게 적용될 수 있으며, D90이 최대 치수로서 200~500㎛인 것이 바람직하며, 300~400㎛인 것이 가장 바람직하게 적용될 수 있다.Therefore, in the present invention, the celecoxib in the form of particles used in step (a) may be advantageously applied to a celecoxib having a relatively large particle size, and that D 90 is 200 to 500 μm as the largest dimension. Preferably, 300 ~ 400㎛ may be most preferably applied.
상기 (a) 단계에서 사용되는 용매로는 약제학적으로 사용 가능한 것으로 물, 메탄올, 에탄올, 이소프로판올과 같은 C1-C4 저급 알코올, 에틸에테르, 아세톤, 디클로로메탄 또는 이들의 혼합용매가 사용될 수 있다. 바람직하게는 에탄올 및 디클로로메탄 혼합용매가 사용될 수 있다. 사용되는 용매의 양은 세레콕시브 원료, 수용성 고분자 담체 및 가용화제를 충분히 용해시킬 수 있는 정도라면 특별히 제한되는 것은 아니나, 전술한 바람직한 에탄올 및 디클로로메탄 혼합용매를 사용할 경우 가능한 적은 양으로 세레콕시브를 완전히 용해시키기 위해서는 에탄올 20~40부피% 및 디클로로메탄 60~80부피%로 구성된 혼합용매를 사용하는 것이 바람직하고, 에탄올 25~35부피% 및 디클로로메탄 65~75부피%로 구성된 혼합용매를 사용하는 것이 더욱 바람직하다.The solvent used in step (a) may be pharmaceutically usable and may be water, methanol, ethanol, C1-C4 lower alcohols such as isopropanol, ethyl ether, acetone, dichloromethane or a mixed solvent thereof. Preferably ethanol and dichloromethane mixed solvents may be used. The amount of the solvent used is not particularly limited as long as it can sufficiently dissolve the celecoxib raw material, the water-soluble polymer carrier, and the solubilizing agent. However, if the above-mentioned preferred ethanol and dichloromethane mixed solvents are used, the amount of the celecoxib may be reduced. In order to dissolve completely, it is preferable to use a mixed solvent composed of 20 to 40% by volume of ethanol and 60 to 80% by volume of dichloromethane, and to use a mixed solvent composed of 25 to 35% by volume of ethanol and 65 to 75% of dichloromethane. More preferred.
용매를 이용한 용해는 세레콕시브를 먼저 용매에 완전히 용해시킨 후 세레콕시브가 용해된 용액에 수용성 고분자 담체 및 가용화제를 용해시키는 것이 바람직하다.For dissolution using a solvent, it is preferable to dissolve celecoxib completely in a solvent first, and then dissolve the water-soluble polymer carrier and the solubilizer in the solution in which the celecoxib is dissolved.
본 발명에서는 종래 방법과 달리 (b) 고체분산체 용액 형성 후 추가로 흡착제를 형성된 고체분산체 용액에 혼합하여 혼합 액제를 형성한다. 이후, 혼합 액제를 분무 건조하는 대신, (c) 혼합 액제를 자연 건조 및 분쇄하여 혼합 고체제를 형성하고, (d) 혼합 고체제에 붕해제, 활택제 등 부형제를 또한 단순 혼합함으로써 간단하게 세레콕시브 고체분산체를 제조할 수 있다.In the present invention, unlike the conventional method (b) after forming the solid dispersion solution, the adsorbent is further mixed with the formed solid dispersion solution to form a mixed liquid. Thereafter, instead of spray-drying the mixed liquid, (c) the mixed liquid is naturally dried and pulverized to form a mixed solid, and (d) a simple mixing of an excipient such as a disintegrant and a lubricant into the mixed solid can be performed simply. Coxy solid dispersions can be prepared.
한편, 가용화제의 경우 일부(약 30~50중량%)는 (a) 고체분산체 용액 형성 단계에 투입하고, 나머지는 (d) 단계에서 부형제와 함께 혼합시켜 제조할 수도 있으며, 세레콕시브의 경우 일부(약 70~90중량%)는 (b) 혼합 액제 형성 단계에 투입하고, 나머지는 (d) 단계에서 부형제와 함께 혼합시켜 제조할 수도 있다.On the other hand, in the case of a solubilizing agent (about 30 to 50% by weight) may be prepared by (a) solid dispersion solution forming step, the remainder may be prepared by mixing with excipients in step (d), In some cases (about 70-90% by weight) may be prepared by (b) mixing the liquid mixture forming step, the remainder is mixed with the excipient in step (d).
이와 같이 제조된 세레콕시브 고체분산체는 각종 제형의 경구 제제로 제조될 수 있으며, 예컨대, 원형 모양의 정제로서 총 중량이 450㎎이며 경도가 6~7Kp가 되도록 타정하여 제조될 수 있다.The celecoxib solid dispersion prepared as described above may be prepared in oral formulations of various formulations, for example, as tablets in a circular shape and may be prepared by tableting to a total weight of 450 mg and a hardness of 6 to 7 Kp.
이하, 실시예 및 시험예를 통하여 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
고체분산체 용매 선정Solid Dispersion Solvent Selection
입자 크기가 상대적으로 큰 세레콕시브에 대해 최적 용해도를 갖는 용매를 선정하기 위해 하기 표 1에 나타낸 각 용매 100㎖에 대하여 D90=324.5㎛인 세레콕시브의 용해도(상온 25℃ 기준)를 측정하고 그 결과를 표 1에 함께 나타내었다.In order to select a solvent having an optimum solubility for celecoxib having a relatively large particle size, the solubility of celecoxib at D 90 = 324.5 μm was measured for 100 ml of each solvent shown in Table 1 below. The results are shown in Table 1 together.
표 1
Figure PCTKR2014003020-appb-T000001
 Table 1
Figure PCTKR2014003020-appb-T000001
표 1을 참조하면, 에탄올 및 디클로로메탄 1:1 몰비의 혼합용매에서 세레콕시브의 용해도가 가장 높게 나타났으며, 보다 적합한 에탄올 및 디클로로메탄 혼합 비율을 선정하기 위해 다양한 혼합 비율에서의 용해도를 측정하고 그 결과를 하기 표 2에 나타내었다.Referring to Table 1, the solubility of celecoxib in the mixed solvent of ethanol and dichloromethane 1: 1 molar ratio was the highest, and the solubility at various mixing ratios was measured to select a more suitable ethanol and dichloromethane mixing ratio. The results are shown in Table 2 below.
표 2
Figure PCTKR2014003020-appb-T000002
 TABLE 2
Figure PCTKR2014003020-appb-T000002
표 2를 참조하면, 에탄올 및 디클로로메탄 몰비가 3:7~4:6일 경우에 세레콕시브의 용해도가 가장 우수한 것을 확인할 수 있다.Referring to Table 2, it can be confirmed that the solubility of celecoxib is the best when the ethanol and dichloromethane molar ratio is 3: 7 to 4: 6.
시험예 1: 수용성 고분자 담체 종류 및 함량에 따른 용출률 확인Test Example 1: Check the dissolution rate according to the type and content of the water-soluble polymer carrier
종래 세레콕시브 고체분산체 제조 시 담체로서 사용되는 PVP(폴리비닐피롤리돈)가 입자 크기가 보다 큰 세레콕시브의 경우에도 다른 중합체에 비해 용출률이 가장 높게 나타난 것을 별도의 시험에서 확인하고, PVP 분자량별 상이한 종류에 따른 용출률을 비교하고자 PVP K25, PVP K30 및 PVP K90을 이용하여 하기 제조예에 따라 세레콕시브 고체분산체를 제조하고 각각에 대하여 용출률 시험을 수행하였다. PVP K90의 경우에는 제조 공정 중 경화(딱딱함) 상태가 심하여 실제 캡슐에 충진하여 용출률 확인을 실시할 수 없었다.In a separate test, PVP (polyvinylpyrrolidone) (PVP), which is used as a carrier in the preparation of celecoxib solid dispersions, exhibited the highest dissolution rate in comparison with other polymers even in the case of celecoxib having a larger particle size. In order to compare the dissolution rate according to different types of PVP molecular weight, celecoxib solid dispersions were prepared using PVP K25, PVP K30, and PVP K90 according to the following preparation examples, and dissolution rate tests were performed for each. In the case of PVP K90, the hardening (hardness) during the manufacturing process was so severe that it was not possible to check the dissolution rate by filling the actual capsule.
[세레콕시브 고체분산체 제조예 1]Celecoxib Solid Dispersion Preparation Example 1
하기 표 3의 함량으로 세레콕시브 및 PVP를 에탄올 및 디클로로메탄 혼합용매에 용해시켜 고체분산체 용액을 형성하고, 고체분산체 용액에 유당을 혼합하여 혼합 액제를 형성하였다. 혼합 액제를 건조기에서 완전히 건조한 후 분쇄기를 이용하여 분쇄(30mesh)한 후 소디움라우릴설페이트(SLS) 및 전분글리콘산나트륨을 혼합하고 이를 0호 캡슐에 충진하여 세레콕시브 고체분산체를 제조하였다.In the following Table 3, celecoxib and PVP were dissolved in a mixed solvent of ethanol and dichloromethane to form a solid dispersion solution, and lactose was mixed with the solid dispersion solution to form a mixed solution. The mixed solution was completely dried in a dryer, and then pulverized (30mesh) using a pulverizer, followed by mixing sodium lauryl sulfate (SLS) and sodium starch glycolate, and filling the capsule No. 0 to prepare a celecoxib solid dispersion. .
표 3
Figure PCTKR2014003020-appb-T000003
 TABLE 3
Figure PCTKR2014003020-appb-T000003
표 3의 실시예 1 내지 3의 세레콕시브 고체분산체에 대하여 대한 약전 용출 시험법 제2법 패들법을 사용하여 하기 조건하에서 용출시험을 수행하고 그 결과를 도 1에 나타내었다.For the celecoxib solid dispersions of Examples 1 to 3 in Table 3, the dissolution test was performed under the following conditions using the Pharmacologic Dissolution Test Method No. 2 Paddle Method and the results are shown in FIG. 1.
[용출시험 조건][Dissolution test condition]
- 시험방법: 제2법(패들법)-Test method: Method 2 (paddle method)
- 기구: LABFINE Dissolution testerInstrument: LABFINE Dissolution tester
- 용출액: pH 12 용출액Eluent: pH 12 eluent
- 온도: 37±0.5℃Temperature: 37 ± 0.5 ℃
- 패들 회전 속도: 50rpmPaddle rotation speed: 50 rpm
도 1을 참조하면, PVP K25(실시예 3)보다는 PVP K30(실시예 1, 2)에서 담체 함량 대비 용출률이 우수한 것으로 나타났으며, 세레콕시브 100중량부 기준으로 12.5중량부(실시예 2) 수준에서 용출률이 가장 우수한 것으로 나타났다.Referring to Figure 1, it was found that the dissolution rate is superior to the carrier content in PVP K30 (Examples 1 and 2) than PVP K25 (Example 3), 12.5 parts by weight based on 100 parts by weight of celecoxib (Example 2) The dissolution rate was the highest at) level.
시험예 2: 제형에 따른 용출률 확인Test Example 2 Check the Dissolution Rate According to the Formulation
시험예 1에서와 같이, 고체분산체 용액 형성 후 흡착제로서 유당을 사용할 경우 혼합 시 용액 상태로 되어, 실제 생산 시 시설에 따라 제조가 불가한 경우가 있으며, 분말 형태로 제조하고자 한다면 세레콕시브 대비 약 20배 정도의 유당이 필요하게 된다. 따라서, 흡착제로서 메타규산알루민산마그네슘(상표명: 노이시린)을 사용하여 하기 제조예에 따라 세레콕시브 고체분산체를 제조하여 시험하였다. 메타규산알루민산마그네슘의 경우 밀도가 낮아 캡슐에 충진하기 어려운 관계로 정제로서 제형 개발 시 용출 확인을 시험하였으며, 비교를 위해 동일 함량으로 유당을 사용하여 가혹 조건에서 탈용매한 캡슐제를 함께 제조하였다.As in Test Example 1, when lactose is used as an adsorbent after the solid dispersion solution is formed, it becomes a solution state at the time of mixing, and may not be manufactured depending on the actual production facility. You will need about 20 times more lactose. Therefore, the celecoxib solid dispersion was manufactured and tested according to the following preparation example using magnesium aluminate silicate (trade name: Noicin) as an adsorbent. In the case of magnesium metasilicate alumina, it was difficult to fill the capsule because of its low density, and thus the dissolution confirmation was tested during the development of the formulation as a tablet. For comparison, the capsule was desolvated under harsh conditions using lactose at the same content. .
[세레콕시브 고체분산체 제조예 2]Celecoxib Solid Dispersion Preparation Example 2
하기 표 4의 함량으로 세레콕시브 및 PVP를 에탄올 및 디클로로메탄 혼합용매에 용해시켜 고체분산체 용액을 형성하고, 고체분산체 용액에 유당(또는 메타규산알루민산마그네슘)을 혼합하여 혼합 액제를 형성하였다. 혼합 액제를 건조기에서 완전히 건조한 후 분쇄기를 이용하여 분쇄(30mesh)한 후 소디움라우릴설페이트, 전분글리콘산나트륨 및 스테아린산마그네슘을 혼합하고, 캡슐 샘플의 경우 1호 캡슐에 충진하고, 정제의 경우 약 7Kp 경도가 되도록 나정으로 타정하여 세레콕시브 고체분산체를 제조하였다.The celecoxib and PVP were dissolved in a mixed solvent of ethanol and dichloromethane in the content of Table 4 to form a solid dispersion solution, and lactose (or magnesium metasilicate aluminate) was mixed with the solid dispersion solution to form a mixed solution. It was. The mixed solution is completely dried in a drier, and then pulverized (30mesh) using a grinder, followed by mixing sodium lauryl sulfate, sodium starch glycolate and magnesium stearate, and filling into capsule No. 1 for a capsule sample and about tablets. Cerecoxib solid dispersion was prepared by tableting with uncoated tablet to have a hardness of 7 Kp.
표 4
Figure PCTKR2014003020-appb-T000004
 Table 4
Figure PCTKR2014003020-appb-T000004
표 4의 실시예 4 및 5의 세레콕시브 고체분산체에 대하여 시험예 1과 동일한 방법으로 용출시험을 수행하고 그 결과를 도 2에 나타내었다.Dissolution test was carried out in the same manner as in Test Example 1 for the celecoxib solid dispersion of Examples 4 and 5 of Table 4 and the results are shown in FIG.
도 2를 참조하면, 흡착제로 메타규산알루민산마그네슘을 사용하여 제조된 정제가 유당을 사용하여 제조된 캡슐보다도 용출률이 우수한 것을 알 수 있다.Referring to FIG. 2, it can be seen that a tablet prepared using magnesium metasilicate aluminate as an adsorbent has a higher dissolution rate than a capsule prepared using lactose.
시험예 3: 흡착제 종류에 따른 용출률 확인Test Example 3 Check the Dissolution Rate According to the Type of Adsorbent
시험예 2에서와 같이 정제 형태로 제조 시 다양한 흡착제 사용에 따른 용출률을 비교하기 위해 하기 제조예에 따라 세레콕시브 고체분산체를 제조하였다.Celecoxib solid dispersions were prepared according to the following preparation examples in order to compare the dissolution rate according to the use of various adsorbents when prepared in tablet form as in Test Example 2.
[세레콕시브 고체분산체 제조예 3]Celecoxib Solid Dispersion Preparation Example 3
하기 표 5의 함량으로 세레콕시브 및 PVP를 에탄올 및 디클로로메탄 혼합용매에 용해시켜 고체분산체 용액을 형성하고, 고체분산체 용액에 각각의 흡착제를 혼합하여 혼합 액제를 형성하였다. 혼합 액제를 건조기에서 완전히 건조한 후 분쇄기를 이용하여 분쇄(30mesh)한 후 소디움라우릴설페이트, 전분글리콘산나트륨 및 스테아린산마그네슘을 혼합하고, 약 7Kp 경도가 되도록 나정으로 타정하여 세레콕시브 고체분산체를 제조하였다. 이때, 메타규산알루민산마그네슘 적용 시(실시예 9) 사용되는 용매의 양을 줄이면서 초기 5분의 용출률을 약전 기준에 근접하도록 나타낼 수 있는지 확인하기 위해, 세레콕시브는 고체분산체 용액 형성 시 80중량%를 투입시키고, 나머지 20중량%는 최종 부형제와 함께 투입하였다.In the following Table 5, celecoxib and PVP were dissolved in a mixed solvent of ethanol and dichloromethane to form a solid dispersion solution, and the respective adsorbents were mixed with the solid dispersion solution to form a mixed solution. The mixed liquid is completely dried in a drier, and then pulverized (30mesh) using a grinder, followed by mixing sodium lauryl sulfate, sodium starch glycolate, and magnesium stearate, and tableting to a hardness of about 7 Kp to celecoxib solid dispersion. Was prepared. In this case, in order to check whether the initial 5 minutes of dissolution rate can be expressed close to the pharmacopeia standard while reducing the amount of solvent used when applying magnesium metasilicate (Example 9), celecoxib is used to form a solid dispersion solution. 80% by weight was added and the remaining 20% by weight was added with the final excipient.
표 5
Figure PCTKR2014003020-appb-T000005
 Table 5
Figure PCTKR2014003020-appb-T000005
표 5의 실시예 6 내지 9의 세레콕시브 고체분산체에 대하여 시험예 1과 동일한 방법으로 용출시험을 수행하고 그 결과를 도 3에 나타내었다.Dissolution test was carried out in the same manner as in Test Example 1 for the celecoxib solid dispersion of Examples 6 to 9 of Table 5 and the results are shown in FIG.
도 3을 참조하면, 흡착제로 메타규산알루민산마그네슘을 사용할 경우(실시예 9) 초기 5분 용출률은 감소하면서 전체적으로 가장 우수한 용출률을 나타낸 것을 확인할 수 있다. 한편, 유당을 사용할 경우(실시예 6)에는 시험예 2와 마찬가지로 용매 상태로 조제되어 실제 생산 시 생산이 불가할 수 있고, 메타규산알루민산마그네슘과 유당을 혼합하여 사용할 경우(실시예 7)에는 상대적으로 용출률이 낮아진 것을 알 수 있다.Referring to FIG. 3, when magnesium metasilicate aluminate is used as the adsorbent (Example 9), the initial five-minute dissolution rate is decreased and the highest dissolution rate is generally observed. On the other hand, in the case of using lactose (Example 6), it may be impossible to produce during production as prepared in the solvent state as in Test Example 2, when using a mixture of magnesium aluminate silicate and lactose (Example 7) It can be seen that the dissolution rate was relatively low.
시험예 4: 흡착제 및 담체 조성에 따른 용출률 확인Test Example 4 Check the dissolution rate according to the composition of the adsorbent and the carrier
시험예 3에서 확인된 바와 같이, 흡착제 중 가장 우수한 용출률을 나타내는 메타규산알루민산마그네슘을 사용할 때 담체로 사용되는 PVP K30의 최적 함량을 확인하기 위해 하기 표 6의 조성에서 시험예 3과 동일한 방법으로 세레콕시브 고체분산체를 제조하였다.As confirmed in Test Example 3, to determine the optimum content of PVP K30 used as a carrier when using magnesium metasilicate aluminate showing the best dissolution rate among the adsorbents in the composition of Table 6 in the same manner as in Test Example 3 Celecoxib solid dispersion was prepared.
표 6
Figure PCTKR2014003020-appb-T000006
 Table 6
Figure PCTKR2014003020-appb-T000006
표 6의 실시예 10 내지 13의 세레콕시브 고체분산체에 대하여 시험예 1과 동일한 방법으로 용출시험을 수행하고 그 결과를 도 4에 나타내었다.The dissolution test was performed on the celecoxib solid dispersions of Examples 10 to 13 of Table 6 in the same manner as in Test Example 1, and the results are shown in FIG. 4.
도 4를 참조하면, 세레콕시브 100중량부 기준으로 PVP 7.5중량부(실시예 11) 수준에서 용출률이 가장 우수한 것을 알 수 있다.Referring to Figure 4, it can be seen that the dissolution rate is the best at the level of 7.5 parts by weight (Example 11) PVP based on 100 parts by weight of celecoxib.
시험예 5: 부형제 함량에 따른 용출률 확인Test Example 5 Check the dissolution rate according to the excipient content
시험예 4에서 확인된 바와 같이, 가장 우수한 용출률을 나타내는 흡착제 및 담체 조성에서 가용화제, 붕해제 및 활택제의 최적 함량을 확인하기 위해 하기 표 7의 조성에서 시험예 3과 동일한 방법으로 세레콕시브 고체분산체를 제조하였다.As confirmed in Test Example 4, celecoxib in the same manner as in Test Example 3 in the composition of Table 7 to determine the optimum content of the solubilizer, the disintegrant and the lubricant in the adsorbent and carrier composition showing the best dissolution rate. Solid dispersion was prepared.
표 7
Figure PCTKR2014003020-appb-T000007
 TABLE 7
Figure PCTKR2014003020-appb-T000007
표 7의 실시예 14 내지 17의 세레콕시브 고체분산체에 대하여 시험예 1과 동일한 방법으로 용출시험을 수행하고 그 결과를 도 5에 나타내었다.The dissolution test of the celecoxib solid dispersion of Examples 14 to 17 in Table 7 was carried out in the same manner as in Test Example 1, and the results are shown in FIG. 5.
도 5를 참조하면, 세레콕시브 100중량부 기준으로 붕해제는 10중량부(실시예 15 참조) 수준, 활택제는 5중량부(실시예 15 참조) 수준 및 가용화제는 7.5중량부(실시예 17 참조) 수준에서 용출률이 가장 우수한 것을 알 수 있다.Referring to Figure 5, based on 100 parts by weight of celecoxib disintegrant is 10 parts by weight (see Example 15) level, the lubricant is 5 parts by weight (see Example 15) level and the solubilizer is 7.5 parts by weight (execution) It is understood that the dissolution rate is the best at the level.
시험예 6: 흡착제 함량에 따른 용출률 확인Test Example 6 Check the dissolution rate according to the adsorbent content
시험예 1 내지 5에서의 바람직한 조성을 고려하여 최종적으로 흡착제의 최적 함량을 확인하기 위해 하기 표 8의 조성에서 시험예 3과 동일한 방법으로 세레콕시브 고체분산체를 제조하였다.In order to finally determine the optimum content of the adsorbent in consideration of the preferred compositions in Test Examples 1 to 5, the celecoxib solid dispersion was prepared in the same manner as in Test Example 3 in the composition of Table 8 below.
표 8
Figure PCTKR2014003020-appb-T000008
 Table 8
Figure PCTKR2014003020-appb-T000008
표 8의 실시예 18 및 19의 세레콕시브 고체분산체와 대조 제제로서 시판중인 쎄레브렉스 캡슐(200㎎, 화이자 제약)에 대하여 각각 시험예 1과 동일한 방법으로 용출시험을 수행하고 그 결과를 도 6 및 도 7에 나타내었다.(도 6 및 도 7에서 대조 제제의 경우 실시예 18 및 19 각각에 대응하여 별도 용출시험을 수행한 관계로 용출률 측정값에 약간의 오차 있음.)The dissolution test was carried out in the same manner as in Test Example 1 for the cerebrex capsule (200 mg, Pfizer Pharmaceuticals) commercially available as the celecoxib solid dispersion and the control formulation of Examples 18 and 19 of Table 8, and the results are shown in FIG. And FIG. 7. (In the case of the control formulation in FIGS. 6 and 7, there was a slight error in the dissolution rate measurement value due to the separate dissolution test corresponding to Examples 18 and 19, respectively.)
도 6을 참조하면, 실시예 18에 따라 제조된 세레콕시브 고체분산체의 경우 대조 제제에 비해 전체적으로 용출률이 낮게 나타난 것을 알 수 있다. 이에, 흡착제 함량을 최적 수준으로 증가시키고, 붕해제 및 활택제를 각각 크로스카멜로오스나트륨 및 스테아릴푸마르산나트륨으로 대체하고 그 함량을 최적 수준으로 증가시킬 경우(실시예 19) 대조 제제의 경우와 유사한 수준의 용출률을 나타낸 것을 확인할 수 있다(도 7 참조).Referring to Figure 6, the celecoxib solid dispersion prepared according to Example 18 it can be seen that the dissolution rate is lower than the control formulation as a whole. Therefore, when the adsorbent content is increased to the optimum level, and the disintegrant and the lubricant are replaced with croscarmellose sodium and sodium stearyl fumarate, respectively, and the content is increased to the optimum level (Example 19), it is similar to that of the control formulation. It can be seen that the level of dissolution rate is shown (see FIG. 7).
시험예 7: 생체 유사 조건에서의 용출률 확인Test Example 7 Confirmation of Dissolution Rate in Bio-like Conditions
시험예 6에 따라 pH 12 용출액에서의 용출률 시험의 경우, 최적 성분 조성에서 대조 제제와 유사한 수준의 용출률을 나타낸 것을 확인하였으나, 생체 유사 환경에서의 대조 제제와의 용출률을 비교하기 위해 상기 실시예 19에 따라 제조된 세레콕시브 고체분산체와 대조 제제에 대하여 시험예 1과 동일한 방법으로 용출시험을 수행하되, pH 1.2 및 4.0 용출액에서의 용출시험을 수행하고 그 결과를 도 8 및 도 9에 나타내었다.In the case of dissolution rate test in pH 12 eluate according to Test Example 6, it was confirmed that the dissolution rate was similar to that of the control in the optimum component composition, but to compare the dissolution rate with the control in a similar environment in Example 19 The dissolution test was carried out in the same manner as in Test Example 1 for the celecoxib solid dispersion and the control formulation prepared according to the dissolution test in pH 1.2 and 4.0 eluate and the results are shown in FIGS. 8 and 9 It was.
도 8 및 도 9를 참조하면, 실시예 19 및 대조 제제 모두에서 용출률이 2~3% 수준으로 나타난 것을 알 수 있다. 이는 세레콕시브가 극히 난용성 약물인 관계로 거의 용출되지 않은 것을 나타낸 것이며, 이에, 보다 명확한 비교를 위해 용출액에 계면활성제(소디움라우릴설페이트, 1% v/v)를 첨가하여 용출시험을 수행하고 그 결과를 도 10 및 도 11에 나타내었다. 본 시험예에서는 추가 비교를 위해 본 발명에 따른 고체분산체 제조방법을 적용하지 않고 세레콕시브 원료를 그대로 사용하여 제조된 제제(비교예)에 대한 시험결과를 함께 나타내었다.8 and 9, it can be seen that the dissolution rate was shown to be 2-3% in both Example 19 and the control formulation. This shows that celecoxib is extremely poorly soluble drug and hardly eluted. For the sake of clarity, a dissolution test was performed by adding a surfactant (sodium lauryl sulfate, 1% v / v) to the eluate. The results are shown in FIGS. 10 and 11. In this test example, the test results for the preparation (comparative example) prepared using the celecoxib raw material as it is without applying the method for producing a solid dispersion according to the present invention for further comparison.
도 10 및 도 11을 참조하면, pH 4.0 용출액에서의 용출률은 대조 제제에 비하여 본 발명에 따라 제조된 세레콕시브 고체분산체가 다소 낮게 나타났으나, pH 1.2 용출액에서의 용출률은 대조 제제에 비하여 보다 더 우수한 것을 알 수 있다. 알려진 바와 같이, 난용성 약물의 생체이용율 평가에 있어 pH 1.2 용출액에서의 용출률이 보다 중요하므로, 본 발명에 따라 제조된 세레콕시브 고체분산체의 경우 대조 제제에 비해서도 우수한 용출률을 나타낸 것을 확인할 수 있다.Referring to FIGS. 10 and 11, the dissolution rate in the pH 4.0 eluate was slightly lower than that of the celecoxib solid dispersion prepared according to the present invention compared to the control formulation, but the dissolution rate in the pH 1.2 eluate was higher than that of the control formulation. It can be seen that better. As is known, the dissolution rate in the pH 1.2 eluate is more important in evaluating the bioavailability of poorly soluble drugs, so it can be seen that the celecoxib solid dispersion prepared according to the present invention showed an excellent dissolution rate compared to the control formulation. .
이상으로 본 발명의 바람직한 실시예를 상세하게 설명하였다. 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다.The preferred embodiment of the present invention has been described in detail above. The description of the present invention is for illustrative purposes, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention.
따라서, 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 의미, 범위 및 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.Therefore, the scope of the present invention is shown by the claims below rather than the detailed description, and all changes or modifications derived from the meaning, scope, and equivalent concepts of the claims are included in the scope of the present invention. Should be interpreted.

Claims (10)

  1. 세레콕시브, 수용성 고분자 담체, 가용화제 및 흡착제를 포함하는 세레콕시브 고체분산체.Celecoxib solid dispersion comprising a celecoxib, a water-soluble polymer carrier, a solubilizer and an adsorbent.
  2. 제1항에 있어서,The method of claim 1,
    상기 수용성 고분자 담체는 폴리비닐피롤리돈(PVP)인 것을 특징으로 하는 세레콕시브 고체분산체.The water-soluble polymer carrier is a celecoxib solid dispersion, characterized in that the polyvinylpyrrolidone (PVP).
  3. 제1항에 있어서,The method of claim 1,
    상기 가용화제는 소디움라우릴설페이트인 것을 특징으로 하는 세레콕시브 고체분산체.Celecoxib solid dispersion, characterized in that the solubilizer is sodium lauryl sulfate.
  4. 제1항에 있어서,The method of claim 1,
    상기 흡착제는 메타규산알루민산마그네슘인 것을 특징으로 하는 세레콕시브 고체분산체.Celecoxib solid dispersion, characterized in that the adsorbent is magnesium metasilicate aluminate.
  5. 제1항에 있어서,The method of claim 1,
    상기 세레콕시브 고체분산체는 상기 세레콕시브 100중량부에 대하여 상기 수용성 고분자 담체 3~20중량부, 상기 가용화제 3~20중량부 및 상기 흡착제 50~100중량부 함량으로 구성된 것을 특징으로 하는 세레콕시브 고체분산체.The celecoxib solid dispersion is composed of 3 to 20 parts by weight of the water-soluble polymer carrier, 3 to 20 parts by weight of the solubilizer and 50 to 100 parts by weight of the adsorbent based on 100 parts by weight of the celecoxib. Celecoxib solid dispersion.
  6. 제5항에 있어서,The method of claim 5,
    상기 세레콕시브 100중량부에 대하여 크로스카멜로오스나트륨 붕해제 5~25중량부 및 스테아릴푸마르산나트륨 활택제 3~20중량부를 더 포함하는 것을 특징으로 하는 세레콕시브 고체분산체.Celecoxib solid dispersion further comprises 5 to 25 parts by weight of croscarmellose sodium disintegrant and 3 to 20 parts by weight of sodium stearyl fumarate lubricant based on 100 parts by weight of the celecoxib.
  7. 제1항 내지 제6항 중 어느 한 항의 세레콕시브 고체분산체를 유효성분으로 함유하는 약제학적 정제.Pharmaceutical tablet containing the celecoxib solid dispersion of any one of Claims 1-6 as an active ingredient.
  8. (a) 세레콕시브, 수용성 고분자 담체 및 가용화제를 용매에 용해시켜 고체분산체 용액을 형성하는 단계;(a) dissolving celecoxib, a water soluble polymer carrier, and a solubilizer in a solvent to form a solid dispersion solution;
    (b) 상기 고체분산체 용액에 흡착제를 혼합하여 혼합 액제를 형성하는 단계;(b) mixing the adsorbent with the solid dispersion solution to form a mixed liquid;
    (c) 상기 혼합 액제를 자연 건조 및 분쇄하여 혼합 고체제를 형성하는 단계; 및(c) naturally drying and pulverizing the mixed liquid to form a mixed solid; And
    (d) 상기 혼합 고체제에 부형제를 혼합하는 단계;(d) mixing an excipient with the mixed solid;
    를 포함하는 세레콕시브 고체분산체 제조방법.Celecoxib solid dispersion production method comprising a.
  9. 제8항에 있어서,The method of claim 8,
    상기 (a) 단계에서 상기 세레콕시브는 입자 크기(D90)가 200~500㎛인 것을 특징으로 하는 세레콕시브 고체분산체 제조방법.Wherein (a) the celecoxib is the particle size (D 90) is 200 ~ 500㎛ of celecoxib solid dispersion method, characterized in that in step.
  10. 제8항에 있어서,The method of claim 8,
    상기 용매는 에탄올 20~40부피% 및 디클로로메탄 60~80부피%로 구성된 것을 특징으로 하는 세레콕시브 고체분산체 제조방법.The solvent is a method for producing celecoxib solid dispersion, characterized in that consisting of 20 to 40% by volume of ethanol and 60 to 80% by volume of dichloromethane.
PCT/KR2014/003020 2014-03-28 2014-04-08 Celecoxib solid dispersion and method for preparing same WO2015147366A1 (en)

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