WO2018203636A1 - Composition ayant une solubilité dans l'eau et une biodisponibilité améliorées - Google Patents

Composition ayant une solubilité dans l'eau et une biodisponibilité améliorées Download PDF

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Publication number
WO2018203636A1
WO2018203636A1 PCT/KR2018/004997 KR2018004997W WO2018203636A1 WO 2018203636 A1 WO2018203636 A1 WO 2018203636A1 KR 2018004997 W KR2018004997 W KR 2018004997W WO 2018203636 A1 WO2018203636 A1 WO 2018203636A1
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Prior art keywords
sorafenib
composition
weight
bioavailability
water solubility
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PCT/KR2018/004997
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English (en)
Korean (ko)
Inventor
박상엽
임혜정
이사원
서민효
Original Assignee
주식회사 삼양바이오팜
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Priority claimed from KR1020180049305A external-priority patent/KR102082775B1/ko
Application filed by 주식회사 삼양바이오팜 filed Critical 주식회사 삼양바이오팜
Priority to US16/610,312 priority Critical patent/US20200078463A1/en
Priority to EP18794991.2A priority patent/EP3620156A4/fr
Priority to CN201880029667.0A priority patent/CN110603035A/zh
Priority to JP2019560150A priority patent/JP7046978B2/ja
Publication of WO2018203636A1 publication Critical patent/WO2018203636A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to oral compositions including water-soluble drugs sorafenib and polymethacrylate copolymer, and improved water solubility and bioavailability and a method for preparing the same.
  • Sorafenib (4- ⁇ 4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -phenoxy ⁇ -pyridine-2-carboxylic acid methyl amide) is used for renal cell carcinoma, hepatocellular carcinoma, TKI (Tyrosine Kinase Inhibitor) is a target anticancer agent used for thyroid cancer and is marketed as an oral tablet at home and abroad.
  • TKI Tyrosine Kinase Inhibitor
  • Korean Patent No. 1395932 discloses a pharmaceutical composition for treating a hyperproliferative disorder, including cancer, which is a tablet comprising p-toluenesulfonic acid salt of sorafenib in an amount of 55% or more by weight of the composition.
  • a pharmaceutical composition for treating a hyperproliferative disorder including cancer
  • a tablet comprising p-toluenesulfonic acid salt of sorafenib in an amount of 55% or more by weight of the composition.
  • a pharmaceutical composition for treating a hyperproliferative disorder including cancer
  • a tablet comprising p-toluenesulfonic acid salt of sorafenib in an amount of 55% or more by weight of the composition.
  • 3-20% microcrystalline cellulose as filler 5-12% sodium croscarmellose as disintegrant, 0.5-8% hypromellose as binder, 0.2-0.8% magnesium stearate as lubricant
  • Pharmaceutical compositions comprising
  • sorafenib has a very low solubility in water of 0.00171 mg / ml and the absolute bioavailability is unknown in humans.
  • the relative bioavailability of tablets is 38-49% relative to oral solutions. to be.
  • Another object of the present invention is to provide a method for preparing an oral composition having improved water solubility and bioavailability, including sorafenib and a polymethacrylate copolymer.
  • One aspect of the present invention relates to an oral composition having improved water solubility and bioavailability, comprising sorafenib or a pharmaceutically acceptable salt thereof, and a polymethacrylate copolymer.
  • step 1) 1) forming an oral formulation with the mixture of step 1):
  • It relates to a method for producing an oral composition comprising a water solubility and improved bioavailability.
  • compositions comprising sorafenib and polymethacrylate copolymers according to the present invention can achieve the same effect in the body even when using relatively small amounts of drugs because the water solubility and bioavailability of sorafenib are improved.
  • such a composition is known to be less affected by the diet, it may be very beneficial to the patient because there are relatively few side effects that can occur due to the small individual differences in absorption, there is an economic advantage due to the use of less expensive drugs Can be. That is, the water solubility and bioavailability of sorafenib are remarkably improved by the polymethacrylate copolymer, so that even if the dose of the drug is reduced, a formulation having the same bioavailability can be developed. It is possible to provide a formulation that reduces the manufacturing cost.
  • Figure 1 is a graph showing the results of the dissolution test performed at pH 1.2 for the solid dispersion and Nexava ® tablets of Example 2 (200 mg as sorafenib).
  • “Sorafenib” includes sorafenib free base, isomers of drugs, or mixtures thereof.
  • “Pharmaceutically acceptable salts of sorafenib” includes all types or forms of pharmaceutically acceptable salts with sorafenib as an active ingredient. In each case it may be one that forms various hydrates, or various crystalline forms.
  • a pharmaceutically acceptable salt of sorafenib can be sorafenib tosylate, and can be amorphous, crystalline Form 1, Form 2, Form 3 or mixtures thereof of Sorafenib tosylate. .
  • the present invention provides an oral composition having improved water solubility and bioavailability, including sorafenib and a polymethacrylate copolymer, and a method for preparing the same.
  • Oral compositions of the invention may preferably be in the form of solid oral preparations, in particular tablets or capsules.
  • the sorafenib may be in various forms, in particular in the form of micronized to several to several tens of micrometers. More preferably micronized to several micrometers in size. Even more preferably, it may be in nanonized form to several hundred nanometers in size. As the particle size of the drug decreases, the dissolution rate is improved to increase water solubility and bioavailability.
  • the polymethacrylate copolymer is preferably a cationic polymer with dimethylaminoethyl methacrylate, more preferably poly (butylmethacrylate-co- (2-dimethylamino Ethyl) methacrylate-co-methylmethacrylate).
  • the polymethacrylate copolymer has a weight average molecular weight of 3,000 to 200,000, preferably 5,000 to 150,000, more preferably 10,000 to 100,000, even more preferably 20,000 to 80,000, most preferably 37,000 to 57,000 g / mole Can be. If the weight average molecular weight is less than 3,000 g / mole, the water solubility improvement may be low. If the weight average molecular weight exceeds 200,000 g / mole, disintegration may be delayed.
  • the state of the polymethacrylate copolymer is not particularly limited, but may be in a granular or powder state.
  • the polymethacrylate copolymer may be Eudragit ® E PO (Evonik, Germany) or Eudragit ® E 100 (Evonik, Germany).
  • the weight average molecular weight of the polymethacrylate copolymer may be about 47,000 g / mole.
  • Eudragit ® E polymers are typically coating agents, which encapsulate sensitive drugs or mask the taste and odor of a drug when it is necessary to protect the drug from moisture or when the patient's medication compliance is low. It is used for the purpose of easily swallowing the medicine by providing a smooth, shiny surface, but in the present invention is used as an additive to improve the water solubility and bioavailability of sorafenib.
  • the polymethacrylate copolymer is, for example, in an amount of 0.05 to 5 parts by weight, preferably 0.1 to 4 parts by weight, more preferably 0.2 to about 5 parts by weight based on 1 part by weight of sorafenib or a pharmaceutically acceptable salt thereof. It may be used in an amount of 3 parts by weight, even more preferably in an amount of 0.25 to 2 parts by weight. If the polymethacrylate copolymer is less than the above lower limit, sorafenib improves the water solubility and the bioavailability is insignificant, and the effect may be inferior. May become large and cause discomfort when the patient takes it.
  • the present invention may include other additional components in addition to the sorafenib and polymethacrylate copolymers.
  • additional components include diluents, disintegrants, glidants and coating bases.
  • the diluents are for example lactose (anhydrides or hydrates such as monohydrates), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, It may be one or more selected from the group consisting of maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, and mixtures thereof, but is not limited thereto.
  • lactose, microcrystalline cellulose or mixtures thereof may be selected. Most preferably a mixture of starch, lactose and micelle crystalline cellulose can be selected.
  • Diluents may also serve as binders.
  • the diluent may be used in an amount of, for example, 0.1 to 50 parts by weight, preferably 1 to 30 parts by weight, more preferably 2 to 15 parts by weight, based on 100 parts by weight of the total formulation (eg, tablet). If the diluent is less than the above lower limit, it may be difficult to prepare the formulation, such as low tableting, and if the diluent is outside the above upper limit, the preparation becomes too large and may cause inconvenience when the patient takes it. have.
  • the disintegrants are, for example, croscarmellose sodium (CrosCMC-Na), carboxymethylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), May be one or more selected from the group consisting of starch (wheat, rice, corn or potato starch), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolyzed starch, and mixtures thereof, but is not limited thereto. no.
  • it may be croscarmellose sodium (CrosCMC-Na) or L-HPC (low-substituted hydroxypropyl cellulose) or a mixture thereof.
  • the disintegrant may be used, for example, in an amount of 1 to 30 parts by weight, preferably in an amount of 2 to 20 parts by weight, based on 100 parts by weight of the total formulation (eg, tablet). If the disintegrant is less than the aforementioned lower limit, there may be a problem of elution rate delay due to the disintegration rate delay, and if it is out of the above upper limit, there may be a problem in productivity such as tableting disorder.
  • the glidants are, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed (colloidal) silica , Magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof, but may be one or more selected from.
  • magnesium stearate 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 , Magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof,
  • the glidant is, for example, in an amount of 0.1 to 3 parts by weight, preferably in an amount of 0.2 to 3 parts by weight, more preferably in an amount of 0.5 to 2 parts by weight, based on 100 parts by weight of the total formulation (eg, tablet). Can be used. If the lubricant is less than the above lower limit, there may be a problem in productivity such as tableting disorder, and if the lubricant is outside the above upper limit, there may be a problem in dissolution delay or productivity.
  • the coating base is a hydrophilic polymer, for example, polyvinylpyrrolidone (PVP), polyvinylacetate (PVA), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium salt and calcium salt), ethyl cellulose, Methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low substitution degree HPC), polyvinyl alcohol, polymers of acrylic acid and salts thereof, vinylpyrrolidone-vinylacetate Copolymers (e.g., Kollidon ® VA64, BASF), polycoat IR, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof It may be one or more selected from the group consisting of, but is not limited thereto. Preferably it may be polyvinylacetate (PVA), hydroxypropylmethylcellulose (HPMC), polycoat IR.
  • PVP
  • the coating base may be used, for example, in an amount of 0.2 to 10 parts by weight, preferably in an amount of 0.5 to 7 parts by weight, and more preferably in an amount of 1 to 5 parts by weight, based on 100 parts by weight of the tablet (coated tablet) before coating. . If the hydrophilic polymer is less than the above-described lower limit, there may be a problem that a part of the entire surface of the uncoated tablet is not covered with the coating base, and if the hydrophilic polymer is outside the above-mentioned upper limit, there may be a problem of excessive delay in dissolution rate.
  • various biologically inert ingredients may be additionally added for additional purposes such as coating efficiency, drug stability, appearance, color, protection, retention, bonding, performance improvement, and manufacturing process improvement. Can be used.
  • the biologically inert component which may be further included in the coating layer is a plasticizer, lubricant, colorant, flavoring agent, surfactant, stabilizer, antioxidant, foaming agent, antifoaming agent, desiccant (eg, paraffin, wax It may be one or more selected from the group consisting of.
  • the plasticizer may be 100% by weight or less (eg, 0.1 to 100% by weight), specifically 50% by weight or less (eg, 0.1 to 50% by weight), and more specifically, based on the dry weight of the entire polymer used in each coating layer. 30 wt% or less (eg, 0.1-30 wt%).
  • the plasticizer may be 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 may be one or more selected from the group consisting of, but is not limited thereto.
  • the lubricant may be included in an amount of 100 wt% or less (eg, 0.1 to 100 wt%) based on the dry weight of the entire polymer used for each coating layer.
  • the glidants are, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed (colloidal) Type) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl mono stearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof, but may be one or more selected from It is not.
  • additives may be mixed in order to improve physical properties, manufacturability, compressibility, appearance, taste, and drug stability of the tablet or capsule.
  • additives include, for example, stabilizers, solubilizers, sweeteners, copulating agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, copulating agents, binders, suspending agents , Hardeners, antioxidants, brighteners, flavoring agents, flavoring agents, pigments, coating agents, wetting agents, wetting agents, fillers, defoamers, fresheners, chewing agents, antistatic agents, colorants, dragees, isotonic agents, emollients, emulsifiers, tackifiers, Thickeners, foaming agents, pH adjusting agents, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, dissolution
  • Sorafenib and polymethacrylate copolymers can be formulated in a variety of ways in the preparation of oral compositions.
  • sorafenib and polymethacrylate copolymers can be formulated by simple mixing. This mixture can be mixed with other additional ingredients to be tableted by tableting in a direct fashion or encapsulated by filling into capsules.
  • sorafenib and other additional constituents may be granulated in various ways and then the polymethacrylate copolymer may be postmixed and compressed into tablets, or filled into capsules and encapsulated.
  • examples of granulation in various ways include wet granules, dry granules, and the like. Wet granules can be used with high speed mixers or fluidized bed granulators, and dry granules can be used with roller compactors and extruders.
  • sorafenib and polymethacrylate copolymers can be mixed together, granulated in various ways, tableted by mixing other additional components in post-mixing, tableted, or filled into capsules and encapsulated.
  • the polymethacrylate copolymer is dissolved in a solvent such as ethanol and used as a binder to prepare wet granules, and then mixed with other additional components by post-mixing, tableting or tableting. Can be encapsulated.
  • sorafenib and polymethacrylate copolymers are mixed, melt-extruded into pellets at appropriate temperature conditions using a melt extruder, and then filled into capsules or mixed with other additional ingredients to obtain other pellets. It can be tableted by definition.
  • sorafenib and polymethacrylate copolymer may be formulated into a solid dispersion obtained by dissolving the solvent in an appropriate solvent and then removing the solvent by spray drying or the like.
  • Such solid dispersions may be mixed with other additional components to be compressed into tablets or encapsulated by filling into capsules.
  • the buffer solution (1) and acetonitrile were mixed at 30:70 (v / v) to obtain a dilution solution.
  • sorafenib tosylate standard was precisely taken into a 100 ml volumetric flask, dissolved well with a diluent, and the standard solution was prepared as a standard solution (300 ⁇ g / ml).
  • 1 ml of the standard solution (300 ⁇ g / ml) was precisely taken, and 2 ml of the diluted solution was added to prepare a standard solution (100 ⁇ g / ml).
  • 1 ml of the standard solution (300 ⁇ g / ml) was precisely taken, and 4 ml of the diluted solution was added to prepare a standard solution (60 ⁇ g / ml).
  • Standard solution and sample solution were injected into the column at appropriate time intervals under the following conditions, and the peak area was calculated to calculate the content of sorafenib tosylate in the tablet (%).
  • sorafenib tosylate crystalline form III
  • pH 1.2 buffer 1 ml of pH 1.2 buffer was added thereto. It was shaken at 1,100 rpm for 24 hours. Thereafter, the filter was filtered with a syringe filter having a pore size of 0.45 ⁇ m, and then the content analysis was performed according to the method of Test Example 1 by HPLC.
  • micronized sorafenib tosylate (crystalline form III, average 2 ⁇ m) with 137 g of Eudragit E PO, mixed with 30 g of microcrystalline cellulose, 45 g of croscarmellose, and 4.5 g of magnesium stearate, using a single tablet
  • the tablets were compressed using a 16.4 mm long axis and 6.4 mm short axis punches to obtain tablets with improved water solubility and bioavailability.
  • Example 2 The solid dispersion composition and the dissolution test on the reference product is Nexavar ® tablet Pharmacopoeia paddle method pH 1.2 buffer solution with 37 °C 900 mL 50 rpm in General Test Methods dissolution test method for on was carried out obtained in (a seashell penip 200 mg equivalent). The analysis was the same as the HPLC analysis of Test Example 1, but the concentration of the standard solution was measured by preparing to 304 ⁇ g / ml.
  • Example 2 The results are shown in FIG. It can be seen that the solid dispersion of Example 2 was significantly improved in dissolution compared to the reference drug.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne: une composition ayant une solubilité dans l'eau et une biodisponibilité améliorées, contenant du sorafénib et un copolymère de polyméthacrylate; et son procédé de préparation.
PCT/KR2018/004997 2017-05-02 2018-04-30 Composition ayant une solubilité dans l'eau et une biodisponibilité améliorées WO2018203636A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US16/610,312 US20200078463A1 (en) 2017-05-02 2018-04-30 Composition having improved water solubility and bioavailability
EP18794991.2A EP3620156A4 (fr) 2017-05-02 2018-04-30 Composition ayant une solubilité dans l'eau et une biodisponibilité améliorées
CN201880029667.0A CN110603035A (zh) 2017-05-02 2018-04-30 具有改善的水溶解度及生物利用率的组合物
JP2019560150A JP7046978B2 (ja) 2017-05-02 2018-04-30 水溶解度及びバイオアベイラビリティが改善された組成物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2017-0056115 2017-05-02
KR20170056115 2017-05-02
KR1020180049305A KR102082775B1 (ko) 2017-05-02 2018-04-27 수용해도 및 생체이용율이 개선된 조성물
KR10-2018-0049305 2018-04-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115813861A (zh) * 2022-12-28 2023-03-21 药源生物科技（启东）有限公司 一种提高难溶性药物溶解度的固体分散体及制备方法

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WO2013105895A1 (fr) * 2012-01-13 2013-07-18 Xspray Microparticles Ab Composition pharmaceutique contenant des nanoparticules hybrides amorphes stables d'au moins un inhibiteur de la protéine kinase et d'au moins un constituant polymère stabilisant et matriciel
KR101395932B1 (ko) 2011-12-29 2014-05-19 대한민국 개 브루셀라균 유래 리보솜 단백질 ｌ7／ｌ12 발현 세포주와 발현 단백질을 이용한 진단방법
EP2801349A1 (fr) * 2013-05-06 2014-11-12 Siegfried AG Formulation pharmaceutique orale
US20150224060A1 (en) * 2015-01-03 2015-08-13 David Wong Gastric retentive tablet compositions

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Publication number Priority date Publication date Assignee Title
KR101395932B1 (ko) 2011-12-29 2014-05-19 대한민국 개 브루셀라균 유래 리보솜 단백질 ｌ7／ｌ12 발현 세포주와 발현 단백질을 이용한 진단방법
WO2013105895A1 (fr) * 2012-01-13 2013-07-18 Xspray Microparticles Ab Composition pharmaceutique contenant des nanoparticules hybrides amorphes stables d'au moins un inhibiteur de la protéine kinase et d'au moins un constituant polymère stabilisant et matriciel
EP2801349A1 (fr) * 2013-05-06 2014-11-12 Siegfried AG Formulation pharmaceutique orale
US20150224060A1 (en) * 2015-01-03 2015-08-13 David Wong Gastric retentive tablet compositions

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Title
MANDAL, U. K.: "Gastro-retentive drug delivery systems and their in vivo success; a recent update", ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES II, vol. 11, no. 5, 2016, pages 575 - 584, XP055612523 *
See also references of EP3620156A4 *
WANG, X.-Q.: "Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 419, 2011, pages 339 - 346, XP028306649, DOI: doi:10.1016/j.ijpharm.2011.08.003 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115813861A (zh) * 2022-12-28 2023-03-21 药源生物科技（启东）有限公司 一种提高难溶性药物溶解度的固体分散体及制备方法

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