WO2020091439A1 - Formulation orale comprenant du sunitinib et procédé de préparation de celle-ci - Google Patents

Formulation orale comprenant du sunitinib et procédé de préparation de celle-ci Download PDF

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WO2020091439A1
WO2020091439A1 PCT/KR2019/014540 KR2019014540W WO2020091439A1 WO 2020091439 A1 WO2020091439 A1 WO 2020091439A1 KR 2019014540 W KR2019014540 W KR 2019014540W WO 2020091439 A1 WO2020091439 A1 WO 2020091439A1
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acid
sunitinib
weight
free base
oral
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PCT/KR2019/014540
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English (en)
Korean (ko)
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임혜정
박상엽
최인자
서민효
이사원
이재영
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주식회사 삼양바이오팜
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Publication of WO2020091439A1 publication Critical patent/WO2020091439A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the present invention relates to an oral preparation comprising sunitinib and a method for preparing the same, and more specifically, a hard capsule preparation containing conventional sunitinib malate and physicochemical and Pharmacologically equivalent or more, but the convenience of taking, handling, safety, etc. are more improved for oral solid preparations, and methods for manufacturing the same.
  • Sunitinib a VEGF (vascular endothelial growth factor) inhibitor
  • VEGF vascular endothelial growth factor
  • SU11248 vascular endothelial growth factor
  • It is a multi-target tyrosine kinase inhibitor that selectively blocks molecular targets (VEGFR1, VEGFR2, VEGFR3, PDGFRa, PDGFRb, KIT, FLT3, CSF1R).
  • the commercially available sunitinib formulation contains sunitinib malate as an active ingredient, which is a yellow to orange powder of pKa 8.95 that dissolves well in dimethylsulfoxide (DMSO) but has low solubility in ethanol and water. It is known that it exhibits a solubility of about 25 mg / mL or more in an acidic aqueous medium due to the nature of the weak base.
  • the molecular weight of sunitinib is 398.4 (532.6 as sunitinib malate) and the maximum plasma concentration (Cmax) is usually observed between 6 and 12 hours (Tmax) after oral administration.
  • Korean Patent Publication No. 2007-0119745 also discloses a formulation for treating cancer using sunitinib malate.
  • sunitinib malate as the active ingredient occupies the largest specific gravity of the composition of the whole composition, but because it has a bulky and poor flow property, it requires a large amount of additives during the formulation development, or is combined with granulation, granulation, and compression. There are problems such as requiring additional processes.
  • Suten® capsules are the main ingredients of sunitinib malate and excipients of mannitol, croscarmellose sodium, povidone, and magnesium stearate packed together in a gelatin capsule and packaged in a plastic bottle.
  • the doses of Suten® capsules on the market are 12.5 mg, 25 mg and 50 mg, including sunitinib malate 16.7 mg, 33.4 mg and 66.8 mg, respectively.
  • various types of sunitinib salts and preparations containing the same have been developed to facilitate the formulation of sunitinib and to improve the usability.
  • U.S. Patent No. 9206163 discloses a process for preparing sunitinib and acid addition salts thereof, and U.S. Patent No.
  • WO2010-039798 is a combination of a composition of sunitinib base and L-malic acid and a pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharides or derivatives thereof, It is disclosed that a suspension formed by dissolving sunitinib L-malate in water and adding microcrystalline cellulose or the like to dry to obtain an amorphous or semicrystalline combination of cellulose, etc. and a composition of sunitinib base and L-malic acid is obtained. .
  • the salt form of sunitinib is known to have a higher storage stability and solubility than the free base, but may have difficulty in quality control due to low initial dissolution rate according to the characteristics of the capsule preparation and variation in solubility depending on pH.
  • capsules are often susceptible to moisture due to the nature of gelatin, and thus require attention in the production and storage process.
  • gelatin capsules may stick to each other due to storage conditions such as temperature and humidity.
  • the capsule may stick to the throat or esophagus during the swallowing process, which may lead to drug exposure or pain, so there is a need to change the capsule into a tablet form to compensate for this.
  • the drug has a shielding effect due to the thick gelatin capsule film, but the hardness of the capsule film is weak, so if the PTP is individually packaged, the packaging material When taken out, there is a risk that the capsule is broken and the drug is exposed. Therefore, when the capsule is changed to a tablet, it is necessary to ensure sufficient shielding effect and safety in the packaging material by performing a sufficient coating using a coating mechanism having proven stability, and having a level equal to or greater than that of the gelatin capsule film.
  • Suten® capsule formulations differ in excipient ratio to active ingredient depending on the amount, and contain a relatively high proportion of excipients for the lowest single dose of 12.5 mg formulation. This difference in composition ratio can affect the rate of drug release in the body, so precautions need to be taken in prescriptions when dose control is required. In addition, since the volume of the capsule is also not reduced in proportion to the content, the patient may experience discomfort when taking a prescription in which a combination of several short dosage forms is required.
  • the object of the present invention is to improve the stability and dissolution deviation of the formulation containing the sunitinib free base to more than or equal to that of the conventional formulation containing sunitinib malate, pharmacologically equivalent efficacy and effect over the commercially available formulation It is to provide a formulation having improved productivity while having.
  • Another object of the present invention is to prepare a tablet composition for sunitinib using a sunitinib free base or a pharmaceutically acceptable salt thereof, thereby improving stability and dissolution deviations compared to commercial capsule formulations containing sunitinib malate. It is to provide a tablet composition that is increased to equal to or greater and has excellent pharmacological efficacy and improved productivity.
  • Another object of the present invention is to provide a method for preparing a formulation containing sunitinib free base.
  • One aspect of the present invention relates to an oral preparation comprising sunitinib free base and an organic acid as an additive.
  • the organic acid is selected from fumaric acid, malic acid, tartaric acid, maleic acid, carboxylic acid, acrylic acid, tartaric acid, citric acid, acetic acid, succinic acid, lactic acid, succinic acid, malonic acid, glutaric acid and combinations thereof.
  • the oral preparation may further include additives selected from diluents, binders, disintegrants, lubricants, and combinations thereof.
  • the oral preparation may be a solid preparation selected from granules, tablets, capsules and dry syrups, for example tablets.
  • the oral preparation may include sunitinib free base 5 to 30% by weight based on the total weight of the preparation.
  • the oral preparation may include 0.01 to 5 parts by weight of an organic acid based on 1 part by weight of sunitinib.
  • the content of the diluent contained in the oral tablet composition is 1 to 30 parts by weight based on 1 part by weight of the active ingredient, the content of disintegrant is 1 to 10 based on 100 parts by weight of the total composition It is parts by weight, and the content of the lubricant may be 0.1 to 5 parts by weight based on 100 parts by weight of the total composition.
  • the oral tablet composition may further include a binder.
  • the content ratio of each component may be constant regardless of the content of the active ingredient in the oral tablet composition.
  • the volume of the tablet in the oral tablet composition may be proportional to the content of the active ingredient.
  • Another aspect of the present invention preparing a mixture of sunitinib free base, diluent and disintegrant; Mixing the mixture by adding a lubricant to the mixture; And it relates to a method for producing an oral preparation comprising the step of mixing by further adding an organic acid.
  • the method for preparing the oral preparation may further include a step of tableting a mixture in which an organic acid is additionally added.
  • oral formulations containing sunitinib free base are included with a relatively low active ingredient specific gravity in the formulation due to the relatively small molecular weight compared to sunitinib malate of sunitinib free base. This can minimize the effect on the physical properties of the formulation.
  • a small molecular weight may not only be advantageous in the application of the formulation process, but also the production yield may be improved, and in view of productivity, considering that most of the active ingredients are expensive.
  • the organic acid in the formulation, it is possible to minimize the change in solubility of the sunitinib free base according to the pH change, and the dissolution rate is superior to the conventional formulation prepared using sunitinib malate as an active ingredient, and the drug
  • the release variation is small and effective, and it can have a pharmacological treatment effect equal to or greater than that of conventional formulations and nonclinical studies.
  • the oral tablet composition containing sunitinib free base is reduced in volume of the formulation compared to the capsule formulation, thereby increasing patient convenience and ease of handling in the production process, and packaging and storage.
  • the stability problem in the process also has an advantage that can be improved.
  • the drug release variation is small and effective compared to the existing hard capsule formulations, and even in a non-clinical trial, equivalent therapeutic effects can be expected as pharmacological equivalence of the hard capsule formulations is confirmed.
  • the use of fewer active ingredients compared to commercial formulations can have an equivalent effect, and due to the low active ingredient content, the formulation process application is advantageous as well as the production yield can be improved.
  • the tablet composition is prepared using the sunitinib free base from which the salt has been removed, the molecular weight of the free base is relatively small, and thus the specific gravity of the active ingredient in the composition is low, which has the advantage of having less influence on the tablet manufacturing process. Since the active ingredient of is expensive, it may be more advantageous in terms of productivity.
  • FIG. 1 is a graph showing the dissolution pattern in a pH 1.2 solution of an oral solid preparation prepared according to Examples and Comparative Examples of the present invention.
  • Figure 2 is a graph showing the dissolution pattern in a pH 4.0 solution of an oral solid preparation prepared according to Examples and Comparative Examples of the present invention.
  • FIG. 3 is a graph showing the dissolution pattern in water of an oral solid preparation prepared according to Examples and Comparative Examples of the present invention.
  • the present invention provides an oral solid preparation composition
  • an oral solid preparation composition comprising sunitinib and a diluent, a disintegrant, a lubricant, an organic acid and a coating base.
  • “sunitinib” may be sunitinib free base or an isomer thereof, or a mixture thereof.
  • it may be to form various hydrates in each case and various crystal forms in each case.
  • it may be various hydrates such as sunitinib anhydride, monohydrate, dihydrate, trihydrate, or various solvates, or mixtures thereof.
  • the formulation containing sunitinib can be used for the treatment of cancer diseases such as liver cancer, renal cell cancer, breast cancer, colon cancer, lung cancer, endocrine tumor, thyroid cancer, leukemia, prostate cancer, lymphoma and pancreatic cancer, particularly renal cell cancer. It can be effectively used in the treatment of.
  • cancer diseases such as liver cancer, renal cell cancer, breast cancer, colon cancer, lung cancer, endocrine tumor, thyroid cancer, leukemia, prostate cancer, lymphoma and pancreatic cancer, particularly renal cell cancer. It can be effectively used in the treatment of.
  • sunitinib may be used in a finely divided form, wherein the average particle size (X50) of the finely divided sunitinib may be less than 100 ⁇ m, for example, may be less than 50 ⁇ m, for example, less than 30 ⁇ m. Can be, for example, less than 20 ⁇ m. Further, the average particle size (X50) of finely divided sunitinib may be 0.1 ⁇ m or more, for example, 1 ⁇ m or more. When using sunitinib in a range outside the above-mentioned average particle size, there may be a dissolution rate decrease or a process obstacle.
  • the average particle size (X50) may mean the average particle size of the lower 50% of the total particles.
  • the average particle size can be measured, for example, using a light diffraction particle size meter.
  • the expression "differentiated" here means that the powder is very small in size, for example, the average diameter of which is micrometer or nanometer.
  • the sunitinib free base may include, but is not limited to, about 5 wt% to about 30 wt% or about 10 wt% to about 20 wt%, based on the total weight of the formulation, and the severity of the disease to be treated , According to the patient's age, weight, health, gender, patient's sensitivity to the drug, route of administration, rate of discharge, duration of treatment, factors including drugs used in combination with or used concurrently with sunitinib, and other factors well known in the medical field. It can be decided accordingly. Since the sunitinib free base has a relatively small molecular weight compared to the conventionally used sunitinib malate, it may contain fewer active ingredients than conventional sunitinib preparations.
  • organic acid is a generic term for an organic compound showing acidity, specifically, fumaric acid, malic acid, tartaric acid, maleic acid, carboxylic acid, acrylic acid, tartaric acid, citric acid, acetic acid, succinic acid, lactic acid, succinic acid, malonic acid, glutaric acid or It may be a mixture of these, but may not be limited thereto.
  • the organic acid may be used as an additive to improve the solubility of the active ingredient sunitinib free base in an aqueous medium and lower the dissolution deviation.
  • the organic acid includes an organic acid having a carboxylic acid, and may be, for example, a dibasic acid having two carboxyl functional groups, but is not limited thereto.
  • it may be malic acid, maleic acid, tartaric acid, citric acid, fumaric acid, tartaric acid or mixtures thereof, for example fumaric acid, maleic acid or mixtures thereof, for example fumaric acid.
  • organic acids are organic acids excluding malic acid.
  • the organic acid may be used in an appropriate amount depending on physical properties such as pKa and stability of each component, for example, 0.01 to 5 parts by weight based on 1 part by weight of sunitinib, for example, 0.05 to 3 parts by weight, for example It can be used in an amount of 0.1 to 1 part by weight. If the organic acid is less than the above-mentioned lower limit, there is a lack in the effect of reducing elution deviation, and if it is outside the above-mentioned upper limit, the property of the highly reactive substance may affect the stability of the formulation.
  • the diluent is, for example, lactose (anhydride or hydrate, for example monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, Magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, deck Strath, maltose, sucrose, glucose, fructose, maltodextrin, dexlate, dextrin, and mixtures thereof, may be one or more selected from the group consisting of, but is not limited thereto.
  • mannitol, microcrystalline cellulose or mixtures thereof can be selected.
  • the diluent may be used in an amount of, for example, 1 to 30 parts by weight, for example, 2 to 20 parts by weight, more preferably 3 to 15 parts by weight based on 1 part by weight of sunitinib. If the diluent is less than the above-mentioned lower limit, it is difficult to manufacture into a tablet, and if it exceeds the above-mentioned upper limit, the weight of the preparation becomes too large, so it is difficult to formulate and there may be difficulty in taking.
  • the binder can be used in the manufacture of granules, but can also be included in the preparation of simple mixtures.
  • the binder is any material that does not affect the action of the active ingredient
  • the binder may be a hydrophilic binder.
  • the binder may be selected from the group consisting of povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, calcium hydrogen phosphate, calcium carbonate, and any combination thereof. However, it is not limited thereto.
  • the binder is povidone.
  • the binder may be used in an amount of, for example, 0.5 to 10 parts by weight, for example, 1 to 5 parts by weight based on 100 parts by weight of the total formulation composition. If the binder is less than the above-described lower range, the binding strength of the mixture is poor and the tablet is not compressed well, and if it is outside the above-mentioned upper range, there may be a tableting disorder such as sticking when preparing the formulation.
  • the disintegrant may be, for example, croscarmellose sodium (CrosCMC-Na), carboxymethylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), Starch (wheat, rice, corn or potato starch), sodium carboxymethyl starch, sodium starch glycolate, partially hydrolyzed starch, and mixtures thereof, and may be one or more selected from the group. It may be, for example, sodium starch glycolate.
  • the disintegrant may be used in an amount of, for example, 1 to 10 parts by weight, for example, 2 to 5 parts by weight based on 100 parts by weight of the total formulation. If the disintegrant is less than the above-described lower limit range, there may be a problem of delaying dissolution rate due to the disintegration rate delay, and if it is outside the above-described upper limit range, there may be a problem in productivity such as tableting disorder during tablet manufacturing.
  • the lubricants 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 mono stearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof. no. For example, it may be magnesium stearate.
  • the tablet When the oral preparation is a tablet, the tablet may be used in an amount of 0.1 to 5.0 parts by weight, 0.3 to 2.0 parts by weight, or 0.5 to 1.5 parts by weight based on 100 parts by weight of the total tablet. If the amount of the lubricant used is too small than the above-mentioned range, there may be problems in productivity such as tableting disorder, and, conversely, if it is too much than the above-mentioned range, there may be a problem in elution delay or productivity.
  • sunitinib has lower water solubility than sunitinib malate, but it is possible to increase the water solubility to more than sunitinib malate by adjusting the pH in the formulation by addition of an organic acid and reduce the variation of elution. Can be.
  • the desired properties can be secured by using a relatively small amount of organic acid than the amount of malic acid bound to sunitinib malate, thereby lowering the content of the active ingredient and securing the advantages of process application and yield improvement of various oral solid preparations can do.
  • the oral solid preparation can be any solid preparation known in the art, for example granules, tablets, capsules or dry syrups.
  • the oral solid preparation is a tablet containing sunitinib free base and a pharmaceutically acceptable additive.
  • the tablets can be prepared in the order of granulation (optional), mixing, tableting, coating after weighing the active ingredients and additives.
  • Granulation can be made by dry granulation, wet granulation or the like. If granulation is not performed, the process is simplified because it is mixed and compressed immediately after weighing. In addition, the direct exposure method may be most preferable because the exposure of the worker to the drug is minimized.
  • the remaining amount of the diluent is added and mixed.
  • a disintegrant, a binder, and / or a lubricant are added in stages and mixed, and then, an organic acid is added.
  • an organic acid is added.
  • the binder is first mixed with the drug in another way, and then a diluent is added to further mix, followed by addition of a disintegrant and a lubricant, followed by mixing, and finally mixing the organic acid in the final step to prepare a semi-finished product for tableting can do.
  • the tablet may be a tablet or dragee, a film coated tablet, for example, a film coated tablet capable of shielding and moisture-proofing the drug.
  • the coating layer of the film-coated tablet may be a single layer or multiple layers, for example, a single layer.
  • the coating base for preparing the film-coated tablet is a hydrophilic polymer, for example, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methyl Cellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low substitution HPC), polymers of polyvinyl alcohol, acrylic acid and salts thereof, vinylpyrrolidone-vinyl acetate copolymer Coalescence (e.g., Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof.
  • PVP polyvinylpyrrolidone
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the coating base is, for example, based on 100 parts by weight of the tablet (screw) before coating, for example, in an amount of 1 to 30 parts by weight, for example, in an amount of 2 to 20 parts by weight, even more for example 3 to 10 parts by weight It can be used in a negative amount. If the coating amount is less than the above-mentioned lower limit range, there may be a problem that the entire tablet is not covered with the coating base material, and if it is outside the above-described upper limit range, there may be an excessive delay in the dissolution rate.
  • each content ratio of the active ingredient, diluent, disintegrant, lubricant, and coating layer may be constant, and the volume of the tablet may be proportional to the content of the active ingredient.
  • various additives may be mixed to improve the physical properties, manufacturability, compressibility, appearance, taste, and stability of the tablet.
  • the additives include, for example, stabilizers, solubilizers, sweeteners, mating agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, mating agents, binders, suspending agents , Curing agent, antioxidant, brightener, flavoring agent, flavoring agent, pigment, coating agent, wetting agent, wetting control agent, filler, antifoaming agent, refreshing agent, chewing agent, antistatic agent, coloring agent, dragee, isotonic agent, emollient, emulsifier, adhesive,
  • Examples include thickeners, foaming agents, pH adjusting agents, excipients, diluents, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, dissolution aids, solvents,
  • Test Example 1 Change of solubility of sunitinib free base according to organic acid concentration
  • the final mixture was prepared by sieving 2.5 g of sunitinib free base and 11.03 g of mannitol, sieving 0.6 g of povidone and 0.72 g of sodium starch glycolate, and then mixing 0.15 g of magnesium stearate. The mixture was compressed into a rectangular punch at a weight of 300 mg per tablet. The hardness of the tablet was 70 N.
  • a film coating corresponding to a total weight of 3% (w / w) compared to 100% (w / w) of the total weight of the tablets was performed with an Opadry base containing HPMC as a main component.
  • Test example 2 Sunitinib Dissolution test
  • Solution A 3.85 g of ammonium acetate was dissolved in 1 L of distilled water (DW) and then mixed by adding 0.5 mL of acetic acid. The solution was degassed by filtration through 0.45 ⁇ m filter paper.
  • Solution B Methanol and acetonitrile were mixed at a ratio of 1: 4 (v / v), filtered and degassed with a 0.45 ⁇ m filter paper.
  • Table 4 below shows the dissolution rates of sunitinib from the tablets of Examples 1 to 6 and the capsules of Comparative Example 1 measured as a result of the test.
  • the dissolution rate was for judging the equivalence, and was considered to be the equivalent range when 85% or more was achieved. As a result, it was confirmed that all the examples had a dissolution rate in the range equivalent to that of a commercially available hard capsule formulation.
  • Dissolution test device The paddle method of the Korean Pharmacopoeia dissolution test method
  • Test solution pH 1.2, pH 4.0, DW
  • Example 4 Subjected to pharmacokinetic tests were conducted as Examples 3 and 4, and Comparative Example 2, non-clinical studies to be 50 mg Community SUTENT ® capsules comparison of Comparative Example 1 and purified in accordance with the nip, using beagle dogs as the test animals.
  • the number of beagle dogs 20 is divided into four groups, the first group is comparative example 1, the second group is comparative example 2, the third group is test group 3 (example 3), and the fourth group is test group 4 (implement It was named as Example 4).
  • the experimental animals were bled at a fixed time interval up to 48 hours after taking the medicine with 20 mL of water in the fasted state.
  • the oral preparation containing sunitinib free base according to the present invention showed higher AUC and C max than commercially available hard capsule preparations containing sunitinib malate, sunitinib malate It was confirmed to have superior pharmacokinetic properties compared to the formulation containing.
  • sunitinib free base After sieving and mixing 2.5 g of sunitinib free base with 9.53 g of microcrystalline cellulose, 0.6 g of povidone and 0.72 g of sodium starch glycolate are sieved and additionally mixed with 0.15 g of magnesium stearate, followed by fumaric acid
  • the final powder composition was prepared by sifting and mixing 1.5 g. 300.0mg of this mixture was packaged in one packet to prepare sunitinib 50mg powder.
  • sunitinib free base After sieving and mixing 2.5 g of sunitinib free base with 9.53 g of microcrystalline cellulose, 0.6 g of povidone and 0.72 g of sodium starch glycolate are sieved and additionally mixed with 0.15 g of magnesium stearate, followed by maleic acid
  • the final powder composition was prepared by sifting and mixing 1.5 g. 300.0mg of this mixture was packaged in one packet to prepare sunitinib 50mg powder.
  • the final powder composition was prepared by sieving and mixing 2.5 g of sunitinib free base with 11.03 g of mannitol, sieving 0.6 g of povidone and 0.72 g of sodium starch glycolate, and then mixing 0.15 g of magnesium stearate. . 300.0 mg of this mixture was packaged in one packet to prepare sunitinib 50 mg powder.
  • Embodiment was carried out for Examples 7 and 8, and Comparative Example 3 pharmacokinetic testing with a SD rat as 50 mg sunitinib for comparison of SUTENT ® capsules of the powder composition of Comparative Example 1, the experimental animals in accordance with the. 20 SD rats were divided into 4 groups, and the first group was tested in Comparative Example 1, the second group in Comparative Example 3, the third group in Example 7, and the fourth group in Example 8.
  • the composition of each group was orally administered to experimental animals that were fasted at a dose of 15 mg / kg by dispersing in water to a concentration of 6 mg / ml as sunitinib.
  • the powder composition containing sunitinib free base according to the present invention showed higher AUC and C max than commercially available hard capsule preparations containing sunitinib malate, showing sunitinib malate It was confirmed that it has superior pharmacokinetic properties compared to the containing agent.

Abstract

La présente invention concerne une formulation orale comprenant du sunitinib et son procédé de préparation et, plus spécifiquement, une formulation orale solide sous forme de gelule, qui utilise une base libre de sunitinib et est en outre améliorée au niveau de la commodité d'administration, de la facilité de manipulation et de la sécurité tout en étant physicochimiquement et pharmacologiquement équivalente ou supérieure aux formulations de gelules dures classiques comprenant du malate de sunitinib, et un procédé de préparation de celle-ci.
PCT/KR2019/014540 2018-10-31 2019-10-31 Formulation orale comprenant du sunitinib et procédé de préparation de celle-ci WO2020091439A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
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