WO2019199133A1 - Composition de comprimé enrobé à administration par voie orale à base de lénalidomide - Google Patents

Composition de comprimé enrobé à administration par voie orale à base de lénalidomide Download PDF

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WO2019199133A1
WO2019199133A1 PCT/KR2019/004473 KR2019004473W WO2019199133A1 WO 2019199133 A1 WO2019199133 A1 WO 2019199133A1 KR 2019004473 W KR2019004473 W KR 2019004473W WO 2019199133 A1 WO2019199133 A1 WO 2019199133A1
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Prior art keywords
coating
coating layer
lenalidomide
starch
tablet
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PCT/KR2019/004473
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English (en)
Korean (ko)
Inventor
박상엽
임혜정
이사원
서민효
Original Assignee
주식회사 삼양바이오팜
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Priority to JP2020556288A priority Critical patent/JP2021518423A/ja
Publication of WO2019199133A1 publication Critical patent/WO2019199133A1/fr
Priority to JP2023034787A priority patent/JP2023071923A/ja

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    • 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
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • 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
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to an oral tablet composition comprising lenalidomide.
  • myeloma is a blood cancer in which plasma cells are abnormally differentiated and proliferated. Such abnormal plasma cells are called myeloma cells. It mainly occurs in black people, men, and older people aged 65 or older, and in Korea, the frequency of occurrence is increasing.
  • the main therapeutic agents for such multiple myeloma include boltezomib, thalidomide, lenalidomide.
  • Lenalidomide has been developed by Celgene in oral capsule formulations and is available in 25, 20, 15, 10, 7.5, 5 and 2.5 mg quantities.
  • lenalidomide is also a derivative of thalidomide, it cannot be prescribed to pregnant women. Therefore, lenalidomide has been marketed as a hard capsule so that no damage is caused by unintended leakage of the drug. In other words, the drug was filled in a thick hard capsule, similar to thalidomide, to control the outflow and loss of the drug.
  • the domestic brand name is Revlimid ® capsule and contains lenalidomide hemihydrate.
  • the hard capsule Reblimid ® capsule is filled in No. 0 capsules in the case of 25, 20, 15, and 10 mg formulations, and has a long axis of about 2.17 cm, which is considerably long and bulky.
  • capsules even when taken with water may cause the capsule to stick to the throat or esophagus in the swallowing process. At this time, even if a large amount of water does not fall well, and if the drug accidentally popped out, the pain is accompanied, and in some cases may be inflamed. Therefore, when the short length, small volume tablets are developed as well as problems caused by inconvenient capsules as well as problems due to large volume, the patient's convenience of taking may be increased, and the disadvantages of the capsules may be overcome.
  • thalidomide was used in the late 1950s and 1960s as a morning sickness preventive for pregnant women, there was a tragic event that resulted in the birth of tens of thousands of birth defects worldwide due to the unknown side effects of teratogenicity. Like thalidomide, lenalidomide has a side effect of teratogenicity. Therefore, it is forbidden to take and handle pregnant women as well as those of childbearing potential and those who may be pregnant.
  • tablet formulations containing lenalidomide need to be designed and manufactured to have the same drug release rate and release pattern as clinically validated and commercially available capsules.
  • An object of the present invention is to change the formulation of the commercially available lenalidomide formulations as hard capsules to tablets, but the length is short and the volume is easy to take, the selection of the coating base and coating thickness is appropriate for the entire tablet It is to provide a tablet composition that can be completely enclosed over the thickness to separate the drug from the inside of the handler, so that there is no fear of drug leakage during coating.
  • the dissolution pattern in the tablet is the same as the dissolution in the capsule to provide a tablet composition showing not only physicochemical equivalence in the comparative dissolution test, but also in vivo test of laboratory animals and bioequivalence test.
  • the present invention provides a tablet composition and a method for preparing the same, which are equivalent in terms of efficacy and effect pharmacologically with commercially available capsule formulations, with improved appearance, ease of use and handling, ease of manufacture, safety, and the like.
  • lenalidomide can be lenalidomide free base (base drug without a separate salt), or a pharmaceutically acceptable salt or isomer thereof, or mixtures thereof. It may also be in each case forming various hydrates and in each case various crystalline forms. For example, it may be various hydrates or various solvates, such as lenalidomide anhydride, hemihydrate, monohydrate, dihydrate, trihydrate, or mixtures thereof.
  • the present invention provides an uncoated tablet comprising lenalidomide and at least one pharmaceutically acceptable carrier as an active ingredient; And it provides an oral tablet composition comprising a coating layer for coating it.
  • the carrier may include a diluent, a disintegrant, and a lubricant.
  • the surface of the uncoated tablet is coated with a coating base, which can separate the drug from the inside and the tablet handler, and there is no fear that the drug may leak out during coating.
  • the present invention is tableted at the optimum tableting pressure to have a hardness in the appropriate range, so that the commercially available capsule formulation and the elution pattern appear equally.
  • the diluent may be selected from one or more of the group consisting of sugars, sugar alcohols, celluloses, starches, inorganic salts and mixtures thereof;
  • the disintegrant may be selected from one or more from the group consisting of swellable disintegrants, wet disintegrants, and mixtures thereof;
  • the glidant may be selected from one or more from the group consisting of soluble glidants, insoluble glidants and mixtures thereof.
  • the coating layer of the oral tablet composition may be a single layer or bilayer or more.
  • the oral tablet composition may include 0.5 to 200 parts by weight of diluent, 0.02 to 10 parts by weight of disintegrant, and / or 0.005 to 3.5 parts by weight of lubricant based on 1 part by weight of lenalidomide.
  • 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, It may be, but is not limited to, one or more selected from the group consisting of lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dexrate, dextrin, and mixtures thereof.
  • lactose microcrystalline cellulose, mannitol, starch or mixtures
  • the diluent may be used in an amount of, for example, 2 to 50 parts by weight, or 2 to 45 parts by weight, or 5 to 30 parts by weight, or 10 to 20 parts by weight based on 1 part by weight of lenalidomide. have. If the amount of the diluent is too small than the above-mentioned range, it is difficult to prepare a tablet, on the contrary, if the amount of the diluent is too high, the concentration of the drug is lowered, which may cause a problem in securing content uniformity during the preparation.
  • the disintegrant may be selected from the group consisting of, for example, starch, cellulose, crosslinked polymers, gums, polysaccharides, and mixtures thereof, for example, croscarmellose sodium (CrosCMC-Na).
  • croscarmellose sodium, crospovidone, L-HPC sodium starch glycolate. More preferably croscarmellose sodium.
  • the disintegrant is used in an amount of, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.2 to 1.5 parts by weight, or 0.1 to 1 parts by weight based on 1 part by weight of lenalidomide. Can be. If the amount of the disintegrant is excessively less than the above-mentioned range, there may be a problem of delayed dissolution rate due to the disintegration rate delay. On the contrary, if the amount of the disintegrant is excessively larger than the above-mentioned range, there may be a problem in productivity such as tableting disorder and coating disorder.
  • the lubricant is used as a concept encompassing lubricant, antiadherant, glidant, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, 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, hardened vegetable oil, hard liquid paraffin , Polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate, and mixtures thereof, but is not limited thereto. It doesn't happen.
  • the lubricant may preferably be magnesium stearate, stearic acid, highly dispersed
  • the lubricant is used in an amount of, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.1 to 1 parts by weight, or 0.1 to 0.5 parts by weight based on 1 part by weight of lenalidomide. Can be. If the amount of the lubricant is too small than the above-mentioned range may be a problem in productivity, such as tableting disorder, on the contrary, too much than the above-mentioned range may have a problem in elution delay or productivity.
  • the coating base is a hydrophilic polymer, for example, hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and salts thereof, polymethacrylate, poly (Butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymers (e.g., HPMC), hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and salts thereof, polymethacrylate, poly (Butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymers (e.g.
  • HPMC hydroxypropylmethyl cellulose
  • PVA polyvinyl alcohol
  • macrogol polyvinyl alcohol graft copolymer polymer of acrylic acid and salts thereof,
  • Eudragit® E, Evonik carboxymethylcellulose (sodium salt and Calcium salt), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (HPC of low degree of substitution), polyvinylpyrrolidone (PVP), vinyl Pyrrolidone-vinylacetate copolymers (e.g., Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan and mixtures thereof Configuration It is at least one selected from the group, but is not limited to this.
  • the coating base is hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl meth) Acrylate) copolymers (eg Eudragit® E, Evonik).
  • HPMC hydroxypropylmethylcellulose
  • PVA polyvinyl alcohol
  • macrogol polyvinyl alcohol graft copolymer poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl meth) Acrylate) copolymers (eg Eudragit® E, Evonik).
  • the coating layer is for example 0.05 to 10 parts by weight, or 0.1 to 3 parts by weight, or more than 0.1 to less than 3, or 0.2 to 2.5 parts by weight, or 0.5 to 1 part by weight based on lenalidomide It can be used in an amount of 2 parts by weight. If the amount of the coating base is excessively less than the above-mentioned range, there may be a problem that the whole uncoated tablet is not covered with the coating base and disintegrates too early. Conversely, if the amount of the coating base is too high, there may be a problem of excessive delay of the dissolution rate.
  • the thickness of the coating layer may be measured by a scanning electron microscope (SEM) method. At this time, it is preferable that the entire surface of the tablet is uniformly coated with a predetermined thickness, and the average thickness can be confirmed by measuring the average of five or more.
  • the average thickness of the coating layer may be 1 ⁇ m or more and 300 ⁇ m or less. Preferably 10 micrometers or more and 200 micrometers or less may be sufficient. Even more preferably, it may be 15 ⁇ m or more and 150 ⁇ m or less. Most preferably, it may be 20 micrometers or more and 100 micrometers or less.
  • the average thickness of the coating layer is thinner than the above-mentioned range, it is difficult to coat the entire tablet evenly, and dust may occur during handling. If the average thickness of the coating layer is thicker than the above-mentioned range, the dissolution delay, excessive processing time, etc. For this reason, the desired purpose cannot be achieved.
  • one or more coating bases may be mixed and used, and a sufficient amount may be coated to protect the entire tablet by forming a coating layer with the coating base.
  • the coating layer may be more preferably at least two layers.
  • the coating base may be different for each layer to act as shielding, water blocking, and oxidation prevention for drug exposure, respectively. Double coating can increase the protection from the external environment.
  • Primary coating bases that come in direct contact with bare tablets include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymers (e.g.
  • the coating base may be polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g. Eudragit E, Evonik), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan or combinations thereof.
  • PVA polyvinyl alcohol
  • macrogol polyvinyl alcohol graft copolymer poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g. Eudragit E, Evonik), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan or combinations thereof.
  • the first coating is preferably formed with hydroxypropylmethylcellulose (HPMC) to form a film blocking the drug
  • the second coating is sequentially made with a macrogol polyvinyl alcohol graft copolymer to form a bilayer coating film.
  • the first coating with hydroxypropylmethylcellulose (HPMC) to form a film to block the drug, and the second coating with polyvinyl alcohol (PVA) in order to the moisture-proof coating film By forming a, it is possible to form a double layer coating film having a more excellent function, but is not limited thereto.
  • the coating solvent may be ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water or the like or a mixed solvent thereof.
  • ethanol, water, or mixtures thereof can be used.
  • a primary coating is formed using a mixture of ethanol and water, or a mixture of methylene chloride and ethanol, or a mixture of isopropyl alcohol and ethanol as a coating solvent, and then a secondary coating is formed using water as a coating solvent.
  • a primary coating is formed using a mixture of ethanol and water, or a mixture of methylene chloride and ethanol, or a mixture of isopropyl alcohol and ethanol as a coating solvent, and then a secondary coating is formed using water as a coating solvent.
  • a secondary coating is formed using water as a coating solvent.
  • 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 selected from the group consisting of plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, antifoaming agents, paraffins and waxes, etc. It may be one or more.
  • the plasticizers that may be further included in the coating layer are, for example, triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, acetyl triethyl citrate, acetyl triethyl It may be one or more selected from the group consisting of citrate, propylene glycol, triacetin, polyethylene glycol, cetyl alcohol, stearyl alcohol and cetostearyl alcohol, but is not limited thereto.
  • the plasticizer is 100% by weight or less (eg, 0 to 100% by weight or 0.1 to 100% by weight), specifically 50% by weight or less, based on 100% by weight of the total polymer used in each coating layer. , 0 to 50 wt% or 0.1 to 50 wt%), more specifically 30 wt% or less (eg, 0 to 30 wt% or 0.1 to 30 wt%), but is not limited thereto.
  • the glidants that may be further included in the coating layer 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 It may be one or more selected from the group consisting of type (colloidal type) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl mono stearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof, but is not limited thereto. It is not.
  • the glidant may be included in an amount of 100 wt% or less (eg, 0 to 100 wt% or 0.1 to 100 wt%) when the dry weight of the entire polymer used in each coating layer is 100 wt%, but is not limited thereto. It is not.
  • the tablet composition of the present invention comprises mixing lenalidomide and one or more pharmaceutically acceptable carriers as an active ingredient, tableting the mixture to prepare a tablet (coated tablet) before coating, and then coating the surface of the uncoated tablet with a coating base.
  • a method for producing an oral tablet composition of the present invention is provided.
  • the tablet of the present invention may be prepared in the order of granulation, mixing, tableting, coating after weighing the raw materials, or mixing, tableting (direct tableting), coating after weighing the raw materials.
  • Granulation can be carried out in the manner of dry granules, wet granules and the like.
  • a binder solution when granulating into wet granules, a binder solution is prepared, a diluent or the like is added together with the drug, and the mixed mixture is granulated together with the binder solution, then sieved and dried to obtain granules. After mixing the remaining ingredients in the post-mixing and tableting.
  • the binder solution may be a water-soluble polymer such as hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), L-HPC (low substitution degree HPC), polyvinylpyrroli Don (PVP), vinylpyrrolidone-vinylacetate copolymer (e.g.
  • sugar alcohols such as sucrose, sorbitol, maltitol, xylitol, Erythritol and the like can be dissolved in water, ethanol or a mixed solution thereof.
  • a mixture of drugs, diluents, binders, and the like is compressed using a roller compactor, and then sieved, and then mixed with the remaining components by post-mixing. After tableting.
  • the process is simplified because it is mixed and tableted immediately after weighing. Since the drug itself has a side effect of teratogenicity, it may be necessary to wear protective equipment of the worker during the manufacturing process, preferably a pregnant woman or a person who may be pregnant may be excluded. In addition, the direct method of minimizing the worker's exposure to the drug may be most desirable. However, the present application is not limited thereto.
  • the hardness of uncoated tablets may vary depending on the shape, weight and size of the tablet, but the maximum average hardness is 300N and the minimum average hardness is 20N. Preferably, the maximum average hardness is 250N and the minimum average hardness is 30N. More preferably, the maximum average hardness is 230N and the minimum average hardness is 35N, in particular 40N to 200N. If the hardness of the uncoated tablet is too high than the above-mentioned range, there may be a delay in release of the drug due to the disintegration delay. On the contrary, if the hardness of the uncoated tablet is too low, the release of the drug is too fast. There may be a break in the city.
  • the hardness refers to a value obtained by measuring the long axis when measured on tablets such as a rectangle, and means the average hardness of six tablets randomly selected.
  • the disintegration time may be one of the important factors for estimating the release time of the drug. Therefore, in the tableting process, the tablets should be compressed at an appropriate pressure to have an appropriate hardness, so that the desired disintegration time can be obtained. This may be a factor that determines the dissolution pattern of the tablet together with the amount of coating base in the coating process. Since the dissolution pattern affects the absorption in the body, it may be important to set the appropriate disintegration time by having the appropriate hardness at the appropriate tablet pressure. In addition, since the dissolution pattern of the drug should be the same even if the dose is changed, the disintegration time may be the same for all doses of the tablet.
  • the disintegration time was measured in accordance with the disintegration test No. 17 of the general test method of the KP X 10 amendment, but can be carried out in pH 1.2 buffer solution, the first solution of the test solution, after measuring the disintegration time of six tablets Averaged to get the value.
  • the average disintegration time of the uncoated tablet is between 1 and 20 minutes. Preferably between 1 minute 30 seconds and 15 minutes. More preferably 2 minutes to 10 minutes, still more preferably 2 minutes 30 seconds to 8 minutes, even more preferably 3 minutes to 6 minutes, most preferably 3 minutes 30 seconds to 5 minutes 30 seconds.
  • the coating layer formed on the uncoated tablet may be a single layer or a bilayer or more, more preferably a bilayer or more.
  • the solvent for the coating can vary.
  • the ratio of anhydrous ethanol and water may be 2: 8 to 8: 2, or water alone.
  • water may be used alone as a solvent for the coating of PVA. All of these solvents volatilize during the coating process and do not remain substantially in the final finished product.
  • additives may be further mixed to improve the physical properties, manufacturability, compressibility, appearance, taste and / or stability of the drug, and the like.
  • 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, blowing agents, pH adjusting agents, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, dis
  • the coated tablets of the present invention may exhibit dissolution rates equivalent to comparative formulations prepared in capsules in dissolution tests.
  • initial dissolution rates of 2.5 minutes, 5 minutes, 10 minutes, and 15 minutes are important under acidic conditions such as pH 1.2 buffer solution.
  • Lenalidomide has a pH-dependent solubility that affects the solubility and absorption of the drug depending on where it disintegrates in the body.
  • the solubility of the drug is high at low pH, the release pattern in the stomach after administration may be a major factor in determining the drug absorption pattern. Therefore, matching the disintegration time and dissolution pattern of the formulation similarly to the reference drug is an important requirement to secure the same drug absorption pattern.
  • Dissolution test shall be carried out in accordance with the dissolution test method No. 35 of the general test method of KP X 10 amendments, can be tested at 37 o C with the paddle method 50 rotations / minute, 6 tablets each By measuring the elution amount of the drug at each time point by HPLC can be obtained the average dissolution rate at each time point.
  • Tablet compositions comprising lenalidomide disclosed in the present invention can be usefully used as a composition in the form of tablets with further improved convenience, handleability, safety and the like.
  • the coating layer can separate the drug from the inside of the handler, the lenalidomide drug with teratogenicity does not come out of the coating layer during coating, so that the contact with the coating layer does not come into contact with the drug.
  • the initial dissolution rate is important, such as 2.5 minutes, 5 minutes, 10 minutes, 15 minutes under acidic conditions such as pH 1.2, the tablet composition according to the present invention showed the same pattern as the dissolution of commercially available capsules .
  • Example 1 to 4 are graphs showing the results of elution comparison tests of the eluate of Example 2 and Comparative Example 1 in pH 1.2, pH 4.0, water, and pH 6.8, respectively.
  • 5 to 8 are graphs showing the results of elution comparison tests of the eluate of Example 3 and Comparative Example 1 in pH 1.2, pH 4.0, water, and pH 6.8, respectively.
  • FIG. 9 is a diagram showing the results of FT-IR analysis on the surface of the tablet obtained in Example 1.
  • FIG. 9 is a diagram showing the results of FT-IR analysis on the surface of the tablet obtained in Example 1.
  • Example 1 The tablets of Example 1 were prepared according to the following preparation methods with the ingredients and contents shown in Table 1 below. As Comparative Example 1, a commercially available levimid 25 mg capsule was used.
  • Composition (mg / tablet) % Composition Comparative Example 1 Lenalidomide anhydride 25.0 5.81 Reference Relevide 25mg Capsule with Lenalidomide Hemihydrate 25.87mg Anhydrous lactose 200.0 46.51 Microcrystalline cellulose 159.0 36.98 Croscarmellose sodium 12.0 2.79 Magnesium stearate 4.0 0.93 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0
  • the previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding.
  • the primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 25.0 5.81 Anhydrous lactose 200.0 46.51 Microcrystalline cellulose 159.0 36.98 Croscarmellose sodium 12.0 2.79 Magnesium stearate 2.0 0.46 Aerosil 1.0 0.23 Stearic acid 1.0 0.23 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0
  • the uncoated tablet prepared above was subjected to double coating in the same manner as the uncoated coating of Example 1.
  • Example 2 The tablets of Example 2 were prepared according to the following preparation methods with the ingredients and contents shown in Table 3 below.
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 25.0 5.81 Mannitol 200.0 46.51 Microcrystalline cellulose 159.0 36.98 Starch sodium glycolate 12.0 2.79 Calcium stearate 4.0 0.93 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0
  • microcrystalline cellulose, sodium starch glycolate, and calcium stearate were sieved into the mixture, followed by final mixing. This mixture was compressed into a rectangular punch. The hardness of uncoated tablets was 143 N.
  • the previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding.
  • the primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.
  • Uncoated tablet was prepared by the same ingredients, contents, and preparation methods as those of Uncoated Tablet of Example 2, except that the hardness of uncoated tablet was 155 N.
  • the previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding.
  • the primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.
  • Uncoated tablet was prepared by the same ingredients, contents, and preparation methods as those of Uncoated Tablet of Example 2, except that the hardness of uncoated tablet was 163 N.
  • the previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding.
  • the primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.
  • Example 1 Masson Najung Coated tablet Example 1 0.16% 0.00% Comparative Example 2 0.78% 0.00% Example 2 0.03% 0.00% Example 3 0.02% 0.00% Example 4 0.01% 0.00%
  • the wear and tear degree should be controlled to 0.2% or less, and the lower the wear and tear for the safety of the operator is preferable because of the nature of the active ingredient having teratogenicity is preferable.
  • Disintegration time (minutes) Najung Coated tablet Example 1 1 minute 28 seconds 3 minutes 21 seconds Comparative Example 1 (Comparative Treaty) - 4 minutes 38 seconds Comparative Example 2 48 seconds 2 minutes 12 seconds Example 2 3 minutes 45 seconds 4 minutes 18 seconds Example 3 4 minutes 25 seconds 4 minutes 50 seconds Example 4 4 minutes 45 seconds 5 minutes 5 seconds
  • compositions of Examples 1 to 4 all exhibited the preferred disintegration time of Comparative Example 1 (control) and 210 seconds to 350 seconds.
  • the dissolution rate was measured by liquid chromatography with the sample collected at each dissolution time, and the dissolution pattern is shown in FIGS. 1 to 4.
  • Example 2 exhibited a dissolution pattern equivalent to that of Comparative Example 1 (control) (with a dissolution rate difference of 60% and a dissolution rate within 15% of 85% of the control drug).
  • Example 3 and Comparative Example 1 with (Le Bulletin mid ® capsule preparation) Comparative dissolution profile test was performed in the same manner as in Test Example 3. The dissolution rate was measured by liquid chromatography with the liquid sample collected at each dissolution time, and the dissolution pattern is shown in FIGS. 5 to 8.
  • Example 3 showed an elution pattern on the same level as Comparative Example 1 (control).
  • test animals were fasted for 24 hours before the start of the experiment, divided into two groups, and the test substance and the comparative substance were orally administered with water from the fasting partner, respectively.
  • Blood was collected at fixed intervals up to 24 hours after the test, followed by a two-week washout period, followed by crossover testing.
  • the collected blood samples were separated from plasma and stored frozen, and the concentration was analyzed by LC / MS / MS equipment to obtain blood concentrations over time.
  • the AUC and Cmax were obtained from the data and compared with the reference drug. The results are summarized as follows.
  • FT-IR analysis was performed on the surface of the lenalidomide and the coated tablet of Example 1 and the inside of the tablet. 9 shows the results of the FT-IR analysis of the surface of the coated tablet. From this, it was confirmed that the lenalidomide component is detected inside the tablet but not on the surface.
  • the average thickness of the coating layer was measured by dividing the middle point of the tablet by observing the cross section with a scanning electron microscope (SEM) and recording an average of five thickness values.
  • Coating rate Disintegration time Average thickness of coating layer ( ⁇ m) 0% (uncoated) 2 minutes 20 seconds 0.0 5% 3 minutes 24 seconds 60.6 9% 3 minutes 54 seconds 85.7 13% 4 minutes 41 seconds 122.6 21% 8 minutes 28 seconds 154.2 32% 10 minutes 7 seconds 309.2
  • Test results showed that the disintegration time was suitable when the coating rate was 5% to 13%.
  • the coating agent content ratio was changed as shown in Table 8 to measure the disintegration rate and wear.
  • Lenalidomide content Coating content (mg) Weight ratio to lenalidomide Disintegration (sec) Wear and tear (%) 2.5mg 0.25 0.1 218 0.012% 3 1.2 234 0.000% 7.5 3 431 0.008% 25mg 2.5 0.1 257 0.050% 30 1.2 300 0.000% 75 3 496 0.019%
  • Subjects were divided into two groups, and each of the test substance and the comparative substance was taken at a fixed time interval up to 24 hours after taking the medicine with water on an empty stomach, and after 2 weeks, the group was changed to take the same medicine and collected.
  • the collected blood samples were separated from plasma and stored frozen and analyzed by concentration with LC / MS / MS equipment to obtain blood concentrations over time.
  • AUC and Cmax were obtained from the data, and the results were summarized below. It is shown in Table 9.
  • Example 1 is evaluated as having bioequivalence as compared to the formulation of Comparative Example 1.

Abstract

L'invention concerne une composition de type comprimé qui est une composition de comprimé oral comprenant du lénalidomide, permettant d'accroître la sécurité et de simplifier l'administration et la manipulation et similaires. Le médicament à l'intérieur et un manipulateur pouvant être séparés au moyen d'une couche d'enrobage, un médicament de lénalidomide ayant une tératogénicité n'est pas présent sur la couche d'enrobage.
PCT/KR2019/004473 2018-04-13 2019-04-12 Composition de comprimé enrobé à administration par voie orale à base de lénalidomide WO2019199133A1 (fr)

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KR20150091165A (ko) * 2012-12-07 2015-08-07 사노피 항-cd38 항체 및 레날리도마이드를 포함하는 조성물
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