WO2019199132A1 - Composition de comprimé oral de lénalidomide dans diverses quantités - Google Patents

Composition de comprimé oral de lénalidomide dans diverses quantités Download PDF

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WO2019199132A1
WO2019199132A1 PCT/KR2019/004472 KR2019004472W WO2019199132A1 WO 2019199132 A1 WO2019199132 A1 WO 2019199132A1 KR 2019004472 W KR2019004472 W KR 2019004472W WO 2019199132 A1 WO2019199132 A1 WO 2019199132A1
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Prior art keywords
lenalidomide
weight
content
oral tablet
parts
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PCT/KR2019/004472
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English (en)
Korean (ko)
Inventor
박상엽
임혜정
이사원
서민효
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주식회사 삼양바이오팜
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Priority to JP2020556301A priority Critical patent/JP2021518424A/ja
Publication of WO2019199132A1 publication Critical patent/WO2019199132A1/fr
Priority to JP2023034767A priority patent/JP2023071921A/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
    • A61K9/2072—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
    • 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
    • A61K9/28—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
    • A61K9/2886—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

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. Therefore, patients, especially older patients, may be uncomfortable to take.
  • the capsule even if taken with water, the capsule may stick to the throat or esophagus in the swallowing process. At this time, even if a large amount of water does not fall well, if the drug accidentally popped out of the pain is accompanied, and in some cases may be inflamed.
  • Revelmide ® capsules are filled in No.
  • the relatively low content of lenalidomide capsule formulations contain excipients at a relatively higher content ratio compared to the highest content of lenalidomide 25 mg capsules, and therefore, Elution patterns may not appear equally between high content lenalidomide capsule formulations.
  • a high content lenalidomide capsule formulation is prescribed, replacing it with a low content lenalidomide capsule formulation (eg, lenalidomide 25 mg capsule to lenalidomide 5 mg capsule Replacing with five, or replacing lenalidomide 25 mg capsule with lenalidomide 15 mg capsule and 10 mg capsule).
  • lenalidomide has a pH-dependent solubility, which affects solubility and absorption of the drug depending on which part of the body disintegrates. Therefore, when developing several dosage forms, it is important to have similar disintegration time and dissolution pattern of each formulation to ensure uniform drug absorption.
  • 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. Accordingly, the present invention provides a tablet composition which is equivalent in terms of efficacy and effect pharmacologically to commercially available capsule formulations, and further improves in appearance, taking and handling convenience, ease of manufacture, safety, and the like.
  • lenalidomide may be lenalidomide free base, 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 oral tablet composition comprising lenalidomide and at least one pharmaceutically acceptable carrier as an active ingredient. More specifically, it provides an oral tablet composition comprising lenalidomide, diluent, disintegrant, lubricant.
  • the active ingredient lenalidomide in the oral tablet composition according to the present invention may be present in various doses per unit dosage form, preferably 1 mg to 50 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 25 mg. May be present in dose.
  • the content ratio of the diluent, disintegrant, lubricant and coating agent is constant regardless of the dose of lenalidomide. Therefore, when administering a relatively low content of lenalidomide formulation, it is possible to increase the convenience of medication, and further, when a high content of lenalidomide formulation is prescribed, it can be easily replaced with a low content of lenalidomide formulation.
  • the diluent of the oral tablet composition may be at least one selected from 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 oral tablet composition may include 2 to 50 parts by weight of diluent, 0.05 to 10 parts by weight of disintegrant, and 0.05 to 10 parts by weight of lubricant based on 1 part by weight of lenalidomide.
  • the oral tablet composition may include 2 to 45 parts by weight of diluent, 0.2 to 1.5 parts by weight of disintegrant, and 0.1 to 3 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 thereof may be selected. More preferably, the diluent may be a mixture of two or more kinds. Most preferably a mixture of lactose and microcrystalline cellulose can be selected. Diluents may also serve as binders.
  • the diluent is, for example, 2 to 50 parts by weight, or more than 2 to less than 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. It can be used in negative amounts. 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.
  • starch cellulose
  • crosslinked polymers gums, polysaccharides, and mixtures thereof.
  • 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, May be one or more selected from the group consisting of 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 is not.
  • the lubricant may preferably be magnesium stearate, stearate
  • the lubricant is, for example, 0.05 to 10 parts by weight, or greater than 0.05 to less than 4 parts, or 0.1 to 5 parts by weight, or 0.1 to 3 parts by weight, based on 1 part by weight of lenalidomide, Or in an amount of 0.1 to 1 parts by weight. 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.
  • Oral tablet composition of the present invention preferably further comprises a coating layer.
  • Coating bases are hydrophilic polymers, for example, hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymers, polymers of acrylic acid and salts thereof, polymethacrylates, poly (butylmeth) Methacrylate, 2-dimethylaminoethyl methacrylate, methylmethacrylate) copolymers (eg Eudragit® E, Evonik), carboxymethylcellulose (sodium salt and calcium salt) , Ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low substitution degree HPC), polyvinyl pyrrolidone (PVP), vinylpyrrolidone Vinylacetate copolymers (e.g., Kollidon VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, x
  • 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 base 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 3.5 parts by weight, or 0.1 to 2.5 parts by weight based on 1 part by weight of lenalidomide. Can be. If the amount of the coating base is too small than the above-mentioned range, the whole uncoated tablet may not be covered with the coating base or the coating may be damaged during handling. On the contrary, if the amount of the coating base is too high, there may be a problem of excessive delay of the dissolution rate.
  • the coating layer When the coating layer is formed as a single layer, 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.
  • 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 double layer coating film.
  • HPMC hydroxypropylmethylcellulose
  • 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 It is possible to form a two-layer coating film having a more excellent function by forming a.
  • Each of the primary and secondary coatings may be 0.02 to 5, 0.05 to 2.5, 0.05 to 1.5, or 0.05 to 1 part by weight.
  • 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 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. It can be prepared through a step comprising the.
  • 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.
  • the tablet of the present invention comprises a first step of mixing lenalidomide and a diluent; A second step of further mixing a disintegrant and a lubricant in the mixture of the first step; And tableting the mixture of the second step.
  • the second step may further comprise adding a diluent. When two or more diluents are used, different diluents may be used for the first and second stages, respectively.
  • Granulation can be carried out in the manner of dry granules, wet granules and the like.
  • 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 is a water soluble polymer such as hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), L-HPC (low substitution degree HPC), polyvinyl pyrroli Don (PVP), vinylpyrrolidone-vinylacetate copolymer (e.g. Kollidon VA64, BASF), or sugars, sugar alcohols such as sucrose, sorbitol, maltitol, xylitol, Erythritol and the like can be dissolved in water, ethanol or a mixed solution thereof.
  • HPMC hydroxypropylmethyl cellulose
  • PVA polyvinyl alcohol
  • HPC hydroxypropyl cellulose
  • L-HPC low substitution degree HPC
  • PVP polyvinyl pyrroli Don
  • PVN vinylpyrrolidone-vinylacetate copolymer
  • sugars sugar alcohols such as sucrose, sorbitol, maltitol
  • the mixture of drug, diluent, binder, and the like is compressed using a roller compactor, and then sieved, and then mixed with the remaining ingredients by post-mixing. After tableting.
  • the ratio of drugs in the tablets is low, it may be important to ensure mixing uniformity. Therefore, careful consideration may be required to ensure uniformity from the mixing stage. Mixing of the drug and the diluent, disintegrant, glidant, etc. step by step without mixing at the same time can improve the mixing uniformity of the mixture.
  • the dosage of the drug may vary, it may be necessary to set the tablet shape, weight and size for each tablet to make it with an appropriate punch. It is preferable to make the excipient to be used the same kind about each dose, and to make the ratio which uses an excipient the same.
  • the volume of the tablet may also be proportional to the dose of lenalidomide, that is, the volume of the tablet may decrease proportionally as the dose of lenalidomide decreases.
  • the disintegration time of the uncoated tablet may be one of important factors for estimating the release time of the drug. Since the dissolution pattern of the drug should be equal even if the dose of the active ingredient is different, it is preferable that the disintegration time is satisfied for 210 to 350 seconds for all doses of tablets.
  • the dissolution test shall be carried out in accordance with Dissolution Test No. 35 of the general test method of the KP X 10 Amendment (KP X), but can be tested at 37 o C with 50 rotations / minute of the second method, and 6 tablets each.
  • KP X KP X 10 Amendment
  • HPLC HPLC
  • the dissolution pattern of the drug is equivalent even if the dose of the active ingredient is changed.
  • the tablets of the present invention can satisfy the AUC (Area under curve) and Cmax (maximum blood concentration) values within 80 to 125% compared to conventional capsule formulations in a bioequivalence test (In vivo PK test). Preferably 90 to 110%, most preferably 95% to 105%.
  • 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 present invention provides a tablet with a constant content ratio of each component in the composition irrespective of the dose of lenalidomide, thereby increasing the convenience of the medication when administering a relatively low content of lenalidomide formulation, and further, a high content of lenali If a domide formulation is prescribed it can be easily replaced with a low content lenalidomide formulation.
  • FIG. 2 shows the dissolution patterns for Comparative Examples 1 to 4.
  • Figure 3 shows the elution pattern of the combination of the comparative example for 25 mg lenalidomide.
  • 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 4.0 0.93 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0
  • Lenalidomide 25mg tablet was prepared in the same amount and component ratio as Table 1 above. Specifically, 5.0 g of lenalidomide and 40.0 g of anhydrous lactose were sieved and mixed, followed by sieving 31.8 g of microcrystalline cellulose, 2.4 g of croscarmellose sodium, and 0.8 g of magnesium stearate, followed by final mixing. This mixture was compressed into a rectangular punch with a hardness of about 153 N based on 400 mg weight per tablet.
  • the previously prepared 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.
  • the volume of the tablets obtained is about 0.31 cm 3 .
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 20.0 5.81 Anhydrous lactose 160.0 46.51 Microcrystalline cellulose 127.2 36.98 Croscarmellose sodium 9.6 2.79 Magnesium stearate 3.2 0.93 Opadry (HPMC series) 8.0 2.33 Opadry (PVA series) 16.0 4.65 Sum 344.0 100.0
  • Double coating is carried out in the same manner as the uncoated coating of Example 1.
  • the volume of the tablets obtained is about 0.25 cm 3 .
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 15.0 5.81 Anhydrous lactose 120.0 46.51 Microcrystalline cellulose 95.4 36.98 Croscarmellose sodium 7.2 2.79 Magnesium stearate 2.4 0.93 Opadry (HPMC series) 6.0 2.33 Opadry (PVA series) 12.0 4.65 Sum 258.0 100.0
  • 15 mg tablets of lenalidomide were prepared in the same content and composition ratios as in Table 3.
  • the mixture was sieved and mixed, and compressed into a rectangular punch with a hardness of about 170N.
  • Double coating is carried out in the same manner as the uncoated coating of Example 1.
  • the volume of the tablets obtained is about 0.19 cm 3 .
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 10.0 5.81 Anhydrous lactose 80.0 46.51 Microcrystalline cellulose 63.6 36.98 Croscarmellose sodium 4.6 2.79 Magnesium stearate 1.6 0.93 Opadry (HPMC series) 4.0 2.33 Opadry (PVA series) 8.0 4.65 Sum 172.0 100.0
  • Lenalidomide 10 mg tablets were prepared according to the contents and component ratios as shown in Table 4 above. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a rectangular punch with a hardness of about 140N.
  • Double coating is carried out in the same manner as the uncoated coating of Example 1.
  • the volume of the tablets obtained is about 0.16 cm 3 .
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 7.5 5.81 Anhydrous lactose 60.0 46.51 Microcrystalline cellulose 47.7 36.98 Croscarmellose sodium 3.6 2.79 Magnesium stearate 1.2 0.93 Opadry (HPMC series) 3.0 2.33 Opadry (PVA series) 6.0 4.65 Sum 129.0 100.0
  • 7.5 mg tablets of lenalidomide were prepared in the same content and composition ratios as in Table 5.
  • the mixture was sieved and mixed, and compressed into a circular punch with a hardness of about 93N.
  • Double coating is carried out in the same manner as the uncoated coating of Example 1.
  • the volume of the tablets obtained is about 0.09 cm 3 .
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 5.0 5.81 Anhydrous lactose 40.0 46.51 Microcrystalline cellulose 31.8 36.98 Croscarmellose sodium 2.4 2.79 Magnesium stearate 0.8 0.93 Opadry (HPMC series) 2.0 2.33 Opadry (PVA series) 4.0 4.65 Sum 86 100.0
  • Lenalidomide 5 mg tablets were prepared according to the contents and component ratios of Table 6. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a circular punch with a hardness of about 80N.
  • Double coating is carried out in the same manner as the uncoated coating of Example 1.
  • the volume of the tablets obtained is about 0.06 cm 3 .
  • Composition (mg / tablet) % Composition Lenalidomide anhydride 2.5 5.81 Anhydrous lactose 20.0 46.51 Microcrystalline cellulose 15.9 36.98 Croscarmellose sodium 1.2 2.79 Magnesium stearate 0.4 0.93 Opadry (HPMC series) 1.0 2.33 Opadry (PVA series) 2.0 4.65 Sum 43.0 100.0
  • Double coating is carried out in the same manner as the uncoated coating of Example 1.
  • the volume of the tablets obtained is about 0.03 cm 3 .
  • a commercially available levimid capsule was used as a comparative example as shown in Table 8 below.
  • Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Reference Relevide 25mg Capsules with Lenalidomide Hemihydrate 25.87mg Reference Relevide 15mg Capsule with Lenalidomide Hemihydrate 15.52mg Reference Relevide 10mg Capsules with Lenalidomide Hemihydrate 10.35mg Reference drug Reblimid 5mg capsule with 5.17mg of lenalidomide hemihydrate
  • Example 1 0.02% 0.00%
  • Example 2 0.02% 0.00%
  • Example 3 0.01% 0.00%
  • Example 4 0.01% 0.00%
  • Example 5 0.01% 0.00%
  • Example 6 0.01% 0.00%
  • Example 7 0.01% 0.00%
  • the formulations of Examples 1 to 7 and Comparative Example 1 have a disintegration time in a preferred range of 210 seconds to 350 seconds.
  • Test Example 3 comparative dissolution test
  • the dissolution rate was measured in 0.01M HCl solution according to the dissolution test method described in the lenalidomide section of the US FDA Dissolution method with Examples and Comparative Examples (Reblimide ® capsule formulation).
  • UV absorbance photometer (wavelength 210 nm)
  • Solvent A (% by volume) Solvent B (% by volume) 0.0 80 20 11.5 80 20 12.0 20 80 17.0 20 80 17.5 80 20 25.0 80 20
  • Solvent A 1.36 g of potassium dihydrogen phosphate dissolved in 1000 ml of water, and then filtered by adjusting the pH of the solution to 3.5 ⁇ 0.05 using orthophosphate.
  • Solvent B a solution in which methanol and acetonitrile were mixed at a ratio of 90:10 (v / v) and filtered
  • dissolution rate was compared by combining the respective Examples and Comparative Examples as shown in Table 12 so that the total amount of lenalidomide. As a result, it was observed that the variation of the combination of the examples was significantly lower than that of the comparative example (Table 12 and Figs.
  • Example 1 and Example 7 the change in the content of the formulation and the change in the impurity level were evaluated for 6 months under the accelerated conditions of 40 °C / 75% RH conditions and long-term storage conditions 25 °C / 60% RH conditions.
  • the determination of impurity levels an HPLC analysis method using the following conditions was used.
  • UV absorbance photometer (wavelength 210 nm)
  • Solvent A (% by volume)
  • Solvent B (% by volume) 0.0 90 10 15.0 90 10 40.0 45 55 52.0 45 55 53.0 90 10 60.0 90 10
  • -Solvent A A solution obtained by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 ml of water and then adjusting the pH of the solution to 3.5 ⁇ 0.05 using orthophosphate.
  • -Solvent B methanol and acetonitrile in 90:10 / v) mixed and filtered solution
  • 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. It is shown in Table 14.
  • Example 1 was evaluated for bioequivalence when compared to the formulation of the comparator.
  • the tablet quality was evaluated by varying only the content of excipients. Wear degree was evaluated according to Test Example 1, and disintegration rate was evaluated according to Test Example 2.
  • the parts by weight of each excipient are parts by weight based on 1 part by weight of lenalidomide.
  • diluent preferably 15 to 45 parts by weight
  • lubricant per 1 part by weight of lenalidomide, regardless of the content of lenalidomide per tablet
  • the amount is greater than 0.05 to less than 4 parts by weight
  • the coating agent is greater than or equal to 0.1 to less than 3 parts by weight
  • wear and tear of 0.5% or less and a disintegration time of 210 to 350 seconds are achieved to produce lenalidomide of desirable quality.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention concerne une composition de comprimé oral comprenant du lénalidomide et son procédé de préparation et, plus spécifiquement, une composition sous forme de comprimé présentant une équivalence physico-chimique avec une préparation de lénalidomide qui est préparée dans une capsule dure et assurant l'équivalence dans un test non clinique et un test de bioéquivalence ainsi que présentant ainsi des effets thérapeutiques pharmacologiques équivalents, et permettant une meilleure sécurité et une plus grande facilité d'administration et de manipulation et analogues.
PCT/KR2019/004472 2018-04-13 2019-04-12 Composition de comprimé oral de lénalidomide dans diverses quantités WO2019199132A1 (fr)

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JP2020556301A JP2021518424A (ja) 2018-04-13 2019-04-12 様々な用量のレナリドミドの経口用錠剤組成物
JP2023034767A JP2023071921A (ja) 2018-04-13 2023-03-07 様々な用量のレナリドミドの経口用錠剤組成物

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CN115825287A (zh) * 2022-12-26 2023-03-21 吉斯凯(苏州)制药有限公司 一种拉米夫定片中羧甲淀粉钠的含量测定方法

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KR20160146770A (ko) * 2014-05-01 2016-12-21 테바 파마슈티컬즈 오스트레일리아 피티와이 엘티디 레날리도마이드 또는 포말리도마이드 및 ｃｄ38 항체-감쇠 인터페론-알파 구성체의 조합, 및 이의 용도
KR20180042115A (ko) * 2016-10-14 2018-04-25 주식회사 삼양바이오팜 레날리도마이드의 경구용 정제 조성물

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US20120046315A1 (en) * 2008-11-14 2012-02-23 Katrin Rimkus Intermediate and oral administrative formats containing lenalidomide
KR20150091165A (ko) * 2012-12-07 2015-08-07 사노피 항-cd38 항체 및 레날리도마이드를 포함하는 조성물
KR20160146770A (ko) * 2014-05-01 2016-12-21 테바 파마슈티컬즈 오스트레일리아 피티와이 엘티디 레날리도마이드 또는 포말리도마이드 및 ｃｄ38 항체-감쇠 인터페론-알파 구성체의 조합, 및 이의 용도
CN105534981A (zh) * 2016-03-04 2016-05-04 四川美大康华康药业有限公司 一种来那度胺组合物片剂及其制备方法
KR20180042115A (ko) * 2016-10-14 2018-04-25 주식회사 삼양바이오팜 레날리도마이드의 경구용 정제 조성물

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115825287A (zh) * 2022-12-26 2023-03-21 吉斯凯(苏州)制药有限公司 一种拉米夫定片中羧甲淀粉钠的含量测定方法
CN115825287B (zh) * 2022-12-26 2023-09-08 吉斯凯(苏州)制药有限公司 一种拉米夫定片中羧甲淀粉钠的含量测定方法

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JP2021518424A (ja) 2021-08-02
KR20190120092A (ko) 2019-10-23
KR102286497B1 (ko) 2021-08-05

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