Oral tablet composition of lenalidomide

Abstract

The present invention relates to an oral tablet composition comprising lenalidomide and a method for preparing the same, and more particularly, to a composition in the form of a tablet exhibiting physicochemical equivalence with a lenalidomide formulation prepared as a hard capsule, and a method for preparing the same, and to a method for preparing the same. The pharmaceutical composition exhibits an equivalent pharmacological therapeutic effect by ensuring equivalence even in non-clinical tests and bioequivalence tests, and is further improved in ease of administration, handling, safety, and the like.

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of September 11, 2017, application number 201780063692.6 and invention name “Oral tablet composition of lenalidomide”. This application claims the priority of KR10-2016-0133746 (October 14, 2016) and KR 10-2017-0113112 (September 5, 2017). Technical Field

[0002] The present invention relates to an oral tablet composition containing lenalidomide and a method for preparing the same, and more particularly, to a composition in tablet form and a method for preparing the same, wherein the composition in tablet form shows physicochemical equivalence with a lenalidomide preparation prepared as a hard capsule, and also ensures equivalence in non-clinical trials and bioequivalence tests and shows equivalent pharmacological therapeutic effects, and further improves the convenience of administration, handling, safety, etc. Background Art

[0003] Multiple myeloma is a blood cancer caused by abnormal differentiation and proliferation of plasma cells. This abnormal plasma cell is called myeloma cell. Myeloma cells can produce tumors, melt bones and cause pain and are prone to fracture, and invade the bone marrow to reduce the number of white blood cells, red blood cells, and platelets, thereby increasing the risk of anemia, infection, and bleeding. In addition, myeloma cells produce M protein, which is an abnormal immunoglobulin, so that the concentration of blood becomes thicker and causes blood hyperviscosity syndrome or damages the kidneys. Multiple myeloma mainly occurs in black men, men, and elderly people over 65 years old, and the incidence rate in South Korea has recently increased. The main therapeutic agents for this multiple myeloma are bortezomib, thalidomide, and lenalidomide. Bortezomib, an injection, maintains a stable market demand and is growing. As for oral agents, lenalidomide replaces the existing position of thalidomide and is growing rapidly in the market.

[0004] Lenalidomide is the next generation drug of thalidomide, and it shows a more excellent therapeutic effect due to its more powerful cancer cell killing and immune regulation. It is known that in the existing treatment, when lenalidomide and dexamethasone are used together for treatment in the case of recurrence or difficult treatment, the disease-free survival time is 13.4 months and the total survival time is 38 months, which is very effective. In terms of side effects, it is known that there are almost no problems such as peripheral neuropathy that occur in the existing thalidomide, but the side effect of bone marrow suppression becomes slightly more serious, but there is no big problem with the administration of white blood cell promoting factors, etc. Due to this advantage, its market demand has grown sharply.

[0005] Celgene has developed an oral capsule formulation of lenalidomide and commercialized it in doses of 25 mg, 20 mg, 15 mg, 10 mg, 7.5 mg, 5 mg, and 2.5 mg. The product name marketed in Korea is Capsules comprising lenalidomide hemihydrate. In addition, due to the hard capsule formulation The 25mg, 20mg, 15mg, and 10mg dosage forms of the capsule are all filled in a No. 0 capsule, and the major axis is about 2.17cm, which is quite long and large in size. Therefore, it is somewhat inconvenient for patients, especially for elderly patients, to take the capsule. Moreover, as for the capsule, even if it is taken with water, there are cases where the capsule sticks to the throat or esophagus and gets stuck during the swallowing process. At this time, even if a large amount of water is drunk, the capsule is not easy to fall off. If the drug is released accidentally, it will be accompanied by pain and may cause inflammation depending on the situation. Therefore, when developing in the form of a tablet with a short length and small size, not only can the problems caused by the large size be solved, but also the problems caused by the inconvenient capsule can be solved, thereby improving the convenience of taking for patients and overcoming the shortcomings of the capsule.

[0006] Thalidomide was used as an anti-nausea agent for pregnant women from the second half of the 1950s to the 1960s, but due to undiscovered teratogenic side effects, tens of thousands of deformed babies were born worldwide. Like thalidomide, lenalidomide also has teratogenic side effects, so it is prohibited for pregnant women, women of childbearing age or women who may become pregnant to take and handle it. In order to prevent such side effects, when preparing capsules, thick gelatin capsules wrap the drug, so it can be considered that shielding is indeed achieved. However, in the case of tablets (especially uncoated tablets), the drug is directly present on the surface of the tablet, so it is possible to be exposed to handlers who are not related to the user, and when it is divided along the score line and taken, or when it is broken due to weak hardness during the process of taking it out of the PTP package, or when it is not brittle and produces debris, the drug may be exposed to the handler and the people around. In addition, when the tablet is a coated tablet, the drug may be exposed to the handler and the surrounding people in some cases where the drug is not coated in sufficient amount due to a low coating rate, or the drug continues to seep out during the coating process, resulting in the drug being present on the surface of the coating layer.

[0007] Therefore, there is a need for a coated tablet that is different from the conventional case in that a sufficient amount of coating agent is used to achieve complete coating, so that not only the entire tablet is protected by a coating of a certain thickness or more, but also the drug can be completely shielded from handlers and the like.

[0008] At the same time, it is necessary to design and prepare the capsule in a manner that has the same drug release rate and release pattern as the capsule that has been clinically verified and commercially available. To this end, it is necessary to compress the tablets at the optimal tableting pressure to have a hardness in an appropriate range, select a suitable coating agent, and design the capsule in a manner that has an appropriate coating rate in order to obtain a similar dissolution pattern. It is necessary not only to ensure in vitro physicochemical equivalence in dissolution solutions of various pH values, but also to show equivalence in non-clinical trials using experimental animals and in vivo pharmacokinetic tests using bioequivalence tests on subjects. Summary of the invention

[0009] Technical issues to be solved

[0010] The object of the present invention is to provide a tablet composition and a method for preparing the same, wherein the tablet composition is to change the dosage form of the lenalidomide preparation sold in the market as a hard capsule into a tablet, and to make the tablet short in length and small in volume, so that it is easy to take, and the selection of the coating agent and the appropriate coating thickness can completely wrap the entire tablet with a certain thickness or more, so that the internal drug can be separated from the handler, and the drug can be prevented from leaking out during coating. In addition, the object of the present invention is to provide a tablet composition and a method for preparing the same dissolution pattern in the tablet as in the capsule, so that the physicochemical equivalence is not only shown in the comparative dissolution test, but also in the in vivo test of the experimental animal and the bioequivalence test. Therefore, the present invention provides a tablet composition and a method for preparing the same, which has equivalent pharmacological efficacy and effect to commercially available capsule preparations, and the appearance, convenience of taking and handling, ease of preparation, safety, etc. are further improved and improved.

[0011] Technical Solution

[0012] Definition of terms

[0013] Unless expressly stated otherwise, several terms used throughout this specification may be defined as follows.

[0014] Unless otherwise specifically mentioned throughout the specification, “comprising” or “including” means including any constituent elements (or components) without special limitation, and should not be interpreted as excluding the addition of other constituent elements (or components).

[0015] In addition, "lenalidomide" can be a lenalidomide base (a basic drug without additional salts), or a pharmaceutically acceptable salt or an isomer thereof, or a mixture thereof. In addition, various hydrates can be formed in various cases, and various crystalline forms can also be formed in various cases. For example, various hydrates or various solvates such as lenalidomide anhydride, hemihydrate, monohydrate, dihydrate and trihydrate, or mixtures thereof, can be used.

[0016] Furthermore, the expression "micronized" means powdered in a very small size, for example, powdered in a size with an average diameter of micrometers or nanometers.

[0017] In order to solve the above technical problems, the present invention provides an oral tablet composition, which comprises lenalidomide as an active ingredient and one or more pharmaceutically acceptable carriers. In more detail, the present invention provides an oral tablet composition in which the surface of an uncoated tablet is coated with a coating agent.

[0018] In a specific example, the oral tablet composition may include: lenalidomide as an active ingredient; a diluent selected from sugars, sugar alcohols, cellulose, starch, inorganic salts and mixtures thereof; a disintegrant selected from swelling disintegrants, wetting disintegrants and mixtures thereof; and a lubricant selected from soluble lubricants, insoluble lubricants and mixtures thereof. The oral tablet composition may have an area under the curve (AUC) of 140 to 7100 ng·hr / mL, C max It may be 42 to 2100 ng / mL, but is not limited thereto.

[0019] In a specific example, when the test is performed by a paddle method at 50 rpm in 900 mL of a dissolution solution with a pH of 1.2, the dissolution rate of the oral tablet composition in 2.5 minutes may be 1 to 50%, but is not limited thereto.

[0020] In a specific example, when the paddle method is used to test in 900 mL of a dissolution solution with a pH of 1.2 at 50 rpm, the dissolution rate of the oral tablet composition in 5 minutes may be 10 to 95%, but the present invention is not limited thereto.

[0021] In a specific example, the disintegration time of the oral tablet composition in a buffer solution with a pH of 1.2 may be 1 to 20 minutes, but is not limited thereto.

[0022] In a specific example, the oral tablet composition may have a hardness of 10 to 300 N and a friability of less than 2%, but is not limited thereto.

[0023] In a specific example, the coating layer of the oral tablet composition may be more than a single layer, and / or the total thickness of the coating film may be more than 1 μm, but is not limited thereto.

[0024] In a specific example, the oral tablet composition may include 0.5 to 200 parts by weight of a diluent, 0.02 to 10 parts by weight of a disintegrant and / or 0.005 to 3.5 parts by weight of a lubricant relative to 1 part by weight of lenalidomide, but is not limited thereto.

[0025] In one specific example, the volume of the tablet may be smaller than that of a size 0 capsule, but is not limited thereto.

[0026] In addition, the present invention provides a method for preparing the oral tablet composition of the present invention, which comprises the following steps: mixing lenalidomide as an active ingredient and one or more pharmaceutically acceptable carriers, and tableting the mixture to prepare a tablet before coating (uncoated tablet), and then coating the surface of the uncoated tablet with a coating agent.

[0027] In the present invention, lenalidomide can be used in a micronized form. The average particle size (×50) of the micronized lenalidomide can be, for example, less than 100 μm, preferably less than 50 μm, more preferably less than 30 μm, and further preferably less than 15 μm. In addition, the average particle size (×50) of the micronized lenalidomide can be, for example, 0.1 μm or more, preferably 0.2 μm or more, more preferably 0.5 μm or more, and further preferably 1 μm or more. When lenalidomide that deviates from the aforementioned average particle size range is used, the dissolution rate will be reduced or the process will be hindered. The average particle size (×50) refers to the particle size equivalent to 50% of the weight percentage in the particle size distribution curve, for example, which can be measured using a light diffraction particle size measuring instrument.

[0028] In the tablet composition of the present invention, the pharmaceutically acceptable carrier contained in the uncoated tablet may be, for example, one or more selected from the group consisting of a diluent, a disintegrant and a lubricant.

[0029] In one embodiment, the diluent can be selected from sugar, sugar alcohol, cellulose, starch, inorganic salt and mixtures thereof.

[0030] In one embodiment, the disintegrant can be selected from a swelling disintegrant, a wetting disintegrant and a mixture thereof.

[0031] The sugar is a concept including all monosaccharides, polysaccharides and their pharmaceutically acceptable derivatives, starch is a concept including all starches and their pharmaceutically acceptable derivatives, and cellulose is a concept including all celluloses and their pharmaceutically acceptable derivatives, which are well known and available to those skilled in the art and are not particularly limited to specific components.

[0032] The diluent can be, for example, selected from lactose (anhydride or hydrate, such as 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, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrates, dextrin and a mixture thereof, but is not limited thereto. Preferably, lactose, microcrystalline cellulose, mannitol, starch or a mixture thereof can be selected. Most preferably, a mixture of lactose and microcrystalline cellulose can be selected. There can also be a situation where the diluent acts as a binder at the same time.

[0033] In a specific example, based on 1 part by weight of lenalidomide, the diluent can be used in an amount of, for example, 0.5 to 200 parts by weight, preferably 1 to 100 parts by weight, more preferably 2 to 50 parts by weight, further preferably 3 to 30 parts by weight, and further preferably 4 to 20 parts by weight. When the amount of the diluent used is too small compared to the aforementioned range, it is difficult to prepare the tablets. On the other hand, when the amount of the diluent used is too large compared to the aforementioned range, the concentration of the drug is reduced, so there is a problem in ensuring the uniformity of the content during preparation.

[0034] The disintegrant can be selected from starch, cellulose, cross-linked polymers, gums, polysaccharides and mixtures thereof, for example, cross-linked sodium carboxymethyl cellulose (croscarmellose sodium, CrosCMC-Na), carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone (cross-linked polyvinyl pyrrolidone), low-substituted hydroxypropyl cellulose (L-HPC), starch (wheat, rice, corn or potato starch), sodium carboxymethyl starch, sodium glycolate starch, alginic acid, sodium carboxymethyl cellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch and mixtures thereof. Preferably, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, L-HPC, sodium glycolate starch can be selected from one or more, but are not limited thereto. Preferably, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, L-HPC, sodium glycolate starch can be selected from one or more. More preferably, cross-linked sodium carboxymethyl cellulose can be selected from one or more.

[0035] In a specific example, based on 1 part by weight of lenalidomide, the disintegrant can be used, for example, in an amount of 0.02 to 10 parts by weight, preferably 0.05 to 5 parts by weight, more preferably 0.1 to 2.5 parts by weight, further preferably 0.15 to 1.5 parts by weight, and further preferably 0.2 to 1 part by weight. When the amount of the disintegrant used is less than the aforementioned range, there is a problem of delayed dissolution rate due to delayed disintegration rate. On the other hand, when the amount of the disintegrant used is more than the aforementioned range, there are problems in productivity such as tableting obstacles and coating obstacles.

[0036] In one embodiment, the lubricant can be selected from a soluble lubricant, an insoluble lubricant, and a mixture thereof.

[0037] The lubricant is used with the concept including lubricant (lubricant), antiadherent (antiadherent), glidant (glidant), for example, it can be selected from magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, starch (wheat, rice, corn or potato starch), talcum, highly dispersed (colloidal) silicon dioxide, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, solidified vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, triacetin, sucrose dodecanoate and their mixture in one or more, but is not limited to this. The lubricant can preferably be magnesium stearate, stearic acid, highly dispersed (colloidal) silicon dioxide. More preferably, it can be magnesium stearate.

[0038] In a specific example, based on 1 part by weight of lenalidomide, the lubricant can be used, for example, in an amount of 0.005 to 3.5 parts by weight, preferably 0.015 to 2.0 parts by weight, more preferably 0.03 to 0.75 parts by weight, further preferably 0.05 to 0.5 parts by weight, and further preferably 0.1 to 0.35 parts by weight. When the amount of lubricant used is too small compared to the aforementioned range, there are problems with productivity such as tableting obstacles. On the other hand, when the amount of lubricant used is too large compared to the aforementioned range, there are problems with dissolution delay or productivity.

[0039] The coating agent is a hydrophilic polymer, for example, it can be selected from hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyethylene glycol-polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (for example, Eudragit (registered trademark) E, Evonik), carboxymethyl cellulose (sodium salt and calcium salt), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), polyvinyl pyrrolidone (PVP), vinyl pyrrolidone-vinyl acetate copolymer (for example, Kollidon (registered trademark) VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum and mixtures thereof. At least one of them, but not limited thereto. Preferably, the coating agent may be hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyethylene glycol-polyvinyl alcohol graft copolymer, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (eg, Eudragit (registered trademark) E, Evonik Company).

[0040] In a specific example, based on 100 parts by weight of the uncoated tablet, the coating agent can be used in an amount of, for example, 1 to 30 parts by weight, preferably 2 to 25 parts by weight, more preferably 3 to 20 parts by weight, further preferably 4 to 15 parts by weight, further preferably 5 to 15 parts by weight, and most preferably 6 to 15 parts by weight. When the amount of the hydrophilic polymer used is less than the aforementioned range, the entire uncoated tablet cannot be covered by the coating agent, and when the amount of the hydrophilic polymer used is greater than the aforementioned range, the dissolution rate is excessively delayed.

[0041] After the cross section of the tablet is cut, the thickness of the coating layer can be measured by a scanning electron microscope (SEM) or the like. At this time, the entire surface of the tablet is preferably coated uniformly with a certain thickness, and more than 5 tablets can be measured and the average value can be taken to confirm the average thickness. When the cross section is observed, the average thickness of the coating layer can be 1 μm or more and 300 μm or less, more preferably 3 μm or more and 275 μm or less, further preferably 5 μm or more and 250 μm or less, further preferably 7 μm or more and 225 μm or less, further preferably 10 μm or more and 200 μm or less, further preferably 15 μm or more and 180 μm or less, and most preferably 20 μm or more and 150 μm or less. When the average thickness of the coating layer is thinner than the aforementioned range, it is difficult to coat the entire tablet uniformly, and dust will be generated during processing. When the average thickness of the coating layer is thicker than the aforementioned range, the desired purpose cannot be achieved due to reasons such as delayed dissolution and excessive process time.

[0042] When the coating layer is formed as a single layer, one or more coating agents can be mixed and used, and the coating is performed in sufficient amount, so that the coating agent can form a thin film on the entire tablet and be protected. The coating layer is more preferably double-layered or more. For example, when coating with double layers or more, the coating agent of each layer can be different, so that the exposure of the drug can be shielded, moisture can be blocked, oxidation can be prevented, etc. can be respectively played. In a specific example, it is preferred that hydroxypropyl methylcellulose (HPMC) can be used for a coating to form a film that blocks the drug, and polyethylene glycol-polyvinyl alcohol graft copolymer is used for a secondary coating in sequence to form a double-layer coating film. In a specific example, it is preferred that hydroxypropyl methylcellulose (HPMC) can be used for a coating to form a film that blocks the drug, and polyvinyl alcohol (PVA) is used for a secondary coating in sequence to form a moisture-proof coating film, so that a double-layer coating film with more excellent functions can be formed, but it is not limited thereto.

[0043] In order to prevent the drug from being dissolved by the coating solution instantly and seeping out during coating and being included in the coating layer when forming the coating layer, it is necessary to carefully select the type and component of the solvent used when preparing the coating solution. Moreover, with regard to coating conditions, it is also necessary to establish conditions that can be quickly dried after coating the uncoated tablets with the coating solution. The coating solvent can use ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, dichloromethane, isopropanol, water, etc. or their mixed solvents, but is not limited to this. Preferably, ethanol, water or their mixtures can be used. More preferably, a mixture of ethanol and water or a mixture of dichloromethane and ethanol or a mixture of isopropanol and ethanol can be used as a coating solvent for a single coating, followed by water as a coating solvent for a secondary coating.

[0044] In the process of preparing coated tablets as described above, various biologically inert ingredients can be further used for additional purposes such as coating efficiency, drug stability, appearance, color, protection, retention, binding, performance improvement, and manufacturing process improvement.

[0045] In a specific embodiment, the biologically inert component that may be further included in the coating layer may be one or more selected from plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, defoaming agents, paraffin and wax.

[0046] The plasticizer that can be further included in the coating layer can be, for example, selected from triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, acetyl triethyl citrate, acetyl triethyl citrate, propylene glycol, triacetin, polyethylene glycol, cetyl alcohol, stearyl alcohol and cetyl stearyl alcohol. One or more, but not limited thereto. When the dry weight of all polymers used in each coating layer is 100% by weight, the plasticizer can be included in an amount of 100% by weight or less (e.g., 0 to 100% by weight or 0.1 to 100% by weight), specifically 50% by weight or less (e.g., 0 to 50% by weight or 0.1 to 50% by weight), and more specifically 30% by weight or less (e.g., 0 to 30% by weight or 0.1 to 30% by weight), but not limited thereto.

[0047] The lubricant that can be further included in the coating layer can be, for example, one or more selected from magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed (colloidal) silicon dioxide, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof, but is not limited thereto. When the dry weight of all polymers used in each coating layer is 100% by weight, the lubricant can be included in an amount of 100% by weight or less (e.g., 0 to 100% by weight or 0.1 to 100% by weight), but is not limited thereto.

[0048] In a specific example, the tablet of the present invention can be prepared by weighing the raw material components, and then (optionally) granulating, mixing, tableting and coating in this order. Granulation can be performed by dry granulation, wet granulation or the like.

[0049] In a specific example, when granulation is performed by wet granulation, a binder solution is prepared, and the mixture mixed with the medicine by adding a diluent, etc. is formed into particles together with the binder solution, and then sieved and dried to obtain particles. Afterwards, tableting is performed after the remaining components are mixed by subsequent mixing. The binder solution can be by water-soluble polymers, such as hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), polyvinyl pyrrolidone (PVP), vinyl pyrrolidone-vinyl acetate copolymer (for example, Kollidon (registered trademark) VA64, BASF company), or sugars, sugar alcohols, such as white sugar, sorbitol, maltitol, xylitol and erythritol, etc. are dissolved in water or ethanol or their mixed solutions to use.

[0050] In a specific example, when granulation is performed by dry granulation, a mixture of a mixed drug, a diluent, a binder, etc. is compressed using a roller compactor or the like, and then sieved, and then the remaining ingredients are mixed by post-mixing and tableted.

[0051] When direct tableting is performed without granulation, the tablets are mixed and compressed immediately after weighing, so the process is simple. Since the drug itself has teratogenic side effects, the operator needs to wear protective equipment during the preparation process, and pregnant women or people who may be pregnant are excluded as much as possible. Moreover, direct tableting is most preferred to minimize the operator's exposure to the drug. However, the present application is not limited thereto.

[0052] When the drug content in the tablet is low, it is important to ensure uniformity of the mixture. Therefore, special care may be required to ensure uniformity of the mixture from the mixing step on. The uniformity of the mixture can be improved when the drug is mixed with the diluent, disintegrant, lubricant, etc. in separate steps rather than adding them all at once.

[0053] For example, in one embodiment, a portion of the diluent and the drug may be added and mixed, and then a further portion of the diluent may be added and mixed, and the remaining amount of the diluent may be added and mixed again, and then a disintegrant and a lubricant may be added separately in steps to prepare the mixture for final tableting.

[0054] For example, in another embodiment, the disintegrant and the drug may be mixed first, then a portion of the diluent may be added and further mixed, a portion of the diluent may be added again and further mixed, and finally a lubricant may be added to prepare the mixture for final tableting.

[0055] Since the dosage of the drug will be different, it is necessary to set the shape, weight and specifications of the tablet for each tablet and make it with an appropriate punch. For each dose, the same type of excipient can be used. In addition, for each dose, the excipient can be used in different or the same ratio. Preferably, in order to achieve acceptability and ease, the same excipient can be used for all doses and designed to the same ratio so that the dose of lenalidomide and the dose of each excipient are proportional to the total weight of the tablet.

[0056] The shape of the tablet can be various shapes such as rectangle, oval, rhombus, circle and polygon (for example, triangle, quadrilateral, pentagon, hexagon, etc.). The shape of the tablet can be determined by comprehensive judgment based on the convenience of taking by the patient, the ease of manufacturing and management of the punch, the ease of preparation related to tablet compression, coating, packaging and handling of the tablet, whether the dissolution mode can be adjusted, the ease of adjustment of physical property related variables such as tablet hardness, friability, disintegration, etc. Moreover, the appropriate shape can be selected according to each dose.

[0057] The total weight of the uncoated tablets is preferably such that the average weight of the tablets does not exceed 1100 mg, more preferably does not exceed 880 mg, further preferably does not exceed 660 mg, further preferably does not exceed 550 mg, and most preferably does not exceed 440 mg.

[0058] The lower limit of the average value of the total weight of the uncoated tablets is preferably 5 mg or more, more preferably 10 mg or more, further preferably 20 mg or more, further preferably 30 mg or more, and most preferably 40 mg or more.

[0059] The length of the longest axis (diameter in the case of a round shape) of the uncoated tablet is preferably less than the length of a size 0 capsule of 2.17 cm, more preferably 2 cm or less, further preferably 1.8 cm or less, and further preferably 1.6 cm or less.

[0060] The length of the shortest axis (diameter in the case of a round shape) of the uncoated tablet is preferably 1 mm or more, more preferably 2 mm or more, further preferably 3 mm or more, and further preferably 4 mm or more.

[0061] The hardness of the uncoated tablet may vary depending on the shape, weight and size of the tablet, but the suitable hardness of the uncoated tablet is a maximum average hardness of 300N and a minimum average hardness of 10N. Preferably, the suitable hardness of the uncoated tablet is a maximum average hardness of 250N and a minimum average hardness of 20N. More preferably, the suitable hardness of the uncoated tablet is a maximum average hardness of 230N and a minimum average hardness of 30N. Most preferably, the suitable hardness of the uncoated tablet is a maximum average hardness of 210N and a minimum average hardness of 40N. When the hardness of the uncoated tablet is too high than the aforementioned range, the release of the drug may be delayed due to the delay in disintegration. On the other hand, when the hardness of the uncoated tablet is too low than the aforementioned range, the tablet may be fragile and may be broken during coating, transportation, storage, packaging, and administration.

[0062] The hardness is a value measured along the long axis when measuring a rectangular tablet or the like, and is an average hardness of six randomly selected tablets.

[0063] In the present invention, the friability of the uncoated tablet may be within 2%. More preferably, the friability may be within 1%. Further preferably, the friability may be within 0.5%.

[0064] In the present invention, the disintegration time of the uncoated tablet can be one of the important factors for estimating the release time of the drug. Therefore, the desired disintegration time can be obtained only when the tablet is compressed with appropriate pressure and has appropriate hardness in the tablet compression process, which can become a factor determining the dissolution pattern of the tablet together with the coating amount of the coating agent in the coating process. The dissolution pattern affects the absorption in the body, so it is important to adjust the appropriate disintegration time by making the tablet have appropriate hardness through appropriate tablet compression pressure. Moreover, even if the dosage is different, the dissolution pattern of the drug should be the same, so the disintegration time should be the same for tablets of all dosages.

[0065] The disintegration time can be measured according to the disintegration test method No. 17 in the conventional test method of the Korean Pharmacopoeia 10th edition (KP X), and can be measured in a buffer solution with a pH of 1.2 as the first test solution, and the disintegration time of 6 tablets is measured and the average value is obtained. In a specific example, the average disintegration time of the uncoated tablet is 1 to 20 minutes, preferably between 1 minute 30 seconds and 15 minutes, more preferably 2 to 10 minutes, further preferably 2 minutes 30 seconds to 8 minutes, further preferably 3 to 6 minutes, and most preferably 3 minutes 30 seconds to 5 minutes 30 seconds. In the present invention, the coating layer formed on the uncoated tablet can be a single layer or two or more layers, and more preferably two or more layers.

[0066] The solvent used for coating can be various solvents. For example, in order to coat HPMC, the ratio of anhydrous ethanol to water can be set to 2:8 to 8:2, or water can be used alone. In addition, for example, in order to coat PVA, water can be used alone as a solvent. These solvents will all evaporate during the coating process, so they will not remain in the final product in essence.

[0067] In order to improve the physical properties, preparation, compressibility, appearance, taste and / or stability of the tablet, the tablet can be further mixed with various additives. Such additives can include, for example, stabilizers, solubilizers, sweeteners, flavor enhancers, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, flavor enhancers, adhesives, suspending agents, curing agents, antioxidants, brighteners, flavoring agents, flavoring agents, pigments, coating agents, wetting agents, moisture regulators, fillers, defoamers, cooling agents, chewing agents, antistatic agents, colorants, sugar coatings, isotonic agents, softeners, emulsifiers, adhesives, tackifiers, foaming agents, pH regulators, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, cosolvents, solvents and fluidizers, but are not limited thereto, as long as they are pharmaceutically acceptable, any additive can be used. The coated tablets of the present invention can show the same dissolution rate as the comparative preparation prepared into capsules in the dissolution test. In particular, under acidic conditions such as a buffer solution with a pH of 1.2, the initial dissolution rate at 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, etc. is important.

[0068] The dissolution test can be conducted according to the dissolution test method No. 35 in the conventional test method of the Korean Pharmacopoeia 10th edition (KP X), and can be tested at 37°C at 50 rpm by the paddle method of the second method. The 6 tablets are tested separately, and the dissolution rate of the drug at each time point is measured by HPLC, thereby obtaining the average dissolution rate at each time point.

[0069] The average dissolution rate of lenalidomide at each time point of the coated tablet of the present invention may be, for example, 1 to 50% at 2.5 minutes, 10 to 95% (or 20 to 90%) at 5 minutes, 40% to 105% at 10 minutes, and 70% to 105% at 15 minutes.

[0070] In a specific example, when the paddle method is used to test at 50 rpm in 900 mL of a dissolution solution having a pH of 1.2, the average dissolution rate of the coated tablet of the present invention at 2.5 minutes is preferably 2 to 48%, more preferably 5 to 45%, and further preferably 10 to 40%.

[0071] In a specific example, when the paddle method is used in 900 mL of a dissolution solution with a pH of 1.2 at 50 rpm, the dissolution rate of the coated tablet of the present invention in 5 minutes is preferably 20 to 90%, more preferably 30 to 87.5%, further preferably 40 to 85%, and further preferably 50 to 80%. In a specific example, when the paddle method is used in 900 mL of a dissolution solution with a pH of 1.2 at 50 rpm, the dissolution rate of the coated tablet of the present invention in 10 minutes is preferably 50% or more, more preferably 60% or more, further preferably 70% or more, and further preferably 80% or more.

[0072] In a specific example, when the test is conducted by a paddle method at 50 rpm in 900 mL of an eluent having a pH of 1.2, the dissolution rate of the coated tablet of the present invention at 15 minutes is preferably 75% or more, more preferably 77.5% or more, further preferably 80% or more, and even more preferably 85% or more.

[0073] In the bioequivalence test (in vivo PK test), the AUC (area under the curve) and C of the coated tablets of the present invention were significantly higher than those of the capsule formulations. max The value of (maximum blood concentration) may be within a range of 80 to 125%, preferably 90 to 110%, and most preferably 95 to 105%.

[0074] In a bioequivalence study conducted on healthy adult volunteers (males), the pharmacokinetic parameter AUC (area under the curve) can be 140 to 7100 ng·hr / mL, preferably 280 to 5700 ng·hr / mL, more preferably 425 to 4250 ng·hr / mL, further preferably 570 to 2800 ng·hr / mL, further preferably 700 to 2100 ng·hr / mL, and most preferably 1000 to 1800 ng·hr / mL.

[0075] In a bioequivalence study conducted on healthy adult volunteers (males), the pharmacokinetic parameter C max It can be 42 to 2100 ng / mL, preferably 84 to 1680 ng / mL, more preferably 120 to 1260 ng / mL, further preferably 160 to 840 ng / mL, further preferably 210 to 630 ng / mL, and most preferably 310 to 525 ng / mL. The tablet composition of the present invention as described above can be used for the same purpose as the existing lenalidomide preparation, for example, it can be used to treat and / or prevent multiple myeloma, myelodysplastic syndrome, etc.

[0076] Beneficial Effects

[0077] The tablet composition containing lenalidomide disclosed in the present invention shows physicochemical equivalence with the lenalidomide preparation prepared into hard capsules, and also ensures equivalence in non-clinical trials and bioequivalence tests and shows equivalent pharmacological therapeutic effects. In addition, the convenience of administration, handling, safety, etc. are further improved. Therefore, it is expected that the composition can be effectively used as a composition in tablet form. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 The tablet of Example 1 and the capsule of Comparative Example 1 in the dissolution solution with a pH of 1.2 are shown. Figure 2 is a graph of the comparative dissolution test results.

[0079] Figure 2 : is a graph showing the results of a comparative dissolution test of the tablet of Example 1 and the capsule preparation of Comparative Example 1 in a dissolution solution having a pH of 4.0.

[0080] Figure 3 This is a graph showing the results of a comparative dissolution test of the tablet of Example 1 and the capsule preparation of Comparative Example 1 in a dissolution solution having a pH of 6.8.

[0081] Figure 4 It is a graph showing the results of a comparative dissolution test of the tablet of Example 1 and the capsule preparation of Comparative Example 1 in water. DETAILED DESCRIPTION

[0082] In order to help understand the present invention, preferred embodiments are provided below. However, the following embodiments are only used to illustrate the present invention, and the present invention is not limited thereto.

[0083] Example 1

[0084] <Preparation of Uncoated Tablets>

[0085] 5.0 g of lenalidomide and 40.0 g of anhydrous lactose were sieved and mixed, and then 31.8 g of microcrystalline cellulose, 2.4 g of cross-linked carboxymethyl cellulose sodium and 0.8 g of magnesium stearate were sieved and added thereto, and then finally mixed. The mixture was tableted with a rectangular punch based on a weight of 400 mg per tablet. The hardness of the uncoated tablet was about 155N.

[0086] <Coating of Uncoated Tablets>

[0087] The uncoated tablets prepared were double coated with two coating agents, wherein the two coating agents were 7.5% (w / w) in total relative to the total weight of 100% (w / w) of the uncoated tablets. A primary coating (2.5% (w / w)) was performed with an Opadry base having HPMC as a main component, and then a secondary coating (5% (w / w)) was performed with an Opadry base having PVA as a main component. The operating conditions for the primary coating are shown in Table 1 below, and the operating conditions for the secondary coating are shown in Table 2 below.

[0088] [Table 1]

[0089]

[0090] [Table 2]

[0091]

[0092]

[0093] Example 2

[0094] <Preparation of Uncoated Tablets>

[0095] 5.0 g of lenalidomide and 40.0 g of anhydrous lactose were sieved and mixed, and then 31.8 g of microcrystalline cellulose, 2.4 g of cross-linked carboxymethyl cellulose sodium, 0.4 g of magnesium stearate, 0.2 g of aerosil and 0.2 g of stearic acid were sieved and added thereto, and then finally mixed. The mixture was tableted with a rectangular punch based on a weight of 400 mg per tablet. The hardness of the uncoated tablet was 150N.

[0096] <Coating of Uncoated Tablets>

[0097] The uncoated tablets prepared were double coated with two coating agents, wherein the two coating agents were 6% (w / w) in total relative to the total weight of 100% (w / w) of the uncoated tablets. The Opadry base containing HPMC as the main component was used for the first coating (2% (w / w)), and then the Opadry base containing polyethylene glycol-polyvinyl alcohol graft copolymer as the main component was used for the second coating (4% (w / w)).

[0098] Example 3

[0099] <Preparation of Uncoated Tablets>

[0100] 5.0 g of lenalidomide and 40.0 g of spray-dried mannitol were sieved and mixed, and then 31.8 g of microcrystalline cellulose, 2.4 g of sodium starch glycolate and 0.8 g of calcium stearate were sieved and added thereto, and then finally mixed. The mixture was tableted with a rectangular punch based on a weight of 400 mg per tablet. The hardness of the uncoated tablet was 165N.

[0101] <Coating of Uncoated Tablets>

[0102] The uncoated tablets were coated with an Opadry base containing HPMC as a main component at 5% (w / w) relative to 100% (w / w) of the total weight of the uncoated tablets.

[0103] Test Example 1: Measurement of physical properties of tablets

[0104] Friability Measurement

[0105] According to the method described in the Tablet Friability item of USP 1216, using a Pharmatest friabiltiy tester, friability of 10 tablets was measured and shown in the following Table 3 (measurement time = 4 minutes).

[0106] [Table 3]

[0107] friability Example 1 (uncoated tablets) 0.02％ Example 2 (uncoated tablets) 0.02％ Example 3 (uncoated tablets) 0.01％

[0108] Disintegration test

[0109] According to the disintegration test method of the Korean Pharmacopoeia 10th edition, Example 1 was subjected to a disintegration test in a solution of pH 1.2 with n=3, and the results are shown in Table 4 below.

[0110] [Table 4]

[0111] Disintegration time (minutes) Example 1 (uncoated tablets) 4 minutes 25 seconds Example 2 (uncoated tablets) 4 minutes 38 seconds Example 3 (uncoated tablets) 4 minutes 45 seconds

[0112] Test Example 2: Dissolution Test

[0113] Under the following conditions, with n=6, a dissolution test was conducted on Example 1, and the results are shown in Table 5 below.

[0114] [Table 5]

[0115] Dissolution rate (%) Example 1 (coated tablets) 94.1％ Example 2 (coated tablets) 92.5％ Example 3 (coated tablets) 95.4％

[0116] Test method: Paddle method of dissolution test method of Korean Pharmacopoeia

[0117] Dissolution liquid: 0.01N HCl solution

[0118] Rotation speed: 50rpm

[0119] Temperature: 37℃

[0120] Dissolution benchmark time point: 15 minutes

[0121] Analysis method: HPLC analysis

[0122] HPLC analysis conditions

[0123] Detector: Ultraviolet spectrophotometer (measurement wavelength 210nm)

[0124] Chromatographic column: C18 column with a length of 250 mm, a diameter of 4.6 mm, and a 5 μm column or an equivalent column

[0125] Flow rate: 1.0mL / min

[0126] Injection volume: 10 μL

[0127] Mobile phase: as shown in Table 6 below

[0128] [Table 6]

[0129] Time (minutes) Solvent A (volume %) Solvent B (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

[0130] Solvent A: A solution prepared by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 ml of water, adjusting the pH of the solution to 3.5±0.05 using orthophosphate, and filtering the solution.

[0131] Solvent B: A solution prepared by mixing methanol and acetonitrile at a ratio of 90:10 (v / v) and filtering the mixture.

[0132] Test Example 3: Comparative Dissolution

[0133] According to the dissolution test method in the conventional test method of the 8th edition of the Korean Pharmacopoeia, the dissolution test method of Example 1 and Comparative Example The time-based dissolution rate was measured in water at pH 1.2, pH 4.0, and pH 6.8.

[0134] The dissolution rate was measured by liquid chromatography using the test solution collected at each dissolution time point, and the dissolution conditions are shown in Figures 1 to 4 middle.

[0135] <Dissolution conditions>

[0136] Dissolution test apparatus: Paddle method of Korean Pharmacopoeia dissolution test method

[0137] Test solution: pH 1.2, pH 4.0, pH 6.8, water

[0138] Rotation speed: 50rpm

[0139] Temperature: 37℃

[0140] Dissolution benchmark time point:

[0141] 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes (pH 1.2)

[0142] 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes (pH 4.0)

[0143] 5 min, 10 min, 15 min, 30 min, 45 min, 60 min (pH 6.8, water)

[0144] Analysis method: HPLC analysis

[0145] Example 4. Thickness of coating layer based on coating rate

[0146] Tablets of different hardness were prepared by tableting in the same manner as in Example 1, with the long axis of the tablet being 15 mm and the short axis being 5.8 mm, and coating with Opadry (containing PVA). The coating rate can be confirmed by the increase in weight after coating compared to the tablet weight.

[0147] With regard to the average thickness of the coating layer, the tablet was cut in half and then observed and measured using a scanning electron microscope (SEM), and the average value of 5 thickness values ​​was recorded and shown in Table 7 below.

[0148] [Table 7]

[0149] Coating rate Disintegration time (minutes: seconds) Average thickness of coating layer (μm) 0% (uncoated tablets) 2:20 0.0 5％ 3:24 60.6 9％ 3:54 85.7 13％ 4:41 122.6 21％ 8:28 154.2 32％ 10:07 309.2

[0150] Example 5. Preparation of Lenalidomide Tablets of Various Doses

[0151] Tablets for each dose were prepared in substantially the same manner as in Example 1.

[0152] The evaluation results of each tablet are shown in Table 8 below.

[0153] [Table 8]

[0154]

[0155]

[0156] Test Example 4. Bioequivalence test of lenalidomide

[0157] In order to compare the test substance lenalidomide preparation (25 mg dose) prepared in Example 1 with the comparative substance (registered trademark) tablets (Celgene, 25 mg dose) were compared with the 41 healthy adult male volunteers for a bioequivalence study.

[0158] The subjects were divided into two groups, and the test substance and the comparative substance were taken with water in the fasting state, and then blood was collected at prescribed time intervals until 24 hours. After 2 weeks, the groups were switched and the same drugs were taken and blood was collected. The collected blood samples were separated into plasma and frozen for storage. The concentration was analyzed by LC / MS / MS equipment to obtain the blood concentration based on time, and the AUC and C were obtained from the data. max The results are collated and shown in Table 9 below.

[0159] [Table 9]

[0160] project AUC <![CDATA[C max ]]> Comparison of substances 1416.7 420.564 Test substance 1366.9 420.334 Test substance / comparator substance 0.9648 0.9995

Claims

1. A tablet composition for oral administration, comprising: Direct compression tablets comprising Lenalidomide as the active ingredient; a diluent selected from the group consisting of sugars, sugar alcohols, cellulose, starch, and mixtures thereof; a disintegrant selected from the group consisting of cross-linked sodium carboxymethylcellulose, sodium starch glycolate, and mixtures thereof; and a lubricant selected from magnesium stearate, calcium stearate, sodium stearyl fumarate and mixtures thereof, in, Relative to 1 part by weight of lenalidomide, the content of the diluent is 2-50 parts by weight, the content of the disintegrant is 0.15-1.5 parts by weight, and the content of the lubricant is 0.03-0.75 parts by weight; wherein the tablet is coated with 3-20 parts by weight of a coating agent relative to 100 parts by weight of an uncoated tablet; wherein the area under the curve (AUC) of the oral tablet composition is 140 to 7100 ng·hr / mL; C max 42 to 2100 ng / mL; and The disintegration time of the oral tablet composition in a buffer solution with a pH of 1.2 is 1 to 20 minutes.

2. The oral tablet composition according to claim 1, in, Relative to 1 part by weight of lenalidomide, the content of the diluent is 4-20 parts by weight, the content of the disintegrant is 0.2-1 parts by weight, and the content of the lubricant is 0.1-3.5 parts by weight; The tablets are coated with 6-15 parts by weight of a coating agent relative to 100 parts by weight of uncoated tablets.

3. The oral tablet composition according to claim 1, in, When tested by a paddle method at 50 revolutions per minute in 900 mL of a dissolution solution having a pH of 1.2, the oral tablet composition has a dissolution rate of 1 to 50% in 2.5 minutes.

4. The oral tablet composition according to claim 3, in, The oral tablet composition has a dissolution rate of 10 to 95% in 5 minutes.

5. The oral tablet composition according to claim 1, in, The oral tablet composition has a hardness of 10 to 300N.

6. The oral tablet composition according to claim 1, in, The friability of the oral tablet composition is within 2%.

7. The oral tablet composition according to claim 1, in, The coating layer is a single layer or more.

8. The oral tablet composition according to claim 1, in, The total thickness of the coating film is 1 μm or more.

9. The oral tablet composition according to claim 1, in, The coating agent is selected from polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carboxymethyl cellulose and its salts, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol-polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer, vinyl pyrrolidone-vinyl acetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan gum and mixtures thereof.

10. The oral tablet composition according to any one of claims 1 to 4, in, The diluent is selected from lactose, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, cyclodextrin, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, starch hydrolyzed oligosaccharides, dextrin and mixtures thereof.

11. The oral tablet composition according to any one of claims 1 to 4, in, The tablet has a smaller volume than a size 0 capsule.

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