WO2021194253A1 - Oral tablet composition of pomalidomide and method for preparing same - Google Patents

Abstract

The present invention relates to an oral tablet composition containing pomalidomide and a method for preparing same and, more specifically, to a composition in a tablet form, in which physicochemical equivalence with existing pomalidomide formulations prepared in a hard capsule is shown, equivalence is secured in a non-clinical test and a bioequivalence test as well and thus equivalent pharmacological therapeutic effects are shown, and ease of administration, handling and safety are further improved, and to a method for preparing same.

Description

Oral tablet composition of pomalidomide and method for preparing same

The present invention relates to an oral tablet composition containing pomalidomide and a method for preparing the same, and more particularly, to a conventional pomalidomide formulation prepared in a hard capsule, showing physicochemical equivalents, and also to non-clinical tests and biological tests. In the equivalence test, equivalence is secured and the same pharmacological therapeutic effect is obtained, and the convenience of administration, handling, safety, etc. are further improved to a tablet-form composition and a method for preparing the same.

Multiple myeloma is a blood cancer in which plasma cells are abnormally differentiated and proliferated, and these abnormal plasma cells are called myeloma cells. The main treatments for multiple myeloma include boltezomib, thalidomide, lenalidomide, and pomalidomide.

The chemical name for pomalidomide is 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. The efficacy and effectiveness of pomalidomide has been demonstrated in combination therapy with bortezomib and dexamethasone in the treatment of multiple myeloma patients who have received one or more previous treatments including lenalidomide, and at least two prior regimens containing lenalidomide and bortezomib. It is in combination therapy with dexamethasone for the treatment of relapsed and refractory multiple myeloma patients.

Pomalidomide was developed as an oral capsule formulation by Celgene, and has been commercialized and used in doses of 4mg, 3mg, 2mg, and 1mg. The product name released in Korea is POMALYST ^® Capsule. On the other hand, the hard capsule formulation, POMALYST ^® capsule, is filled in No. 2 capsules in 4 mg, 3 mg, and 2 mg formulations, and the long axis reaches about 17.6 mm, so it is quite long and has a large volume. Therefore, patients, especially elderly patients, may have some inconvenience in taking it. In addition, in the case of capsules, even if they are taken with water, the capsule may stick to the throat or esophagus during swallowing, which may cause it to become stuck. At this time, even if you drink a lot of water, it may not come off well, and if you accidentally burst the drug, pain is accompanied, and in some cases, inflammation may occur.

Therefore, there is a need to develop a pomalidomide formulation in the form of a tablet having a short length and a small volume in order to solve the problem caused by the large volume of the capsule and the inconvenient problem when taking the capsule, and to increase the convenience of taking the patient.

Like thalidomide, which has been used as an anti-morning agent for pregnant women but has teratogenic side effects, pomalidomide also has teratogenic side effects, so it is forbidden to take and handle not only pregnant women, but also those of childbearing age or those who may become pregnant. In order to prevent these side effects, when it is manufactured as a capsule, it can be considered that the drug is reliably shielded because a thick gelatin capsule is surrounded, but in the case of tablets (especially uncoated tablets), the drug is present directly on the surface of the tablet, so that the drug is present on the surface of the tablet. There may be a risk of exposure to handlers unrelated to the product, and if divided with a dividing line or taken out of the PTP (pressure through package) package, the hardness is weak and it is broken, or the crumbs are sharp due to poor friability. In this case, there may be a risk of drug exposure to the handler and those around him. In addition, if the tablet is a coated tablet, the coating rate is low and a sufficient amount is not coated, so there are some or multiple areas where the drug is exposed, or when the drug is continuously oozing out during coating and the drug is present on the surface of the coating layer, etc. Likewise, handlers and those around them may be exposed to the drug.

Therefore, unlike the usual case, a sufficient amount of a coating base is applied to achieve a complete coating, so that the entire tablet is protected with a coating of a certain thickness or more, and a coated tablet capable of completely shielding the drug from the handler, etc. may be required.

At the same time, it may be necessary to design and manufacture the capsules that have been clinically verified and have the same drug release rate and release pattern as those on the market. For this purpose, it is essential not only to have a hardness in an appropriate range by tableting with an optimal compression pressure, but also to select an appropriate coating base and design to have an appropriate coating rate so that the dissolution pattern is similar. It may be necessary not only to secure in vitro physicochemical equivalence in these various pH eluates, but also to show equivalence in in vivo pharmacokinetic studies of non-clinical tests using experimental animals and bioequivalence tests using subjects.

In order to solve the above problems of the existing pomalidomide formulations marketed as hard capsules, an object of the present invention is to provide an oral tablet composition comprising pomalidomide and a method for preparing the same.

One aspect of the present invention, pomalidomide as an active ingredient; and one or more pharmaceutically acceptable carriers; provides an oral tablet composition comprising.

In one embodiment, the pharmaceutically acceptable carrier may be at least one selected from a diluent, a disintegrant and a lubricant.

In one embodiment, the diluent is starch, pregelatinized starch, mannitol, lactose, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, maltitol, sorbitol, xylitol, lactose , dextrose, maltose, sucrose, glucose, fructose, maltodextrin, and may be at least one selected from the group consisting of mixtures thereof.

In one embodiment, the disintegrant is croscarmellose sodium, carboxymethylcellulose, crospovidone, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, sodium starch glycolate, partially hydrolyzed starch, and their It may be at least one selected from the group consisting of mixtures.

In one embodiment, the lubricant is sodium stearyl fumarate, magnesium stearate, fumaric acid, stearic acid, calcium stearate, polyethylene glycol, talc, highly disperse silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl mono It may be at least one selected from the group consisting of stearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof.

In one embodiment, the oral tablet composition comprises: a tablet (uncoated tablet) before coating comprising pomalidomide and one or more pharmaceutically acceptable carriers; and a coating layer formed on the surface of the uncoated tablet by a coating base.

In one embodiment, the coating base is hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethylcellulose and sodium and calcium salts thereof, ethylcellulose, methylcellulose , hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), macrogol polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, poly Methacrylate, poly(butyl methacrylate/2-dimethylaminoethyl methacrylate/methyl methacrylate) copolymer (eg, Eudragit® E, Evonik), vinyl p consisting of a rolidone-vinylacetate copolymer (e.g. Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan and mixtures thereof. It may be one or more selected from the group.

In one embodiment, the oral tablet composition may optionally further include a binder.

In one embodiment, the oral tablet composition may be substantially free of water or ethanol.

In one embodiment, the coating layer may be a single layer or more.

In one embodiment, the total thickness of the coating layer may be an average of 1㎛ or more.

In one embodiment, the hardness of the uncoated tablet may be 10N to 300N.

In one embodiment, the friability of the uncoated tablet may be within 2%.

In one embodiment, the disintegration time of the uncoated tablet may be within 20 minutes.

In one embodiment, in the oral tablet composition, even if the dose of pomalidomide is different, the components of the tablet are the same, the ratio of the components is the same, and the dose of pomalidomide and the weight of the tablet are proportional. can

In one embodiment, the volume of the oral tablet composition may be smaller than the No. 2 capsule.

In one embodiment, the oral tablet composition may exhibit a dissolution rate of 20 to 90% at 5 minutes when tested at 50 rotations/minute by the paddle method in 900 mL of the dissolution solution of pH 1.2.

Another aspect of the present invention provides a method for preparing an oral tablet composition comprising mixing pomalidomide as an active ingredient and one or more pharmaceutically acceptable carriers, and tableting the resulting mixture.

In one embodiment, the method for preparing the oral tablet composition may further include coating the surface of the tablet (uncooked tablet) obtained as a result of the tableting with a coating base.

The oral tablet composition of pomalidomide provided according to the present invention shows physicochemical equivalence with the pomalidomide formulation prepared in a hard capsule, and the equivalence is ensured in non-clinical and bioequivalence tests, showing the same pharmacological therapeutic effect. , It is expected to be usefully used as a tablet-form composition with improved convenience, handling, safety, and the like.

In particular, the tablet composition of the present invention has a shorter length and smaller volume than a capsule, making it easy to take, and can separate the drug and the handler inside the tablet through an appropriate coating base and coating thickness. You can make it worry-free. In addition, since the dissolution pattern in the tablet is the same as the dissolution in the capsule, it shows physicochemical equivalence in the comparative dissolution test, as well as in the in vivo test of experimental animals and bioactivity tests. While they are equivalent in efficacy and effect, they are further improved and improved in appearance, convenience in taking and handling, ease of manufacture, and safety.

Definition of Terms

Unless explicitly stated otherwise, some terms used throughout this specification may be defined as follows.

Throughout this specification, unless otherwise specified, "including" or "containing" refers to including any component (or component) without particular limitation, and excludes the addition of other components (or components). not to be construed as

In addition, "pomalidomide" may be a free base of pomalidomide (a base drug without a separate salt), or a pharmaceutically acceptable salt or isomer thereof, or a mixture thereof. It may also be one which in each case forms various hydrates, and in each case various crystalline forms. For example, it may be various hydrates or various solvates, such as pomalidomide anhydride, hemihydrate, monohydrate, dihydrate, trihydrate, or mixtures thereof.

Also, the expression “micronized” means powdered to a very small size, for example, an average diameter of the order of micrometers or nanometers.

In the present invention, pomalidomide may be used in a micronized form. The average particle size (X50) of the micronized pomalidomide may be, for example, less than 100 μm, or may be less than 50 μm, or may be less than 30 μm, or may be less than 15 μm. In addition, the average particle size (X50) of the micronized pomalidomide may be, for example, 0.1 μm or more, or 0.2 μm or more, or 0.5 μm or more, or 1 μm or more. In the case of using pomalidomide in a range outside the above-mentioned average particle size, there may be a decrease in the dissolution rate or an obstacle in the process. The average particle size (X50) means an average particle size of particles of the lower 50% of all particles, which may be measured using, for example, an optical diffraction particle size meter.

The pharmaceutically acceptable carrier included in the tablet composition of the present invention may be, for example, at least one selected from a diluent, a disintegrant and a lubricant.

The diluent may be, for example, starch, pregelatinized starch, mannitol, lactose (anhydrous or hydrated, e.g. monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium It may be one or more selected from the group consisting of trisilicate, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, and mixtures thereof, but is not limited thereto. In one embodiment, the diluent may be selected from starch, pregelatinized starch, mannitol, lactose, microcrystalline cellulose, or a mixture thereof. The diluent may also act as a binder in some cases.

In one embodiment, the diluent may be used in an amount of, for example, 30 to 95 parts by weight, or 40 to 95 parts by weight, based on 100 parts by weight of the tablet (uncoated tablet) before coating. If the amount of the diluent used is excessively less than the above range, it may be difficult to manufacture a tablet, and if the amount of the diluent is excessively greater than the above range, the concentration of the drug may be lowered, and thus there may be a problem in ensuring content uniformity during manufacturing.

The disintegrant is, for example, croscarmellose sodium (CrosCMC-Na), carboxymethylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low substituted hydroxypropylcellulose), It may be one or more selected from the group consisting of sodium carboxymethyl starch, sodium starch glycolate, partially hydrolyzed starch, and mixtures thereof, but is not limited thereto. In one embodiment, the disintegrant is croscarmellose sodium (CrosCMC-Na), crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), sodium starch Glycolates or mixtures thereof may be selected.

In one embodiment, the disintegrant may be used in an amount of, for example, 1 to 10 parts by weight, or 2 to 5 parts by weight, based on 100 parts by weight of the tablet (uncoated tablet) before coating. If the amount of disintegrant used is too less than the above-mentioned range, there may be a problem with the dissolution rate delay due to the disintegration rate delay, and on the contrary, if it is excessively larger than the above-mentioned range, there may be problems in productivity such as tableting failure and coating failure.

The lubricant is, for example, sodium stearyl fumarate, magnesium stearate, fumaric acid, stearic acid, calcium stearate, polyethylene glycol, talc, highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, It may be at least one selected from the group consisting of glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof, but is not limited thereto.

In one embodiment, the lubricant may be used in an amount of, for example, 0.1 to 3 parts by weight, 0.2 to 2 parts by weight, or 1 to 2 parts by weight, based on 100 parts by weight of the tablet (uncoated tablet) before coating. If the amount of the lubricant used is excessively less than the above range, there may be problems in productivity such as tableting disorder, and on the contrary, if it is excessively larger than the above range, there may be problems in dissolution delay or productivity.

In one embodiment, the oral tablet composition of the present invention may optionally further include a binder. The binder is, for example, a water-soluble polymer such as hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), poly Vinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymer (for example, Kollidon (registered trademark) VA64, BASF), or saccharides, sugar alcohols, such as sucrose , sorbitol, maltitol, xylitol, erythritol, povidone, or a mixture thereof may be selected from the group consisting of. The binder may be used in an amount of, for example, 1 to 10 parts by weight, 2 to 8 parts by weight, or 3 to 7 parts by weight, based on 100 parts by weight of the tablet (uncoated tablet) before coating. If the amount of the binder used is too little or more than the above-mentioned range, the hardness of the tablet may be affected, resulting in poor quality or difficulty in achieving an appropriate level of dissolution rate or bioavailability.

In one embodiment, the oral tablet composition of the present invention comprises: a tablet before coating (uncoated tablet) comprising pomalidomide and one or more pharmaceutically acceptable carriers; and a coating layer formed on the surface of the uncoated tablet by a coating base.

In one embodiment, the coating base is a hydrophilic polymer, for example, hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, a polymer of acrylic acid and its salts, polymethacrylic Late, poly(butylmethacrylate/2-dimethylaminoethyl methacrylate/methylmethacrylate) copolymer (e.g. Eudragit® E, Evonik), carboxymethylcellulose ( sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone ( PVP), vinylpyrrolidone-vinylacetate copolymer (eg Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan And it may be one or more selected from the group consisting of mixtures thereof, but is not limited thereto. In one embodiment, the coating base is hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly(butyl methacrylate/2-dimethylaminoethyl methacrylate/ methyl methacrylate) copolymers (eg, Eudragit® E, Evonik) or mixtures thereof may be selected.

In one embodiment, the coating base is, for example, in an amount of 1 to 15 parts by weight, 1 to 10 parts by weight, 3 to 10 parts by weight, or 5 to 8 parts by weight, based on 100 parts by weight of the tablet (uncoated tablet) before coating. can be used as If the amount of the coating base is too less than the above range, there may be a problem that the entire uncoated tablet is not covered with the coating base, and on the contrary, if it is too much than the above range, there may be a problem of excessive delay of the dissolution rate.

After cutting the cross section of the tablet, the thickness of the coating layer can be measured using a scanning electron microscope (SEM) or the like. At this time, it is preferable that the entire surface of the tablet is uniformly coated with a certain thickness, and the average thickness can be confirmed by measuring 5 or more and averaging them. When observing the cross section, the average thickness of the coating layer is 1 μm or more and 300 μm or less, or 3 μm or more and 275 μm or less, or 5 μm or more and 250 μm or less, or 7 μm or more and 225 μm or less, or 10 μm or more and 200 μm or less, Or 15 μm or more and 180 μm or less, or 20 μm or more and 150 μm or less. If the average thickness of the coating layer is thinner than the above range, it is difficult to coat the entire tablet evenly, and dust may be generated during handling. Unable to achieve desired purpose

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 the film formed from the coating base. In one embodiment, the coating layer may be a double layer or more. For example, in the case of coating with more than a double layer, the coating base may be different for each layer, so that each layer may play a role of shielding against drug exposure, blocking moisture, preventing oxidation, and the like. In one embodiment, a film is formed to block the drug by first coating with hydroxypropylmethylcellulose (HPMC), and a second coating is sequentially applied with polyvinyl alcohol (PVA) to form a moisture-proof coating film It can be made to form a double-layer coating film having. In one embodiment, the primary coating and the secondary coating may be in a weight ratio of 1: 1 to 3, or 1: 1-2.

It may be necessary to carefully select the type and composition of the solvent used in the preparation of the coating solution in order to prevent the drug from being melted and oozing out by the coating solution during coating and included in the coating layer formation. In addition, it may be necessary to establish the coating condition as a condition in which the coating solution can be dried quickly after being coated on the uncoated tablet. The coating solvent may be ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water, etc., and a mixed solvent thereof may be used, but is not limited thereto. In one embodiment, as the coating solvent, ethanol, water, methylene chloride, isopropyl alcohol, or a mixture thereof may be used. Also, in one embodiment, a first 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, followed by a secondary coating using water as a coating solvent can be formed

In the process of manufacturing the coated tablet as described above, various biologically inactive ingredients are added for additional purposes such as coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance improvement, and manufacturing process improvement. Can be used.

According to one embodiment, the biologically inactive component that may be additionally included in the coating layer is selected from the group consisting of a plasticizer, a lubricant, a colorant, a flavoring agent, a surfactant, a stabilizer, an antioxidant, a foaming agent, an antifoaming agent, paraffin, a wax, and the like. There may be more than one type.

The plasticizer that may be further included in the coating layer is, 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 (eg, when the dry weight of the total polymer used in each coating layer is 100% by weight) , 0 to 50% by weight or 0.1 to 50% by weight), more specifically 30% by weight or less (eg, 0 to 30% by weight or 0.1 to 30% by weight), but is not limited thereto.

The lubricant that may be further included in the coating layer, 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 at least one selected from the group consisting of type (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof, but is limited thereto it is not The lubricant may be included in an amount of 100% by weight or less (eg, 0 to 100% by weight or 0.1 to 100% by weight) when the dry weight of the total polymer used in each coating layer is 100% by weight, but is limited thereto it is not

In one embodiment, the tablet of the present invention may be prepared in the order of (optionally) granulation, mixing, tableting, and coating after weighing the raw materials. The granulation may be performed in a manner such as dry granulation, wet granulation, or the like.

In one embodiment, in the case of granulation with wet granules, a binder solution is prepared, a diluent, etc. are added with the drug, and the mixture is mixed with the binder solution to form granules, then sieved and dried to obtain granules. Thereafter, the remaining ingredients are mixed by post-mixing and then tableted. The binder solution may be used by dissolving the binder in a suitable solvent, for example, water, ethanol, or a mixture thereof.

In one embodiment, in the case of granulation with dry granules, a mixture of a drug and a diluent is compressed using a roller compactor, etc., then sieved, and then the remaining components are mixed with post-mixing, and then tableted.

In the case of direct hitting without granulation, the process is simplified by mixing and tableting immediately after weighing. Since the drug itself has a teratogenic side effect, it may be necessary to wear protective equipment for workers during the manufacturing process, and it may be good to exclude pregnant women or people with potential for pregnancy as much as possible. In addition, the direct hit method that minimizes the worker's exposure to drugs may be the most desirable. However, the present invention is not limited thereto.

In one embodiment, in the case of tablets or direct compression tablets after granulation with the dry granules, a binder may be optionally included and prepared without using a solvent such as water, ethanol, or a mixture thereof, The content may be significantly low or may be substantially absent. The “substantially free of” may mean including less than about 1% by weight, less than about 0.5% by weight, less than about 0.1% by weight, less than about 0.05% by weight, or less than 0.01% by weight. When the oral tablet composition is prepared under conditions that do not contain the binder or solvent, it may be advantageous in achieving high stability, effective disintegration rate, or bioavailability.

When the ratio of the drug in the tablet is low, it is very important to ensure mixing uniformity. Therefore, careful consideration may be required to ensure mixing uniformity from the mixing stage. Mixing uniformity of the mixture may be improved if the drug, diluent, disintegrant, lubricant, etc. are not added at once and dispersed in stages.

For example, in one embodiment, after adding and mixing a part of the diluent and the drug, a part of the diluent is further added and mixed, and the remaining amount of the diluent is added and mixed, and then the disintegrant and the lubricant are added step by step. The mixture for final tableting may be prepared.

For example, in another embodiment, the disintegrant is first mixed with the drug, a part of the diluent is added and further mixed, a part of the diluent is added and further mixed, and finally a lubricant is added and a mixture for final tableting is added. can be prepared

In the case of pomalidomide, the dosage of the drug may vary, such as 4 mg, 3 mg, 2 mg, 1 mg, etc., so it may be necessary to set the tablet shape, weight, and size for each tablet and manufacture it with an appropriate punch. For each dose, the excipients used may be of the same type. In addition, for each dose, the ratio of the excipient used may be different or the same. Preferably, for ease of licensing, the total dose is designed in equal proportions using the same excipients so that the dose of pomalidomide and the dose of each excipient and the weight of the total tablet are proportional.

The shape of the tablet may vary, such as rectangular, oval, diamond-shaped, circular, polygonal (eg, triangular, square, pentagonal, hexagonal, etc.). The shape of the tablet is related to the patient's convenience, the ease of punch manufacturing and management, the manufacturing-related ease of tablet tableting and coating, packaging and handling, whether the dissolution pattern can be adjusted, the hardness of the tablet, friability, disintegration, etc. It can be determined by comprehensively judging the ease of control of variables. In addition, it is possible to select and select a suitable shape according to each capacity.

The total weight of the tablets (uncoated tablets) before coating is that the average weight of the tablets does not exceed 1100 mg, or does not exceed 880 mg, or does not exceed 660 mg, or does not exceed 550 mg, or 440 mg, even in the case of the maximum dose may not exceed , or may not exceed 350 mg.

The lower limit of the average value of the total weight of the tablet (uncoated tablet) before coating is 5 mg or more, or 10 mg or more, or 20 mg or more, or 30 mg or more, or 40 mg or more, or 50 mg or more, especially even at the lowest dose; or It may be 60 mg or more, or 70 mg or more, or 80 mg or more.

The length of the longest axis (diameter in the case of round) of the tablet (uncoated tablet) before coating should be smaller than the length of No. 2 capsule, which is 17.6 mm, especially even at the highest dose, or 17.0 mm or less, or 16.0 mm or less , or 15.0 mm or less, or 14.0 mm or less, or 13.5 mm or less.

The length of the shortest axis (diameter in the case of round) of the tablet (uncoated tablet) before coating may be 1 mm or more, or 2 mm or more, or 3 mm or more, or 4 mm or more, especially even at the lowest dose.

To set the weight of the tablet (uncoated tablet) before coating, for example, when the composition of excipients is proportional to the dose of the entire series, the total weight of the uncoated tablet can be determined in the following way.

The hardness of the tablet (uncoated tablet) before coating may vary depending on the shape, weight and size of the tablet, but in all cases, the maximum average hardness is 300N, the minimum average hardness is 10N, or the maximum average hardness is 250N, and the minimum average hardness is 250N. It is appropriate that the hardness is 20N, or the maximum average hardness is 230N, the minimum average hardness is 30N, or the maximum average hardness is 210N and the minimum average hardness is 40N. If the hardness of the uncoated tablet is excessively higher than the above range, there may be a delay in release of the drug due to disintegration delay. Conversely, if the hardness of the uncoated tablet is excessively lower than the above range, the tablet is weak and may break during coating, transport, storage, packaging, and taking. can

The above hardness means a value measured on the long axis when measuring for tablets such as rectangular, and means the average hardness for 6 randomly selected tablets.

In the present invention, the friability of the tablet (uncoated tablet) before coating may be within 2%, or within 1%, or within 0.5%.

In the present invention, the disintegration time of the tablet (uncoated tablet) before coating is one of the very important factors that can estimate the release time of the drug. Therefore, in the tableting process, it is necessary to tablet with an appropriate pressure to have an appropriate hardness, so that a desired disintegration time can be obtained, which is a factor that determines the dissolution pattern of the tablet together with the coating amount of the coating base in the coating process. Since the dissolution pattern ultimately affects absorption in the body, it is very important to have an appropriate hardness with an appropriate tableting pressure, and to set an appropriate disintegration time. In addition, even if the dose is changed, the dissolution pattern of the drug must be the same, so the disintegration time may be the same for all tablets in the end.

The disintegration time is measured according to the disintegration test method No. 17 among the general test methods of the 10th revision of the Korean Pharmacopoeia (KP X), but it can be carried out in the pH 1.2 buffer solution, the first solution, and the average disintegration time of 6 tablets is measured. to find the value In one embodiment, the average disintegration time of the uncoated tablet is between 1 minute and 20 minutes, or between 1 minute 30 seconds and 15 minutes, or between 2 minutes and 10 minutes, or between 2 minutes 30 seconds and 8 minutes, or between 3 minutes and 6 minutes. , or from 3 minutes 30 seconds to 5 minutes 30 seconds. In the present invention, the coating layer formed on the tablet (uncoated tablet) before coating may be a single layer or a double layer or more, or may be a double layer or more.

For example, the ratio of the total amount of the coated material to 100% by weight of the tablet (uncoated tablet) before coating may be 7.5% (w/w). In one embodiment, 2.5% (w/w) of Opadry containing HPMC and 5% (w/w) of Opadry containing PVA may be used to form the coating layer.

For example, the ratio of the total amount of the coated material to 100% by weight of the tablet (uncoated tablet) before coating may be 6.5% (w/w). In one embodiment, 2.5% (w/w) of Opadry containing HPMC and 4% (w/w) of Opadry containing PVA may be used to form the coating layer.

Solvents for coating may vary. For example, for HPMC coating, absolute ethanol:water 8:2 or 7:3, or 5:5, or 3:7, or 2:8, or water alone. Also, for example, for coating of PVA, water alone may be used. All of these solvents are volatilized during the coating process and remain virtually non-existent in the final finished product.

In the tablet, various additives may be additionally mixed to improve the physical properties, manufacturability, compressibility, appearance, taste, stability of the drug, and the like of the tablet. Such additives include, for example, stabilizers, solubilizers, sweeteners, flavoring agents, pigments, wetting agents, fillers, stabilizers, surfactants, glidants, solubilizers, buffers, sweeteners, adsorbents, flavoring agents, binders, suspending agents. , curing agent, antioxidant, brightening agent, flavoring agent, flavoring agent, pigment, coating agent, wetting agent, wetting agent, filler, defoaming agent, refreshing agent, chewing agent, antistatic agent, colorant, dragee, isotonic agent, emollient, emulsifier, adhesive, Thickeners, foaming agents, pH adjusters, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, solubilizing agents, solvents, fluidizing agents, etc., but are not limited thereto, and any pharmaceutically acceptable ones may be used . The coated tablet of the present invention may show a dissolution rate equivalent to that of the comparative formulation prepared as a capsule in a dissolution test. In particular, the initial dissolution rate such as 2.5 minutes, 5 minutes, 10 minutes, and 15 minutes under acidic conditions such as a buffer solution of pH 1.2 is very important.

The dissolution test is carried out according to the dissolution test method No. 35 among the general test methods of the 10th revision of the Korean Pharmacopoeia (KP X), but the second method, the paddle method, can be tested at 37°C at 50 revolutions/min. The average dissolution rate at each time point can be obtained by measuring the elution amount of the drug at each time point by HPLC.

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

In one embodiment, the coated tablet of the present invention has an average dissolution rate of 2 to 48%, or 5 to 45%, or 10 at 2.5 minutes when tested with a paddle method at 50 rotations/min in 900 mL of an eluate of pH 1.2. to 40%.

In one embodiment, the coated tablet of the present invention has a dissolution rate of 20 to 90%, or 30 to 87.5%, or 40 to 90% at 5 minutes when tested by the paddle method at 50 rotations/minute in 900 mL of an eluate of pH 1.2. 85%, or 50 to 80%.

In one embodiment, the coated tablet of the present invention has a dissolution rate of 50% or more, or 60% or more, or 70% or more, at 10 minutes when tested at 50 rotations/min by the paddle method in 900 mL of an eluate of pH 1.2, or 80% or more.

In one embodiment, the coated tablet of the present invention has a dissolution rate of 75% or more, or 77.5% or more, or 80% or more at 15 minutes when tested at 50 rotations/min by the paddle method in 900 mL of an eluate of pH 1.2, or 85% or more.

The coated tablet of the present invention, in the bioequivalence test (In vivo PK test), AUC (Area under curve) and C _max (highest blood concentration) values 80 to 125%, or 90% compared to the capsule formulation (100%) to 110%, or 95% to 105%.

As described above, the tablet composition of the present invention can be used for the same use as the conventional pomalidomide preparation, for example, for treatment and/or prevention of multiple myeloma.

Hereinafter, preferred embodiments are presented to help the understanding of the present invention. However, the following examples are only for illustrating the present invention, and do not limit the present invention thereto.

[Example]

A. Preparation of dry granulation method: Examples 1-4

Tablets were prepared by dry granulation method using each component in the amounts shown in Table 1 above. After mixing while sequentially adding Cross carmellose sodium and Povidone as disintegrants, and Spray dried mannitol and Starch 1500 as diluents to the active ingredient pomalidomide, a Roller compactor (CPMMRC, Chamunda) was used to prepare dry granules and , and sieved through a 25 mesh sieve. Thereafter, Pruv as a lubricant was added, mixed after mixing, and then manually compressed with a single-shot tablet press (EK-0, Korsch) using a rectangular punch to obtain uncoated tablets. On the obtained uncoated tablet, using a pan coater (Hi-coater, Freund), HPMC-based coating agent 1 was coated with 2.5% of the weight of the uncoated tablet, and then PVA-based coating base 2 was applied with 4% of the mass of the first uncoated tablet. The final coated tablet was obtained by coating.

B. Wet granulation method Preparation Example: Examples 5-8

Tablets were prepared by a wet granulation method using each component in the amounts shown in Table 1 above. After mixing while sequentially adding Spray dried mannitol and Starch 1500 as diluents to the active ingredient pomalidomide, Povidone was dissolved in a mixed solution of ethanol and purified water (30:70) at 15% (w/v) (30:70). ) solution in a plastic bag and sieved using a 20 mesh sieve, dried in an oven at 40° C. so that the LOD is 2% or less, and sieved again through a 25 mesh sieve for sieving. After that, cross carmellose sodium as a disintegrant and Pruv as a lubricant were added and mixed, and then manually compressed with a single-shot tablet press (EK-0, Korsch) using a rectangular punch to obtain uncoated tablets. On the obtained uncoated tablet, using a pan coater (Hi-coater, Freund), HPMC-based coating agent 1 was coated with 2.5% of the weight of the uncoated tablet, and then PVA-based coating base 2 was applied with 4% of the mass of the first uncoated tablet. The final coated tablet was obtained by coating.

C. Preparation example of direct hitting method after mixing: Examples 9-12

Tablets were prepared by direct hitting after mixing using each component in the amounts shown in Table 1 above. Cross carmellose sodium as a disintegrant was added to the active ingredient pomalidomide and mixed, and then Povidone as a binder was added thereto and mixed. Then, as a diluent, spray dried mannitol was divided into two parts and mixed, and then, Starch 1500 as a diluent was divided into two parts and mixed. Finally, Pruv as a lubricant was added and mixed after mixing, and then manually compressed with a single-shot tablet press (EK-0, Korsch) using a rectangular punch to obtain uncoated tablets. On the obtained uncoated tablet, using a pan coater (Hi-coater, Freund), HPMC-based coating agent 1 was coated with 2.5% of the weight of the uncoated tablet, and then PVA-based coating base 2 was applied with 4% of the mass of the first uncoated tablet. The final coated tablet was obtained by coating.

D. Dry granulation method Preparation Example: Examples 13-17

Tablets were prepared by dry granulation using each component in the amounts shown in Table 2 above. After mixing while sequentially adding and mixing the active ingredient pomalidomide, the disintegrant, binder, diluent 2, and diluent 1, dry granules were prepared using a roller compactor (CPMMRC, Chamunda), and sieved through a 25 mesh sieve. After that, a lubricant was added and mixed after mixing, and then manually compressed with a single-shot tablet press (EK-0, Korsch) using a rectangular punch to obtain uncoated tablets. On the obtained uncoated tablet, using a pan coater (Hi-coater, Freund), Coating Base 1 was coated with 2.5% of the mass of the uncoated tablet, and then Coating Base 2 was coated with 4% of the mass of the first uncoated tablet to obtain a final coated tablet.

E. Wet granulation method Preparation Example: Examples 18-22

Tablets were prepared by a wet granulation method using each component in the amounts shown in Table 2 above. After mixing while sequentially adding diluent 2 and diluent 1 to the active ingredient pomalidomide, the binder was dissolved or dispersed in a mixed solution (30:70) of ethanol and purified water at 15% (w/v). After kneading the solution in a plastic bag and sieving it using a 20 mesh sieve, it was dried in an oven at 40° C. so that the LOD was 2% or less, and sieved again through a 25 mesh sieve for sieving. After that, a disintegrant and a lubricant were added, mixed, and then manually compressed with a single-shot tablet press (EK-0, Korsch) using a rectangular punch to obtain uncoated tablets. On the obtained uncoated tablet, using a pan coater (Hi-coater, Freund), Coating Base 1 was coated with 2.5% of the mass of the uncoated tablet, and then Coating Base 2 was coated with 4% of the mass of the first uncoated tablet to obtain a final coated tablet.

F. Direct hitting method after mixing Preparation Examples: Examples 23-27

Tablets were prepared by direct hitting after mixing using each component in the amounts shown in Table 2 above. A disintegrant was added to the active ingredient pomalidomide and mixed, and then a binder was added thereto and mixed. Then, the diluent 2 was divided into two parts and mixed, and then the diluent 1 was divided into two parts and mixed. Finally, a lubricant was added and mixed after mixing, and then manually compressed with a single-shot tablet press (EK-0, Korsch) using a rectangular punch to obtain uncoated tablets. On the obtained uncoated tablet, using a pan coater (Hi-coater, Freund), coating base 1 was coated with 2.5% of the mass of the uncoated tablet, and then coated base 2 was coated with 4% of the mass of the first uncoated tablet to obtain a final coated tablet.

[Test Example]

For the tablets of Examples 1-27, friability measurement, disintegration test and stability test were performed as described below.

The average hardness measured for 5 uncoated tablets using a hardness measuring instrument (8M, Dr. schleuniger) was 200±20 N for Examples 1, 5, 9, 13-27, and 170±17 for Examples 2, 6, and 10. N, Examples 3, 7, and 11 were tableted to 140±15 N, and Examples 4, 8, and 12 to 80±10 N.

Test Example 1. Friability measurement

Friability was measured using a friability tester (LabFine, Korea) for 4 g or more of tablets by the method described in the US Pharmacopoeia 1216 Tablet Friability (measurement time: 4 minutes). Friability measured for each uncoated tablet and coated tablet is shown in Table 3 below.

Test Example 2: Disintegration test

According to the disintegration test method of the 10th revision of the Korean Pharmacopoeia, a disintegration test was performed in a pH 1.2 solution with n = 6 for Examples, and the results are shown in Table 4 below.

Test Example 3: Stability

For the formulations of Examples 1 to 4, storage stability after packaging was evaluated under accelerated conditions (under 40°C% RH, first, 1 month, 3 months and 6 months) and long-term conditions (under 25°C% RH, first, 3 months, 6 months, 12 months). An HPLC analysis method using the following conditions was used for the degree of generation of related substances.

Column: Zorbax SB-CN, 150 mm×4.6 mm id, 5 μm particle size

Temperature: Not controlled

Mobile phase:

A: 10/90 methanol/0.1% trifluoroacetic acid

B: 80/20 methanol/0.1% trifluoroacetic acid

Flow rate: 1.0 mL/min

Injection volume: 25 μL

Detection: UV light absorption spectrometer (measurement wavelength 240 nm)

Run time: 60 minutes

At all analysis time points during the stability test period, the amount of related substances generated from each formulation of Examples 1 to 4 was maintained at 0.2% or less, and it was confirmed that the amount of related substances generated over the stability test period was negligible. became These results indicate that the formulations provided in the present invention have adequate stability. The related substances used as the evaluation criteria in the stability test are as follows:

Benzyl (2,6-Dioxopiperidin-3-yl)carbamate

2-(2,6,-Dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione

5-amino-2(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

Other unknown related substances

Claims (18)

1. pomalidomide as an active ingredient; And one or more pharmaceutically acceptable carriers; oral tablet composition comprising a.
2. The oral tablet composition according to claim 1, wherein the pharmaceutically acceptable carrier is at least one selected from a diluent, a disintegrant and a lubricant.
3. 3. The method of claim 2, wherein the diluent is starch, pregelatinized starch, mannitol, lactose, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, maltitol, sorbitol, xylitol, lactose , dextrose, maltose, sucrose, glucose, fructose, maltodextrin, and at least one selected from the group consisting of mixtures thereof, oral tablet composition.
4. 3. The method of claim 2, wherein the disintegrant is croscarmellose sodium, carboxymethylcellulose, crospovidone, low-substituted hydroxypropylcellulose, starch, sodium carboxymethyl starch, sodium starch glycolate, partially hydrolyzed starch, and At least one selected from the group consisting of mixtures thereof, oral tablet composition.
5. According to claim 2, wherein the lubricant is sodium stearyl fumarate, magnesium stearate, fumaric acid, stearic acid, calcium stearate, polyethylene glycol, talc, highly disperse silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl mono At least one selected from the group consisting of stearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof, an oral tablet composition.
6. [Claim 2] The tablet of claim 1, wherein the tablet comprises pomalidomide and at least one pharmaceutically acceptable carrier (uncoated tablet); and a coating layer formed on the surface of the uncoated tablet by a coating base.
7. 7. The method of claim 6, wherein the coating base is hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethylcellulose and its sodium and calcium salts, ethylcellulose, methylcellulose , hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (L-HPC), macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and its salts, poly Methacrylate, poly(butylmethacrylate/2-dimethylaminoethyl methacrylate/methylmethacrylate) copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partially hydrolyzed starch, At least one selected from the group consisting of alginate, xanthan, and mixtures thereof, oral tablet composition.
8. The oral tablet composition according to claim 2, optionally further comprising a binder.
9. The oral tablet composition according to claim 2, which is substantially free of water or ethanol.
10. According to claim 6, wherein the coating layer is a single layer or more, oral tablet composition.
11. The oral tablet composition according to claim 6, wherein the total thickness of the coating layer is 1 μm or more on average.
12. The oral tablet composition according to claim 6, wherein the uncoated tablet has a hardness of 10N to 300N.
13. The oral tablet composition according to claim 6, wherein the friability of the uncoated tablet is within 2%.
14. The oral tablet composition according to claim 6, wherein the disintegration time of the uncoated tablet is within 20 minutes.
15. 15. The oral tablet composition according to any one of claims 1 to 14, wherein the volume is smaller than that of the No. 2 capsule.
16. 15. The oral tablet composition according to any one of claims 1 to 14, wherein the dissolution rate is 20 to 90% at 5 minutes when tested at 50 rotations/minute by the paddle method in 900 mL of the dissolution solution of pH 1.2. .
17. A method for preparing an oral tablet composition comprising mixing pomalidomide as an active ingredient and one or more pharmaceutically acceptable carriers, and tableting the resulting mixture.
18. The method of claim 17, further comprising coating the surface of the tablet (uncooked tablet) obtained as a result of tableting with a coating base.