JP7581052B2 - Oral coated tablet composition of lenalidomide - Google Patents

Description

This relates to an oral tablet composition containing lenalidomide.

Multiple myeloma is a blood cancer characterized by abnormal differentiation and proliferation of plasma cells. These abnormal plasma cells are called myeloma cells. It occurs mainly in men (especially black men) and people aged 65 or older, and the incidence rate has been gradually increasing in Korea in recent years. The main treatments for multiple myeloma include bortezomib, thalidomide, and lenalidomide.

Lenalidomide was developed by Celgene as an oral capsule formulation and is available in doses of 25, 20, 15, 10, 7.5, 5, and 2.5 mg.

Lenalidomide is also a derivative of thalidomide, so it cannot be prescribed to pregnant women. For this reason, lenalidomide was marketed as a hard capsule to prevent harm from unintentional leakage of the drug. In other words, like thalidomide, the drug was packed into a thick hard capsule to control leakage and loss of the drug.

The brand name in Korea is Revlimid® Capsules, and contains lenalidomide hemihydrate. Revlimid® Capsules, which are hard capsule formulations, are filled into size 0 capsules in all cases of 25, 20, 15, and 10 mg formulations, and are quite long and bulky, with a major axis of about 2.17 cm. Therefore, patients, especially elderly patients, may find it inconvenient to take the drug. Furthermore, even if taken with water, the capsule may stick to the throat or esophagus during swallowing. In this case, the capsule may not be removed from the site even if the patient drinks a large amount of water. If the drug is accidentally released from the capsule, it may cause pain and, in some cases, inflammation. Therefore, if a tablet form with a short length and small volume is developed, the above problems caused by the inconvenient and bulky capsules can be solved, and patients can take the medicine more easily. That is, the disadvantages of capsules can be overcome.

In the late 1950s and 1960s, thalidomide was used to prevent morning sickness in pregnant women, but tragically, tens of thousands of deformed children were born worldwide due to unexpected teratogenic side effects. Lenalidomide, which is similar to thalidomide, is prohibited from being administered to or used to treat pregnant women, women of childbearing age, or women of childbearing potential, due to its teratogenic side effects. To prevent such side effects, a thick gelatin capsule may be used to surround the drug during capsule manufacture, providing a safe shield. However, in the case of tablets (especially plain tablets), the drug is directly present on the surface of the tablet, and may be exposed to handlers who are not involved in its use. If patients take divided doses along the dividing line of the tablet, or if the tablet breaks when removed from the PTP package due to its fragility, or if it crumbles due to poor friability, there is a risk of exposure to the drug by handlers and bystanders.

In addition, tablet formulations containing lenalidomide must be designed and manufactured to provide the same drug release rate and release pattern as the clinically validated commercially available capsule formulation.

The object of the present invention is to provide a tablet composition in which the dosage form of a commercially available hard capsule formulation of lenalidomide is changed to a tablet, which is short in length, not bulky, and easy to take, and which completely envelops the entire tablet to a certain thickness by appropriately selecting a coating base and a coating thickness, thereby isolating the internal drug and the handler from each other and preventing the drug from being released during the coating process.

Another object of the present invention is to provide a tablet composition that has a dissolution pattern equivalent to that in a capsule and that not only shows physicochemical equivalence in comparative dissolution tests, but also shows equivalence in in vivo tests in experimental animals and bioequivalence tests.

Therefore, the present invention provides a tablet composition and a method for producing the same, which has the same pharmacological efficacy and effects as commercially available capsule formulations, but has been further developed to have improved appearance, ease of administration and handling, ease of production, safety, etc.

Definitions of Terms Unless otherwise stated, certain terms used herein may be defined as follows:

Unless the context clearly indicates otherwise, "comprise" or "contains" means the inclusion of any component (or components) without specific limitation and should not be construed as excluding other components (or components).

"Lenalidomide" may also be lenalidomide base (a base without salt), or a pharma- ceutically acceptable salt thereof or an isomer thereof, or a mixture thereof. In each case, it may also be various hydrates, or in each case, various crystal forms. For example, it may be lenalidomide anhydrate, various hydrates such as hemihydrate, monohydrate, dihydrate, trihydrate, or various solvates, or a mixture thereof.

In order to solve the above problems, the present invention provides an oral tablet composition comprising an uncoated tablet containing lenalidomide as an active ingredient and one or more pharma- ceutically acceptable carriers; and a coating layer coating the uncoated tablet. Here, the carrier may contain a diluent, a disintegrant, and a lubricant.

The oral tablet composition of the present invention has a coating base on the surface of the plain tablet, which separates the drug inside from the tablet handler, reducing the risk of the drug being released during the coating process.

The present invention also compresses tablets with an appropriate compression pressure to provide a suitable range of hardness and to show the same dissolution pattern as commercially available capsule formulations.

In one embodiment, the diluent may be selected from the group consisting of sugars, sugar alcohols, cellulose, starch, inorganic salts, and mixtures thereof; the disintegrant may be selected from the group consisting of swelling disintegrants, wettable disintegrants, and mixtures thereof; and the lubricant may be one or more selected from the group consisting of soluble lubricants, insoluble lubricants, and mixtures thereof.

In one embodiment, the coating layer of the oral tablet composition may be a single layer or two or more layers.

In one embodiment, the oral tablet composition may contain 0.5 to 200 parts by weight of diluent, 0.02 to 10 parts by weight of disintegrant, and/or 0.005 to 3.5 parts by weight of lubricant, relative to 1 part by weight of lenalidomide.

In the present invention, the diluent may be, for example, one or more selected from the group consisting of lactose (anhydrous or hydrated, e.g., 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, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrates, dextrin, and mixtures thereof, but is not limited thereto. Preferably, lactose, microcrystalline cellulose, mannitol, starch, or a mixture thereof may be selected. Most preferably, a mixture of lactose and microcrystalline cellulose may be selected, and the diluent may also act as a binder.

In one embodiment, the diluent may be used in an amount of, for example, 2 to 50 parts by weight, or 2 to 45 parts by weight, or 5 to 30 parts by weight, or 10 to 20 parts by weight per part by weight of lenalidomide. If the amount of diluent used is much less than the above range, it is difficult to manufacture tablets. On the other hand, if the amount of diluent used is much more than the above range, the drug concentration may be low, which may cause problems in ensuring content uniformity during tablet manufacture.

In the present invention, the disintegrant may be selected from the group consisting of, for example, starch, cellulose, cross-linked polymers, gums, polysaccharides, and mixtures thereof. For example, the disintegrant may be one or more selected from the group consisting of croscarmellose sodium (CrosCMC-Na), carboxymethylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), L-HPC (low-substituted hydroxypropylcellulose), starch (wheat, rice, corn, or potato starch), sodium carboxymethyl starch, sodium starch glycolate, alginic acid, sodium carboxymethylcellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch, and mixtures thereof, but is not limited thereto. Preferably, the disintegrant may be croscarmellose sodium, crospovidone, L-HPC, or sodium starch glycolate. More preferably, the disintegrant may be croscarmellose sodium.

In one embodiment, the disintegrant may be used in an amount of, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.2 to 1.5 parts by weight, or 0.1 to 1 part by weight, per part by weight of lenalidomide. If the amount of disintegrant used is much less than the above range, the disintegration rate may be slowed down, resulting in a problem of slow dissolution rate. On the other hand, if the amount of disintegrant used is much more than the above range, productivity problems such as poor compression or poor coating may occur.

In the present invention, the lubricant is a concept that encompasses lubricants, anti-adhesives, and flow promoters. For example, the lubricant may be one or more selected from the group consisting of magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, starch (wheat, rice, corn, or potato starch), talc, highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, hydrogenated vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate, and mixtures thereof, but is not limited thereto. The lubricant may preferably be magnesium stearate, stearic acid, or highly dispersed (colloidal) silica. More preferably, it may be magnesium stearate.

In one embodiment, the lubricant may be used in an amount of, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.1 to 1 part by weight, or 0.1 to 0.5 parts by weight, per part by weight of lenalidomide. If the amount of lubricant used is too small compared to the aforementioned range, problems with productivity such as tableting problems may occur, whereas if the amount is too large compared to the aforementioned range, delayed dissolution and problems with productivity may occur.

In the present invention, the coating base may be an aqueous polymer, such as, but not limited to, one or more selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymers (e.g., Eudragit (registered trademark) E, Evonik), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon (registered trademark) VA64, manufactured by BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof. Preferably, the coating base may be hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g., Eudragit (registered trademark) E, Evonik).

In one embodiment, the coating layer may be used in an amount of, for example, 0.05 to 10 parts by weight, or 0.1 to 3 parts by weight, or more than 0.1 to less than 3, or 0.2 to 2.5 parts by weight, or 0.5 to 2 parts by weight, per part by weight of lenalidomide. If the amount of coating base used is much less than the above range, there is a problem that the entire plain tablet is not covered with the coating base. On the other hand, if the amount of coating base used is much more than the above range, the dissolution rate may be excessively delayed.

The thickness of the coating layer after cutting the tablet in half can be measured by 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 constant thickness, and the average thickness can be obtained by measuring and averaging five or more tablets. When observing the cross section, the average thickness of the coating layer may be 1 μm or more and 300 μm or less. More preferably, it may be 10 μm or more and 200 μm or less, even more preferably 15 μm or more and 150 μm or less, and most preferably 20 μm or more and 100 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 uniformly, and dust may be generated during handling. If the average thickness of the coating layer is thicker than the above range, the desired purpose may not be achieved due to reasons such as delayed dissolution and excessive processing time.

When the coating layer is formed as a single layer, one or more types of coating base may be mixed and used, or the entire tablet may be coated with a sufficient amount of coating base to form a coating layer. The coating layer is preferably two or more layers. For example, when coating with more than two layers, each layer may be made of a different coating base to protect the tablet from exposure to drugs, moisture, oxidation, etc. When double-coated, the protection from the external environment can be increased. The primary coating base that comes into direct contact with the uncoated tablet may be hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon (registered trademark) VA64, manufactured by BASF), polyethylene glycol (PEG), sodium carboxymethylcellulose (Na-CMC), or a combination thereof. The secondary coating base that is further coated on the primary coating may be polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g., Eudragit (registered trademark) E, Evonik), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, or a combination thereof. In one embodiment, it is preferable to form a two-layer coating layer by performing a first coating using hydroxypropylmethylcellulose (HPMC) to form a barrier against the drug, and then performing a second coating using a macrogol polyvinyl alcohol graft polymer. In one embodiment, a two-layer coating layer with better functionality can be formed by performing a first coating using hydroxypropylmethylcellulose (HPMC) to form a barrier against the drug, and then performing a second coating using polyvinyl alcohol (PVA) to form a moisture barrier, but is not limited thereto.

In order to prevent the drug from being instantly dissolved by the coating solution during coating and being included in the coating layer, the type and composition of the solvent used in the preparation of the coating solution must be carefully selected. Furthermore, the coating conditions must be established under conditions that allow the coating solution to be coated on the plain tablet and then dried quickly. The coating solvent may be, but is not limited to, ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water, etc., or a mixture thereof. Preferably, ethanol, water, or a mixture thereof can be used. More preferably, a mixture of ethanol and water, a mixture of methylene chloride and ethanol, or a mixture of isopropyl alcohol and ethanol can be used to form a primary coating, and then a secondary coating can be formed using water.

In the process of producing coated tablets as described above, various additional biologically inactive ingredients can be used for the purpose of improving coating efficiency, drug stability, appearance, color, protection, retention, binding, performance, and manufacturing process, etc.

In one embodiment, the biologically inactive component that may be further contained in the coating layer may be one or more selected from the group consisting of plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, antifoaming agents, paraffin, wax, etc.

The plasticizer that may be further contained in the coating layer may be, for example, one or more selected from the group consisting of triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, triethyl acetyl citrate, propylene glycol, triacetin, polyethylene glycol, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol, but is not limited thereto.

When the dry weight of the total polymer used in each coating layer is taken as 100% by weight, the plasticizer may be present in an amount of 100% by weight or less (e.g., 0-100% by weight or 0.1-100% by weight), specifically 50% by weight or less (e.g., 0-50% by weight or 0.1-50% by weight), more specifically 30% by weight or less (e.g., 0-30% by weight or 0.1-30% by weight), but is not limited thereto.

The lubricant that may be further contained in the coating layer may be, but is not limited to, one or more selected from the group consisting of magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn, or potato starch), talc, highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, and mixtures thereof. The lubricant may be contained in an amount of 100% by weight or less (for example, 0 to 100% by weight or 0.1 to 100% by weight) when the total dry weight of the polymer used in each coating layer is taken as 100% by weight, but is not limited to this.

The tablet composition of the present invention provides a method for producing an oral tablet composition comprising mixing lenalidomide as an active ingredient and one or more pharma- ceutically acceptable carriers, compressing the mixture to produce a pre-coated tablet (plain tablet), and then coating the surface of the plain tablet with a coating base.

Specifically, the tablets of the present invention can be produced in the order of weighing the raw ingredients, granulating, mixing, tableting, and coating, or in the order of weighing the raw ingredients, mixing, tableting (direct tableting), and coating. Granulation can be carried out by methods such as dry granulation and wet granulation.

In one embodiment, when granulating using wet granulation, the granules are obtained by preparing a binder solution, forming granules from a mixture of the drug and diluent, sieving, and drying. The remaining ingredients are then mixed and compressed. The binder solution can be prepared by dissolving a water-soluble polymer, such as hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon (registered trademark) VA64, manufactured by BASF), or a sugar or sugar alcohol, such as white sugar, sorbitol, maltitol, xylitol, or erythritol, in water, ethanol, or a mixture thereof.

In one embodiment, when granulating using dry granulation, the mixture of drug, diluent and binder is pressed and sieved using a roller compactor or the like. The remaining ingredients are then mixed and compressed.

Direct compression instead of granulation has the advantage of simplifying the process since the ingredients are mixed and compressed immediately after weighing the raw materials. Protective equipment must be worn during the manufacturing process because the drug itself has teratogenic side effects. Pregnant women and women of childbearing potential should be excluded. In addition, it may be preferable to use direct compression, which minimizes worker exposure to the drug, but is not limited to this.

The hardness of the uncoated tablet varies depending on the shape, weight, and size of the tablet, but a maximum average hardness of 300N and a minimum average hardness of 20N are preferred. Preferably, the maximum average hardness is 250N and the minimum average hardness is 30N. More preferably, the maximum average hardness is 230N and the minimum average hardness is 35N, and in particular, 40N to 200N. If the hardness of the uncoated tablet is much higher than the above range, the release of the drug may be delayed due to delayed disintegration. On the other hand, if the hardness of the uncoated tablet is much lower than the above range, the tablet may become brittle and break during coating, transportation, storage, and administration.

The hardness is the value measured on the long axis in the case of rectangular tablets, and refers to the average hardness of six randomly selected tablets.

In the present invention, the disintegration time of the plain tablet is one of the important factors that can determine the release time of the drug. Therefore, it is necessary to have an appropriate hardness by compressing with an appropriate pressure during the tableting process. As a result, the tablet can have a desired disintegration time, which can be a factor that determines the dissolution pattern of the drug, in addition to the coating amount of the coating base in the coating process. Since the dissolution pattern affects the absorption in the body, it may be important to set an appropriate disintegration time by providing an appropriate hardness by an appropriate tableting pressure. Furthermore, the dissolution pattern of the drug must be the same even if the dosage is changed. That is, the disintegration time must be the same for all tablets with different dosages.

The disintegration time can be measured in a pH 1.2 buffer solution as the first test liquid according to the No. 17 disintegration test method in the 10th edition of the Korean Pharmacopoeia general test method (KP X). The disintegration time is determined by measuring and averaging six tablets. In one embodiment, the average disintegration time of the plain tablet is 1 minute to 20 minutes. It is preferably 1 minute 30 seconds to 15 minutes, more preferably 2 minutes 10 minutes, even more preferably 2 minutes 30 seconds to 8 minutes, even more preferably 3 minutes 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 plain tablet may be a single layer, two or more layers, and more preferably two or more layers.

The solvent for the coating can vary. For example, for HPMC coating, the solvent may have anhydrous ethanol and water in a ratio between 2:8 and 8:2, or may be water alone. Further, for example, water alone can be used as the solvent for coating PVA. All of these solvents volatilize during the coating process and do not substantially remain in the final product.

The tablet may further contain various additives to improve the physical properties, manufacturability, compressibility, appearance, taste and/or stability of the drug. Examples of such additives include, but are not limited to, stabilizers, solubilizers, sweeteners, flavorings, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, flavorings, binders, suspending agents, hardeners, antioxidants, glossing agents, flavorings, flavorings, pigments, coating agents, wetting agents, wetting regulators, fillers, antifoaming agents, refreshing agents, chewing agents, antistatic agents, coloring agents, sugar coating agents, isotonic agents, softeners, emulsifiers, adhesives, thickeners, foaming agents, pH regulators, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, solubilizing agents, solvents, and fluidizing agents. Any additive may be used as long as it is pharma- ceutically acceptable.

The coated tablet of the present invention can exhibit a dissolution rate equivalent to that of a comparative formulation manufactured into a capsule. In particular, the initial dissolution rate at 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, etc. is important under acidic conditions such as a buffer solution of pH 1.2. Lenalidomide has a pH-dependent solubility, and the solubility and absorption of the drug are affected depending on the site in the body where it disintegrates. In particular, since the solubility of the drug is high at low pH, the release pattern in the stomach after administration can be said to be the main factor that determines the drug absorption pattern. Therefore, adjusting the disintegration time and dissolution pattern of the formulation to be similar to that of the control drug is an important factor in ensuring the same drug absorption pattern.

The dissolution test is performed at 37°C and 50 rpm according to the paddle method, which is the second method, in accordance with No. 35 dissolution test method among the general test methods in the 10th edition of the Korean Pharmacopoeia (KP X). The average dissolution rate at a given time point can be obtained by testing each of the six tablets and measuring their dissolution rates at each time point by HPLC.

The tablet composition containing lenalidomide disclosed in the present invention can be usefully used as a tablet-form composition with improved ease of administration, ease of handling, safety, etc. In particular, the coating layer can separate the internal drug from the handler, so that the teratogenic lenalidomide drug is not released into the coating layer and does not come into contact with the drug even when it comes into contact with the coating layer. In addition, the initial dissolution rate at 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, etc. under acidic conditions equivalent to a pH 1.2 buffer solution is important, and the tablet composition according to the present invention showed the same dissolution pattern as that of conventional commercially available capsules.

1 is a graph showing the results of a comparative dissolution test of Example 2 and Comparative Example 1 using a dissolution medium having a pH of 1.2. 1 is a graph showing the results of a comparative dissolution test of Example 2 and Comparative Example 1 using a dissolution medium of pH 4.0. 1 is a graph showing the results of a comparative dissolution test of Example 2 and Comparative Example 1 using water as an eluent. 1 is a graph showing the results of a comparative dissolution test of Example 2 and Comparative Example 1 using a dissolution medium of pH 6.8. 1 is a graph showing the results of a comparative dissolution test of Example 3 and Comparative Example 1 using a dissolution medium having a pH of 1.2. 1 is a graph showing the results of a comparative dissolution test of Example 3 and Comparative Example 1 using a dissolution medium of pH 4.0. 1 is a graph showing the results of a comparative dissolution test of Example 3 and Comparative Example 1 using water as an eluent. 1 is a graph showing the results of a comparative dissolution test of Example 3 and Comparative Example 1 using a dissolution medium of pH 6.8. FIG. 2 shows the results of FT-IR analysis of the surface of the tablet obtained in Example 1.

The present invention will be described in more detail with reference to the following examples. However, these examples are intended only to illustrate the present invention, and the scope of the present invention is not limited by these examples in any way.

Example 1 and Comparative Example 1
Tablets of Example 1 were prepared according to the following preparation method using the ingredients and contents shown in Table 1 below. As Comparative Example 1, commercially available Revlimid 25 mg capsules were used.

<Production of uncoated tablets>
Lenalidomide and anhydrous lactose were sieved and mixed. Then, microcrystalline cellulose, croscarmellose sodium, magnesium stearate were sieved and finally mixed. The mixture was compressed with a rectangular punch. The hardness of the uncoated tablet was 120N.

<Coating of uncoated tablets>
The tablets prepared above were double-coated with two types of coating agents in a total amount of 7.5% (w/w) for the purpose of drug shielding. A first coating (2.5% (w/w)) was performed with Opadry® containing HPMC as the main component, and a second coating (5% (w/w)) was performed with Opadry® containing PVA as the main component.

Comparative Example 2
Tablets of Comparative Example 2 were prepared using the ingredients and contents shown in Table 2 below according to the following preparation method.

<Production of uncoated tablets>
Lenalidomide and anhydrous lactose were sieved and mixed. Then, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, AEROSIL, stearic acid were sieved and finally mixed. The mixture was compressed with rectangular punches. The hardness of the uncoated tablet was 15N.

<Coating of uncoated tablets>
The thus-prepared uncoated tablets were double-coated in the same manner as in Example 1.

Example 2
Tablets of Example 2 were prepared using the ingredients and contents shown in Table 3 below according to the following preparation method.

<Production of uncoated tablets>
Lenalidomide and spray-dried mannitol were sieved and mixed. Then rice microcrystalline cellulose, sodium starch glycolate, calcium stearate were sieved and finally mixed. The mixture was compressed with rectangular punches. The hardness of the uncoated tablet was 143N.

<Coating of uncoated tablets>
The tablets prepared above were double-coated with two types of coating agents in a total amount of 7.5% (w/w) for the purpose of drug shielding. A first coating (2.5% (w/w)) was performed with Opadry® containing HPMC as the main component, and a second coating (5% (w/w)) was performed with Opadry® containing PVA as the main component.

Example 3
<Production of uncoated tablets>
Uncoated tablets were produced using the same ingredients, contents and production method as in Example 2, except that the hardness of the uncoated tablets was 155 N.

<Coating of uncoated tablets>
The tablets prepared above were double-coated with two types of coating agents in a total amount of 7.5% (w/w) for the purpose of drug shielding. A first coating (2.5% (w/w)) was performed with Opadry® containing HPMC as the main component, and a second coating (5% (w/w)) was performed with Opadry® containing PVA as the main component.

Example 4
<Production of uncoated tablets>
Uncoated tablets were produced using the same ingredients, contents and production method as in Example 2, except that the uncoated tablets were compressed at a hardness of 163 N.

<Coating of uncoated tablets>
The tablets prepared above were double-coated with two types of coating agents in a total amount of 7.5% (w/w) for the purpose of drug shielding. A first coating (2.5% (w/w)) was performed with Opadry® containing HPMC as the main component, and a second coating (5% (w/w)) was performed with Opadry® containing PVA as the main component.

Test Example 1: Measurement of friability The friability was measured for 10 tablets using a Pharmatest friability tester according to the method described in the United States Pharmacopeia 1216 Tablet Friability Test. The difference between the plain tablets and the coated tablets in Examples 1 to 4 and Comparative Example 2 is shown in Table 4 below (measurement time = 4 minutes).

In general production processes, friability must be controlled to 0.2% or less, and due to the characteristics of the active ingredients that are teratogenic, it is preferable to keep the friability low for the safety of workers.

Test Example 2: Disintegration Test According to the disintegration test method of the 10th edition of the Korean Pharmacopoeia, a disintegration test was carried out for Examples 1 to 4 and Comparative Examples 1 and 2 in a pH 1.2 solution (n=3), and the results are shown in Table 5 below.

As a result of the experiment, the compositions of Examples 1 to 4 all showed favorable disintegration times of 210 to 350 seconds, the same as Comparative Example 1 (control drug).

Test Example 3: Comparative dissolution Using Example 2 and Comparative Example 1 (Revlimid (registered trademark) capsule formulation), the dissolution rates were measured over time in water at pH 1.2, pH 4.0, and pH 6.8 according to the dissolution test method in the general testing methods of the Korean Pharmacopoeia, 8th Edition.
The dissolution rates were measured by liquid chromatography using the test solutions collected at each dissolution time. The dissolution files are shown in Figures 1 to 4.
<Elution conditions>
Dissolution test apparatus: Paddle method of Korean Pharmacopoeia dissolution test Test liquid: pH 1.2, pH 4.0, pH 6.8, water Rotation speed: 50 rpm
Temperature: 37°C
Dissolution reference time:
5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes (pH 1.2, pH 4.0)
5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes (pH 6.8, water)
Analysis method: HPLC analysis method

As a result of the experiment, the composition of Example 2 showed a dissolution pattern similar to that of Comparative Example 1 (control drug) (the control drug's dissolution rate was 60%, and the difference in dissolution rate with the test drug at 85% was within 15%).

Test Example 4: Comparative dissolution A comparative dissolution test was carried out using Example 3 and Comparative Example 1 (Revlimid (registered trademark) capsule formulation) in the same manner as in Test Example 3. The dissolution rate was measured by liquid chromatography using the test solution collected at each dissolution time. The dissolution files are shown in Figures 5 to 8.
As a result of the experiment, the composition of Example 3 showed a dissolution pattern comparable to that of Comparative Example 1 (control drug).

Test Example 5: Non-clinical study To compare the test substance lenalidomide tablets (25 mg dose) prepared in Example 2 and Example 3 with the comparative substance Revlimid (registered trademark) capsules (Celgene, 25 mg dose), the blood lenalidomide concentration was analyzed after oral administration to beagle dogs to confirm the pharmacokinetic profile.
Before the start of the experiment, the test animals were fasted for 24 hours, and then divided into two groups, and the test substance and the comparative substance were orally administered with water in a fasting state. After the test, blood was collected at a set interval up to 24 hours, and after a washout period of two weeks, a crossover test was performed. Plasma was separated from the collected blood samples and frozen and stored. The samples were analyzed by an LC/MS/MS device to obtain the blood concentration. The AUC and Cmax were calculated from the data, and the results are shown in Table 6 below.

As a result of the experiment, Examples 2 and 3 were evaluated to be bioequivalent to Comparative Example 1.

Test Example 6: FT-IR
In order to confirm whether the active ingredient, lenalidomide, can be detected on the surface of the double-coated tablet, FT-IR analysis was performed on the surface and interior of the coated tablet of lenalidomide and Example 1. The FT-IR analysis results of the coated tablet surface are shown in Figure 9. It was confirmed that the lenalidomide ingredient was detected inside the tablet but not on the surface.

Test Example 7: Physical properties of tablets depending on coating rate The uncoated tablets of Example 1 were coated with Opadry (PVA-based) at different coating rates of 5 to 32% based on the weight of the uncoated tablet to produce tablets. The final coating rate was calculated as the increase in weight after coating relative to the tablet weight.

<Disintegration time depending on coating rate>
The coated tablets prepared according to the disintegration test method of the 10th edition of the Korean Pharmacopoeia were subjected to a disintegration test in a pH 1.2 solution (n=3), and the results are shown in Table 7 below.

<Film thickness of coating layer depending on coating rate>
The average coating layer thickness was determined by cutting the tablet in half, observing the average coating layer thickness with a scanning electron microscope (SEM), and recording the average of five thickness values, as shown in Table 7 below.

The test results showed that the optimum disintegration time was achieved when the coating rate was between 5% and 13%.

Test Example 8: Physical properties of tablets depending on coating agent content Based on the ingredients, contents and preparation method of Example 2, the coating agent content ratio was changed as shown in Table 8 below, and the disintegration rate and friability were measured.

It was confirmed that when 0.1 part by weight of the coating agent was used for coating with 1 part by weight of the main ingredient, there was almost no difference from the uncoated tablets before coating. Therefore, it can be said that the coating has almost no effect.
Furthermore, when 3 parts by weight of the coating agent was used per 1 part by weight of the main component, the disintegration time became excessively long.
A friability of 0.5% or less and a disintegration time of 210 to 350 seconds (3 minutes 30 seconds to 5 minutes) was judged to be suitable.

Test Example 9. Bioequivalence Study of Lenalidomide A bioequivalence study was conducted on 41 healthy male volunteers to compare the test substance lenalidomide tablet (25 mg dose) prepared in Example 1 with Revlimid® capsule (Celgene, 25 mg dose) in Comparative Example 1.
The subjects were divided into two groups, and the test and comparative substances were given with water under fasting conditions, and blood was collected at predetermined intervals for up to 24 hours. After two weeks, the same drugs were tested in different groups. Blood was collected, and plasma was separated from the collected blood samples and frozen and stored. The samples were analyzed by LC/MS/MS equipment to obtain blood concentrations. AUC and Cmax were calculated from the data, and the results are shown in Table 9 below.

From the above data, it was evaluated that the tablet of Example 1 has bioequivalence when compared with the dosage form of Comparative Example 1.

Claims (4)

a core tablet comprising lenalidomide, a diluent, a disintegrant and a lubricant; and a coating layer coating the core tablet;
Including,
the content of the diluent is 10 to 20 parts by weight, the content of the disintegrant is 0.1 to 1 part by weight, the content of the lubricant is 0.1 to 1 part by weight, and the content of the coating layer is 0.1 to 3 parts by weight, relative to 1 part by weight of lenalidomide;
the diluent is a combination of anhydrous lactose and microcrystalline cellulose or a combination of mannitol and microcrystalline cellulose;
the disintegrant is croscarmellose sodium or sodium starch glycolate;
The lubricant is magnesium stearate,
The coating layer is a double layer and contains a combination of hydroxypropyl methylcellulose and polyvinyl alcohol, the first coating layer in contact with the plain tablet contains hydroxypropyl methylcellulose, and the second coating layer in contact with the outside contains polyvinyl alcohol . 2. The tablet for oral administration according to claim 1, wherein the weight of the coating layer is 0.2 to 2.5 parts by weight per part by weight of lenalidomide. 2. The tablet for oral administration according to claim 1, wherein the coating layer has a thickness of 15 μm to 150 μm. 2. The tablet for oral administration according to claim 1, wherein the hardness of the uncoated tablet is 20N to 300N.