WO2019199133A1 - Orally administered coated tablet composition of lenalidomide - Google Patents

Abstract

Disclosed is a tablet-type composition, which is an oral tablet composition comprising lenalidomide, allowing enhanced safety and easier administration and handling and the like. Since a drug inside and a handler can be separated by means of a coating layer, a lenalidomide drug having teratogenicity is not present on the coating layer.

Description

Oral Coating Tablet Composition of Lenalidomide

The present invention relates to an oral tablet composition comprising lenalidomide.

Multiple myeloma is a blood cancer in which plasma cells are abnormally differentiated and proliferated. Such abnormal plasma cells are called myeloma cells. It mainly occurs in black people, men, and older people aged 65 or older, and in Korea, the frequency of occurrence is increasing. The main therapeutic agents for such multiple myeloma include boltezomib, thalidomide, lenalidomide.

Lenalidomide has been developed by Celgene in oral capsule formulations and is available in 25, 20, 15, 10, 7.5, 5 and 2.5 mg quantities.

Because lenalidomide is also a derivative of thalidomide, it cannot be prescribed to pregnant women. Therefore, lenalidomide has been marketed as a hard capsule so that no damage is caused by unintended leakage of the drug. In other words, the drug was filled in a thick hard capsule, similar to thalidomide, to control the outflow and loss of the drug.

The domestic brand name is Revlimid ^® capsule and contains lenalidomide hemihydrate. On the other hand, the hard capsule Reblimid ^® capsule is filled in No. 0 capsules in the case of 25, 20, 15, and 10 mg formulations, and has a long axis of about 2.17 cm, which is considerably long and bulky. Thus, patients, especially older patients, may have some inconveniences. In addition, capsules, even when taken with water may cause the capsule to stick to the throat or esophagus in the swallowing process. At this time, even if a large amount of water does not fall well, and if the drug accidentally popped out, the pain is accompanied, and in some cases may be inflamed. Therefore, when the short length, small volume tablets are developed as well as problems caused by inconvenient capsules as well as problems due to large volume, the patient's convenience of taking may be increased, and the disadvantages of the capsules may be overcome.

Although thalidomide was used in the late 1950s and 1960s as a morning sickness preventive for pregnant women, there was a tragic event that resulted in the birth of tens of thousands of birth defects worldwide due to the unknown side effects of teratogenicity. Like thalidomide, lenalidomide has a side effect of teratogenicity. Therefore, it is forbidden to take and handle pregnant women as well as those of childbearing potential and those who may be pregnant. In order to prevent such side effects, when the capsule is made of the drug is surrounded by a thick gelatin capsule, it can be considered that a certain shielding was achieved, but in the case of tablets (especially uncoated tablet), the drug is present directly on the surface of the tablet There is a risk of exposure to unrelated handlers.If you take a split line with a dividing line, or take it out of the PTP package and break it due to its low hardness, Drugs may be exposed to people at home.

In addition, tablet formulations containing lenalidomide need to be designed and manufactured to have the same drug release rate and release pattern as clinically validated and commercially available capsules.

An object of the present invention is to change the formulation of the commercially available lenalidomide formulations as hard capsules to tablets, but the length is short and the volume is easy to take, the selection of the coating base and coating thickness is appropriate for the entire tablet It is to provide a tablet composition that can be completely enclosed over the thickness to separate the drug from the inside of the handler, so that there is no fear of drug leakage during coating. In addition, the dissolution pattern in the tablet is the same as the dissolution in the capsule to provide a tablet composition showing not only physicochemical equivalence in the comparative dissolution test, but also in vivo test of laboratory animals and bioequivalence test. Accordingly, the present invention provides a tablet composition and a method for preparing the same, which are equivalent in terms of efficacy and effect pharmacologically with commercially available capsule formulations, with improved appearance, ease of use and handling, ease of manufacture, safety, and the like.

Definition of Terms

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

Unless otherwise specified throughout the specification, "including" or "containing" refers to including any component (or component) without particular limitation, and excludes the addition of other components (or components) Not interpreted as

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

In order to solve the above problems, the present invention provides an uncoated tablet comprising lenalidomide and at least one pharmaceutically acceptable carrier as an active ingredient; And it provides an oral tablet composition comprising a coating layer for coating it. Herein, the carrier may include a diluent, a disintegrant, and a lubricant.

In the oral tablet composition of the present invention, the surface of the uncoated tablet is coated with a coating base, which can separate the drug from the inside and the tablet handler, and there is no fear that the drug may leak out during coating.

In addition, the present invention is tableted at the optimum tableting pressure to have a hardness in the appropriate range, so that the commercially available capsule formulation and the elution pattern appear equally.

In one embodiment, the diluent may be selected from one or more of the group consisting of sugars, sugar alcohols, celluloses, starches, inorganic salts and mixtures thereof; The disintegrant may be selected from one or more from the group consisting of swellable disintegrants, wet disintegrants, and mixtures thereof; The glidant may be selected from one or more from the group consisting of soluble glidants, insoluble glidants and mixtures thereof.

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

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

In the present invention the diluent is for example lactose (anhydride or hydrate, for example monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, Calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, It may be, but is not limited to, one or more selected from the group consisting of lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dexrate, dextrin, and mixtures thereof. Preferably lactose, microcrystalline cellulose, mannitol, starch or mixtures thereof may be selected. Most preferably a mixture of lactose and microcrystalline cellulose can be selected. Diluents may also serve as binders.

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 based on 1 part by weight of lenalidomide. have. If the amount of the diluent is too small than the above-mentioned range, it is difficult to prepare a tablet, on the contrary, if the amount of the diluent is too high, the concentration of the drug is lowered, which may cause a problem in securing content uniformity during the preparation.

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

In one embodiment, the disintegrant is used in an amount of, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.2 to 1.5 parts by weight, or 0.1 to 1 parts by weight based on 1 part by weight of lenalidomide. Can be. If the amount of the disintegrant is excessively less than the above-mentioned range, there may be a problem of delayed dissolution rate due to the disintegration rate delay. On the contrary, if the amount of the disintegrant is excessively larger than the above-mentioned range, there may be a problem in productivity such as tableting disorder and coating disorder.

In the present invention, the lubricant is used as a concept encompassing lubricant, antiadherant, glidant, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, starch (wheat, rice , Corn or potato starch), talc, highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin , Polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate, and mixtures thereof, but is not limited thereto. It doesn't happen. The lubricant may preferably be magnesium stearate, stearic acid, highly dispersed (colloidal) silica. More preferably, it may be magnesium stearate.

In one embodiment, the lubricant is used in an amount of, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.1 to 1 parts by weight, or 0.1 to 0.5 parts by weight based on 1 part by weight of lenalidomide. Can be. If the amount of the lubricant is too small than the above-mentioned range may be a problem in productivity, such as tableting disorder, on the contrary, too much than the above-mentioned range may have a problem in elution delay or productivity.

In the present invention, the coating base is a hydrophilic polymer, for example, hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and salts thereof, polymethacrylate, poly (Butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymers (e.g. Eudragit® E, Evonik), carboxymethylcellulose (sodium salt and Calcium salt), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (HPC of low degree of substitution), polyvinylpyrrolidone (PVP), vinyl Pyrrolidone-vinylacetate copolymers (e.g., Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan and mixtures thereof Configuration It is at least one selected from the group, but is not limited to this. Preferably the coating base is hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl meth) Acrylate) copolymers (eg Eudragit® E, Evonik).

In one embodiment, the coating layer is for example 0.05 to 10 parts by weight, or 0.1 to 3 parts by weight, or more than 0.1 to less than 3, or 0.2 to 2.5 parts by weight, or 0.5 to 1 part by weight based on lenalidomide It can be used in an amount of 2 parts by weight. If the amount of the coating base is excessively less than the above-mentioned range, there may be a problem that the whole uncoated tablet is not covered with the coating base and disintegrates too early. Conversely, if the amount of the coating base is too high, there may be a problem of excessive delay of the dissolution rate.

After cutting the cross section of the tablet, the thickness of the coating layer may be measured by a scanning electron microscope (SEM) method. At this time, it is preferable that the entire surface of the tablet is uniformly coated with a predetermined thickness, and the average thickness can be confirmed by measuring the average of five or more. When the cross section is observed, the average thickness of the coating layer may be 1 μm or more and 300 μm or less. Preferably 10 micrometers or more and 200 micrometers or less may be sufficient. Even more preferably, it may be 15 µm or more and 150 µm or less. Most preferably, it may be 20 micrometers or more and 100 micrometers or less. If the average thickness of the coating layer is thinner than the above-mentioned range, it is difficult to coat the entire tablet evenly, and dust may occur during handling.If the average thickness of the coating layer is thicker than the above-mentioned range, the dissolution delay, excessive processing time, etc. For this reason, the desired purpose cannot be achieved.

When the coating layer is formed as a single layer, one or more coating bases may be mixed and used, and a sufficient amount may be coated to protect the entire tablet by forming a coating layer with the coating base. The coating layer may be more preferably at least two layers. For example, in the case of coating with more than two layers, the coating base may be different for each layer to act as shielding, water blocking, and oxidation prevention for drug exposure, respectively. Double coating can increase the protection from the external environment. Primary coating bases that come in direct contact with bare tablets include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymers (e.g. Kollidon® VA64, BASF), polyethylene glycol (PEG), sodium carbomethylcellulose (Na-CMC), or a combination thereof, and a secondary coating further coated on the primary coating. The coating base may be polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (e.g. Eudragit E, Evonik), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan or combinations thereof. In one embodiment, the first coating is preferably formed with hydroxypropylmethylcellulose (HPMC) to form a film blocking the drug, and the second coating is sequentially made with a macrogol polyvinyl alcohol graft copolymer to form a bilayer coating film. In one embodiment, preferably, the first coating with hydroxypropylmethylcellulose (HPMC) to form a film to block the drug, and the second coating with polyvinyl alcohol (PVA) in order to the moisture-proof coating film By forming a, it is possible to form a double layer coating film having a more excellent function, but is not limited thereto.

It may be necessary to carefully select the type and composition of the solvent used in preparing the coating liquid in order to prevent the drug from being melted by the coating liquid at the time of coating and contained in the coating layer formation. In addition, the coating conditions may need to establish a condition that can be quickly dried after the coating liquid is coated on the uncoated tablet. The coating solvent may be ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water or the like or a mixed solvent thereof. Preferably ethanol, water, or mixtures thereof can be used. More preferably, a primary coating is formed using a mixture of ethanol and water, or a mixture of methylene chloride and ethanol, or a mixture of isopropyl alcohol and ethanol as a coating solvent, and then a secondary coating is formed using water as a coating solvent. Can be.

In the process of preparing the coated tablet as described above, various biologically inert ingredients may be additionally added for additional purposes such as coating efficiency, drug stability, appearance, color, protection, retention, bonding, performance improvement, and manufacturing process improvement. Can be used.

According to one embodiment, the biologically inert component which may be further included in the coating layer is selected from the group consisting of plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, foaming agents, antifoaming agents, paraffins and waxes, etc. It may be one or more.

The plasticizers that may be further included in the coating layer are, for example, triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, acetyl triethyl citrate, acetyl triethyl It may be one or more selected from the group consisting of citrate, propylene glycol, triacetin, polyethylene glycol, cetyl alcohol, stearyl alcohol and cetostearyl alcohol, but is not limited thereto. The plasticizer is 100% by weight or less (eg, 0 to 100% by weight or 0.1 to 100% by weight), specifically 50% by weight or less, based on 100% by weight of the total polymer used in each coating layer. , 0 to 50 wt% or 0.1 to 50 wt%), more specifically 30 wt% or less (eg, 0 to 30 wt% or 0.1 to 30 wt%), but is not limited thereto.

The glidants that may be further included in the coating layer are, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc, highly dispersed It may be one or more selected from the group consisting of type (colloidal type) silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl mono stearate, silicon dioxide, calcium silicate, magnesium silicate and mixtures thereof, but is not limited thereto. It is not. The glidant may be included in an amount of 100 wt% or less (eg, 0 to 100 wt% or 0.1 to 100 wt%) when the dry weight of the entire polymer used in each coating layer is 100 wt%, but is not limited thereto. It is not.

The tablet composition of the present invention comprises mixing lenalidomide and one or more pharmaceutically acceptable carriers as an active ingredient, tableting the mixture to prepare a tablet (coated tablet) before coating, and then coating the surface of the uncoated tablet with a coating base. Provided is a method for producing an oral tablet composition of the present invention.

Specifically, the tablet of the present invention may be prepared in the order of granulation, mixing, tableting, coating after weighing the raw materials, or mixing, tableting (direct tableting), coating after weighing the raw materials. Granulation can be carried out in the manner of dry granules, wet granules and the like.

In one embodiment, when granulating into wet granules, a binder solution is prepared, a diluent or the like is added together with the drug, and the mixed mixture is granulated together with the binder solution, then sieved and dried to obtain granules. After mixing the remaining ingredients in the post-mixing and tableting. The binder solution may be a water-soluble polymer such as hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), L-HPC (low substitution degree HPC), polyvinylpyrroli Don (PVP), vinylpyrrolidone-vinylacetate copolymer (e.g. Kollidon VA64, BASF), or sugars, sugar alcohols such as sucrose, sorbitol, maltitol, xylitol, Erythritol and the like can be dissolved in water, ethanol or a mixed solution thereof.

In one embodiment, when granulating to dry granules, a mixture of drugs, diluents, binders, and the like is compressed using a roller compactor, and then sieved, and then mixed with the remaining components by post-mixing. After tableting.

In the case of straightening without granulation, there is an advantage that the process is simplified because it is mixed and tableted immediately after weighing. Since the drug itself has a side effect of teratogenicity, it may be necessary to wear protective equipment of the worker during the manufacturing process, preferably a pregnant woman or a person who may be pregnant may be excluded. In addition, the direct method of minimizing the worker's exposure to the drug may be most desirable. However, the present application is not limited thereto.

The hardness of uncoated tablets may vary depending on the shape, weight and size of the tablet, but the maximum average hardness is 300N and the minimum average hardness is 20N. Preferably, the maximum average hardness is 250N and the minimum average hardness is 30N. More preferably, the maximum average hardness is 230N and the minimum average hardness is 35N, in particular 40N to 200N. If the hardness of the uncoated tablet is too high than the above-mentioned range, there may be a delay in release of the drug due to the disintegration delay. On the contrary, if the hardness of the uncoated tablet is too low, the release of the drug is too fast. There may be a break in the city.

The hardness refers to a value obtained by measuring the long axis when measured on tablets such as a rectangle, and means the average hardness of six tablets randomly selected.

In the present invention, the disintegration time may be one of the important factors for estimating the release time of the drug. Therefore, in the tableting process, the tablets should be compressed at an appropriate pressure to have an appropriate hardness, so that the desired disintegration time can be obtained. This may be a factor that determines the dissolution pattern of the tablet together with the amount of coating base in the coating process. Since the dissolution pattern affects the absorption in the body, it may be important to set the appropriate disintegration time by having the appropriate hardness at the appropriate tablet pressure. In addition, since the dissolution pattern of the drug should be the same even if the dose is changed, the disintegration time may be the same for all doses of the tablet.

The disintegration time was measured in accordance with the disintegration test No. 17 of the general test method of the KP X 10 amendment, but can be carried out in pH 1.2 buffer solution, the first solution of the test solution, after measuring the disintegration time of six tablets Averaged to get the value. In one embodiment the average disintegration time of the uncoated tablet is between 1 and 20 minutes. Preferably between 1 minute 30 seconds and 15 minutes. More preferably 2 minutes to 10 minutes, still more preferably 2 minutes 30 seconds to 8 minutes, even more preferably 3 minutes to 6 minutes, most preferably 3 minutes 30 seconds to 5 minutes 30 seconds. In the present invention, the coating layer formed on the uncoated tablet may be a single layer or a bilayer or more, more preferably a bilayer or more.

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

In the tablet, various additives may be further mixed to improve the physical properties, manufacturability, compressibility, appearance, taste and / or stability of the drug, and the like. Such additives include, for example, stabilizers, solubilizers, sweeteners, copulating agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, copulating agents, binders, suspending agents , Hardeners, antioxidants, brighteners, flavoring agents, flavoring agents, pigments, coating agents, wetting agents, wetting agents, fillers, defoamers, fresheners, chewing agents, antistatic agents, colorants, dragees, isotonic agents, emollients, emulsifiers, tackifiers, Thickeners, blowing agents, pH adjusting agents, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, dissolution aids, solvents and glidants, and the like, but are not limited thereto and may be used as long as they are pharmaceutically acceptable. .

The coated tablets of the present invention may exhibit dissolution rates equivalent to comparative formulations prepared in capsules in dissolution tests. In particular, initial dissolution rates of 2.5 minutes, 5 minutes, 10 minutes, and 15 minutes are important under acidic conditions such as pH 1.2 buffer solution. Lenalidomide has a pH-dependent solubility that affects the solubility and absorption of the drug depending on where it disintegrates in the body. In particular, since the solubility of the drug is high at low pH, the release pattern in the stomach after administration may be a major factor in determining the drug absorption pattern. Therefore, matching the disintegration time and dissolution pattern of the formulation similarly to the reference drug is an important requirement to secure the same drug absorption pattern.

Dissolution test shall be carried out in accordance with the dissolution test method No. 35 of the general test method of KP X 10 amendments, can be tested at 37 ^o C with the paddle method 50 rotations / minute, 6 tablets each By measuring the elution amount of the drug at each time point by HPLC can be obtained the average dissolution rate at each time point.

Tablet compositions comprising lenalidomide disclosed in the present invention can be usefully used as a composition in the form of tablets with further improved convenience, handleability, safety and the like. In particular, since the coating layer can separate the drug from the inside of the handler, the lenalidomide drug with teratogenicity does not come out of the coating layer during coating, so that the contact with the coating layer does not come into contact with the drug. In addition, the initial dissolution rate is important, such as 2.5 minutes, 5 minutes, 10 minutes, 15 minutes under acidic conditions such as pH 1.2, the tablet composition according to the present invention showed the same pattern as the dissolution of commercially available capsules .

1 to 4 are graphs showing the results of elution comparison tests of the eluate of Example 2 and Comparative Example 1 in pH 1.2, pH 4.0, water, and pH 6.8, respectively.

5 to 8 are graphs showing the results of elution comparison tests of the eluate of Example 3 and Comparative Example 1 in pH 1.2, pH 4.0, water, and pH 6.8, respectively.

9 is a diagram showing the results of FT-IR analysis on the surface of the tablet obtained in Example 1. FIG.

Hereinafter, preferred embodiments will be presented to aid in understanding the present invention. However, the following examples are only for illustrating the present invention, and the present invention is not limited thereto.

EXAMPLE  1 and Comparative example  One

The tablets of Example 1 were prepared according to the following preparation methods with the ingredients and contents shown in Table 1 below. As Comparative Example 1, a commercially available levimid 25 mg capsule was used.

Composition (mg / tablet) % Composition Comparative Example 1 Lenalidomide anhydride 25.0 5.81 Reference Relevide 25mg Capsule with Lenalidomide Hemihydrate 25.87mg Anhydrous lactose 200.0 46.51 Microcrystalline cellulose 159.0 36.98 Croscarmellose sodium 12.0 2.79 Magnesium stearate 4.0 0.93 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0

<Manufacture of uncoated tablets>

After sieving and mixing lenalidomide and anhydrous lactose, the resulting mixture was sieved through microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, followed by final mixing. This mixture was compressed into a rectangular punch. The hardness of uncoated tablet was 120N.

<Coated coat>

The previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding. The primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.

Comparative example  2

To the ingredients and contents shown in Table 2 below according to the preparation method was prepared in Comparative Example 2.

<Manufacture of uncoated tablets>

Composition (mg / tablet) % Composition Lenalidomide anhydride 25.0 5.81 Anhydrous lactose 200.0 46.51 Microcrystalline cellulose 159.0 36.98 Croscarmellose sodium 12.0 2.79 Magnesium stearate 2.0 0.46 Aerosil 1.0 0.23 Stearic acid 1.0 0.23 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0

After sieving and mixing lenalidomide and anhydrous lactose, the resulting mixture was sieved through microcrystalline cellulose, croscarmellose sodium, magnesium stearate, aerosil, stearic acid, and finally mixed. This mixture was compressed into a rectangular punch. The hardness of uncoated tablets was 15N.

<Coated coat>

The uncoated tablet prepared above was subjected to double coating in the same manner as the uncoated coating of Example 1.

EXAMPLE  2

The tablets of Example 2 were prepared according to the following preparation methods with the ingredients and contents shown in Table 3 below.

Composition (mg / tablet) % Composition Lenalidomide anhydride 25.0 5.81 Mannitol 200.0 46.51 Microcrystalline cellulose 159.0 36.98 Starch sodium glycolate 12.0 2.79 Calcium stearate 4.0 0.93 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0

<Manufacture of uncoated tablets>

After sieving and mixing lenalidomide and spray-dried mannitol, microcrystalline cellulose, sodium starch glycolate, and calcium stearate were sieved into the mixture, followed by final mixing. This mixture was compressed into a rectangular punch. The hardness of uncoated tablets was 143 N.

<Coated coat>

The previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding. The primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.

EXAMPLE  3

<Manufacture of uncoated tablets>

Uncoated tablet was prepared by the same ingredients, contents, and preparation methods as those of Uncoated Tablet of Example 2, except that the hardness of uncoated tablet was 155 N.

<Coated coat>

The previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding. The primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.

EXAMPLE  4

<Manufacture of uncoated tablets>

Uncoated tablet was prepared by the same ingredients, contents, and preparation methods as those of Uncoated Tablet of Example 2, except that the hardness of uncoated tablet was 163 N.

<Coated coat>

The previously prepared uncoated tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding. The primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA.

Test Example  One: Masson  Measure

The friability was measured using a Pharmatest friabiltiy tester on 10 tablets by the method described in the U.S. Pharmacopoeia 1216 Tablet Friability to compare Test Examples 1, 2, 3, 4 and The difference between the bare and coated tablets of Example 2 is shown below. (Measurement time = 4 minutes)

Masson Najung Coated tablet Example 1 0.16% 0.00% Comparative Example 2 0.78% 0.00% Example 2 0.03% 0.00% Example 3 0.02% 0.00% Example 4 0.01% 0.00%

In the general production process, the wear and tear degree should be controlled to 0.2% or less, and the lower the wear and tear for the safety of the operator is preferable because of the nature of the active ingredient having teratogenicity is preferable.

Test Example  2: Disintegration  exam

According to the disintegration test method of the tenth revision of the Korean Pharmacopoeia, disintegration test was performed in Examples 1.2, 3, 4 and Comparative Examples 1 and 2 in a pH 1.2 solution with n = 3, and the results are shown below.

Disintegration time (minutes) Najung Coated tablet Example 1 1 minute 28 seconds 3 minutes 21 seconds Comparative Example 1 (Comparative Treaty) - 4 minutes 38 seconds Comparative Example 2 48 seconds 2 minutes 12 seconds Example 2 3 minutes 45 seconds 4 minutes 18 seconds Example 3 4 minutes 25 seconds 4 minutes 50 seconds Example 4 4 minutes 45 seconds 5 minutes 5 seconds

As a result of the experiment, the compositions of Examples 1 to 4 all exhibited the preferred disintegration time of Comparative Example 1 (control) and 210 seconds to 350 seconds.

Test Example  3: comparative dissolution

Subjected to the dissolution rate according to pH 1.2 and pH 4.0, pH 6.8, time in water was determined according to Example 2 and Comparative Example 1 with (Le Bulletin mid ^® capsule preparation) 8 amended pharmacopoeia for General Test Methods dissolution test method of.

The dissolution rate was measured by liquid chromatography with the sample collected at each dissolution time, and the dissolution pattern is shown in FIGS. 1 to 4.

<Elution condition>

Dissolution Test Apparatus- Paddle Method of KEPCO Dissolution Test Method

Test solution-pH1.2, pH4.0, pH6.8, water

Rotational Speed-50rpm

Temperature: 37 ℃

Elution point: 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)

Analytical Method: HPLC Method

As a result of the experiment, the composition of Example 2 exhibited a dissolution pattern equivalent to that of Comparative Example 1 (control) (with a dissolution rate difference of 60% and a dissolution rate within 15% of 85% of the control drug).

Test Example  4: comparative dissolution

Example 3 and Comparative Example 1 with (Le Bulletin mid ^® capsule preparation) Comparative dissolution profile test was performed in the same manner as in Test Example 3. The dissolution rate was measured by liquid chromatography with the liquid sample collected at each dissolution time, and the dissolution pattern is shown in FIGS. 5 to 8.

As a result of the experiment, the composition of Example 3 showed an elution pattern on the same level as Comparative Example 1 (control).

Test Example  5: Nonclinical  exam

Oral administration in beagle dogs to compare the test substance lenalidomide tablets (25 mg dose) prepared in Examples 2 and 3 with the comparable levimide® capsule (SEELZIN, 25 mg dose) After analyzing the concentration of lenalidomide in blood was confirmed the pharmacokinetic profile.

The test animals were fasted for 24 hours before the start of the experiment, divided into two groups, and the test substance and the comparative substance were orally administered with water from the fasting partner, respectively. Blood was collected at fixed intervals up to 24 hours after the test, followed by a two-week washout period, followed by crossover testing. The collected blood samples were separated from plasma and stored frozen, and the concentration was analyzed by LC / MS / MS equipment to obtain blood concentrations over time. The AUC and Cmax were obtained from the data and compared with the reference drug. The results are summarized as follows.

 Item AUC Cmax Example 2 / Comparative Example 1 102.8% 116.7% Example 3 / Comparative Example 1 99.7% 117.9%

Experimental results showed that Examples 2 and 3 both had biological equivalence with respect to Comparative Example 1.

Test Example  6: FT-IR

In order to confirm whether the active ingredient lenalidomide component is detected on the surface of the double-coated tablet, FT-IR analysis was performed on the surface of the lenalidomide and the coated tablet of Example 1 and the inside of the tablet. 9 shows the results of the FT-IR analysis of the surface of the coated tablet. From this, it was confirmed that the lenalidomide component is detected inside the tablet but not on the surface.

Test Example  7. On coating rate  Physical properties of the tablet

Tablets coated with the uncoated tablet of Example 1 at 5 to 32% of the uncoated tablet by weight using Opadry (PVA series) were prepared. Final coating rate was calculated as weight increase after coating to tablet weight.

<Disintegration time according to coating rate>

According to the disintegration test method of the 10th amendment of the Korean Pharmacopoeia, disintegration test was carried out in a solution of pH 1.2 with n = 3, and the results are shown below.

<Thickness of Coating Layer According to Coating Rate>

The average thickness of the coating layer was measured by dividing the middle point of the tablet by observing the cross section with a scanning electron microscope (SEM) and recording an average of five thickness values.

Coating rate Disintegration time Average thickness of coating layer (νm) 0% (uncoated) 2 minutes 20 seconds 0.0 5% 3 minutes 24 seconds 60.6 9% 3 minutes 54 seconds 85.7 13% 4 minutes 41 seconds 122.6 21% 8 minutes 28 seconds 154.2 32% 10 minutes 7 seconds 309.2

Test results showed that the disintegration time was suitable when the coating rate was 5% to 13%.

Test Example  8. Properties of Tablets According to Coating Content

Based on the composition, content and preparation method of Example 2, the coating agent content ratio was changed as shown in Table 8 to measure the disintegration rate and wear.

Lenalidomide content Coating content (mg) Weight ratio to lenalidomide Disintegration (sec) Wear and tear (%) 2.5mg 0.25 0.1 218 0.012% 3 1.2 234 0.000% 7.5 3 431 0.008% 25mg 2.5 0.1 257 0.050% 30 1.2 300 0.000% 75 3 496 0.019%

When the coating agent was coated with 0.1 part by weight based on 1 part by weight of the main component, it was confirmed that there is almost no difference from the uncoated tablet before coating. Therefore, it can be said that there is little coating effect.

In addition, when coating with 3 parts by weight of the coating agent with respect to 1 part by weight of the main component, a problem that the disintegration time is too long.

It is judged to be suitable when the abrasion degree is 0.5% or less and the disintegration time is 210 to 350 sec (3 m 30s to 5 m).

Test Example  9. Of lenalidomide  Bioequivalence test

Conducted a test prepared in Example 1 material LES flying it also polyimide tablets (25mg dose) in Comparative Example 1, the rail assembly mid ^® (trademark) capsule (three Elgin, 25mg dose), and the resource healthy 41 men who to compare for Bioequivalence tests were conducted on the subjects.

Subjects were divided into two groups, and each of the test substance and the comparative substance was taken at a fixed time interval up to 24 hours after taking the medicine with water on an empty stomach, and after 2 weeks, the group was changed to take the same medicine and collected. The collected blood samples were separated from plasma and stored frozen and analyzed by concentration with LC / MS / MS equipment to obtain blood concentrations over time. AUC and Cmax were obtained from the data, and the results were summarized below. It is shown in Table 9.

Item AUC Cmax Comparative Example 1 1416.7 420.564 Example 1 1366.9 420.334 Example 1 / Comparative Example 1 0.9648 0.9995

From the above data, the tablet of Example 1 is evaluated as having bioequivalence as compared to the formulation of Comparative Example 1.

Claims (8)

Uncoated tablets including lenalidomide, diluents, disintegrants and glidants, and Coating layer coating the uncoated tablet Oral tablet composition comprising a. The oral tablet composition of claim 1, wherein the coating layer is a monolayer or bilayer or more. The coating base of the coating layer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropyl. Cellulose, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, macrogol polyvinyl alcohol graft copolymers, polymers of acrylic acid and salts thereof, polymethacrylates, poly (butyl methacrylates, 2-dimethylaminoethyl methacrylates, Methylmethacrylate) copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan and mixtures thereof . The method of claim 3, wherein the coating layer is a bilayer, The primary coating layer in contact with the bare tablets contains hydroxypropylmethylcellulose, Oral tablet composition in contact with the outside contains a polyvinyl alcohol. The oral tablet composition according to any one of claims 1 to 4, wherein the weight of the coating layer is 0.2 to 2.5 parts by weight based on 1 part by weight of lenalidomide. The oral tablet composition according to any one of claims 1 to 4, wherein the coating layer has a thickness of 15 µm to 150 µm. The tablet composition for oral use according to any one of claims 1 to 4, wherein the hardness of the uncoated tablet is 20N to 300N. The method according to any one of claims 1 to 4, Diluents are lactose, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride , Sodium chloride, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, At least one selected from the group consisting of dexrate, dextrin, and mixtures thereof, Disintegrants include croscarmellose sodium, carboxymethylcellulose, crospovidone, low-substituted hydroxypropylcellulose, starch, sodium carboxymethyl starch, sodium starch glyconate, alginic acid, carboxymethylcellulose sodium, agar, xylan, gellan gum, At least one selected from the group consisting of xanthan gum, partially hydrolyzed starch, and mixtures thereof, Glidants include magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, starch, talc, highly disperse silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, Silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate and these Oral tablet composition selected from the group consisting of a mixture of.

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