KR102286498B1 - Oral Coated Tablet Formulation of Lenalidomide - Google Patents

Abstract

Disclosed is a tablet composition containing lenalidomide for oral administration, in which the convenience of administration, handling, safety, etc. are further improved. The teratogenic lenalidomide drug does not exist in the coating layer because the coating layer can separate the drug from the handler.

Description

Oral Coated Tablet Formulation 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, and these abnormal plasma cells are called myeloma cells. It mainly occurs in blacks, men, and the elderly over the age of 65, and in the case of Korea, the incidence has been gradually increasing in recent years. The main therapeutic agents for multiple myeloma include voltezomib, thalidomide, and lenalidomide.

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

Because lenalidomide is also a derivative of thalidomide, it cannot be prescribed to pregnant women. Therefore, lenalidomide was marketed as a hard capsule to prevent damage from unintentional leakage of the drug. That is, drug leakage and disappearance were controlled by filling the thick hard capsules with the same thickness as thalidomide.

The brand name released in Korea is Revlimid ^® capsule, which contains lenalidomide hemihydrate. On the other hand, Revlimid ^® capsules, a hard capsule formulation, are all filled in No. 0 capsules in the case of 25, 20, 15, and 10 mg dosage forms. 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, when developed in the form of a tablet having a short length and a small volume, the problem caused by an inconvenient capsule as well as a problem due to a large volume can be solved, so that patients' convenience can be increased, and the disadvantages of the capsule can be overcome.

From the late 1950s to the 1960s, thalidomide was used as an anti-morning agent for pregnant women, but unfortunately, due to the side effects of teratogenicity that were not known, there was a tragic event that resulted in the birth of tens of thousands of birth defects worldwide. Lenalidomide, like thalidomide, has side effects of teratogenicity, so it is forbidden to take and handle not only pregnant women, but also people 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 treatment. There may be a risk of drug exposure to people in

In addition, the tablet formulation containing lenalidomide needs to be designed and manufactured so that the drug release rate and release pattern are identical to those of capsules that have been clinically verified and are commercially available.

Republic of Korea Patent Publication No. 534498

The object of the present invention is to change the formulation of the lenalidomide formulation marketed as a hard capsule into a tablet, but it is short in length and small in volume, so it is easy to take, and the selection of the coating base and the thickness of the coating are appropriate so that the entire tablet is constant. It is to provide a tablet composition that can be completely surrounded by more than thickness to separate the drug and the handler inside, and there is no risk of the drug leaking out during coating. In addition, since the dissolution pattern in the tablet is the same as that in the capsule, it is to provide a tablet composition that not only shows physicochemical equivalence in a comparative dissolution test, but also shows equivalence in in vivo tests of experimental animals and bioactivity tests. Accordingly, it is an object to provide a tablet composition and a method for preparing the same, which are equivalent in pharmacological efficacy and effect to a commercially available capsule formulation, but with improved appearance, convenience in taking and handling, ease of manufacture, safety, and the like.

Definition of Terms

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

Throughout this specification, unless otherwise specified, "included" 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, "lenalidomide" may be lenalidomide free base (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 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 as an active ingredient and one or more pharmaceutically acceptable carriers; And it provides an oral tablet composition comprising a coating layer for coating the same. Here, the carrier may include a diluent, a disintegrant, and a lubricant.

In the oral tablet composition of the present invention, since the surface of the uncoated tablet is coated with a coating base, it is possible to separate the drug inside and the tablet handler, and there is no risk of the drug leaking out during coating.

In addition, the present invention is to have a hardness in an appropriate range by tableting with an optimal compression pressure, so that the dissolution pattern and the commercially available capsule formulations appear equally.

In one embodiment, the diluent may be one or more selected from the group consisting of sugars, sugar alcohols, cellulose, starch, inorganic salts, and mixtures thereof; The disintegrant may be one or more selected from the group consisting of swellable disintegrants, wettable disintegrants, and mixtures thereof; At least one lubricant may be 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 a double layer or more.

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

In the present invention, the diluent is, for example, lactose (anhydrous or hydrate, for example monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized 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 one or more selected from the group consisting of lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrate, 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. 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, 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. there is. 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.

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, croscarmellose sodium (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 at least one selected from the group consisting of sodium liconate, alginic acid, sodium carboxymethylcellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch, and mixtures thereof, but is not limited thereto. Preferably, it may be croscarmellose sodium, crospovidone, L-HPC, or sodium starch glycolate. More preferably, it may be 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 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.

In the present invention, the lubricant was used as a concept encompassing lubricant, antiadherant, and 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, hydrogenated vegetable oil, light liquid paraffin , polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate, and mixtures thereof may be at least one selected from the group consisting of, but limited thereto it's not going to be 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 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 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 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 (eg, Eudragit® E, Evonik), carboxymethylcellulose (sodium salt and calcium salt), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinyl pyrrolidone-vinylacetate copolymer (eg Kollidon® VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginates, xanthan and mixtures thereof It may be one or more selected from the group consisting of, but is not limited thereto. Preferably, the coating base is hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) acrylate) copolymer (eg Eudragit® E, Evonik).

In one embodiment, the coating layer is, for example, from 0.05 to 10 parts by weight, or from 0.1 to 3 parts by weight, or from more than 0.1 to less than 3 parts by weight, or from 0.2 to 2.5 parts by weight, or from 0.5 to 10 parts by weight based on 1 part by weight of lenalidomide. It can be used in an amount of 2 parts by weight. If the amount of the coating base used 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 disintegrates too early, and on the contrary, if it is too much than the above range, there may be an excessive delay in 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 may be 1 μm or more and 300 μm or less. Preferably, it may be 10 μm or more and 200 μm or less. More preferably, it may be 15 μm or more and 150 μm or less. Most preferably, it may be 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 evenly, and dust may be generated during handling. The desired purpose cannot be achieved for any reason.

When the coating layer is formed as a single layer, one or more coating bases can be mixed and used, and a sufficient amount can be coated to protect the entire tablet by forming a film with the coating base. The coating layer may be more preferably 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 plays a role of shielding against drug exposure, blocking moisture, preventing oxidation, and the like. In case of double coating, it is possible to increase the protection from the external environment. As the primary coating agent in direct contact with the uncoated tablet, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymer (for example, Kollidon (registered trademark) VA64, BASF), polyethylene glycol (PEG), sodium carbomethyl cellulose (Na-CMC) or a combination thereof may be a secondary coating additionally on the primary coating The coating base is polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (eg Eudragit). (registered trademark) E, Evonik), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, or a combination thereof. In one embodiment, the first coating is preferably made with hydroxypropylmethylcellulose (HPMC) to form a drug blocking film, and the second coating is sequentially performed with macrogol polyvinyl alcohol graft copolymer to form a double-layer coating film In one embodiment, preferably, a first coating with hydroxypropylmethylcellulose (HPMC) to form a film blocking the drug, and a second coating with polyvinyl alcohol (PVA) sequentially to form a moisture-proof coating film It is possible to form a double-layer coating film having a superior function by forming, but is not limited thereto.

It may be necessary to carefully select the type and composition of the solvent used in the preparation of the coating solution 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 conditions for the coating solution to dry quickly after the coating solution is coated on the uncoated tablet. As the coating solvent, ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water, etc. or a mixed solvent thereof may be used. Preferably, ethanol, water, or a mixture thereof may be used. More preferably, a mixture of ethanol and water, or a mixture of methylene chloride and ethanol, or a mixture of isopropyl alcohol and ethanol is used as a coating solvent to form a primary coating, and then water is used as a coating solvent to form a secondary coating. can

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 and a wax. 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 additionally 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 not 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 for each coating layer is 100% by weight, but is limited thereto it is not

The tablet composition of the present invention is prepared by mixing lenalidomide and one or more pharmaceutically acceptable carriers as an active ingredient, tableting the mixture to prepare a tablet (uncoated tablet) before coating, and then coating the surface of the uncoated tablet with a coating base. It provides a method for preparing the oral tablet composition of the present invention, comprising:

Specifically, the tablet of the present invention may be prepared in the order of granulation, mixing, tableting, and coating after weighing the raw material, or mixing, tableting (direct tableting), and coating after weighing the raw material. 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, and a mixture obtained by adding a diluent and the like with a drug 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 is a water-soluble polymer, for example, hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrol Don (PVP), vinylpyrrolidone-vinylacetate copolymer (eg Kollidon VA64, BASF), or saccharides, sugar alcohols such as sucrose, sorbitol, maltitol, xylitol, Erythritol can be used by dissolving it in water, ethanol, or a mixed solution thereof.

In one embodiment, in the case of granulation with dry granules, a mixture of a drug, a diluent, a binder, etc. is compressed using a roller compactor, etc., and then sieved, and then the remaining components are mixed. will be tweaked later.

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. In addition, the direct hit method that minimizes the worker's exposure to drugs may be the most desirable. However, the present application is not limited thereto.

The hardness of the raw tablet may vary depending on the shape, weight and size of the tablet, but it is appropriate that 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 suitably 30N. More preferably, the maximum average hardness is 230N, and the minimum average hardness is 35N, particularly 40N to 200N. If the hardness of the uncoated tablet is too high than the above range, there may be a delay in the release of the drug due to disintegration delay. Conversely, if it is too low than the above range, the release of the drug is too fast and the tablet is weak, so coating, transport, storage, packaging, and administration There may be times when it breaks.

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 disintegration time may be one of the important factors for estimating 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 it can have a desired disintegration time, which can be a factor influencing the dissolution pattern of the tablet together with the coating amount of the coating base in the coating process. Since the dissolution pattern affects absorption in the body, it may be important to have an appropriate hardness with an appropriate tableting pressure 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 17th disintegration test method among the general test methods of the 10th revision of the Korean Pharmacopoeia (KP X), but it can be carried out in the pH1.2 buffer solution, the first solution of the test solution, and after measuring the disintegration time of 6 tablets The average is obtained. In one embodiment, the average disintegration time of the uncoated tablet is between 1 minute and 20 minutes. Preferably it is between 1 minute and 30 seconds and 15 minutes. More preferably 2 minutes to 10 minutes, still more preferably 2 minutes 30 seconds to 8 minutes, still 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 uncoated tablet may be a single layer or a double layer or more, and more preferably a double layer or more.

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

Various additives may be added to the tablet to improve physical properties, manufacturability, compressibility, appearance, taste, and/or stability of the drug. 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 adjusting agents, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, solubilizing agents, solvents and 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 important. Lenalidomide has pH-dependent solubility, so it affects the solubility and absorption of the drug depending on where in the body it disintegrates. Especially at low pH, the solubility of the drug is high, so the release pattern in the stomach after taking it can be considered as a major factor in determining the drug absorption pattern. Therefore, matching the disintegration time and dissolution pattern of the formulation to be similar to that of the reference drug is an important requirement for securing the same drug absorption pattern.

Dissolution test is Pharmacopoeia 10th revision (KP X) General Test, but in accordance with the dissolution test method 35 of the method, the first, and can be tested in the second entity paddle method of 50 revolutions / minute to 37 ^o C, the test for 6 tablets each for Thus, the elution amount of the drug at each time point can be measured by HPLC to obtain the average dissolution rate at each time point.

The tablet composition containing lenalidomide disclosed in the present invention can be usefully used as a tablet-form composition with improved convenience, handling, safety, and the like. In particular, since the coating layer can separate the drug from the handler inside, the teratogenic drug lenalidomide does not seep into the coating layer during coating, so that even if it comes into contact with the coating layer, it does not come into contact with the drug. In addition, initial dissolution rates such as 2.5 minutes, 5 minutes, 10 minutes, and 15 minutes are important under acidic conditions such as a buffer solution of pH 1.2. .

1 to 4 are graphs showing the results of the dissolution comparison test of Example 2 and Comparative Example 1 in the eluate of pH 1.2, pH 4.0, water, and pH 6.8, respectively.
5 to 8 are graphs showing the results of the dissolution comparison test of Example 3 and Comparative Example 1 in the eluate of pH 1.2, pH 4.0, water, and pH 6.8, respectively.
9 is a view showing the results of FT-IR analysis of the surface of the tablet obtained in Example 1.

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 1 and comparative example One

The tablet of Example 1 was prepared according to the following preparation method with the components and contents shown in Table 1 below. As Comparative Example 1, a commercially available 25 mg capsule of Revlimid was used.

Composition (mg/tablet) Composition percentage (%) Comparative Example 1 Lenalidomide Anhydrous 25.0 5.81 Control drug Revlimid 25mg capsules
(Including lenalidomide hemihydrate 25.87mg)
Lactose Anhydrous 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

<Manufacturing of uncooked tablets>

After mixing lenalidomide and anhydrous lactose through a sieve, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate were sieved and mixed thereto, followed by final mixing. This mixture was compressed with a rectangular punch. The hardness of the uncoated tablets was 120N.

<Najeong's Coating>

A total of 7.5% (w/w) of the previously prepared uncoated tablets compared to the uncoated tablets was double-coated with two kinds of peeling agents for the purpose of drug shielding. After the primary coating was made at 2.5% (w/w) with an Opadry base containing HPMC as a main component, the secondary coating was applied at 5% (w/w) with an Opadry base containing PVA as a main component.

comparative example 2

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

<Manufacturing of uncooked tablets>

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 25.0 5.81 Lactose Anhydrous 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, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, aerosil, and stearic acid were sieved and finally mixed. This mixture was compressed with a rectangular punch. The hardness of uncoated tablets was 15N.

<Najeong's Coating>

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

Example 2

The tablet of Example 2 was prepared according to the following preparation method with the components and contents shown in Table 3 below.

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 25.0 5.81 mannitol 200.0 46.51 Microcrystalline Cellulose 159.0 36.98 Sodium starch 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

<Manufacturing of uncooked tablets>

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

<Najeong's Coating>

A total of 7.5% (w/w) of the previously prepared uncoated tablets compared to the uncoated tablets was double-coated with two kinds of peeling agents for the purpose of drug shielding. After the primary coating was made at 2.5% (w/w) with an Opadry base containing HPMC as a main component, the secondary coating was applied at 5% (w/w) with an Opadry base containing PVA as a main component.

Example 3

<Manufacturing of uncooked tablets>

Uncooked tablets were prepared with the same ingredients, content, and manufacturing method as those of Example 2, except that the raw tablet was tableted to a hardness of 155N.

<Najeong's Coating>

A total of 7.5% (w/w) of the previously prepared uncoated tablets compared to the uncoated tablets was double-coated with two kinds of peeling agents for the purpose of drug shielding. After the primary coating was made at 2.5% (w/w) with an Opadry base containing HPMC as a main component, the secondary coating was applied at 5% (w/w) with an Opadry base containing PVA as a main component.

Example 4

<Manufacturing of uncooked tablets>

Uncooked tablets were prepared using the same ingredients, content, and manufacturing method as those of Example 2, except that the raw tablet was tableted with a hardness of 163N.

<Najeong's Coating>

A total of 7.5% (w/w) of the previously prepared uncoated tablets compared to the uncoated tablets was double-coated with two kinds of peeling agents for the purpose of drug shielding. After the primary coating was made at 2.5% (w/w) with an Opadry base containing HPMC as a main component, the secondary coating was applied at 5% (w/w) with an Opadry base containing PVA as a main component.

test example One: Masondo measurement

The friability is measured by the method described in the US Pharmacopoeia 1216 Tablet Friability section, and the tablet friability is measured for 10 tablets using a Pharmatest friabiltiy tester, and Test Examples 1, 2, 3, 4 and comparison The difference between the uncoated tablet and the coated tablet of Example 2 is shown below. (measurement time = 4 minutes)

Masondo Na-jeong 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 a general production process, the degree of friability should be managed at 0.2% or less, and it is preferable that the degree of friability be lowered for the safety of workers due to the nature of the active ingredient having teratogenicity.

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 = 3 for Examples 1, 2, 3, 4 and Comparative Examples 1 and 2, and the results are shown below.

Disintegration time (min) Na-jeong coated tablet Example 1 1 minute 28 seconds 3 minutes 21 seconds Comparative Example 1 (control drug) - 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 a preferred disintegration time of 210 seconds to 350 seconds with Comparative Example 1 (control drug).

test example 3: Comparative dissolution

With Example 2 and Comparative Example 1 (Revlimid ^® capsule formulation), the dissolution rate with time in pH 1.2 and pH 4.0, pH 6.8, and water was measured according to the dissolution test method of the 8th revision of the Korean Pharmacopoeia.

The dissolution rate was measured with a liquid chromatography using the test solution collected at each dissolution time period, and the dissolution aspect is shown in FIGS. 1 to 4 .

<Elution conditions>

Dissolution test apparatus- Paddle method of dissolution test method of the Korean Pharmacopoeia

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

Rotational speed - 50rpm

Temperature: 37℃

Elution reference time: 5 min, 10 min, 15 min, 30 min, 45 min (pH 1.2, pH 4.0)

5 min, 10 min, 15 min, 30 min, 45 min, 60 min (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 drug) (the dissolution rate difference of the control drug was 60% and the dissolution rate difference from the test drug was within 15% at 85%).

test example 4: Comparative dissolution

Comparative dissolution test was carried out in the same manner as in Test Example 3 with Example 3 and Comparative Example 1 (Revlimid ^{® capsule formulation).} The dissolution rate was measured with a liquid chromatography using the test solution collected at each dissolution time period, and the dissolution aspect is shown in FIGS. 5 to 8

As a result of the experiment, the composition of Example 3 exhibited a dissolution pattern equivalent to that of Comparative Example 1 (control drug).

test example 5: non-clinical test

Oral administration in beagle dogs to compare the test substance lenalidomide tablets (25 mg dose) prepared in Examples 2 and 3 with Revlimid (registered trademark) capsules (Celgin, 25 mg dose) as a comparator. Then, the pharmacokinetic profile was confirmed by analyzing the concentration of lenalidomide in the blood.

After the test animals were fasted for 24 hours before the start of the experiment, they were divided into two groups and each test substance and a comparative substance were orally administered with water to a fasting partner. After the test, blood was collected at regular intervals up to 24 hours, and after a washout period of 2 weeks, a crossover test was performed. The collected blood samples were stored frozen after separation of plasma, and the concentration was analyzed with LC/MS/MS equipment to obtain blood concentrations over time, and AUC and Cmax were calculated 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%

As a result of the experiment, both Examples 2 and 3 were found to have bioequivalence with respect to Comparative Example 1.

test example 6: FT-IR

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

test example 7. in coating rate Physical properties of tablets according to

Tablets were prepared in which the uncoated tablets of Example 1 were coated at different ratios of 5 to 32% based on the weight of the uncoated tablets using Opadry (PVA series). The final coating rate was calculated as the weight increase after coating compared to the tablet weight.

<Disintegration time according to coating rate>

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=3 for the tablets prepared above by coating rate, 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 midpoint of the tablet and observing the cross section with a scanning electron microscope (SEM), and the average of five thickness values was recorded.

coating rate disintegration time Average thickness of coating layer (νm) 0% (naked) 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

As a result of the test, it was found that the disintegration time was suitable when the coating rate was 5% to 13%.

test example 8. Physical properties of tablets according to coating agent content

Based on the component, content and manufacturing method of Example 2, the disintegration rate and friability were measured by varying the coating agent content ratio as shown in Table 8.

Lenalidomide content Coating agent content (mg) Weight ratio to lenalidomide disintegration (sec) Friability (%) 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%

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

In addition, when the coating agent was coated with 3 parts by weight based on 1 part by weight of the main component, there was a problem that the disintegration time was excessively long.

If the friability is 0.5% or less and the disintegration time is 210~350sec (3m 30s~5m), it is judged to be suitable.

test example 9. of lenalidomide bioequivalence test

41 healthy adult male volunteers to compare the test substance lenalidomide tablet (25 mg dose) prepared in Example 1 with Revlimid ^® (registered trademark) capsule (Celgene, 25 mg dose) of Comparative Example 1. A bioequivalence test was conducted for

The subjects were divided into two groups, and after taking the test substance and the comparative substance with water in an emptying state, blood was drawn at regular time intervals up to 24 hours. The collected blood samples were stored frozen after separation of plasma, and the concentration was analyzed with LC/MS/MS equipment to obtain the blood concentration over time, and AUC and Cmax were obtained from the data, and the results are summarized below. shown in Table 9 of

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 to have bioequivalence when compared to the formulation of Comparative Example 1.

Claims (8)

uncoated tablets containing lenalidomide, a diluent, a disintegrant and a lubricant; and
Including; a coating layer for coating the uncoated tablet;
Based on 1 part by weight of lenalidomide, 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 coating layer The content of is 0.1 to 3 parts by weight,
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 hydroxypropylmethylcellulose and polyvinyl alcohol, wherein the primary coating layer in contact with the bare tablet contains hydroxypropylmethylcellulose, and the secondary coating layer in contact with the outside contains polyvinyl alcohol containing,
Oral tablet composition. delete According to claim 1, wherein the content of the coating layer is 0.2 to 2.5 parts by weight based on 1 part by weight of lenalidomide, oral tablet composition. According to claim 1, wherein the thickness of the coating layer is 15㎛ to 150㎛, oral tablet composition. The oral tablet composition according to claim 1, wherein the uncoated tablet has a hardness of 20N to 300N. delete delete delete

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