JP2023071921A - Lenalidomide oral tablet composition in various doses - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral tablet composition comprising lenalidomide and a method for preparing the same, where the composition exhibits physicochemical equivalence to a hard-capsule lenalidomide preparation and has equivalent pharmacological therapeutic effects in a non-clinical test and a bioequivalence test, and where the composition is improved in case of administration, handleability, safety, and the like.

SOLUTION: An oral tablet composition contains, in appropriate proportions: as a diluent, lactose, microcrystalline cellulose, mannitol, starch, or a mixture thereof; as a disintegrant, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, sodium starch glycolate, or a mixture thereof; and, as a lubricant, magnesium stearate, stearic acid, highly dispersible silica, or a mixture thereof. A coating layer is applied to the composition as needed.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2023,JPO&INPIT

Description

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

Multiple myeloma is a hematologic cancer characterized by abnormal differentiation and proliferation of plasma cells. These abnormal plasma cells are called myeloma cells. It occurs mainly in males (especially black males) and elderly people aged 65 and over, and in recent years, the incidence has been gradually increasing in South Korea. The main therapeutic agents for such 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 and should never be prescribed to pregnant women. Therefore, lenalidomide was marketed as a hard capsule to prevent harm from unintended release of the drug. That is, the outflow and disappearance of the drug were controlled by filling a thick hard capsule with the drug in the same manner as thalidomide.

Its brand name in Korea is Revlimid® capsules, which contain lenalidomide hemihydrate. Revlimid® Capsules, a hard capsule formulation, are filled in No. 0 capsules in all cases of 25, 20, 15 and 10 mg formulations and are rather long and bulky with a long axis of about 2.17 cm. ing. Therefore, patients, especially elderly patients, may find it inconvenient to take. Furthermore, even when taken with water, capsules can stick to the throat and esophagus during swallowing. In this case, even if the patient drinks a lot of water, the capsule may not be removed from the site. If the drug is accidentally released from the capsule, it can cause pain and possibly inflammation. In particular, the formulations of Revlimid (registered trademark) capsules are all filled in No. 0 capsules, despite the fact that 25, 20, 15 and 10 mg formulations have different active ingredient contents, and 20, 15 and 10 mg It is also very inconvenient for patients who have to take relatively low content capsules. In addition, capsule formulations containing 7.5 and 5 mg of lenalidomide on the market use No. 2 capsules, and capsule formulations containing 2.5 mg contain No. 4 capsules. Patients who have to take low content capsules such as 7.5, 5, and 2.5 mg, even though the content of the active ingredient is 30% or less, there is little difference in capsule size. However, it can be very inconvenient when taking it.

Therefore, even patients prescribed relatively low doses of lenalidomide (e.g., 20 mg or less) must take large capsule formulations that are long, bulky, and inconvenient to take. It was inconvenient.

In addition, the lenalidomide capsule formulation with a relatively low content contains excipients at a relatively higher content ratio when compared to the lenalidomide 25 mg capsule formulation, which is the highest content formulation, so the lenalidomide capsule formulation has a low content. and high lenalidomide capsule formulations may not exhibit comparable dissolution patterns. Therefore, when a high-strength lenalidomide capsule formulation is prescribed, replacing it with a low-strength lenalidomide capsule formulation (e.g., replacing lenalidomide 25 mg capsules with 5 lenalidomide 5 mg capsules or lenalidomide 25 mg capsules) Substitution of capsules with lenalidomide 15 mg capsules and 10 mg capsules) should be used with caution.

Lenalidomide, on the other hand, has pH-dependent solubility, which can greatly affect drug solubility and absorption depending on where in the body it disintegrates. Therefore, when developing different single-dose formulations, controlling the disintegration time and dissolution pattern of each formulation to be similar is an important requirement to ensure a uniform drug absorption pattern.

The purpose of the present invention is to change the dosage form of the commercially available hard capsule lenalidomide preparation to a tablet, which is short in length, not bulky, easy to take, and has an appropriate coating base and coating thickness. By selecting a tablet composition that can separate the drug inside and the handler from each other by completely enveloping the entire tablet over a certain thickness and prevent the drug from being released during the coating process It is to provide things. Therefore, it has the same pharmacological efficacy and effect as the commercially available capsule formulation, and is further developed into a tablet composition with improved appearance, convenience in administration and handling, ease of production, safety, etc. to provide.

Another object of the present invention is to provide a tablet having a constant content ratio of each component in the composition, regardless of the dose of lenalidomide, thereby enhancing the convenience of administration when administering a lenalidomide preparation with a relatively low content. Moreover, when a high-content lenalidomide formulation is prescribed, it can be easily substituted for several low-content lenalidomide formulations if there is no high-content formulation.

Definition of Terms Unless otherwise stated, some terms used herein may be defined as follows.

Unless the context clearly indicates otherwise, "comprising" or "contains" means including, without limitation, any component (or component), and other components ( or constituents).

"Lenalidomide" may also be a lenalidomide base (a salt-free base), or a pharmaceutically acceptable salt or isomer thereof, or a mixture thereof. It may also be in different hydrates in each case and in different crystalline forms in each case. For example, various hydrates such as lenalidomide anhydrate, hemihydrate, monohydrate, dihydrate, and trihydrate, or various solvates, or mixtures thereof may be used.

To solve the above problems, the present invention provides an oral tablet composition comprising lenalidomide and one or more pharmaceutically acceptable carriers as active ingredients. More specifically, an oral tablet composition is provided comprising lenalidomide, a diluent, a disintegrant and a lubricant.

In the oral tablet composition according to the present invention, the active ingredient, lenalidomide, may be in various doses per unit dosage form, preferably 1 mg to 50 mg, more preferably 2 mg to 30 mg, even more preferably 2.5 mg to 2.5 mg. A dose of 25 mg may be used.

The oral tablet composition of the present invention has a constant content ratio of the diluent, disintegrant, lubricant and coating agent regardless of the dose of lenalidomide. Therefore, when a relatively low-content lenalidomide preparation is administered, the convenience of administration is improved, and when a high-content lenalidomide preparation is prescribed, it can be easily replaced with a low-content lenalidomide preparation.

In one embodiment, the diluent of the oral tablet composition may be one or more selected from the group consisting of sugars, sugar alcohols, cellulose, starch, inorganic salts and mixtures thereof; one or more selected from the group consisting of disintegrants, wet disintegrants, and mixtures thereof; lubricants selected from one or more of the group consisting of soluble lubricants, insoluble lubricants, and mixtures thereof; good too.

In one embodiment, the oral tablet composition comprises 1 part lenalidomide to 2-50 parts diluent, 0.05-10 parts disintegrant, 0.05-10 parts lubricant. Preferably, the oral tablet composition comprises 2-45 parts by weight of diluent, 0.2-1.5 parts by weight of disintegrant, and 0.1-3 parts by weight of lubricant to 1 part by weight of lenalidomide.

In the present invention, said diluents are, for example, lactose (anhydrous or hydrate, e.g. monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, carbonate Calcium, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, One or more selected from the group consisting of kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrate, dextrin, and mixtures thereof may be, but are not limited to. Preferably, it may be lactose, microcrystalline cellulose, mannitol, starch or mixtures thereof. More preferably, the diluent may be a mixture of two or more. Most preferably, it may be a mixture of lactose and microcrystalline cellulose. Diluents can also act as binders.

In the present invention, the diluent is, for example, 2 to 50 parts by weight, or more than 2 to less than 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 1 part by weight of lenalidomide. Used in parts by weight amounts. If the amount of diluent used is much less than the above range, it will be difficult to manufacture tablets. obtain.

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

In one embodiment, the disintegrant is for example 0.05-10 parts by weight, or 0.1-5 parts by weight, or 0.2-1.5 parts by weight, or 0.05-10 parts by weight, or 0.2-1.5 parts by weight, per 1 part by weight of lenalidomide. Amounts of 1 to 1 part by weight may be used. If the amount of the disintegrant used is much less than the above range, there may be a problem of delayed dissolution rate due to delayed disintegration rate. On the other hand, if the amount of the disintegrant used is much larger than the above range, productivity problems such as poor compression and poor coating may occur.

In the present invention, the term "lubricant" is a concept encompassing lubricants, anti-tacking agents, and glidants.
For example, 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, Polyoxy Monostearate. It may be one or more selected from the group consisting of ethylene, glyceryl triacetate, sucrose monolaurate and mixtures thereof, but is not limited thereto. Said 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 for example from 0.05 to 10 parts by weight, or from more than 0.05 to less than 4 parts by weight, or from 0.1 to 5 parts by weight, or from 0.05 part by weight to 1 part by weight of lenalidomide. An amount of 1 to 3 parts by weight, or 0.1 to 1 part by weight may be used. If the amount of lubricant used is much less than the above range, productivity problems such as poor compression may occur. On the other hand, if the amount of the lubricant is much higher than the above range, problems may arise in terms of elution delay and productivity.

Preferably, the oral tablet composition of the present invention further comprises a coating layer.
The coating base may be a hydrophilic polymer, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and its salts, polymethacrylate, Poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymers (e.g. Eudragit® E, Evonik), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose , ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (e.g., Kollidon VA64, manufactured by BASF) , gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan and mixtures thereof, but not limited thereto. Preferably, the coating base is hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer ( For example, Eudragit E, Evonik).

In one embodiment, the coating base is, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.1 to 3.5 parts by weight, or 0 .1 to 2.5 parts by weight. If the amount of the coating base used is much less than the above range, problems may occur such that the entire uncoated tablet is not covered with the coating base or the coating is damaged during handling. On the other hand, if the amount of the coating base is much larger than the above range, the dissolution rate may be excessively delayed.

When the coating layer is formed as a single layer, one or more coating bases may be mixed and used, or the entire tablet may be coated with a sufficient amount of coating base to form the coating layer. The coating layer is preferably two layers or more. For example, when coating with more than two layers, each layer may be made of a different coating base to protect the tablet from drug exposure, moisture, oxidation, and the like. In one embodiment, a primary coating with hydroxypropyl methylcellulose (HPMC) is applied to form a barrier to the drug, followed by a secondary coating with macrogol polyvinyl alcohol grafted polymer to finally form a bilayer. Forming a coating layer is preferred. In one embodiment, a primary coating of hydroxypropyl methylcellulose (HPMC) is applied to form a barrier to the drug, followed by a secondary coating of polyvinyl alcohol (PVA) to form a moisture barrier, resulting in superior performance. can form a two-layer coating layer having Each of the primary and secondary coatings may be 0.02-5, 0.05-2.5, 0.05-1.5, or 0.05-1 parts by weight.

During the process of manufacturing the coated tablets as described above, various additional biological agents are added for the purpose of improving coating efficiency, drug stability, appearance, color, protection, retention, binding, performance, manufacturing methods, etc. Inactive ingredients can be used.

In one embodiment of the present invention, the biologically inert ingredients that may be further included in said coating layer are plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, oxidation It may be one or more selected from the group consisting of inhibitors, foaming agents, antifoaming agents, paraffins, waxes, and the like.

The tablet composition of the present invention is produced by mixing lenalidomide as an active ingredient and one or more pharmaceutically acceptable carriers, compressing the mixture to produce a pre-coated tablet (uncoated tablet), and then preparing the surface of the uncoated tablet. with a coating base.

Specifically, the tablet of the present invention is manufactured in the order of granulation, mixing, tableting, and coating after weighing raw ingredients, or by weighing raw ingredients, mixing, and tableting (direct compression). , coating order. In one embodiment, the tablet of the present invention comprises a first step of mixing lenalidomide and a diluent; a second step of further mixing the first step mixture with a disintegrant and a lubricant; A tableting step can be included. The second step can further include adding a diluent. When two or more diluents are used, diluents different from each other can be used in the first step and the second step.

Granulation can be performed by methods such as dry granulation and wet granulation. In one embodiment, when granulating by wet granulation, the granules are obtained by preparing a binder solution, forming granules from a mixture of drug, diluent, etc., sieving and drying. The remaining ingredients were then mixed and then compressed. The binder solution comprises water-soluble polymers 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), sugars, sugar alcohols such as sucrose, sorbitol, maltitol, xylitol, erythritol, etc. are added to water or ethanol. Alternatively, it can be produced by dissolving in a mixed solution thereof.

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

Direct compression instead of granulation has the advantage of a simpler process as the ingredients are mixed and compressed immediately after weighing the ingredients. Due to the teratogenic side effects of the drug itself, protective equipment must be worn during the manufacturing process. Pregnant women or women who may become pregnant should be excluded. Additionally, it may be most preferable to use direct compression, which minimizes worker exposure to the drug.

Ensuring uniformity of blending is important when the ratio of drug in the tablet is low. Therefore, care must be taken from the mixing process to ensure uniformity of the mix. Mixing uniformity of the mixture can be improved when the drug, diluent, disintegrant, lubricant, and the like are mixed sequentially rather than mixed together.

Since the dose of drug can vary, it is necessary to set the shape, weight and size for each tablet and manufacture it with suitable punches. The same excipients can be used for each dose. Furthermore, the proportion of excipients used may be the same for each dose. By thus designing with the same excipients and having the same proportions for each dose of lenalidomide, the dose of lenalidomide, the dose of each excipient and the total weight of the tablet can be proportional. . Furthermore, the tablet volume can also be proportional to the dose of lenalidomide, ie, as the dose of lenalidomide decreases, the tablet volume decreases proportionally.

When manufactured in this manner, the total weight and volume of the relatively low-content lenalidomide preparation can be reduced, thereby enhancing the convenience of administration. Moreover, when a high-content lenalidomide preparation is prescribed, it becomes easy to replace it with a low-content lenalidomide preparation.

In the present invention, the disintegration time of the uncoated tablet is one of the important factors that can determine the drug release time. Since the dissolution pattern of the drug should be the same even if the dosage of the active ingredient is changed, it is preferable to satisfy the disintegration time of 210 seconds to 350 seconds for tablets of all dosages.

The dissolution test is performed according to No. 1 of the general test methods in the 10th edition (KP X) of the Korean Pharmacopoeia. 35 dissolution test method, and according to the second method, the paddle method, at 37° C. and 50 rpm. The average dissolution rate at a time point can be obtained by testing each of 6 tablets and measuring their dissolution rate at each time point by HPLC. It is preferable that the elution pattern of the drug is the same even if the dose of the active ingredient is changed.

In the bioequivalence test (in vivo PK test), the tablet of the present invention has an AUC (Area under curve) and C _max (maximum blood concentration) value within 80 to 125% compared to conventional capsule formulations. can be satisfied, preferably 90% to 110%, and most preferably 95% to 105%.

The tablet composition containing lenalidomide disclosed in the present invention can be usefully used as a tablet-form composition with further improved convenience of administration, handling, safety and the like.

In addition, the present invention provides a tablet in which the content ratio of each component in the composition is constant regardless of the dose of lenalidomide, thereby enhancing the convenience of administration when administering a lenalidomide formulation with a relatively low content. If a high-strength lenalidomide formulation is prescribed, it can be easily substituted for a low-strength lenalidomide formulation.

FIG. 2 shows elution patterns for the compositions of Examples 1-7. FIG. 4 is a diagram showing elution patterns for Comparative Examples 1 to 4; FIG. 10 shows the elution pattern of the comparative example combination against 25 mg of lenalidomide. FIG. 13 shows the elution pattern of the example combinations against lenalidomide 25 mg.

The invention is further illustrated by the following examples. However, these examples are for the purpose of illustrating the present invention only, and the scope of the present invention is not limited by these examples.

Example 1: Preparation of Lenalidomide 25 mg Tablets

<Manufacturing uncoated tablets>
A lenalidomide 25 mg tablet was prepared with the same content and ingredient ratio as in Table 1 above. Specifically, 5.0 g of lenalidomide and 40.0 g of anhydrous lactose were sieved and mixed. Then 31.8 g microcrystalline cellulose, 2.4 g croscarmellose sodium and 0.8 g magnesium stearate were sieved and finally mixed. Compressed with a rectangular punch to a weight of 400 mg per tablet. The hardness of the uncoated tablet was about 153N.

<Coating of uncoated tablets>
The above-prepared tablets were double-coated with two types of coating agents at a total amount of 7.5% (w/w) relative to the uncoated tablets for the purpose of drug shielding. After primary coating (2.5% (w/w)) with Opadry (registered trademark) containing HPMC as the main component, secondary coating (5% (w/w)) with Opadry (registered trademark) containing PVA as the main component w/w)) was performed. The tablet volume obtained was about 0.31 cm ³ .

Example 2: Preparation of Lenalidomide 20 mg Tablets

<Manufacturing uncoated tablets>
A lenalidomide 20 mg tablet was prepared with the same content and ingredient ratio as in Table 2 above. It was sieved, blended and compressed with a rectangular punch in the same manner as the preparation of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 200N.

<Coating of uncoated tablets>
Double coating was performed in the same manner as the coating of the uncoated tablets in Example 1. The tablet volume obtained was about 0.25 cm ³ .

Example 3: Preparation of Lenalidomide 15 mg Tablets

<Manufacturing uncoated tablets>
A lenalidomide 15 mg tablet was prepared with the same content and ingredient ratio as in Table 3 above. It was sieved, blended and compressed with a rectangular punch in the same manner as the preparation of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 170N.

<Coating of uncoated tablets>
Double coating was performed in the same manner as the coating of the uncoated tablets in Example 1. The resulting tablet volume was approximately 0.19 cm ³ .

Example 4: Preparation of Lenalidomide 10 mg Tablets

<Manufacturing uncoated tablets>
A lenalidomide 10 mg tablet was prepared with the same content and ingredient ratio as in Table 4 above. It was sieved, blended and compressed with a rectangular punch in the same manner as the preparation of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 140N.

<Coating of uncoated tablets>
Double coating was performed in the same manner as the coating of the uncoated tablets in Example 1. The tablet volume obtained was about 0.16 cm ³ .

Example 5: Preparation of Lenalidomide 7.5 mg Tablets

<Manufacturing uncoated tablets>
A lenalidomide 7.5 mg tablet was prepared with the same content and ingredient ratio as in Table 5 above. It was sieved, blended and compressed with a rectangular punch in the same manner as the preparation of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 93N.

<Coating of uncoated tablets>
Double coating was performed in the same manner as the coating of the uncoated tablets in Example 1. The tablet volume obtained was about 0.09 cm ³ .

Example 6: Preparation of Lenalidomide 5 mg Tablets

<Manufacturing uncoated tablets>
Lenalidomide 5 mg tablets were prepared with the same content and ingredient ratio as in Table 6 above. It was sieved, blended and compressed with a rectangular punch in the same manner as the preparation of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 80N.

<Coating of uncoated tablets>
Double coating was performed in the same manner as the coating of the uncoated tablets in Example 1. The tablet volume obtained was about 0.06 cm ³ .

Example 7: Preparation of Lenalidomide 2.5 mg Tablets

<Manufacturing uncoated tablets>
A lenalidomide 2.5 mg tablet was prepared with the same content and ingredient ratio as in Table 7 above. It was sieved, blended and compressed with a rectangular punch in the same manner as the preparation of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 50N.

<Coating of uncoated tablets>
Double coating was performed in the same manner as the coating of the uncoated tablets in Example 1. The resulting tablet volume was approximately 0.03 cm ³ .

Comparative Example: Control Drug Revlimid (registered trademark) Capsules As shown in Table 8 below, Revlimid capsules currently on the market were used as comparative examples.

Test Example 1: Friability Measurement Friability is measured using a Pharmatest friability tester for tablets weighing 4 g or more according to the method described in USP 1216 Tablet Friability Test. Table 9 below shows the differences between the uncoated tablets and the coated tablets for Examples 1 to 7 (measurement time = 4 minutes).

Test Example 2: Disintegration test According to the disintegration test method of the 10th edition of the Korean Pharmacopoeia, a disintegration test was performed on Examples 1 to 7 and Comparative Example 1 in a pH 1.2 solution (n = 6). are shown in Table 10 below.

The formulations of Examples 1-7 and Comparative Example 1 had a disintegration time within the preferred range of 210 seconds to 350 seconds.

Test Example 3: Comparative dissolution test Using the example and comparative example (Revlimid (registered trademark) capsule formulation), dissolution was performed in a 0.01 M HCl solution according to the dissolution test method described in the US FDA dissolution test method, lenalidomide section. rate was measured.
<Elution conditions>
Dissolution test apparatus: paddle method of Korean Pharmacopoeia dissolution test method Test liquid: 0.01 M HCl solution Rotation speed: 50 rpm
Temperature: 37°C
Elution standard time points: 5 minutes, 10 minutes, 15 minutes, 30 minutes Analysis method: HPLC analysis method HPLC analysis conditions Detector: Ultraviolet absorption photometer (measurement wavelength 210 nm)
Column: 250 mm length, 4.6 mm diameter, 5 μm C18 column or equivalent Flow rate: 1.0 mL/min Injection volume: 10 μL
Mobile phase: listed in Table 11 below

- Solvent A: after dissolving 1.36 g of potassium dihydrogen phosphate in 1000 mL of water, adjusting the pH of the solution to 3.5 ± 0.05 using orthophosphate, Filtered solution - Solvent B: Methanol and acetonitrile mixed in a ratio of 90:10 (v/v), filtered solution

As shown in FIGS. 1 and 2, it was confirmed that the elution patterns of Examples 1 to 7 are all comparable (dissolution rates are included within the upper and lower limits of the curves at all elution time points). On the other hand, it was found that the elution patterns of Comparative Examples 1 to 4 differ in initial elution depending on dose.

In addition, in order to compare the deviation of the dissolution rate between Examples and Comparative Examples, the total amount of lenalidomide was set to 25 mg. As a result, it was observed that the deviation was significantly lower in the case of the combination of Examples than in the combination of Comparative Examples (Table 12 and FIGS. 3 and 4).

Test Example 4: Stability test In contrast to Examples 1 and 7, changes in the content of the formulation and Impurity level changes were evaluated for 6 months. Impurity levels were measured using the HPLC analytical method using the following conditions.
Detector: Ultraviolet absorption photometer (measurement wavelength 210 nm)
Column: Eclipse XDB-C18, 4.6 mm x 150 mm, 5 μm or equivalent column Mobile Phase: Listed in Table 13 below

- Solvent A: 1.36 g of potassium dihydrogen phosphate was dissolved in 1000 mL of water, then the pH of the solution was adjusted to 3.5 ± 0.05 using orthophosphate and filtered. Solution - Solvent B: Methanol and acetonitrile mixed at a ratio of 90:10 (v/v), filtered solution Flow rate: 0.8 mL/min Injection volume: 10 μL
Column temperature: 27°C
Sample analysis temperature: 5°C

From the above studies, content changes and impurity levels in both formulations of Examples 1 and 7 remained unchanged from the beginning of the study over the duration of the study. It was found that this result indicates that the formulations with the compositional ratios provided by the present invention are stable at both high and low doses. Therefore, it is implied that all single dose formulations within the range have adequate stability.

Test Example 5: Lenalidomide Bioequivalence Study To compare the test substance Lenalidomide tablets (25 mg dose) prepared in Example 1 with the reference substance Blamide® (Celgene, 25 mg dose), 41 A bioequivalence study was performed on 10 healthy male volunteers.
The subjects were divided into two groups, given the test substance and the comparison substance in water under fasting conditions, and blood was collected at predetermined intervals for up to 24 hours. Two weeks later, the groups were changed to test the same drug. Blood was collected, plasma was separated from the collected blood samples and they were cryopreserved. Samples were analyzed by LC/MS/MS instrumentation to obtain blood concentrations. AUC and C _max were calculated from the data, and the results are shown in Table 14 below.

From the data above, the tablet of Example 1 was evaluated to be bioequivalence when compared to the comparative dosage form.

Test Example 6: Tablet quality test according to excipient content Based on the tablets prepared in Examples 1 and 7, the tablet quality was evaluated by varying the excipient content. Friability was evaluated according to Test Example 1, and disintegration rate was evaluated according to Test Example 2. The parts by weight of each excipient are the weight ratio to 1 part by weight of lenalidomide.

As shown in Table 15 above, regardless of the lenalidomide content per tablet, more than 2 to less than 50 parts by weight (preferably 15 to 45 parts by weight) of a diluent and 0 parts by weight of a lubricant are added to 1 part by weight of lenalidomide. .05 to less than 4 parts by weight and 0.1 to less than 3 parts by weight of the coating agent achieves a friability of 0.5% or less and a disintegration time of 210 to 350 seconds to produce lenalidomide of preferred quality. was possible.

Claims (7)

An oral tablet composition comprising lenalidomide; a diluent; a disintegrant; and a lubricant;
The diluent content is 10 to 20 parts by weight per 1 part by weight of lenalidomide,
The content of the disintegrant is 0.1 to 1 part by weight with respect to 1 part by weight of lenalidomide,
The lubricant content is 0.1 to 1 part by weight with respect to 1 part by weight of lenalidomide,
the diluent is selected from the group consisting of lactose, microcrystalline cellulose, mannitol, starch, and mixtures thereof;
the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, and mixtures thereof;
An oral tablet composition, wherein the lubricant is selected from the group consisting of magnesium stearate, stearic acid, highly dispersed silica, and mixtures thereof. 2. The oral tablet composition of claim 1, further comprising a coating layer. The oral tablet composition according to claim 2, wherein the content of the coating layer is 0.1-5 parts by weight per 1 part by weight of lenalidomide. The tablet composition for oral use according to any one of claims 1 to 3, wherein the content of said lenalidomide is 1 mg to 50 mg. The content ratio of lenalidomide, diluent, disintegrant and lubricant, or the content ratio of lenalidomide, diluent, disintegrant, lubricant and coating layer is constant regardless of the content of lenalidomide. oral tablet composition of 4. The oral tablet composition according to claim 2 or 3, wherein the coating layer is two or more layers. The coating base of the coating layer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol polyvinyl alcohol. Graft copolymer, polymer of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer, vinylpyrrolidone-vinyl acetate copolymer, gelatin, guar gum, partial 6. The oral tablet composition of Claim 5 selected from the group consisting of hydrolyzed starch, alginate, xanthan and mixtures thereof.

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