JP2021518424A - Oral tablet composition of various doses of lenalidomide - Google Patents

Abstract

The present invention relates to an oral tablet composition containing lenalidomide and a method for producing the same. More specifically, it shows physicochemical equivalence with hard capsule renalidemid preparations and has the same pharmacological and therapeutic effects in non-clinical and bioequivalence studies, ease of administration, handleability, safety, etc. The present invention relates to a composition in the form of an improved tablet and a method for producing the same. [Selection diagram] Fig. 1

Description

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

Multiple myeloma is a hematological malignancies characterized by abnormal differentiation and proliferation of plasma cells. These abnormal plasma cells are called myeloma cells. It mainly occurs in men (especially black men) 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 are bortezomib, thalidomide and lenalidomide.

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

Since lenalidomide is also a derivative of thalidomide, it cannot be prescribed to pregnant women. Therefore, lenalidomide was marketed as a hard capsule so as not to cause damage due to an unintended outflow of the drug. That is, the outflow and disappearance of the drug were controlled by filling the thick hard capsule with the drug in the same manner as thalidomide.

The brand name in South Korea is Lebramide® Capsules, which contains lenalidomide hemihydrate. Rebramide® capsule, which is a rigid capsule preparation, is filled in No. 0 capsule in all cases of 25, 20, 15 and 10 mg preparations, and its long axis is about 2.17 cm, which is quite long and bulky. ing. Therefore, patients, especially elderly patients, may find it inconvenient to take. In addition, capsules may stick to the throat and esophagus during swallowing, even when taken with water. In this case, the capsule may not be removed from the site, even if the patient drinks a large amount of water. If the drug is accidentally released from the capsule, it can cause pain and, in some cases, inflammation. In particular, in the case of the 25, 20, 15, and 10 mg formulations of Rebramide® capsules, all of them are filled in No. 0 capsules, even though the content of the active ingredient is different, and 20, 15, 10 mg. It also causes great inconvenience to patients who have to take capsules with a relatively low content such as the content. In addition, the commercially available capsule product with a content of 7.5 mg and 5 mg uses No. 2 capsule, and the capsule product with a content of 2.5 mg uses No. 4 capsule, which is compared with the capsule product with a maximum content of 25 mg. When, despite the content of the active ingredient being 30% or less, there is almost no difference in capsule size, and patients who have to take low content capsules such as 7.5, 5, 2.5 mg. However, you may feel a great inconvenience when taking it.

Therefore, patients prescribed to administer lenalidomide in relatively low content (eg, 20 mg or less) must also take large capsules that are long, bulky, and inconvenient to take. There was an inconvenience.

In addition, the lenalidomide capsule formulation with a relatively low content contains an excipient at a relatively higher content ratio when compared with the lenalidomide 25 mg capsule formulation, which is the highest content formulation, and therefore the lenalidomide capsule formulation with a relatively low content. And the high content lenalidomide capsule preparation may not show the same dissolution pattern as each other. Therefore, when a high content lenalidomide capsule formulation is prescribed, replace it with a low content lenalidomide capsule formulation (eg, replace lenalidomide 25 mg capsules with 5 lenalidomide 5 mg capsules, or lenalidomide 25 mg. Care should be taken when substituting capsules for lenalidomide 15 mg capsules and 10 mg capsules).

Lenalidomide, on the other hand, has pH-dependent solubility and can have a significant effect on drug solubility and absorption depending on where it is disrupted in the body. Therefore, when developing various single-dose formulations, adjusting the disintegration time and dissolution pattern of each formulation to be similar is an important requirement for ensuring a uniform drug absorption pattern.

An object of the present invention is to change the dosage form of a commercially available hard capsule lenalidomide preparation to a tablet, which is short in length, not bulky, easy to take, and suitable for selection of coating base and coating thickness. By selecting the tablet composition, the internal drug and the handler can be separated from each other by completely wrapping the entire tablet over a certain thickness, and the release of the drug during the coating process can be prevented. To provide things. Therefore, a tablet composition having the same pharmacological efficacy and effect as a capsule preparation on the market and further developed to improve appearance, convenience of administration and handling, ease of manufacture, safety, etc. To provide.

Another object of the present invention is to provide 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 the lenalidomide preparation having a relatively low content is administered. Moreover, when a high content lenalidomide preparation is prescribed, it can be easily replaced with some low content lenalidomide preparations in the absence of a high content.

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

In the context, "contains" or "contains" means to include any component (or component) without any special limitation, unless explicitly indicated otherwise, and other components (contains). Or components) should not be interpreted as excluding.

Further, "lenalidomide" may be a lenalidomide base (salt-free base), a pharmaceutically acceptable salt thereof or an isomer thereof, or a mixture thereof. Further, in each case, it may be various hydrates, and in each case, it may be in various crystalline forms. For example, it may be various hydrates such as renalidemid anhydride, hemihydrate, monohydrate, dihydrate, trihydrate, or various solvates, or a mixture thereof.

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

In the oral tablet composition according to the present invention, the active ingredient lenalidomide may be in various doses per unit preparation, but is preferably 1 mg to 50 mg, more preferably 2 mg to 30 mg, still more preferably 2.5 mg to. It may be a dose of 25 mg.

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 the lenalidomide preparation having a relatively low content is administered, the convenience of administration is enhanced, and when the lenalidomide preparation having a high content is prescribed, this can be easily replaced with the lenalidomide preparation having a low content.

In one embodiment, the diluent for the oral tablet composition may be selected from the group consisting of sugars, sugar alcohols, celluloses, starches, inorganic salts and mixtures thereof; the disintegrant may be swellable. One or more may be selected from the group consisting of disintegrants, wetting disintegrants, and mixtures thereof; the lubricants may be selected from one or more groups consisting of soluble lubricants, insoluble lubricants and mixtures thereof. May be good.

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

In the present invention, the diluent is, for example, lactose (anhydrous or hydrate, for example, 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, martitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrin, dextrin and mixtures thereof. However, it is not limited to these. Preferably, it may be lactose, microcrystalline cellulose, mannitol, starch or a mixture 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 may combine the roles of 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, 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. Used in parts by weight. If the amount of the diluent used is much smaller than the above range, it is difficult to produce tablets, and if it is much larger than the above range, the concentration of the drug becomes low, and there is a problem in ensuring content uniformity during production. obtain.

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, carboxymethyl cellulose, crospovidone, L-HPC (low substitution hydroxypropyl cellulose), starch (wheat, rice, corn or potato starch), sodium carboxymethyl starch, sodium starch glycolate, alginic acid, carboxy. It may be, but is not limited to, one or more selected from the group consisting of sodium methylcellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch and mixtures thereof. Preferably, it may be croscarmellose sodium, crospovidone, L-HPC, sodium starch glycolate. More preferably, it may be croscarmellose sodium.

In one embodiment, the disintegrant is, 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. It may be used in an amount of 1 to 1 part by weight. If the amount of the disintegrant used is much smaller than the above range, there may be a problem of delay in elution rate due to delay in 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 lubricant is a concept that includes a lubricant, an anti-adhesive agent, and a flow accelerator. 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 behate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxymonostearate It may be, but is not limited to, one or more selected from the group consisting of ethylene, glyceryl triacetate, sucrose monolaurate and mixtures thereof. 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, for example, 0.05 to 10 parts by weight, or more than 0.05 to less than 4 parts by weight, or 0.1 to 5 parts by weight, or 0. It may be used in an amount of 1 to 3 parts by weight or 0.1 to 1 part by weight. If the amount of lubricant used is much smaller than the above range, productivity problems such as poor compression may occur. On the other hand, if the amount of lubricant is much larger than the above range, problems may occur in elution delay and productivity.

The oral tablet composition of the present invention preferably further comprises a coating layer.
The coating base may be a hydrophilic polymer, such as hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and its salt, polymethacrylate, and the like. Poly (butylmethacrylate, 2-dimethylaminoethylmethacrylate, methylmethacrylate) copolymers (eg, Eudragit® E, Evonik), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose , Ethylhydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low substitution HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (for example, Kollidon VA64, manufactured by BASF). , Gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and a mixture thereof, which may be one or more selected from the group, but is not limited thereto. Preferably, the coating base is a hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer ( For example, it may be 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, relative to 1 part by weight of renalidemid. .1 to 2.5 parts by weight may be used. If the amount of the coating base used is much smaller than the above range, there may be a problem 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 kinds of coating bases may be mixed and used, or the entire tablet may be coated with a sufficient amount of the coating base to form the coating layer. The coating layer is preferably two or more layers. For example, when coating with more than two layers, each layer may be made with different coating bases to protect the tablets from exposure to drugs, moisture, oxidation and the like. In one embodiment, a primary coating with hydroxypropyl methylcellulose (HPMC) is applied to form a barrier against the drug, followed by a secondary coating with macrogol polyvinyl alcohol graft polymer to finally provide a bilayer. It is preferable to form a coating layer. In one embodiment, better function is achieved by performing a primary coating with hydroxypropyl methylcellulose (HPMC) to form a barrier against the drug and then a secondary coating with polyvinyl alcohol (PVA) to form a moisture-proof barrier. It is possible to form a two-layer coating layer having. Each of the primary coating and the secondary coating may be 0.02 to 5, 0.05 to 2.5, 0.05 to 1.5, or 0.05 to 1 part by weight.

In the process of manufacturing coated tablets as described above, various additional biology for the purpose of further improving coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance, manufacturing method, etc. Inactive ingredients can be used.

In one embodiment of the invention, the biologically inert components that may be further included in the coating layer are plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, oxidations. It may be one or more selected from the group consisting of an inhibitor, a foaming agent, an antifoaming agent, paraffin, wax and the like.

The tablet composition of the present invention is prepared by mixing lenalidomide as an active ingredient and one or more pharmaceutically acceptable carriers, and tableting the mixture to produce a pre-coating tablet (uncoated tablet), and then the surface of the uncoated tablet. Can be produced through a process involving coating with a coating base.

Specifically, the tablets of the present invention are manufactured in the order of granulation, mixing, tableting, and coating after the nominal amount of the raw material component, or after the nominal amount of the raw material component, mixing, tableting (direct tableting). , Can be manufactured in the order of coating. In one embodiment, the tablet of the present invention comprises a first step of mixing renalidemid and a diluent; a second step of further mixing a disintegrant and a lubricant with the mixture of the first step; and a mixture of the second step. It can include a step of tableting. The second step can further include the step of adding a diluent. When there are two or more diluents, different diluents can be used in the first step and the second step.

Granulation can be performed by a method such as dry granules or wet granules. In one embodiment, when granulated with wet granules, the granules are obtained by making a binder solution, forming the granules from a mixture such as a diluent with the drug, sieving and drying. Then, the remaining components were mixed and then compressed. The binder solution is a water-soluble polymer such as hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), L-HPC (low substitution HPC), polyvinylpyrrolidone (PVP), and the like. Vinylpyrrolidone-vinylacetate copolymer (eg, Kollidon® VA64, manufactured by BASF), or sugars, sugar alcohols, such as sucrose, sorbitol, maltitol, xylitol, erythritol, etc. in water or ethanol. Alternatively, it can be produced by dissolving it in a mixed solution of these.

In one embodiment, when granulated with dry granules, a mixture of drug, diluent and binder was pressed and screened using a roller compactor or the like. Then, the remaining components were mixed and then compressed.

Direct compression instead of granulation has the advantage of simplifying the process because the ingredients are mixed and compressed immediately after the nominal amount of the raw material. Protective equipment must be worn during the manufacturing process due to the teratogenic side effects of the drug itself. Pregnant and potentially pregnant women should be excluded. In addition, it may be most preferable to use direct compression, which minimizes worker exposure to the drug.

When the proportion of the drug in the tablet is low, it is important to ensure the uniformity of the mixture. Therefore, care must be taken from the mixing step to ensure the uniformity of mixing. Mixing uniformity of a mixture can be improved when drugs, diluents, disintegrants, lubricants, etc. are mixed sequentially rather than together.

Since the dosage of the drug can vary, it is necessary to set the shape, weight and size for each tablet and manufacture it with a suitable punch. The same excipient can be used for each dose. Furthermore, the proportion of excipients used may be the same for each dose. By designing each dose of lenalidomide to have the same excipient and the same proportion, the dose of lenalidomide, the dose of each excipient and the total weight of the tablet can be proportional to each other. .. Furthermore, the volume of the tablet can also be proportional to the dose of lenalidomide, i.e., the volume of the tablet decreases proportionally as the dose of lenalidomide decreases.

When manufactured in this manner, the total weight and volume of the lenalidomide preparation having a relatively low content can be reduced, and the convenience of administration can be improved at the time 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 release time of the drug. In the end, it is preferable that the disintegration time be between 210 and 350 seconds for all doses of tablets, as the drug elution pattern must be the same across different doses of active ingredient.

The dissolution test is No. 1 among the general test methods in the 10th edition (KPX) of the Korean Pharmacopoeia. According to the 35 dissolution test method, the paddle method, which is the second method, is carried out at 37 ° C. and 50 rpm. The average dissolution rate at a time point can be obtained by testing each of the 6 tablets and measuring their dissolution rate at each time point by HPLC. It is preferable that the dissolution 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 tablets of the present invention have AUC (Area under curve) and C _max (maximum blood concentration) values within 80 to 125% of those of conventional capsule preparations. Can be satisfied, preferably 90 to 110% can be satisfied, and most preferably 95% to 105% can be satisfied.

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

Further, 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 the lenalidomide preparation having a relatively low content is administered. When a high content lenalidomide preparation is prescribed, it can be easily replaced with a low content lenalidomide preparation.

It is a figure which showed the elution pattern with respect to the composition of Examples 1-7. It is a figure which showed the dissolution pattern with respect to the comparative examples 1 to 4. It is a figure which showed the dissolution pattern of the combination of the comparative example with respect to lenalidomide 25 mg. It is a figure which showed the dissolution pattern of the combination of an Example with respect to 25 mg of lenalidomide.

The present invention will be described in more detail with reference to the following examples. However, these examples are for the purpose of exemplifying the present invention only, and the scope of the present invention is not limited to these examples.

Example 1: Production of lenalidomide 25 mg tablet

<Manufacturing of uncoated locks>
Lenalidomide 25 mg tablets were produced with the same content and component 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 of microcrystalline cellulose, 2.4 g of croscarmellose sodium and 0.8 g of magnesium stearate were sieved and finally mixed. It was compressed with a rectangular punch against a weight of 400 mg per tablet. The hardness of the uncoated tablet was about 153N.

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

Example 2: Production of lenalidomide 20 mg tablet

<Manufacturing of uncoated locks>
Lenalidomide 20 mg tablets were produced with the same content and component ratio as in Table 2 above. It was sieved, mixed and compressed with a rectangular punch in the same manner as in the production of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 200 N.

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

Example 3: Production of lenalidomide 15 mg tablet

<Manufacturing of uncoated locks>
Lenalidomide 15 mg tablets were prepared with the same content and component ratio as in Table 3 above. It was sieved, mixed and compressed with a rectangular punch in the same manner as in the production of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 170 N.

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

Example 4: Production of lenalidomide 10 mg tablet

<Manufacturing of uncoated locks>
Lenalidomide 10 mg tablets were produced with the same content and component ratio as in Table 4 above. It was sieved, mixed and compressed with a rectangular punch in the same manner as in the production of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 140 N.

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

Example 5: Production of lenalidomide 7.5 mg tablet

<Manufacturing of uncoated locks>
Lenalidomide 7.5 mg tablets were prepared with the same content and component ratio as in Table 5 above. It was sieved, mixed and compressed with a rectangular punch in the same manner as in the production of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 93N.

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

Example 6: Production of lenalidomide 5 mg tablet

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

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

Example 7: Production of lenalidomide 2.5 mg tablet

<Manufacturing of uncoated locks>
Lenalidomide 2.5 mg tablets were produced with the same content and component ratio as in Table 7 above. It was sieved, mixed and compressed with a rectangular punch in the same manner as in the production of the uncoated tablets of Example 1. The hardness of the uncoated tablet was about 50 N.

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

Comparative Example: Control Rebramide® Capsule As shown in Table 8 below, a currently commercially available Rebramide capsule was used as a comparative example.

Test Example 1: Measurement of abrasion degree The abrasion degree is measured by the method described in the abrasion degree test item of 1216 tablets of the United States Pharmacopeia using a Pharmacopoeia wear rate tester (Pharmatest friability tester) for tablets of 4 g or more. The differences between the uncoated tablets and the coated tablets with respect to Examples 1 to 7 are shown in Table 9 below (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), and the results were obtained. Is shown in Table 10 below.

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

Test Example 3: Comparative dissolution test Elution in 0.01 M HCl solution using Examples and Comparative Examples (Rebramide® capsule formulation) according to the dissolution test method described in the lenalidomide section of the US FDA dissolution test method. The rate was measured.
<Elution conditions>
Dissolution test equipment: Paddle method test solution of the Korean Pharmacopoeia dissolution test method: 0.01M HCl solution Rotation speed: 50 rpm
Temperature: 37 ° C
Elution reference time point: 5 minutes, 10 minutes, 15 minutes, 30 minutes Analysis method: HPLC analysis method HPLC analysis conditions Detector: Ultraviolet absorptiometer (measurement wavelength 210 nm)
Column: Length 250 mm, Diameter 4.6 mm, 5 μm C18 column or equivalent column 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, adjust the pH of the solution to 3.5 ± 0.05 using phosphoric acid (orthophosphate). Filtered solution-Solvent B: A filtered solution of methanol and acetonitrile mixed at a ratio of 90:10 (v / v).

As shown in FIGS. 1 and 2, it was confirmed that the elution patterns of Examples 1 to 7 were all about the same level (the elution rate was included within the upper and lower limit curves at all elution time points). On the other hand, it was found that the elution patterns of Comparative Examples 1 to 4 differed in the initial elution depending on the dose.

In addition, in order to compare the deviations of the elution rates of the examples and the comparative examples, the elution rates were compared by combining each example and the comparative example so that the total amount of lenalidomide was 25 mg, as shown in Table 12 below. 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 Compared to Example 1 and Example 7, the content change of the pharmaceutical product under the acceleration condition of 40 ° C./75% RH condition and the long-term storage condition of 25 ° C./60% RH condition. The change in impurity level was evaluated for 6 months. The impurity level was measured by using an HPLC analysis method using the following conditions.
Detector: Ultraviolet absorptiometer (measurement wavelength 210 nm)
Column: Eclipse XDB-C18, 4.6 mm x 150 mm, 5 μm or equivalent column Mobile phase: Table 13 below

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

From the above test, the content change and the impurity level in both the formulations of Example 1 and Example 7 were maintained throughout the test period without any significant change from the initial test. This result was found to indicate that the composition ratio formulation provided in the present invention is stable at both high doses and low doses. Therefore, it means that all the single-quantity formulations in the range have appropriate stability.

Test Example 5: Bioequivalence test of lenalidomide In order to compare the test substance lenalidomide tablet (25 mg dose) produced in Example 1 with the comparative substance Bramid® (Celgene, 25 mg dose) 41 A bioequivalence test was performed on healthy male volunteers.
The subjects were divided into two groups, the test substance and the comparative substance were given with water under fasting, and blood was collected at predetermined intervals for up to 24 hours. Two weeks later, different groups were tested for the same drug. Blood was collected, plasma was separated from the collected blood samples, and they were cryopreserved. The sample was analyzed by LC / MS / MS apparatus to obtain blood concentration. AUC and C _max were calculated from the data, and the results are shown in Table 14 below.

From the above data, the tablets of Example 1 were evaluated to be bioequivalent when compared to the dosage form of the comparative substance.

Test Example 6: Tablet Quality Test Based on Excipient Content Based on the tablets produced in Examples 1 and 7, the tablet quality was evaluated with different excipient contents. The degree of abrasion was evaluated according to Test Example 1, and the disintegration rate was evaluated according to Test Example 2. The weight portion of each excipient is the weight ratio to 1 part by weight of lenalidomide.

As shown in Table 15, the diluent is more than 2 parts by weight to less than 50 parts by weight (preferably 15 to 45 parts by weight) and the lubricant is 0, based on 1 part by weight of lenalidomide, regardless of the content of lenalidomide per tablet. When the weight is more than .05 to less than 4 and the amount of the coating agent is 0.1 or more and less than 3 parts by weight, the degree of abrasion is 0.5% or less and the decay time is 210 to 350 seconds, and the production of lenalidomide of preferable quality is achieved. Was possible.

Claims (10)

An oral tablet composition comprising lenalidomide; a diluent; a disintegrant; and a lubricant;
The content of the diluent is 2 to 50 parts by weight with respect to 1 part by weight of lenalidomide.
The content of the disintegrant is 0.05 to 10 parts by weight with respect to 1 part by weight of lenalidomide.
An oral tablet composition having a lubricant content of 0.05 to 10 parts by weight with respect to 1 part by weight of lenalidomide. The content of the diluent is 2 to 45 parts by weight with respect to 1 part by weight of lenalidomide.
The content of the disintegrant was 0.2 to 1.5 parts by weight with respect to 1 part by weight of lenalidomide.
The oral tablet composition according to claim 1, wherein the content of the lubricant is 0.1 to 3 parts by weight with respect to 1 part by weight of lenalidomide. The oral tablet composition according to claim 1, further comprising a coating layer. The oral tablet composition according to claim 3, wherein the content of the coating layer is 0.1 to 5 parts by weight with respect to 1 part by weight of lenalidomide. The oral tablet composition according to any one of claims 1 to 4, wherein the content of lenalidomide is 1 mg to 50 mg. The fifth aspect of claim 5, wherein the content ratios of lenalidomide, the diluent, the disintegrant and the lubricant, or the content ratios of the lenalidomide, the diluent, the disintegrant, the lubricant and the coating layer are constant regardless of the content of the lenalidomide. Oral tablet composition. The oral tablet composition according to claim 3 or 4, wherein the coating layer is two or more layers. The oral tablet composition according to claim 6, wherein the tablet volume is proportional to the content of lenalidomide. One or more diluents selected from the group consisting of sugars, sugar alcohols, celluloses, starches, inorganic salts and mixtures thereof; disintegrants from swelling disintegrants, wet disintegrants, and mixtures thereof. The oral tablet composition according to claim 1, wherein one or more selected from the group consisting of; and one or more selected from the group consisting of a soluble lubricant, an insoluble lubricant and a mixture thereof. thing. The coating base of the coating layer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol polyvinyl alcohol. Graft copolymer, polymer of acrylic acid and its salts, polymethacrylate, poly (butylmethacrylate, 2-dimethylaminoethylmethacrylate, methylmethacrylate) copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partial Selected from the group consisting of hydrolyzed starch, alginate, xanthan and mixtures thereof,
Diluters include lactose, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, phosphoric acid. Tricalcium, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, martitol, sorbitol, xylitol, lactose, dextrin, maltose , Sculose, glucose, fructose, malt dextrin, dextrin, dextrin and mixtures thereof.
Disintegrants are croscarmellose sodium, carboxymethyl cellulose, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium carboxymethyl starch, sodium starch glycolate, alginic acid, sodium carboxymethyl cellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed. One or more selected from the group consisting of decomposed starch and mixtures thereof,
Lubricants include magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, starch, talc, highly dispersed 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, sculose monolaurate and these The oral tablet composition according to claim 6, wherein one or more of them are selected from the group consisting of a mixture of.

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