KR102286497B1 - Oral Tablet Formulation of Lenalidomide with various doses - Google Patents

Abstract

The present invention relates to an oral tablet composition containing lenalidomide and a method for preparing the same. In the equivalence test, equivalence is ensured and the pharmaceutical composition has an equivalent pharmacological therapeutic effect, while convenience, handling, safety, etc. are further improved.

Description

Oral tablet composition of various doses of lenalidomide {Oral Tablet Formulation of Lenalidomide with various doses}

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 experience discomfort 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. In particular, in ^{the case of the 25, 20, 15, and 10 mg formulations, Revlimid ®} capsules are all filled in No. 0 capsules, despite the different contents of the active ingredients, so they are relatively similar to capsules with 20, 15, and 10 mg contents. It causes great inconvenience even to patients who need to take capsules with a low content. In addition, the currently marketed capsule formulations containing 7.5 and 5 mg of lenalidomide use No. 2 capsules, and capsule formulations with 2.5 mg contents use No. 4 capsules. Although the content of the active ingredient is 30% or less, there is no difference in the size of the capsules, so patients who need to take capsules with a low content such as 7.5, 5, or 2.5 mg feel great inconvenience when taking them.

Therefore, even patients prescribed to administer lenalidomide in a relatively small amount (eg, 20 mg or less) have the inconvenience of taking a large capsule formulation that is long, bulky, and inconvenient to take. there is.

In addition, since the lenalidomide capsule formulation with a relatively low content contains excipients in a relatively higher content ratio compared to the lenalidomide 25 mg capsule formulation, which is the highest content formulation, the low content lenalidomide capsule formulation and The dissolution pattern equivalent to each other may not appear between the high content lenalidomide capsule formulations. Therefore, when a high-content lenalidomide capsule formulation is prescribed, it should be replaced with a low-content lenalidomide capsule formulation (e.g., lenalidomide 25 mg capsules and lenalidomide 5 mg capsules). Substitution of 5 capsules, or replacement of lenalidomide 25 mg capsules with lenalidomide 15 mg capsules and 10 mg capsules) requires caution.

On the other hand, lenalidomide has a pH-dependent solubility, which greatly affects the solubility and absorption of the drug depending on where in the body it disintegrates. Therefore, when developing multiple dosage forms, matching the disintegration time and dissolution pattern of each dosage form is an important requirement to secure a uniform drug absorption pattern.

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. Accordingly, it is an object to provide a tablet composition that is equivalent in pharmacological efficacy and effect to a commercially available capsule formulation, and has further improved and improved appearance, convenience in administration and handling, ease of manufacture, safety, and the like.

In addition, an object of the present invention is to provide a tablet with a constant content ratio of each component in the composition regardless of the dose of lenalidomide, thereby enhancing the convenience of taking a formulation with a relatively low content of lenalidomide, and furthermore, a high content of lenalidomide. This is to make it possible to easily replace lenalidomide preparations with several low-content lenalidomide preparations when prescribed lenalidomide preparations do not have a high content.

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

Also, "lenalidomide" may be lenalidomide free base, 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 oral tablet composition comprising lenalidomide as an active ingredient and one or more pharmaceutically acceptable carriers. More specifically, it provides an oral tablet composition 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 present 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 25 mg. may be present in a dose.

In the oral tablet composition of the present invention, the content ratio of the diluent, disintegrant, lubricant and coating agent is constant regardless of the dose of lenalidomide. Therefore, when a relatively low content of lenalidomide preparation is administered, it is possible to improve the convenience of taking the drug, and furthermore, 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; 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 oral tablet composition may contain 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 based on 1 part by weight of lenalidomide. Preferably, the oral tablet composition may contain 2 to 45 parts by weight of a diluent, 0.2 to 1.5 parts by weight of a disintegrant, and 0.1 to 3 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. More preferably, the diluent may be a mixture of two or more kinds. Most preferably a mixture of lactose and microcrystalline cellulose may be selected. The diluent may also act as a binder in some cases.

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 based on 1 part by weight of lenalidomide. It can be used in negative amounts. 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, carboxymethyl cellulose, crospovidone , L-HPC (low-substituted hydroxypropylcellulose), starch (wheat, rice, corn or potato starch), sodium carboxymethyl starch, sodium starch glycolate, alginic acid, sodium carboxymethylcellulose, agar, xylan, gellan gum , may be at least one selected from the group consisting of 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, It may be one or more selected from the group consisting of polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate, and mixtures thereof. it is not 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 0.1 to 3 parts by weight, based on 1 part by weight of lenalidomide, or 0.1 to 1 part by weight. 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.

It is preferable that the oral tablet composition of the present invention further comprises a coating layer.

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 its salts, polymethacrylate, poly(butyl methacrylate) acrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (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), polyvinyl pyrrolidone (PVP), vinyl pyrrolidone - At least one selected from the group consisting of vinyl acetate copolymers (eg Kollidon VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof. However, it 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) copolymers (eg Eudragit E, Evonik).

In one embodiment, the coating base 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 3.5 parts by weight, or 0.1 to 2.5 parts by weight, based on 1 part by weight of lenalidomide. can 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 or the coating is damaged during handling.

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 one embodiment, the first coating is preferably made with hydroxypropylmethylcellulose (HPMC) to form a film blocking the drug, 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 By forming a double-layer coating film having a superior function can be formed. Each of the primary and secondary coatings 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 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 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 can be manufactured through a step including

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. 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 a disintegrant and a lubricant in the mixture of the first step; and tableting the mixture of the second step. The second step may further include adding a diluent. When two or more diluents are used, different diluents may be used in the first step and the second step, respectively.

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, hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinyl pyrrol 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.

When the ratio of drug in the tablet is low, it may be important to ensure mixing uniformity. Therefore, careful consideration may be required to ensure mixing uniformity from the mixing stage. Mixing uniformity of the mixture may be improved if the drug and the diluent, disintegrant, lubricant, etc. are mixed in stages instead of at once.

Because the dosage of the drug may vary, it may be necessary to set the tablet shape, weight, and size for each tablet and manufacture it with an appropriate punch. For each dose, it is preferable that the excipients to be used be of the same kind, and the proportions of the excipients to be used are the same. As described above, by designing to use the same excipient in the same ratio for each dose of lenalidomide, the dose of lenalidomide, the dose of each excipient, and the weight of the entire tablet can be proportional. Furthermore, the volume of the tablet may also be proportional to the dose of lenalidomide, that is, the volume of the tablet may be proportionally decreased as the dose of lenalidomide decreases.

When prepared in this way, the total total weight and volume of the lenalidomide preparation having a relatively low content is reduced, so that the convenience of administration can be improved. Further, when a high content lenalidomide preparation is prescribed, it is easy to replace it with a low content lenalidomide preparation.

In the present invention, the disintegration time of the uncoated tablet may be one of the important factors that can estimate the release time of the drug. Even if the dose of the active ingredient is different, the dissolution pattern of the drug should be the same, so it is preferable that the disintegration time for all tablets in the end satisfies 210 seconds to 350 seconds.

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. Even if the dose of the active ingredient is different, the dissolution pattern of the drug is preferably the same.

The tablet of the present invention can satisfy the values of AUC (Area under curve) and Cmax (highest blood concentration) within 80 to 125% of that of the conventional capsule formulation in the bioequivalence test (In vivo PK test), preferably 90 to 110% may be satisfied, and most preferably 95% to 105% may be satisfied.

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 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 improving the convenience of taking the drug when administering a relatively low content lenalidomide formulation, and furthermore, a high content of lenalidomide When a domide preparation is prescribed, it can be easily replaced with a low-content lenalidomide preparation.

1 shows the dissolution patterns for the compositions of Examples 1 to 7.
Figure 2 shows the dissolution patterns for Comparative Examples 1 to 4.
Figure 3 shows the dissolution pattern of the combination of the comparative example for lenalidomide 25 mg.
Figure 4 depicts the dissolution pattern of the combination of examples for lenalidomide 25 mg.

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 One. lenalidomide Preparation of 25 mg 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 4.0 0.93 Opadry (HPMC series) 10.0 2.33 Opadry (PVA series) 20.0 4.65 Sum 430.0 100.0

<Preparation of uncooked tablets> 25 mg tablets of lenalidomide were prepared with the same content and ratio as in Table 1 above. Specifically, 5.0 g of lenalidomide and 40.0 g of anhydrous lactose were sieved and mixed, and then 31.8 g of microcrystalline cellulose, 2.4 g of croscarmellose sodium, and 0.8 g of magnesium stearate were sieved and mixed, followed by final mixing. This mixture was tableted with a rectangular punch to a hardness of about 153N based on the weight of 400 mg per tablet.

<Najeong's Coating>

A total of 7.5% (w/w) of the previously prepared tablets compared to the uncoated tablet was double-coated with two kinds of coating agents for the purpose of drug masking. 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. The volume of the obtained tablet is about 0.31 cm ³ .

Example 2. lenalidomide Preparation of 20 mg tablets

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 20.0 5.81 Lactose Anhydrous 160.0 46.51 Microcrystalline Cellulose 127.2 36.98 croscarmellose sodium 9.6 2.79 Magnesium Stearate 3.2 0.93 Opadry (HPMC series) 8.0 2.33 Opadry (PVA series) 16.0 4.65 Sum 344.0 100.0

<Preparation of Uncooked Tablets> 20 mg tablets of lenalidomide were prepared with the same content and component ratio as in Table 2 above. Sifted and mixed in the same manner as in the preparation of the uncoated tablet of Example 1, and tableted with a rectangular punch at about 200N.

<Najeong's Coating>

Double coating is carried out in the same way as the coating of the uncoated tablet of Example 1. The volume of the obtained tablet is about 0.25 cm ³

Example 3. lenalidomide Preparation of 15 mg tablets

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 15.0 5.81 Lactose Anhydrous 120.0 46.51 Microcrystalline Cellulose 95.4 36.98 croscarmellose sodium 7.2 2.79 Magnesium Stearate 2.4 0.93 Opadry (HPMC series) 6.0 2.33 Opadry (PVA series) 12.0 4.65 Sum 258.0 100.0

<Preparation of uncooked tablets> 15 mg tablets of lenalidomide were prepared with the same content and ratio as in Table 3 above. Sifted and mixed in the same manner as in the preparation of the uncoated tablet of Example 1, and tableted with a rectangular punch to a hardness of about 170N.

<Najeong's Coating>

Double coating is carried out in the same way as the coating of the uncoated tablet of Example 1. The volume of the obtained tablet is about 0.19 cm ³

Example 4. lenalidomide Preparation of 10 mg tablets

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 10.0 5.81 Lactose Anhydrous 80.0 46.51 Microcrystalline Cellulose 63.6 36.98 croscarmellose sodium 4.6 2.79 Magnesium Stearate 1.6 0.93 Opadry (HPMC series) 4.0 2.33 Opadry (PVA series) 8.0 4.65 Sum 172.0 100.0

<Preparation of Uncooked Tablets> Lenalidomide 10 mg tablets were prepared with the same content and component ratio as in Table 4 above. Sifted and mixed in the same manner as in the preparation of the uncoated tablet of Example 1, and tableted with a rectangular punch to a hardness of about 140N.

<Najeong's Coating>

Double coating is carried out in the same way as the coating of the uncoated tablet of Example 1. The volume of the obtained tablet is about 0.16 cm ³

Example 5. lenalidomide Preparation of 7.5 mg tablets

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 7.5 5.81 Lactose Anhydrous 60.0 46.51 Microcrystalline Cellulose 47.7 36.98 croscarmellose sodium 3.6 2.79 Magnesium Stearate 1.2 0.93 Opadry (HPMC series) 3.0 2.33 Opadry (PVA series) 6.0 4.65 Sum 129.0 100.0

<Preparation of uncooked tablets> Lenalidomide 7.5 mg tablets were prepared with the same content and ingredient ratio as in Table 5 above. Sifted and mixed in the same manner as in the preparation of the uncoated tablet of Example 1, and tableted with a circular punch to a hardness of about 93N.

<Najeong's Coating>

Double coating is carried out in the same way as the coating of the uncoated tablet of Example 1.

The volume of the obtained tablet is about 0.09 cm ³

Example 6. lenalidomide Preparation of 5 mg tablets

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 5.0 5.81 Lactose Anhydrous 40.0 46.51 Microcrystalline Cellulose 31.8 36.98 croscarmellose sodium 2.4 2.79 Magnesium Stearate 0.8 0.93 Opadry (HPMC series) 2.0 2.33 Opadry (PVA series) 4.0 4.65 Sum 86 100.0

<Preparation of uncooked tablets> 5 mg tablets of lenalidomide were prepared with the same content and component ratio as in Table 6 above. Sifted and mixed in the same manner as in the preparation of the raw tablet of Example 1, and tableted with a circular punch with a hardness of about 80N.

<Najeong's Coating>

Double coating is carried out in the same way as the coating of the uncoated tablet of Example 1.

The volume of the obtained tablet is about 0.06 cm ³ .

Example 7. lenalidomide Preparation of 2.5 mg tablets

Composition (mg/tablet) Composition percentage (%) Lenalidomide Anhydrous 2.5 5.81 Lactose Anhydrous 20.0 46.51 Microcrystalline Cellulose 15.9 36.98 croscarmellose sodium 1.2 2.79 Magnesium Stearate 0.4 0.93 Opadry (HPMC series) 1.0 2.33 Opadry (PVA series) 2.0 4.65 Sum 43.0 100.0

<Preparation of uncooked tablets> A 2.5 mg tablet of lenalidomide was prepared with the same content and component ratio as in Table 7 above. Sifted and mixed in the same manner as in the preparation of the uncoated tablet of Example 1, and tableted with a circular punch with a hardness of about 50N.

<Najeong's Coating>

Double coating is carried out in the same way as the coating of the uncoated tablet of Example 1.

The volume of the obtained tablet is about 0.03 cm ³ .

comparative example : control drug Revlimid ^® capsule

As shown in Table 8 below, a currently commercially available Revlimid capsule was used as a comparative example.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Reference drug Revlimid 25mg capsules (including 25.87mg lenalidomide hemihydrate) Control drug Revlimid 15mg capsules
(Contains 15.52mg of lenalidomide hemihydrate) Control drug Revlimid 10mg capsules
(Contains 10.35mg of lenalidomide hemihydrate) Control drug Revlimid 5mg capsules
(Contains 5.17mg of lenalidomide hemihydrate)

test example One. Masondo measurement

Friability is the method described in the US Pharmacopoeia 1216 Tablet Friability section, and Examples 1, 2, 3, 4, 5 by measuring the tablet friability using a Pharmatest friability tester for tablets 4 g or more. , 6 and 7, the differences between the uncoated and coated tablets are shown below. (measurement time = 4 minutes)

Masondo Na-jeong coated tablet Example 1 0.02% 0.00% Example 2 0.02% 0.00% Example 3 0.01% 0.00% Example 4 0.01% 0.00% Example 5 0.01% 0.00% Example 6 0.01% 0.00% Example 7 0.01% 0.00%

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 = 6 for Examples 1, 2, 3, 4, 5, 6, 7 and Comparative Example 1, and the results are shown below. indicated.

disintegration time Example 1 4 minutes 09 seconds Example 2 4 minutes 51 seconds Example 3 4 minutes 45 seconds Example 4 5 minutes 35 seconds Example 5 4 minutes 55 seconds Example 6 4 minutes 46 seconds Example 7 3 minutes 30 seconds Comparative Example 1 4 minutes 38 seconds

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

test example 3: Comparative dissolution test

The dissolution rate was measured in 0.01M HCl solution according to the dissolution test method described in the lenalidomide section of the US FDA Dissolution method with Examples and Comparative Examples (revlimid ^{® capsule formulation).}

<Elution conditions>

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

Test solution- 0.01M HCl solution

Rotational speed - 50rpm

Temperature: 37℃

Dissolution reference time: 5 minutes, 10 minutes, 15 minutes, 30 minutes

Analytical method: HPLC method

HPLC analysis conditions

Detector: UV absorbance spectrometer (measurement wavelength 210 nm)

Column: 250 mm length, 4.6 mm diameter, 5 μm C18 column or equivalent column

Flow rate: 1.0 mL/min

Injection volume: 10 μL

Mobile phase:

hours (minutes) Solvent A (vol%) Solvent B (vol%) 0.0 80 20 11.5 80 20 12.0 20 80 17.0 20 80 17.5 80 20 25.0 80 20

-Solvent A: A solution filtered by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 ml of water and adjusting the pH of the solution to 3.5 ± 0.05 using orthophosphate

- Solvent B: A solution filtered by mixing methanol and acetonitrile in a ratio of 90:10 (v/v)

As shown in Figures 1 and 2, the dissolution patterns of Examples 1 to 7 were all found to be of the same degree (dissolution rates are included within the upper and lower limit curves at all elution time points). On the other hand, it can be seen that the dissolution patterns of Comparative Examples 1 to 4 differ in the initial dissolution for each dose.

In addition, in order to compare the dissolution rate deviations between Examples and Comparative Examples, the dissolution rates were compared by combining each Example and Comparative Example as shown in Table 12 below so that the total amount of lenalidomide was 25 mg. As a result, it was observed that the deviation was significantly lower in the case of the combination of Examples compared to the combination of Comparative Examples (Table 12 and FIGS. 3 and 4).

Combination of Revlimid Capsules
(control group) Content (25mg) Elution time (min) 0 2.5 5 10 15 30 (Comparative Example 4) + (Comparative Example 3) *2 0.0% 12.7% 61.1% 87.1% 91.3% 94.4% (Comparative Example 2) + (Comparative Example 3) 0.0% 12.3% 59.7% 89.7% 94.3% 97.7% (Comparative Example 4)*3+ (Comparative Example 3) 0.0% 26.4% 66.9% 85.3% 88.2% 91.2% Comparative Example 1 0.0% 26.9% 68.9% 79.7% 85.4% 92.8% STD 0.00% 8.16% 4.43% 4.23% 3.83% 2.78% Combination of Example Tablets Content (25mg) Elution time (min) 0 2.5 5 10 15 30 (Example 6) + (Example 4) *2 0.0% 48.8% 92.2% 100.6% 101.1% 101.6% (Example 3) + (Example 4) 0.0% 44.3% 94.9% 99.1% 99.6% 100.9% (Example 6)*3+ (Example 4) 0.0% 51.8% 88.1% 101.7% 102.4% 102.6% Example 1 0.0% 48.3% 95.1% 101.1% 101.8% 102.4% STD 0.00% 3.07% 3.26% 1.14% 1.20% 0.79%

test example 4: Stability test

For Examples 1 and 7, changes in the formulation content and impurity levels were evaluated for 6 months under accelerated conditions of 40°C/75% RH and long-term storage conditions of 25°C/60% RH. For the measurement of impurity levels, HPLC analysis using the following conditions was used.

Detector: UV absorbance spectrometer (measurement wavelength 210 nm)

Column: Eclipse XDB-C18, 4.6 mm × 150 mm, 5 μm or equivalent column

Mobile phase:

hours (minutes) Solvent A (vol%) Solvent B (vol%) 0.0 90 10 15.0 90 10 40.0 45 55 52.0 45 55 53.0 90 10 60.0 90 10

- Solvent A: A solution of 1.36 g of potassium dihydrogen phosphate dissolved in 1000 ml of water and filtered by adjusting the pH of the solution to 3.5 ± 0.05 using orthophosphate - Solvent B: methanol and acetonitrile 90:10 (v /v) mixed and filtered solution

Flow rate: 0.8 mL/min

Injection volume: 10 μL

Column temperature: 27 ℃

Sample analysis temperature: 5 ℃

From the above test, both the content change and the impurity level in the formulations of Examples 1 and 7 were maintained without significant change from the initial test period over the test period. This result indicates that the formulations of the compositional ratio provided in the present invention are stable at both high and low doses, and thus all the formulations of small amounts within the range have adequate stability.

test example 5. of lenalidomide bioequivalence test

To compare the test substance lenalidomide tablets (25 mg dose) prepared in Example 1 with the comparative substance Revlimid ^® tablets (Celgene, 25 mg dose), 41 healthy adult male volunteers were recruited. A bioequivalence test was performed on the subject.

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 14.

Item AUC Cmax comparative substance 1416.7 420.564 test substance 1366.9 420.334 Test Substance/Comparative Substance 0.9648 0.9995

From the above data, it is evaluated that the tablet of Example 1 has bioequivalence when compared to the formulation of the comparative material.

test example 6. Tablet quality test according to excipient content

Based on the tablets prepared in Examples 1 and 7, only the content of excipients was changed to evaluate the tablet quality. Friability was evaluated according to Test Example 1, and the disintegration rate was evaluated according to Test Example 2. Parts by weight of each excipient are parts by weight based on 1 part by weight of lenalidomide.

parts by weight Lenalidomide (mg) content Tablet total weight (mg) tabletting disorder disintegration (sec) Friability (%) diluent 2 2.5mg 5 Unable to form tablets 10 25 30.0 Sticking 10 damage 16 40 45.0 - 213 0.153% 50 125 127.5 - 153 0.229% 2 25mg 50 75.0 Sticking 27 damage 16 400 400.0 - 262 0.085% 50 1250 1275.0 - 31 0.667% lubricant 0.05 2.5mg 0.125 40.0 - 152 0.512% 0.16 0.4 40.0 - 213 0.153% 4 10 40.0 capping 1990 damage 0.05 25mg 1.25 400.0 - 174 0.174% 0.16 4 400.0 - 253 0.085% 4 100 400.0 capping 3000 damage coating agent 0.1 2.5mg 0.25 40.3 - 218 0.012% 1.2 3 43.0 - 234 0.000% 3 7.5 47.5 - 431 0.008% 0.1 25mg 2.5 402.5 - 257 0.050% 1.2 30 430.0 - 300 0.000% 3 75 475.0 - 496 0.019%

As shown in Table 15 above, more than 2 to less than 50 parts by weight of diluent 2 to less than 50 parts by weight (preferably 15 to 45 parts by weight), lubricant based on 1 part by weight of lenalidomide, irrespective of the content of lenalidomide per tablet In the case of more than 0.05 and less than 4 parts by weight, and 0.1 or more to less than 3 parts by weight of the coating agent, it was possible to produce lenalidomide of desirable quality by achieving a friability of 0.5% or less and a disintegration time of 210 to 350 seconds.

Claims (10)

lenalidomide; diluent; disintegrant; And an oral tablet composition comprising a lubricant,
The content of the diluent is more than 10 parts by weight to 20 parts by weight based on 1 part by weight of lenalidomide,
The content of the disintegrant is 0.1 part by weight to 1 part by weight based on 1 part by weight of lenalidomide,
The content of the lubricant is 0.1 part by weight to 1 part by weight based on 1 part by weight of lenalidomide,
The diluent is a combination of anhydrous lactose and microcrystalline cellulose,
The disintegrant is croscarmellose sodium,
The lubricant is magnesium stearate,
Oral tablet composition. The oral tablet composition according to claim 1, wherein the content of the disintegrant is 0.2 parts by weight to 1 part by weight based on 1 part by weight of lenalidomide. The oral tablet composition of 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 based on 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. According to claim 5, regardless of the content of lenalidomide, each content ratio of lenalidomide, diluent, disintegrant and lubricant, or lenalidomide, diluent, disintegrant, lubricant and coating layer Each content ratio is a constant oral tablet composition. 5. The oral tablet composition of claim 3 or 4, wherein the coating layer is two or more layers. The oral tablet composition according to claim 6, wherein the volume of the tablet is proportional to the content of lenalidomide. delete The method of claim 6, wherein the coating base of the coating layer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropyl Cellulose, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, macrogol polyvinyl alcohol graft copolymer, polymer of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methylmethacrylate) copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginates, xanthan and mixtures thereof. .

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