WO2019199132A1 - Lenalidomide oral tablet composition in various amounts - Google Patents

Abstract

The present invention relates to an oral tablet composition comprising lenalidomide and a method for preparing same and, more specifically, to a composition in a tablet form showing physicochemical equivalence with a lenalidomide preparation which is prepared in a hard capsule and securing equivalence in a non-clinical test and a bioequivalence test as well and thus showing equivalent pharmacological therapeutic effects, and allowing enhanced safety and easier administration and handling and the like.

Description

Oral Tablet Composition of Lenalidomide at 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. Such abnormal plasma cells are called myeloma cells. It mainly occurs in black people, men, and older people aged 65 or older, and in Korea, the frequency of occurrence is increasing. The main therapeutic agents for such multiple myeloma include boltezomib, thalidomide, lenalidomide.

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

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

The domestic brand name is Revlimid ^® capsule and contains lenalidomide hemihydrate. On the other hand, the hard capsule Reblimid ^® capsule is filled in No. 0 capsules in the case of 25, 20, 15, and 10 mg formulations, and has a long axis of about 2.17 cm, which is considerably long and bulky. Therefore, patients, especially older patients, may be uncomfortable to take. In the case of capsules, even if taken with water, the capsule may stick to the throat or esophagus in the swallowing process. At this time, even if a large amount of water does not fall well, if the drug accidentally popped out of the pain is accompanied, and in some cases may be inflamed. In particular, Revelmide ^® capsules are filled in No. 0 capsules in the 25, 20, 15, and 10 mg formulations, despite the different active ingredients. It also causes great inconvenience for patients who need to take low-capacity capsules. In addition, the capsule formulation of the commercially available lenalidomide 7.5, 5mg No. 2 capsules, the capsule formulation of 2.5mg content No. 4 capsules, compared to the highest content of the formulation of lenalidomide 25mg capsules Even though the content of the active ingredient is less than 30%, there is no difference in the size of the capsule, patients who need to take low-capacity capsules such as 7.5, 5, 2.5mg will also feel great inconvenience when taking.

Therefore, patients who are prescribed to administer relatively low amounts of lenalidomide (eg, 20 mg or less) also have the inconvenience of taking large capsule formulations that are long, bulky and inconvenient to take. have.

In addition, the relatively low content of lenalidomide capsule formulations contain excipients at a relatively higher content ratio compared to the highest content of lenalidomide 25 mg capsules, and therefore, Elution patterns may not appear equally between high content lenalidomide capsule formulations. Thus, when a high content lenalidomide capsule formulation is prescribed, replacing it with a low content lenalidomide capsule formulation (eg, lenalidomide 25 mg capsule to lenalidomide 5 mg capsule Replacing with five, or replacing lenalidomide 25 mg capsule with lenalidomide 15 mg capsule and 10 mg capsule).

On the other hand, lenalidomide has a pH-dependent solubility, which affects solubility and absorption of the drug depending on which part of the body disintegrates. Therefore, when developing several dosage forms, it is important to have similar disintegration time and dissolution pattern of each formulation to ensure uniform drug absorption.

An object of the present invention is to change the formulation of the commercially available lenalidomide formulations as hard capsules to tablets, but the length is short and the volume is easy to take, the selection of the coating base and coating thickness is appropriate for the entire tablet It is to provide a tablet composition that can be completely enclosed over the thickness to separate the drug from the inside of the handler, so that there is no fear of drug leakage during coating. Accordingly, the present invention provides a tablet composition which is equivalent in terms of efficacy and effect pharmacologically to commercially available capsule formulations, and further improves in appearance, taking and handling convenience, ease of manufacture, safety, and the like.

In addition, it is an object of the present invention to provide a tablet with a constant content ratio of each component in the composition irrespective of the dose of lenalidomide, thereby increasing the convenience of medication when administering a relatively low content of lenalidomide formulation, furthermore, In the case where a lenalidomide formulation is prescribed but there is no high content, it is to be easily replaced with several low content lenalidomide formulations.

Definition of Terms

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

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

In addition, "lenalidomide" may be lenalidomide free base, or a pharmaceutically acceptable salt or isomer thereof, or mixtures thereof. It may also be in each case forming various hydrates and in each case various crystalline forms. For example, it may be various hydrates or various solvates, such as lenalidomide anhydride, hemihydrate, monohydrate, dihydrate, trihydrate, or mixtures thereof.

In order to solve the above problems, the present invention provides an oral tablet composition comprising lenalidomide and at least one pharmaceutically acceptable carrier as an active ingredient. More specifically, it provides an oral tablet composition comprising lenalidomide, diluent, disintegrant, lubricant.

The active ingredient lenalidomide in the oral tablet composition according to the present invention may be present in various doses per unit dosage form, preferably 1 mg to 50 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 25 mg. May be present in 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 administering a relatively low content of lenalidomide formulation, it is possible to increase the convenience of medication, and further, when a high content of lenalidomide formulation is prescribed, it can be easily replaced with a low content of lenalidomide formulation.

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

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

In the present invention the diluent is for example lactose (anhydride or hydrate, for example monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, Calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, It may be, but is not limited to, one or more selected from the group consisting of lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dexrate, dextrin, and mixtures thereof. Preferably lactose, microcrystalline cellulose, mannitol, starch or mixtures thereof may be selected. More preferably, the diluent may be a mixture of two or more kinds. Most preferably a mixture of lactose and microcrystalline cellulose can be selected. Diluents may also serve 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 based on 1 part by weight of lenalidomide. It can be used in negative amounts. If the amount of the diluent is too small than the above-mentioned range, it is difficult to prepare a tablet, on the contrary, if the amount of the diluent is too high, the concentration of the drug is lowered, which may cause a problem in securing content uniformity during the preparation.

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

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

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

In one embodiment, the lubricant is, for example, 0.05 to 10 parts by weight, or greater than 0.05 to less than 4 parts, 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 in an amount of 0.1 to 1 parts by weight. If the amount of the lubricant is too small than the above-mentioned range may be a problem in productivity, such as tableting disorder, on the contrary, too much than the above-mentioned range may have a problem in elution delay or productivity.

Oral tablet composition of the present invention preferably further comprises a coating layer.

Coating bases are hydrophilic polymers, for example, hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymers, polymers of acrylic acid and salts thereof, polymethacrylates, poly (butylmeth) Methacrylate, 2-dimethylaminoethyl methacrylate, methylmethacrylate) copolymers (eg Eudragit® E, Evonik), carboxymethylcellulose (sodium salt and calcium salt) , Ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low substitution degree HPC), polyvinyl pyrrolidone (PVP), vinylpyrrolidone Vinylacetate copolymers (e.g., Kollidon VA64, BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan and mixtures thereof It may be more than one species, but is not limited thereto. Preferably the coating base is hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl meth) 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 be. If the amount of the coating base is too small than the above-mentioned range, the whole uncoated tablet may not be covered with the coating base or the coating may be damaged during handling. On the contrary, if the amount of the coating base is too high, there may be a problem of excessive delay of the dissolution rate.

When the coating layer is formed as a single layer, one or more coating bases may be mixed and used, and a sufficient amount may be coated to protect the entire tablet by forming a coating layer with the coating base. The coating layer may be more preferably at least two layers. For example, in the case of coating with more than two layers, the coating base may be different for each layer to act as shielding, water blocking, and oxidation prevention for drug exposure, respectively. In one embodiment, the first coating is preferably formed with hydroxypropylmethylcellulose (HPMC) to form a film blocking the drug, and the second coating is sequentially made with a macrogol polyvinyl alcohol graft copolymer to form a double layer coating film. In one embodiment, preferably, the first coating with hydroxypropylmethylcellulose (HPMC) to form a film to block the drug, and the second coating with polyvinyl alcohol (PVA) in order to the moisture-proof coating film It is possible to form a two-layer coating film having a more excellent function by forming a. 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 preparing the coated tablet as described above, various biologically inert ingredients may be additionally added for additional purposes such as coating efficiency, drug stability, appearance, color, protection, retention, bonding, performance improvement, and manufacturing process improvement. Can be used.

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

The tablet composition of the present invention comprises mixing lenalidomide and one or more pharmaceutically acceptable carriers as an active ingredient, tableting the mixture to prepare a tablet (coated tablet) before coating, and then coating the surface of the uncoated tablet with a coating base. It can be prepared through a step comprising the.

Specifically, the tablet of the present invention may be prepared in the order of granulation, mixing, tableting, coating after weighing the raw materials, or mixing, tableting (direct tableting), coating after weighing the raw materials. 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 comprise adding a diluent. When two or more diluents are used, different diluents may be used for the first and second stages, respectively.

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

In one embodiment, when granulating into dry granules, the mixture of drug, diluent, binder, and the like is compressed using a roller compactor, and then sieved, and then mixed with the remaining ingredients by post-mixing. After tableting.

In the case of straightening without granulation, there is an advantage that the process is simplified because it is mixed and tableted immediately after weighing. Since the drug itself has a side effect of teratogenicity, it may be necessary to wear protective equipment of the worker during the manufacturing process, preferably a pregnant woman or a person who may be pregnant may be excluded. In addition, the direct method of minimizing the worker's exposure to the drug may be most desirable.

If the ratio of drugs in the tablets is low, it may be important to ensure mixing uniformity. Therefore, careful consideration may be required to ensure uniformity from the mixing stage. Mixing of the drug and the diluent, disintegrant, glidant, etc. step by step without mixing at the same time can improve the mixing uniformity of the mixture.

Since the dosage of the drug may vary, it may be necessary to set the tablet shape, weight and size for each tablet to make it with an appropriate punch. It is preferable to make the excipient to be used the same kind about each dose, and to make the ratio which uses an excipient the same. Thus, by using the same excipients in the same ratio for each dose of lenalidomide can be proportional to the dose of lenalidomide, the dose of each excipient and the weight of the total tablet. Furthermore, the volume of the tablet may also be proportional to the dose of lenalidomide, that is, the volume of the tablet may decrease proportionally as the dose of lenalidomide decreases.

When prepared in this way, the total gross weight and volume of the relatively low content of lenalidomide formulation is reduced, thereby increasing the convenience of medication when administered. Furthermore, if a higher content of lenalidomide formulation is prescribed, it is also easy to replace it with a low content of lenalidomide formulation.

In the present invention, the disintegration time of the uncoated tablet may be one of important factors for estimating the release time of the drug. Since the dissolution pattern of the drug should be equal even if the dose of the active ingredient is different, it is preferable that the disintegration time is satisfied for 210 to 350 seconds for all doses of tablets.

The dissolution test shall be carried out in accordance with Dissolution Test No. 35 of the general test method of the KP X 10 Amendment (KP X), but can be tested at 37 ^o C with 50 rotations / minute of the second method, and 6 tablets each. By measuring the elution amount of the drug at each time point by HPLC can be obtained the average dissolution rate at each time point. It is preferable that the dissolution pattern of the drug is equivalent even if the dose of the active ingredient is changed.

The tablets of the present invention can satisfy the AUC (Area under curve) and Cmax (maximum blood concentration) values within 80 to 125% compared to conventional capsule formulations in a bioequivalence test (In vivo PK test). Preferably 90 to 110%, most preferably 95% to 105%.

Tablet compositions comprising lenalidomide disclosed in the present invention can be usefully used as a composition in the form of tablets with further improved convenience, handleability, safety and the like.

In addition, the present invention provides a tablet with a constant content ratio of each component in the composition irrespective of the dose of lenalidomide, thereby increasing the convenience of the medication when administering a relatively low content of lenalidomide formulation, and further, a high content of lenali If a domide formulation is prescribed it can be easily replaced with a low content lenalidomide formulation.

1 shows the elution patterns for the compositions of Examples 1-7.

2 shows the dissolution patterns for Comparative Examples 1 to 4. FIG.

Figure 3 shows the elution pattern of the combination of the comparative example for 25 mg lenalidomide.

4 shows the elution pattern of the combination of examples for 25 mg lenalidomide.

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

EXAMPLE  One. Lenalidomide  Preparation of 25mg Tablets

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

<Manufacture of uncoated tablets>

Lenalidomide 25mg tablet was prepared in the same amount and component ratio as Table 1 above. Specifically, 5.0 g of lenalidomide and 40.0 g of anhydrous lactose were sieved and mixed, followed by sieving 31.8 g of microcrystalline cellulose, 2.4 g of croscarmellose sodium, and 0.8 g of magnesium stearate, followed by final mixing. This mixture was compressed into a rectangular punch with a hardness of about 153 N based on 400 mg weight per tablet.

<Coated coat>

The previously prepared tablets were subjected to double coating with two types of epidermis at a total of 7.5% (w / w) compared to uncoated tablets for the purpose of drug shielding. The primary coating was made with 2.5% (w / w) based on an Opadry base composed of HPMC, and the secondary coating was performed at 5% (w / w) based on an Opadry based composed of PVA. The volume of the tablets obtained is about 0.31 cm ³ .

EXAMPLE  2. Lenalidomide  Preparation of 20mg Tablets

Composition (mg / tablet) % Composition Lenalidomide anhydride 20.0 5.81 Anhydrous lactose 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

<Manufacture of uncoated tablets>

20 mg tablets of lenalidomide were prepared in the same content and composition ratios as in Table 2. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a rectangular punch at about 200 N.

<Coated coat>

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

EXAMPLE  3. Lenalidomide  Preparation of 15mg Tablets

Composition (mg / tablet) % Composition Lenalidomide anhydride 15.0 5.81 Anhydrous lactose 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

<Manufacture of uncoated tablets>

15 mg tablets of lenalidomide were prepared in the same content and composition ratios as in Table 3. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a rectangular punch with a hardness of about 170N.

<Coated coat>

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

EXAMPLE  4. Lenalidomide  Preparation of 10mg Tablets

Composition (mg / tablet) % Composition Lenalidomide anhydride 10.0 5.81 Anhydrous lactose 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

<Manufacture of uncoated tablets>

Lenalidomide 10 mg tablets were prepared according to the contents and component ratios as shown in Table 4 above. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a rectangular punch with a hardness of about 140N.

<Coated coat>

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

EXAMPLE  5. Lenalidomide  Preparation of 7.5mg Tablets

Composition (mg / tablet) % Composition Lenalidomide anhydride 7.5 5.81 Anhydrous lactose 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

<Manufacture of uncoated tablets>

7.5 mg tablets of lenalidomide were prepared in the same content and composition ratios as in Table 5. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a circular punch with a hardness of about 93N.

<Coated coat>

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

The volume of the tablets obtained is about 0.09 cm ³ .

EXAMPLE  6. Lenalidomide  Preparation of 5mg Tablets

Composition (mg / tablet) % Composition Lenalidomide anhydride 5.0 5.81 Anhydrous lactose 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

<Manufacture of uncoated tablets>

Lenalidomide 5 mg tablets were prepared according to the contents and component ratios of Table 6. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a circular punch with a hardness of about 80N.

<Coated coat>

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

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

EXAMPLE  7. Lenalidomide  Preparation of 2.5mg Tablets

Composition (mg / tablet) % Composition Lenalidomide anhydride 2.5 5.81 Anhydrous lactose 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

<Manufacture of uncoated tablets>

To prepare the lenalidomide 2.5mg tablets in the content and composition ratio as shown in Table 7. In the same manner as in the preparation of the uncoated tablet of Example 1, the mixture was sieved and mixed, and compressed into a circular punch with a hardness of about 50N.

<Coated coat>

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

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

Comparative example : Reference medicine Revlimid ^®  Capsule

A commercially available levimid capsule was used as a comparative example as shown in Table 8 below.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Reference Relevide 25mg Capsules with Lenalidomide Hemihydrate 25.87mg Reference Relevide 15mg Capsule with Lenalidomide Hemihydrate 15.52mg Reference Relevide 10mg Capsules with Lenalidomide Hemihydrate 10.35mg Reference drug Reblimid 5mg capsule with 5.17mg of lenalidomide hemihydrate

Test Example  One. Masson  Measure

The friability was measured by using the Pharmatest friability tester for more than 4 g of tablets by the method described in the U.S. Pharmacopoeia 1216 Tablet Friability. Examples 1, 2, 3, 4, 5 , 6 and 7 shows the difference between uncoated and coated tablets. (Measurement time = 4 minutes)

Masson Najung 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  exam

Disintegration test was carried out in pH 1.2 solution with n = 6 for Examples 1, 2, 3, 4, 5, 6, 7 and Comparative Example 1 according to the disintegration test method of the Korean Pharmacopoeia 10 amendments. 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 in 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 (Reblimide ^® capsule formulation).

<Elution condition>

Dissolution Test Apparatus- Paddle Method of KEPCO Dissolution Test Method

Test solution-0.01M HCl solution

Rotational Speed-50rpm

Temperature: 37 ℃

Elution point: 5 minutes, 10 minutes, 15 minutes, 30 minutes

Analytical Method: HPLC Method

HPLC  Analysis conditions

Detector: UV absorbance photometer (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:

Minutes Solvent A (% by volume) Solvent B (% by volume) 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: 1.36 g of potassium dihydrogen phosphate dissolved in 1000 ml of water, and then filtered by adjusting the pH of the solution to 3.5 ± 0.05 using orthophosphate.

Solvent B: a solution in which methanol and acetonitrile were mixed at a ratio of 90:10 (v / v) and filtered

As shown in Figs. 1 and 2, the dissolution patterns of Examples 1 to 7 were found to be all of equivalent degree (the dissolution rate was included within the upper and lower curves at all dissolution 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 according to the capacity.

In addition, in order to compare the dissolution rate deviation between the Examples and Comparative Examples, dissolution rate was compared by combining the respective Examples and Comparative Examples as shown in Table 12 so that the total amount of lenalidomide. As a result, it was observed that the variation of the combination of the examples was significantly lower than that of the comparative example (Table 12 and Figs.

Combination of Revlimid Capsules (Control) Content (25 mg) Elution time (minutes) 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% Example Combination of Tablets Content (25 mg) Elution time (minutes) 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 Example 1 and Example 7, the change in the content of the formulation and the change in the impurity level were evaluated for 6 months under the accelerated conditions of 40 ℃ / 75% RH conditions and long-term storage conditions 25 ℃ / 60% RH conditions. For the determination of impurity levels an HPLC analysis method using the following conditions was used.

Detector: UV absorbance photometer (wavelength 210 nm)

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

Mobile phase:

Minutes Solvent A (% by volume) Solvent B (% by volume) 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 obtained by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 ml of water and then adjusting the pH of the solution to 3.5 ± 0.05 using orthophosphate.-Solvent B: methanol and acetonitrile in 90:10 / 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 Example 1 and Example 7 content change and impurity level in the formulation were maintained without significant change with the initial test over the test period. This result indicates that the formulations of the composition ratios provided in the present invention are stable at both high and low doses, and thus mean that all of the single doses in the range have adequate stability.

Test Example  5. Of lenalidomide  Bioequivalence test

Subjected to healthy adult males 41 name of the resource in order to compare the comparison substance rail assembly mid ^® (R) tablets (three Elgin, 25mg dose) for the test material prepared LES flying it also polyimide tablets (25mg dose) Example 1 Bioequivalence tests were performed on the subjects.

Subjects were divided into two groups, and each of the test substance and the comparative substance was taken at a fixed time interval up to 24 hours after taking the medicine with water on an empty stomach, and after 2 weeks, the group was changed to take the same medicine and collected. The collected blood samples were separated from plasma and stored frozen and analyzed by concentration with LC / MS / MS equipment to obtain blood concentrations over time. It is 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, the tablets of Example 1 were evaluated for bioequivalence when compared to the formulation of the comparator.

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 only the content of excipients. Wear degree 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 parts by weight based on 1 part by weight of lenalidomide.

Parts by weight Lenalidomide (mg) content Tablet total weight (mg) Tableting obstacle Disintegration (sec) Wear and tear (%) diluent 2 2.5mg 5 No tablet formation 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 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 (preferably 15 to 45 parts by weight), lubricant, per 1 part by weight of lenalidomide, regardless of the content of lenalidomide per tablet When the amount is greater than 0.05 to less than 4 parts by weight, and the coating agent is greater than or equal to 0.1 to less than 3 parts by weight, wear and tear of 0.5% or less and a disintegration time of 210 to 350 seconds are achieved to produce lenalidomide of desirable quality.

Claims (10)

Lenalidomide; diluent; Disintegrants; And oral tablet composition comprising a lubricant, The content of the diluent is 2 to 50 parts by weight based on 1 part by weight of lenalidomide, The content of the disintegrant is 0.05 to 10 parts by weight based on 1 part by weight of lenalidomide, The amount of the lubricant is 0.05 to 10 parts by weight based on 1 part by weight of lenalidomide. Oral tablet compositions. The method of claim 1, The content of the diluent is 2 to 45 parts by weight based on 1 part by weight of lenalidomide, The content of the disintegrant is 0.2 to 1.5 parts by weight based on 1 part by weight of lenalidomide, Oral tablet composition is 0.1 to 3 parts by weight based on 1 part by weight of lenalidomide. The oral tablet composition of claim 1, further comprising a coating layer. 4. The oral tablet composition of claim 3, wherein the coating layer has a content of 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. The method according to claim 5, wherein the content ratio of lenalidomide, diluent, disintegrant and glidant, or lenalidomide, diluent, disintegrant, lubricant and coating layer is independent of the content of lenalidomide. Each content ratio is a constant oral tablet composition. The oral tablet composition according to claim 3 or 4, wherein the coating layer is two or more layers. 7. The oral tablet composition of claim 6, wherein the volume of the tablet is proportional to the content of lenalidomide. The compound of claim 1, wherein the diluent is at least one selected from the group consisting of sugars, sugar alcohols, celluloses, starches, inorganic salts, and mixtures thereof; Disintegrants are selected from one or more selected from the group consisting of swellable disintegrants, wet disintegrants, and mixtures thereof; And glidants are at least one selected from the group consisting of soluble glidants, insoluble glidants, and mixtures thereof. The coating base of the coating layer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropyl Cellulose, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, macrogol polyvinyl alcohol graft copolymers, polymers of acrylic acid and salts thereof, polymethacrylates, poly (butyl methacrylates, 2-dimethylaminoethyl methacrylates, Methyl methacrylate) copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan and mixtures thereof, Diluents are lactose, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride , Sodium chloride, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, At least one selected from the group consisting of dexrate, dextrin, and mixtures thereof, Disintegrants include croscarmellose sodium, carboxymethylcellulose, crospovidone, low-substituted hydroxypropylcellulose, starch, sodium carboxymethyl starch, sodium starch glyconate, alginic acid, carboxymethylcellulose sodium, agar, xylan, gellan gum, At least one selected from the group consisting of xanthan gum, partially hydrolyzed starch, and mixtures thereof, Glidants include magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, starch, talc, highly disperse silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, Silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate and these Oral tablet composition selected from the group consisting of a mixture of.

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