KR102286499B1 - Pharmaceutical composition comprising lenalidomide - Google Patents

Abstract

Disclosed are lenalidomide tablet formulations.

Description

Pharmaceutical composition comprising lenalidomide {PHARMACEUTICAL COMPOSITION COMPRISING LENALIDOMIDE}

The present invention relates to formulations of lenalidomide. Specifically, it relates to a solid formulation for oral administration of lenalidomide.

Lenalidomide (Formula: 3-(4'-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione) is disclosed in Korean Patent Publication No. The compound disclosed in No. 534498 is used as a treatment for multiple myeloma. Lenalidomide is an IMiDs (Immunomodulatory imide drugs) compound belonging to a new group of immunomodulators. Its structure is similar to that of thalidomide, but the biological activity is stronger and thus the effect is superior. In addition, it is evaluated to have fewer side effects than thalidomide.

Conventional lenalidomide appeared in capsule form. The commercialized product is Celgene's Revlimid capsule, which is a hard capsule, and has been approved in dosages of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, and 25 mg.

Revlimid capsules are all filled in No. 0 capsules for formulations of 10 mg, 15 mg, 20 mg, and 25 mg doses, which are quite long and bulky, with a major axis reaching about 2.17 cm. Therefore, there is a disadvantage that it is inconvenient to take in the case of elderly patients.

Also, when taking the capsules with water, there is a problem that the capsules stick to the throat or esophagus during swallowing.

However, since tablets do not need to use capsules of a fixed size such as No. 0, the volume can be further reduced, and when taken with water, it is less prone to sticking to the throat or esophagus than capsules.

However, since capsules are manufactured by filling granules in capsules, tablets have a problem in that content uniformity is lower than that of capsules.

Therefore, in order to utilize the advantages of the above tablets, the present inventors tried to develop a tablet of lenalidomide with excellent drug content uniformity and similar dissolution pattern to conventional capsules, and thus biologically equivalent.

Republic of Korea Patent Publication No. 534498

An object of the present invention is to provide a tablet composition by changing the dosage form of a lenalidomide preparation marketed as a hard capsule into a tablet, but having a short length and small volume, which is easy to take. In addition, since the dissolution pattern in the tablet is the same as that in the capsule, it is to provide a tablet composition that not only shows physicochemical equivalence in a comparative dissolution test, but also shows equivalence in in vivo tests of experimental animals and bioactivity tests. Accordingly, it is an object to provide a tablet composition which is equivalent in pharmacological efficacy and effect to a commercially available capsule formulation, but with improved appearance and ease of administration, and a method for preparing the same.

In order to solve the above problems, the present invention provides a tablet composition for oral administration containing lenalidomide.

The tablet composition of the present invention can be prepared by tableting lenalidomide having a D50 of greater than 2 μm.

In the present invention, D[4,3] of lenalidomide is preferably 3 to 70 μm.

In addition, in the present invention, D90 of lenalidomide is preferably 8 to 180 μm.

In addition, in the present invention, D10 of lenalidomide is preferably 0.5 to 10 μm.

Lenalidomide is very sensitive to drug content uniformity due to the presence of low-dose drugs such as 2.5 mg. Although the present invention is implemented as a tablet, the drug content uniformity is excellent.

In addition, since one embodiment of the present invention is implemented as a tablet, it overcomes the disadvantages of hard capsules, such as a large volume, and a tendency to stick to the throat or esophagus when taken with water.

In addition, the present invention also has bioequivalence when compared to the conventionally commercially available hard capsules, and one embodiment of the present invention blocks the bad taste of the drug and the leakage of the drug by coating. Specifically, the present invention has the same dissolution result as the reference drug Revlimid capsule, and therefore the values of AUC and Cmax in the bioequivalence test are within 80 to 125% of that of the conventional capsule, preferably 90 to 110 %, most preferably 95 to 105%.

1 is a graph showing the dissolution comparison test results of the control drug ^{Revlimid ®} capsule and the tablet of Example 1 in a pH 1.2 solution.
2 is a graph showing the dissolution comparison test results of the control drug ^{Revlimid ®} capsule and the tablet of Comparative Example 1 in a pH 1.2 solution.
3 is a graph showing the dissolution comparison test results of the control drug ^{Revlimid ®} capsule and the tablet of Comparative Example 2 in a pH 1.2 solution.
4 is a scanning electron microscope photograph of the micronized raw material corresponding to D10 3㎛, D50 13㎛, D90 44㎛, D[4, 3] 19㎛ of lenalidomide.
5 is a scanning electron micrograph of the micronized raw material corresponding to D10 4㎛, D50 51㎛, D90 219㎛, D[4, 3] 84㎛ of lenalidomide.

As used herein, the term lenalidomide refers to a main ingredient of which the active ingredient is lenalidomide, for example, lenalidomide or a pharmaceutically acceptable salt, isomer, crystalline form, anhydride, hydrate, solvate or these A mixture of any two or more of them encompasses all.

As used herein, the additive refers to an inactive ingredient that can be added pharmaceutically, such as pharmaceutical excipients. For example, it may mean a diluent, a disintegrant, a lubricant, a coating base, etc., all of which can be used components are known, and unless otherwise specified in the present specification, a person skilled in the art can use any one of the components that can be suitably adopted. I understand.

The present invention is to develop a tablet that can replace the conventionally commercially available hard capsules.

Lenalidomide requires a low dose formulation of 2.5 mg. A low-dose formulation cannot expect the desired drug effect even with a small loss of the drug. Therefore, uniformity of drug content in the manufacturing process is very important.

However, unlike hard capsules, in which the entire process is to fill the capsule with the granules after mixing the drug with other pharmaceutical additives, the tablet is accompanied by the process of tableting, and heat generated during tableting or process disturbances in the tableting machine As a result, there is a possibility that the drug may be lost. Therefore, lenalidomide had a limitation in having no choice but to market the formulation as a hard capsule.

However, hard capsules require the use of capsules of a set standard, and there are those whose size is large enough to hinder the convenience of taking medication. In addition, when the hard capsules are taken with water, adhesion is created on the surface of the gelatin capsules, which is accompanied by discomfort that the preparations stick to the throat or esophagus. Therefore, there is a need to develop lenalidomide tablets.

The present inventors came up with various means to ensure the uniformity of content of the drug, which is a conventional limitation that could not be developed as a tablet, and to achieve the same dissolution aspect as the capsule in order to express the biologically equivalent medicinal effect to the capsule.

In the meantime, the present inventor surprisingly found that when the particle size of lenalidomide was adjusted, the drug content uniformity could be ensured and the dissolution aspect could be achieved equally with the reference drug Revlimid capsule, thereby contributing to the completion of the present invention. reached

In particular, capsules have different dissolution mechanisms because the contents of the capsules are released as the hard capsules melt and the drug is eluted, whereas in tablets, the drug is eluted as the uncoated tablet disintegrates. In particular, since the contents of hard capsules consist of powder of small particles with a large surface area, a certain dissolution rate is guaranteed when only the capsule is dissolved. It is not easy to guarantee Therefore, it is very difficult to match the dissolution patterns of capsules and drugs equally when developing tablets. However, surprisingly, it was found that the dissolution pattern of the drug can be adjusted by controlling the particle size.

As can be seen from FIGS. 4 and 5 , the raw material itself of lenalidomide has various particle sizes. Although there is a perception that the dissolution rate can be improved as the particle size of the drug is small, this is a theory corresponding to a poorly soluble drug. However, it was not possible to realize that the dissolution rate would change dramatically to the extent that it affects the bioavailability. Therefore, when the dissolution rate of the drug is insufficient, attempts to control the particle size of lenalidomide cannot generally be made. However, surprisingly, as shown in FIGS. 1 to 3 , the dissolution pattern was completely different depending on the particle size of lenalidomide.

In the present invention, lenalidomide may be used in a micronized form. The particle size of undifferentiated lenalidomide can be expressed using D10, D50, D90, and the like, and in addition, it can be expressed as an average using D[4,3], etc. D10 refers to the diameter of the particle corresponding to the lower 10% in terms of volume distribution, and D50 and D90 refer to the diameter of the particle corresponding to 50% and 90%, respectively. D[4,3] means the volume average diameter. This can be measured using, for example, an optical diffraction particle sizer.

The invention is characterized in that it employs lenalidomide with a D50 greater than 2 μm. When lenalidomide is formulated into tablets by tableting, raw materials having a particle size satisfying the above conditions must be used to ensure uniformity of content and desired dissolution characteristics, and bioequivalence with conventional capsules can be achieved. In addition, when it is finer than the above range, it may cause a process disorder during tableting. Lenalidomide has a D50 of 2.5 to 50 μm, more preferably 3 to 40 μm, still more preferably 5 to 30 μm, still more preferably 7 to 20 μm, most preferably 10 to 15 μm.

Lenalidomide preferably has a D[4,3] of 3 to 70 μm. More preferably, D[4,3] is 5 to 60 μm, still more preferably 8 to 45 μm, still more preferably 10 to 30, and most preferably 15 to 25 μm.

Lenalidomide preferably has a D90 of 8 to 180 μm. More preferably, D90 is 12 to 140 μm, still more preferably 15 to 100 μm, still more preferably 25 to 75 and most preferably 35 to 55 μm.

Lenalidomide preferably has a D10 of 0.5 to 10 μm. More preferably, D10 is 0.7 to 8 μm, still more preferably 1 to 6 μm, still more preferably 1.2 to 4.5, and most preferably 1.5 to 3.5 μm.

The present invention can be implemented as tablets by mixing lenalidomide having a D50 of 2.5 to 50 μm with a pharmaceutically acceptable additive and tableting.

In this case, the additive may include a diluent, a disintegrant, and a lubricant.

The diluent may be selected from the group consisting of sugars, sugar alcohols, cellulose, starch, inorganic salts and mixtures thereof. Non-limiting examples include lactose (anhydrous or hydrate, e.g. 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, lactose, dextrose, At least one selected from the group consisting of maltose, sucrose, glucose, fructose, maltodextrin, dextrate, dextrin, and mixtures thereof may be considered. Among them, lactose or microcrystalline cellulose may be preferably selected.

The above diluent may also act as a binder in some cases.

The diluent is 0.5 to 200 parts by weight, preferably 1 to 100 parts by weight, more preferably 2 to 50 parts by weight, even more preferably 3 to 30 parts by weight, even more, based on 1 part by weight of lenalidomide. Preferably 4 to 20 parts by weight may be used. The above content range is suitable for manufacturing into tablets.

The disintegrant may be selected from the group consisting of swellable disintegrants, wettable disintegrants and mixtures thereof. Non-limiting examples may be selected from the group consisting of starch, cellulose, crosslinked polymers, gums, polysaccharides, and mixtures thereof, for example, croscarmellose sodium, carboxymethylcellulose, crospovidone, L-HPC, starch , sodium carboxymethyl starch, sodium starch glycolate, alginic acid, sodium carboxymethylcellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch, and mixtures thereof may be at least one selected from the group consisting of . Preferably, it may be croscarmellose sodium, crospovidone, L-HPC, sodium starch glycolate, and more preferably croscarmellose sodium.

The disintegrant is 0.02 to 10 parts by weight, preferably 0.05 to 5 parts by weight, more preferably 0.1 to 2.5 parts by weight, even more preferably 0.15 to 1.5 parts by weight, even more, based on 1 part by weight of lenalidomide. More preferably, 0.2 to 1 part by weight may be used. If it is less than the above content range, a satisfactory dissolution rate may be achieved due to a delay in disintegration rate, and if it is large, it may cause tabletting failure, coating failure, etc., which may not be suitable for productivity.

The lubricant may be selected from the group consisting of soluble lubricants, insoluble lubricants, and mixtures thereof. Non-limiting examples of magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, starch, talc, colloidal silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate , silicon dioxide, calcium silicate, magnesium silicate, hydrogenated vegetable oil, light liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate and It may be one or more selected from the group consisting of mixtures thereof. Preferably it may be magnesium stearate, stearic acid, colloidal silica, More preferably, it may be magnesium stearate.

The lubricant is 0.005 to 3.5 parts by weight, preferably 0.015 to 2.0 parts by weight, more preferably 0.03 to 0.75 parts by weight, even more preferably 0.05 to 0.5 parts by weight, even more, based on 1 part by weight of lenalidomide. More preferably, it can be used in an amount of 0.1 to 0.35 parts by weight. If the content is less than the above range, it is not suitable for productivity because it causes tabletting disorders, etc., and if it is more, there may be problems in dissolution delay or productivity.

In the present invention, lenalidomide and necessary additives are mixed and then tableted to prepare uncoated tablets. If necessary, in the present invention, lenalidomide and an additive may be combined into granules according to a wet or dry method before tableting, and then the granules may be used for tableting. At this time, the wet granulation and the dry granulation can be appropriately adopted by those skilled in the art according to need among known techniques.

In particular, in the present invention, the order of mixing the additives may be important when the granules are not co-aggregated but simply mixed and tableted.

The uncoated tablet of the present invention can be implemented with a smaller size than the conventional hard capsules of lenalidomide. Although the size will vary depending on the dose, it is preferable to make the longest axis (diameter in the case of a round shape) of the uncoated tablet smaller than the capsule No. 0 of about 2.17 cm in the case of the 25 mg formulation, which is the highest dose. For example, it is set to 2 cm or less, More preferably, it is set to 1.8 cm or less, More preferably, it is set as 1.6 cm or less.

The raw tablet of the present invention preferably has a maximum average hardness of 300 N and a minimum average hardness of 10 N. More preferably, the maximum average hardness is 250 N, and the minimum average hardness is 20 N. Even more preferably, the maximum average hardness is 230 N and the minimum average hardness is 30 N. Most preferably, the maximum average hardness is 210 N and the minimum average hardness is 40 N. If the hardness is higher than the gastric hardness, there may be a delay in the release of the drug due to disintegration delay.

In the present invention, after manufacturing the uncoated tablet, the surface can be coated with a coating base.

The coating base is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, 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, methyl methacrylate) copolymer; vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginates, xanthan and mixtures thereof.

The coating base is 1 to 30 parts by weight, preferably 2 to 25 parts by weight, more preferably 3 to 20 parts by weight, even more preferably 4 to 15 parts by weight, even more preferably based on 100 parts by weight of the uncoated tablet. 5 to 15 parts by weight, most preferably 6 to 15 parts by weight, may be used. If it is less than the above range, the entire uncoated tablet may not be sufficiently coated, and if it is more than the above range, a delay in the dissolution rate may occur.

The coating aims to prevent the drug from being lost. Therefore, if necessary, the secondary coating may be performed after the primary coating, and the thickness of the coating may be appropriately selected. However, as described above, the dissolution of the drug should not be delayed due to the coating, so it is necessary to select an appropriate range.

The remaining components or methods necessary for coating can be suitably adopted by a person skilled in the art.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, it should be noted that the following examples are only for illustrating the present invention, and the protection scope of the present invention is not limited thereto.

Example One

<Manufacturing of uncooked tablets>

As a result of particle size analysis, tablets were made using lenalidomide with D10 3㎛, D50 13㎛, D90 44㎛, D[4, 3] 19㎛, and make a mixture with the composition shown in the table below, and the mixture was 1 It was tableted with a rectangular punch based on the weight of 400 mg per tablet.

Ingredient name Quantity (g) 1 serving (mg) lenalidomide 5 25 lactose anhydrous 40 200 Microcrystalline Cellulose 31.8 159 Croscarmellose Sodium 2.4 12 Magne stearate?? 0.8 4 Total 80 400

<Coating of uncoated tablets> The prepared uncoated tablets were double-coated with two kinds of skin-repellent agents corresponding to a total of 7.5% (w/w) compared to 100% (w/w) of the total weight of the uncoated tablets. After a primary coating (2.5% (w/w)) with an Opadry base containing HPMC as a main component, a secondary coating (5% (w/w)) with an Opadry base containing PVA as a main component was performed. The primary coating operation conditions are shown in Table 2 below, and the secondary coating operation conditions are shown in Table 3 below.

time set temperature Inlet
Temp Outlet
Temp Air
Pressure Fan
Speed liquid injection
speed Warming up: 10 minutes 40 56 32 - 10 - process conditions 38 56 32 0.1 10 4-5

time set temperature Inlet
Temp Outlet
Temp Air
Pressure Fan
Speed liquid injection
speed Warming up: 10 minutes 45 66 34 - 10 - process conditions 45 66 34 0.1 10 2.0

comparative example One

As a result of particle size analysis, tablets were prepared in the same manner as in Example 1, except that lenalidomide having D10 4 μm, D50 51 μm, D90 219 μm, and D[4, 3] 84 μm was used.

Comparative Example 2

As a result of particle size analysis, tablets were prepared in the same manner as in Example 1, except that lenalidomide having a D50 of 2 μm and a D90 of 5 μm was used.

test example 1: dissolution test

A dissolution test was performed with n = 6 under the following conditions for the reference drug ^{Revlimid ® capsule and Example 1, and the results are shown in FIG. 1 .}

Test method: Paddle method of the Korean Pharmacopoeia test method

Eluent: pH 1.2 solution

Rotational speed: 50 rpm

Temperature: 37℃

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: listed in Table 4 below

time (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 obtained by dissolving 1.36 g of potassium dihydrogen phosphate in 1000 ml of water, adjusting the pH of the solution to 3.5±0.05 using orthophosphate, and filtering Solvent B: Methanol and acetonitrile 90:10 (v/ A solution filtered by mixing in the ratio v)

test example 2: Comparative dissolution test

A ^{dissolution test was performed under the conditions of Test Example 1 for the reference drug Revlimid ®} capsule and Comparative Examples 1 and 2, respectively, at n=6, and the results are shown in FIGS. 2 and 3 .

As shown in FIGS. 1 to 3 , controlling the particle size of lenalidomide played a major role in matching the dissolution pattern with the reference drug equally. Specifically, when the particle size D50 of lenalidomide exceeded 2 μm, the dissolution pattern was equivalent to that of the reference drug as in Example 1, and when the D50 was 51 μm or more, the dissolution pattern was significantly different as in Comparative Example 1. In addition, when the D50 is 2 μm or less, as in Comparative Example 2, an abrupt dissolution pattern is shown in the initial stage, so there is a concern about a rapid Cmax value improvement and side effects thereof.

Claims (8)

As a solid preparation for oral administration containing lenalidomide,
It is prepared by tableting a mixture containing lenalidomide, a diluent, a disintegrant and a lubricant,
D10 of lenalidomide is 1.5 to 3.5 μm, D50 is 10 to 15 μm, D90 is 35 to 55 μm, D[4,3] is 15 to 25 μm,
Based on 1 part by weight of lenalidomide, the content of the diluent is 4 to 20 parts by weight, the content of the disintegrant is 0.2 to 1 part by weight, the content of the lubricant is 0.1 to 0.35 parts by weight,
The diluent is a combination of anhydrous lactose and microcrystalline cellulose,
The disintegrant is croscarmellose sodium,
The lubricant is magnesium stearate,
Solid preparation for oral administration. delete delete delete delete delete delete delete

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