JP2023036924A - Pharmaceutical composition containing lenalidomide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide tablet compositions having a short length, not being bulky, and easy to take, and to provide methods for producing the same.

SOLUTION: Provided is a solid formulation for oral administration comprising lenalidomide, which is manufactured by tableting a mixture containing lenalidomide, a diluent, a disintegrant and a lubricant, D10 of the lenalidomide being 1.5 μm to 3.5 μm, D50 being 10 μm to 15 μm, D90 being 35 μm to 55 μm, D[4,3] being between 15 μm and 25 μm, and with respect to 1 pts.wt. of the lenalidomide: a content of the diluent being 4 to 20 pts.wt; a content of the disintegrant being 0.1 to 2.5 pts.wt.; and a content of the lubricant being 0.03 to 0.75 pt.wt.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2023,JPO&INPIT

Description

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

Lenalidomide (general formula: 3-(4′-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione) is a compound disclosed in Patent Document 1. and is used as a therapeutic agent for multiple myeloma. Lenalidomide is an IMiDs (Immunomodulatory imide drugs) compound belonging to a new class of immunomodulators, which is similar in structure to thalidomide, but more effective due to its stronger biological activity. Moreover, it was evaluated that side effects were further reduced compared to thalidomide.

Conventional lenalidomide appeared as a capsule. Commercialized products include Celgene's Revlimid Capsules hard capsules, licensed in doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 25 mg.

Revlimid capsules are filled in size 0 capsules in all cases of doses of 10 mg, 15 mg, 20 mg and 25 mg formulations and are rather long and bulky with a long axis of about 2.17 cm. Therefore, there is a disadvantage that it is inconvenient for elderly patients to take the drug.
Furthermore, even when taken with water, capsules can stick to the throat and esophagus during swallowing.

However, tablets can be further reduced in volume because there is no need to use a fixed size capsule, such as No. 0, and they are less likely to stick to the neck or esophagus than capsules when taken with water.

However, since capsules are manufactured by filling granules into capsules, there is a problem that tablets are inferior to capsules in content uniformity.

Therefore, in order to utilize the advantages of the above-mentioned tablets, the present inventors developed a lenalidomide tablet that has excellent drug content uniformity, a dissolution pattern similar to that of conventional capsules, and a biologically equivalent efficacy. tried to develop.

Korean Patent No. 534498

An object of the present invention is to change the dosage form of the commercially available hard capsule formulation of lenalidomide into a tablet, and to provide a tablet composition that is short in length, not bulky, and easy to take.

Another object of the present invention is that the dissolution pattern in the tablet is equivalent to that in the capsule, showing not only physico-chemical An object of the present invention is to provide a tablet composition showing equivalence in tests.

Therefore, the present invention provides a tablet composition having the same pharmacological efficacy and effect as the capsule formulation on the market, and further developed to have improved appearance, ease of administration, etc., and a method for producing the same. do.

To solve the above problems, the present invention provides an oral tablet composition containing lenalidomide.
A tablet composition of the present invention can be prepared by compressing lenalidomide having a D50 of greater than 2 μm.
In the present invention, D[4,3] of lenalidomide is preferably 3 to 70 μm.
Further, in the present invention, D90 of lenalidomide is preferably 8 to 180 μm.
Furthermore, in the present invention, D10 of lenalidomide is preferably 0.5 to 10 μm.

Lenalidomide is very sensitive to drug content uniformity, as there are drugs with a low dose such as 2.5 mg. there is

In addition, since one embodiment of the present invention is realized in a tablet, it overcomes the disadvantages of hard capsules in that they are bulky and that they tend to stick to the throat and esophagus during swallowing, even when taken with water. Overcame.

Furthermore, the present invention has bioequivalence when compared with the conventionally marketed hard capsules. also blocked. Specifically, the present invention has the same dissolution results as the control drug Revlimid capsules, and as a result, in the bioequivalence test, the AUC and C _max values are 80 to 80 compared to the conventional capsules. It is within 125%, preferably within 90-110%, and most preferably within 95-105%.

1 is a graph showing comparative dissolution test results of a control drug, Revlimid (registered trademark) capsules, and tablets of Example 1, in a pH 1.2 solution. 2 is a graph showing the comparative dissolution test results of the control drug Revlimid (registered trademark) capsules and the tablet of Comparative Example 1 in a pH 1.2 solution. 2 is a graph showing the comparative dissolution test results of the control drug Revlimid (registered trademark) capsules and the tablet of Comparative Example 2 in pH 1.2 solution. Scanning electron micrograph of micronized raw material corresponding to D10 3 μm, D50 13 μm, D90 44 μm, D[4,3] 19 μm of lenalidomide. Scanning electron micrograph of micronised material corresponding to D10 4 μm, D50 51 μm, D90 219 μm, D[4,3] 84 μm of lenalidomide.

In the present specification, lenalidomide means a main component raw material in which the active ingredient is lenalidomide. Examples include lenalidomide or its pharmaceutically acceptable salts, isomers, crystal forms, anhydrates, hydrates, solvates or mixtures of two or more thereof.

As used herein, an excipient means a known pharmaceutically addable inactive ingredient such as pharmaceutical excipients. For example, diluents, disintegrants, lubricants, coating bases, etc., all of which are known components that can be used. Unless otherwise described in this specification, it may be understood as any one of components that can be appropriately adopted by those of ordinary skill in the art.

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

Lenalidomide requires a low dose formulation of 2.5 mg. A low-dose formulation cannot be expected to have the desired efficacy even if only a small amount of the drug is lost. Therefore, content uniformity of the drug during the manufacturing process is very important.

However, unlike hard capsules, in which the entire process is to mix the drug and other pharmaceutical excipients and then fill the granules into capsules, tablets are accompanied by a tableting process and are produced from tableting. Drug can be lost due to heat and process disturbances in the tableting machine. Therefore, lenalidomide had the limitation of being marketed as a hard capsule formulation.

However, hard capsules require the use of capsules of specified specifications, and some of them are so bulky that their size interferes with the convenience of taking the medicine. In addition, when a hard capsule is taken with water, the surface of the gelatin capsule develops an adhesive force, which may stick to the throat or esophagus during swallowing. Therefore, there was a need to develop lenalidomide tablets.

The present inventors have achieved uniformity of drug content, which was a conventional limitation that could not be developed in tablets, and have a dissolution pattern equivalent to that of capsules in order to achieve bioequivalent efficacy as capsules. In order to achieve a certain goal, I have been doing a lot of research.

Surprisingly, the present inventors found that when adjusting the particle size of lenalidomide, it is possible to ensure the uniformity of the drug content and achieve the same dissolution pattern as the control drug Revlimid capsules. and completed the invention.

In particular, capsules are such that the contents inside the capsule are released while the hard capsule is dissolved, and the drug is eluted. On the other hand, tablets have different dissolution mechanisms because the drug is dissolved while the uncoated tablet is disintegrating. In particular, in hard capsules, the content inside the capsule consists of fine particles with a large surface area. Due to their fixed size and small surface area, it is not easy to ensure a desired dissolution rate. Therefore, when developing tablets, it is extremely difficult to control the dissolution patterns of capsules and drugs to be equivalent. Surprisingly, however, we have found that the elution pattern of the drug can be adjusted by adjusting the particle size.

As shown in Figures 4 and 5, lenalidomide itself has various particle sizes. There is a perception that the smaller the drug particle size, the higher the dissolution rate, but this is a theory that corresponds to a poorly soluble drug. It was not recognized that adjustments could alter elution rates in such a way as to affect bioavailability. Therefore, attempts to control the particle size of lenalidomide have generally not been made when the drug dissolution rate is insufficient. Surprisingly, however, as shown in FIGS. 1 to 3, the elution pattern was shown to be completely different depending on the particle size of lenalidomide.

In the present invention, lenalidomide can be used in micronized form. The particle size of micronized lenalidomide can be indicated using D10, D50, D90, and the like. Alternatively, D[4, 3] or the like can be used to show the average. D10 means the diameter of particles corresponding to the bottom 10% of volume distribution. D50 and D90 mean diameters of particles corresponding to 50% and 90%, respectively. D[4,3] means the volume average diameter. This can be measured, for example, using an optical diffraction granulometer.

The present invention is characterized by adopting lenalidomide with a D50 greater than 2 μm. When formulating lenalidomide into tablets by tableting, in order to ensure content uniformity and the desired dissolution pattern, raw materials with a particle size that satisfies the above conditions must be used. Can provide academic equivalence. In addition, if it is smaller than the above range, it may induce process failure during tableting. Lenalidomide has a D50 of 2.5-50 μm, more preferably 3-40 μm, even more preferably 5-30 μm, even more preferably 7-20 μm, most preferably 10-15 μm.

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

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

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

The present invention can be embodied in tablets by mixing lenalidomide having a D50 of 2.5-50 μm with pharmaceutically acceptable excipients and compressing.

At this time, additives may include diluents, disintegrants, and lubricants.

Diluents can 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, gelatinized starch, calcium carbonate, cyclodextrins. , calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate , magnesium oxide, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrate, dextrin, and mixtures thereof. good too. Preferably, lactose or microcrystalline cellulose may be chosen.

Said diluent may also act as a binder.

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, still more preferably 3 to 30 parts by weight, and even more preferably 1 part by weight of lenalidomide. An amount of 4 to 20 parts by weight can be used. When manufacturing tablets, the above content ranges are suitable.

Disintegrants may be selected from the group consisting of swelling disintegrants, wet 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. Croscarmellose sodium, crospovidone, L-HPC, sodium starch glycolate may be preferred. More preferably, it may be 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, more preferably 0.15 to 10 parts by weight, per 1 part by weight of lenalidomide. 1.5 parts by weight, even more preferably 0.2 to 1 part by weight may be used. If the amount of the disintegrant used is less than the above range, a satisfactory dissolution rate may not be achieved due to delayed disintegration rate. On the other hand, if the amount of the disintegrant used is more than the above range, productivity problems such as poor compression or poor coating may occur.

Lubricants may be selected from the group consisting of soluble lubricants, insoluble lubricants, and mixtures thereof. Non-limiting examples include 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, mono Glyceryl Stearate, Silicon Dioxide, Calcium Silicate, Magnesium Silicate, Hydrogenated Vegetable Oil, Hard Liquid Paraffin, Polyethylene Glycol, Sodium Lauryl Sulfate, Magnesium Lauryl Sulfate, Sodium Benzoate, Polyoxyethylene Monostearate, Glyceryl Triacetate, Sucrose Mono. It may be one or more selected from the group consisting of laurate and mixtures thereof. Said lubricant may preferably 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, still more preferably 1 part by weight of lenalidomide. An amount of 0.05 to 0.5 parts by weight, even more preferably 0.1 to 0.35 parts by weight may be used. If the amount of lubricant used is less than the above range, productivity problems such as poor compression may occur. On the other hand, if the amount of lubricant used is more than the above range, there is a possibility that problems with elution delay and productivity will occur.

The present invention can be produced into uncoated tablets by mixing lenalidomide and necessary additives and then compressing. If necessary, in the present invention, lenalidomide and additives are granulated into granules by a wet or dry method before tableting, and then the granules can be used for tableting. At this time, wet granules and dry granules can be appropriately selected from published techniques by ordinary technicians as needed.

In particular, in the present invention, when granules are simply mixed and tableted without granulation, the order of mixing additives may be important.

The uncoated tablet of the present invention can be realized in a smaller size than conventional lenalidomide hard capsules. Although the size varies depending on the dose, even in the case of the 25 mg formulation, which has the highest capacity, the longest axis of the uncoated tablet (in the case of a circle, the diameter) is No. Preferably, the length of the No. 0 capsule is less than 2.17 cm. For example, it may be 2 cm or less, preferably 1.8 cm or less, more preferably 1.6 cm or less.

The uncoated tablet of the present invention preferably has a maximum average hardness of 300N and a minimum average hardness of 10N. More preferably, the maximum average hardness is 250N and the minimum average hardness is 20N. More preferably, the maximum average hardness is 230N and the minimum average hardness is 30N. Most preferred is a maximum average hardness of 210N and a minimum average hardness of 40N. When the hardness of the uncoated tablet is higher than the above range, the drug release may be delayed due to delayed disintegration. On the other hand, if the hardness of the uncoated tablet is lower than the above range, the tablet may become brittle and crack during coating, transportation, storage and administration.

According to the present invention, after the uncoated tablet is produced, the surface can be coated with a coating base.

Coating bases include polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and salts thereof, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol-polyvinyl alcohol graft copolymer. Copolymers, polymers of acrylic acid and its salts, polymethacrylates, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymers, vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrated It may be selected from the group consisting of degraded starch, alginate, 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, still more preferably 4 to 15 parts by weight, still more preferably 100 parts by weight of the uncoated tablet. It can be used in an amount of 5-15 parts by weight, most preferably 6-15 parts by weight. If the amount of the hydrophilic polymer used is less than the above range, there is a problem that the entire uncoated tablet is not covered with the coating base. On the other hand, if the amount of hydrophilic polymer used is more than the above range, the dissolution rate may be excessively delayed.

The coating is intended to prevent the drug from being lost. Therefore, if necessary, after the primary coating, the secondary coating may be carried out, and the film thickness of the coating can be appropriately selected. However, as described above, the coating should not delay the elution of the drug, and an appropriate range should be selected.

Other components and methods required for coating can be appropriately selected by those of ordinary skill in the art.

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

Example 1
<Manufacturing uncoated tablets>
Tablets were manufactured using lenalidomide with particle size analysis results D10 3 μm, D50 13 μm, D90 44 μm, D[4,3] 19 μm. A mixture was prepared with a composition as shown in Table 1 below, and this mixture was tableted with a rectangular punch at a weight of 400 mg per tablet.

<Coating of uncoated tablets>
The prepared uncoated tablet was double-coated with two types of coating agents in an amount of 7.5% (w/w) in total with respect to 100% (w/w) of the total weight of the uncoated tablet. After primary coating (2.5% (w/w)) with Opadry (registered trademark) containing HPMC as the main component, secondary coating (5% (w/w)) with Opadry (registered trademark) containing PVA as the main component w/w)) was performed. The working conditions of the first coating are shown in Table 2 below, and the working conditions of the second coating are shown in Table 3 below.

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

Comparative example 2
Tablets were produced in the same manner as in Example 1, except that lenalidomide with D50 of 2 μm and D90 of 5 μm was used as a result of particle size analysis.

Test Example 1: Dissolution Test A dissolution test was performed on the control drug Revlimid (registered trademark) capsules and Example 1 under the following conditions (n=6), and the results are shown in FIG.
Test method: Korean Pharmacopoeia Dissolution Test Method Paddle method Eluent: pH 1.2 solution Rotational speed: 50 rpm
Temperature: 37°C
Analysis method: HPLC analysis method HPLC analysis conditions Detector: Ultraviolet absorption photometer (measurement wavelength 210 nm)
Column: 250 mm length, 4.6 mm diameter, 5 μm C18 column or equivalent Flow rate: 1.0 mL/min Injection volume: 10 μL
Mobile phase: listed in Table 4 below

Solvent A: Dissolve 1.36 g of potassium dihydrogen phosphate in 1000 mL of water, adjust the pH of the solution to 3.5 ± 0.05 using orthophosphoric acid, and then filter solution Solvent B: Methanol and After mixing acetonitrile at a ratio of 90:10 (v/v), filtered solution

Test Example 2: Comparative Dissolution Test A dissolution test was performed under the conditions of Test Example 1 for the control drug Revlimid (registered trademark) capsules and Comparative Examples 1 and 2, respectively (n=t), and the results are shown in FIGS. It is shown in FIG.
As shown in Figures 1-3, adjusting the particle size of lenalidomide played a major role in adjusting the elution pattern to be comparable to that of the control drug. Specifically, when the particle size D50 of lenalidomide exceeds 2 μm, the elution pattern is equivalent to that of the control drug as in Example 1, and when the D50 is 51 μm or more, the elution pattern is similar to that of Comparative Example 1. very different. In addition, when D50 is 2 μm or less, a rapid elution pattern was exhibited at the initial stage as in Comparative Example 2, and there was concern about a rapid increase in Cmax value and the resulting side effects.

Claims (2)

A solid dosage form for oral administration comprising lenalidomide,
Manufactured by compressing a mixture containing lenalidomide, a diluent, a disintegrant and a lubricant,
D10 of said lenalidomide is 1.5 μm to 3.5 μm, D50 is 10 μm to 15 μm, D90 is 35 μm to 55 μm, D[4,3] is 15 μm 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 0.1 to 2.5 parts by weight, and the content of the lubricant is 0.03 to 0.03 parts by weight. A solid preparation for oral administration, which is 0.75 parts by weight. A method for manufacturing a solid dosage form for oral administration comprising lenalidomide, comprising:
Compressing a mixture comprising lenalidomide, a diluent, a disintegrant and a lubricant;
D10 of said lenalidomide is 1.5 μm to 3.5 μm, D50 is 10 μm to 15 μm, D90 is 35 μm to 55 μm, D[4,3] is 15 μm 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 0.1 to 2.5 parts by weight, and the content of the lubricant is 0.03 to 0.03 parts by weight. 0.75 parts by weight, the method.

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