JP2021518422A - Pharmaceutical composition containing lenalidomide - Google Patents

Abstract

The present invention relates to a dosage form of a lenalidomide tablet, and is characterized in that it is produced by tableting lenalidomide having a D50 of lenalidomide of more than 2 μm. [Selection diagram] Fig. 1

Description

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

Lenalidomide (general formula: 3- (4'-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidine-2,6-dione) is a compound disclosed in Patent Document 1. It is used as a therapeutic agent for multiple bone marrow species. Lenalidomide is an IMiDs (Immunomodulatory immediate drugs) compound belonging to a new immunomodulatory group, and has a structure similar to that of thalidomide, but is more effective due to its stronger biological activity. Moreover, it was evaluated that the side effects were further reduced compared to thalidomide.

Conventional lenalidomide has emerged as a capsule. Commercialized products include hard capsules of Celgene's Lebramide capsules, approved at doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 25 mg.

Rebramide capsules are packed in No. 0 capsules in all cases of the dosages of 10 mg, 15 mg, 20 mg and 25 mg, and the major axis is considerably long and bulky at about 2.17 cm. Therefore, elderly patients have a disadvantage that it is inconvenient to take.
In addition, capsules may stick to the throat and esophagus during swallowing, even when taken with water.

However, tablets can be further reduced in volume because they do not need to use capsules of a fixed size, such as No. 0, and are less likely to stick to the neck or esophagus when taken with water than capsules.

However, since capsules are produced by filling granules in capsules, tablets have a problem of inferior content uniformity as compared with capsules.

Therefore, in order to take advantage of the above-mentioned tablets, the present inventors have prepared lenalidomide tablets having excellent drug content uniformity, similar dissolution patterns to conventional capsules, and biologically equivalent drug efficacy. I tried to develop it.

Korean Patent No. 534498

An object of the present invention is to change the dosage form of a commercially available hard capsule lenalidomide preparation to a tablet to provide a tablet composition having a short length, not being 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, which not only shows physicochemical equivalence in the comparative dissolution test, but also in vivo in the laboratory animal and bioequivalence test. It is an object of the present invention to provide a tablet composition showing equivalence in a test.

Therefore, the present invention provides a tablet composition having the same pharmacological efficacy and effect as a commercially available capsule preparation, and further developed to improve the appearance, ease of administration, and the like, and a method for producing the same. do.

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 produced by tableting lenalidomide having a D50 of more than 2 μm.
In the present invention, the D [4,3] of lenalidomide is preferably 3 to 70 μm.
Further, in the present invention, the D90 of lenalidomide is preferably 8 to 180 μm.
Further, in the present invention, the D10 of lenalidomide is preferably 0.5 to 10 μm.

Lenalidomide is very sensitive to drug content uniformity in the presence of low-dose drugs such as 2.5 mg, but the present invention is excellent in drug content uniformity even though it is made into tablets. There is.

Further, since one embodiment of the present invention has been realized as a tablet, it has the disadvantages of being bulky and that it tends to stick to the throat and esophagus during swallowing even when taken with water. Overcame.

Further, the present invention has bioequivalence as compared with the conventional hard capsules on the market, and one embodiment of the present invention is coated to have adverse effects due to the bitterness of the drug and the outflow of the drug. Also shut off. Specifically, the present invention has the same dissolution results as the control drug, Rebramide capsules, so that _{the values of AUC and C max} in the bioequivalence test are 80 to 80 to those of the conventional capsules. It is within 125%, preferably within 90-110%, and most preferably 95-105%.

It is a graph which showed the dissolution comparative test result of the Lenalidomide (registered trademark) capsule of a control | tablet of Example 1 in a pH 1.2 solution. It is a graph which showed the dissolution comparative test result of the Lenalidomide (registered trademark) capsule of the control drug, and the tablet of Comparative Example 1 in a pH 1.2 solution. It is a graph which showed the dissolution comparative test result of the control drug Lenalidomide (registered trademark) capsule, and the tablet of Comparative Example 2 in a pH 1.2 solution. It is a scanning electron micrograph of the pulverized raw material corresponding to D10 3 μm, D50 13 μm, D90 44 μm, D [4,3] 19 μm of lenalidomide. It is a scanning electron micrograph of the pulverized raw material corresponding to D10 4 μm, D50 51 μm, D90 219 μm, D [4,3] 84 μm of lenalidomide.

As used herein, the term lenalidomide means a main component raw material in which the active ingredient is lenalidomide. For example, it comprises renalidemid or a pharmaceutically acceptable salt thereof, an isomer, a crystalline form, an anhydride, a hydrate, a solvate or a mixture of two or more thereof.

As used herein, the term "additive" means a known pharmaceutically addable inert ingredient, such as pharmaceutical additives. For example, it means a diluent, a disintegrant, a lubricant, a coating base, etc., all of which are known to have usable components. Unless otherwise described herein, it may be understood as any one of the components which can be appropriately adopted by ordinary engineers.

The present invention is for developing a tablet that can replace a conventionally commercially available hard capsule.

Lenalidomide is required to be formulated in a low dose of 2.5 mg. With a low-dose formulation, even a small amount of drug disappearance cannot be expected to have the desired efficacy. Therefore, the uniformity of drug content in the manufacturing process is very important.

However, unlike hard capsules, where the process of mixing the drug with other pharmaceutical additives and then filling the capsules with the granules is complete, the tablets involve a tableting process and arise from tableting. The drug may disappear due to the heat generated and the process failure in the tableting machine. Therefore, lenalidomide has a limitation that there is no choice but to market a preparation of a hard capsule.

However, hard capsules must use capsules of a specified standard, and some of them are so bulky that their size hinders the convenience of administration. In addition, when taken with water, hard capsules have adhesive strength on the surface of gelatin capsules and may stick to the throat or esophagus during swallowing. Therefore, it was necessary to develop lenalidomide tablets.

The present inventors ensured the uniformity of drug content, which was a conventional limit that could not be developed for tablets, and the dissolution pattern was equivalent to that of capsules in order to exhibit a medicinal effect biologically equivalent to that of capsules. We have been studying hard to achieve something.

Surprisingly, when adjusting the particle size of lenalidomide, the present inventors can ensure the homogeneity of the drug content and may achieve the same dissolution pattern as the control drug, levramide capsules. Was found, and the invention was completed.

In particular, in the capsule, the contents in the capsule are released while the hard capsule is dissolved, and the drug is eluted. On the other hand, tablets have different elution mechanisms because the drug is eluted while the uncoated tablet disintegrates. In particular, in hard capsules, the content inside the capsule is composed of fine powder with a large surface area, so if only the capsule is dissolved, a certain dissolution rate can be guaranteed. Since it has a constant size and a small surface area, it is not easy to secure a desired dissolution rate. Therefore, when developing tablets, it is extremely difficult to equalize the elution patterns of capsules and drugs. However, surprisingly, it was found that the elution pattern of the drug can be adjusted by adjusting the particle size.

As shown in FIGS. 4 and 5, the raw material itself of lenalidomide has various particle sizes. There is a recognition that the smaller the particle size of the drug, the higher the dissolution rate, but this is the theory that corresponds to a poorly soluble drug, and lenalidomide has a good solubility in an acidic solution such as the above environment, so the drug particles can be used. There was no recognition that the dissolution rate could be changed so clearly that it would affect the bioavailability even if adjusted. Therefore, no attempt has been made to control the particle size of lenalidomide when the elution rate of the drug is inadequate. However, surprisingly, 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 a micronized form. The particle size of the pulverized lenalidomide can be indicated by using D10, D50, D90 and the like. In addition, it can be shown on average by using D [4,3] or the like. D10 means the diameter of the particles corresponding to the lower 10% when examining the volume distribution. D50 and D90 mean the diameters of the particles 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 size measuring device.

The present invention is characterized by adopting lenalidomide having a D50 of more than 2 μm. When lenalidomide is formulated into tablets by tableting, a raw material having a particle size satisfying the above conditions must be used in order to ensure uniformity of content and the desired dissolution pattern, which is a bioequivalence with conventional capsules. It can have scientific equivalence. In addition, when it is smaller than the above range, it may induce a process failure at the time of tableting. Lenalidomide has a D50 of 2.5 to 50 μm, more preferably 3 to 40 μm, even more preferably 5 to 30 μm, even more preferably 7 to 20 μm, and most preferably 10 to 15 μm.

Lenalidomide preferably has a D [4,3] of 3 to 70 μm. D [4,3] is more preferably 5 to 60 μm, 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. D90 is more preferably 12 to 140 μm, more preferably 15 to 100 μm, still more preferably 25 to 75 μm, and most preferably 35 to 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, still more preferably 1.2 to 4.5 μm, and most preferably 1.5 to 3.5 μm.

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

At this time, the additive may include a diluent, a disintegrant, and a lubricant.

Diluents can be selected from the group consisting of sugars, sugar alcohols, celluloses, starches, inorganic salts and mixtures thereof. Non-limiting examples include lactose (anhydrous or hydrate, eg 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, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate , Magnesium oxide, mannitol, martitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrin, dextrin, and a mixture thereof. May be good. Preferably, lactose or microcrystalline cellulose may be selected.

The diluent can 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, still more preferably 1 part by weight, based on 1 part by weight of lenalidomide. It can be used in an amount of 4 to 20 parts by weight. When produced into tablets, the content range is suitable.

The disintegrant 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, carboxymethyl cellulose, crospovidone, L-HPC, starch, carboxymethyl starch sodium, sodium starch glycolate, alginic acid, carboxymethyl cellulose sodium, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch, And one or more selected from the group consisting of a mixture thereof. Preferably, it may be croscarmellose sodium, crospovidone, L-HPC, sodium starch glycolate. 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, still more preferably 0.15 to 5 parts by weight, based on 1 part by weight of renalidemid. 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 elution rate may not be achieved due to the delay in the disintegration rate. On the other hand, if the amount of the disintegrant used is larger than the above range, there may be a problem in productivity such as poor compression or poor coating.

The lubricant 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 ester, starch, talc, colloidal silica, magnesium oxide, magnesium carbonate, glyceryl behate, mono. Glyceryl stearate, silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sculose mono It may be one or more selected from the group consisting of laurate and a mixture thereof. The lubricant may preferably be magnesium stearate, stearic acid, or 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 0.05 to 0.75 parts by weight, based on 1 part by weight of renalidemid. It may be used in an amount of 0.05 to 0.5 parts by weight, more preferably 0.1 to 0.35 parts by weight. If the amount of lubricant used is less than the above range, productivity problems such as compression failure may occur. On the other hand, if the amount of the lubricant used is larger than the above range, problems may occur in elution delay and productivity.

INDUSTRIAL APPLICABILITY The present invention can be produced as an uncoated tablet after mixing lenalidomide and a necessary additive. If necessary, the present invention can also be used for tableting using the granules after granulating lenalidomide and an additive into granules by a wet or dry method before tableting. At this time, the wet granules and the dry granules can be appropriately adopted by ordinary engineers from the published technology as needed.

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

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

The uncoated 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. 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 of the uncoated tablet is higher than the above range, the release of the drug may be delayed due to the 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 ingestion.

In the present invention, the surface can be coated with a coating base after producing an uncoated lock.

The coating base is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol polyvinyl alcohol graft copolymer weight. Coalescence, polymer of acrylic acid and salts thereof, polymethacrylate, poly (butylmethacrylate, 2-dimethylaminoethylmethacrylate, methylmethacrylate) copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partially hydrated It may be selected from the group consisting of degraded starch, alginate, xanthane 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 1 to 30 parts by weight, based on 100 parts by weight of the uncoated tablet. It can be used in an amount of 5 to 15 parts by weight, most preferably 6 to 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 the hydrophilic polymer used is larger than the above range, the dissolution rate may be excessively delayed.

The coating is intended to prevent the drug from disappearing. Therefore, if necessary, the primary coating may be followed by the secondary coating, and the film thickness of the coating can be appropriately selected. However, as mentioned above, the coating should not delay the elution of the drug and it is necessary to select an appropriate range.

Other ingredients and methods required for coating can be appropriately adopted by ordinary technicians.

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

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

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

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

Comparative Example 2
As a result of the particle size analysis, tablets were produced by the same method as in Example 1 except that lenalidomide having a D50 of 2 μm and a D905 of 5 μm was used.

Test Example 1: Dissolution test A control drug, Lenalidomide® capsule, and Example 1 were subjected to an dissolution test under the following conditions (n = 6), and the results are shown in FIG.
Test method: Paddle method of Korean Pharmacopoeia elution test method Eluent: pH1.2 solution Rotation speed: 50 rpm
Temperature: 37 ° C
Analytical method: HPLC analytical method HPLC analytical conditions Detector: Ultraviolet absorptiometer (measurement wavelength 210 nm)
Column: 250 mm long, 4.6 mm in 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

Solvent A: 1.36 g of potassium dihydrogen phosphate was dissolved in 1000 mL of water, the pH of the solution was adjusted to 3.5 ± 0.05 with orthophosphoric acid, and then filtered. Solvent B: With methanol A solution obtained by mixing acetonitrile at a ratio of 90:10 (v / v) and then filtering.

Test Example 2: Comparative dissolution test A dissolution test was performed on the control drug Lenalidomide (registered trademark) capsule and Comparative Examples 1 and 2, respectively, under the conditions of Test Example 1 (n = t), and the results are shown in FIG. 2 and FIG. It is shown in FIG.
As shown in FIGS. 1 to 3, adjusting the particle size of lenalidomide played a major role in equally adjusting the elution pattern with the control drug. Specifically, when the particle size D50 of lenalidomide exceeds 2 μm, the dissolution pattern is equivalent to that of the control drug as in Example 1, and when D50 is 51 μm or more, the dissolution pattern is as in Comparative Example 1. It was very different. Further, when D50 was 2 μm or less, a rapid elution pattern was exhibited at the initial stage as in Comparative Example 2, so that there _{was concern about a rapid improvement in C max} value and side effects due to it.

Claims (8)

A solid preparation for oral administration containing lenalidomide.
A solid preparation for oral administration, which is produced by tableting lenalidomide having a D50 of lenalidomide of more than 2 μm. The solid preparation for oral administration according to claim 1, wherein the D50 of lenalidomide is more than 2 μm to 50 μm or less. The solid preparation for oral administration according to claim 1, wherein the D50 of lenalidomide is 2.5 μm to 50 μm. The solid preparation for oral administration according to claim 1, wherein the D50 of lenalidomide is 3 μm to 40 μm. The solid preparation for oral administration according to claim 1, wherein the D50 of lenalidomide is 5 μm to 30 μm. The solid preparation for oral administration according to claim 1, wherein the D [4,3] of lenalidomide is 3 to 70 μm. The solid preparation for oral administration according to claim 1, wherein the D90 of lenalidomide is 8 to 180 μm. The solid preparation for oral administration according to claim 1, wherein the D10 of lenalidomide is 0.5 to 10 μm.

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