JP7585043B2 - Pharmaceutical compositions containing lenalidomide - Google Patents

Description

The present invention relates to a formulation of lenalidomide. Specifically, the present invention relates to a solid formulation 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 treatment for multiple myeloma. Lenalidomide is a new immunomodulatory imide drug (IMiDs) compound that is similar in structure to thalidomide, but has stronger biological activity and is therefore more effective. In addition, it has been evaluated to have fewer side effects than thalidomide.

Conventionally, lenalidomide has been available in capsule form. Commercially available products include Celgene's Revlimid Capsules, a hard capsule formulation, approved 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 dosages of 10 mg, 15 mg, 20 mg, and 25 mg, and are quite long (approximately 2.17 cm) and bulky, which makes them inconvenient for elderly patients to take.
Furthermore, even when taken with water, the capsule may stick to the throat or esophagus during swallowing.

However, tablets can be further reduced in volume because they do not require the use of fixed-size capsules such as size 0, and are less likely than capsules to stick to the neck or esophagus when taken with water.

However, because capsules are manufactured by filling capsules with granules, tablets have the problem of less uniform content than capsules.

Therefore, in order to utilize the advantages of the above-mentioned tablets, the inventors attempted to develop a lenalidomide tablet with excellent drug content uniformity, a similar dissolution pattern to conventional capsules, and biologically equivalent pharmacological effects.

Korean Patent No. 534498

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

Another object of the present invention is to provide a tablet composition that has a dissolution pattern in the tablet equivalent to that in the capsule, and that not only shows physicochemical equivalence in comparative dissolution tests, but also shows equivalence in in vivo tests in experimental animals and bioequivalence tests.

Therefore, the present invention provides a tablet composition and a method for producing the same, which has the same pharmacological efficacy and effects as commercially available capsule formulations, but has been further developed to have improved appearance and ease of administration.

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 produced by tableting lenalidomide having a D50 of more than 2 μm.
In the present invention, D[4,3] of lenalidomide is preferably 3 to 70 μm.
Furthermore, 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 available in low doses such as 2.5 mg and is very sensitive to the uniformity of the drug content, but the present invention has excellent drug content uniformity even in the form of tablets.

In addition, one embodiment of the present invention is realized in the form of a tablet, which overcomes the disadvantages of hard capsules, such as their bulkiness and their tendency to stick to the throat or esophagus during swallowing, even when taken with water.

Furthermore, the present invention has bioequivalence when compared to conventional hard capsules, and one embodiment of the present invention uses a coating to block the bitter taste of the drug and the adverse effects of drug leakage. Specifically, the present invention has the same dissolution results as the control drug, Revlimid capsules, and therefore, in a bioequivalence test, the AUC and _Cmax values are within 80-125%, preferably within 90-110%, and most preferably 95-105% of those of conventional capsules.

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

In this specification, lenalidomide means a main ingredient raw material whose active ingredient is lenalidomide. For example, it includes lenalidomide or its pharma- ceutically acceptable salts, isomers, crystalline forms, anhydrates, hydrates, solvates, or mixtures of two or more of these.

In this specification, the term "additive" refers to a known medicamentously addable inactive ingredient, such as a pharmaceutical excipient. For example, it refers to a diluent, disintegrant, lubricant, coating base, etc., all of which are known ingredients that can be used. Unless otherwise specified in this specification, it may be understood as any one of the ingredients that a person of ordinary skill in the art can appropriately select.

The present invention aims to develop a tablet that can replace conventional hard capsules.

Lenalidomide is required to be formulated in a low dose of 2.5 mg. With a low dose formulation, even the loss of a small amount of drug means that the intended efficacy cannot be expected. Therefore, uniformity of the drug content during the manufacturing process is extremely important.

However, unlike hard capsules, which involve mixing the drug with other pharmaceutical additives and then filling the resulting granules into capsules, tablets require a compression process, and there is a risk of the drug being lost due to heat generated during compression or process disturbances in the tablet press. Therefore, lenalidomide was limited to only being marketed as a hard capsule formulation.

However, hard capsules require the use of capsules of a set standard, and some are so bulky that their size impedes ease of taking the medication. In addition, when hard capsules are taken with water, the gelatin capsule surface becomes adhesive, and the capsule may stick to the throat or esophagus during swallowing. For these reasons, there was a need to develop a lenalidomide tablet.

The inventors have conducted extensive research to ensure uniformity of drug content, a limitation that was previously not possible with tablets, and to achieve a dissolution pattern equivalent to that of capsules in order to achieve a drug efficacy that is biologically equivalent to that of capsules.

The inventors surprisingly discovered that by adjusting the particle size of lenalidomide, it is possible to ensure uniformity of the drug content and achieve a dissolution pattern equivalent to that of the control drug, Revlimid capsules, and thus completed the invention.

In particular, with capsules, the contents within the capsule are released as the hard capsule dissolves, and the drug is dissolved. On the other hand, with tablets, the drug is dissolved as the plain tablet disintegrates, so the dissolution mechanisms are different. In particular, with hard capsules, the contents within the capsule consist of fine powder with a large surface area, so a certain degree of dissolution rate is guaranteed if only the capsule is dissolved, but with tablets, the plain tablet has a certain size and a small surface area, so it is not easy to guarantee the desired dissolution rate. Therefore, when developing tablets, it is extremely difficult to adjust the dissolution pattern of the capsule and the drug to be the same. However, surprisingly, it has been discovered that it is possible to adjust the dissolution pattern of the drug by adjusting the particle size.

As shown in Figures 4 and 5, the raw material of lenalidomide itself has various particle sizes. It is recognized that the smaller the particle size of the drug, the faster the dissolution rate, but this theory applies to poorly soluble drugs, and since lenalidomide has good solubility in acidic solutions such as the above environment, there was no recognition that adjusting the particle size of the drug could significantly change the dissolution rate to the extent that it would affect the bioavailability. Therefore, when the drug's dissolution rate is insufficient, attempts to adjust the particle size of lenalidomide have not generally been made. However, surprisingly, as shown in Figures 1 to 3, it was shown that 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 the micronized lenalidomide may be expressed using D10, D50, D90, etc. Alternatively, it may be expressed on average using D[4,3], etc. D10 means the diameter of the particles that fall into the bottom 10% when examining the volume distribution. D50 and D90 mean the diameters of the particles that fall into the 50% and 90% range, respectively. D[4,3] means the volume average diameter. This may be measured, for example, using a light diffraction particle sizer.

The present invention is characterized by adopting lenalidomide with a D50 of more than 2 μm. When lenalidomide is formulated into tablets by tableting, a raw material whose particle size satisfies the above conditions must be used to ensure the uniformity of the content and the desired dissolution pattern, and bioequivalence with conventional capsules can be achieved. Furthermore, if the particle size is smaller than the above range, process failures may be induced during 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. More preferably, D[4,3] is 5 to 60 μm, more preferably 8 to 45 μm, even more preferably 10 to 30, and most preferably 15 to 25 μm.

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

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

The present invention can be embodied in a tablet by mixing lenalidomide having a D50 of 2.5 to 50 μm with a pharma- ceutically acceptable excipient and compressing the mixture into a tablet.

In this case, additives may include diluents, disintegrants, and lubricants.

The diluent may be selected from the group consisting of sugar, sugar alcohol, cellulose, starch, inorganic salts, and mixtures thereof. Non-limiting examples include lactose (anhydrous or hydrated, e.g., 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, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrates, dextrin, and mixtures thereof. Lactose and microcrystalline cellulose may be preferably selected.

The diluent may also act as a binder.

The diluent can be used in an amount of 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, and even more preferably 4 to 20 parts by weight, per part by weight of lenalidomide. The above content range is suitable when producing tablets.

The disintegrant may be selected from the group consisting of a swelling disintegrant, a moist disintegrant, and a mixture thereof. Non-limiting examples include starch, cellulose, crosslinked polymers, gums, polysaccharides, and mixtures thereof. For example, the disintegrant may be one or more selected from the group consisting of 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. Preferably, the disintegrant may be croscarmellose sodium, crospovidone, L-HPC, or sodium starch glycolate. More preferably, the disintegrant may be croscarmellose sodium.

The disintegrant may be used in an amount of 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, and even more preferably 0.2 to 1 part by weight, per part by weight of lenalidomide. If the amount of disintegrant used is less than the above range, a satisfactory dissolution rate may not be achieved due to a delayed disintegration rate. On the other hand, if the amount of disintegrant used is more than the above range, productivity problems such as poor compression or poor coating may occur.

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 esters, starch, talc, colloidal silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, 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 monolaurate, and mixtures thereof. The lubricant may preferably be magnesium stearate, stearic acid, or colloidal silica. More preferably, it may be magnesium stearate.

The lubricant may be used in an amount of 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, and even more preferably 0.1 to 0.35 parts by weight, per part by weight of lenalidomide. If the amount of lubricant used is less than the above range, problems with productivity such as poor compression may occur. On the other hand, if the amount of lubricant used is more than the above range, delayed dissolution and problems with productivity may occur.

In the present invention, lenalidomide and necessary additives can be mixed and compressed into plain tablets. If necessary, in the present invention, lenalidomide and additives can be granulated into granules by a wet or dry method before compression, and then the granules can be used for tableting. In this case, wet granules and dry granules can be appropriately selected by a person of ordinary skill in the art as necessary from the publicly disclosed technology.

In particular, when the granules are simply mixed and compressed into tablets without granulation, the order in which the additives are mixed can be important.

The uncoated tablets of the present invention can be realized in a smaller size than conventional lenalidomide hard capsules. The size varies depending on the dose, but even in the case of the highest-volume 25 mg formulation, the longest axis of the uncoated tablet (diameter if circular) is preferably shorter than the length of No. 0 capsule, which is 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 tablets of the present invention preferably have 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. Even more preferably, the maximum average hardness is 230N and the minimum average hardness is 30N. Most preferably, the maximum average hardness is 210N and the minimum average hardness is 40N. If the hardness of the uncoated tablets is higher than the above range, the release of the drug due to delayed disintegration may be delayed. On the other hand, if the hardness of the uncoated tablets is lower than the above range, the tablets may become brittle and break during coating, transportation, storage, and administration.

In the present invention, after the uncoated tablets are produced, the surface can be coated with a coating base.

The coating base may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol polyvinyl alcohol graft copolymer, polymers of acrylic acid and its salts, polymethacrylate, poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer, vinylpyrrolidone-vinyl acetate copolymer, gelatin, guar gum, partially hydrolyzed starch, alginate, xanthan, and mixtures thereof.

The coating base can be used in an amount of 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 5 to 15 parts by weight, and most preferably 6 to 15 parts by weight, per 100 parts by weight of the uncoated tablet. If the amount of 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 purpose of the coating is to prevent the loss of the drug. Therefore, if necessary, a secondary coating may be applied after the primary coating, and the coating thickness can be selected appropriately. However, as mentioned above, the coating must not cause a delay in the dissolution of the drug, so an appropriate range must be selected.

Other ingredients and methods required for coating can be selected as appropriate by a person of ordinary skill in the art.

The present invention will be described in more detail with reference to the following examples. However, these examples are intended only to illustrate the present invention, and the scope of the present invention is not limited by these examples in any way.

Example 1
<Production of uncoated tablets>
Lenalidomide with particle size analysis results of D10 3 μm, D50 13 μm, D90 44 μm, and D[4,3] 19 μm was used to prepare tablets. A mixture was prepared according to the composition shown in Table 1 below, and the mixture was compressed into tablets with a rectangular punch to a weight of 400 mg per tablet.

<Coating of uncoated tablets>
The prepared uncoated tablets were double-coated with two types of coating agents in a total amount of 7.5% (w/w) based on the total weight of the uncoated tablets (100% (w/w)). After the first coating (2.5% (w/w)) was performed with Opadry® containing HPMC as the main component, the second coating (5% (w/w)) was performed with Opadry® containing PVA as the main component. The first coating conditions are shown in Table 2 below, and the second coating conditions are shown in Table 3 below.

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

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

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

Solvent A: 1.36 g of potassium dihydrogen phosphate was dissolved in 1000 mL of water, and the pH of the solution was adjusted to 3.5±0.05 with orthophosphoric acid, followed by filtration. Solvent B: Methanol and acetonitrile were mixed in a ratio of 90:10 (v/v), followed by filtration.

Test Example 2: Comparative Dissolution Test A dissolution test was carried out (n=t) under the conditions of Test Example 1 for the control drug Revlimid® capsule and Comparative Examples 1 and 2, respectively, and the results are shown in Figures 2 and 3.
As shown in Figures 1 to 3, adjusting the particle size of lenalidomide played a major role in adjusting the dissolution pattern to be equivalent to that of the control drug. Specifically, when the particle size D50 of lenalidomide exceeded 2 μm, the dissolution pattern was equivalent to that of the control drug as in Example 1, whereas when D50 was 51 μm or more, the dissolution pattern was significantly different as in Comparative Example 1. In addition, when D50 was 2 μm or less, a rapid dissolution pattern was shown in the early stage as in Comparative Example 2, raising concerns about a rapid increase in _Cmax value and the resulting side effects.

Claims (2)

A solid formulation for oral administration comprising lenalidomide,
A tablet comprising lenalidomide, a diluent, a disintegrant and a lubricant, and a coating on the surface of the tablet,
the lenalidomide has a D10 of 1.5 μm to 3.5 μm, a D50 of 10 μm to 30 μm, a D90 of 35 μm to 75 μm , and a D[4,3] of 10 μm to 30 μm ;
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, and the content of the lubricant is 0.1 to 0.35 parts by weight, relative to 1 part by weight of the lenalidomide;
the diluent is a mixture of anhydrous lactose and microcrystalline cellulose;
The disintegrant is croscarmellose sodium,
The lubricant is magnesium stearate,
The coating base contained in the coating is selected from the group consisting of hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol-polyvinyl alcohol graft copolymers, and mixtures thereof;
A solid preparation for oral administration , in which the coating base is used in an amount of 4 to 15 parts by weight per 100 parts by weight of the uncoated tablet . A method for producing a solid formulation for oral administration comprising lenalidomide, comprising the steps of:
The method includes compressing a mixture containing lenalidomide, a diluent, a disintegrant and a lubricant to prepare a core tablet, and coating the core tablet with a coating base,
the lenalidomide has a D10 of 1.5 μm to 3.5 μm, a D50 of 10 μm to 30 μm, a D90 of 35 μm to 75 μm , and a D[4,3] of 10 μm to 30 μm ;
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, and the content of the lubricant is 0.1 to 0.35 parts by weight, relative to 1 part by weight of the lenalidomide;
the diluent is a mixture of anhydrous lactose and microcrystalline cellulose;
The disintegrant is croscarmellose sodium,
The lubricant is magnesium stearate,
The coating base is selected from the group consisting of hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol-polyvinyl alcohol graft copolymers, and mixtures thereof;
The method , wherein the coating base is used in an amount of 4 to 15 parts by weight per 100 parts by weight of the uncoated tablet .