Lenalidomide pharmaceutical composition and preparation method thereof

Abstract

The invention relates to a lenalidomide medicine solid dispersion and a preparation method thereof, the solid dispersion comprises 40% of lenalidomide and 60% of a water-soluble carrier, and the water-soluble carrier is povidone; the invention also provides a lenalidomide capsule and a preparation method thereof. The lenalidomide pharmaceutical composition provided by the invention is large in drug loading capacity, and a prepared solid preparation is high in bioavailability, good in solubility and stable and controllable in quality; the preparation method is simple in process, good in reproducibility, high in operability and suitable for large-scale production.

Description

[0001] This patent is a divisional application, the parent application being the invention application entitled "A Lenalidomide Pharmaceutical Composition and Preparation Method Thereof", application number 202011296593.2, and application date November 18, 2020. Technical Field

[0002] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a lenalidomide pharmaceutical composition and its preparation method. Background Technology

[0003] Lenalidomide is an anti-tumor drug developed by Celgene Pharmaceuticals in the United States. It is an analogue of thalidomide, but with fewer side effects and does not cause birth defects. Clinically, it is mainly used to treat myelodysplastic syndromes (MDS), multiple myeloma (MM), leukemia, and mantle cell lymphoma. It was approved by the FDA in 2005. Lenalidomide is a new generation of immunomodulatory agent with both anti-angiogenic and anti-tumor properties, exhibiting a dual mechanism of action.

[0004] Lenalidomide, chemically named 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, has the structural formula shown in Formula I below and the molecular formula C. 13 H 13 N3O3, with a molecular weight of 259.2606, is soluble in DMSO (100 mg / ml).

[0005]

[0006] According to the IF document of the Japan Society of Hospital Pharmacists, lenalidomide is a yellowish-white or light yellow powder that is extremely poorly soluble in water, ethanol (95%), or 2-propanol, and insoluble in acetonitrile or methanol. Its saturated solubility at room temperature in pH 1.2 solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and water is 18 mg / ml, 0.51 mg / ml, 0.44 mg / ml, and 0.3 mg / ml, respectively. Due to the poor solubility of lenalidomide, its dissolution rate in oral solid dosage forms is affected, which directly impacts the drug's bioavailability. Therefore, research into new dosage forms of lenalidomide has emerged to improve bioavailability and reduce adverse reactions.

[0007] Solid dispersions are dispersion systems in which drugs are uniformly dispersed in a carrier in highly dispersed states such as molecules, amorphous, or microcrystalline. They can increase the dissolution rate of poorly soluble drugs and improve bioavailability. Therefore, we considered increasing the drug loading of solid dispersions to improve the bioavailability of lenalidomide. However, the upper limit of drug loading for commercially available lenalidomide solid dispersions is typically 20%. Higher drug loading makes it easier for crystal form to coarsen, affecting drug dissolution. Therefore, it is necessary to select a suitable carrier to ensure that the prepared high-drug-loading (20-40%) solid dispersion has good solubility and stability.

[0008] The patent with publication number CN101537184A provides a pharmaceutical composition for a poorly soluble water drug and its preparation method. Example 6 in the specification discloses a capsule or tablet with lenalidomide as the active ingredient. The specific preparation method is as follows: lenalidomide, povidone and eutectic resin are dissolved in ethanol and sprayed onto the surface of lactose granules / pills. Then, other excipients such as magnesium stearate are mixed and filled into capsules or compressed into tablets. However, this technical solution has the following defects: (1) Using a mixture of povidone and eutectic resin as a carrier, the drug release is slow and the required blood drug concentration cannot be reached in a short time; (2) Lenalidomide has an amino group in its molecular structure. Lactose excipients may undergo the Maillard reaction, which increases the impurities in the solid oral preparation and easily causes changes in appearance and color; (3) The process in this technical solution is complicated. Crystal form changes may occur during the preparation process or the reproducibility of the granulation process is poor, which has a significant impact on the drug dissolution.

[0009] Patent CN103705485A discloses a composition for treating myelodysplastic syndrome and its preparation method, comprising lenalidomide, a carrier, a solubilizer, a disintegrant, a lubricant, a flow aid, and a binder, wherein the weight ratio of lenalidomide in the solid dispersion is 3-17%, and the solid dispersion is prepared by grinding. However, this technical solution has the following defects: (1) The formulation uses poloxamer as a carrier, and when the proportion of lenalidomide in the solid dispersion is increased, especially when the proportion is 20-40%, it is uncertain whether crystals will precipitate; (2) In this technical solution, povidone is only used as a solubilizer or binder.

[0010] In summary, choosing a suitable carrier that not only satisfies the requirements for good solubility and quality stability of high-drug-load solid dispersions, but also ensures that the bioavailability of the prepared lenalidomide solid formulation is higher than that of the reference formulation and that it can release the drug rapidly is a technical problem that has not yet been solved by those skilled in the art. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a lenalidomide pharmaceutical composition and its preparation method. By selecting povidone as a water-soluble carrier, the bioavailability of the prepared lenalidomide solid dosage form is higher than that of the reference formulation. At the same time, the lenalidomide solid dispersion with high drug loading still has good solubility and quality stability. In addition, by preparing the lenalidomide solid dispersion by solvent method and controlling the drying temperature and film thickness, the total impurity content and solvent residue of the product can be guaranteed to be within the limit range.

[0012] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0013] A lenalidomide solid dispersion, by weight percentage, is composed of 2%-40% lenalidomide and 60%-98% water-soluble carrier, wherein the water-soluble carrier is polyvinyl ketone.

[0014] A method for preparing lenalidomide solid dispersion as described above, using a solvent method, includes the following steps:

[0015] a) Weigh out lenalidomide and water-soluble carrier by weight percentage, dissolve them together in an organic solvent, and mix thoroughly;

[0016] b) Dry using a double-drum dryer at a temperature of 55-65℃, with a film thickness ≤1.0mm.

[0017] Preferably, the organic solvent used in the preparation method is selected from one or more of ethanol, isopropanol, and isopropanone.

[0018] Preferably, the drying temperature in the preparation method is 60°C, and the film thickness is ≤0.6 mm.

[0019] A lenalidomide oral solid dosage form comprising a lenalidomide solid dispersion as described above and pharmaceutically acceptable excipients.

[0020] Preferably, the excipient is selected from one or more of disintegrants, adhesives, and lubricants.

[0021] Preferably, the oral solid dosage form is a tablet or capsule.

[0022] A lenalidomide oral solid dosage form, by weight percentage, comprises the following components: 96.9% solid dispersion, 1.55% croscarmellose sodium, 1.55% magnesium stearate, and the solid dispersion comprises the following components by weight percentage: 40% lenalidomide, 60% povidone.

[0023] A method for preparing an oral solid dosage form of lenalidomide as described above includes the following steps:

[0024] (1) Granulate the above solid dispersion;

[0025] (2) Mix the granulated solid dispersion from step (1) with the excipient;

[0026] (3) Use a tablet press to compress the tablets or fill them into empty capsules.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] This invention provides an oral solid dosage form containing a high drug loading of lenalidomide. A specific amount of povidone is used as the carrier for the solid dispersion, which is prepared by solvent extraction in isopropanol. This ensures that the final product, even with a high drug loading of lenalidomide, dissolves completely, releasing the drug rapidly within 15 minutes. It exhibits superior bioavailability compared to the original drug and maintains stable and controllable quality. Furthermore, the preparation method provided by this invention is simple and environmentally friendly, significantly reducing the risk of crystal transformation during the preparation of oral solid dosage forms. The preparation process also demonstrates good reproducibility and processability. Detailed Implementation

[0029] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0030] Example 1: Lenalidomide pharmaceutical composition: 5mg, capsules, prescription quantity is 1000 capsules (see Table 1).

[0031] Table 1: Prescription Table for Example 1

[0032] Raw material names Dosage (g / 1000 capsules) Percentage (%) in solid dispersions Percentage of the total prescription (%) Lenalidomide 5.00 2.00 1.95 Povidone 245.00 98.00 95.70 Anhydrous ethanol 500.00 / / Sodium carboxymethyl starch 3.00 / 1.17 magnesium stearate 3.00 / 1.17 Total (excluding solvents) 256.00 100.00 100.00

[0033] The preparation method is as follows:

[0034] (1) Dissolve the prescribed amount of lenalidomide and povidone in anhydrous ethanol and dry them at 60°C using a double-drum dryer;

[0035] (2) The scraped solid dispersion was granulated using a 24-mesh sieve;

[0036] (3) Add the solid dispersion, sodium carboxymethyl starch and magnesium stearate to the mixer, set the speed to 10 rpm, and mix for 5 min;

[0037] (4) Fill into No. 2 gelatin empty capsules.

[0038] Example 2: Lenalidomide pharmaceutical composition: 25mg, capsules, prescription quantity is 1000 capsules (see Table 2).

[0039] Table 2: Prescription Table for Example 2

[0040] Raw material names Dosage (g / 1000 capsules) Percentage (%) in solid dispersions Percentage of the total prescription (%) Lenalidomide 25.00 40.00 38.76 Povidone 37.50 60.00 58.14 Isopropanol 100.00 / / Cross-linked carboxymethyl cellulose sodium 1.00 / 1.55 magnesium stearate 1.00 / 1.55 Total (excluding solvents) 64.50 100.00 100.00

[0041] The preparation method is the same as in Example 1, except that the above-mentioned components are replaced, and the gelatin empty capsules in step (4) are replaced with No. 3.

[0042] Example 3: Lenalidomide pharmaceutical composition: 25mg tablets, prescription quantity is 1000 tablets (see Table 3).

[0043] Table 3: Prescription Table for Example 3

[0044] Raw material names Dosage (g / 1000 capsules) Percentage (%) in solid dispersions Percentage of the total prescription (%) Lenalidomide 25.00 20％ 19.69 Polyethylene glycol 4000 100.00 80％ 78.74 Isopropyl ketone 50.00 / / Cross-linked polyvinylpyrrolidone 1.00 / 0.79 magnesium stearate 1.00 / 0.79 Total (excluding solvents) 127.00 100.00 100.00

[0045] Preparation method:

[0046] (1) Dissolve the prescribed amount of lenalidomide and polyethylene glycol 4000 in isoacetone and dry them using a double-drum dryer at 60°C;

[0047] (2) The scraped solid dispersion was granulated using a 24-mesh sieve;

[0048] (3) Add the solid dispersion, cross-linked polyvinylpyrrolidone and magnesium stearate to a mixer, set the speed to 10 rpm, and mix for 5 min;

[0049] (4) Use a tablet press to compress tablets.

[0050] Example 4: Lenalidomide pharmaceutical composition: 25mg, capsules, prescription quantity is 1000 capsules (see Table 4).

[0051] Table 4: Prescription Table for Example 4

[0052] Raw material names Dosage (g / 1000 capsules) Percentage (%) in solid dispersions Percentage of the total prescription (%) Lenalidomide 25.00 10.00 9.77 Polosham 188 225.00 90.00 87.89 ethanol 500.00 / / Cross-linked polyvinylpyrrolidone 3.00 / 1.17 magnesium stearate 3.00 / 1.17 Total (excluding solvents) 256.00 100.00 100.00

[0053] The preparation method is the same as in Example 1, except that the above-mentioned components are replaced.

[0054] Example 5: Lenalidomide pharmaceutical composition: 25mg, capsules, prescription quantity is 1000 capsules (see Table 5).

[0055] Table 5: Prescription Table for Example 5

[0056] Raw material names Dosage (g / 1000 capsules) Percentage (%) in solid dispersions Percentage of the total prescription (%) Lenalidomide 25.00 40.00 38.76 Polosham 37.50 60.00 58.14 Isopropanol 100.00 / / Cross-linked carboxymethyl cellulose sodium 1.00 / 1.55 magnesium stearate 1.00 / 1.55 Total (excluding solvents) 64.50 100.00 100.00

[0057] The preparation method is the same as in Example 2, except that the above-mentioned components are replaced.

[0058] Example 6: Lenalidomide pharmaceutical composition: 25mg, capsules, prescription quantity is 1000 capsules (see Table 6).

[0059] Table 6: Prescription Table for Example 6

[0060] Raw material names Dosage (g / 1000 capsules) Percentage (%) in solid dispersions Percentage of the total prescription (%) Lenalidomide 25.00 40.00 38.76 Polyethylene glycol 4000 37.50 60.00 58.14 Isopropanol 100.00 / / Cross-linked carboxymethyl cellulose sodium 1.00 / 1.55 magnesium stearate 1.00 / 1.55 Total (excluding solvents) 64.50 100.00 100.00

[0061] The preparation method is the same as in Example 2, except that the above-mentioned components are replaced.

[0062] Example 7: Screening test of process parameters for solvent method:

[0063] (1) Temperature screening test: Following the preparation method of Example 1, only the temperature in step (2) was changed, and the percentage content of total impurities and residual solvent was detected. The test results are shown in the table below:

[0064]

[0065] Analysis and Conclusions: ① At drying temperatures of 50–65℃, there was no significant increase in lenalidomide-related substances. When the temperature was increased to 70℃, a slight increase in related substances occurred during the preparation of the solid dispersion. ② When the drying temperature was within the range of 55–70℃, the residual solvent in the solid dispersion could be controlled within the limit. At 50℃, the residual solvent in the solid dispersion exceeded the limit. After comprehensive consideration, the optimal temperature range was determined to be 55–65℃, which ensures both that the residual solvent does not exceed the limit and that there is no significant increase in related substances.

[0066] (2) Film thickness screening test:

[0067] Film thickness Residual solvent 0.6mm 0.09 1.0mm 0.30 1.2mm 0.52

[0068] Analysis and Conclusion: The film thickness affects the drying efficiency of the solid dispersion and also has an impact on the residual solvent. The thinner the film, the more completely the solvent can evaporate. As shown in the table above, the film thickness should be controlled below 1.0 mm, preferably below 0.6 mm.

[0069] Commercially available lenalidomide capsules (Revlimid, 25mg) were used as the reference preparation for the tests in Examples 8-11.

[0070] Example 8: Screening test of water-soluble carrier

[0071] I. Crystallization

[0072] Crystallization: The drug and carrier are co-dissolved in an organic solvent. As the solvent evaporates, the drug concentration gradually increases. When saturation is reached, the drug molecules begin to aggregate and crystallize. As the solvent evaporates, the carrier gradually becomes viscous and eventually becomes a solid, preventing the drug from agglomerating and crystallizing. The solid dispersion has the best quality when the drug exists entirely in an amorphous or molecular state.

[0073] During the drying process using a twin-drum dryer, 10 samples were taken in chronological order to test the uniformity of the solid dispersion content; the results are shown in Table 7 below.

[0074] Table 7: Mixing uniformity of Examples 1 to 6

[0075]

[0076]

[0077] II. In vitro dissolution curve

[0078] This invention employs the dissolution and release determination method (General Rule 0931, Method II) of the 2015 edition of the Chinese Pharmacopoeia, Part IV. pH 4.5 acetate buffer and pH 6.8 phosphate buffer were used as dissolution media, and the rotation speed was 50 rpm. Samples were taken at 5 min, 10 min, 15 min, 20 min, and 30 min, respectively, and the dissolution rate was calculated using HPLC. The results are shown in Table 8 below.

[0079] Table 8: In vitro dissolution curves of Examples 1-6 and the reference formulation (0 months)

[0080]

[0081]

[0082] Analysis and Conclusion:

[0083] When the drug loading is low (≤20%), the content uniformity of Examples 1, 3 and 4 all meet the requirements, and there is no significant difference in dissolution. It is believed that under the condition of low drug loading, the type of carrier has no significant effect on the solid dispersion.

[0084] When the drug loading is high (40%), povidone, poloxamer and polyethylene glycol 4000 are used as carriers for drug loading, respectively. Only Example 2 (povidone as carrier) meets the requirements. Examples 5 (poloxamer as carrier) and 6 (polyethylene glycol 4000 as carrier) both have crystallization phenomenon, which leads to the uniformity of solid dispersion content exceeding the limit.

[0085] In addition, compared with Example 2, the dissolution curves of Examples 5 and 6 showed a significant slowdown in both media, with a cumulative dissolution rate of less than 85% at 15 minutes and less than 90% at 30 minutes. This may be because some of the raw materials in the solid dispersion existed in crystalline form, which delayed the dissolution of the drug.

[0086] In summary, with povidone as the carrier, both high drug loading (20%–40%) and low drug loading (2%) can completely dissolve lenalidomide and prevent crystallization.

[0087] Example 9: Powder Flowability Test

[0088] Compression index: A certain amount of powder is placed into a graduated cylinder under vibration-free conditions, and the apparent volume V1 is measured. The volume is then gently tapped until the final volume remains unchanged (V2). Compression index = (V1 - V2) / V1 × 100%

[0089] USP <1174> The criteria for judging liquidity and compression indices are as follows:

[0090]

[0091]

[0092] Angle of repose measurement: Refer to USP <1174> For powder flowability testing, the fixed funnel method is used. The funnel is fixed at a suitable height on a horizontally placed graph paper, with the distance from the bottom of the funnel to the graph paper being H. Powder is carefully poured into the funnel until the tip of the cone formed at the bottom touches the funnel outlet. The radius r of the cone can be measured from the graph paper. The angle of repose α is calculated as follows: α = tan -1 (H / r)

[0093] USP <1174> The criteria for judging medium fluidity and angle of repose are as follows:

[0094] Liquidity Angle of repose (°) very good 25～30 very good 31～35 Good—no auxiliary materials needed 36～40 Acceptable—requires the addition of auxiliary materials 41～45 Difference 46～55 Very bad 55～65 Very, very bad >66

[0095] The powder characteristics of the lenalidomide pharmaceutical compositions of the present invention (Examples 1-6) and the reference formulation are shown in Table 9.

[0096] Table 9: Powder characteristics of Examples 1-6 and the reference formulation

[0097] Sample Name Compression index (%) Angle of repose (°) Example 1 16.9 37.7 Example 2 17.7 38.8 Example 3 18.6 37.4 Example 4 16.7 39.5 Example 5 17.9 39.7 Example 6 19.2 38.4 Reference formulation 22.7 42.3

[0098] Analysis and Conclusion: Based on the criteria for compressibility index and angle of repose, the total compressibility index of the powder prepared from the reference formulation was between 21 and 25%, and the angle of repose was between 41 and 45°, indicating acceptable flowability. The total compressibility index of the powder prepared from Examples 1 to 6 was between 16 and 20%, and the angle of repose was between 36 and 40°, indicating better flowability. These results demonstrate that the lenalidomide pharmaceutical compositions of the present invention (Examples 1 to 6) have better powder flowability than the reference formulation.

[0099] Example 10: Stability Comparison Study

[0100] Stability studies were conducted on Examples 1 to 4 and the reference formulation. Examples 1 to 4 were packaged in aluminum-plastic blister packs, and the reference formulation was packaged in commercially available packaging. The samples were placed in a 40°C, RH 75% environmental pharmaceutical stability test chamber for 6 months. Samples were taken to detect the content and related substances, and the dissolution curves were compared with those obtained at 0 months.

[0101] The accelerated test results of the lenalidomide pharmaceutical compositions of the present invention (Examples 1 to 4) and the reference formulations are shown in Table 10 below.

[0102] Table 10: Accelerated Test Content and Related Substances of Examples 1-4 and Reference Preparation

[0103]

[0104] Analysis and Conclusions: In Examples 1-4, the content and related substances showed no significant changes after 6 months of accelerated treatment; in the reference formulation, the content showed no significant changes after 6 months of accelerated treatment, but the total impurities increased significantly; the above results indicate that the lenalidomide pharmaceutical compositions of the present invention (Examples 1-4) have better stability compared with the reference formulation.

[0105] The results of the accelerated in vitro dissolution curves (accelerated for 6 months) of the lenalidomide pharmaceutical compositions of the present invention (Examples 1 to 4) and the reference formulation are shown in Table 11 below.

[0106] Table 11: Dissolution curves of accelerated 6-month test for Examples 1-4 and the reference formulation

[0107]

[0108]

[0109] Analysis and Conclusion: The accelerated dissolution rates of Examples 1-4 after 6 months showed no change compared to month 0, with cumulative dissolution exceeding 85% in both pH 4.5 and pH 6.8 dissolution media. The accelerated dissolution rate of the reference formulation after 6 months showed a significant decrease compared to month 0, with a reduction of approximately 10% in cumulative dissolution within 15 minutes in both pH 4.5 and pH 6.8 dissolution media. Therefore, as shown in Tables 10-11, the content, related substances, and dissolution curves of Examples 1-4 after 6 months showed no change compared to month 0; the content of the reference formulation after 6 months showed no change compared to month 0, but related substances increased, and the cumulative dissolution within 15 minutes decreased. This indicates that the lenalidomide pharmaceutical compositions of the present invention (Examples 1-4) have better quality stability than the reference formulation.

[0110] In summary, the optimal formulation of the present invention is determined to be Example 2, which consists of the following components: 96.9% solid dispersion, 1.55% croscarmellose sodium, 1.55% magnesium stearate, and the solid dispersion consists of the following components in the following mass percentages: 40% lenalidomide and 60% povidone.

[0111] Example 11: Bioavailability Comparison

[0112] Male and female Wistar rats weighing 200±10g were randomly divided into three groups and administered the drug by gavage. Two rats were administered the drug at each time point. The drug was prepared into a solution of the required concentration with purified water. The dosage (based on lenalidomide) was 2.25mg / kg. The plasma concentration of lenalidomide at different time points after administration was determined by high performance liquid chromatography. The results are shown in Table 12.

[0113] Table 12: Mean Pharmacokinetic Parameters

[0114]

[0115]

[0116] Analysis and Conclusion: Analysis of pharmacokinetic parameters in rats showed that the lenalidomide drug composition prepared in this invention has higher bioavailability compared to the reference formulation, with the high-load active ingredient (Example 2) exhibiting even higher bioavailability. However, the GMR ratio of the optimal formulation in patent CN103705485A to the reference formulation was significantly lower than that in Example 2 of this invention.

Claims

1. A solid dispersion of lenalidomide, characterized in that, consists of, by weight percentage:

2. The lenalidomide solid dispersion of claim 1, wherein, The said lenalidomide solid dispersion is prepared by dissolving lenalidomide and povidone in isopropyl alcohol by solvent method.

3. The use of the lenalidomide solid dispersion according to claim 1 in the preparation of oral solid preparations of lenalidomide.

4. Use according to claim 3, characterized in that, The said oral solid preparation is capsule or tablet.

5. An oral solid formulation of lenalidomide, characterized in that, consists of, by weight percentage:

6. The oral solid dosage of lenalidomide according to claim 5, characterized in that, The said oral solid preparation is capsule.

7. The oral solid dosage of lenalidomide according to claim 6, characterized in that, The said oral solid preparation is 25mg in specification.

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