Pipericil pharmaceutical composition and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pipericil pharmaceutical composition and a preparation method thereof. The pipericil pharmaceutical composition comprises pipericil, at least one surfactant and at least one adsorbent, the preparation process is simple, the dissolution rate is high under various pH conditions, the dissolution uniformity is good, the improved pharmacokinetic effect is achieved, and the pipericil pharmaceutical composition is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a palbociclib pharmaceutical composition and its preparation method. Background Technology

[0002] Globally, breast cancer is the most common malignant tumor in women. Palbociclib is indicated for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer and should be used in combination with an aromatase inhibitor as initial endocrine therapy for postmenopausal women.

[0003]

[0004] Palbociclib is a yellow to orange crystalline powder, belonging to the BCS II class of compounds in the Biopharmaceutics Classification System. It is slightly soluble in dimethyl sulfoxide and N,N-dimethylformamide, and very slightly soluble in methanol and water. Its solubility is pH-dependent; it is highly soluble at pH ≤ 4, and its solubility decreases significantly at pH > 4. The pH of the human digestive tract gradually increases from the stomach to the intestines. This means that after medication is ingested, it dissolves in the stomach and enters the intestines. Due to the higher pH environment in the intestines, the dissolved drug precipitates, thus reducing its bioavailability. According to the original manufacturer's published information on palbociclib capsules, its absolute bioavailability is low, approximately 46%, and it should be taken with food. In an empty stomach, its bioavailability is approximately 13%.

[0005] CN115671072A, by controlling the dosage of key excipients and critical process parameters, including those used in dry granulation, reduces process uncertainties to a certain extent, simplifies the process flow, eliminates the need for API pulverization, reduces impurity generation, ensures uniformity of content within a batch, and maintains consistent dissolution across different batches, thus avoiding potential risks to clinical application due to batch-to-batch variations. CN108066312A, by controlling the particle size of raw materials and excipients, achieves good mixing flowability, allowing for direct mixing and capsule filling, while significantly improving stability, which is beneficial for the safe use and long-term storage of clinical drugs. CN112274493A, by selecting an appropriate range of fine powder proportions, improves the uniformity of total mixed particle content obtained during palbociclib capsule preparation and solves the problem of poor dissolution uniformity at each sampling time point. However, the above palbociclib formulations still suffer from slow dissolution under high pH conditions.

[0006] Therefore, there is a need for a palbociclib pharmaceutical composition that dissolves rapidly and has high uniformity and improved pharmacokinetic effects. Summary of the Invention

[0007] In view of the shortcomings of the prior art, the present invention provides a palbociclib pharmaceutical composition. The palbociclib pharmaceutical composition of the present invention has a simple preparation process, high dissolution rate and good dissolution uniformity under various pH conditions, and improves pharmacokinetic effects.

[0008] This invention is specifically implemented through the following scheme:

[0009] A palbociclib pharmaceutical composition, characterized in that it comprises palbociclib, at least one surfactant, and at least one adsorbent.

[0010] Preferably, the surfactant is selected from one or a combination of glyceryl mono- and glyceryl di-caprylate, glyceryl caprylate-caprylate-polyethylene glycol, propylene glycol mono-caprylate, polyoxyethylene 40 hydrogenated castor oil, and tricaprylate.

[0011] More preferably, the surfactant is glyceryl mono- and di-caprylate-caprylate.

[0012] Preferably, the adsorbent is kaolin or colloidal silica.

[0013] Preferably, the weight ratio of palbociclib, surfactant and adsorbent is 125:4.5-13.5:40-60; more preferably 125:6-10:45.

[0014] Preferably, the pharmaceutical composition further includes a filler, a disintegrant, and a lubricant.

[0015] The ratio of palbociclib to filler, disintegrant, and lubricant is 125:200-300:15-25:3-8.

[0016] The filler includes one or a combination of microcrystalline cellulose, lactose, mannitol, sorbitol and xylitol, preferably a combination of microcrystalline cellulose and mannitol.

[0017] The disintegrant is selected from one or a combination of crospovidone, crospovidone sodium carboxymethyl cellulose and sodium carboxymethyl starch, preferably crospovidone.

[0018] The lubricant is selected from one or a combination of magnesium stearate, calcium stearate and sodium stearate fumarate, preferably magnesium stearate.

[0019] Preferably, the composition is a capsule.

[0020] In a preferred embodiment, the palbociclib capsules comprise the following components:

[0021]

[0022]

[0023] The present invention also provides a method for preparing the palbociclib pharmaceutical composition, characterized by comprising the following steps: adding a surfactant and an adsorbent into a wet granulation mixer and mixing them evenly, then adding palbociclib, a filler and a disintegrant, mixing evenly, sieving, continuing to mix evenly, then adding a lubricant, mixing evenly and filling the mixture into gelatin empty capsules.

[0024] Preferably, the mesh size of the sieve is 1.0 mm.

[0025] Compared with existing technologies, the preparation process of palbociclib capsules of the present invention is simple, with high dissolution and good dissolution uniformity under various pH conditions, resulting in improved pharmacokinetic effects and making it suitable for large-scale industrial production. Detailed Implementation

[0026] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely provided for illustrative purposes and are not intended to limit the present invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0027] Example 1

[0028]

[0029] Add mono- and dicaprylic / capric triglycerides and kaolin to a wet granulation machine and mix evenly. Add palbociclib, microcrystalline cellulose, mannitol and crospovidone, mix evenly and then sieve with a sieve mesh size of 1.0 mm. Continue to mix evenly, then add magnesium stearate and mix evenly. Finally, fill the mixture into gelatin empty capsules.

[0030] Example 2

[0031]

[0032]

[0033] Add mono- and dicaprylic / capric triglycerides and kaolin to a wet granulation machine and mix evenly. Add palbocic acid, lactose and croscarmellose sodium, mix evenly and then sieve with a sieve mesh size of 1.0 mm. Continue to mix evenly, then add calcium stearate and mix evenly. Finally, fill the mixture into gelatin empty capsules.

[0034] Example 3

[0035]

[0036] Add mono- and dicaprylic / capric triglycerides and kaolin to a wet granulation machine and mix evenly. Add palbociclib, mannitol and sodium carboxymethyl starch, mix evenly and then sieve with a sieve mesh size of 1.0 mm. Continue to mix evenly, then add sodium stearate fumarate, mix evenly and then fill into gelatin empty capsules.

[0037] Example 4

[0038]

[0039] Add mono- and dicaprylic / capric triglycerides and kaolin to a wet granulation machine and mix evenly. Add palbociclib, microcrystalline cellulose, mannitol and crospovidone, mix evenly and then sieve with a sieve mesh size of 1.0 mm. Continue to mix evenly, then add magnesium stearate and mix evenly. Finally, fill the mixture into gelatin empty capsules.

[0040] Example 5

[0041]

[0042] Polyethylene glycol glycerol esters with caprylic and caprylic acid were added to a wet granulation machine and mixed evenly. Palbociclib, microcrystalline cellulose, mannitol and crospovidone were added and mixed evenly. The mixture was then sieved with a sieve mesh size of 1.0 mm and mixed evenly. Magnesium stearate was then added and mixed evenly. The mixture was then filled into gelatin empty capsules.

[0043] Example 6

[0044]

[0045] Add mono- and dicaprylic / capric triglycerides and kaolin to a wet granulation machine and mix evenly. Add palbociclib, microcrystalline cellulose, mannitol and crospovidone, mix evenly and then sieve with a sieve mesh size of 1.0 mm. Continue to mix evenly, then add magnesium stearate and mix evenly. Finally, fill the mixture into gelatin empty capsules.

[0046] Example 7

[0047]

[0048]

[0049] Add mono- and dicaprylic / capric triglycerides and colloidal silica to a wet granulation machine and mix evenly. Add palbociclib, microcrystalline cellulose, mannitol and crospovidone, mix evenly and then sieve with a sieve mesh size of 1.0 mm. Continue to mix evenly, then add magnesium stearate and mix evenly. Finally, fill the mixture into gelatin empty capsules.

[0050] Comparative Example 1

[0051]

[0052] Weigh out the prescribed amounts of palbociclib, microcrystalline cellulose, lactose, sodium carboxymethyl starch, colloidal silica, and an added portion of magnesium stearate, controlling the moisture content of sodium carboxymethyl starch to 5 wt.%. Except for the added magnesium stearate, premix the weighed materials at 12 rpm for 1 min, then granulate them through a 1.0 mm sieve, continue mixing at 12 rpm for 15 min, then add the added magnesium stearate and continue mixing for 8 min. Install the granulation sieve, adjust the feed speed to 50 rpm, the pressure roller to 50 bar, and the roller speed to 15 rpm, monitoring the flake density to 1.2 g / cm³. 3 Collect particles through an 18-mesh sieve; add an additional portion of magnesium stearate to the obtained particles and mix at 10 rpm for 8 minutes to obtain total mixed particles; fill the total mixed particles into capsules using a capsule filling machine, controlling the capsule filling machine speed to 30,000 capsules / h, and the final product is obtained.

[0053] Comparative Example 2

[0054]

[0055]

[0056] Palbociclib, microcrystalline cellulose, mannitol, crospovidone, and colloidal silica are thoroughly mixed, sieved, and the mixture is then mixed with a sieve with a mesh size of 1.0 mm. After the mixture is homogeneous, succinic acid is added and the mixture is continued to be mixed. Magnesium stearate is then added and the mixture is homogeneous. Finally, the mixture is filled into gelatin hollow capsules.

[0057] Comparative Example 3

[0058]

[0059] Palbociclib and excipients are pulverized separately. After controlling the particle size of the raw materials and excipients, the raw materials and excipients are mixed evenly and then directly filled into capsules.

[0060] Comparative Example 4

[0061]

[0062] Palbociclib was pulverized and passed through a 100-mesh sieve. It was then mixed evenly with microcrystalline cellulose, lactose, sodium carboxymethyl starch, and 2 / 3 of the amount of silica. The mixture was then dry-granulated and passed through a 20-mesh sieve. The remaining amount of silica was then added, and the mixture was mixed evenly before being filled into capsules.

[0063] Comparative Example 5

[0064]

[0065]

[0066] Sodium dodecyl sulfate and palpirate were added to a wet granulation machine and mixed evenly. Microcrystalline cellulose, mannitol and crospovidone were added and mixed evenly. The mixture was then sieved with a sieve mesh size of 1.0 mm and mixed evenly. Magnesium stearate was then added and mixed evenly. The mixture was then filled into gelatin empty capsules.

[0067] Verification of Examples

[0068] 1. Dissolution test

[0069] Twelve capsules each from the examples and comparative samples were taken and dissolved according to the 2020 edition of the Chinese Pharmacopoeia, Part IV, <0931 Determination of Dissolution and Release> (Method II). Dissolution media were 37°C, 900 mL of pH 4.5 acetate buffer, and 900 mL of pH 6.8 phosphate buffer, respectively, at a rotation speed of 50 rpm. Samples were taken at each time point, and the average dissolution value of each group of capsules was calculated. The relative standard deviation (RSD) is also shown. The test results are shown in Table 1-4.

[0070] Table 1. Dissolution results of palbociclib capsules in pH 4.5 acetate buffer.

[0071]

[0072] Table 2. Dissolution results of palbociclib capsules in pH 4.5 acetate buffer.

[0073]

[0074]

[0075] Table 3. Dissolution results of palbociclib capsules in pH 6.8 phosphate buffer.

[0076]

[0077] Table 4. Dissolution results of palbociclib capsules in pH 6.8 phosphate buffer.

[0078]

[0079] 2. Pharmacokinetic Experiments

[0080] Six healthy Beagle dogs weighing 12.5-15 kg were grouped into four groups (Example 1, Comparative Example 1, Comparative Example 3, and 125 mg commercially available reference formulation). (Group). Dogs were fasting for 12 hours before the experiment. Before administration, each dog was fed 100g of dog food mixed with 16.4g of hot butter. Each dog was given one capsule of the above-mentioned medication, administered with water. Dogs were allowed free access to water during the study period.

[0081] Blood samples were collected from each group of animals at the following time points: 0 h (before administration of the test drug), and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 24, 32, and 48 h after drug administration. Plasma concentrations of palbociclib were analyzed by LC-MS / MS. Pharmacokinetic parameters for each dog were calculated using a non-compartmental model in WinNonlin software. The results are shown in Table 5.

[0082] Table 5. Pharmacokinetic Experiment Results

[0083]

Claims

1. A palbociclib pharmaceutical composition, characterized in that, It includes palbociclib, at least one surfactant, and at least one adsorbent.

2. The palbociclib pharmaceutical composition according to claim 1, characterized in that, The surfactant is selected from one or a combination of mono- and di-caprylic / capric glycerides, caprylic / capric glycerides, propylene glycol monocaprylic / capric glycerides, polyoxyethylene 40 hydrogenated castor oil, and tricaprylic / capric glycerides.

3. The palbociclib pharmaceutical composition according to claim 2, characterized in that, The surfactant is glyceryl mono- and di-caprylate-caprylate.

4. The palbociclib pharmaceutical composition according to claim 1, characterized in that, The adsorbent is kaolin or colloidal silica.

5. The palbociclib pharmaceutical composition according to claim 1, characterized in that, The weight ratio of palbociclib, surfactant, and adsorbent is 125:4.5-13.5:40-60; preferably 125:6-10:

45.

6. The palbociclib pharmaceutical composition according to claim 1, characterized in that, It also includes fillers, disintegrants, and lubricants.

7. The palbociclib pharmaceutical composition according to claim 6, characterized in that, The filler comprises one or a combination of microcrystalline cellulose, lactose, mannitol, sorbitol and xylitol; the disintegrant is selected from one or a combination of crospovidone, crospovidone sodium carboxymethyl cellulose and sodium carboxymethyl starch; the lubricant is selected from one or a combination of magnesium stearate, calcium stearate and sodium stearate fumarate.

8. The palbociclib pharmaceutical composition according to claim 1, characterized in that, The composition is in the form of capsules.

9. A method for preparing the palbociclib pharmaceutical composition according to any one of claims 1-8, characterized in that, The process includes the following steps: adding surfactant and adsorbent to a wet granulation machine and mixing them evenly, then adding palbociclib, filler and disintegrant, mixing evenly, sieving, continuing to mix evenly, then adding lubricant, mixing evenly, and finally filling the gelatin empty capsules.

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