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US20230226063A1 - Pharmaceutical formulation of palbociclib and a preparation method thereof - Google Patents

Pharmaceutical formulation of palbociclib and a preparation method thereof Download PDF

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US20230226063A1
US20230226063A1 US17/954,421 US202217954421A US2023226063A1 US 20230226063 A1 US20230226063 A1 US 20230226063A1 US 202217954421 A US202217954421 A US 202217954421A US 2023226063 A1 US2023226063 A1 US 2023226063A1
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Prior art keywords
palbociclib
acid
pharmaceutically acceptable
auxiliary material
acceptable salt
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US17/954,421
Inventor
Zeren Wang
Jun Xu
Long Qu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Hlk Pharmaceuticals Co Ltd
Shenzhen Pharmacin Co Ltd
Original Assignee
Shenzhen Hlk Pharmaceuticals Co Ltd
Shenzhen Pharmacin Co Ltd
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Priority claimed from US15/613,853 external-priority patent/US10449195B2/en
Application filed by Shenzhen Hlk Pharmaceuticals Co Ltd, Shenzhen Pharmacin Co Ltd filed Critical Shenzhen Hlk Pharmaceuticals Co Ltd
Priority to US17/954,421 priority Critical patent/US20230226063A1/en
Assigned to Shenzhen Pharmacin Co., Ltd. reassignment Shenzhen Pharmacin Co., Ltd. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Shenzhen HLK Pharmaceuticals Co., Ltd.
Assigned to Shenzhen HLK Pharmaceuticals Co., Ltd. reassignment Shenzhen HLK Pharmaceuticals Co., Ltd. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: QU, LONG, WANG, ZEREN, XU, JUN
Publication of US20230226063A1 publication Critical patent/US20230226063A1/en
Abandoned legal-status Critical Current

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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the pharmaceutical field. More specifically, the present invention relates to a pharmaceutical formulation of palbociclib and a preparation method thereof.
  • the palbociclib of the present invention may be a palbociclib free base or any of its pharmaceutically acceptable salts.
  • palbociclib is an inhibitory agent for cyclin-dependent kinases (CDKs) 4 and 6, which inhibits the synthesis of DNA primarily by preventing cells from G1 phase to S phase via the inhibition of CDK4/6 activity, and can be used to treat metastatic breast cancer.
  • CDKs cyclin-dependent kinases
  • Clinical trial studies have shown that palbociclib combined with letrozole is very effective in postmenopausal patients with locally infiltrating breast cancer or in newly diagnosed estrogen receptor (ER)-positive and HER-2-negative patients. Its chemical structure is as follows:
  • palbociclib is an insoluble drug.
  • palbociclib has been approved for sale in the United States. According to the instructions for the approved product of palbociclib in the United States, one of seven patients has poor absorption upon administration of the palbociclib product. For these patients, the efficacy of said product will be relatively low. It is likely that the poor solubility of the drug causes the poor absorption in some patients. Thus, in the present, it is very necessary to further improve the dosage form of palbociclib so as to increase the dissolution rate and bioavailability thereof.
  • the in vitro dissolution of an oral solid formulation product of an insoluble drug has a certain correlation with its in vivo absorption.
  • an in vitro dissolution method is employed in the present invention to assess the capacity of the formulation product to be absorbed in vivo.
  • the present invention has surprisingly found that the dissolution of the oral solid formulation product prepared by mixing the API of palbociclib with a pharmaceutically acceptable acidic auxiliary material and optionally adding another pharmaceutically acceptable excipient can be significantly increased relative to the oral solid formulation products prepared in the prior art.
  • the present invention has also surprisingly found that, the disadvantage that the API having a small particle size cannot be used for the preparation of formulations as disclosed in the international patent application WO2014128588 can be overcome by pulverizing the API of palbociclib to reduce its particle size to D90 at 20 ⁇ m or less and then mixing with a pharmaceutically acceptable acidic auxiliary material, or by mixing the API of palbociclib with the pharmaceutically acceptable acidic auxiliary material, co-pulverizing to reduce the particle size of the mixture to D90 at 20 ⁇ m or less, and optionally adding another pharmaceutically acceptable excipient; and after an oral dosage form is prepared, the in vitro dissolution can be significantly increased.
  • the present invention has also surprisingly found that the API of palbociclib and the pharmaceutically acceptable acidic auxiliary material can be co-dissolved in a solvent and the concentration of the API of palbociclib in the solvent can be up to 50 mg/ml or more; and when a hydrophilic high-molecular material is further added and dissolved evenly and the solvent is removed by volatilization, an amorphous solid dispersion is formed. After an oral solid formulation product is prepared by optionally further adding another pharmaceutically acceptable excipient, its dissolution is further significantly increased.
  • the present invention has also surprisingly found that the method for preparing a solid dispersion of the present invention can also convert the acidic auxiliary material into an amorphous state and the amorphous state can be maintained for a long period of time, which is advantageous for maintaining the amorphous state of the API of palbociclib.
  • the in vitro dissolution of palbociclib is increased, and thereby its in vivo bioavailability can be improved.
  • the present invention provides a pharmaceutical formulation of palbociclib, which comprises a palbociclib free base or a pharmaceutically acceptable salt thereof and an acidic auxiliary material.
  • the palbociclib free base or the salt thereof is a solid.
  • the particle size (D90) of palbociclib in the pharmaceutical formulation is 20 ⁇ m or less.
  • the particle size (D90) of palbociclib and the acidic auxiliary material in the pharmaceutical formulation is 20 ⁇ m or less.
  • the acidic auxiliary material is one or more selected from the group consisting of a pharmaceutically acceptable water-soluble organic acid or a hydrate or an acidic salt thereof, a water-soluble acidic amino acid or a hydrate or an acidic salt thereof, an acidic salt of a water-soluble amino acid or a hydrate thereof, or an acidic salt of a water-soluble inorganic acid or a hydrate thereof.
  • the water-soluble organic acid is one or more selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid;
  • the water-soluble acidic amino acid is one or more selected from the group consisting of glutamic acid and aspartic acid;
  • the acidic salt of a water-soluble amino acid is one or more selected from the group consisting of the acidic salts of glycine, alanine and serine;
  • the acidic salt of the water-soluble inorganic acid is one or more selected from the group consisting of dihydric phosphate and bisulfate.
  • the acidic auxiliary material is preferably one or more selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid, more preferably tartaric acid.
  • the mass ratio of the acidic auxiliary material to palbociclib is from 0.2:1 to 5:1, preferably from 0.5:1 to 2:1.
  • the pharmaceutical formulation is a tablet or capsule.
  • the dosage of the tablet or capsule is from 25 mg to 500 mg, preferably from 50 mg to 150 mg.
  • the present invention also provides a solid dispersion of palbociclib, which comprises a palbociclib free base or a pharmaceutically acceptable salt thereof, an acidic auxiliary material and a hydrophilic high-molecular material.
  • the hydrophilic high-molecular material is one or more selected from the group consisting of povidone K30 (PVP-K30), copovidone VA64 (PVP-VA64), Soluplus, hydroxypropylmethylcellulose E5 (HPMC-E5), hydroxypropylmethylcellulose acetate succinate (HPMC-AS-HF), hydroxypropyl- ⁇ -cyclodextrin and sulfobutylether- ⁇ -cyclodextrin.
  • the acidic auxiliary material is selected from one or more pharmaceutically acceptable organic acids and optionally one or more pharmaceutically acceptable inorganic acids.
  • the pharmaceutically acceptable organic acid is preferably selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, aliphatic sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, isethionic acid, etc.) and aromatic sulfonic acids (e.g., benzenesulfonic acid, p-toluenesulfonic acid, etc.), and the pharmaceutically acceptable inorganic acid is preferably selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and the like.
  • “optionally” means that the pharmaceutically acceptable inorganic acid can be present or absent and, if the pharmaceutically acceptable inorganic acid is present, the amount of the pharmaceutically acceptable organic acid can be reduced
  • the mass ratio of the hydrophilic high-molecular material to palbociclib is from 0.1:1 to 10:1, and the mass ratio of the acidic auxiliary material to palbociclib is from 0.2:1 to 5:1; preferably, the mass ratio of the hydrophilic high-molecular material to palbociclib is from 1:1 to 3:1, and the mass ratio of the acidic auxiliary material to palbociclib is from 0.5:1 to 2:1.
  • the present invention also provides a method for the preparation of a pharmaceutical formulation, comprising: mixing an API of palbociclib with a pharmaceutically acceptable acidic auxiliary material, preferably at a certain mass ratio, and further, optionally adding another pharmaceutically acceptable excipient.
  • the present invention also provides another method for the preparation of a pharmaceutical formulation, comprising: pulverizing the API of palbociclib to control the particle size at 20 ⁇ m or less, and then mixing with the pharmaceutically acceptable acidic auxiliary material, or adding the acidic auxiliary material to the API, mixing and co-pulverizing to control the particle size at 20 ⁇ m or less; and further, optionally adding another pharmaceutically acceptable excipient.
  • the present invention also provides a method for the preparation of a solid dispersion, comprising: mixing palbociclib with an acidic auxiliary material; adding a solvent (including but not limited to water, ethanol, acetone and a mixture thereof, preferably water or a mixture thereof with other solvents, e.g.
  • a solvent including but not limited to water, ethanol, acetone and a mixture thereof, preferably water or a mixture thereof with other solvents, e.g.
  • the concentration of the API of palbociclib in the solvent can be up to 50 mg/ml or more, thereby improving the preparation efficiency of the solid dispersion.
  • the present invention also provides the use of a pharmaceutical formulation or a solid dispersion for the treatment of breast cancer.
  • palbociclib refers to a palbociclib free base or a pharmaceutically acceptable salt thereof, which can be used interchangeably.
  • the excipient is well known and may be an adhesive, a filler, a disintegrant, a lubricant, a preservative, an antioxidant, a flavoring agent, a fragrance, a cosolvent, an emulsifier, a solubilizer, an osmotic pressure regulator, a coloring agent and the like.
  • palbociclib is pulverized, or the palbociclib is mixed with the acidic auxiliary material and co-pulverized, for example, by means of the airflow pulverization technique, in order to reduce the particle size to D90 at 20 ⁇ m or less.
  • the pharmaceutical formulation is an oral solid formulation product, such as a tablet or a capsule.
  • a product is generally prepared by mixing the API with another pharmaceutically acceptable auxiliary material, such as an excipient, a lubricant, a disintegrant and the like, so as to prepare the oral solid formulation product.
  • the palbociclib oral solid formulation product which has been approved for sale in the United States (the trade name is Ibrance), was manufactured by the above-mentioned technique, according to the description in its drug instructions.
  • the present invention successfully prepares the solid dispersion of palbociclib for the first time by means of a special combination.
  • the solid dispersion is a kind of formulation technique, and useful for a formulation product of an insoluble drug.
  • an amorphous solid dispersion is prepared from the insoluble API together with a hydrophilic pharmaceutical high-molecular auxiliary material.
  • the methods for the preparation of the amorphous solid dispersion include a solvent method and a melting method.
  • the solvent method includes dissolving the API and the auxiliary material together in a solvent and then volatilizing the solvent.
  • the melting method includes co-melting the API and the high-molecular auxiliary material and rapidly cooling the same. In view of the high melting point of palbociclib, reaching 271° C., and the insolubility in most of solvents, it is impossible to prepare the amorphous solid dispersion in accordance with the solid dispersion technique in the prior art.
  • the formulation prepared by mixing the API of palbociclib with the acidic auxiliary material exhibits a cumulative dissolution rate of 47.8% in a dissolution medium at pH 6.0 for 60 minutes, increased from 34.0% of the product prepared by the prior formulation technique ( FIG. 1 ).
  • the formulation prepared by pulverizing palbociclib (having a particle size at 20 ⁇ m or less, FIG. 2 ), or the formulation prepared by mixing and co-pulverizing palbociclib and the acidic auxiliary material exhibits a further increased cumulative dissolution rate of 66.6% and 68.7%, respectively, at pH 6.0 for 60 minutes ( FIG. 3 ).
  • the solid dispersion prepared by mixing the API of palbociclib with the acidic material and then with the hydrophilic high-molecular material exhibits a dynamic solubility of 85%, increased from 58% of the API of palbociclib itself, as shown in a dynamic solubility test performed in a buffer at pH 6.0 with stirring for 60 minutes ( FIG. 4 ).
  • the preparation method of the solid dispersion of the present invention can also convert the acidic auxiliary material such as tartaric acid into an amorphous state ( FIG. 5 ) and the amorphous state is maintained over one week of storage in a stabilizing box at 40° C./75% RH, which is advantageous for maintaining the amorphous state of the palbociclib solid dispersion for a long period of time.
  • the acidic auxiliary material such as tartaric acid
  • FIG. 1 shows the in vitro dissolution of the capsule formulation prepared from palbociclib with the acidic auxiliary material or without the acidic auxiliary material;
  • FIG. 2 shows the particle size of the pulverized palbociclib
  • FIG. 3 shows the in vitro dissolution of the capsule formulation prepared by mixing the pulverized palbociclib with the acidic auxiliary material, and of the capsule formulation prepared by co-pulverizing the API of palbociclib and tartaric acid to reduce the particle size;
  • FIG. 4 shows the dynamic solubility of the solid dispersion prepared by mixing the API of palbociclib with the acidic material and then with a hydrophilic high-molecular material, compared to the API of palbociclib itself, as tested in a buffer at pH 6.0 with stirring for 60 minutes;
  • FIG. 5 shows the amorphous state of the acidic auxiliary material tartaric acid in the solid dispersion of the present invention
  • FIG. 6 shows an XRPD pattern of the API of palbociclib used in the present invention
  • FIG. 7 shows an XRPD pattern of a palbociclib solid dispersion prepared with HPMC-AS-HF
  • FIG. 8 shows an XRPD pattern of a palbociclib solid dispersion prepared with PVP-VA64
  • FIG. 9 shows an XRPD pattern of a palbociclib solid dispersion prepared with PVP-K30;
  • FIG. 10 shows an XRPD pattern of a palbociclib solid dispersion prepared with Soluplus.
  • FIG. 11 shows an XRPD pattern of a palbociclib solid dispersion prepared with HPMC-E5.
  • the pressed large tablets were crushed and passed through a 10-mesh sieve, and dispensed into gelatin capsules at a loading of 350 mg per capsule.
  • the dissolution rate was measured by a basket method at pH 6.0, at a rotation speed of 100 rpm and at the selected time points of 5, 10, 15, 20, 30, 45 and 60 minutes.
  • the pressed large tablets were crushed and passed through a 10-mesh sieve, and dispensed into gelatin capsules at a loading of 350 mg per capsule.
  • the dissolution rate was measured by a basket method at pH 6.0, at a rotation speed of 100 rpm and at the selected time points of 5, 10, 15, 20, 30, 45 and 60 minutes.
  • the airflow co-pulverized mixture of the API of palbociclib and tartaric acid (comprising 1500 mg of palbociclib and 1200 mg of tartaric acid) was added with 345 mg of lactose, 840 mg of microcrystalline cellulose, 210 mg of sodium carboxymethyl starch and 84 mg of silica, and mixed in a three dimensional mixer for 15 minutes.
  • 125 mg of the API of palbociclib was weighed and placed into a 10 ml penicillin bottle; 1.991 ml of double distilled water and 8.63 ⁇ l of 36% hydrochloric acid solution (having a density of 1.18 g/mL) were added, so that the molar ratio of hydrochloric acid to the API of palbociclib was 1:1. Then 200 mg of tartaric acid was added and completely mixed and dissolved under the action of ultrasound. 100 mg of PVP VA64 was added to the above solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
  • 125 mg of the API of palbociclib was weighed and placed into a 10 ml penicillin bottle; 2 ml of double distilled water and 27.3 mg of phosphoric acid were added, so that the molar ratio of phosphoric acid to the API of palbociclib was 1:1. Then 200 mg of tartaric acid was added and completely mixed and dissolved under the action of ultrasound. 100 mg of PVP VA64 was added to the above solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
  • the XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2 ⁇ °): 3-40; scanning step (2 ⁇ °):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength ( ⁇ ): 1.54060; K-Alpha2 wavelength ( ⁇ ): 1.54443; Power setting: 40 mA, 45 kV.
  • the obtained XRPD pattern of the API of palbociclib was shown in FIG. 6 ; and the XRPD pattern of the solid dispersion prepared with PVP-K30 was shown in FIG. 9 .
  • the palbociclib solid dispersion prepared with PVP-VA64 in Example 4 was sent for XRPD test.
  • the XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2 ⁇ °): 3-40; scanning step (2 ⁇ °):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength ( ⁇ ): 1.54060; K-Alpha2 wavelength ( ⁇ ): 1.54443; Power setting: 40 mA, 45 kV.
  • the obtained XRPD pattern was shown in FIG. 8 .
  • the palbociclib solid dispersion prepared with Soluplus in Example 5 was sent for XRPD test.
  • the XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2 ⁇ °): 3-40; scanning step (2 ⁇ °):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength ( ⁇ ): 1.54060; K-Alpha2 wavelength ( ⁇ ): 1.54443; Power setting: 40 mA, 45 kV.
  • the obtained XRPD pattern was shown in FIG. 10 .
  • the solid dispersion prepared with HPMC-E5 in Example 6 was sent for XRPD test.
  • the XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2 ⁇ °): 3-40; scanning step (2 ⁇ °):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength ( ⁇ ): 1.54060; K-Alpha2 wavelength ( ⁇ ): 1.54443; Power setting: 40 mA, 45 kV.
  • the obtained XRPD pattern was shown in FIG. 11 .
  • the solid dispersion prepared with HPMC-AS-HF in Example 7 was sent for XRPD test.
  • the XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2 ⁇ °): 3-40; scanning step (2 ⁇ °):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength ( ⁇ ): 1.54060; K-Alpha2 wavelength ( ⁇ ): 1.54443; Power setting: 40 mA, 45 kV.
  • the obtained XRPD pattern was shown in FIG. 7 .

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Abstract

The present invention belongs to the pharmaceutical field, and in particular, it relates to a pharmaceutical formulation of palbociclib and a preparation method thereof. The pharmaceutical formulation comprises palbociclib, an acidic auxiliary material, and optionally a hydrophilic high-molecular material, which has better solubility and in vitro dissolution property as compared with the conventional formulation and can be used for enhancing in vivo absorption and bioavailability of palbociclib.

Description

    CROSS-REFERENCE
  • This application is a continuation application of Ser. No. 16/554,112 filed Aug. 28, 2019, which is a continuation application of Ser. No. 15/613,853 tiled Jun. 5, 2017, issued as U.S. Pat. No. 10,449,195 on Oct. 22, 2019, which is a continuation application of PCT/CN2016/086546 filed Jun. 21, 2016, each of which is entirely incorporated herein by reference.
    • TECHNICAL FIELD
  • The present invention belongs to the pharmaceutical field. More specifically, the present invention relates to a pharmaceutical formulation of palbociclib and a preparation method thereof. The palbociclib of the present invention may be a palbociclib free base or any of its pharmaceutically acceptable salts.
    • BACKGROUND ART
  • World Health Organization statistics show that breast cancer is the world's second cause of cancer deaths in women. Over the past few decades, the incidence of breast cancer showed an increasing trend. It is expected that by 2020, there will be more than 1.7 million new cases of breast cancer each year. By 2012, there are 1.67 million new cases of breast cancer worldwide, accounting for 25% of all new cases of cancer, wherein 883,000 cases are in developed countries and 794,000 cases are in developing countries. The growth rate of new eases of breast cancer in developing countries is slightly higher than that in developed countries. There are 522,000 cases of breast cancer deaths, ranking fifth in lethality rate in all cancers. In underdeveloped areas, the breast cancer causes 324,000 women deaths, accounting for 14.3% of all cases of cancer deaths, and is the most frequent lethal cancer. In developed areas, there are 198,000 cases of breast cancer deaths in women, accounting for 15.4% of all cases of cancer deaths, second only to lung cancer. Therefore, breast cancer is still one of the world's important health problems. According to the international patent WO2003/062236, palbociclib is an inhibitory agent for cyclin-dependent kinases (CDKs) 4 and 6, which inhibits the synthesis of DNA primarily by preventing cells from G1 phase to S phase via the inhibition of CDK4/6 activity, and can be used to treat metastatic breast cancer. Clinical trial studies have shown that palbociclib combined with letrozole is very effective in postmenopausal patients with locally infiltrating breast cancer or in newly diagnosed estrogen receptor (ER)-positive and HER-2-negative patients. Its chemical structure is as follows:
  • Figure US20230226063A1-20230720-C00001
  • The structure and preparation method of said compound and its salts have been described in the international patent WO2003/062236 and U.S. Pat. No. 6,936,612. The preparation methods of free bases and salts of various acids are also described in the international patent application WO2005/005426 and U.S. Pat. Nos. 7,345,171 and 7,863,278. According to the description in the international patent application WO2005/005426, the solubility of the palbociclib free base in water is poor, which leads to a low bioavailability and is disadvantageous for the absorption in human body. The free base has a strong adhesive property upon impact, and said adhesive property is related to the specific surface area of the particles, so its particle size must be controlled in a certain range. According to the international patent application WO2014128588, it is necessary to use an active pharmaceutical ingredient (API) of palbociclib free base having a larger particle size in order to improve the physichemical properties and the capacity to produce a formulation product. If the palbociclib free base is reacted with an acid to generate salts so as to increase the solubility, the salts have a poor solid nature and thereby are disadvantageous for being developed as a solid formulation, according to the reports in the previously known patents.
  • At the same time, palbociclib is an insoluble drug. At present, palbociclib has been approved for sale in the United States. According to the instructions for the approved product of palbociclib in the United States, one of seven patients has poor absorption upon administration of the palbociclib product. For these patients, the efficacy of said product will be relatively low. It is likely that the poor solubility of the drug causes the poor absorption in some patients. Thus, in the present, it is very necessary to further improve the dosage form of palbociclib so as to increase the dissolution rate and bioavailability thereof.
    • SUMMARY OF THE INVENTION
  • It is an object of the present invention to develop a novel pharmaceutical product for improving the dissolution and bioabsorption of palbociclib. According to the prior art and common knowledge, it is generally considered that the in vitro dissolution of an oral solid formulation product of an insoluble drug has a certain correlation with its in vivo absorption. Thus, an in vitro dissolution method is employed in the present invention to assess the capacity of the formulation product to be absorbed in vivo.
  • The present invention has surprisingly found that the dissolution of the oral solid formulation product prepared by mixing the API of palbociclib with a pharmaceutically acceptable acidic auxiliary material and optionally adding another pharmaceutically acceptable excipient can be significantly increased relative to the oral solid formulation products prepared in the prior art.
  • The present invention has also surprisingly found that, the disadvantage that the API having a small particle size cannot be used for the preparation of formulations as disclosed in the international patent application WO2014128588 can be overcome by pulverizing the API of palbociclib to reduce its particle size to D90 at 20 μm or less and then mixing with a pharmaceutically acceptable acidic auxiliary material, or by mixing the API of palbociclib with the pharmaceutically acceptable acidic auxiliary material, co-pulverizing to reduce the particle size of the mixture to D90 at 20 μm or less, and optionally adding another pharmaceutically acceptable excipient; and after an oral dosage form is prepared, the in vitro dissolution can be significantly increased.
  • The present invention has also surprisingly found that the API of palbociclib and the pharmaceutically acceptable acidic auxiliary material can be co-dissolved in a solvent and the concentration of the API of palbociclib in the solvent can be up to 50 mg/ml or more; and when a hydrophilic high-molecular material is further added and dissolved evenly and the solvent is removed by volatilization, an amorphous solid dispersion is formed. After an oral solid formulation product is prepared by optionally further adding another pharmaceutically acceptable excipient, its dissolution is further significantly increased.
  • The present invention has also surprisingly found that the method for preparing a solid dispersion of the present invention can also convert the acidic auxiliary material into an amorphous state and the amorphous state can be maintained for a long period of time, which is advantageous for maintaining the amorphous state of the API of palbociclib.
  • In the invention, by adding the acidic auxiliary material, reducing the particle size of the API of palbociclib and making the palbociclib in an amorphous manner, the in vitro dissolution of palbociclib is increased, and thereby its in vivo bioavailability can be improved.
  • In particular, the present invention provides a pharmaceutical formulation of palbociclib, which comprises a palbociclib free base or a pharmaceutically acceptable salt thereof and an acidic auxiliary material.
  • In one embodiment, the palbociclib free base or the salt thereof is a solid.
  • In one embodiment, the particle size (D90) of palbociclib in the pharmaceutical formulation is 20 μm or less.
  • In one embodiment, the particle size (D90) of palbociclib and the acidic auxiliary material in the pharmaceutical formulation is 20 μm or less.
  • In one embodiment, the acidic auxiliary material is one or more selected from the group consisting of a pharmaceutically acceptable water-soluble organic acid or a hydrate or an acidic salt thereof, a water-soluble acidic amino acid or a hydrate or an acidic salt thereof, an acidic salt of a water-soluble amino acid or a hydrate thereof, or an acidic salt of a water-soluble inorganic acid or a hydrate thereof.
  • In one embodiment, the water-soluble organic acid is one or more selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid; the water-soluble acidic amino acid is one or more selected from the group consisting of glutamic acid and aspartic acid; the acidic salt of a water-soluble amino acid is one or more selected from the group consisting of the acidic salts of glycine, alanine and serine; and the acidic salt of the water-soluble inorganic acid is one or more selected from the group consisting of dihydric phosphate and bisulfate.
  • In one embodiment, the acidic auxiliary material is preferably one or more selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid, more preferably tartaric acid.
  • In one embodiment, the mass ratio of the acidic auxiliary material to palbociclib is from 0.2:1 to 5:1, preferably from 0.5:1 to 2:1.
  • In one embodiment, the pharmaceutical formulation is a tablet or capsule.
  • In one embodiment, the dosage of the tablet or capsule is from 25 mg to 500 mg, preferably from 50 mg to 150 mg.
  • The present invention also provides a solid dispersion of palbociclib, which comprises a palbociclib free base or a pharmaceutically acceptable salt thereof, an acidic auxiliary material and a hydrophilic high-molecular material.
  • In one embodiment, the hydrophilic high-molecular material is one or more selected from the group consisting of povidone K30 (PVP-K30), copovidone VA64 (PVP-VA64), Soluplus, hydroxypropylmethylcellulose E5 (HPMC-E5), hydroxypropylmethylcellulose acetate succinate (HPMC-AS-HF), hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin.
  • In one embodiment, the acidic auxiliary material is selected from one or more pharmaceutically acceptable organic acids and optionally one or more pharmaceutically acceptable inorganic acids. Among them, the pharmaceutically acceptable organic acid is preferably selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, aliphatic sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, isethionic acid, etc.) and aromatic sulfonic acids (e.g., benzenesulfonic acid, p-toluenesulfonic acid, etc.), and the pharmaceutically acceptable inorganic acid is preferably selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and the like. In the present invention, “optionally” means that the pharmaceutically acceptable inorganic acid can be present or absent and, if the pharmaceutically acceptable inorganic acid is present, the amount of the pharmaceutically acceptable organic acid can be reduced.
  • In one embodiment, the mass ratio of the hydrophilic high-molecular material to palbociclib is from 0.1:1 to 10:1, and the mass ratio of the acidic auxiliary material to palbociclib is from 0.2:1 to 5:1; preferably, the mass ratio of the hydrophilic high-molecular material to palbociclib is from 1:1 to 3:1, and the mass ratio of the acidic auxiliary material to palbociclib is from 0.5:1 to 2:1.
  • The present invention also provides a method for the preparation of a pharmaceutical formulation, comprising: mixing an API of palbociclib with a pharmaceutically acceptable acidic auxiliary material, preferably at a certain mass ratio, and further, optionally adding another pharmaceutically acceptable excipient.
  • The present invention also provides another method for the preparation of a pharmaceutical formulation, comprising: pulverizing the API of palbociclib to control the particle size at 20 μm or less, and then mixing with the pharmaceutically acceptable acidic auxiliary material, or adding the acidic auxiliary material to the API, mixing and co-pulverizing to control the particle size at 20 μm or less; and further, optionally adding another pharmaceutically acceptable excipient.
  • The present invention also provides a method for the preparation of a solid dispersion, comprising: mixing palbociclib with an acidic auxiliary material; adding a solvent (including but not limited to water, ethanol, acetone and a mixture thereof, preferably water or a mixture thereof with other solvents, e.g. the mixture of water and ethanol, the mixture of water and acetone, etc.) for dissolving or dispersing; adding a hydrophilic high-molecular material, dissolving or dispersing evenly; and removing the solvent by heating, for example, evaporating the solvent to dry by vacuum drying or heating drying or freeze drying or other drying ways, in order to achieve the purpose of dispersing the drug in the high-molecular solid carrier to a high degree, so as to prepare the solid dispersion.
  • In the preparation of the solid dispersion of the present invention, the concentration of the API of palbociclib in the solvent (e.g., water) can be up to 50 mg/ml or more, thereby improving the preparation efficiency of the solid dispersion.
  • The present invention also provides the use of a pharmaceutical formulation or a solid dispersion for the treatment of breast cancer.
  • In the present invention, palbociclib refers to a palbociclib free base or a pharmaceutically acceptable salt thereof, which can be used interchangeably.
  • For those skilled in the art, the excipient is well known and may be an adhesive, a filler, a disintegrant, a lubricant, a preservative, an antioxidant, a flavoring agent, a fragrance, a cosolvent, an emulsifier, a solubilizer, an osmotic pressure regulator, a coloring agent and the like.
  • In the present invention, palbociclib is pulverized, or the palbociclib is mixed with the acidic auxiliary material and co-pulverized, for example, by means of the airflow pulverization technique, in order to reduce the particle size to D90 at 20 μm or less.
  • In the present invention, the pharmaceutical formulation is an oral solid formulation product, such as a tablet or a capsule. Such a product is generally prepared by mixing the API with another pharmaceutically acceptable auxiliary material, such as an excipient, a lubricant, a disintegrant and the like, so as to prepare the oral solid formulation product. The palbociclib oral solid formulation product which has been approved for sale in the United States (the trade name is Ibrance), was manufactured by the above-mentioned technique, according to the description in its drug instructions.
  • The present invention successfully prepares the solid dispersion of palbociclib for the first time by means of a special combination. In the prior art, the solid dispersion is a kind of formulation technique, and useful for a formulation product of an insoluble drug. Usually, an amorphous solid dispersion is prepared from the insoluble API together with a hydrophilic pharmaceutical high-molecular auxiliary material. The methods for the preparation of the amorphous solid dispersion include a solvent method and a melting method. The solvent method includes dissolving the API and the auxiliary material together in a solvent and then volatilizing the solvent. The melting method includes co-melting the API and the high-molecular auxiliary material and rapidly cooling the same. In view of the high melting point of palbociclib, reaching 271° C., and the insolubility in most of solvents, it is impossible to prepare the amorphous solid dispersion in accordance with the solid dispersion technique in the prior art.
  • In the present invention, the formulation prepared by mixing the API of palbociclib with the acidic auxiliary material exhibits a cumulative dissolution rate of 47.8% in a dissolution medium at pH 6.0 for 60 minutes, increased from 34.0% of the product prepared by the prior formulation technique (FIG. 1 ).
  • Further, the formulation prepared by pulverizing palbociclib (having a particle size at 20 μm or less, FIG. 2 ), or the formulation prepared by mixing and co-pulverizing palbociclib and the acidic auxiliary material exhibits a further increased cumulative dissolution rate of 66.6% and 68.7%, respectively, at pH 6.0 for 60 minutes (FIG. 3 ).
  • Further, the solid dispersion prepared by mixing the API of palbociclib with the acidic material and then with the hydrophilic high-molecular material, exhibits a dynamic solubility of 85%, increased from 58% of the API of palbociclib itself, as shown in a dynamic solubility test performed in a buffer at pH 6.0 with stirring for 60 minutes (FIG. 4 ).
  • The preparation method of the solid dispersion of the present invention can also convert the acidic auxiliary material such as tartaric acid into an amorphous state (FIG. 5 ) and the amorphous state is maintained over one week of storage in a stabilizing box at 40° C./75% RH, which is advantageous for maintaining the amorphous state of the palbociclib solid dispersion for a long period of time.
    • DESCRIPTION OF DRAWINGS
  • In order to clearly describe the technical solutions of the present invention, a brief description will be given below with reference to the drawings. It is apparent that these drawings merely represent some specific embodiments described in the present application. The invention includes, but not limited to, the following drawings.
  • FIG. 1 shows the in vitro dissolution of the capsule formulation prepared from palbociclib with the acidic auxiliary material or without the acidic auxiliary material;
  • FIG. 2 shows the particle size of the pulverized palbociclib;
  • FIG. 3 shows the in vitro dissolution of the capsule formulation prepared by mixing the pulverized palbociclib with the acidic auxiliary material, and of the capsule formulation prepared by co-pulverizing the API of palbociclib and tartaric acid to reduce the particle size;
  • FIG. 4 shows the dynamic solubility of the solid dispersion prepared by mixing the API of palbociclib with the acidic material and then with a hydrophilic high-molecular material, compared to the API of palbociclib itself, as tested in a buffer at pH 6.0 with stirring for 60 minutes;
  • FIG. 5 shows the amorphous state of the acidic auxiliary material tartaric acid in the solid dispersion of the present invention;
  • FIG. 6 shows an XRPD pattern of the API of palbociclib used in the present invention;
  • FIG. 7 shows an XRPD pattern of a palbociclib solid dispersion prepared with HPMC-AS-HF;
  • FIG. 8 shows an XRPD pattern of a palbociclib solid dispersion prepared with PVP-VA64;
  • FIG. 9 shows an XRPD pattern of a palbociclib solid dispersion prepared with PVP-K30;
  • FIG. 10 shows an XRPD pattern of a palbociclib solid dispersion prepared with Soluplus; and
  • FIG. 11 shows an XRPD pattern of a palbociclib solid dispersion prepared with HPMC-E5.
    •  DESCRIPTION OF EMBODIMENTS
  • To further understand the present invention, preferred embodiments of the present invention will be described below with reference to examples. These descriptions are merely illustrative for features and advantages of the novel pharmaceutical formulation of the present invention, without limiting the scope of the present invention.
    • Example 1 Preparation of the Capsule Dosage Form From the Acidic Auxiliary Material and Palbociclib by Dry Granulation and Filling
  • 1500 mg of the API of palbociclib, 345 mg of lactose, 1200 mg of tartaric acid, 840 mg of microcrystalline cellulose, 210 mg of sodium carboxymethyl starch and 84 mg of silica were weighed and mixed in a three dimensional mixer for 15 minutes, then 21 mg of magnesium stearate was added and mixed for another 2 minutes in the three dimensional mixer. After mixing, the mixture was passed through a 40-mesh sieve and tableted with a mechanical single-punch tableting machine at a pressure of 5 MPa, each tablet weighing 1050 mg. The pressed large tablets were crushed and passed through a 10-mesh sieve, and dispensed into gelatin capsules at a loading of 350 mg per capsule. The dissolution rate was measured at pH 6.0 and at the selected time points of 5, 10, 15, 20, 30, 45 and 60 minutes.
  • At the same time, a comparative test without the acidic auxiliary material was performed in parallel. 1500 mg of the API of palbociclib, 1545 mg of lactose, 840 mg of microcrystalline cellulose, 210 mg of sodium carboxymethyl starch and 84 mg of silica were weighed and mixed in a three dimensional mixer for 15 minutes, then 21 mg of magnesium stearate was added and mixed for another 2 minutes in the three dimensional mixer. After mixing, the mixture was passed through a 40-mesh sieve and tableted with a mechanical single-punch tableting machine at a pressure of 5 MPa, each tablet weighing 1050 mg. The pressed large tablets were crushed and passed through a 10-mesh sieve, and dispensed into gelatin capsules at a loading of 350 mg per capsule. The dissolution rate was measured by a basket method at pH 6.0, at a rotation speed of 100 rpm and at the selected time points of 5, 10, 15, 20, 30, 45 and 60 minutes.
  • The measurement results of the dissolution of the capsules with the acidic auxiliary material and without the acidic auxiliary material were illustrated by the two curves in FIG. 1 respectively.
    • Example 2 Preparation of a Capsule by Mixing the Acidic Material with Palbociclib, Followed by Pulverization, and Dry Granulation and Filling
  • 1500 mg of the API of palbociclib, which had been pulverized by airflow, was weighed and mixed with 1200 mg of tartaric acid, 345 mg of lactose, 840 mg of microcrystalline cellulose, 210 mg of sodium carboxymethyl starch and 84 mg of silica in a three dimensional mixer for 15 minutes. Then, 21 mg of magnesium stearate was added and mixed for another 2 minutes in the three dimensional mixer. After mixing, the mixture was passed through a 40-mesh sieve and tableted with a mechanical single-punch tableting machine at a pressure of 5 MPa, each tablet weighing 1050 mg. The pressed large tablets were crushed and passed through a 10-mesh sieve, and dispensed into gelatin capsules at a loading of 350 mg per capsule. The dissolution rate was measured by a basket method at pH 6.0, at a rotation speed of 100 rpm and at the selected time points of 5, 10, 15, 20, 30, 45 and 60 minutes. The airflow co-pulverized mixture of the API of palbociclib and tartaric acid (comprising 1500 mg of palbociclib and 1200 mg of tartaric acid) was added with 345 mg of lactose, 840 mg of microcrystalline cellulose, 210 mg of sodium carboxymethyl starch and 84 mg of silica, and mixed in a three dimensional mixer for 15 minutes. Then, 21 mg of magnesium stearate was added and mixed for another 2 minutes in the three dimensional mixer. After mixing, the mixture was passed through a 40-mesh sieve and tableted with a mechanical single-punch tableting machine at a pressure of 5 MPa, each tablet weighing 1050 mg. The pressed large tablets were crushed and passed through a 10-mesh sieve, and dispensed into gelatin capsules at a loading of 350 mg per capsule. The dissolution rate was measured by a basket method at pH 6.0, at a rotation speed of 100 rpm and at the selected time points of 5, 10, 15, 20, 30, 45 and 60 minutes. The dissolution results of the formulation prepared by pulverizing palbociclib alone and of the formulation prepared by co-pulverizing palbociclib and tartaric acid were shown in FIG. 3 .
    • Example 3 Preparation of a Solid Dispersion by Mixing Palbociclib with the Acidic Material and Then with PVP-K30
  • 100 mg of the API of palbociclib and 200 mg of tartaric acid were weighed and placed into a 10 ml penicillin bottle, added with 2 ml of purified water, mixed and dissolved. 200 mg of PVP-K30 (manufactured by BASF, Germany, full name: povidone K30) was added to the solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
    • Example 4 Preparation of a Solid Dispersion by Mixing Palbociclib with the Acidic Material and Then with a Solid Carrier PVP-VA64
  • 100 mg of the API of palbociclib and 200 mg of tartaric acid were weighed and placed into a 10 ml penicillin bottle, added with 2 ml of double distilled water, mixed and dissolved. 200 mg of PVP-VA64 (manufactured by BASF, Germany, full name: Copovidone) was added to the solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight for 18 hours at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
    • Example 5 Preparation of a Solid Dispersion by Mixing Palbociclib with the Acidic Material and Then with a Solid Carrier Soluplus
  • 100 mg of the API of palbociclib and 200 mg of tartaric acid were weighed and placed into a 10 ml penicillin bottle, added with 2 ml of double distilled water, mixed and dissolved. 200 mg of Soluplus (manufactured by BASF, Germany, full name: polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) was added to the solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
    • Example 6 Preparation of a Solid Dispersion by Mixing Palbociclib with the Acidic Material and Then with a Solid Carrier HPMC-E5
  • 100 mg of the API of palbociclib and 200 mg of tartaric acid were weighed and placed into a 10 ml penicillin bottle, added with 2 ml of double distilled water, mixed and dissolved. 200 mg of HPMC-E5 (manufactured by BASF, Germany, full name: hydroxypropylmethylcellulose E5) was added to the solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
    • Example 7 Preparation of a Solid Dispersion by Mixing Palbociclib with the Acidic Material and Then with a Solid Carrier HPMC-AS-HF
  • 100 mg of the API of palbociclib and 200 mg of tartaric acid were weighed and placed into a 10 ml penicillin bottle, added with 2 ml of double distilled water, mixed and dissolved. 200 mg of HPMC-AS-HF (manufactured by BASF, Germany, full name: hydroxypropylmethylcellulose AS-HF) was added to the solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
    • Example 8 Preparation of a Solid Dispersion by Mixing Palbociclib with the Acidic Material and Hydrochloric Acid and Then with a Solid Carrier PVP VA64
  • 125 mg of the API of palbociclib was weighed and placed into a 10 ml penicillin bottle; 1.991 ml of double distilled water and 8.63 μl of 36% hydrochloric acid solution (having a density of 1.18 g/mL) were added, so that the molar ratio of hydrochloric acid to the API of palbociclib was 1:1. Then 200 mg of tartaric acid was added and completely mixed and dissolved under the action of ultrasound. 100 mg of PVP VA64 was added to the above solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
    • Example 9 Preparation of a Solid Dispersion by Mixing Palbociclib with the Acidic Material and Phosphoric Acid and Then with a Solid Carrier PVP VA64
  • 125 mg of the API of palbociclib was weighed and placed into a 10 ml penicillin bottle; 2 ml of double distilled water and 27.3 mg of phosphoric acid were added, so that the molar ratio of phosphoric acid to the API of palbociclib was 1:1. Then 200 mg of tartaric acid was added and completely mixed and dissolved under the action of ultrasound. 100 mg of PVP VA64 was added to the above solution and dissolved by ultrasound together with hand shaking. In a fume hood, water was volatilized by means of stirring under heating; and nitrogen was introduced to facilitate water evaporation. Stop heating and stirring when the content of the penicillin bottle was gelatinous and there was no more liquid reduction. It was placed into a vacuum dryer, overnight at 40° C., and removed the next day, and thereby, the solid dispersion was prepared.
    • Example 10
  • The palbociclib solid dispersion prepared with PVP-K30 in Example 3 and the API of palbociclib both were sent for XRPD test. The XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2θ°): 3-40; scanning step (2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å): 1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV. The obtained XRPD pattern of the API of palbociclib was shown in FIG. 6 ; and the XRPD pattern of the solid dispersion prepared with PVP-K30 was shown in FIG. 9 .
    • Example 11
  • The palbociclib solid dispersion prepared with PVP-VA64 in Example 4 was sent for XRPD test. The XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2θ°): 3-40; scanning step (2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å): 1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV. The obtained XRPD pattern was shown in FIG. 8 .
    • Example 12
  • The palbociclib solid dispersion prepared with Soluplus in Example 5 was sent for XRPD test. The XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2θ°): 3-40; scanning step (2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å): 1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV. The obtained XRPD pattern was shown in FIG. 10 .
    • Example 13
  • The solid dispersion prepared with HPMC-E5 in Example 6 was sent for XRPD test. The XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2θ°): 3-40; scanning step (2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å): 1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV. The obtained XRPD pattern was shown in FIG. 11 .
    • Example 14
  • The solid dispersion prepared with HPMC-AS-HF in Example 7 was sent for XRPD test. The XRPD test was performed with Panalytical's XPERT-3 X-ray diffractometer. About 10 mg of sample was evenly tiled on a monocrystalline silicon sample tray and subjected to the XRPD test with the following parameters: scanning range (2θ°): 3-40; scanning step (2θ°):0.0263; scanning time (seconds): 46.665; K-Alpha wavelength (Å): 1.54060; K-Alpha2 wavelength (Å): 1.54443; Power setting: 40 mA, 45 kV. The obtained XRPD pattern was shown in FIG. 7 .
    • Example 15
  • 62.5 mg of the solid dispersion prepared in Example 3 (containing 12.5 mg of the API of palbociclib in proportion) and 12.5 mg of the API of palbociclib were weighed separately, placed into two 100 ml beakers, respectively, and marked with T1 and T2. 90 ml of phosphate buffer (pH 6.0) was added to the two beakers respectively and a magnetic stir bar was placed therein. The two beakers were placed on a magnetic stirrer separately. 1 ml of the solution was removed separately from each of the beakers at the time points of 5, 10, 20, 40, and 60 minutes and filtered through a 0.45 μm micro PES polyethersulfone filter membrane. The filtrate was analyzed by high performance liquid chromatography, the content of the API of palbociclib was determined and the dissolution percentage was calculated. The results were shown in FIG. 4 .
  • The description of the above examples is only intended to help understanding the central concept of the present invention. It should be noted that those skilled in the art may make improvements and modifications to the novel formulation and its preparation method according to the present invention without departing from the principles of the present invention, and such improvements and modifications also fall within the scope of protection of the claims in the present invention.

Claims (21)

1-20. (canceled)
21. A method of making a composition comprising an amorphous solid dispersion, comprising:
combining palbociclib or a pharmaceutically acceptable salt thereof, an acidic auxiliary material, a solvent, and a hydrophilic high-molecular weight material;
dissolving or dispersing the palbociclib or a pharmaceutically acceptable salt thereof, and
removing the solvent.
22. The method of claim 21, wherein the acidic auxiliary material is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, an aliphatic sulfonic acid, an aromatic sulfonic acid, and combinations thereof.
23. The method of claim 21, wherein the concentration of the palbociclib or the pharmaceutically acceptable salt thereof in the solvent is 50 mg/ml or more.
24. The method of claim 21, wherein the concentration of the palbociclib or the pharmaceutically acceptable salt thereof in the solvent is up to 50 mg/ml.
25. The method of claim 21, wherein the removing the solvent comprises evaporating the solvent by vacuum drying, heating drying, freeze drying, or combinations thereof.
26. The method of claim 21, wherein the solvent comprises water, ethanol, acetone, or a mixture thereof.
27. The method of claim 21, wherein a mass ratio of the acidic auxiliary material to the palbociclib or the pharmaceutically acceptable salt thereof ranges from 0.5:1 to 5:1.
28. The method of claim 22, wherein the acidic auxiliary material is tartaric acid.
29. The method of claim 21, wherein the hydrophilic high-molecular weight material is one or more selected from the group consisting of povidone K30, copovidone VA64, Soluplus, hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose acetate succinate, hydroxypropyl-P-cyclodextrin and sulfobutyl ether-P-cyclodextrin.
30. The method of claim 21, wherein a mass ratio of the hydrophilic high-molecular weight to the palbociclib or the pharmaceutically acceptable salt thereof ranges from 0.1:1 to 10:1.
31. The method of claim 21, wherein a mass ratio of the hydrophilic high-molecular weight to the palbociclib or the pharmaceutically acceptable salt thereof ranges from 0.1:1 to 10:1 and wherein a mass ratio of the acidic auxiliary material to the palbociclib or the pharmaceutically acceptable salt thereof ranges from 0.5:1 to 5:1.
32. The method of claim 22, wherein the acidic auxiliary material is an aliphatic sulfonic acid.
33. The method of claim 32, wherein the aliphatic sulfonic acid is selected from the group consisting of methanesulfonic acid, ethanesulfonic acid and isethionic acid, and the aromatic sulfonic acid is selected from the group consisting of benzenesulfonic acid and p-toluenesulfonic acid.
34. The method of claim 21, wherein the composition is orally administered.
35. The method of claim 21, wherein the palbociclib or the pharmaceutically acceptable salt thereof is present in an amount of 25 to 500 mg.
36. The method of claim 21, wherein the composition is in the dosage form of a tablet or a capsule.
37. A composition comprising an amorphous solid dispersion, wherein the composition is made according to the method of claim 21.
38. A method of treating breast cancer, comprising administering to a subject having breast cancer the composition of claim 37.
39. A method of making a composition comprising an amorphous solid dispersion, comprising:
(a) pulverizing palbociclib or a pharmaceutically acceptable salt thereof and thereby obtaining pulverized palbociclib at a particle size to D90 at 20 μm or less;
(b) mixing the pulverized palbociclib with an acidic auxiliary material;
(c) co-pulverizing the mixture from (b) and thereby obtain a pulverized mixture of palbociclib and acidic auxiliary material at a particle size to D90 at 20 μm or less; and
wherein the method comprises adding another pharmaceutically acceptable excipient.
40. A method of improving in vitro dissolution and in vivo bioavailability of palbociclib, comprising
(a) pulverizing palbociclib or a pharmaceutically acceptable salt thereof and thereby obtaining pulverized palbociclib at a particle size to D90 at 20 μm or less;
(b) mixing the pulverized palbociclib with an acidic auxiliary material; and
(c) co-pulverizing the mixture from (b) and thereby obtain a pulverized mixture of palbociclib and acidic auxiliary material at a particle size to D90 at 20 μm or less.
US17/954,421 2016-03-29 2022-09-28 Pharmaceutical formulation of palbociclib and a preparation method thereof Abandoned US20230226063A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025156193A1 (en) * 2024-01-25 2025-07-31 Zhejiang Qizheng Pharmaceutical Co., Ltd. Palbociclib dosage form

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2686840C1 (en) 2015-06-04 2019-05-06 Пфайзер Инк. Solid dosage forms of pallbocyclob
CN109078006B (en) * 2016-03-29 2021-04-20 深圳市药欣生物科技有限公司 Medicinal preparation of palbociclib and preparation method thereof
US10449195B2 (en) 2016-03-29 2019-10-22 Shenzhen Pharmacin Co., Ltd. Pharmaceutical formulation of palbociclib and a preparation method thereof
CN108017629A (en) * 2016-11-04 2018-05-11 上海奥博生物医药技术有限公司 A kind of Pa Boxini amorphous states
CN108210454A (en) * 2016-12-14 2018-06-29 深圳市华力康生物医药有限公司 A kind of Orally taken emulsion of Pabuk former times profit cloth and preparation method thereof
US20200054560A1 (en) * 2017-04-21 2020-02-20 Alnova Pharmaceuticals, Ltd. Palbociclib compositions and methods thereof
CN110997666A (en) * 2017-09-19 2020-04-10 浙江华海药业股份有限公司 N-formyl palbociclib, preparation method and application thereof, palbociclib preparation and quality control method thereof
CN108014343A (en) * 2017-12-21 2018-05-11 孟斯琴 A kind of pharmaceutical composition for treating breast cancer and preparation method thereof
CN108066312B (en) * 2017-12-29 2020-03-20 山东裕欣药业有限公司 Palbociclib pharmaceutical composition and preparation method thereof
CN108066303A (en) * 2017-12-31 2018-05-25 湖南博隽生物医药有限公司 A kind of anticancer pharmaceutical composition and preparation method thereof
CN108653222A (en) * 2018-07-03 2018-10-16 威海贯标信息科技有限公司 A kind of Pa Boxini tablet compositions
CN109288806A (en) * 2018-08-22 2019-02-01 深圳市华力康生物医药有限公司 A kind of effervescent tablet of Pabuk former times benefit cloth and its application
JP7149449B2 (en) * 2020-07-02 2022-10-06 ＡＲＴｈａｍ Ｔｈｅｒａｐｅｕｔｉｃｓ株式会社 Oral pharmaceutical composition and manufacturing method thereof
CN114246841B (en) * 2020-09-24 2024-02-02 南京济群医药科技股份有限公司 A kind of composition and medicine of palbociclib isethionate
CN114306245A (en) * 2020-09-29 2022-04-12 深圳市药欣生物科技有限公司 Pharmaceutical composition of amorphous solid dispersion and preparation method thereof
CN114748426A (en) * 2020-12-28 2022-07-15 上海博志研新药物技术有限公司 Pabociclib solid dispersion, preparation method and application thereof
TW202345842A (en) 2022-03-25 2023-12-01 大陸商深圳市藥欣生物科技有限公司 Pharmaceutical compositions of protac compounds and uses thereof
WO2024242504A1 (en) * 2023-05-25 2024-11-28 주식회사 삼양홀딩스 Oral composition of palbociclib
KR20250062261A (en) 2023-10-30 2025-05-08 신풍제약주식회사 Pharmaceutical composition of palbociclib having improved solubility and stability and preparing method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016193860A1 (en) * 2015-06-04 2016-12-08 Pfizer Inc. Solid dosage forms of palbociclib

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000309588A (en) * 1999-04-28 2000-11-07 Taisho Pharmaceut Co Ltd Solid dispersion
CA2561516A1 (en) * 2004-03-30 2005-10-13 Pfizer Products Inc. Combinations of signal transduction inhibitors
KR100627687B1 (en) * 2005-04-20 2006-09-25 주식회사 씨티씨바이오 Sibutramine free base containing composition and preparation method thereof
KR101489401B1 (en) * 2006-01-27 2015-02-03 앱탈리스 파마테크, 인코포레이티드 Drug Delivery Systems Containing Weakly Basic Drugs and Organic Acids
CN102106806B (en) * 2009-12-29 2013-04-17 上海中西制药有限公司 Method for preparing solid preparation and solid preparation
CN102106807B (en) * 2009-12-29 2013-03-27 上海中西制药有限公司 Method for preparing solid preparation and solid preparation
PH12012502432A1 (en) * 2010-06-09 2013-02-11 Abbvie Inc Solid dispersions containing kinase inhibitors
CN105616419A (en) * 2014-11-07 2016-06-01 江苏豪森药业集团有限公司 Pharmaceutical composition containing cyclin inhibitor solid dispersion, and preparation method thereof
CN104434809B (en) * 2014-12-10 2018-10-16 北京科莱博医药开发有限责任公司 A kind of olaparib solid dispersion preparation and preparation method thereof
WO2016156070A1 (en) * 2015-04-02 2016-10-06 Sandoz Ag Modified particles of palbociclib
CN104887641B (en) * 2015-04-08 2017-12-01 上海鲁源医药科技有限公司 Pabuk former times profit cloth gastric floating tablet and preparation method thereof
WO2017021111A1 (en) * 2015-08-05 2017-02-09 Ratiopharm Gmbh New crystalline form and acetic acid adducts of palbociclib
WO2017036390A1 (en) * 2015-09-01 2017-03-09 上海方楠生物科技有限公司 Composition of palbociclib or pharmaceutically acceptable salt thereof and pharmaceutical excipient, and preparation method therefor
CN109078006B (en) * 2016-03-29 2021-04-20 深圳市药欣生物科技有限公司 Medicinal preparation of palbociclib and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016193860A1 (en) * 2015-06-04 2016-12-08 Pfizer Inc. Solid dosage forms of palbociclib

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025156193A1 (en) * 2024-01-25 2025-07-31 Zhejiang Qizheng Pharmaceutical Co., Ltd. Palbociclib dosage form

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