OLAPARIB ORAL SUSTAINED AND CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION AND USES THEREOF

Abstract

An olaparib oral sustained and controlled release pharmaceutical composition contains an olaparib in an improved dissolution form and a release rate adjusting matrix polymer. The pharmaceutical composition has controllable in-vivo absorption behavior, plasma concentration and PARP enzyme inhibition level, and improved drug load and/or oral absorption and/or bioavailability and/or plasma concentration control and/or enzyme inhibition level control of olaparib, and can be used as the only preparation or in combination with other therapies to treat a cancer.

Claims

1. An olaparib oral sustained and controlled release pharmaceutical composition, which comprises an olaparib in an improved dissolution form; and a release rate adjusting matrix polymer, wherein the olaparib oral sustained and controlled release pharmaceutical composition has a steady-state plasma concentration valley value C.sub.min,ss of 0.2 to 4 g/mL; and a steady-state plasma concentration peak value C.sub.max,ss of 0.8 to 15 g/mL.

2. An olaparib oral sustained and controlled release pharmaceutical composition according to claim 1, wherein the olaparib oral sustained and controlled release pharmaceutical composition has a steady-state plasma concentration valley value C.sub.min,ss of 0.5 to 3 g/mL; and a steady-state plasma concentration peak value C.sub.max,ss of 1 to 12 g/mL, and the steady plasma concentration peak to valley ratio is preferably less than 6, more preferably less than 4.

3. An olaparib oral sustained and controlled release pharmaceutical composition according to claim 1, wherein the olaparib pharmaceutical composition has a controlled release behavior, and the release behavior and release amount thereof in a predetermined period of time are controllable in a release medium meeting sink conditions, when the release behavior is measured in a buffer solution with a pH of 1.2 to 7.8 at 37 C. using the apparatus II of the dissolution test method in the Chinese Pharmacopoeia, the release amount in 1 h is less than 50%, preferably less than 40%, more preferably 10 to 30% of the total amount of olaparib; and the release amount in 16 h is greater than 80% of the total, preferably >90% of the total amount of olaparib.

4. An olaparib oral sustained and controlled release pharmaceutical composition according to claim 1, wherein the olaparib in an improved dissolution form includes: an olaparib salt, an olaparib co-grinding mixture, an olaparib nanocrystal and an olaparib solid dispersion; preferably, the release rate adjusting matrix polymer is selected from the group consisting of a cellulose derivative, a starch or a derivative thereof, an alginate, an acrylic or methacrylic acid derivative, a polyethylene oxide, a gum, and a carbohydrate-based polymer, preferably, one or a combination of two or more selected from the group consisting of hydroxypropyl cellulose, polyethylene glycol, hypromellose, methylcellulose, hydroxyethylcellulose, ethylcellulose, cellulose acetate, sodium alginate, povidone, copolyvidone, acrylic resin, carbomer, preferably one or a combination of two or more selected from the group consisting of hydroxypropylcellulose, sodium alginate, hypromellose, and carbomer; preferably, the olaparib salt is selected from the group consisting of hydrochloride, besylate, sulfate, maleate, and camphorate; preferably, the olaparib co-grinding mixture consists of the pharmaceutically active ingredient olaparib, a matrix polymer for solubilization and other additives, and is prepared by co-grinding the components; in the co-grinding mixture, based on the total weight of the co-grinding mixture, the olaparib is 5 to 60 wt %, preferably 20 to 40 wt %, and the matrix polymer for solubilization is 40 to 95 wt %, preferably 40 to 80 wt %, the other additives is 0 to 15 wt %, preferably 0.2 to 10 wt %; preferably, the olaparib nanocrystal consists of the pharmaceutically active ingredient olaparib, a matrix polymer for solubilization, and/or other additives, and is obtained by prepared the components into nanosized particles by high pressure homogenization or coprecipitation; in the olaparib nanocrystal, based on the total weight of the olaparib nanocrystal, the olaparib is 10 to 99 wt %, preferably 20 to 50 wt %; the matrix polymer for solubilization is 1 to 75 wt %, preferably 1 to 65 wt %, and the other additives are 0 to 10 wt %, preferably 0 to 5% wt %; preferably the nanocrystal has a particle size of 50 to 1000 nm; preferably, the solid dispersion consists of the pharmaceutically active ingredient olaparib, a matrix polymer for solubilization and other additives, and is prepared by solvent evaporation or melt extrusion, in the solid dispersion, based on the total weight of the solid dispersion, olaparib is 5 to 50 wt %, preferably 10 to 40 wt %, more preferably 20 to 40 wt %, the matrix polymer for solubilization is 45 to 95 wt %, preferably 50 to 80 wt %, and the other additives are 0 to 12 wt %, preferably 0 to 10 wt %; preferably, the matrix polymer for solubilization is one or a combination of two or more selected from the group consisting of povidone, copovidone, polyoxyethylene, Soluplus, hypromellose phthalate, hydroxypropylcellulose succinate acetate, polyethylene glycol, poloxamer, polymethacrylic acid, polyethyl acrylate, 2-hydroxypropyl--cyclodextrin, hypromellose, polymethacrylate, hydroxypropyl cellulose, cellulose acetate phthalate, and other pharmaceutically acceptable polymers for solubilization; preferably, the other additives are one or a combination of two or more selected from the group consisting of pharmaceutically acceptable surfactants, a lubricant, a colloidal silica, a plasticizer, and the like.

5. An olaparib oral sustained and controlled release pharmaceutical composition according to claim 1, wherein the composition comprises 50 to 900 parts by weight, preferably 80 to 700 parts by weight, more preferably 120 to 600 parts by weight, of an olaparib in an improved dissolution form; and 0.1 to 300 parts by weight, preferably 20 to 250 parts by weight, more preferably 50 to 180 parts by weight, of the release rate adjusting matrix polymer; preferably, the olaparib oral sustained and controlled release pharmaceutical composition further comprises 1 to 400 parts by weight, preferably 2 to 300 parts by weight, more preferably 5 to 250 parts by weight of other additives; preferably, the olaparib oral sustained and controlled release pharmaceutical composition comprises: 50 to 600 parts by weight of an olaparib salt, and 10 to 250 parts by weight of a release rate adjusting matrix polymer, preferably further comprising 1 to 300 parts by weight of other additives; or 50 to 700 parts by weight of an olaparib co-grinding mixture, and 10 to 200 parts by weight of a release rate adjusting matrix polymer, preferably further comprising 1 to 150 parts by weight of other additives; or 50 to 800 parts by weight of an olaparib nanocrystal, and 0.1 to 250 parts by weight of a release rate adjusting matrix polymer, preferably further comprising 1 to 200 parts by weight of other additives r; or 50 to 900 parts by weight of an olaparib solid dispersion, and 20 to 300 parts by weight of a release rate adjusting matrix polymer, preferably further comprising 1 to 200 parts by weight of other additives, wherein, the other additives are pharmaceutical excipients, preferably selected from the group consisting of release regulators, semi-permeable controlled release coating materials, seal coating materials, solubilizing agents, disintegrants, coating powders, plasticizers, porogens, expansive materials, fillers, osmotic pressure regulators, lubricants, adhesives, dyes, anti-adherents, opacifiers, diluents and/or other pharmaceutically acceptable additives.

6. An olaparib oral sustained and controlled release pharmaceutical composition according to claim 1, which is a sustained and controlled release preparation containing a single sustained release phase or an immediate and sustained double release preparation containing both immediate release phase and sustained release phase, wherein, preferably, the sustained release phase is selected from the group consisting of a controlled release tablet, a controlled release pellet, a controlled release composition in a tablet, a controlled release composition in a tablet or pellet core, a controlled release layer composition incorporated into a double layer tablet, and any combination thereof; preferably, the immediate release phase is selected from the group consisting of an immediate release tablet, an immediate release pellet, an immediate release composition in a tablet, an immediate release coat layer wrapping around a controlled release tablet or pellet core, and an immediate release layer composition in a double-layer controlled release tablet and any combination thereof.

7. An olaparib oral sustained and controlled release pharmaceutical composition according to claim 6, wherein in the immediate and sustained double release preparation, the pharmaceutically active ingredient in the immediate release phase accounts for 10 to 50 wt %, preferably 20 to 40 wt % of the total amount of the pharmaceutically active ingredient; the pharmaceutically active ingredient in the sustained release phase accounts for 50 to 90 wt %, preferably 60 to 80 wt % of the total amount of the pharmaceutically active ingredient.

8. An olaparib oral sustained and controlled release pharmaceutical composition according to claim 6, which is tablets or capsules, and is preferably selected from the group consisting of an osmotic pump controlled release tablet, an osmotic pump immediate and sustained double release tablet, a matrix type sustained release tablet, a matrix type immediate and sustained double release double layer tablet, a matrix type immediate and sustained double release coated tablet, a sustained release tablet based on sustained release pellets, an immediate and sustained double release tablet based on sustained release pellets and immediate release pellets, a capsule containing matrix type sustained release pellets, a capsule containing sustained release coated pellets, a capsule containing sustained release pellets with immediate release coat, an immediate and sustained double release capsule containing immediate release pellets and matrix type sustained release pellets, an immediate and sustained double release capsule containing immediate release pellets and sustained release coated pellets, a capsule containing matrix-type sustained release microtablets, a capsule containing matrix-type sustained release microtablets with immediate release coat, and a capsule containing immediate release microtablets and matrix type sustained release microtablets.

9. A method for preventing or treating a tumor in a subject, comprising: administering to the subject an effective amount of the olaparib oral sustained and controlled release pharmaceutical composition of claim 1, preferably, the tumor is selected from the group consisting of the tumors with defects in DNA repair function, in particular selected from the group consisting of a combination of two or more cancers related to BRCA gene mutation, such as ovarian cancer, gastric cancer and breast cancer, and a tumor associated with BRCA1 and BRCA2 gene mutation.

10. The method according to claim 9, wherein the expected total dose of the olaparib oral sustained and controlled release pharmaceutical composition which needs to be administered daily, is 100 to 1400 mg calculated by olaparib, and the amount of the pharmaceutically active ingredient olaparib contained in a single finished tablet or capsule is 20 to 400 mg, preferably 50 to 300 mg.

Description

DRAWINGS

[0129] FIG. 1 is a schematic view showing the structure of an osmotic pump type controlled release tablet;

[0130] FIG. 2 is a schematic structural view of an osmotic pump type immediate and sustained double release tablet;

[0131] FIG. 3 is a schematic structural view of a matrix type immediate and sustained double release double-layer tablet;

[0132] FIG. 4 is a schematic structural view of a matrix type immediate and sustained double-release release coated tablet;

[0133] FIG. 5 is a structural view of a capsule containing immediate release pellets and matrix type sustained release pellets;

[0134] FIG. 6 is a structural view of a capsule containing sustained release pellets with immediate release coat;

[0135] FIG. 7 is a structural view of a capsule containing immediate release microtablets and sustained release microtablets;

[0136] FIG. 8 is a graph showing the release profiles of the double-layer osmotic pump controlled release tablet of Example 1 in release media at pH 1.2, 4.5 and 6.8;

[0137] FIG. 9 is a graph showing the release profiles of the preparations of Examples 2, 5, 6, 7, 9 and 11 in a release medium at pH 6.8;

[0138] FIG. 10 is a graph showing the release profile of the matrix type sustained release tablet of Example 3 in a release medium at pH 6.8;

[0139] FIG. 11 is a graph showing the release profile of the immediate and sustained double-release matrix type tablet of Example 4;

[0140] FIG. 12 is a graph showing the dissolution profile of the immediate release capsule preparation of Comparative Example 1.

[0141] FIG. 13 is a graph showing the in vivo plasma concentration-time curves of the immediate release capsule of Comparative Example 1 and the double-layer osmotic pump controlled release tablet of Example 1;

[0142] FIG. 14 is a graph showing the in vivo plasma concentration-time curves of the immediate release capsule of Comparative Example 1 and the immediate and sustained double-release tablet of Example 4;

[0143] FIG. 15 is a graph showing the in vivo plasma concentration-time curves of the immediate release capsule of Comparative Example 1 and the immediate and sustained double-release tablet of Example 2;

[0144] FIG. 16 is a graph showing PARP enzyme inhibition rate-time curves of the immediate release capsule of Comparative Example 1 and the immediate and sustained double-release tablet of Example 2 in canine PBMC.

BEST MODE FOR CARRYING OUT THE INVENTION

[0145] The following examples generally describe the preparation and/or characterization of typical compositions of the invention, wherein all percentages are by weight unless otherwise indicated. The following examples are illustrative of the invention and are not to be construed as limiting the scope of the invention. In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0146] Test animals: Beagle dogs were half males and half females, weighing 8 to 10 kg, from Beijing Marshall Biotechnology Co., Ltd. The test animals were subjected to adaptive feeding at the Experimental Animal Center of Shanghai Institute of Materia Medica for 14 days before the test day.

[0147] A single-punch tablet press (TDP-1, Guangzhou Xulang Machinery Equipment Co., Ltd.) was adopted to press tablets.

[0148] The three-dimensional mixer was a T2F model available from TURBULA.

[0149] The melt extruder was a Pharma 11 model available from Thermo Fisher.

Example 1 Double-Layer Osmotic Pump Controlled Release Tablets

[0150]

TABLE-US-00001 dose (100 tablets) Components of drug layer of core Olaparib 5 g Copolyvidone(VA64) 10 g Polyvidone(K90) 2 g Magnesium stearate 0.3 g Components of push layer of core Carboxymethyl starch sodium 8.4 g Hypromellose (K15M) 1.7 g Carbomer(971P) 0.6 g Sodium chloride 5.8 g copolyvidone (VA64) 3.6 g Red ferric oxide 0.2 g Magnesium stearate 0.2 g

[0151] A solid dispersion was prepared from Olaparib and copolyvidone VA64 by solvent evaporation. That is, olaparib and copolyvidone VA64 were simultaneously dissolved in ethanol/acetone (25/75, v/v), evaporated off the organic solvent under reduced pressure, dried in a vacuum drying oven, and ground and pulverized through a 60 mesh screen to be ready for tableting. For the obtained solid dispersion, in water under sink conditions at 37 C. and 100 rpm, the pharmaceutically active ingredient was dissolved out 90% or more in 30 min. However, under the same conditions, the olaparib compound powder was dissolved out less than 60% in 2h.

[0152] Then, the solid dispersion and other excipients in prescription amounts were passed through a 60 mesh screen and mixed by a three-dimensional mixer at 30 rpm for 25 min to obtain a drug layer composition to be ready for tableting.

[0153] The push layer excipients were accurately weighed and passed through a 60 mesh screen and mixed by a three-dimensional mixer at 30 rpm for 30 min to obtain a push layer composition.

[0154] An osmotic pump double-layer core comprising a drug layer and a push layer was pressed from the above-described drug layer composition and the push layer composition by direct pressing.

[0155] The pressed core was coated with a 4% cellulose acetate solution to form a controlled release coat layer with a weight increment of 10%, so as to obtain a double-layer osmotic pump controlled release tablet.

[0156] The dissolution degree of the double-layer osmotic pump controlled release tablets was determined on the apparatus II of the dissolution test method (Chinese Pharmacopoeia 2010, second edition, appendix X, C). The measurements were operated following the method at 37 C., using buffers of pH 1.2, 4.5, and 6.8 as the release media (7.65 mL of hydrochloric acid was diluted with water to 1000 mL to obtain a release medium of pH 1.2; 250 mL of a 0.2 mol/L potassium dihydrogen phosphate solution was added with 0 mL and 112 mL of a 0.2 mol/L sodium hydroxide solution, to respectively obtain release media of pH 4.5 and 6.8) respectively, at a rotary speed of 75 rpm, 6 mL of the solution was taken at 0.5, 1, 2, 4, 6, 8, 10, 12, 13, 16 h, respectively, and centrifuged, the supernatant was taken as the test solution to determine the release degree.

[0157] According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010, second edition, appendix IV, A), the absorbance was measured at a wavelength of 278 nm, so as to measure the release degree of the prescription tablet.

[0158] The release results in release media with different pH are shown in FIG. 8. The results showed that the double-layer osmotic pump controlled release tablets were basically not affected by pH. The active ingredient olaparib could be released at a constant rate, less than 10% in 1 h, 50% in 6 h, and more than 90% in 12 h. The overall release time can be 12 to 13 h.

Example 2 Immediate and Sustained Double Release Double Layer Osmotic Pump Controlled Release Tablets

[0159]

TABLE-US-00002 dose (100 tablets) Components of drug layer of cores olaparib 4 g copolyvidone(VA64) 16.8 g polyvidone(K90) 1.5 g sodium dodecyl sulfate 0.5 g magnesium stearate 0.3 g Components of push layer of cores Carboxymethyl starch sodium 7.0 g Hypromellose (K15M) 1.6 g Carbomer(971P) 0.5 g Sodium chloride 5.0 g copolyvidone (VA64) 3.0 g Black ferric oxide 0.1 g magnesium stearate 0.1 g

[0160] The olaparib and copolyvidone were sieved through a 60 mesh screen for 3 times, and then mixed by a three-dimensional mixer at 30 rpm for 25 min. The mixture was slowly added to a preheated melt extruder, and the extrudate was collected, pulverized, passed through a 60 mesh screen to give an olaparib solid dispersion. Then, the olaparib solid dispersion and other excipients except magnesium stearate in prescription amounts were passed through a 60 mesh screen and mixed by a three-dimensional mixer at 30 rpm for 25 min, and magnesium stearate was added and the mixing continued for 5 min to obtain a drug layer composition to be ready for tableting.

[0161] The push layer excipients were accurately weighed and passed through a 60 mesh screen and mixed by a three-dimensional mixer at 30 rpm for 30 min to obtain a push layer composition.

[0162] An osmotic pump double-layer core comprising a drug layer and a push layer was pressed from the above-described drug layer composition and the push layer composition by direct pressing.

[0163] The pressed core was coated with a 3% cellulose acetate0.2% PEG4000 solution to form a controlled release coat layer with weight increment of 10% to give a double-layer osmotic pump controlled release tablet.

[0164] The olaparib solid dispersion was dissolved in acetone, and the solution was coated on the obtained double-layer osmotic pump tablet in a ratio of the drug content in the immediate release layer to that in the sustained release layer of 2:8, to give an immediate and sustained double release double-layer osmotic pump tablet, in which the active ingredient accounted for 20% in the immediate release layer and 80% in the sustained release layer.

[0165] The dissolution degree of the immediate and sustained double release double-layer osmotic pump controlled release tablets was determined on the apparatus II of the dissolution test method (Chinese Pharmacopoeia 2010, second edition, appendix X, C). The measurements were operated following the method at 37 C., using a buffer of pH 6.8 as the release medium (250 mL of 0.2 mol/L potassium dihydrogen phosphate solution was added with 112 mL of 0.2 mol/L sodium hydroxide solution, to obtain a release medium of pH 6.8), at a rotary speed of 75 rpm, 6 mL of the solution was taken at 0.5, 1, 2, 4, 6, 8, 10, 12, 13, 16 h, respectively, and centrifuged, the supernatant was taken as the test solution to determine the release degree.

[0166] According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010, second edition, appendix IV, A), the absorbance was measured at a wavelength of 278 nm, so as to measure the release degree of the prescription tablet.

[0167] The release results in the release medium of pH 6.8 are shown in FIG. 9. It was shown that the immediate and sustained double release double layer osmotic pump controlled release tablets could release the drug in the immediate release layer within 2 h, and the drug in the sustained release layer could be released at a constant rate, more than 80% or more of the drug can be released within 16 h, and the drug releasing time is up to 16 h.

Example 3 Sustained Release Matrix Type Tablets

[0168]

TABLE-US-00003 name dose (100 tablets) olaparib 8 g Polyvidone K30 24 g hydroxy propyl cellulose (K4M) 4 g sodium dodecyl sulfate 0.2 g magnesium stearate 0.2 g

[0169] Olaparib and povidone K30 were sieved through a 60 mesh screen for 3 times, and then mixed by a three-dimensional mixer at 30 rpm for 25 min. The mixture was slowly added to a preheated melt extruder, and the clear extrudate was collected, pulverized and passed through a 60 mesh screen to give an olaparib solid dispersion. The solid dispersion, hydroxypropylcellulose (K4M) as the release rate adjusting matrix polymer, sodium lauryl sulfate in prescription amounts were sieved through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, and then added with a prescription amount of magnesium stearate and mixed for further 5 min, and compressed to prepare a sustained release matrix type tablet with suitable hardness.

[0170] The method for measuring the release degree of the olaparib sustained release matrix type tablets was the same as that in Example 1, using a buffer of pH 6.8 as a release medium.

[0171] The results are shown in FIG. 10. The sustained release matrix type tablets can release less than 20% of olaparib in 1 h, about 80% in 8 h, more than 90% in 16 h, and the drug release time was up to 10 h.

Example 4 Immediate and Sustained Double Release Matrix Type Double-Layer Tablets

[0172]

TABLE-US-00004 dose(g) (1000 tablets) Immediate release layer olaparib 20 Soluplus 75 colloidal silica 1 Crosslinked polyvidone (PVPP XL) 10 mannitol 5 magnesium stearate 3 Sustained release layer olaparib 100 Polyvidone K30 300 colloidal silica 3.5 HPMC K15M 70 magnesium stearate 3

[0173] Immediate release layer: olaparib, colloidal silica and Soluplus in prescription amounts were sieved through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, and then slowly added to a preheated melt extruder, and the extrudate was collected, pulverized and passed through a 60 mesh screen to give an olaparib solid dispersion.

[0174] The resulting olaparib solid dispersion was mixed uniformly with a prescription amount of other materials such as the disintegrant PVPP XL and other excipients such as mannitol and magnesium stearate to be ready for tableting.

[0175] Sustained release layer: olaparib, colloidal silica and povidone K30 in prescription amounts are sieved through a 60 mesh screen and mixed uniformly, slowly added to a preheated melt extruder, and the extrudate was collected, pulverized and passed through a 60 mesh screen to give an olaparib solid dispersion.

[0176] The resulting olaparib solid dispersion was mixed uniformly with a prescription amount of a release rate adjusting polymer HPMC K15M and the lubricant magnesium stearate to be ready for tableting.

[0177] Tableting: a direct compression method is used to prepare an immediate and sustained double release matrix type double-layer tablet with a suitable hardness.

[0178] The dissolution degree of the controlled release preparation was determined on the apparatus II of the dissolution test method (Chinese Pharmacopoeia 2010, second edition, appendix X, C). The measurements were operated following the method at 37 C., using a buffer of pH 6.8 as the release medium, at a rotary speed of 75 rpm, 6 mL of the solution was taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 13 and 16 h, respectively, and centrifuged, and the supernatant was taken as the test solution to determine the release degree.

[0179] According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010, second edition, appendix IV, A), the absorbance was measured at a wavelength of 278 nm, so as to measure the release degree of the obtained tablet.

[0180] The release results were shown in FIG. 11. The immediate and sustained double release matrix type double-layer tablet can rapidly release about 20% of the drug in 30 min, and about 60% of the drug was released in about 8 h, and the drug was completely released in about 16 h. The release behavior can control the plasma concentration range of olaparib, can immediately reach the plasma concentration required for PARP inhibition after oral administration, and maintain the concentration level for a long time.

Example 5 Sustained Release Matrix Type Coated Tablets Containing an Immediate Release Coat Layer

[0181]

TABLE-US-00005 name dose (1) Preparation of sustained release core (100 pieces) olaparib 8 g poloxamer 188 24 g sodium alginate 7 g magnesium stearate 0.2 g (2) Immediate release coat olaparib 2 g poloxamer 188 5 g talc 1 g polyethyleneglycol 4000 2 g 95% ethanol 90 g water 10 g

[0182] The preparation method was as follows.

[0183] Preparation of the sustained release core of the sustained release matrix type coated tablets: olaparib and poloxamer 188 in prescription amounts were sieved through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, and then slowly added to a preheated melt extruder, the extrudate was collected, pulverized and passed through a 60 mesh screen to give an olaparib solid dispersion. The prepared olaparib solid dispersion was mixed uniformly with the dissolution rate adjusting matrix polymer sodium alginate, and then added and mixed uniformly with a lubricant magnesium stearate, and compressed by direct pressing to give a sustained release tablet core with suitable hardness.

[0184] Coating of immediate release coat: According to the prescription of the immediate release coat, an immediate release coating solution was prepared, and the sustained release tablet cores were placed in a high-efficiency coating pan for coating the immediate release coat; finally, they were dried at 45 C. for 12 h to remove excess organic solvent and water so as to give the sustained release matrix type coated tablets.

[0185] The release degree was determined in the same manner as in Example 1, using a buffer of pH 6.8 as the release medium. The release curve is shown in FIG. 9.

Example 6 Capsules Containing Sustained Release Pellets, or Immediate and Sustained Double-Release Capsules Containing Immediate Release Pellets and Sustained Release Pellets

[0186] (1) Sustained Release Pellets

TABLE-US-00006 name dose I) Drug-loaded pellet cores Olaparib chloride 100 g microcrystalline cellulose blank pellet cores 400 g hydroxy propyl cellulose SSL 100 g 95% ethanol 400 ml II) Seal coating drug loaded pellet cores 600 g polyvidone (K30) 50 g 95% ethanol 200 ml III) Sustained release coat drug loaded pellet cores with seal coating 650 g Sure lease (aqueous dispersion) 200 ml water 200 ml

[0187] (2) Immediate Release Pellets

TABLE-US-00007 name dose olaparib chloride 25 g copolyvidone (VA64) 50 g microcrystalline cellulose blank pellet core 100 g 95% ethanol 300 ml

[0188] The preparation method was as follows.

[0189] Immediate release pellets: olaparib chloride and VA64 were dissolved or dispersed in a 95% ethanol solution so as to prepare a drug-loading solution, which was sprayed on a prescription amount of microcrystalline cellulose blank pellet cores by fluidized bed coating, to give immediate release pellets.

[0190] Sustained Release Pellets:

[0191] A release rate adjusting matrix hydroxypropyl cellulose SSL was weighed and dispersed in a 95% ethanol solution, so as to prepare a coating solution with a solid content of 10%, and stirred well on a magnetic stirrer;

[0192] A prescription amount of olaparib chloride was weighed and uniformly dispersed in the above coating solution, to be ready for being used as a drug-loading coating solution.

[0193] Microcrystalline cellulose blank pellet cores were added to a fluidized bed, and the operating parameters such as air volume and temperature were adjusted, the prepared drug-loading coating solution was sprayed to load the drug to give the drug-loaded pellet cores.

[0194] The component of the seal coating layer film was dissolved or dispersed in a 95% ethanol solution, and sprayed into a prescription amount of the drug-loaded pellet cores by fluidized bed coating to give a drug-loaded pellet cores with seal coating layer.

[0195] The aqueous dispersion of the sustained release coating solution was diluted with an appropriate amount of an aqueous solution, mixed well, and used as a coating solution for the sustained release coat film, which was sprayed onto the drug-loaded pellet cores with seal coating layer by fluidized bed coating so as to give sustained release pellets.

[0196] Capsule filling: The prepared sustained release pellets were encapsulated to prepare sustained release capsules.

[0197] The prepared immediate release pellets and sustained release pellets were thoroughly mixed in prescription amounts, and then filled into capsules to prepare immediate and sustained double-release capsules.

[0198] The release degree was determined in the same manner as that in Example 1, using a buffer of pH 6.8 as the release medium. The release curves of the sustained release capsules and the immediate and sustained double-release capsules were shown in FIG. 9, respectively.

Example 7 Sustained and Controlled Release Tablets Based on Sustained Release Pellets

[0199] (1) Sustained Release Pellets

TABLE-US-00008 name dose I) Drug-loaded pellet cores olaparib 100 g Sucrose blank pellet cores 400 g copolyvidone (VA64) 200 g 95% ethanol 400 ml II) Seal coating drug-loaded pellet core 700 g Hypromellose (E5) 50 g 95% ethanol 200 ml III) Sustained release coat drug-loaded pellet cores with seal coating 750 g Eudragit NE30D 150 g talc 5 g PEG 4000 15 g water 750 ml

[0200] The preparation method was as follows:

[0201] Drug-loaded pellet cores: Olaparib and VA64 were dissolved or dispersed in a 95% ethanol solution to be formulated into a drug-loading solution, which was sprayed into a prescription amount of sucrose blank pellet cores by fluidized bed coating, to give drug-loaded pellet cores.

[0202] Sustained Release Pellets:

[0203] The components of the seal coating layer film were dissolved or dispersed in a 95% ethanol solution, and sprayed onto a prescription amount of drug-loaded pellet cores by fluidized bed coating to give drug-loaded pellet cores with seal coating.

[0204] The aqueous dispersion of the sustained release coating solution was added with talc and an appropriate amount of an aqueous solution and mixed well to give a coating solution for the sustained release coat film, which was sprayed onto the drug-loaded pellets cores with seal coating by fluidized bed coating to give sustained release pellets.

[0205] Sustained and controlled release tablets: microcrystalline cellulose was added into ethanol to form pellets, which were evenly mixed with the sustained release pellets, and then added with silica or magnesium stearate, uniformly mixed and then tableted.

[0206] Immediate and sustained double-release tablets: the above-prepared immediate release pellets (drug loaded pellet cores) and sustained release pellets were thoroughly mixed in prescription amounts, and then added with silica or magnesium stearate, evenly mixed, and then tableted. The release degree was determined in the same manner as that in Example 1 by using a buffer of pH 6.8 as the release medium. The release curve is shown in FIG. 9.

Example 8 Sustained and Controlled Release Tablets Based on Sustained Release Pellets

[0207] 60 g of olaparib besylate, 140 g of microcrystalline cellulose, and 100 g of lactose were sieved and mixed through a 80 mesh screen, and then transferred into a wet granulator, whose parameters were adjusted. A 1 wt % aqueous solution of hypromellose E15 as a binder was added to prepare a soft material, which was then extruded and spheronized to prepare olaparib-containing pellets, wherein the extrusion screen had a pore size of 0.5 mm, the extrusion speed was 20 r/min, the spheronization speed was 1000 r/min, and the drying was performed at 40 C. on the fluidized bed. The 30 to 40 mesh drug-containing pellets were sieved to be ready for use.

[0208] The sieved olaparib pellets were placed in a fluidized bed, and coated with a prepared coating solution, to prepare olaparib sustained release pellets. The formulation of the coating solution: an acrylic resin 14.5%, a plasticizer triethyl citrate 5%, an anti-sticking agent talc 10.5% and water for balance.

[0209] 25 g of olaparib sustained release pellets, 5 g of drug-containing pellets, 12 g of microcrystalline cellulose, 16 g of lactose, 12 g of a 5 wt % pvpK30 solution, were weighed and pelletized through a 18 mesh screen, dried in a 40 C. oven, sieved through a 18 mesh screen, added with 0.6 g of stearic acid, mixed and tableted.

Example 9 Sustained and Controlled Release Capsule Base on Microtablets

[0210] Sustained Release Microtablets

TABLE-US-00009 name dose olaparib 8 g copolyvidone (PVP VA64) 22 g polyoxyethylene (N10) 5 g ethylcellulose (10cp) 2 g magnesium stearate 0.3 g.sup.

[0211] Immediate Release Microtablets

TABLE-US-00010 name dose olaparib 8 g copolyvidone (PVP VA64) 22 g Crosslinked polyvidone 3 g magnesium stearate 0.3 g.sup.

[0212] Sustained-release microtablets: Olaparib and copolyvidone VA64 were sieved through a 60 mesh screen for 3 times, and added into a ball grinder to be ground to give an olaparib co-grinding mixture with an average particle diameter of less than 30 Gin. The co-grinding mixture, a release rate adjusting matrix polymer polyoxyethylene and ethyl cellulose in prescription amounts were sieved through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, and then added with magnesium stearate and mixed for 5 min, then pressed to be microtablets having a diameter of 4 mm.

[0213] Immediate release microtablets: Olaparib and copolyvidone VA64 were sieved through a 60 mesh screen for 3 times, and added to a ball grinder to be ground to give an olaparib co-grinding mixture with an average particle diameter of less than 30 m. The co-grinding mixture and crosslinked polyvidone in prescription amounts were passed through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, then added with magnesium stearate and mixed for 5 min, then pressed to be microtablets having a diameter of 4 mm.

[0214] Capsule filling: The sustained release microtablets prepared above were filled into capsules to prepare sustained release capsules.

[0215] The prepared immediate release microtablets and the sustained release microtablets in prescription amounts were thoroughly mixed, and then filled into capsules to prepare immediate and sustained double-release capsules. The release degree was determined in the same manner as that in Example 1 by using a buffer of pH 6.8 as the release medium. The release curve is shown in FIG. 9.

Example 10 Sustained and Controlled Release Capsules Based on Microtablets

[0216] Sustained Release Microtablets

TABLE-US-00011 name dose olaparib 8 g 2-hydroxypropyl--cyclodextrin 30 g Carbomer 934 10 g sodium stearyl fumarate 0.3 g

[0217] Immediate Release Microtablets

TABLE-US-00012 name dose olaparib 8 g 2-hydroxypropyl--cyclodextrin 30 g lactose 8 g croscarmellose sodium 2 g sodium stearyl fumarate 0.3 g.sup.

[0218] Sustained release microtablets: Olaparib and 2-hydroxypropyl--cyclodextrin were sieved through a 60 mesh screen for 3 times, added with 100 ml of water, and sheared at a high speed to give a crude suspension, which was then homogenized in a high-pressure homogenizer to an average particle diameter of less than 1000 nm, and then the nanocrystal solution was lyophilized in a lyophilizer to remove moisture. The nanocrystalline powders were passed through a 60 mesh screen and sieved with a release rate adjusting matrix polymer carbomer 934 in prescription amounts through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, added with sodium stearyl fumarate and mixed for 5 min, and pressed into microtablets with a diameter of 3 mm.

[0219] Immediate release microtablets: Olaparib and 2-hydroxypropyl-1-cyclodextrin were sieved through a 60 mesh screen for 3 times, added with 100 ml of water, and sheared at a high speed to give a crude suspension, which was then homogenized in a high-pressure homogenizer to an average particle diameter of less than 1000 nm, and then the nanocrystal solution was lyophilized in a lyophilizer to remove moisture. The nanocrystalline powders were passed through a 60 mesh screen and sieved with lactose, croscarmellose sodium in prescription amounts through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, and then added with sodium stearyl fumarate and mixed for 5 min, and pressed into microtablets with a diameter of 3 mm.

[0220] Capsule filling: The sustained release microtablets prepared above were filled into capsules to prepare sustained release capsules.

[0221] The prepared immediate release microtablets and the sustained release microtablets in prescription amounts were thoroughly mixed, and then filled into capsules to prepare immediate and sustained double-release capsules.

Example 11 Single Layer Osmotic Pump Controlled Release Tablets

[0222]

TABLE-US-00013 Components of cores dose olaparib 50 g Hypromellose E5 150 polyvidone(K90) 52 g polyvidone (K30) 30 g Sodium chloride 100 g sodium dodecyl sulfate 5 g magnesium stearate 4 g

[0223] Olaparib and hypromellose E5 in prescription amounts were passed through a 60 mesh screen and mixed in a three-dimensional mixer at 30 rpm for 25 min, and then slowly added into a preheated melt extruder. The extrudate was collected and pulverized through a 60 mesh screen to give an olaparib solid dispersion. The olaparib solid dispersion prepared above was sieved through a 60 mesh screen with other excipients except magnesium stearate and uniformly mixed in a three-dimensional mixer, and then mixed with magnesium stearate for 5 min to give a drug layer composition to be ready for tableting.

[0224] The cores of the single layer osmotic pump tablets were prepared by directly pressing the above-described drug layer composition. The pressed cores were coated with a 4% cellulose acetate0.2% PEG4000 solution to be coated with a controlled release layer with weight increment of 5% to give the single-layer osmotic pump controlled release tablets. The release degree was determined in the same manner as that in Example 1 by using a buffer of pH 6.8 as the release medium. The release curve is shown in FIG. 9.

Comparative Example 1 Immediate Release Capsules

[0225] Preparation method: At 65 C., 10 wt % of olaparib was dispersed in Glucire 44/14, stirred for 12 h, and then filled into hypromellose capsules (0#) at about 60 C.

[0226] The dissolution degree was determined on the apparatus I of the dissolution test method (Chinese Pharmacopoeia 2010, second edition, appendix X, C). The measurements were operated following the method at 37 C., using 500 mL of Tris buffer of pH 6.8 as the release medium, at a rotary speed of 100 rpm, 6 mL of the solution was taken at 15, 30, 45, 60, 75, 90, 105, 120 min, and centrifuged, the supernatant was taken as the test solution to determine the release degree.

[0227] According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2010, second edition, appendix IV, A), the absorbance was measured at a wavelength of 278 nm, so as to measure the release degree of the capsule.

[0228] The release results were shown in FIG. 12. The active ingredient olaparib in the immediate release capsule was released more than 90% in about 45 min, and completely released within 2 h.

Experimental Example 1

[0229] The olaparib capsule of Comparative Example 1 (reference capsule) and the double-layer osmotic pump controlled release tablet of Example 1 (test tablet) were separately administered to fed beagle dogs (n=3) with 50 mL of water. 1 mL of the extremities venous blood was taken before administration (0 h) and 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12 and 24 h after administration of the capsule preparation, 1 mL of the extremities venous blood was taken before administration (0 h) and 1.0, 2.0, 4.0, 6.0, 8.0, 10, 12 and 24 h after administration of the double-layer osmotic pump controlled release tablets. The blood samples were centrifuged for 10 min at 4 C. under 4000 rpm, and then, the upper plasma was taken for the plasma concentration detection on LC-MS. The results were shown in FIG. 13.

[0230] Compared with T.sub.1/2 (2.6 h), C.sub.max (1590.1 ng/mL) and AUC.sub.0-h (7155.7 h*ng/mL) of the capsule preparation, the double-layer osmotic pump controlled release tablets have an extended T.sub.1/2 of 6.1 h with a prolongation of about 135%; a decreased C.sub.max of 922.9 ng/mL with a decrease of about 42%; and an AUC.sub.0-h of 7881.3 h*ng/mL with a change of <10%.

Experimental Example 2

[0231] 100 mg equivalent of the olaparib capsule of Comparative Example 1 (reference capsule) and the immediate and sustained double-release matrix type double-layer tablets of Example 4 (immediate and sustained double-release tablet) were respectively administered to fed beagle dogs (n=3) with 25 mL of water. Blood was taken at the scheduled time after administration, and the blood samples were centrifuged at 4 C. at 4000 rpm for 10 min, then the upper plasma was taken for the plasma concentration detection on LC-MS. The results were shown in FIG. 14.

[0232] Compared with the C.sub.max (4374.9 ng/mL), T.sub.1/2 (3.84 h) and AUC.sub.0-h (22570 h*ng/mL) of the capsule preparation, the immediate and sustained double-release matrix type double-layer tablets have a reduced C.sub.max of 2397.2 ng/mL with a decrease of about 45%; an extended T.sub.1/2 of 9.92 h with an increase of 158%; and an AUC.sub.0-h of 29110 h*ng/mL with a change of <30%. From the plasma concentration-time curve in FIG. 14, it can be seen that, compared with the immediate release capsule, the immediate and sustained double-release matrix type double-layer tablets can maintain a stable plasma concentration at high level for a long time, which is beneficial for performing the enzyme inhibition effect and anti-tumor effect, while providing a larger dose space for drug dose climbing and optimal drug performance.

Experimental Example 3

[0233] The olaparib capsule of Comparative Example 1 (reference capsule) and the immediate and sustained double-release double-layer osmotic pump tablet of Example 2 (immediate and sustained double-release preparation) were separately administered to fed beagle dogs (n=3) with 25 mL of water respectively. Blood was taken at the scheduled time after administration, and the blood samples were centrifuged at 4 C. at 4000 rpm for 10 min, then the upper plasma was taken for the plasma concentration detection on LC-MS. The results were shown in FIG. 15. PBMC were extracted from whole blood samples taken at 0 h, 0.5 h, 6 h, 10 h, 15 h, and 24 h, and PARP enzyme inhibition was detected by Trevigen HT PARP in vivo Pharmacodynamic Assay II kit. The results are shown in FIG. 16.

[0234] Compared with the C.sub.max (4576.3 ng/mL), T1/2 (3.42 h) and AUC.sub.0-h (25163 h*ng/mL) of the capsule preparation, the immediate and sustained double-release double-layer osmotic pump tablets have a reduced C.sub.max of 2154.2 ng/mL with a decrease of about 53%; an extended T.sub.1/2 of 12.96 h with an increase of 279%; and an AUC.sub.0-h of 32259 h*ng/mL. The enzyme inhibition of the immediate release capsules was less than 50% at 10 h, while the enzyme inhibition of the immediate and sustained double-release double-layer osmotic pump tablets was greater than 90% at 10 h, and the time of the enzyme inhibition level greater than IC90 was up to 10 h. From the plasma concentration-time curve in FIGS. 15 and 16, it can still be seen that, compared with the immediate release capsule, the immediate and sustained double-release double-layer osmotic pump tablets can maintain a stable plasma concentration at high level for a long time, which is beneficial for performing the enzyme inhibition effect and anti-tumor effect, while providing a larger dose space for drug dose climbing and optimal drug performance.