DISSOLUTION-ENHANCED OLAPARIB COMPOSITION

Abstract

Provided is a dissolution-enhanced olaparib composition, a preparation method therefor, a use thereof, and a medicament including the dissolution-enhanced olaparib composition. The dissolution-enhanced olaparib composition includes: olaparib; copovidone and a dissolution enhancer, wherein based on 100 parts by weight of olaparib, 100 or more and less than 200 parts by weight of copovidone, and 20 to 150 parts by weight of a dissolution enhancer. The dissolution-enhanced olaparib composition and the medicament prepared therefrom have controllable stability, increased oral absorption of the active ingredient, reduced excipient dosage, improved medication convenience, and are easy for industrial production.

Claims

1. A dissolution-enhanced olaparib composition, comprising: olaparib; copovidone and a dissolution enhancer; wherein, in the dissolution-enhanced olaparib composition, based on 100 parts by weight of olaparib, the copovidone is 100 or more and less than 200, and the dissolution enhancer is 20 to 150.

2. The dissolution-enhanced olaparib composition of claim 1, wherein the dissolution enhancer is selected from water-soluble cyclodextrin derivatives.

3. The dissolution-enhanced olaparib composition of claim 1, further comprising other pharmaceutical excipients selected from the group consisting of surfactants, glidants, lubricants, and plasticizers.

4. A method for preparing the dissolution-enhanced olaparib composition of claim 1, comprising mixing olaparib with copovidone, the dissolution enhancer and the optional other pharmaceutical excipients uniformly to obtain a uniform dispersion.

5. (canceled)

6. (canceled)

7. A dissolution-enhanced olaparib medicament, comprising the dissolution-enhanced olaparib composition of claim 1.

8. The dissolution-enhanced olaparib medicament of claim 7, further comprising other pharmaceutical excipient, wherein the other pharmaceutical excipient is one or more selected from the group consisting of lubricants, glidants, and coating agents.

9. The dissolution-enhanced olaparib medicament of claim 7, wherein the medicament is a preparation suitable for transmucosal administration to a patient.

10. A method for prevention or treatment of a tumor, comprising administering a subject in need thereof the dissolution-enhanced olaparib medicament of claim 7.

11. The dissolution-enhanced olaparib composition of claim 1, wherein, in the dissolution-enhanced olaparib composition, based on 100 parts by weight of olaparib, the copovidone is 150 to 195 parts by weight, and the dissolution enhancer is 25 to 120 parts by weight.

12. The dissolution-enhanced olaparib composition of claim 1, wherein the dissolution enhancer is one or a combination of two or more selected from methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, and hydroxypropyl-γ-cyclodextrin.

13. The dissolution-enhanced olaparib composition of claim 1, wherein the dissolution enhancer is hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, or a combination thereof.

14. The dissolution-enhanced olaparib composition of claim 3, wherein, the surfactant is one or more selected from sodium lauryl sulfate, docusate sodium, cetrimide, benzethonium chloride, cetylpyridinium chloride, lauric acid, polyoxyethylene alkyl ether, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, polyoxyl 40 stearate, octyl/decyl mono and diglycerides, polyoxyethylene stearate and poloxamer, the glidant is one or more selected from colloidal silica, animal or vegetable fats, and waxes, and the lubricant is one or more selected from polyethylene glycol, magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl mono/dibehenate, polyethylene glycol glyceryl behenate and glyceryl distearate.

15. The dissolution-enhanced olaparib composition of claim 3, wherein, based on 100 parts by weight of olaparib, the surfactant is 0 to 20 parts by weight, the glidant is 0 to 15 parts by weight, and the lubricant is 0 to 15 parts by weight.

16. The dissolution-enhanced olaparib composition of claim 3, wherein, based on 100 parts by weight of Olaparib, the surfactant is 0-10 parts by weight, the glidant is 0 to 10 parts by weight, and the lubricant is 0-10 parts by weight.

17. The dissolution-enhanced olaparib medicament of claim 9, wherein the preparation is a tablet.

18. The method of claim 10, wherein the tumor is selected from tumors with defective DNA repair function.

19. The method of claim 10, wherein the tumor is selected from cancers associated with two or more BRCA gene mutation.

20. The method of claim 10, wherein the tumor is selected from ovarian cancer, gastric cancer, breast cancer, and tumors associated with BRCA1 and BRCA2 gene mutations.

Description

DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1 shows in vitro dissolution curves (n=6) of various dissolution enhanced preparations prepared in Preparation Example 3, Comparative Example 1 and Comparative Example 2 of the present invention.

[0051] FIG. 2 shows in vitro dissolution curves (n=6) of various dissolution enhanced preparations prepared in Preparation Example 3 and Comparative Examples 3-7 of the present invention.

[0052] FIG. 3 shows in vitro dissolution curves (n=6) of various dissolution enhanced preparations prepared in Preparation Example 3, Comparative Example 3, Comparative Example 4 and Comparative Example 8 of the present invention at 0 month and 6 months under accelerated conditions.

[0053] FIG. 4 shows plasma concentration-time curves (n=3) of various dissolution enhanced preparations prepared according to Formulation 9 of Preparation Example 3, Comparative Example 1, and Comparative Example 3 of the present invention and commercially available tablets.

BEST MODE

[0054] The following examples generally record the preparation method and/or characterization results of typical compositions of the present invention, and all percentages are by weight, unless otherwise specified. The following examples are specific illustrations of the present invention, and should not be considered as limiting the scope of the present invention. In the following embodiments, the processes and methods that are not described in detail are conventional methods known in the art.

[0055] In the present invention, the sources and trade names of the reagents and equipment used are indicated at the first appearance, and unless otherwise specified, the same reagents used thereafter are the same as those indicated for the first time. Conventional unindicated reagents are purchased from Sinopharm Chemical Reagent Co., Ltd. Among them, olaparib refers to the free base API, which is provided by Shanghai Biobond Pharmaceutical Co., Ltd.

[0056] Experimental animals: 12 beagle dogs, which are half male and half female and weigh 8-10 kg, were purchased from Beijing Marshall Biotechnology Co., Ltd. The test animals were adaptively reared in the test site of the Experimental Animal Center of Shanghai Institute of Materia Medica for 14 days before the test day.

EXAMPLE

Preparation Example 1

[0057]

TABLE-US-00002 TABLE 1 Parts by weight Components Formulation 1 Formulation 2 Formulation 3 Formulation 4 Olaparib 84 105 81 96 Copovidone 162 145.5 144 120 sulfobutyl-β-cyclodextrin 45 / 66 / Hydroxypropyl-β-cyclodextrin / 43.5 / 75 Colloidal silica 3 4.5 6 3 Sodium Stearyl Fumarate / 1.5 3 / PEG6000 6 / / 6

[0058] Preparation method: Copovidone (PVP VA64, produced by BASF, Germany), the dissolution enhancer (sulfobutyl-β-cyclodextrin (produced by Cyclolab Ltd., Hungary), hydroxypropyl-β-cyclodextrin (produced by Roquette, France)), olaparib and colloidal silica (produced by Evonik Industries AG, Germany) were mixed and extruded with a twin-screw extruder (screw diameter 11 mm, Thermo Scientific company) to obtain a dissolution-enhanced olaparib composition.

[0059] The dissolution-enhanced olaparib composition prepared in this example was pulverized, added with other excipients according to the formulations in Table 1 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine. Among them, sodium stearyl fumarate is produced by JRS PHARMA GmbH & Co. KG, German, and PEG6000 is produced by Dow Chemical, USA.

Preparation Example 2

[0060]

TABLE-US-00003 TABLE 2 Parts by weight Components Formulation 5 Formulation 6 Formulation 7 Formulation 8 Olaparib 81 108 90 99 Copovidone 141 108 165 118.5 sulfobutyl-β-cyclodextrin 72 / 39 / Hydroxypropyl-β-cyclodextrin / 75 / 75 Colloidal silica 3 3 3 3 Sodium Stearyl Fumarate 3 / 3 / PEG6000 / 6 / 4.5

[0061] Preparation method: Copovidone (PVP VA64, produced by BASF, Germany), the dissolution enhancer (sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin) and olaparib were dissolved in a solvent of methanol/acetone =1:4, evaporated to remove the solvent to obtain a dissolution-enhanced olaparib composition.

[0062] The dissolution-enhanced olaparib composition prepared in this example was pulverized, added with other excipients according to the formulations in Table 2 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Preparation Example 3

[0063]

TABLE-US-00004 TABLE 3 Parts by weight Components Formulation 9 Formulation 10 Formulation 11 Formulation 12 olaparib 90 96 99 81 Copovidone 160.5 127.5 105 144 Hydroxypropyl-β-cyclodextrin 45 64.5 81 52.5 Colloidal silica 3 3 3 6 labrasol / / / 9 sodium lauryl sulfate / 6 / / Span 20 / / 9 / Sodium Stearyl Fumarate 1.5 / 3 1.5 glyceryl behenate / 3 / / Opadry / / / 6

[0064] Among them, sodium lauryl sulfate is produced by BASF, Germany, glyceryl behenate and labrasol are produced by Gattefossé, France, and Span20 is produced by Nanjing Well Pharmaceutical co., LTD.

[0065] Preparation method: Copovidone, hydroxypropyl-β-cyclodextrin as the dissolution enhancer, olaparib, colloidal silica, labrasol, sodium lauryl sulfate and Span 20 were mixed and extruded with a twin-screw extruder to obtain a dissolution-enhanced olaparib composition.

[0066] The dissolution-enhanced olaparib composition prepared in this example was pulverized, added with other excipients (sodium stearyl fumarate and glyceryl behenate) according to the formulations in Table 3 and mixed well, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine. Among them, the tablets obtained from Formulation 12 were taken, placed in a coating pan and film-coated with Opadry (produced by Shanghai Colorcon Coating Technology Co., Ltd.). Among them, Formulation 9 was compressed into tablets which contain 150 mg, 200 mg or 250 mg of olaparib per tablet with the tablet weight of 500 mg, 667 mg and 883 mg, respectively.

Comparative Example 1

[0067]

TABLE-US-00005 TABLE 4 Components Parts by weight Olaparib 75 Copovidone 172.5 Colloidal silica 5.5 Mannitol 44 Sodium Stearyl Fumarate 3

[0068] Preparation method: Copovidone, olaparib and colloidal silica were mixed according to the formulation in Table 4, and then the powdery mixture was extruded with a twin-screw extruder to obtain a dissolution-enhanced olaparib composition.

[0069] The obtained dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 4 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Comparative Example 2

[0070]

TABLE-US-00006 TABLE 5 Components Parts by weight Olaparib 90 Copovidone 205 Colloidal silica 3 Sodium Stearyl Fumarate 1.5

[0071] Preparation method: Copovidone, olaparib and colloidal silica were mixed according to the formulation in Table 5, and then the powdery mixture was extruded with a twin-screw extruder to obtain a dissolution-enhanced olaparib composition.

[0072] The obtained dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 5 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Comparative Example 3

[0073]

TABLE-US-00007 TABLE 6 Components Parts by weight Olaparib 90 Povidone K25 160.5 Hydroxypropyl-β-cyclodextrin 45 Colloidal silica 3 Sodium Stearyl Fumarate 1.5

[0074] Preparation method: Povidone, olaparib and colloidal silica were dissolved in a solvent of methanol/acetone=1:4 according to the formulation in Table 6, and evaporated to remove the solvent to obtain a dissolution-enhanced olaparib composition.

[0075] The dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 6 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Comparative Example 4

[0076]

TABLE-US-00008 TABLE 7 Components Parts by weight Olaparib 90 Hydroxypropyl-β-cyclodextrin 205.5 Colloidal silica 3 Sodium Stearyl Fumarate 1.5

[0077] Preparation method 1: Hydroxypropyl-β-cyclodextrin, olaparib and colloidal silica were mixed according to the formulation in Table 7, and then the powdery mixture was extruded with a twin-screw extruder. It was observed that the extrudate was whitish and opaque even when the temperature was higher than 230° C., and further increased temperature may deteriorate the stability of the drug and consume large energy, indicating that the formulation is not suitable for melt extrusion.

[0078] Preparation method 2: Hydroxypropyl-β-cyclodextrin and olaparib were dissolved in a solvent of methanol/acetone=1:4 according to the formulation in Table 7, and then evaporated to remove the solvent to obtain a dissolution-enhanced olaparib composition.

[0079] The dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 7 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Comparative Example 5

[0080]

TABLE-US-00009 TABLE 8 Components Parts by weight Olaparib 90 Copovidone 190.5 SDS 15 Colloidal silica 3 Sodium Stearyl Fumarate 1.5

[0081] Preparation method: Copovidone, olaparib and sodium lauryl sulfate were dissolved in a solvent of methanol/acetone=1:4 according to the formulation in Table 8, and then evaporated to remove the solvent to obtain a dissolution-enhanced olaparib composition.

[0082] The dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 8 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Comparative Example 6

[0083]

TABLE-US-00010 TABLE 9 Components Parts by weight Olaparib 90 Copovidone 160.5 HPMC E5 45 Colloidal silica 3 Sodium Stearyl Fumarate 1.5

[0084] Preparation method: Copovidone, HPMC E5 (produced by Dow Chemical) and olaparib were dissolved in a solvent of methanol/acetone=1:4 according to the formulation in Table 9, and then evaporated to remove the solvent to obtain a dissolution-enhanced olaparib composition (it had to be prepared by the solvent method because the materials had significantly darkened color and degradation occurred when melt extrusion was performed at a temperature above 200° C.).

[0085] The dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 9 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Comparative Example 7

[0086]

TABLE-US-00011 TABLE 10 Components Parts by weight Olaparib 90 Hydroxypropyl-β-cyclodextrin 160.5 HPMCAS 45 Colloidal silica 3 Sodium Stearyl Fumarate 1.5

[0087] Preparation method: Hydroxypropyl-β-cyclodextrin, HPMCAS (produced by Shin-Etsu Chemical Co., Ltd., Japan) and olaparib were dissolved in a solvent of methanol/dichloromethane=1:1 according to the formulation in Table 10, and then evaporated to remove the solvent to obtain a dissolution-enhanced olaparib composition.

[0088] The dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 10 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Comparative Example 8

[0089]

TABLE-US-00012 TABLE 11 Components Parts by weight Olaparib 90 Copovidone 43.5 Hydroxypropyl-β-cyclodextrin 162 Colloidal silica 3 Sodium Stearyl Fumarate 1.5

[0090] Preparation method: Copovidone, olaparib and colloidal silica were mixed in a solvent of methanol/acetone=1:4 according to the formulation in Table 11, and then evaporated to remove the solvent to obtain a dissolution-enhanced olaparib composition.

[0091] The dissolution-enhanced olaparib composition was pulverized, added with other excipients according to the formulation in Table 11 and mixed uniformly, and compressed into tablets which contain 150 mg of olaparib per tablet by a single punch tablet machine.

Experimental Example

Experimental Example 1

Solubility Test

[0092] The dissolution-enhanced olaparib compositions prepared in Preparation Examples 1-3 and Comparative Examples 1-8 and the olaparib API (free base) were taken in an amount equivalent to 10 mg of olaparib, dispersed in 5 ml of a pH 4.0 buffer (citric acid: 21 g/L: disodium hydrogen phosphate 71.63 g/L=61.45:38.55) as the solvent and shaken in a shaker at 100 rpm for 2 h at 37° C., and sampled. The samples were centrifugal filtered and measured by HPLC to determine the supersaturated solubility. The average value was obtained from 2 parallel runs. The results are shown in Table 12.

[0093] The operation conditions of the HPLC were:

[0094] Apparatus: A liquid chromatograph with a UV detector;

[0095] Chromatographic Waters Sunfire C18, 4.6 mm*50 mm

[0096] column:

[0097] Eluent: A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile;

TABLE-US-00013 Time A % B % Gradient program: 0 75 25 3.0 55 45 3.5 0 100 4.0 0 100 7.0 75 25

[0098] Flow rate: 1 ml/min;

[0099] Temperature: 40° C.;

[0100] Wavelength: 276 nm;

[0101] Injection volume: 10 μl

TABLE-US-00014 TABLE 12 Test results of the supersaturated solubility of olaparib of the various formulations Supersaturated solubility at 37° C. for 2 h (μg/ml) Olaparib API Formulation 1 Formulation 2 Formulation 3 Formulation 4 118.0 879.0 884.2 929.1 920.0 Formulation 5 Formulation 6 Formulation 7 Formulation 8 Formulation 9 913.5 853.3 867.6 910.8 990.1 Formulation Formulation Formulation Comparative Comparative 10 11 12 Example 1 Example 2 952.5 933.3 1018.9 780.5 777.8 Comparative Comparative Comparative Comparative Comparative Example 3 Example 4 Example 5 Example 6 Example 7 825.5 1014.5 722.1 761.2 537.7 Comparative Example 8 1001.9

[0102] It can be seen from the results that:

[0103] (1) Compared with the API, the combination of copovidone and the water-soluble cyclodextrin derivative significantly improves the supersaturated solubility of olaparib;

[0104] (2) Compared with copovidone alone, the combination of copovidone and the water-soluble cyclodextrin derivative further improves the supersaturated solubility of olaparib (>850 μg/ml vs about 780 μg/ml);

[0105] (3) Compared with the combination of copovidone with SDS, a commonly used excipient with dissolution enhancing effect, or with HPMC E5 or HPMCAS, the commonly used excipients with solubilizing effect, the combination of copovidone and the water-soluble cyclodextrin derivative as the dissolution enhancer can further improve the supersaturated solubility of olaparib;

[0106] (4) Compared with the water-soluble cyclodextrin derivative alone, the combination of copovidone and the water-soluble cyclodextrin derivative has the equivalent effect on enhancing the dissolution of olaparib, but with better stability under the same dosage ratio of olaparib and excipients;

[0107] (5) Compared with the combination of povidone and the water-soluble cyclodextrin derivative, the combination of copovidone and the water-soluble cyclodextrin derivative has a better effect on improving the supersaturated solubility of olaparib (990.1 μg/ml vs 825.5 μg/ml).

Experimental Example 2

Dissolution Test

[0108] The dissolution behaviors of the preparations prepared in Preparation Examples 1-3 and Comparative Examples 1-7 were measured according to the following dissolution test method.

[0109] The dissolution of the obtained tablets (150 mg specification) was measured on the apparatus of the third method of the dissolution test method (Chinese Pharmacopoeia 2015, Volume IV, General Chapters, 0931). The operation was performed according to the method at 37° C. in 250 ml of a pH 4.0 buffer (citric acid 21 g/L: disodium hydrogen phosphate 71.63 g/L=61.45:38.55) as the release medium on a dissolution apparatus at 50 rpm. 2 ml of a solution was taken after 15, 30, 60, 90, 120, 180 min respectively, and centrifuged. The supernatant was diluted by one time with an acetonitrile-water (1:1) solution as the solvent to be used as the test solution, and the dissolution was determined by HPLC, and 6 runs were operated in parallel.

[0110] The operation conditions of the HPLC were:

[0111] Apparatus: A liquid chromatograph with a UV detector;

[0112] Chromatographic Waters Sunfire C18, 4.6 mm*50 mm

[0113] column:

[0114] Eluent: A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile;

TABLE-US-00015 Time A % B % Gradient program: 0 75 25 3.0 55 45 3.5 0 100 4.0 0 100 7.0 75 25

[0115] Flow rate: 1 ml/min;

[0116] Temperature: 40° C.;

[0117] Wavelength: 276 nm;

[0118] Injection volume: 10 μl

[0119] The results of dissolution determination are shown in FIGS. 1-2. The results show that:

[0120] (1) The dissolution in 60 min of olaparib in formulations 9-12 was greater than 80%, which is consistent with that of the formulation of Comparative Example 1 containing 14.7% of mannitol, indicating that olaparib in the tablets of the present invention can be effectively dissolved without addition of a filler and a disintegrant;

[0121] (2) For the solid dispersion prepared by using copovidone alone, olaparib cannot be effectively dissolved after the solid dispersion is prepared into tablets, if mannitol was not added into the formulation;

[0122] (3) The olaparib tablets (without addition of a disintegrant or a filler) prepared by using combination of povidone and the water-soluble cyclodextrin derivative as the dissolution enhancer, copovidone and SDS, copovidone and HPMC E5 or copovidone and HPMCAS, have significantly slower dissolution than the preparation prepared by using combination of copovidone and the water-soluble cyclodextrin derivative as the dissolution enhancer;

[0123] (4) The olaparib tablets prepared by using the water-soluble cyclodextrin derivative has a faster dissolution of olaparib in 60 min and a consistent dissolution of olaparib in 90 min compared with the preparation prepared by using combination of copovidone and the water-soluble cyclodextrin derivative.

Experimental Example 3

Stability Study

[0124] The solid olaparib preparations prepared in Preparation Example 3, Comparative Example 3, Comparative Example 4, and Comparative Example 8 of the present invention were placed under accelerated conditions at 40±2° C. and 75%±5% RH for 6 months, and the dissolution behavior (n=6) of the drug was determined following the conditions described in Experimental Example 1, and the dissolution curves were plotted (see FIG. 3).

[0125] It can be seen from the results that the solid olaparib preparations prepared in Preparation Example 3 of the present invention had significantly improved dissolution stability of olaparib, compared with the solid olaparib preparation of Comparative Example 3 prepared by using combination of povidone and the water-soluble cyclodextrin derivative, the solid olaparib preparation of Comparative Example 4 prepared by using the water-soluble cyclodextrin derivative alone, and the solid olaparib preparation of Comparative Example 8 prepared by using combination of copovidone and the water-soluble cyclodextrin derivative in a ratio that is not preferred in the present invention.

Experimental Example 4

Pharmacokinetic Studies

[0126] The preparation of Formulation 9 of Preparation Example 3, the commercially available tablets (150 mg specification, Lynparza®, produced by AbbVie, Germany), and the preparations of Comparative Examples 1 and 3 (150 mg specification) were respectively administered to fasted beagle dogs (n=3) with 50 mL of water separately. Blood was collected at 0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration. The blood sample was centrifuged at 4° C. at 4000 rpm for 10 min. The upper plasma was taken and used for plasma concentration detection by LC-MS. The results are shown in FIG. 4 and Table 13.

[0127] It can be seen from the plasma concentration-time curves of FIG. 4 and the results of Table 13 that, compared to the commercially available tablets, Comparative Example 1 (copovidone and mannitol) and Comparative Example 3 (povidone and the water-soluble cyclodextrin derivative), the preparation of the formulation 9 of Preparation Example 3 had a significantly improved AUC (the formulation 9 had an AUC which is higher by 25.9% than that of commercially available tablets, by 38.4% than that of Comparative Example 1, and by 156.7% than that of Comparative Example 3), the preparation of the formulation 9 does not need to add additional mannitol to promote the dissolution of olaparib, and the amount of excipients can be reduced by more than 100 mg compared with the commercially available tablets and Comparative Example 1, and the preparation of the formulations 9 is easy for the patient to swallow, and meanwhile, it provides a larger dose space for increasing the drug dose and exerting the best effect.

TABLE-US-00016 TABLE 13 Pharmacokinetic parameters in dogs after administration of various preparations (n =3) Relative Cmax AUC.sub.(0-24 h) bioavailability Preparation (μg/ml) (μg:h/ml) (%) Formulation 9, 15.93 ± 1.87 120.67 ± 8.65  125.9% Preparation Example 3 Commercial olaparib 14.35 ± 1.22 95.83 ± 6.73* 100.0% tablets Comparative Example 1 14.00 ± 1.20 87.22 ± 6.04* 91.0% Comparative Example 3  8.67 ± 1.32*  47.0 ± 3.91* 49.0% Remarks: *Compared with the Cmax and AUC of the formulation 9 of Preparation Example 3, P < 0.05 after statistically calculation.