Rapidly disintegrating solid oral dosage forms containing dasatinib

Abstract

The instant application relates to the field of pharmaceutical compositions comprising dasatinb. Furthermore, the instant application relates to a method of treating proliferative disorders in a patient in need thereof, comprising administering a therapeutically effective amount of said compositions.

Claims

1. A tablet for oral administration, comprising: dasatinib 1,2-propanediol solvate, dasatinib (R)-1,2 propanediol solvate, dasatinib (S)-1,2-propanediol solvate or a combination thereof; at least one pharmaceutically acceptable excipient; and a coating layer; wherein the tablet releases at least about 70% of the dasatinib within 20 minutes when the tablet is tested in a USP Type 2 in 500 mL of 0.01 M hydrochloric acid at about 370 C. and about 75 RPM.

2. The tablet of claim 1, comprising dasatinib 1,2-propanediol solvate.

3. The tablet of claim 1, comprising dasatinib (R)-1,2-propanediol solvate.

4. The tablet of claim 1, comprising dasatinib (S)-1,2-propanediol solvate.

5. The tablet of claim 1, wherein the amount of dasatinib is equivalent to 20, 50, 70, 80, 100, or 140 mg of dasatinib.

6. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one filler/binder selected from a group consisting of mannitol, microcrystalline cellulose, lactose, isomalt, or a mixture thereof.

7. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one filler/binder and the at least one filler/binder is present in an amount of from about 20% to about 90% by weight of the tablet.

8. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one filler/binder and the at least one filler/binder is present in an amount of from about 30% to about 80% by weight of the tablet.

9. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one disintegrant selected from a group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, or a mixture thereof.

10. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one disintegrant and the disintegrant is present in an amount of from about 0.5% to about 10% by weight of the tablet.

11. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one disintegrant and the disintegrant is present in an amount of from about 2% to about 10% by weight of the tablet.

12. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one glidant selected from a group consisting of anhydrous colloidal silica.

13. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one glidant and the glidant is present in an amount of from about 0% to about 5% by weight of the tablet.

14. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one glidant and the glidant is present in an amount of from about 1 to about 4% by weight of the tablet.

15. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one lubricant selected from a group consisting of sodium stearyl fumerate, magnesium stearate, or a mixture thereof.

16. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one lubricant and the lubricant is present in an amount of from about 0% to about 5% by weight.

17. The tablet of claim 1, wherein the at least one pharmaceutical acceptable excipient comprises at least one lubricant and the lubricant is present in an amount of from about 1% to about 4% by weight.

18. The tablet of claim 1, wherein the coating layer comprises glyceryl monostearate, hypromellose, poly(vinyl alcohol), polyethylene glycol, polysorbate 80, sodium laurylsulfate, talc, titanium dioxide, or a combination thereof.

19. The tablet of claim 1, wherein the coating layer is present in an amount of from about 1.9% to about 2.2% by weight of the tablet.

20. The tablet of claim 1, wherein the tablet exhibits (a) a 90% Confidence Interval for the ratio of the mean AUC (0-∞) which is between 73% and 125%; and (b) a 90% Confidence Interval for the ratio of the mean Cmax, which is between 77% and 125%; and wherein the ratio of the mean refers to an observable of the tablet for oral administration versus a reference listed drug comprising dasatinib monohydrate.

21. The tablet of claim 1, wherein the tablet exhibits (a) a 90% Confidence Interval for the ratio of the mean AUC (0-∞) which is between 73% and 125%; and (b) a 90% Confidence Interval for the ratio of the mean Cmax, which is between 77% and 125%; and wherein the ratio of the mean refers to an observable of the tablet for oral administration versus a reference listed drug comprising dasatinib monohydrate; and wherein the 90% Confidence Interval for the ratio of the mean AUC (0-∞) is established by excluding subjects with AUC (0-∞) less than 5% of the reference listed drug.

22. A method of treating a proliferative disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a composition according to claim 5; wherein said proliferative disorder in a patient is newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase; adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+CML with resistance or intolerance to prior therapy including imatinib; or adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 provides results of a dissolution test, a USP Type 2 in 0.01 M hydrochloric acid at about 37° C. and about 75 RPM, of tablets prepared in Examples 1 to 13.

(2) FIG. 2 displays the results showing comparable bioavailability between the test tablet A and the reference product, Sprycel® 100 mg.

(3) Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the disclosure as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description.

DETAILED DESCRIPTION

(4) In one aspect there is provided a tablet for oral administration, comprising dasatinib, such as dasatinib 1,2-propanediol solvate, dasatinib (R)-1,2-propanediol solvate, dasatinib (S)-1,2-propanediol solvate, or a combination thereof; and at least one pharmaceutically acceptable excipient;

(5) wherein the tablet exhibits at least one of the following characteristics:

(6) (a) a 90% Confidence Interval for the ratio of the mean AUC(0-∞) which is between 80% and 125%; and

(7) (b) a 90% Confidence Interval for the ratio of the mean Cmax, which is between 80% and 125%;

(8) (c) RSABE AUC criterion;

(9) (d) RSABE Cmax criterion and;

(10) (e) the tablet (coated or uncoated) releases at least 80% of the dasatinib within 20 minutes when the tablet is tested in a USP Type 2 in 0.1 M hydrochloric acid at about 37° C.;

(11) wherein the ratio of the mean refers to an observable of the tablet for oral administration vs. the reference listed drug (SPRYCEL® 100 mg).

(12) In one embodiment there is provided a tablet for oral administration, comprising dasatinib, such as dasatinib 1,2-propanediol solvate, dasatinib (R)-1,2-propanediol solvate, dasatinib (S)-1,2-propanediol solvate, or a combination thereof; and at least one pharmaceutically acceptable excipient;

(13) wherein the tablet (coated or uncoated) releases at least 80% of the dasatinib within 20 minutes when the tablet is tested in a USP Type 2 in 0.1 M hydrochloric acid at about 37° C.; and

(14) wherein the tablet exhibits at least one of the following characteristics:

(15) (a) a 90% Confidence Interval for the ratio of the mean AUC(0-∞) which is between 80% and 125%; and

(16) (b) a 90% Confidence Interval for the ratio of the mean Cmax, which is between 80% and 125%;

(17) (c) RSABE AUC criterion;

(18) (d) RSABE Cmax criterion and;

(19) wherein the ratio of the mean refers to an observable of the tablet for oral administration vs. the reference listed drug (SPRYCEL® 100 mg).

(20) In one embodiment the dasatinib is in the form of dasatinib 1,2-propanediol solvate.

(21) In one embodiment the dasatinib is in the form of dasatinib 1,2-propanediol solvate (R) or (S) enantiomer, or a mixture thereof.

(22) In one embodiment the dasatinib is in the form of dasatinib 1,2-propanediol solvate (S) enantiomer.

(23) Dasatinib 1,2-propanediol solvate is also referred to as dasatinib propylene glycol solvate.

(24) In one embodiment the dasatinib is administered to a human subject in a fasted state.

(25) In one embodiment the dasatinib is administered to a human subject in a non-fasted state.

(26) In one embodiment the bioequivalency is established by a 90% Confidence Interval for the ratio of the mean AUC(0-∞) which is between 80% and 125%.

(27) In one embodiment the bioequivalency is established by a mean for AUC(0-∞) which is between 80% and 125%.

(28) In one embodiment the bioequivalency is established by a 90% Confidence Interval for the ratio of the mean AUC(0-t) which is between 80% and 125%.

(29) In one embodiment the bioequivalency is established by a mean for AUC(0-t) which is between 80% and 125%.

(30) In one embodiment the bioequivalency is established by a 90% Confidence Interval for the ratio of the mean for Cmax, which is between 80% and 125%.

(31) In one embodiment the bioequivalency is established by a mean for Cmax, which is between 80% and 125%.

(32) In one embodiment the bioequivalency is established using the reference-scaled average bioeqvivalence (RSABE).

(33) In one embodiment the bioequivalency is established without excluding any subjects.

(34) In one embodiment the bioequivalency is established by excluding subjects with AUC (0-∞)<5% of the reference listed drug.

(35) In one embodiment the bioequivalency is established by excluding subjects with AUC (0-t)<5% of the reference listed drug.

(36) The dasatinib compositions of the present disclosure have unexpectedly dramatic dissolution profiles. Rapid dissolution of an administered active agent is preferable, as faster dissolution generally leads to faster onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of dasatinib it would be useful to increase the drug's dissolution so that it could attain a level close to 100%.

(37) The dasatinib compositions of the present disclosure preferably have a dissolution profile in which within about 5 minutes at least about 20% of the composition is dissolved. In other embodiments of the disclosure, at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of the dasatinib composition is dissolved within about 5 minutes. In other embodiments of the disclosure, preferably at least about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of the dasatinib composition is dissolved within about 10 minutes. In another embodiment of the disclosure, preferably at least about 70%, about 80%, about 90%, or about 100% of the dasatinib composition is dissolved within about 15 minutes. In another embodiment of the disclosure, preferably at least about 70%, about 80%, about 90%, or about 100% of the dasatinib composition is dissolved within about 20 minutes.

(38) Dissolution is preferably measured in a medium which is discriminating. Such a dissolution medium will produce two different dissolution curves for two products having different dissolution profiles in gastric juices; i.e., the dissolution medium is predictive of in vivo dissolution of a composition. An exemplary dissolution medium is an aqueous medium of 0.01 M hydrochloric acid at about 37° C., under so called USP Type 2 conditions i.e. a paddle speed of about 75 rpm in 500 mL. Determination of the amount dissolved can be carried out by any standard procedure recognized in the art.

(39) Pharmaceutical Excipients

(40) A pharmaceutical excipient is a substance formulated alongside the active ingredient of a medication, included for example for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred to as “bulking agents”, “fillers”, or “diluents”), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance concerned such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life.

(41) Fillers/Binders

(42) Fillers add bulk to tablets making small amounts active components easier to handle during the manufacturing process. Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength and give volume to low active dose tablets. Many pharmaceutical excipients have dual functionality and fillers and binders are thus often often treated as one group of pharmaceutical excipients, i.e. fillers/binders. Suitable fillers/binders are different grades of mannitol, microcrystalline cellulose, lactose, isomalt or mixtures thereof. Suitable amounts of fillers/binders are about 20-90% by weight, about 30-80% by weight, about 40-70% by weight, and about 50-60% by weight.

(43) Disintegrants

(44) Disintegrants swell, expand and/or dissolve when wet causing the tablet to break apart in the digestive tract, or in specific segments of the digestion process, releasing the active ingredients for absorption. Suitable disintegrants, such as croscarcellose sodium, crospovidone, and sodium starch glycolate, or mixtures thereof may be used. Suitable amounts of disintegrants are about 0.5-10% by weight, about 1-9% by weight, about 2-8% by weight, about 3-7% by weight, about 4-6% by weight, and about 5% by weight.

(45) Glidants

(46) Glidants are used to promote powder flow by reducing interparticle friction and cohesion. Glidants are often used in combination with lubricants as they have small ability to reduce die wall friction. Any conventional glidant, such as anhydrous colloidal silica may be used. Suitable amounts of glidants are about 0-5% by weight, about 1-4% by weight and about 2-3% by weight.

(47) Lubricants

(48) Lubricants prevent the clumping of active ingredients and prevent the sticking of materials to machines in the manufacturing process. Any conventional lubricant, such as sodium stearyl fumerate or magnesium stearate may be used. Suitable amounts of lubricants are about 0-5% by weight, about 1-4% by weight and about 2-3% by weight.

(49) Coatings

(50) Coatings protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. Any conventional coating material, such as different grades of Opadry may be used. Opadry is a mixture consisting of mainly hypromellose, macrogol 400 and Polysorbate 80. Any conventional coating method, like spraying may be used. Colors are sometimes added to improve the appearance of a tablet. Color consistency is important as it allows easy identification of a medication. Some coatings are therefore colored using Opadry Blue or Opadry White, wherein titanium dioxide is the white color agent.

(51) In another embodiment, there is provided a composition, for use in therapy.

(52) In another embodiment, there is provided a composition, for use in the treatment of proliferative disorders. Typically, said proliferative disorder is selected from tumors and cancers, including, but not limited to, neurofibromatosis, tuberous sclerosis, hemangiomas and lymphangiogenesis, cervical, anal and oral cancers, eye or ocular cancer, stomach cancer, colon cancer, bladder cancer, rectal cancer, liver cancer, pancreas cancer, lung cancer, breast cancer, cervix uteri cancer, corpus uteri cancer, ovary cancer, prostate cancer, testis cancer, renal cancer, brain cancer, cancer of the central nervous system, head and neck cancer, throat cancer, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, larynx cancer, lymphoma, multiple myeloma; cardiac hypertrophy, age-related macular degeneration and diabetic retinopathy.

(53) More typically said proliferative disorder is selected from newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase; adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+CML with resistance or intolerance to prior therapy including imatinib; adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy.

(54) In another embodiment of this aspect, there is provided a composition of, said composition is provided during food intake.

(55) In another aspect, there is provided a method of treating proliferative disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a composition according to the present disclosure. Said proliferative disorder is typically selected from tumors and cancers including, but not limited to, neurofibromatosis, tuberous sclerosis, hemangiomas and lymphangiogenesis, cervical, anal and oral cancers, eye or ocular cancer, stomach cancer, colon cancer, bladder cancer, rectal cancer, liver cancer, pancreas cancer, lung cancer, breast cancer, cervix uteri cancer, corpus uteri cancer, ovary cancer, prostate cancer, testis cancer, renal cancer, brain cancer, cancer of the central nervous system, head and neck cancer, throat cancer, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, larynx cancer, lymphoma, multiple myeloma; cardiac hypertrophy, age-related macular degeneration and diabetic retinopathy.

(56) Said proliferative disorder is more typically selected from newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase; adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+CML with resistance or intolerance to prior therapy including imatinib; adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy.

(57) The desired dose is conveniently presented in a single dose or as a divided dose administered at appropriate intervals, for example as two, three, four or more doses per day. Dependent on the need of the treatment and/or prevention, the desired dose may also be, for example, once every two days, once every three days, or even once a week.

(58) The composition is conveniently administered in unit dosage form; for example containing 20 to 140 mg, conveniently as 20, 50, 70, 80, 100, or 140 mg of active ingredient per unit dosage form.

(59) Pharmaceutical compositions include but are not limited to those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compositions may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Pharmaceutical compositions suitable for oral administration are conveniently presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active substance.

(60) Tablets for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art.

(61) The following examples are provided to illustrate various embodiments of the disclosure and shall not be considered as limiting in scope.

(62) By the phrase “reference listed drug” is meant the approved drug product Sprycel 100 mg to which new generic versions are compared to show that they are bioequivalent. By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart.

EXAMPLES

Example 1

(63) A tablet was prepared based on the following recipe and direct compression:

(64) TABLE-US-00002 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.00 propanediol solvate Mannitol (Roquette Filler/Binder 255.00 200 SD) Microcrystalline Filler/Binder 50.00 cellulose Croscarmellose Disintegrant 50.00 sodium Silica colloidal Glidant 10.00 anhydrous Sodium Stearyl Lubricant 20.00 fumerate Core tablet weight 500 Opadry white Cosmetic coat 10.00 Film coated tablet 510 weight

Example 2

(65) A tablet was prepared based on the following recipe and direct compression:

(66) TABLE-US-00003 Component Function mg/tablet Dasatinib 1,2- Drug substance 113.00 propanediol solvate Mannitol (Roquette Filler/Binder 280.60 200 SD) Microcrystalline Filler/Binder 48.00 cellulose Croscarmellose Disintegrant 9.60 sodium Silica colloidal Glidant 9.60 anhydrous Sodium Stearyl Lubricant 19.20 fumerate Core tablet weight 480 Opadry white Cosmetic coat 10.00 Film coated tablet 490 weight

Example 3

(67) A tablet was prepared based on the following recipe and direct compression:

(68) TABLE-US-00004 Component Function mg/tablet Dasatinib 1,2- Drug substance 113.00 propanediol solvate Mannitol (Roquette Filler/Binder 280.60 500 DC) Microcrystalline Filler/Binder 48.00 cellulose Croscarmellose Disintegrant 9.60 sodium Silica colloidal Glidant 9.60 anhydrous Sodium Stearyl Lubricant 19.20 fumerate Core tablet weight 480 Opadry white Cosmetic coat 10.00 Film coated tablet 490 weight

Example 4

(69) A tablet was prepared based on the following recipe and direct compression:

(70) TABLE-US-00005 Component Function mg/tablet Dasatinib 1,2- Drug substance 113.00 propanediol solvate Mannitol (Roquette Filler/Binder 164.30 200 SD) Microcrystalline Filler/Binder 164.30 cellulose Croscarmellose Disintegrant 9.60 sodium Silica colloidal Glidant 9.60 anhydrous Sodium Stearyl Lubricant 19.20 fumerate Core tablet weight 480 Opadry white Cosmetic coat 10.0 Film coated tablet 490 weight

Example 5

(71) A tablet was prepared based on the following recipe and direct compression:

(72) TABLE-US-00006 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60 propanediol solvate Mannitol (Roquette Filler/Binder 254.00 Pearlitol 200 SD) Microcrystalline Filler/Binder 44.00 cellulose Silica colloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet 450 weight

Example 6

(73) A tablet was prepared based on the following recipe and direct compression:

(74) TABLE-US-00007 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60 propanediol solvate Calcium Phosphate Filler/Binder 44.00 dibasic anhydrous Microcrystalline Filler/Binder 254.00 cellulose Silica colloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet 450 weight

Example 7

(75) A tablet was prepared based on the following recipe and direct compression:

(76) TABLE-US-00008 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60 propanediol solvate Isomalt Filler/Binder 44.00 Microcrystalline Filler/Binder 254.00 cellulose Silica colloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet 450 weight

Example 8

(77) A tablet was prepared based on the following recipe and direct compression:

(78) TABLE-US-00009 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60 propanediol solvate Isomalt Filler/Binder 254.00 Microcrystalline Filler/Binder 44.00 cellulose Silica colloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet 450 weight

Example 9

(79) A tablet was prepared based on the following recipe and direct compression:

(80) TABLE-US-00010 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60 propanediol solvate Isomalt Filler/Binder 245.20 Microcrystalline Filler/Binder 44.00 cellulose Croscarmellose Disintegrant 8.80 Silica colloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet 450 weight

Example 10

(81) A tablet was prepared based on the following recipe and direct compression:

(82) TABLE-US-00011 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60 propanediol solvate Isomalt Filler/Binder 125.90 Mannitol (Pearlitol 200 Filler/Binder 125.90 SD) Microcrystalline Filler/Binder 44.00 cellulose Croscarmellose Disintegrant 2.20 Silica colloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet 450 weight

Example 11

(83) A tablet was prepared based on the following recipe and direct compression:

(84) TABLE-US-00012 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.60 propanediol solvate Isomalt Filler/Binder 125.90 Mannitol (Pearlitol 200 Filler/Binder 125.90 SD) Microcrystalline Filler/Binder 44.00 cellulose Croscarmellose Disintegrant 2.20 Silica colloidal Glidant 8.80 anhydrous Sodium Stearyl Lubricant 17.60 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.00 Film coated tablet 450 weight

Example 12

(85) A tablet was prepared based on the following recipe and direct compression:

(86) TABLE-US-00013 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.6 propanediol solvate Mannitol (Pearlitol 200 Filler/Binder 72.0 SD) Mannitol (Pearlitol 300 Filler/Binder 72.0 DC) Isomalt Filler/Binder 96.8 Microcrystalline Filler/Binder 44.0 cellulose Croscarmellose Disintegrant 13.2 sodium Silica colloidal Glidant 8.8 anhydrous Sodium Stearyl Lubricant 17.6 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.0 Film coated tablet 450 weight

Example 13

(87) A tablet was prepared based on the following recipe and direct compression:

(88) TABLE-US-00014 Component Function mg/tablet Dasatinib 1,2- Drug substance 115.6 propanediol solvate Mannitol (Pearlitol 200 Filler/Binder 77.0 SD) Mannitol (Pearlitol 300 Filler/Binder 77.0 DC) Isomalt Filler/Binder 100.0 Microcrystalline Filler/Binder 44.0 cellulose Silica colloidal Glidant 8.8 anhydrous Sodium Stearyl Lubricant 17.6 fumerate Core tablet weight 440 Opadry white Cosmetic coat 10.0 Film coated tablet 450 weight

(89) The tablets prepared above (non-coated) were subjected to a dissolution test, a USP Type 2 in 0.01 M hydrochloric acid at about 37° C. and about 75 RPM, or as per Ph. Eur. 2.9.3. apparatus II (paddles), and the results are shown in FIG. 1. The results are representative for the present disclosure.

Example 14

(90) Tablets of Example 12 and 13 were manufactured using the following process

(91) The mannitol (Pearlitol 200 SD), mannitol (Pearlitol 300 DC), isomalt, microcrystalline cellulose, croscarmellose sodium and aerosil 200 were transferred to a suitably sized mixing vessel and blended. The resulting excipient blend mixture was then screened. The active component, dasatinib 1,2-propanediol solvate, was screened and added to the blend mixture in a suitably sized mixing vessel and blended. Sodium stearyl fumarate was screened and added to the blend mixture. This was then blended. The Dasatinib 1,2-propanediol solvate tablet blend was compressed into tablets. The resultant tablets were then coated with an aqueous film coating (Opadry® White 03B28796 and sterile water for irrigation mixture).

Example 15

(92) Tablets prepared according to Example 12 using the process of Example 14 were used in a single centre, open-label, randomised, single dose, 3-way crossover comparative PK study in healthy male subjects.

(93) Each subject received the following regimens:

(94) TABLE-US-00015 Route of Period Regimen Product Dose Administration A Tablet A 100 mg Oral, Fasted A Tablet A 100 mg Oral, Fed

(95) Plasma concentration data was tabulated and plotted for each subject for whom concentrations are quantifiable. PK analysis of the concentration time data obtained was performed using appropriate non-compartmental techniques to obtain estimates of the following PK parameters, where possible: Tlag: Time prior to the first measurable (non-zero) concentration Tmax: Time of maximum observed concentration Cmax: Maximum observed concentration C24: Plasma concentration at 24 h AUC(0-last): Area under the curve from 0 time to the last measurable concentration AUC(0-24): Area under the curve from 0 time to 24 h post-dose AUC(0-inf): Area under the curve from 0 time extrapolated to infinity Frel: Relative bioavailability λz: Slope of the apparent elimination phase T½: Apparent elimination half-life MRT: mean residence time
Results

(96) TABLE-US-00016 Variable Product Mean Median Min Max CV % Cmax A fasted 89 80 28 169 47 A fed 100 85 36 214 49 AUCinf A fasted 342 331 146 588 33 A fed 413 390 301 732 29

(97) The PK variables Cmax, AUC(0-24) and AUC(0-∞) of the test formulation A in the fasted state were compared to the historical PK data of the reference drug, Sprycel, obtained from the previous BA/BE studies. FIG. 2 displays the results showing comparable bioavailability between the test tablet A and the reference product, Sprycel® 100 mg.

(98) TABLE-US-00017 Dependent FormRef Test Ratio_% Ref.sub.— CI_90_Lower CI_90_Upper Ln(AUCinf) Sprycel A fasted 93 73 119 Ln(Cmax) Sprycel A fasted 97 77 121

(99) The subject matter of U.S. Provisional Application Nos. 62/849,256 and 62/909,913 is incorporated by reference in its entirety.

(100) The references described herein are incorporated by reference in their entirety to the extent necessary. In the event that there is a difference in meaning between the incorporated terms and the terms disclosed herein and the terms of the related application, the meaning of the terms disclosed herein and the related application will control.

(101) The subject matter of each of U.S. patent application Ser. No. 16/700,310, filed Dec. 2, 2019; U.S. Provisional Application No. 62/849,256, filed on May 17, 2019; and U.S. Provisional Application No. 62/909,913, filed on Oct. 3, 2019 is incorporated by reference in its entirety.

(102) Those skilled in the art will also appreciate that various adaptations and modifications of the preferred and alternative embodiments described above can be configured without departing from the scope and spirit of the disclosure. Therefore, it is to be understood that, within the scope of the appended claims, the disclosure may be practiced other than as specifically described herein.