CN116916895A - Taraxazopanib soft gelatin capsule dosage form - Google Patents

Taraxazopanib soft gelatin capsule dosage form Download PDF

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Publication number
CN116916895A
CN116916895A CN202180090259.8A CN202180090259A CN116916895A CN 116916895 A CN116916895 A CN 116916895A CN 202180090259 A CN202180090259 A CN 202180090259A CN 116916895 A CN116916895 A CN 116916895A
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China
Prior art keywords
capsule
soft gelatin
dosage form
gelatin
pharmaceutical
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CN202180090259.8A
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Chinese (zh)
Inventor
A·F·卡莫迪
L·C·S·派雷特
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Pfizer Inc
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Pfizer Inc
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Priority claimed from PCT/IB2021/060462 external-priority patent/WO2022101828A1/en
Publication of CN116916895A publication Critical patent/CN116916895A/en
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Abstract

A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein: (a) The soft gelatin shell comprises gelatin and at least one plasticizer; and (b) the filler comprises an antioxidant, at least one solvent, and talazapanib or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is used for treating cancer.

Description

Taraxazopanib soft gelatin capsule dosage form
Technical Field
The present invention relates to soft gelatin capsule dosage forms of talazopanib or a pharmaceutically acceptable salt thereof. In particular, the invention relates to soft gelatin capsule dosage forms of talazapanib tosylate. The invention also relates to methods of treatment using the soft gelatin capsule dosage forms of the invention.
Background
Poly (ADP-ribose) polymerase (PARP) is involved in the DNA repair process that occurs naturally in cells. PARP inhibition has been demonstrated to be an effective therapeutic strategy against tumors associated with mutations in the germ line of double-stranded DNA repair genes by induction of synthetic lethality (Sonnenblick, a., et al, nat. Rev. Clin. Oncol,2015,12 (1), 27-4).
Taraxazopanib is a potent oral small molecule PARP inhibitor that is cytotoxic to human cancer cell lines containing genetic mutations that impair deoxyribonucleic acid (DNA) repair, an effect known as synthetic lethality, and prevents DNA repair, replication and transcription by capturing PARP protein on the DNA.
The compounds talazapanib being "(8S, 9R) -5-fluoro-8- (4-fluorophenyl) -9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -8, 9-dihydro-2H-pyrido [4,3,2-de ] phthalazin-3 (7H) -one" and "(8S, 9R) -5-fluoro-8- (4-fluorophenyl) -9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-3-one" (also known as "PF-06944076", "MDV3800" and "BMN 673") are PARP inhibitors having the following structure,
tarazopanib and pharmaceutically acceptable salts thereof, including tosylate, are disclosed in international publication nos. WO 2010/017055 and WO 2012/054698. Other methods of preparing talazapanib and pharmaceutically acceptable salts thereof (including tosylate salts) are described in International publication Nos. WO 2011/097602, WO 2015/069851 and WO 2016/019125. Other methods of treating cancer using talazapanib and pharmaceutically acceptable salts thereof (including tosylate salt) are disclosed in international publication nos. WO 2011/097334 and WO 2017/075091.
(tazopanib) (0.25 mg and 1mg capsules) has been approved in a number of countries, including the united states and the european union, and has been approved or under scrutiny in other countries, it is expected that approval will be obtained for the treatment of adult patients with harmful or suspected harmful gbracam HER 2-negative locally advanced or metastatic breast cancer. Taraxazopanib is being developed as a single drug and for use in combination with other drugs for a variety of human cancers. Other capsule concentrations are 0.5mg and 0.75mg, which have been approved in the united states (see, e.g.) >US Package Insert,2021, 9).
The currently marketed dosage form of talazapanib is an immediate release capsule (see, e.g.US Package Insert, month 10 of 2020). The medicine product consists of tazopanib tosylate bulk drug, the bulk drug is prepared by succinimidyl-4-N-maleimide methyl cyclohexane-1-carboxylate (), and is filled into hydroxypropyl methylcellulose (HPMC) capsules. Typically, such dosage forms are known in the art as powder filled capsules. />Recommended dosage of (2) is1mg, taken orally once a day, with or without feeding. The discontinuation of the administration or the reduction of the dose of tazopanib to 0.75mg, 0.5mg or 0.25mg was allowed once daily to control adverse events when using 0.25mg commercial capsules. Such dosage forms are powder filled capsules containing 0.25mg or 1mg of talazapanib, which are considered in the pharmaceutical sciences as low dose and low drug load formulations. By "low dose" formulation is meant that there is a small amount of active agent in the formulation. "drug loading" is a term known in the pharmaceutical arts and is the ratio of the amount of active drug to the total content of the dosage form. Thus, a "low drug load" formulation refers to a formulation having a small amount of active drug compared to the total content of the dosage form.
Challenges in preparing low dose/low drug load formulations are generally known in the pharmaceutical sciences (gullapelli, R.P., J.Pharm.Sci., october 2010,99 (10), 4107-4148). Formulations comprising simple binary mixtures of drug substances and excipients are known, e.g(talazapanib) 0.25mg and 1mg capsules are susceptible to the following challenges: 1) In various manufacturing processes, the bulk drug is unevenly distributed throughout the powder mixture; 2) Separation of the powder mixture in various manufacturing steps; and 3) loss of efficacy due to entrainment of the drug substance into the manufacturing equipment during the various manufacturing steps.
Furthermore, for low drug load formulations, batch dependence is often observed. As the lot size increases, maintaining potency and content uniformity becomes more challenging.
Thus, there is a need for a tazopanib product, i.eAn alternative formulation was developed. It would be advantageous to provide a dosage form that delivers a low dose of talazapanib or a pharmaceutically acceptable salt thereof with suitable content uniformity and suitable physical and chemical stability. Furthermore, it would be advantageous to provide a pharmaceutical dosage form bioequivalent to the first approved commercial dosage form of talazapirib, i.e. an immediate release capsule comprising talazapirib tosylate . It would also be advantageous to provide such pharmaceutical dosage forms that have a suitable food effect on pharmacokinetics when administered with or without food. Furthermore, it would be advantageous to provide such a pharmaceutical dosage form which contributes to greater flexibility in mass production. These and other advantages of the present invention will be apparent from the description that follows.
Disclosure of Invention
Each of the embodiments of the invention described below may be combined with one or more other embodiments of the invention described herein, which embodiments are inconsistent with one or more of the embodiments of the invention combined therewith. Furthermore, each of the embodiments of the invention described below contemplate within its scope pharmaceutically acceptable salts of the compounds of the invention.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein:
(a) The soft gelatin shell comprises gelatin and at least one plasticizer; and
(b) The filler comprises an antioxidant, at least one solvent, and talazapanib or a pharmaceutically acceptable salt thereof.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is a acid skin gelatin (acid hide gelatin) or an acid bone gelatin acid bone gelatin); the gelatin is acid skin gelatin; or the gelatin is an acid bone gelatin.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein:
(a) The soft gelatin shell comprises acid bone gelatin and at least one plasticizer; and
(b) The filler comprises an antioxidant, at least one solvent, and talazapanib or a pharmaceutically acceptable salt thereof.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin has a gel strength (Bloom strength) of 175-200 Bloom.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin has a gel strength of 195 Bloom.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is a) glycerol; b) Sorbitol; or c) glycerol and sorbitol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is one plasticizer or two plasticizers; the at least one plasticizer is a plasticizer; or the at least one plasticizer is two plasticizers.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is a plasticizer which is glycerol or sorbitol; or the at least one plasticizer is two plasticizers, which are glycerin and sorbitol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is a plasticizer which is glycerol or sorbitol; and further wherein the glycerol is 85% glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is both glycerol and sorbitol plasticizers; and wherein the glycerol is 85% glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is a plasticizer which is glycerol or sorbitol; and further wherein the sorbitol is an anhydrified liquid sorbitol NF.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is both glycerol and sorbitol plasticizers; and further wherein the sorbitol is an anhydrified liquid sorbitol NF.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is a plasticizer which is glycerol or sorbitol; wherein further the glycerol is 85% glycerol; wherein the sorbitol is an anhydrified liquid sorbitol NF.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one plasticizer is both glycerol and sorbitol plasticizers; wherein the glycerol is 85% glycerol; wherein the sorbitol is an anhydrified liquid sorbitol NF.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the antioxidant is tocopherol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the tocopherol is all-rac-alpha-tocopherol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is a) polyethylene glycol; b) Glycerol; or c) polyethylene glycol and glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is one solvent or two solvents; the at least one solvent is a solvent; and the at least one solvent is two solvents.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is a solvent which is polyethylene glycol or glycerol; or the at least one solvent is both polyethylene glycol and glycerin.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is a solvent which is polyethylene glycol or glycerol; and further wherein the polyethylene glycol is polyethylene glycol 400.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is both polyethylene glycol and glycerol; wherein the polyethylene glycol is polyethylene glycol 400.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is a solvent which is polyethylene glycol or glycerol; wherein the glycerol is 85% glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is both polyethylene glycol and glycerol; wherein the glycerol is 85% glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is a solvent which is polyethylene glycol or glycerol; wherein the polyethylene glycol is polyethylene glycol 400; and wherein the glycerol is 85% glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the at least one solvent is both polyethylene glycol and glycerol; wherein the polyethylene glycol is polyethylene glycol 400; and wherein the glycerol is 85% glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is acid skin gelatin and the antioxidant is tocopherol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is acid skin gelatin and the tocopherol is all-rac-alpha-tocopherol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is an acid bone gelatin and the antioxidant is tocopherol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is an acid bone gelatin and the tocopherol is all-rac-alpha-tocopherol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is acid skin gelatin; the at least one plasticizer is a plasticizer which is glycerin or sorbitol; the antioxidant is tocopherol; and the at least one solvent is a solvent which is polyethylene glycol or glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is acid skin gelatin; the at least one plasticizer is both glycerol and sorbitol plasticizers; the antioxidant is tocopherol; and the at least one solvent is two solvents of polyethylene glycol and glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is acid skin gelatin; the at least one plasticizer is a plasticizer which is glycerin or sorbitol; the tocopherol is all-racemic alpha-tocopherol; and the at least one solvent is a solvent which is polyethylene glycol or glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is acid skin gelatin; the at least one plasticizer is both glycerol and sorbitol plasticizers; the tocopherol is all-racemic alpha-tocopherol; and the at least one solvent is two solvents of polyethylene glycol and glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is an acid bone gelatin; the at least one plasticizer is a plasticizer which is glycerin or sorbitol; the antioxidant is tocopherol; and the at least one solvent is a solvent which is polyethylene glycol or glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is an acid bone gelatin; the at least one plasticizer is both glycerol and sorbitol plasticizers; the antioxidant is tocopherol; and the at least one solvent is two solvents of polyethylene glycol and glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is an acid bone gelatin; the at least one plasticizer is a plasticizer which is glycerin or sorbitol; the tocopherol is all-racemic alpha-tocopherol; and the at least one solvent is a solvent which is polyethylene glycol or glycerol.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is an acid bone gelatin; the at least one plasticizer is both glycerol and sorbitol plasticizers; the tocopherol is all-racemic alpha-tocopherol; and the at least one solvent is two solvents of polyethylene glycol and glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form comprises talazapiride or a pharmaceutically acceptable salt thereof in an amount equivalent to about 0.1mg of talazapiride free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form comprises talazapiride or a pharmaceutically acceptable salt thereof in an amount equivalent to about 0.25mg of talazapiride free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form comprises talazapiride or a pharmaceutically acceptable salt thereof in an amount equivalent to about 0.35mg of talazapiride free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form comprises talazapiride or a pharmaceutically acceptable salt thereof in an amount equivalent to about 0.5mg of talazapiride free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form comprises talazapiride or a pharmaceutically acceptable salt thereof in an amount equivalent to about 0.75mg of talazapiride free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form comprises talazapanib or a pharmaceutically acceptable salt thereof in an amount equivalent to about 1mg of talazapanib free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the tazopanib or a pharmaceutically acceptable salt thereof is tazopanib tosylate.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form is for oral administration.
The invention also relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 60% to about 61% by weight gelatin,
about 15% to about 16% by weight of glycerin, and
About 23% sorbitol; and is also provided with
Wherein the filler comprises:
about 0.3% by weight of tocopherol,
about 95% by weight of polyethylene glycol,
about 4% by weight of glycerin, and
tarazopanib or a pharmaceutically acceptable salt thereof, having a free base equivalent (free base equivalent) of about 0.15% to about 0.3% by weight.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is a acid skin gelatin or an acid bone gelatin; the gelatin is acid skin gelatin; or the gelatin is an acid bone gelatin.
The invention also relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 60% to about 61% by weight of an acid bone gelatin,
about 15% to about 16% by weight of glycerin, and
about 23% sorbitol; and is also provided with
Wherein the filler comprises:
about 0.3% by weight of tocopherol,
about 95% by weight of polyethylene glycol,
about 4% by weight of glycerin, and
tarazopanib or a pharmaceutically acceptable salt thereof, having a free base equivalent weight of about 0.15% to about 0.3% by weight.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin has a gel strength of 175-200 Bloom.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin has a gel strength of 195 Bloom.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the glycerol is 85% glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the sorbitol is an anhydrified liquid sorbitol NF.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the tocopherol is all-rac-alpha-tocopherol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the polyethylene glycol is polyethylene glycol 400.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the amount of talazapirib or a pharmaceutically acceptable salt thereof corresponds to about 0.1mg of talazapirib free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the amount of talazapirib or a pharmaceutically acceptable salt thereof corresponds to about 0.25mg of talazapirib free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the amount of talazapirib or a pharmaceutically acceptable salt thereof corresponds to about 0.35mg of talazapirib free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the amount of talazapirib or a pharmaceutically acceptable salt thereof corresponds to about 0.5mg of talazapirib free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the amount of talazapirib or a pharmaceutically acceptable salt thereof corresponds to about 0.75mg of talazapirib free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the amount of talazapirib or a pharmaceutically acceptable salt thereof corresponds to about 1mg of talazapirib free base.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 46.3 mg/capsule of gelatin,
glycerin at about 11.8 mg/capsule, and
about 17.6 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.3 mg/capsule of tocopherol,
about 95.6 mg/capsule of polyethylene glycol,
glycerin at about 4 mg/capsule, and
about 0.1mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
About 46.270 mg/capsule of gelatin,
about 11.790 mg/capsule of glycerin, and
about 17.57 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.300 mg/capsule of tocopherol,
about 95.555 mg/capsule of polyethylene glycol,
about 4.000 mg/capsule of glycerin, and
about 0.1mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 61.1mg of gelatin per capsule,
about 16.6 mg/capsule of glycerin, and
about 23.2 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.4 mg/capsule of tocopherol,
about 119 mg/capsule of polyethylene glycol,
about 5 mg/capsule of glycerin, and
about 0.25mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 61.097 mg/capsule of gelatin,
about 16.610 mg/capsule of glycerin, and
about 23.190 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.375 mg/capsule of tocopherol,
about 119.262 mg/capsule of polyethylene glycol,
About 5.000 mg/capsule of glycerin, and
about 0.25mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 78 mg/capsule of gelatin,
about 20 mg/capsule of glycerin, and
about 30 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.5 mg/capsule of tocopherol,
about 167 mg/capsule of polyethylene glycol,
glycerin at about 7 mg/capsule, and
about 0.35mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 78.130 mg/capsule of gelatin,
about 20.250 mg/capsule of glycerin, and
about 29.66 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.509 mg/capsule of tocopherol,
about 166.966 mg/capsule of polyethylene glycol,
about 7.000 mg/capsule of glycerin, and
about 0.35mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
About 105 mg/capsule of gelatin,
about 27 mg/capsule of glycerin, and
about 40 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.8 mg/capsule of tocopherol,
about 239 mg/capsule of polyethylene glycol,
about 10 mg/capsule of glycerin, and
about 0.5mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 104.930 mg/capsule of gelatin,
about 26.640 mg/capsule of glycerin, and
about 39.830 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 00.750 mg/capsule of tocopherol,
about 238.523 mg/capsule of polyethylene glycol,
about 10.000 mg/capsule of glycerin, and
about 0.5mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 141 mg/capsule of gelatin,
glycerin at about 36 mg/capsule, and
about 54 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 1 mg/capsule of tocopherol,
about 358 mg/capsule of polyethylene glycol,
glycerin at about 15 mg/capsule, and
About 0.75mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 141.260 mg/capsule of gelatin,
about 36.000 mg/capsule of glycerin, and
about 53.620 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 1.125 mg/capsule of tocopherol,
about 357.784 mg/capsule of polyethylene glycol,
about 15.000 mg/capsule of glycerin, and
about 0.75mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 178 mg/capsule of gelatin,
about 45 mg/capsule of glycerin, and
sorbitol at about 67 mg/capsule; and is also provided with
Wherein the filler comprises:
about 1.5 mg/capsule of tocopherol,
about 477 mg/capsule of polyethylene glycol,
about 20 mg/capsule of glycerin, and
about 1mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 177.790 mg/capsule of gelatin,
About 45.310 mg/capsule of glycerin, and
about 67.490 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 1.453 mg/capsule of tocopherol,
about 477.047 mg/capsule of polyethylene glycol,
about 20.000 mg/capsule of glycerin, and
about 1mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin is a acid skin gelatin or an acid bone gelatin; the gelatin is acid skin gelatin; or the gelatin is an acid bone gelatin.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin has a gel strength of 175-200 Bloom.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the gelatin has a gel strength of 195 Bloom.
One embodiment of the invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the glycerol is 85% glycerol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the sorbitol is an anhydrified liquid sorbitol NF.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the tocopherol is all-rac-alpha-tocopherol.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the polyethylene glycol is polyethylene glycol 400.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the tazopanib or a pharmaceutically acceptable salt thereof is tazopanib tosylate.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the tazopanib or a pharmaceutically acceptable salt thereof is tazopanib free base.
One embodiment of the present invention relates to a pharmaceutical soft gelatin capsule dosage form wherein the dosage form is for oral administration.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form according to any of the preceding embodiments, wherein the dosage form, after oral administration to a subjectProvided log transformed AUC 24 The 90% confidence interval for the geometric mean of (2) is the log-transformed AUC of a powder-filled immediate release oral capsule containing an equivalent amount of talazapanib 24 From 80% to 125% of the geometric mean of (c), wherein the individual is in a fasted state.
The present invention relates to a pharmaceutical soft gelatin capsule dosage according to any of the preceding embodiments, wherein the dosage form provides a log-transformed C after oral administration to a subject max The 90% confidence interval for the geometric mean of (2) is the log transformed C of a powder filled oral capsule containing an equivalent amount of talazapanib max From 80% to 125% of the geometric mean of (c), wherein the individual is in a fasted state.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form according to any of the preceding embodiments, wherein the dosage form (a) provides a log-transformed AUC after administration to a subject 24 Is the log-transformed AUC of a powder-filled oral capsule containing an equivalent amount of talazapanib 24 From 80% to 125% of the geometric mean of (c), wherein the individual is in a fasted state; (b) The geometric mean of the log-transformed Cmax provided after administration to a subject in a fasted state is 80% to 125% of the geometric mean of the log-transformed Cmax of a powder-filled oral capsule containing an equivalent amount of talazopanib; or (c) providing both (a) and (b).
The present invention relates to a pharmaceutical soft gelatin capsule dosage form according to any of the preceding embodiments, wherein the dosage form (a) provides a log-transformed AUC after administration to a subject 24 Is the log-transformed AUC of a powder-filled oral capsule containing an equivalent amount of talazapanib 24 From 80% to 125% of the geometric mean of (c), wherein the individual is in a fasted state.
The present invention relates to a pharmaceutical soft gelatin capsule dosage form according to any of the preceding embodiments, wherein the dosage form (a) has a log fed/fasted converted AUC after oral administration to a subject 24 The ratio of the geometric means of (2) is from about 0.8 to about 1.25; (b) Logarithmic conversion of food/fasting C after oral administration to an individual max The ratio of the geometric mean values of (2) is from about 0.8 to about 1.25, a step of; or (c) has both (a) and (b).
The present invention relates to a pharmaceutical soft gelatin capsule dosage form according to any of the preceding embodiments, wherein the dosage form (a) has a log fed/fasted converted AUC after oral administration to a subject 24 The ratio of the geometric means of (2) is from about 0.8 to about 1.25.
The present invention relates to a method of treating cancer in a subject comprising administering to the subject a pharmaceutical soft gelatin capsule dosage form of any of the preceding embodiments.
One embodiment of the invention relates to a method of treating cancer in an individual comprising administering to the individual a pharmaceutical soft gelatin capsule dosage form, wherein the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, and prostate cancer.
One embodiment of the invention relates to a method of treating cancer in an individual comprising administering to the individual a pharmaceutical soft gelatin capsule dosage form, wherein the cancer is breast cancer, and wherein the breast cancer is triple negative breast cancer, hormone positive breast cancer, and HER2 negative breast cancer.
One embodiment of the invention relates to a method of treating cancer in an individual comprising administering to the individual a pharmaceutical soft gelatin capsule dosage form, wherein the cancer is prostate cancer and wherein the prostate cancer is castration-sensitive prostate cancer or castration-resistant prostate cancer.
One embodiment of the invention relates to a method of treating cancer in an individual comprising administering to the individual a pharmaceutical soft gelatin capsule dosage form, wherein the individual is a human.
Drawings
FIG. 1 shows a flow chart of the manufacturing process of a gelatin mass (gelatin mass) for a soft gelatin capsule of talazapirib.
Figure 2 shows a flow chart of the manufacturing process for filling and encapsulating of tazopanib tosylate soft gelatine capsules.
Figure 3 shows the formation of the degradation product cis-tazopanib in a soft gelatin capsule of 0.1mg of tazopanib at 40 ℃/75% relative humidity.
Figure 4 shows the formation of the degradation product cis-tazopanib in a soft gelatin capsule of 0.1mg of tazopanib at 30 ℃/75% relative humidity.
Figure 5 shows the formation of the degradation product cis-tazopanib in a 1mg soft gelatin capsule of tazopanib at 40 ℃/75% relative humidity.
Figure 6 shows the formation of the degradation product cis-tazopanib in a 1mg soft gelatin capsule of tazopanib at 30 ℃/75% relative humidity.
Detailed Description
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It will also be understood that, unless otherwise defined herein, the terms used herein are to be given their conventional meaning as known in the relevant art
As used herein, the singular forms "a", "an", and "the" include plural referents unless otherwise indicated. For example, the plasticizer includes one or more plasticizers.
When used to modify a numerical defined parameter (e.g., the amount of gelatin, the amount of antioxidant, etc.), the term "about" means that the parameter can vary by up to 10% (±10%) above or below the nominal value of the parameter. For example, a formulation having a composition of about 4.0mg is understood to vary between 3.6mg and 4.4 mg.
The abbreviation "w/w" refers to the amount by weight of a substance dissolved in a known amount (by weight) of liquid. The terms "percent by weight" and "weight percent" and the abbreviations "% w/w", "percent w/w", "wt%" are interchangeable and denote in percent the grams of one component in 100g of solution. As a mathematical expression, the weight percent or percentage of solute in a solution is equal to 100 weight of solute/weight of solvent.
As used herein, "pharmaceutically acceptable" means that the ingredient is suitable for oral administration to a patient.
As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some instances, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some cases, the pharmaceutically acceptable salt may be obtained by: salts formed by reacting a compound having an acidic group as described herein with a base, such as an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a salt of an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine), and salts with an amino acid (e.g., arginine, lysine), and the like, or by other methods previously identified.
The term "85% glycerol" as used herein is a mixture of glycerol and water. Glycerol, e.g., 85% glycerol, is used as a solvent for the drug substance in the fill solution and as a direct plasticizer for the gelatin shell. Glycerol, such as 85% glycerol, interacts with gelatin to form a stable, thermoreversible gel network by lowering the glass transition temperature of gelatin.
As used herein, the term "anhydrified liquid sorbitol NF", which may also be referred to as "dry matter of partially dehydrated sorbitol liquid", is a form of sorbitol commonly used in soft gelatin capsules. Sorbitol, such as anhydridized liquid sorbitol NF, acts as an indirect plasticizer by retaining water within the gelatin shell, thus reducing the formation of crystal structures that make the gelatin shell hard and brittle.
The term "polyethylene glycol 400" or "PEG400" as used herein is a fill material commonly used in soft gelatin capsules. For the purposes of the present invention, the drug substance is dissolved in polyethylene glycol 400 while still maintaining acceptable chemical stability.
Embodiments of the present invention relate to a pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein:
(a) The soft gelatin shell comprises gelatin and at least one plasticizer: and
(b) The filler comprises an antioxidant, at least one solvent, and talazapanib or a pharmaceutically acceptable salt thereof.
Soft gelatin capsules are well known and are commonly referred to as soft capsules. Soft gelatin capsules are single unit solid dosage forms or formulations comprising a liquid or semi-solid fill surrounded by a sheet of a hermetically sealed, elastic gelatin-based shell. The capsule is filled and sealed in a continuous process. The filling is encapsulated in a gelatin shell. The soft gelatin shell may be referred to as a gelatin material prior to encapsulation. The fill may be a solution, suspension, or semi-solid, and may be referred to as a fill formulation, fill material, capsule fill, or fill. The fill comprises a drug substance dissolved in a suitable solvent or dispersed in a suitable diluent to produce a homogeneous solution (i.e., liquid fill) or a [ homogeneous ] suspension (i.e., semi-solid fill), respectively. In an embodiment of the invention, the filler is a liquid.
Gelatin, such as gelatin in soft gelatin capsules, is classified by its strength. The term "Bloom" as used herein is a test that measures the strength of gelatin. This test determines the weight (in grams) required for a given post (typically having a diameter of 0.5 inch) to depress the gel surface by 4mm at a particular temperature without fracturing it. This gram is called the Bloom value, and most gelatin is between 30g Bloom (weakest) and 300g Bloom (strongest). The higher the Bloom value, the higher the melting point and gel point of the gelatin and the shorter the gel time. Low Bloom gelatin is typically in the range of 50-125 Bloom. Medium Bloom gelatin is typically in the range of 175-225Bloom. High Bloom gelatins are typically between 225-325 Bloom. The gelatin gel strength of the soft gelatin capsules of the present invention typically ranges from about 150 to about 200Bloom (or grams). In an embodiment of the invention, the soft gelatin capsule has a gelatin gel strength of 175-225Bloom. In an embodiment of the invention, the soft gelatin capsule has a gelatin gel strength of 175-200Bloom. In an embodiment of the invention, the soft gelatin capsule has a gelatin gel strength of 195Bloom. Exemplary manufacturers of soft capsules include Catalent Phama Solutions, somerset, n.j., pharmagel Engineering spa.lodi, italy, and Soft Gel Technologies inc., commerce, california.
The soft gelatin capsule of the present invention is a pharmaceutical dosage form or formulation comprising a gelatin-based shell and a fill. In one embodiment, the soft gelatin capsule is a liquid filled soft gelatin capsule dosage form or formulation.
In an embodiment of the invention, gelatin is a component in the shell of the soft gelatin capsule. The soft gelatin shell comprises gelatin and a plasticizer. The shell may optionally contain opacifying agents and/or dyes. Gelatin is obtained by partially hydrolyzing collagen from the skin, white connective tissue and bones of animals (including cattle, pigs and fish). It is mainly composed of water-soluble protein (4-90% w/w), mineral salt (1-2% w/w) and water (8-15% w/w). The protein portion comprises amino acids linked by amide linkages in the polypeptide chain.
Collagen is a fibrous protein, which is the major component of animal skin, bone and connective tissue. It consists of three helices of three polypeptide chains, with a molecular weight of about 300,000Da. Denaturation involves breaking the hydrogen bonds to destabilize the collagen helix, resulting in a significant decrease in molecular weight and intrinsic viscosity. Hydrolysis of collagen by boiling bone or skin in water results in low yields of impure gelatin with poor physical properties. Thus, commercial manufacture of gelatin involves first removing contaminants and then thermally denaturing either to produce gelatin type a with the aid of dilute acid or to produce gelatin type B with the aid of dilute base. Gelatin is amphoteric in nature, with the isoelectric point of type a gelatin ranging from 6.0 to 9.0 and the isoelectric point of type b gelatin ranging from 4.7 to 5.3. It is believed that alkaline hydrolysis results in a greater degree of deamidation of the asparagine and glutamine amino acids in collagen, resulting in a greater amount of free carboxylic acid, compared to acid hydrolysis. Examples of suitable type a gelatins include, but are not limited to, acid bone gelatin and acid skin gelatin. Examples of suitable type B gelatins include, but are not limited to, lime bone gelatin. In one embodiment, the gelatin is a tarragon gelatin. In a preferred embodiment, the gelatin is an acid bone gelatin. In one embodiment, the gelatin is 195Bloom acid skin gelatin. In a preferred embodiment, the gelatin is 195Bloom acid bone gelatin.
Soft gelatin capsules typically contain water in an amount of from about 1% to about 20%, more preferably from about 3% to about 18%, more preferably from about 5% to about 14% by weight of the gelatin shell after the fill has been encapsulated and water has migrated from the capsule to the fill. Without being bound by theory. It is believed that water in the gelatin capsule, for example 20% to 50% by weight, migrates at least partially prior to filling to aid in gelling the filling and increasing its viscosity.
In one embodiment, the gelatin is present in an amount of about 50% to about 75%, preferably about 55% to about 65%, more preferably about 59% to about 61%, even more preferably about 60% to about 61% by weight of the soft gelatin shell.
In one embodiment, any pharmaceutically acceptable plasticizer may be included as a component in the shell of a soft gelatin capsule. In one embodiment, at least one plasticizer is included. In one embodiment, one or two plasticizers are included. In one embodiment, a plasticizer is included. In a preferred embodiment, two plasticizers are included. Non-limiting examples of suitable plasticizers include polyols such as sorbitol, glycerol, mannitol, xylitol, and sorbitol; dialkyl phthalate; lower alkyl citrate esters wherein the lower alkyl has 1 to 6 carbon atoms; ethylene glycol and polyethylene glycols, including polyethylene glycols having a molecular weight in the range of about 200 to about 2000, methoxy-propylene glycol and 1, 2-propylene glycol; esters of polyhydric alcohols, such as monoacetate, diacetate and triacetate of glycerol, ricinoleic acid and esters thereof; and mixtures of the foregoing. In one embodiment, the plasticizer includes glycerin and sorbitol. In one embodiment, the plasticizer is glycerin and sorbitol, the glycerin is 85% glycerin, and the sorbitol is an anhydrified liquid sorbitol NF.
In one embodiment, the total plasticizer is present in an amount of from about 20% to about 55% by weight of the soft gelatin shell, more preferably from about 30% to about 45% by weight, still more preferably from about 35% to about 40% by weight.
In an embodiment of the invention, the filling comprises an antioxidant, at least one solvent and talazapanib or a pharmaceutically acceptable salt thereof. In one embodiment, the tazopanib or pharmaceutically acceptable salt in the soft capsule fill is tazopanib tosylate. The fill contains an amount of the ingredient that is acceptable for pharmaceutical oral administration.
In embodiments of the present invention, the antioxidant may be included as a component in the fill of a soft gelatin capsule. In an embodiment of the invention, the filler comprises an antioxidant. Non-limiting examples of suitable antioxidants include tocopherol, tocopheryl polyethylene glycol succinate, butylated hydroxytoluene, butylated hydroxyanisole, dodecyl gallate, octyl gallate, propyl gallate, ascorbyl palmitate, sodium ascorbate, and thymol. In one embodiment, the antioxidant is tocopherol, tocopheryl polyethylene glycol succinate, butylated hydroxytoluene, or propyl gallate. In a preferred embodiment, the antioxidant is tocopherol. In a more preferred embodiment, the antioxidant is all-rac- α -tocopherol.
In one embodiment, the antioxidant is present in an amount of about 0.05% to about 1% by weight of the filler and more preferably about 0.1% to about 0.5% by weight.
In embodiments of the present invention, the solvent may be included as a component in the fill of a soft gelatin capsule. In an embodiment of the invention, the filler comprises at least one solvent. In one embodiment, one or two solvents are included. In one embodiment, a solvent is included. In a preferred embodiment, two solvents are included. Non-limiting examples of suitable solvents include propylene glycol, acetone, ethanol, butylene glycol, diethylene glycol monoethyl ether, dipropylene glycol, glycerol, polyethylene glycol, mineral oil, peanut oil, corn oil, and sesame oil. In one embodiment, the solvent is glycerol. In one embodiment, the solvent is glycerol and the glycerol is 85% glycerol. In one embodiment, the solvent is polyethylene glycol. In one embodiment, the polyethylene glycol has a molecular weight in the range of about 200 to about 900. In one embodiment, the polyethylene glycol has a molecular weight of less than 900. In one embodiment, the polyethylene glycol is polyethylene glycol 600 (PEG 600). In one embodiment, the polyethylene glycol is polyethylene glycol 400 (PEG 400). In one embodiment, the solvent comprises polyethylene glycol and glycerol. In a preferred embodiment, the solvents are polyethylene glycol and glycerol. In a more preferred embodiment, the solvent is polyethylene glycol and glycerin, the polyethylene glycol is PEG 400 and the glycerin is 85% glycerin.
In embodiments of the present invention wherein the solvent comprises polyethylene glycol and glycerin, the polyethylene glycol is present in the fill in an amount of about 80% to about 99% by weight, preferably about 94% to about 98% by weight, more preferably about 95% to about 96% by weight of the total weight of the fill; and glycerin is present in the fill in an amount of about 1% to about 10% by weight, preferably about 2% to about 6% by weight, more preferably about 4% by weight, of the total weight of the fill.
In an embodiment of the invention, tazopanib or a pharmaceutically acceptable salt thereof is a component in a soft gelatin capsule fill. In one embodiment of the invention, the dosage form comprises talazapanib or a pharmaceutically acceptable salt thereof, preferably a tosylate salt thereof, in an amount equivalent to about 0.1mg to about 1mg of talazapanib free base. In one embodiment of the invention, the dosage form comprises talazapanib or a pharmaceutically acceptable salt thereof, preferably a tosylate salt thereof, in an amount equivalent to about 0.1mg of talazapanib free base, equivalent to about 0.25mg of talazapanib free base, equivalent to about 0.35mg of talazapanib free base, equivalent to about 0.5mg of talazapanib free base, equivalent to about 0.75mg of talazapanib free base, or equivalent to about 1mg of talazapanib free base.
In an embodiment of the invention, the amount of talazapanib or a pharmaceutically acceptable salt thereof, preferably the tosylate salt thereof, corresponds to about 0.1mg to about 1mg of talazapanib free base. In an embodiment of the invention, the amount of talazapanib or a pharmaceutically acceptable salt thereof, preferably the tosylate salt thereof, corresponds to about 0.1mg of talazapanib free base, relative to about 0.25mg of talazapanib free base, relative to about 0.35mg of talazapanib free base, relative to about 0.5mg of talazapanib free base, relative to about 0.75mg of talazapanib free base, or relative to about 1mg of talazapanib free base.
In an embodiment of the invention, the amount of talazapanib or a pharmaceutically acceptable salt thereof, preferably the tosylate salt thereof, is from about 0.1mg to about 1mg of talazapanib free base equivalent. In an embodiment of the present invention, the amount of tazopanib or a pharmaceutically acceptable salt thereof, preferably the tosylate salt thereof, is about 0.1mg of tazopanib free base equivalent, about 0.25mg of tazopanib free base equivalent, about 0.35mg of tazopanib free base equivalent, about 0.5mg of tazopanib free base equivalent, about 0.75mg of tazopanib free base equivalent, or about 1mg of tazopanib free base equivalent.
Therapeutic methods and uses
As used herein, "abnormal cell growth" refers to cell growth that is not affected by normal regulatory mechanisms (e.g., loss of contact inhibition), unless otherwise indicated. Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous).
The terms "cancer," "cancerous," and "malignant" refer to or describe the physiological condition of a mammal, which is typically characterized by unregulated cell growth. As used herein, "cancer" refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. As used herein, "cancer" refers to solid tumors, cancers of the blood, bone marrow or lymphatic system, named as the type of cells that form them. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of hematological cancers include, but are not limited to, leukemia, lymphoma, and myeloma. The term "cancer" includes, but is not limited to, primary cancer originating from a particular part of the body, metastatic cancer that spreads from where it began to other parts of the body, recurrence of the primary cancer after remission, and secondary primary cancer (secondary primary cancer is a new primary cancer in a person with a history of prior cancer, the prior cancer being of a different type than the latter). Examples of cancers include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More specific examples of such cancers include squamous cell carcinoma, myeloma, lung cancer, small-cell prostate cancer, non-small-cell lung cancer, glioma, hodgkin's lymphoma, non-Huo Gejin lymphoma, follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLCBCL), acute Myelogenous Leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, uterine cancer, endometrial cancer, liver cancer, kidney cancer, renal cell cancer, prostate cancer, castration-sensitive prostate cancer, castration-resistant prostate cancer (CRPC), thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, rectal cancer, brain cancer, gastric cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, and salivary gland cancer.
The term "patient" or "individual" refers to any single individual in need of treatment thereof or in participation in a clinical trial, epidemiological study, or as a control, including human and mammalian veterinary patients, such as cattle, horses, dogs, and cats. In certain preferred embodiments, the individual is a human.
The term "treatment" or "treating" cancer as used herein refers to administering a therapy according to the present invention to an individual suffering from or diagnosed with cancer to achieve at least one positive therapeutic effect, such as reducing the number of cancer cells, reducing the size of a tumor, reducing the rate of infiltration of cancer cells into peripheral organs, or reducing the rate of metastasis or growth of a tumor, reversing, alleviating, inhibiting the progression of, or preventing one or more symptoms of a disease or disorder to which the term applies. The term "treatment" as used herein, unless otherwise indicated, refers to a therapeutic action as defined above as "treatment". The term "treatment" also includes adjuvant and neoadjuvant treatment of an individual. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing proliferation (or destruction) of tumor or cancer cells; inhibit metastasis or tumor cells; reducing or shrinking the tumor size; remission of cancer; alleviating symptoms caused by cancer; improving the quality of life of cancer patients; reducing the dosage of other drugs required to treat cancer; delay the progression of cancer; cure cancer; overcoming one or more resistance mechanisms of the cancer; and/or to extend the survival of cancer patients. Positive therapeutic effects in cancer can be measured using a number of methods (see, e.g., W.A.Weber, J.Nucl.Med.50:1S-10S (200)). In some embodiments, the treatment achieved by the methods of the invention is any one of Partial Remission (PR), complete Remission (CR), total remission (OR), objective Remission Rate (ORR), progression-free survival (PFS), radiological image PFS, disease-free survival (DFS), and total survival (OS). PFS, also referred to as "time to tumor progression", refers to the length of time during and after treatment that the cancer does not grow, including the amount of time the patient experiences CR or PR, and the amount of time the patient experiences Stable Disease (SD). DFS refers to the length of time a patient remains disease free during and after treatment. OS refers to an increase in life expectancy compared to an untreated or untreated individual or patient. In some embodiments, the response to the methods of the invention is either PR, CR, PFS, DFS, ORR, OR or OS. The response to the methods of the invention, including the duration of the soft tissue response, was assessed using the response standard of version 1.1, response Evaluation Criteria in Solid Tumors (RECIST 1.1). In some embodiments, the treatment achieved by the methods of the invention is measured by the time to PSA progression, the time to onset of cytotoxic chemotherapy, and the proportion of patients with PSA response is greater than or equal to 50%. The treatment regimen of the methods of the invention effective to treat a cancer patient may vary depending on factors such as the disease state, age and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the individual. While embodiments of any aspect of the present invention may not be effective in achieving a positive therapeutic effect in each individual, it should achieve a positive therapeutic effect in a statistically significant number of individuals determined by any statistical test known in the art, such as, but not limited to, the Cox log rank test, the Cochran-Mantel-Haenszel log rank test, the Student's t-test, the chi 2-test, the U test according to Mann and Whitney, the Kruskal-Wallis test (H-test), the jonkheere-termat-test, and the Wilcon-test. The term "treatment" also includes in vitro and ex vivo treatment of a cell, e.g., by an agent, a diagnostic agent, a binding compound, or by another cell.
As used herein, an "effective dose" or "effective amount" of a drug, compound or pharmaceutical formulation is an amount sufficient to affect any one or more of the beneficial or desired (including biochemical, histological and/or behavioral symptoms) of the disease, its complications, and intermediate pathological phenotypes that occur during the progression of the disease. For therapeutic purposes, a "therapeutically effective amount" refers to the amount of a compound administered that will alleviate one or more symptoms of the disease being treated to some extent. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (1) reduce the size of a tumor, (2) inhibit (i.e., slow, preferably stop) tumor metastasis, (3) inhibit (i.e., slow, preferably stop) tumor growth or tumor invasion to some extent, (4) alleviate (or preferably eliminate) one or more signs or symptoms associated with cancer to some extent, (5) reduce the dosage of other drugs required to treat the disease, and/or (6) enhance the effect of another drug, and/or delay progression of the disease in the patient. The effective dose may be administered one or more times. For the purposes of the present invention, an effective dose of a drug, compound or pharmaceutical formulation is an amount sufficient to accomplish prophylactic or therapeutic treatment, either directly or indirectly. As understood in the clinical context, an effective dose of a drug, compound or pharmaceutical formulation may or may not be used in combination with another drug, compound or pharmaceutical formulation.
In one embodiment, an effective dose of talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.1mg to about 2mg, preferably at a daily dose of about 0.25mg to about 1.5mg, more preferably at a daily dose of about 0.5mg to about 1.0 mg. In one embodiment, tazopanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.1mg, about 0.25mg, about 0.35mg, about 0.5mg, about 0.75mg, or about 1.0 mg. In one embodiment, tazopanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.1mg, about 0.25mg, about 0.35mg or about 0.5 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.25mg, about 0.35mg or about 0.5 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.5mg, about 0.75mg or about 1.0 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.1 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.25 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.35 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.5 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 0.75 mg. In one embodiment, talazapanib or a pharmaceutically acceptable salt thereof, preferably tosylate thereof, is administered once daily at a daily dose of about 1.0 mg. The amounts of dosages provided herein refer to the dosages of the free base form of talazapirib, or calculated as the free base equivalent of the salt form of talazapirib administered. For example, a dose or amount of talazapanib, such as 0.5, 0.75mg or 1.0mg, refers to the free base equivalent. The dosage regimen may be adjusted to provide the optimal therapeutic response. For example, the dosage may be proportionally reduced or increased depending on the emergency of the treatment situation.
"tumor" when applied to an individual diagnosed with or suspected of having cancer refers to malignant or potentially malignant tumor or tissue mass of any size, and includes primary and secondary tumors. Solid tumors are abnormal growths or tissue masses that generally do not contain cysts or areas of fluid. Examples of solid tumors are sarcomas, carcinomas and lymphomas. Leukemia (cancer in the blood) generally does not form solid tumors (national cancer institute, cancer term dictionary).
"Tumor burden" (Tumor burden), also known as "Tumor burden" (Tumor load), refers to the total amount of Tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body (including lymph nodes and bone marrow). Tumor burden can be determined by a variety of methods known in the art, such as using calipers, or in vivo using imaging techniques, such as ultrasound, bone scanning, computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scanning.
The term "tumor size" refers to the total size of a tumor, which can be measured by the length and width of the tumor. Tumor size can be determined by various methods known in the art, for example, by measuring the size of the tumor when removed from the individual (e.g., using calipers), or by measuring the size of the tumor in vivo using imaging techniques (e.g., bone scan, ultrasound, CR, or MRI scan).
The methods of the invention are useful for treating cancer. In some implementations, the provided methods result in one or more of the following effects: (1) inhibiting proliferation of cancer cells; (2) inhibiting cancer cell invasion; (3) inducing apoptosis of cancer cells; (4) inhibiting metastasis of cancer cells; (5) inhibiting angiogenesis; or (6) overcoming one or more drug resistance mechanisms associated with cancer treatment.
In one embodiment, the invention relates to a method of treating cancer in an individual comprising administering to the individual a pharmaceutical soft gelatin capsule of the invention.
In another aspect, the invention relates to a pharmaceutical soft gelatin capsule of the invention for use in treating cancer in an individual.
In another aspect, the invention relates to a pharmaceutical soft gelatin capsule of the invention for use as a medicament.
In one embodiment of the invention, the subject is a mammal.
In one embodiment of the invention, the individual is a human.
In some embodiments, the methods of the invention are useful for treating cancers, including, but not limited to, cancers of:
circulatory systems such as the heart (sarcomas [ hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma ], myxoma, rhabdomyoma, fibroma, lipoma and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissues;
Respiratory tract, e.g. nasal and middle ear, paranasal sinus, larynx, trachea, bronchi and lungs, e.g. Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrimatoid hamartoma, mesothelioma;
gastrointestinal systems such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, karposi's sarcoma), smooth myoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth myoma);
genitourinary tract, such as kidney (adenocarcinoma, wilms' tumor [ nephroblastoma ], lymphoma, leukemia), bladder and/or urinary tract (squamous cell carcinoma, transitional cell carcinoma or urothelial carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
Liver (e.g., liver cancer, hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (e.g., pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, insulinoma, and glucagon tumor);
bones, for example, osteogenic sarcomas (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticuloendomatosis), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (osteochondral osteogenesis wart), benign chondrioma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor;
nervous system, e.g., central Nervous System (CNS) tumors, primary CNS lymphomas, skull cancers (bone tumors, hemangiomas, granulomas, xanthomas, amoebositis), meninges (meningiomas, gliomas), brain cancers (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors [ pineal tumor ], glioblastomas multiformes, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);
The reproductive system, for example gynaecological, uterine (endometrial carcinoma), cervical (cervical carcinoma, pre-cancerous cervical dysplasia), ovarian (ovarian carcinoma [ serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, unclassified carcinoma ], granulosa-follicular cell tumors, seltoli-Leydig cell tumors, atheroma, malignant teratoma), vulval (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma) and other sites associated with female reproductive organs;
blood systems such as blood (myelogenous leukemia [ acute and chronic ], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma [ malignant lymphoma ];
the oral cavity, such as the lips, tongue, gums, fundus, palate and other parts of the oral cavity, parotid and other parts of salivary glands, tonsils, oropharynx, nasopharynx, piriform sinus, hypopharynx, and other parts of the lips, oral cavity and pharynx;
Skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevus dysplastic nevi, lipoma, hemangioma, cutaneous fibroma and keloids;
adrenal gland: neuroblastoma; and
other tissues include connective and soft tissues, retroperitoneal and peritoneal, ocular, intraocular melanoma and appendages, breast, head or/and neck, anal region, thyroid, parathyroid, adrenal and other endocrine glands and related structures, secondary and undefined malignant tumors of the lymph nodes, secondary malignant tumors of the respiratory and digestive systems, and secondary malignant tumors of other sites.
In one embodiment, examples of "cancer" when used herein in connection with the present invention include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), breast cancer (including triple negative breast cancer, hormone positive breast cancer, HER2 negative breast cancer, HER2 positive breast cancer and triple positive breast cancer), ovarian cancer, colon cancer, rectal cancer, anal region cancer, prostate cancer (including castration-sensitive or hormone-sensitive prostate cancer and hormone refractory prostate cancer, also known as castration-resistant prostate cancer), hepatocellular carcinoma, diffuse large B-cell lymphoma, follicular lymphoma, melanoma and salivary gland tumors, or a combination of one or more of the foregoing cancers.
In one embodiment, examples of "cancer" when used herein in connection with the present invention include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), breast cancer (including triple negative breast cancer, hormone positive breast cancer and HER2 negative breast cancer), ovarian cancer, prostate cancer (including castration-sensitive or hormone-sensitive prostate cancer and hormone refractory prostate cancer, also known as castration-resistant prostate cancer), or a combination of one or more of the foregoing cancers.
In one embodiment, examples of "cancer" when used herein in connection with the present invention include cancers selected from the group consisting of: prostate cancer, androgen receptor positive breast cancer, hepatocellular carcinoma and salivary gland tumor, or a combination of one or more of the foregoing cancers.
In one embodiment, examples of "cancer" when used herein in connection with the present invention include cancers selected from the group consisting of: androgen receptor positive breast cancer, hepatocellular carcinoma and salivary gland tumor, or a combination of one or more of the foregoing cancers.
In one embodiment, examples of "cancer" when used herein in connection with the present invention include cancers selected from the group consisting of: triple negative breast cancer, hormone positive breast cancer, HER2 negative breast cancer, triple positive breast cancer, castration-sensitive prostate cancer, castration-resistant prostate cancer, hepatocellular carcinoma and salivary gland tumor, or a combination of one or more of the foregoing cancers.
In one embodiment, examples of "cancer" when used herein in connection with the present invention include cancers selected from the group consisting of: triple negative breast cancer, hormone positive breast cancer and HER2 negative breast cancer, or a combination of one or more of the foregoing cancers.
In one embodiment, examples of "cancer" when used herein in connection with the present invention include cancers selected from the group consisting of: castration-sensitive prostate cancer and castration-resistant prostate cancer, or a combination of one or more of the foregoing cancers.
In one embodiment of the invention, the cancer is a solid tumor.
In one embodiment of the invention, the cancer is a solid tumor that is androgen dependent.
In one embodiment of the invention, the cancer is a solid tumor that expresses an androgen receptor.
In one embodiment, the cancer is prostate cancer.
In one embodiment, the cancer is a high risk prostate cancer.
In one embodiment, the cancer is locally advanced prostate cancer.
In one embodiment, the cancer is a high risk locally advanced prostate cancer.
In one embodiment, the cancer is castration-sensitive prostate cancer.
In one embodiment, the cancer is metastatic castration-sensitive prostate cancer.
In one embodiment, the cancer is castration-sensitive prostate cancer or metastatic castration-sensitive prostate cancer with DNA damage repair mutations (DDR mutations). DDR mutations include ATM, ATR, BRCA, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C.
In one embodiment, the cancer is hormone sensitive prostate cancer, also known as castration sensitive prostate cancer. Hormone sensitive prostate cancer is generally characterized by histologically or cytologically confirmed prostate cancer, which remains responsive to androgen deprivation therapy.
In one embodiment, the cancer is non-metastatic hormone sensitive prostate cancer.
In one embodiment, the cancer is a high risk, non-metastatic hormone sensitive prostate cancer.
In one embodiment, the cancer is metastatic hormone sensitive prostate cancer.
In one embodiment, the cancer is castration-resistant prostate cancer, also known as hormone refractory prostate cancer or androgen independent prostate cancer. Castration-resistant prostate cancer is generally characterized by histologically or cytologically confirmed prostate cancer that is castration-resistant (e.g., defined as 2 or more consecutive increases in PSA for 1 week or more, optionally resulting in 50% or more increases from nadir, PSA levels of 2ng/mL or more) at castration levels of testosterone (e.g., testosterone levels of 1.7nmol/L or testosterone levels of 50ng/dL or less) achieved by androgen deprivation therapy and/or orchiectomy.
In one embodiment, the cancer is non-metastatic castration-resistant prostate cancer.
In one embodiment, the cancer is non-metastatic castration-resistant prostate cancer.
In one embodiment, the cancer is metastatic castration-resistant prostate cancer.
In one embodiment, the cancer is metastatic castration-resistant prostate cancer with defects in DNA repair.
In one embodiment, the cancer is breast cancer.
In one embodiment, the cancer is locally advanced or metastatic breast cancer.
In one embodiment, the cancer is a triple negative breast cancer.
In one embodiment, the cancer is hormone positive breast cancer, including estrogen positive and/or progesterone positive breast cancer.
In one embodiment, the cancer is HER2 negative breast cancer.
In one embodiment, the cancer is HER2 negative breast cancer mutated in the germ line BRCA.
In one embodiment, the cancer is HER2 positive breast cancer.
In one embodiment, the cancer is a triple positive breast cancer.
In one embodiment, the cancer is ovarian cancer.
In one embodiment, the cancer is small cell lung cancer.
In one embodiment, the cancer is ewing's sarcoma.
In one embodiment, the cancer is hepatocellular carcinoma.
In one embodiment, the cancer is a salivary gland tumor.
In one embodiment, the cancer is locally advanced.
In one embodiment, the cancer is non-metastatic.
In one embodiment, the cancer is metastatic.
In one embodiment, the cancer is refractory.
In one embodiment, the cancer is recurrent.
In one embodiment, the cancer is intolerant to standard treatments.
In one embodiment, the cancer has a CDK12 mutation.
In one embodiment of the invention, the method is administered to an individual diagnosed with cancer that has been resistant to treatment.
In another aspect, the methods of the invention may further comprise administering additional anti-cancer agents, such as anti-neoplastic agents, anti-angiogenic agents, signal transduction inhibitors, and anti-proliferative agents, in amounts effective together to treat the cancer. In some such embodiments, the antineoplastic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones, androgen deprivation therapy, and anti-androgens. In an embodiment of the invention, the additional anti-cancer agent is an anti-androgen. In an embodiment of the invention, the anti-androgen is enzalutamide (enzalutamide) or apalutamide (apalutamide).
Examples
Example 1: preparation of Taraxazopanib 0.1mg, 0.25mg, 0.35mg, 0.5mg, 0.75mg and 1mg soft gelatin capsules Preparation method
The compositions of the pharmaceutical soft gelatin capsules, including the compositions of the fill and shell, as the dosage forms of 0.1mg, 0.25mg, 0.35mg, 0.5mg, 0.75mg and 1mg of tazopanib are set forth in tables 1-6 below, respectively.
Fig. 1 provides a process flow diagram for the manufacture of gelatin material for pharmaceutical soft gelatin capsules as dosage forms of 0.1mg, 0.25mg, 0.35mg, 0.5mg, 0.75mg and 1mg of tazopanib. As shown in fig. 1, the components of the gelatin material are mixed and dissolved at 60-70 ℃. The desired pigment is added and a gelatin material is provided for encapsulation as described below.
Fig. 2 provides a flow chart of the manufacturing process of filling solutions and encapsulation of pharmaceutical soft gelatin capsules as dosage forms of 0.1mg, 0.25mg, 0.35mg, 0.5mg, 0.75mg and 1mg of tazopanib and is listed in the numbered steps below. The entry numbers correspond to the components in tables 1-6 below.
1. Polyethylene glycol 400 (item 2), 85% glycerol (item 3) and all-rac-alpha-tocopherol (item 4) were charged to a suitable mixing vessel and mixed.
2. Talazapanib tosylate (item 1) was mixed with a portion of the mixture from step 1.
3. Half of the mixture from step 1 and the mixture from step 2 are transferred to a suitable mixing unit. The mixing vessel from step 2 was flushed three times with the mixture from step 1 to ensure that all of the tazopanib tosylate (item 1) was transferred to the mixing unit. The remaining mixture from step 1 is added to a suitable mixing unit.
4. The contents from step 3 are mixed.
5. The solution of step 4 was degassed under static vacuum (permanent vacuum).
6. The solution from step 5 is discharged from the mixing tank directly into the filling container of the packaging machine.
7. The gelatin material prepared as described above was used to encapsulate capsules.
8. The resulting capsules were dried in a tunnel on a tray.
9. After drying, the capsules were visually inspected.
TABLE 1
TABLE 2
TABLE 3 Table 3
TABLE 4 Table 4
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TABLE 5
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TABLE 6
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One of ordinary skill in the pharmaceutical arts will appreciate that the values provided in tables 1-6 are single unit theoretical formulations (QQ formulations (Qua Que)). When a drug is scaled up to multiple units, the number of each component is multiplied by the number of units required. Due to differences in balance accuracy and tolerances, there may be subtle differences in QQ values when calculating back from the weight used to make a batch. In addition, during the manufacturing process, certain restrictions are allowed on the filling accuracy of the capsule and the weight of the capsule shell; however, as a weight percentage of the measurement, these values will be the same as the QQ formulation. This is recognized by industry and regulatory authorities.
Example 2: the acid bone gelatin shows improved dissolution compared to the acid skin gelatin in a talazapanib soft gelatin capsule Stability of study
The effect of the type of gelatin (acid skin versus acid bone) used in the preparation of tazopanib soft gelatin capsules was evaluated to determine the effect on the chemical stability of the capsule formulation. Manufacturer gelia is a supplier of acid skin gelatin and acid bone gelatin. As shown in table 7, representative batches of talazapanib soft gelatin capsules were made using two gelatin types and chemical stability was evaluated (0.1 mg capsule formulation and 1mg capsule formulation, 30 counts in 60cc High Density Polyethylene (HDPE) bottles).
TABLE 7
Representative batches were prepared using the general procedure of example 1 and the general compositions of tables 1 and 6 with the following substantial modifications. Batch 1 was prepared using 0.5% tocopherol and no 85% glycerol in the capsule fill and the gelatin material was free of 85% glycerol. Batch 4 was prepared using 0.5% tocopherol and no 85% glycerin in the capsule fill. Batches 2, 3, 5, 6, 7, 8 and 9 were prepared using 0.3% tocopherol and 4% 85% glycerol in the liquid fill and 11% 85% glycerol in the gelatin material.
The capsules remained stable under accelerated conditions 40 ℃/75% relative humidity ("RH") and long term conditions 30 ℃/75% RH. The degradation products, i.e., the cis isomer of tazopanib ("cis-tazopanib"), are degradation products that limit shelf life, as shown below.
Figures 3 to 6 and tables 8 and 9 provide the chemical stability of the capsule formulations stored at 40 ℃/75% rh and 30 ℃/75% rh. Figures 3 and 4 show that the degradation rate of 0.1mg formulation was lower for two batches produced with different lot sizes of acid bone gelatin than for two batches produced with different lot sizes of acid skin gelatin. Similarly, figures 5 and 6 show that a 1mg batch produced with different lot numbers of acid bone gelatin has a lower cis-tazopanib formation rate than a batch produced with different lot numbers of acid skin gelatin. The raw data of fig. 3 to 6 are shown in tables 8 and 9 below.
Table 8: chemical stability of representative batches of Taraxazopanib soft gelatin capsules at 30 ℃/75% RH
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NT: not tested
Table 9: chemical stability of representative batches of Taraxazopanib soft gelatin capsules at 40 ℃/75% RH
NT: not tested
* : test at 1.5 months
According to ICH Harmonised Tripartite Guideline "Impurities in New Drug Products" Q3B (R2) at month 6 and 2 of 2006, 1.0% of the shelf life threshold of cis-talazapanib has been met.
The degradation rate of talazapanib was observed to be significantly lower in soft gelatin capsules prepared with acid bone gelatin than in soft gelatin capsules prepared with acid skin gelatin upon storage under accelerated (40 ℃/75% relative humidity) and long term (30 ℃/75% relative humidity) conditions. This finding was consistent in different batches of acid bone gelatin and acid skin gelatin.
Furthermore, this finding is consistent in formulations having different drug loading levels or concentrations, e.g., a 0.1mg fill formulation has a lower drug loading than a 1mg fill formulation). The ratio of components in the gelatin material is comparable at all concentrations (e.g., 0.1mg, 0.25mg, 0.35mg, 0.5mg, 0.75mg, and 1mg of talazapanib dosage form). The amount of dye used in each formulation resulted in some subtle differences; however, the total gelatin material is considered comparable. The capsule fill was the same at all concentrations except that the amount of talazapanib tosylate was different for the 0.1mg dosage form compared to the 0.25mg, 0.35mg, 0.5mg, 0.75mg and 1mg dosage forms.
Example 3: in the Taraxazopanib soft gelatin capsule, the acid bone gelatin and the acid skin gelatin or the stoneGray bone gelatin comparative display Showing improved chemical stability
The effect of gelatin types (especially acid skin, acid bone and lime bone) from different suppliers was evaluated to determine the effect on the chemical stability of talazapanib soft gelatin capsules. As shown in the first four columns of table 10, representative batches of talazapanib soft gelatin capsules were manufactured using different gelatin types and evaluated for chemical stability (1 mg capsule formulation, 30 counts in 60cc HDPE bottles with heat-sensitive seals).
Table 10: representative batch of 1mg Taraxazopanib Soft gelatin capsules
Lot number Gelatin source Gelatin type Gelatin manufacturer
1 Lime bone B Gelita
2 Lime bone B Gelita
3 Lime bone B Rousselot
4 Lime bone B Rousselot
5 Sour bone A PB Leiner UK
6 Sour bone A PB Leiner UK
7 Acid skin A PB Leiner UK
8 Sour bone A PB Leiner UK
9 Sour bone A PB Leiner UK
10 Sour bone A Rousselot
Representative batches were prepared using the general procedure of example 1 and the general compositions of tables 1 and 6. Batches 1 and 2 were prepared using 150 limestone bone SRM-free gelatin from gelia. Batches 3 and 4 were prepared using 150 limestone bone gelatin from Rousselot. Batches 5 and 6 were prepared using 195 acid bone SRM free gelatin from PB Leiner UK. Batch 7 was prepared using 195 acid skin gelatin from PB Leiner UK. Batches 8 and 9 were prepared using 195 acid bone vertebrae free gelatin from PB Leiner UK. Batch 10 was prepared using 195 acid bone vertebrae free gelatin from Rousselot. The only difference between the shell materials used in the different batches is the gelatin source used. For the dose concentrations evaluated, all remaining ingredients (glycerin, sorbitol and pigment) remained the same in the same proportions.
The overall study design (storage conditions and time points) was based on the long term and acceleration condition criteria during twelve months of ICH Harmonised Tripartite Guideline "Stability Testing Of New Drug Substances And Products" Q1A (R2) at 2/6/2003. The capsules remained stable under long term conditions of 30 ℃/75% rh and accelerated conditions of 40 ℃/75% rh. The degradation product cis-tazopanib is a degradation product that limits shelf life. Tables 11 and 12 provide the initial stability of the capsule formulations and the stability of the capsule formulations stored at 40 ℃/75% rh and 30 ℃/75% rh at the 6 month and 9 month time points, respectively.
Table 11: chemical stability of representative batches of 1mg of Taraxazopanib soft gelatin capsules at 30 ℃/75% RH
ND: no detection of
NMT: no more than
Table 12: chemical stability of representative batches of 1mg of Taraxazopanib soft gelatin capsules at 40 ℃/75% RH
ND: no detection of
NMT: no more than
The chemical stability results reported in tables 11 and 12 indicate that all batches of acid bone gelatin production were degraded less, independent of the supplier.
Example 4: phase 1 bioequivalence study between currently marketed formulations of talazapanib and soft capsule formulations, Food effect study of Talazopanib softgel formulation in patients with advanced solid tumors
Phase 1, open label, 2 sequence, crossover study was performed to establish bioequivalence ("BE") of the currently marketed formulation of talazapanib capsule with a liquid filled soft gelatin capsule formulation of talazapanib after multiple doses in patients with advanced solid tumors, ovarian cancer, breast cancer, prostate cancer, NSCLC, pancreatic cancer and colorectal cancer under fasted conditions. Furthermore, after 2 BE evaluation periods, the effect of food on the pharmacokinetics ("PK") of the talazapanib soft capsule formulation will BE evaluated in a fixed order.
Study design:
patients will be randomly assigned to 1 out of 2 sequences, receiving treatments A, B and C in different orders, as shown below. The first two phases will be evaluated, the first 28 days and the subsequent 21 days. Phase 3 was 21 days for evaluation of the effect of food on the pharmacokinetics of the proposed talazapanib soft gelatin capsule formulation, which formulation would BE incorporated into the fixation sequence after 2 BE evaluation periods (for patients who can tolerate a one-ton high fat/high calorie diet). The patient must continuously receive 1mg once a day for 21 days of continuous administration before proceeding to the next planned treatment, to be considered the completion of the treatment session. The study design is shown in table 13 below.
TABLE 13
Main result determination:
AUC of all Talazopanib treatments 24 Time range: the last day of each treatment session]
Area under the 0 to 24 hour plasma concentration-time curve
All tazopanib treated C max Time range: the last day of each treatment session]
Maximum plasma concentration
Secondary outcome determination:
t of all Talazopanib treatments max Time range: the last day of the treatment period]
C max Time
All tazopanib treated C trough Time range: the last day of the treatment period]
Plasma drug concentration prior to administration
CL/F of all talazapanib treatments [ time frame: last day of treatment period ]
Apparent clearance after oral administration
AUC of all Talazopanib treatments last Time range: the last day of the treatment period]
From time zero to last quantifiable concentration (C last ) Area under the plasma concentration versus time curve for time
Safety and tolerability of the proposed talazapanib soft capsule formulation [ time limit: about 4 years ]
Aes incidence characterized by type, severity (graded by the common term standard for NCI adverse events ("CTCAE") version 5.0), time, severity, and relationship to study treatment
Standard of
Inclusion criteria:
1. histological diagnosis of recurrent, locally advanced or metastatic solid tumours which are unsuitable for treatment with a view to cure.
Solid tumors with known or likely pathogenic germ line or somatic tumor gene defects (e.g., one or more BRCA1 or BRCA2 gene defects, other than ovarian cancer), may benefit from PARPi treatment, either in accordance with current tumor indication approval or with strong scientific evidence support.
At least 1 SOC treatment regimen (if any) appropriate for the respective tumor type is accepted, unless such treatment is deemed unsuitable or refused; ovarian cancer patients must receive at least 1 cytotoxic chemotherapy regimen, including at least 1 platinum-based therapy. Patients (except ovarian cancer patients) did not develop disease progression within 6 months of the beginning of the platinum-containing regimen.
2. Eastern tumor cooperative group ("ECOG") performance scores 0-1.
3. Proper organ function:
absolute neutrophil count ("ANC"). Gtoreq.1500 cells/mm 3
Platelet ≡100,000 cells/mm 3
Hemoglobin of 10.0g/dL or more
Creatine clearance ("CLCR"). Gtoreq.60 mL/min over the past 4 weeks, and no record of CLCR <60L/min, and no change in CLCR >25% >
Aspartate aminotransferase ("AST") and alanine aminotransferase ("AST") are less than or equal to 2.5 times the upper limit of normal ("ULN"); if the liver dysfunction is due to liver metastasis, AST and ALT are less than or equal to 5 XULN;
Total bilirubin is less than or equal to 1.5 XULN (Gilbert syndrome is less than or equal to 3 XULN);
exclusion criteria:
1. ovarian patient: non-epithelial tumors or ovarian tumors of low malignant potential (i.e. borderline tumors) or mucous tumors.
2. The toxicity of previous anti-cancer treatments must be resolved to NCI CTCAE < grade 2, except for hair loss, sensory neuropathy No. 2, or other No. 2 Aes that pose no safety risk, which Aes are acceptable at the discretion of the investigator.
3. Is diagnosed as myelodysplastic syndrome ("MDS") or acute myeloid leukemia ("AML").
4. Active infection requiring systemic treatment within 2 weeks after registration.
5. Active bleeding or any condition where a pathological condition may present a high risk of bleeding (e.g., where bleeding disorders, coagulopathies or tumors are known to involve major blood vessels).
6. Known or suspected brain metastases or active leptomeningeal diseases being treated or in need of treatment. Asymptomatic brain metastases, which are not currently treated, are permissible.
7. The history of HIV, AIDS, hepatitis B virus surface antigen positivity ("HBV"), hepatitis virus ("HCV") RNA positivity, or the detection of the COVID-19 virus positivity is known. Asymptomatic patients were allowed, no active infection was detected, but antibody detection was positive, indicating past infection.
8. The use of P-gp inhibitors, BCRP inhibitors and P-gp inducers is currently or contemplated within 2 weeks or 5 half-lives (whichever is longer) prior to random grouping.
Statistical method
To evaluate BE, the AUC of natural log-transformation after multiple doses over the last day of treatment periods 1 and 2 will BE analyzed using a mixed effect model 24 And C max The model takes sequence, period and treatment as fixed effects, and participants within the sequence as random effects. Estimates of the adjusted average difference (test reference) and corresponding 90% confidence interval will be obtained from the model. The adjusted average variance and 90% confidence interval of variance will be indexed to provide the ratio of the adjusted geometric mean (test/reference) and an estimate of the 90% confidence interval of the ratio. Treatment a (commercial formulation administered under fasted conditions) will be the reference treatment, while treatment B (the proposed talazapanib soft capsule formulation under fasted conditions) will be the trial treatment.
To evaluate food effects, the AUC of natural log transformation after multiple doses of treatment B and C on the last day will be analyzed using a mixed effect model 24 And C max Sequences and treatments act as fixed effects, and participants within the sequences act as random effects. Estimates of the adjusted flat-differences (test references) and corresponding 90% confidence intervals will be obtained from the model. The adjusted average difference and 90% confidence interval of the difference will be indexed to provide an adjusted geometric mean (test/reference) An estimate of the 90% confidence interval of the ratio and the ratio. Treatment B (the proposed tazopanib soft gel capsule formulation under fasted conditions) will be the reference treatment, while treatment C (the proposed tazopanib soft gel capsule formulation is administered with a high fat/high calorie diet) will be the trial treatment.
All publications and patent applications cited in the specification are herein incorporated by reference in their entirety. Although the foregoing invention has been described in some detail by way of illustration and example, it will be apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (22)

1. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein:
(a) The soft gelatin shell comprises gelatin and at least one plasticizer; and
(b) The filler comprises an antioxidant, at least one solvent, and talazapanib or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical soft gelatin capsule dosage form of claim 1, wherein the at least one plasticizer is a) glycerol; b) Sorbitol; or c) glycerol and sorbitol.
3. The pharmaceutical soft gelatin capsule dosage form of claim 1 or 2, wherein the antioxidant is tocopherol.
4. A pharmaceutical soft gelatin capsule dosage form as claimed in any one of claims 1 to 3 wherein the at least one solvent is a) polyethylene glycol; b) Glycerol; or c) polyethylene glycol and glycerol.
5. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 60% to about 61% by weight gelatin,
about 15% to about 16% by weight of glycerin, and
about 23% sorbitol; and is also provided with
Wherein the filler comprises:
about 0.3% by weight of tocopherol,
about 95% by weight of polyethylene glycol,
about 4% by weight of glycerin, and
tarazopanib or a pharmaceutically acceptable salt thereof, having a free base equivalent weight of about 0.15% to about 0.3% by weight.
6. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 46.270 mg/capsule of gelatin,
about 11.790 mg/capsule of glycerin, and
about 17.57 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.300 mg/capsule of tocopherol,
about 95.555 mg/capsule of polyethylene glycol,
About 4.000 mg/capsule of glycerin, and
about 0.1mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 61.097 mg/capsule of gelatin,
about 16.610 mg/capsule of glycerin, and
about 23.190 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.375 mg/capsule of tocopherol,
about 119.262 mg/capsule of polyethylene glycol,
about 5.000 mg/capsule of glycerin, and
about 0.25mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein the soft gelatin shell comprises:
about 78.130 mg/capsule of gelatin,
about 20.250 mg/capsule of glycerin, and
about 29.66 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 0.509 mg/capsule of tocopherol,
about 166.966 mg/capsule of polyethylene glycol,
about 7.000 mg/capsule of glycerin, and
about 0.35mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein the soft gelatin shell comprises:
about 104.930 mg/capsule of gelatin,
About 26.640 mg/capsule of glycerin, and
about 39.830 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 00.750 mg/capsule of tocopherol,
about 238.523 mg/capsule of polyethylene glycol,
about 10.000 mg/capsule of glycerin, and
about 0.5mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill, wherein the soft gelatin shell comprises:
about 141.260 mg/capsule of gelatin,
about 36.000 mg/capsule of glycerin, and
about 53.620 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 1.125 mg/capsule of tocopherol,
about 357.784 mg/capsule of polyethylene glycol,
about 15.000 mg/capsule of glycerin, and
about 0.75mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical soft gelatin capsule dosage form comprising a soft gelatin shell and a fill,
wherein the soft gelatin shell comprises:
about 177.790 mg/capsule of gelatin,
about 45.310 mg/capsule of glycerin, and
about 67.490 mg/capsule sorbitol; and is also provided with
Wherein the filler comprises:
about 1.453 mg/capsule of tocopherol,
about 477.047 mg/capsule of polyethylene glycol,
about 20.000 mg/capsule of glycerin, and
About 1mg of talazapiride free base or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical soft gelatin capsule dosage form of any one of claims 1-11 wherein the gelatin is an acid bone gelatin.
13. The pharmaceutical soft gelatin capsule dosage form of claims 2 or 4-12 wherein the glycerol is 85% glycerol.
14. The pharmaceutical soft gelatin capsule dosage form of claims 2 or 5-13 wherein the sorbitol is anhydrified liquid sorbitol NF.
15. The pharmaceutical soft gelatin capsule dosage form of claims 2 or 5-14 wherein the tocopherol is all-rac-a-tocopherol.
16. The pharmaceutical soft gelatin capsule dosage form of any one of claims 1-15 wherein the dosage form comprises talazapanib or a pharmaceutically acceptable salt thereof in the following amounts: equivalent to about 0.1mg of talazapiride free base; equivalent to about 0.25mg of talazapiride free base; equivalent to about 0.35mg of talazapiride free base; equivalent to about 0.5mg of talazapiride free base; equivalent to about 0.75mg of talazapiride free base; or equivalent to about 1mg of talazapiride free base.
17. The pharmaceutical soft gelatin capsule dosage form of any one of claims 1-16 wherein the tazopanib or pharmaceutically acceptable salt thereof is tazopanib tosylate.
18. The pharmaceutical soft gelatin capsule dosage form of any of the preceding claims, wherein the dosage form is for oral administration.
19. The pharmaceutical soft gelatin capsule dosage form of any of claims 1-18, wherein the dosage form provides a log transformed AUC upon oral administration to a subject 24 The 90% confidence interval for the geometric mean of (2) is the log-transformed AUC of a powder-filled immediate release oral capsule containing an equivalent amount of talazapanib 24 From 80% to 125% of the geometric mean of (c), wherein the individual is in a fasted state.
20. The pharmaceutical soft gelatin capsule dosage form of any of claims 1-18, wherein the dosage form (a) provides a log-transformed AUC upon administration to a subject 24 Is the log-transformed AUC of a powder-filled oral capsule containing an equivalent amount of talazapanib 24 From 80% to 125% of the geometric mean of (c), wherein the individual is in a fasted state; (b) The geometric mean of the log-transformed Cmax provided after administration to a subject in a fasted state is 80% to 125% of the geometric mean of the log-transformed Cmax of a powder-filled oral capsule containing an equivalent amount of talazopanib; or (c) providing both (a) and (b).
21. The pharmaceutical soft gelatin capsule dosage form of any of claims 1-18, wherein the dosage form (a) has a log fed/fasted converted AUC following oral administration to a subject 24 The ratio of the geometric means of (2) is from about 0.8 to about 1.25; (b) Logarithmic conversion of food/fasting C after oral administration to an individual max The ratio of the geometric means of (2) is from about 0.8 to about 1.25; or (c) has both (a) and (b).
22. A method of treating cancer in a subject comprising administering to the subject a pharmaceutical soft gelatin capsule dosage form according to any one of claims 1-21.
CN202180090259.8A 2020-11-13 2021-11-11 Taraxazopanib soft gelatin capsule dosage form Pending CN116916895A (en)

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US202163276554P 2021-11-05 2021-11-05
US63/276,554 2021-11-05
PCT/IB2021/060462 WO2022101828A1 (en) 2020-11-13 2021-11-11 Talazoparib soft gelatin capsule dosage form

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