CN109394685B - VEGFR inhibitor pharmaceutical composition and preparation method thereof - Google Patents

VEGFR inhibitor pharmaceutical composition and preparation method thereof Download PDF

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CN109394685B
CN109394685B CN201810919117.8A CN201810919117A CN109394685B CN 109394685 B CN109394685 B CN 109394685B CN 201810919117 A CN201810919117 A CN 201810919117A CN 109394685 B CN109394685 B CN 109394685B
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CN109394685A (en
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李俊明
杨俊然
王立坤
杜振兴
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Jiangsu Hengrui Medicine Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention relates to a VEGFR inhibitor pharmaceutical composition and a preparation method thereof. In particular, the present invention relates to a pharmaceutical composition comprising N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide having a particle size D90 of less than about 10 μm, which has improved individual variability relative to commercially available formulations, and a method for the preparation thereof.

Description

VEGFR inhibitor pharmaceutical composition and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide with the particle size D90 of less than about 10 mu m and a preparation method thereof.
Background
In recent years, a small molecule inhibitor of VEGFR is gradually becoming a novel non-cytotoxic antitumor drug with great application prospect. Compared with the traditional cytotoxic drug for inhibiting tumor growth, the therapeutic drug for targeting angiogenesis has higher specificity and lower toxicity, is beneficial to overcoming the drug resistance of tumors, and can be used for treating various tumors. N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide (Compound A) is a new generation of small molecule inhibitor of VEGFR having the following structure:
Figure BDA0001763756180000011
the N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide mesylate common tablet (trade name: Estan) sold on the market has higher variation of exposure in the same group among healthy subjects, and has larger exposure difference among the healthy subjects of different sexes of men and women, and the exposure of the female subjects is higher than that of the male subjects under the same administration dose; meanwhile, the clearance rate of gastric cancer patients is reduced due to prolonged gastric emptying time, reduced gastric acidity and poor gastrointestinal blood flow, while other tumor patients have liver injury or kidney injury, and the exposure of gastric cancer patients is lower than that of healthy volunteers and lower than that of other tumor patients, so that the common tablets also show larger degree of inter-individual difference on the actual clinical curative effect. Therefore, there is an urgent need for pharmaceutical formulation researchers to develop new pharmaceutical formulations to solve the problem of large individual differences.
Nanosuspensions (nanosuspensions) were a nanoparticulate drug delivery system developed at the end of the 20 th century. The drug particles are dispersed in water by the stabilizing action of a surface stabilizer, and a stable nano colloidal dispersion is formed by crushing or controlled crystallization technology. Of course, the nano suspension can be prepared by the method regardless of the medicine which is difficult to dissolve in water or the medicine which is difficult to dissolve in water and oil. As an intermediate dosage form, the nanosuspension can be further prepared into a pharmaceutical dosage form suitable for oral administration, injection or other administration routes, so that the absorption and bioavailability of the medicament are improved. Moreover, the nano suspension can improve the content of the medicament in the preparation, and is particularly suitable for oral administration and injection administration of large-dose and insoluble medicaments. In addition, because the prescription does not contain a carrier and a cosolvent, the toxic and side effects of injection administration are low.
For example, US5145684 discloses nanoparticulate pharmaceutical compositions comprising poorly soluble therapeutic or diagnostic agents having adsorbed or associated non-crosslinked surface stabilizers on their surface, wherein the nanoparticles have improved therapeutic efficacy, low toxicity and stability relative to particles comprising large size. Meanwhile, the currently marketed nano-suspension varieties comprise a mammary gland treatment drug paclitaxel, an immunosuppressant sirolimus and an antiemetic drug aprepitant.
However, there is no literature report on the use of nano-formulations to improve the individual variability of a drug among different patients.
Disclosure of Invention
The present invention provides a pharmaceutical composition comprising as an active ingredient N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide having a particle size D90 value of less than about 10 μm.
In alternative embodiments, the particle size D90 value of the active ingredient in the pharmaceutical compositions of the present invention may be selected from the group consisting of less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, less than about 1 μm, less than about 5000nm, less than about 4800nm, less than about 4500nm, less than about 4200nm, less than about 4000nm, less than about 3800nm, less than about 3500nm, less than about 3200nm, less than about 3000nm, less than about 2800nm, less than about 2500nm, less than about 2200nm, less than about 2000nm, less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 200nm, less than about 100nm, less than about 50nm or less, preferably less than about 5000nm, more preferably less than about 3000nm, and most preferably less than about 2000 nm.
Further, the active ingredient in the pharmaceutical compositions of the present invention preferably has a particle size D50 value of less than about 1 μm, preferably a D50 value selected from the group consisting of less than about 1 μm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 450nm, less than about 400nm, less than about 350nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm or less, preferably less than about 800nm, more preferably less than about 700nm, and most preferably less than about 600 nm.
Still further, the active ingredient in the pharmaceutical compositions of the present invention has a particle size D10 value of less than about 300nm, preferably a D50 value of from less than about 300nm, less than about 280nm, less than about 250nm, less than about 220nm, less than about 200nm, less than about 180nm, less than about 150nm, less than about 120nm, less than about 100nm, less than about 90nm, less than about 80nm, less than about 70nm, less than about 60nm, less than about 50nm, less than about 40nm, less than about 30nm, less than about 20nm, less than about 10nm, less than about 5nm or less, preferably less than about 200nm, most preferably less than 100 nm.
Further, the pharmaceutical composition of the present invention further comprises at least one surface stabilizer.
The surface stabilizer of the present invention is a substance which is physically adsorbed on the surface of N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide but does not form a chemical bond with N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide. Surface stabilizers include nonionic, anionic, cationic, ionic, and zwitterionic surface stabilizers.
Representative examples of surface stabilizers include, but are not limited to, hydroxypropylmethyl cellulose (now referred to as "hypromellose"), hydroxypropyl cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin (phospholipid), dextran, gum arabic, docusate sodium, sodium cholate, sodium deoxycholate, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available
Figure BDA0001763756180000031
E.g. Tween
Figure BDA0001763756180000032
And Tween
Figure BDA0001763756180000033
Polyethylene glycols (e.g., carbowax @)
Figure BDA0001763756180000034
And
Figure BDA0001763756180000035
polyoxyethylene stearate, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, D-alpha tocopheryl polyethylene glycol ester (TPGS), amorphous cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol (PVA), polymers of 4- (1,1,3, 3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde (also known as tyloxapol, tetrabutylaldehyde and triton), poloxamers (e.g.,
Figure BDA0001763756180000036
and
Figure BDA0001763756180000037
which is a block copolymer of ethylene oxide and propylene oxide); poloxamines (e.g., Tetromc)
Figure BDA0001763756180000038
Also known as poloxamines
Figure BDA0001763756180000039
It is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, n.j.); tetronic
Figure BDA00017637561800000311
(T-l508)(BASF Wyandotte Corporation)，
Figure BDA00017637561800000310
(an alkylaryl group)Polyacid sulfonates, Rohn and Haas); crodestas
Figure BDA00017637561800000312
(mixture of sucrose stearate and sucrose distearate, Croda Inc.); para-isononylphenoxy poly (glycidol), also known as
Figure BDA00017637561800000315
Or Surfactant
Figure BDA00017637561800000314
(Olin Chemicals,Stamford,CT)；Crodestas
Figure BDA00017637561800000313
(Croda, Inc.); and SA9OHCO (C)18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2Eastman Kodak Co.); decanoyl-N-methylglucamide (glucamide); n-decyl (-D-glucopyranoside; N-decyl (-D-maltopyranoside; N-dodecyl (-D-glucopyranoside; N-dodecyl (-D-maltopyranoside; heptanoyl-N-methylglucamide; N-heptyl- (-D-glucopyranoside; N-heptyl (-D-thioglucoside; N-hexyl (-D-glucopyranoside; nonanoyl-N-methylglucamide; N-nonanoyl (-D-glucopyranoside; octanoyl-N-methylglucamide; N-octyl- (-D-glucopyranoside; octyl (-D-thioglucoside; PEG-phospholipid, PEG-cholesterol derivative, hypromellose acetate succinate (HPMCAS); PEG-vitamin A, PEG-vitamin E, lysozyme, Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), random copolymer of ethyl vinyl pyrrolidone and vinyl acetate, and the like.
Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids and non-polymeric compounds such as zwitterionic stabilizers, poly-n-methylpyridinium, anthracyclpltp pyridinium chloride, cationic phospholipids, chitosan, polylysineVinylimidazole, polybrene, polymethyl methacrylate trimethylammonium bromide (PMMTMABr), hexyldiphenylethylketotrimethylammonium bromide (HDMAB) and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate. Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds, such as stearyl trimethylammonium chloride, benzyl bis (2-chloroethyl) ethyl ammonium bromide, cocotrimethyl ammonium chloride or bromide, cocomethyl dihydroxyethyl ammonium chloride or bromide, decyl triethylammonium chloride, decyl dimethylhydroxyethyl ammonium chloride or bromide, C12-15Dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, tetradecyl trimethyl ammonium methosulfate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (oxyethylene) 4 ammonium chloride or bromide, N-alkyl (C)12-18) Dimethyl benzyl ammonium chloride, N-alkyl (C)14-18) Dimethylbenzyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride monohydrate, dimethyldidecyl ammonium chloride, N-alkyl and (C)12-14) Dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halides, alkyltrimethylammonium and dialkyldimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkanoylaminoalkyldialkylammonium salts and/or ethoxylated trialkylammonium salts, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C)12-14) Dimethyl 1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylphenylalkylammonium chloride, lauryltrimethylammonium chloride, alkylthiomethylammonium chloride, alkylbenzyldimethylammonium bromide, C12,C15,C17Trimethyl ammonium bromide, dodecylbenzyltriethyl ammonium chloride, polydiallyldimethyl ammonium chloride (DADMAC), dimethyl ammonium chloride, alkyldimethyl ammonium halides, trihexadecyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethyl ammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336), POLYQUAT, tetrabutylammonium bromide, benzyltrimethyl ammonium bromide, choline esters (such as choline esters of fatty acids)Alkali esters), benzalkonium chloride, the stearalkonium chlorides (stearalkonium chlorides) class of compounds (such as stearyl trimethyl ammonium chloride and distearyl dimethyl ammonium chloride), cetyl pyridinium bromide or chloride, the halide salts of quaternized polyoxyethylalkylamines, MIRAPOL and alkaquat (alkaril Chemical company), alkylpyridinium salts; amines such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N-dialkylaminoalkyl acrylates and vinylpyridines, amine salts such as dodecylamine acetate, octadecylamine acetate, alkylpyridinium salts and alkylimidazolium salts, and amine oxides; an imide p-pyrrolinium (imidazolium) salt; protonated quaternary acrylamides; methylated quaternary polymers such as poly [ diallyldimethylammonium chloride]And poly [ N-methylvinylpyridinium chloride](ii) a And cationic guar gum. Exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in the following documents: cross and E.Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); p.and D.Rubinggh, Cationic Surfactants Physical Chemistry (Marcel Dekker, 1991); and J.Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
The non-polymeric surface stabilizer is any non-polymeric compound such as benzalkonium chloride, carbonium compounds, Qi compounds, oxonium compounds, halonium compounds, cationic organometallic compounds, quaternary phosphonium compounds, pyridinium compounds, anilinium compounds, ammonium compounds, hydroxylammonium compounds, primary ammonium compounds, secondary ammonium compounds, tertiary ammonium compounds and compounds of the general formula NR1R2R3R4(+) quaternary ammonium compound.
These compounds include, but are not limited to: benzenthonium chloride, cetylpyridinium chloride, behenyltrimethylammonium chloride, dodecylbenzyldimethylammonium chloride, hexadecylbenzyldimethylammonium chloride, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, hexadecylhydrofluoroamine, chloroallylhexamethylenetetramine chloride (Quaternium-15), distearyldimethylammonium chloride (Quaternium-5), dodecyldimethylethylammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylchloroethyl chloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oleyl ether phosphate, diethanolammonium POE (3) oleyl ether phosphate, tallow benzyldimethylammonium chloride, dimethyl (octadecyl) ammonium bentonite, sRarasonium chloride, domiphen bromide, denatonium benzoate, di-n ammonium bromide, Tetradecylbenzyldimethylammonium chloride, dodecyltrimethylammonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine hydrochloride, iodofinamine hydrochloride, meglumine hydrochloride, benzethonium chloride, tetradecyltrimethylammonium bromide, oleyltrimethylammonium chloride, Polyquaternium-l, procaine hydrochloride, cocobetaine, stearylbenzyldimethylammonium bentonite, stearylbenzyldimethylammonium hectorite, octadecyltriethylpropylenediamine dihydrofluoride, tallowyltrimethylammonium chloride and hexadecyltrimethylammonium bromide. Most of these surface stabilizers are known Pharmaceutical Excipients, described in detail in The American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, Handbook of Pharmaceutical Excipients (The Pharmaceutical Press,2000), which are co-published, and specifically incorporated herein by reference.
Further, the surface stabilizer is at least one selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, docusate sodium, sodium cholate, sodium deoxycholate, poloxamer, tween, sodium dodecyl sulfate, polyvinyl alcohol (PVA), methylcellulose, D-alpha Tocopheryl Polyethylene Glycol Succinate (TPGS), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), and hydroxyethyl cellulose. The pharmaceutical composition of the present invention may simultaneously comprise 1 to 10 surface stabilizers, preferably 2 to 5 surface stabilizers. In alternative embodiments, the pharmaceutical compositions of the present invention comprise at least two or three surfaces.
In non-limiting examples, the pharmaceutical compositions of the present invention comprise a combination of surface stabilizers including, but not limited to, sodium lauryl sulfate and hydroxypropylmethyl cellulose, sodium lauryl sulfate and hydroxypropyl cellulose, sodium lauryl sulfate and polyvinyl alcohol, sodium lauryl sulfate and polyvinylpyrrolidone (PVP, e.g., Plasdone), hydroxypropylmethyl cellulose (HPMC) and docusate sodium, poloxamer and copovidone, polyvinylpyrrolidone and docusate sodium, copovidone and docusate sodium, D-alpha Tocopheryl Polyethylene Glycol Succinate (TPGS) and hydroxypropylmethyl cellulose, poloxamer and Tween-80 (Tween80), Tween-20 and sodium lauryl sulfate (SDS), hydroxypropyl cellulose (HPC), and the like.
In alternative embodiments, the surface stabilizer may be present in the pharmaceutical composition of the invention in an amount of about 0.1 to 99.9wt%, preferably about 1.0 to 75.0wt%, and may be about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19.5, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31.5, 32, 5, 35, 45, 40, 5, 6, 6.5, 6, 6.5, 6, 18.5, 19.5, 11, 5, 11.5, 19.5, 11.5, 16.5, 21.5, 16.5, 18., 51. 51.5, 52, 52.5, 53.4, 54, 54.5, 55, 55.5, 56, 56.5, 57, 57.5, 58, 58.5, 59.5, 60, 60.5, 61, 61.5, 62, 62.5, 63.6, 66, 66.5, 65, 65.5, 66, 66.5, 67, 67.5, 68, 68.5, 69.5, 70, 70.5, 71, 71.5, 72, 72.5, 73.5, 74, 74.5, 75 wt%, more preferably 2.5 to 35.0 wt%.
In an alternative embodiment, the active ingredient of the present invention is present in an amount of about 0.5 to 99.9wt%, preferably about 25.0 to 99.0wt%, and may be 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5, 40, 40.5, 41, 41.5, 42, 42.5, 43.4, 44, 44.5, 45, 45.5, 46, 46.5, 47, 47.5, 48, 48.5, 49.5, 50, 50.5, 51, 51.5, 52, 52.5, 53.4, 54, 54.5, 55, 56.5, 56, 57, 5.5, 5, 5.5, 5, 70, 5, 5.5, 5, 5.5, 5, 72, 67, 5, 5.5, 5, 72, 67, 70, 5, 5.5, 5, 5.5.5, 72, 67, 72, 65, 72, 79.5, 80, 80.5, 81, 81.5, 82, 82.5, 83.5, 84, 84.5, 85, 86.5, 85, 85.5, 86, 86.5, 87, 87.5, 88, 88.5, 89, 89.5, 90, 90.5, 91, 91.5, 92, 92.5, 93.5, 94, 94.5, 95, 96.5, 95, 95.5, 96, 96.5, 97, 97.5, 98, 98.5, 99.0wt%, more preferably 65.0 to 97.5 wt%.
Further, the pharmaceutical composition of the present invention further comprises an excipient. In a non-limiting example, the pharmaceutical composition of the present invention may be further prepared into an injection solution or a solid preparation selected from, but not limited to, tablets, pills, granules, lyophilized powder for injection or capsules in an intermediate formulation.
Further, the excipient in the solid preparation is well known or can be determined by those skilled in the art, and is selected from at least one of but not limited to a disintegrant, a filler, a binder, and a lubricant; the injection excipient is selected from, but not limited to, nontoxic physiologically acceptable liquid carriers, such as at least one of physiological saline, water for injection, 5% glucose injection, glucose sodium chloride injection, pH regulator or preservative.
Fillers provide bulk, making the tablet the actual size that it can be processed into, and may also aid in processing, improving physical properties of the solid formulation such as flowability, compressibility, and hardness of the solid formulation. The filler of the present invention is known or determinable by those skilled in the art, and is selected from, but not limited to, at least one of dextrin, lactose, sucrose, calcium hydrogen phosphate, calcium sulfate, starch, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, and mannitol; preferably, the filler is used in an amount of 20 to 90% by weight of the solid formulation, and in embodiments may be 20, 22, 25, 27, 30, 32, 35, 38, 40, 42, 45, 47, 50, 52, 55, 58, 60, 62, 65, 68, 70, 72, 75, 78, 80, 82, 85, 88, 90%, more preferably 35 to 70% by weight of the solid formulation.
The disintegrant of the present invention is known or can be identified by those skilled in the art, and is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, alginic acid; preferably, the disintegrant is used in an amount of 1 to 20% by weight of the solid formulation, in embodiments 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20%, preferably 5 to 15% by weight of the solid formulation.
The binder of the present invention is known or can be identified by those skilled in the art, and is selected from but not limited to at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, alginate, preferably at least one of polyvinylpyrrolidone and hydroxypropylcellulose, more preferably the binder is used in an amount of 0.5 to 10% by weight of the solid formulation, and in embodiments, may be 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10% by weight of the solid formulation.
The lubricant of the present invention is known or can be identified by those skilled in the art, and is selected from but not limited to at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, colloidal silicon dioxide, carnauba wax, sodium stearyl fumarate; preferably, the lubricant of the present invention is used in an amount of 0.1 to 5% by weight of the solid formulation, and in embodiments may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5, 5%, preferably 0.1 to 2% by weight of the solid formulation.
The daily dose of the active ingredient of the present invention is 50 to 700mg, and may be 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, preferably 300 to 600mg, more preferably 400 to 550mg, and most preferably 500 mg.
The present invention also provides a process for preparing the aforementioned pharmaceutical composition comprising the step of contacting the active ingredient with at least one surface stabilizer to provide an active ingredient having a particle size D90 of less than about 10 μm.
The contacting of the present invention includes milling, wet milling, homogenization, precipitation or supercritical fluid particle generation techniques.
In a non-limiting example, the active ingredients selected for use in the present invention were bulk drugs purchased or prepared according to the methods described in the CN201610595409.1 example. The particle size of the active ingredient drug substance particles used is preferably (but not necessarily) less than about 100 μm, as measured by sieving, and if the particle size of the active ingredient drug substance particles is greater than about 100 μm, it is preferably reduced to below 100 μm by conventional grinding methods such as air jet milling or attrition milling.
The selected drug substance of compound a can then be added to a liquid medium, preferably water, which is substantially insoluble in it, to form a primary mixture. The concentration of the active ingredient in the liquid medium is from 0.1 to 60% (W/W), preferably from 5 to 30% (W/W), and may be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30% (W/W). Preferably, but not necessarily, the surface modifier is present in the initial mixture. Preferably, the initial mixture suspension has an apparent viscosity of less than about 2000 centipoise.
The primary mixture can be reduced to below 100um in the dispersed phase by direct mechanical means. The initial mixture is preferably applied directly when grinding with a ball mill. Alternatively, the active ingredient and any surface stabilizer may be dispersed in a liquid medium by any suitable means, such as a roller mill or a Cowles-type mixer, until a uniform dispersion of large agglomerates is formed which is not visible to the naked eye. If a circulating media mill is used for milling, it is preferred to subject the initial mixture to this pre-milling dispersion step.
Conventional mechanical means for reducing the particle size of the active ingredient particles may employ dispersion mills including ball mills, attrition mills, vibratory mills, planetary mills, media mills (e.g., sand mills and bead mills) in suitable form.
The grinding media used in the step of grinding the particles may be selected from rigid media, preferably spherical or granular, having an average particle size of less than about 3mm, more preferably less than about 1 mm. Such media have a shorter processing time and less wear on the grinding equipment while providing the particles of the present invention. The choice of raw materials for the grinding media is not critical. Such as zirconia, 95% ZrO stabilized with magnesium, zirconium silicate, glass milling media can provide particles within the allowable impurity content range for the preparation of pharmaceutical complexes. Also, other media such as stainless steel, titanium dioxide, alumina can be used. Preferably, the specific gravity of the medium is greater than 2.5g/cm 3.
The time of milling varies greatly, depending primarily on the particular mechanical method and processing conditions. For a ball mill, the processing time may need 1 day or more. On the other hand, milling with high shear media for processing times of less than one day (retention times ranging from one minute to several hours) has provided desirable results.
The process of pulverizing particles must be carried out at a temperature at which the active ingredient is not significantly degraded. It is generally preferred to process at a temperature below 50 ℃. The processing equipment may be cooled using conventional cooling equipment, if desired. Such particle generation techniques are well known to those skilled in the art and details of milling, wet milling, homogenisation, precipitation or supercritical fluid particle generation techniques and the like are described in CN1063630C, CN101175481A or CN1515244A and are specifically incorporated herein.
The invention also provides the use of the aforementioned pharmaceutical composition in the manufacture of a medicament for improving individual variability of a patient taking the medicament, the improvement being relative to apatinib mesylate.
The invention also provides a method for improving individual variability of a patient taking a drug, comprising administering to a patient in need of treatment the foregoing pharmaceutical composition, the improvement relative to apatinib mesylate.
As used herein, "D10" refers to the particle size corresponding to a cumulative percent particle size distribution of 10% for a sample. "D50" refers to the particle size corresponding to the cumulative percent particle size distribution of a sample at 50%. "D90" refers to the particle size corresponding to 90% of the cumulative percent particle size distribution for a sample. D4, 3 represents the "quartic/volume" mean diameter, also called the volume (or weight) mean diameter.
The dosage numerical range of the active ingredients or other types of pharmaceutical excipients is calculated by the weight of the tablet core without the coating agent according to the weight of the solid preparation.
Compared with the commercially available apatinib mesylate (trade name: exemestane), the pharmaceutical composition provided by the invention has the effect of reducing the inter-individual difference of the tested patients, and can provide the bioavailability of the active ingredients of the medicine and reduce the administration dosage. Based on this, the daily dose of the active ingredient can be 50-700mg, which is reduced compared with the 850mg daily dose of the existing Eitan preparation, preferably 300-600mg, more preferably 400-550mg, and most preferably 500 mg. Because of the corresponding reduction in daily dosage, which can be formulated as a unit dosage form in the daily dosage administered, the patient can only take the drug once a day, one unit dosage at a time.
The active ingredients according to the invention are present in their free base form, unless otherwise stated, and the use of the free base form of the active ingredient is completely different from the mesylate salts of the active ingredients of the prior art. The inventors have surprisingly found that when using the mesylate salt of the active ingredient as active ingredient, probably due to differences in the pH value in the gastrointestinal tract of the patients taking the drug, the mesylate salt of the active ingredient may be converted into an unabsorbable form in some of the patients, resulting in very significant individual differences between different patients. The present invention, however, greatly improves the individual variability between patients taking the drug using the free base form of the active ingredient.
As used herein, "about" should be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If, depending on the context in which the term is used, its use is not clear to a person skilled in the art, "about" means no more than plus or minus 10% of the particular term.
The pharmaceutical excipients or reagents of the invention can be commercially available, such as hypromellose acetate succinate; the compound N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide may be prepared by the method described in the example with reference to CN 201610595409.1.
Drawings
The above and other objects and features of the present invention will become apparent when taken in conjunction with the following drawings, each of which is illustrated in the accompanying drawings:
FIG. 1: dissolution curves for the A/B/C/D4 group.
FIG. 2: mean APA plasma concentration time curve of A/B/C/D4 group.
Detailed Description
The present invention is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1: preparation and characterization of nanosuspensions
Weighing about 2.5g HPMC, adding 100ml purified water, stirring for dispersion and gradually dissolving, adding 0.25g SDS, stirring for dissolving for use;
weighing about 1.0g of N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide (compound A) into 10ml of the solution, stirring for 30min, and mixing uniformly, wherein the concentration of the compound A is about 100 mg/ml;
a ball milling tank of 50ml is adopted, a small ball with the volume of 20ml is added, the milling speed is 150rpm, the milling is carried out for 60s and stopped for 30s, the appropriate amount of sampling is carried out by an injector respectively before (0h) milling, 10min after (30 min), 1h, 90min and 90min plus 10min (300rpm), the particle size is inspected (the particle size is directly detected by taking the nano suspension agent before (0h) milling and at different time of milling), and the table 1 is shown.
Table 1: particle size results before and after grinding at various times
Figure BDA0001763756180000091
Experimental example 1: physical stability of nanosuspensions
Test one: taking a proper amount of the nanometer suspension, sealing, placing in a room temperature stability test box for 17h and at 40 ℃ for 6h, and inspecting the particle size change of the suspension. As a result, the D90 was increased after the storage at 40 degrees, the D10 and D50 were not changed significantly, and the storage stability at room temperature was good, and the data are shown in Table 2.
Table 2:
Figure BDA0001763756180000092
example 2: nanoparticle tablet preparation
Figure BDA0001763756180000093
1) Nanosuspension preparation
Weighing about 2.5g HPMC (hydroxypropyl methyl cellulose) and 0.25g SDS (sodium dodecyl sulfate) and adding 120ml purified water, stirring and dissolving for standby;
weighing about 16.4mg of N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide (compound A) and adding the mixture into 82ml of the solution, and uniformly stirring the mixture to obtain a mixture, wherein the approximate concentration of the compound A is 200 mg/ml;
using a 500ml ball mill jar, a 120ml volume amount of beads was added and milled (milling speed about 250rpm) to the target particle size. The particle size after grinding is shown in Table 3
TABLE 3
Sample (I) D10 D50 D90 D[4,3]
Compound A 45.5μm 108μm 207μm 77.5μm
After grinding Compound A 0.025μm 0.105μm 1.64μm 3.26μm
2) Granulating
Placing MCC PH 10125 g in a granulator, stirring and shearing, adding a proper amount of the nano suspension to prepare a soft material, granulating, drying and finishing.
3) Tabletting
38.18g of dried granules are collected, 1.9g of PVPP and 0.4g of magnesium stearate are added, and the mixture is uniformly mixed and tabletted.
Example 3: nanocrystalline powder preparation
Figure BDA0001763756180000101
1) Preparation of nanosuspension
About 2.50g HPMC is weighed, added with 150ml purified water, stirred to dissolve, added with 0.25g docusate sodium, stirred to dissolve.
About 15.075g of Compound A was weighed into 100.5ml of the carrier solution, stirred well and sampled to determine the particle size (i.e., the particle size before grinding).
Using a 500ml ball mill jar, 100ml of the drug loaded suspension and 150ml volume of beads were added and milled (milling speed about 250rpm) to the target particle size. The particle size after grinding is shown in Table 4
TABLE 4
Sample (I) D10(μm) D50(μm) D90(μm) D[4,3](μm)
Compound A 22.2 94.3 199 105
After grinding Compound A 0.0343 0.206 2.01 0.644
2) Curing-spray drying
Controlling the inlet and outlet temperature of a spray dryer (GB210, YAMATO), feeding, and the pressure of compressed air is 0.065MPa, spray-drying the compound A nano suspension, and vacuum-drying to obtain the product.
Comparative example 1: preparation of solid Dispersion formulations
Figure BDA0001763756180000102
Figure BDA0001763756180000111
1) Preparation of solid dispersions
500g of methylene chloride/methanol (equal mass ratio) solvent is prepared. 480.2g of solvent was added to a beaker, 16.1g of Uygur was added and stirred to dissolve rapidly, and 8.0g of Compound A was added and stirred to dissolve rapidly. Spray drying to obtain solid dispersion.
2) Granulating
Taking 10.0g of solid dispersion, MCC PH 1017.5 g and gas phase SiO20.23g, mixing, tabletting and granulating.
3) Tabletting
Taking the granules, adding 0.71g of PVPP and 0.15g of magnesium stearate, uniformly mixing, and tabletting.
Comparative example 2: preparation of solid Dispersion formulations
Figure BDA0001763756180000112
1) Preparation of solid dispersions
500g of methylene chloride/methanol (equal mass ratio) solvent is prepared. 480.2g of solvent was added to a beaker, 16.1g of HPMC AS-MG was added and rapidly dissolved by stirring, and 8.0g of Compound A was added and rapidly dissolved by stirring. Spray drying to obtain solid dispersion.
2) Granulating
Taking 12.5g of solid dispersion, MCC PH 1019.38 g and gas phase SiO20.3g, mixing, pressing into tablets, and granulating.
3) Tabletting
And (3) adding 1.02g of PVPP and 0.21g of magnesium stearate into the granules, uniformly mixing, and tabletting.
Comparative example 3: preparation of ordinary quick-release tablet
Figure BDA0001763756180000113
Figure BDA0001763756180000121
1) Preparation of the adhesive
2.5g of PVPk30 was weighed, 47.5g of purified water was added, and the mixture was stirred until dissolved to obtain a 5% aqueous solution of PVPk30 for use.
2) Dry blending
10.33g of compound A, MCC PH1011.82g and PVPP0.3g are mixed evenly for standby.
3) Wet granulating and tabletting
And (3) putting the dry mixed material obtained in the step (2) into a beaker, adding a proper amount of the adhesive obtained in the step (1) to prepare a soft material, sieving and granulating, drying and finishing granules to obtain 11.2g of granules, adding 0.28g of PVPPP and 0.12g of magnesium stearate, uniformly mixing and tabletting.
Example 4: dissolution study
Sample information for testing
Figure BDA0001763756180000122
Respectively taking 1 tablet of the common quick-release tablet D, the nano-particle tablet A, the Ettch L100-55 solid dispersion tablet B and the HPMC AS-MG solid dispersion tablet C for a dissolution test, wherein the dissolution conditions are AS follows: taking 900ml of FessIF (pH6.0) solution simulating satiety intestinal juice as a medium, and the dissolution temperature: 37 ℃, rotation speed: 50rpm, sample point: 5min, 10min, 15min, 30min, 45min, 60min, 90min, 120 min. The dissolved sample solution passes through 0.45 mu m filtrate, the filtrate is taken for HPLC analysis, the drug content is determined, and the cumulative dissolution rate is calculated. See table 5.
TABLE 5
Figure BDA0001763756180000123
Figure BDA0001763756180000131
And (4) conclusion: the cumulative dissolution of the 5 tablets is in the order of: c > B > D > A. Group C rapidly dissolved, with the 45 minute cumulative dissolution reaching a maximum (about 76%) followed by some reduction; second, group B, 38% dissolved in 2 hours; the dissolution was the slowest in groups D and A, only 20% and 9% in 2 hours, respectively.
Example 5: pharmacokinetic Studies
Sample information for testing
Figure BDA0001763756180000132
The scheme is as follows: a, B, C, D four groups were used to administer different formulations A, B, C and one tablet D of compound a (all 125mg standard). Venous blood was collected at 14 time points of 10 minutes before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 36, 48 hours after administration, plasma drug concentration of compound a at 48 hours in vivo was determined by HPLC/MS-MS method, and pharmacokinetic parameters of compound a in vivo were calculated using DAS software. See Table 6
TABLE 6
Figure BDA0001763756180000133
Figure BDA0001763756180000141
And (4) conclusion: using AUC0-48hThe standard deviation/average of (A) was evaluated for individual differences between each of the different formulations, and the values in A, B, C, D groups were about 0.33, 0.22, 0.48, 0.40, it can be seen that the individual differences between the group B formulations are minimal, and it is expected that the data for these formulations will differ more among individuals and the advantages of the group B formulations will be more apparent when used in tumor patients.
Example 6: stabilizer screening
Preparing different types of stabilizer solutions for later use according to the mode of example 1, respectively weighing 350mg of the compound A, adding the compound A into the solutions, and uniformly stirring; a12 ml ball milling tank is adopted, 4.5ml of small balls with the volume are added, the grinding speed is 250rpm, grinding is carried out for 60min, and a proper amount of samples are taken to determine the particle size. See table 7.
TABLE 7
Figure BDA0001763756180000151
Example 7: long term accelerated stability test
The samples of example 3 were placed at 25 ℃ and 60% RH and 40 ℃ and 75% RH for stability.
TABLE 8
Figure BDA0001763756180000152
The stability test results of table 8 show: the nanocrystalline sample can be stably placed for up to 6 months at 25 ℃, 60% RH or 40 ℃ and 75% RH, and shows excellent stability.

Claims (44)

1. A pharmaceutical composition comprising N- [4- (1-cyanocyclopentyl) phenyl ] -2- (4-picolyl) amino-3-pyridinecarboxamide having a particle size D90 value of less than about 5000nm as an active ingredient, the active ingredient having a particle size D50 value of less than about 800nm, and at least one surface stabilizer.
2. The pharmaceutical composition of claim 1, wherein the active ingredient has a particle size D90 value of less than about 3000 nm.
3. The pharmaceutical composition of claim 1, wherein the active ingredient has a particle size D90 value of less than about 2000 nm.
4. The pharmaceutical composition of claim 1, wherein the active ingredient has a particle size D50 value of less than about 700 nm.
5. The pharmaceutical composition of claim 1, wherein the active ingredient has a particle size D50 value of less than about 600 nm.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the active ingredient has a particle size D10 value of less than about 300 nm.
7. The pharmaceutical composition of claim 6, wherein the active ingredient has a particle size D10 value of less than about 200 nm.
8. The pharmaceutical composition of claim 6, wherein the active ingredient has a particle size D10 value of less than about 100 nm.
9. The pharmaceutical composition according to any one of claims 1-5, 7-8, wherein the surface stabilizer is selected from the group consisting of anionic surface stabilizers, cationic surface stabilizers, amphoteric surface stabilizers, nonionic surface stabilizers.
10. The pharmaceutical composition of claim 1, wherein the surface stabilizer is selected from at least one of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, docusate sodium, sodium cholate, sodium deoxycholate, poloxamer, tween, sodium lauryl sulfate, polyvinyl alcohol (PVA), methylcellulose, tocopherol polyethylene glycol D- Α succinate (TPGS), hypromellose acetate succinate, Soluplus, hydroxyethylcellulose.
11. The pharmaceutical composition according to any one of claims 1-5, 7-8, 10, comprising at least two surface stabilizers.
12. The pharmaceutical composition according to any one of claims 1 to 5, 7 to 8 or 10, wherein the surface stabilizer is present in an amount of 0.1 to 99.9wt% based on the total dry weight of the active ingredient and the surface stabilizer.
13. The pharmaceutical composition according to any one of claims 1 to 5, 7 to 8 or 10, wherein the surface stabilizer is present in an amount of 1.0 to 75.0wt% based on the total dry weight of the active ingredient and the surface stabilizer.
14. The pharmaceutical composition according to any one of claims 1 to 5, 7 to 8 or 10, wherein the surface stabilizer is present in an amount of 2.5 to 35.0wt% based on the total dry weight of the active ingredient and the surface stabilizer.
15. The pharmaceutical composition according to claim 11, wherein the surface stabilizer is present in an amount of 0.1 to 99.9wt% based on the total dry weight of the active ingredient and the surface stabilizer.
16. The pharmaceutical composition according to claim 11, wherein the surface stabilizer is present in an amount of 1.0 to 75.0wt% based on the total dry weight of the active ingredient and the surface stabilizer.
17. The pharmaceutical composition according to claim 11, wherein the surface stabilizer is present in an amount of 2.5 to 35.0wt% based on the total dry weight of the active ingredient and the surface stabilizer.
18. The pharmaceutical composition according to any one of claims 1-5, 7-8, 10, 15-17, wherein the active ingredient is present in an amount of 0.5 to 99.9wt% based on the weight of the pharmaceutical composition.
19. The pharmaceutical composition of claim 18, wherein the active ingredient is present in an amount of 25.0 to 99.0wt% based on the weight of the pharmaceutical composition.
20. The pharmaceutical composition of claim 18, wherein the active ingredient is present in an amount of 65.0 to 97.5wt% based on the weight of the pharmaceutical composition.
21. The pharmaceutical composition according to any one of claims 1-5, 7-8, 10, 15-17, 19, 20, wherein the pharmaceutical composition further comprises an excipient.
22. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition is selected from an injection or a solid formulation selected from a tablet, a pill, a granule or a capsule.
23. The pharmaceutical composition according to claim 22, wherein the excipient in the solid formulation is selected from at least one of a disintegrant, a filler, a binder, and a lubricant.
24. The pharmaceutical composition of claim 23, wherein the disintegrant is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, alginic acid.
25. The pharmaceutical composition according to claim 23, wherein the disintegrant is selected from pregelatinized starch.
26. The pharmaceutical composition according to any one of claims 24-25, wherein the disintegrant is present in an amount of 1 to 20% by weight of the solid formulation.
27. The pharmaceutical composition of claim 23, wherein the filler is selected from at least one of dextrin, lactose, sucrose, calcium hydrogen phosphate, starch, calcium sulfate, microcrystalline cellulose, mannitol.
28. The pharmaceutical composition according to claim 23, wherein the filler is selected from anhydrous dibasic calcium phosphate.
29. The pharmaceutical composition of any one of claims 27-28, wherein the filler is present in an amount of 20 to 90% by weight of the solid formulation.
30. The pharmaceutical composition of claim 29, wherein the filler is present in an amount of 35 to 75% by weight of the solid formulation.
31. The pharmaceutical composition of claim 23, wherein the binder is selected from at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, alginate.
32. The pharmaceutical composition of claim 31, wherein the binder is present in an amount of 0.5 to 10% by weight of the solid formulation.
33. The pharmaceutical composition of claim 23, wherein the lubricant is selected from at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, colloidal silicon dioxide, carnauba wax, sodium stearyl fumarate.
34. The pharmaceutical composition of claim 33, wherein the lubricant is present in an amount of 0.1 to 5% by weight of the solid formulation.
35. The pharmaceutical composition according to any one of claims 1-5, 7-8, 10, 15-17, 19, 20, 22-25, 27-28, 30-34, wherein the daily dose of the active ingredient is from 50 to 700 mg.
36. The pharmaceutical composition according to claim 35, wherein the daily dose of the active ingredient is from 300 to 600 mg.
37. The pharmaceutical composition of claim 35, wherein the daily dose of the active ingredient is from 400 to 550 mg.
38. The pharmaceutical composition according to claim 35, wherein the daily dose of the active ingredient is 500 mg.
39. A process for preparing a pharmaceutical composition according to any one of claims 1 to 5, 7 to 8, 10, 15 to 17, 19, 20, 22 to 25, 27 to 28, 30 to 34, 36 to 38, comprising the step of contacting the active ingredient with at least one surface stabilizer to provide the active ingredient with a desired particle size.
40. The method of claim 39, wherein the contacting comprises milling, wet milling, homogenization, precipitation, or supercritical fluid particle generation techniques.
41. The method of claim 40, wherein the contacting is performed in a liquid medium.
42. The method of claim 41, wherein the medium is water.
43. Use of a pharmaceutical composition according to any one of claims 1-5, 7-8, 10, 15-17, 19, 20, 22-25, 27-28, 30-34, 36-38 for the manufacture of a medicament for improving the individual variability of a patient taking the medicament.
44. The use of claim 43, the improvement is relative to apatinib mesylate.
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