CN115397416A

CN115397416A - Pharmaceutical composition containing rivastigmine at molecular level and preparation method and application thereof

Info

Publication number: CN115397416A
Application number: CN202080099785.6A
Authority: CN
Inventors: 贾慧娟; 张加晏; 何学敏; 刘晓红
Original assignee: Tianjin Ruichuang Kangtai Biotechnology Co ltd; Beijing Creatron Institute Of Pharmaceutical Research Co ltd
Current assignee: Tianjin Ruichuang Kangtai Biotechnology Co ltd; Beijing Creatron Institute Of Pharmaceutical Research Co ltd
Priority date: 2020-05-09
Filing date: 2020-05-09
Publication date: 2022-11-25
Anticipated expiration: 2040-05-09
Also published as: CN115397416B; WO2021226738A1

Abstract

A pharmaceutical composition containing Lunvatinib and a preparation method and application thereof, in particular to a composition of Lunvatinib molecular level, and provides a novel composition of Lunvatinib molecular level with better stability. One aim is to provide a composition which can be taken at a lower dose which is 40-50% of the dose of the original marketed product LENVIMA to achieve the same efficacy as the original marketed product LENVIMA, and which significantly reduces the side effects associated with the dose administered; another object is to provide pharmaceutical compositions of the molecular level of ranvatinib which have a lower intra-and inter-individual variability in the organism, reduce nephrotoxicity and neurotoxicity caused by a sudden increase in plasma exposure of the drug or ineffectiveness caused by a sudden decrease in plasma exposure, and improve the safety of administration to patients.

Description

Pharmaceutical composition containing Lunvatinib at molecular level, preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, particularly relates to a pharmaceutical composition containing ranvatinib, and a preparation method and application thereof, and particularly relates to a composition of a ranvatinib molecular level and a low-dose ranvatinib composition.

Background

Patents WO 2002032872 and WO 2004080462 disclose a quinoline derivative 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy phenoxy]The (E) -7-methoxy-6-quinoline formamide (Ranvatinib) has strong angiogenesis inhibition effect and c-Kit kinase inhibition effect, and can be clinically used for treating various tumors such as thyroid cancer, lung cancer, melanoma, pancreatic cancer, renal cancer, liver cancer and the like. In 2015, the Weak company marketed the Alvarenib mesylate capsules in the United states for the treatment of DTC (differentiated thyroid carcinoma), followed by the approval of the treatment of RCC (renal cell carcinoma) and HCC (hepatocellular carcinoma), under the trade name of RCC

The preparation is capsule, the specification is 4mg and 10mg, and the maximum clinical daily dose is 24mg.

The structure of the Lunvatinib is shown as formula I:

the literature reports that the stability of the ranvatinib or the salt thereof is poor, and as reported in patent CN101001629, when the ranvatinib or the salt thereof is prepared into a pharmaceutical composition, the ranvatinib and the salt thereof are decomposed under the storage conditions of humidification and heating, and the decomposition mechanism is shown in figure 1.

Patent CN110404079A also reports the following degradation pathways: 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide and its salts also produce 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxylic acid amide in large quantities under strong acid, strong base, hydrolysis and oxidation conditions, particularly under alkaline + moist heat conditions (as shown in FIG. 2).

According to original materials of the institute

FDA evaluation reports that 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxylic acid amide is genotoxic impurity, so the quality control limit is very low,

the control limit of genotoxic impurity B in raw material is 60ppm, and the control limit in preparation is 400ppm, far lower than the quality control limit of general impurity.

To solve this product stability problem, several solutions have been proposed:

CN101001629 uses a composition containing (i) a compound whose pH value in a 5% (W/W) aqueous solution or suspension is 8 or more, and/or (ii) silicic acid or a salt thereof or a solvate thereof. CN102470133 adopts magnesium carbonate or calcium carbonate as stabilizer and dissolution promoter. Patent CN106177965 contains (a) at least one compound selected from potassium carbonate, potassium bicarbonate and (B) at least one compound selected from calcium hydrogen phosphate, calcium phosphate or calcium sulfate. Patents CN106075456 and CN106551935 adopt calcium hydrogen phosphate to solve the problems of stability and dissolution. The above stability solutions are directed to common formulations, and the stability effect on genotoxic impurity B has not been reported either. In addition, the above schemes all adopt the ordinary HPLC method for detecting impurities, and as described above, the ordinary HPLC method cannot accurately quantify the genotoxic impurity B because the quality control limit of the genotoxic impurity B is in the ppm level, and therefore, the stability effect of the above schemes on the genotoxic impurity B is unknown.

Compared with the common preparation, in the solid dispersion preparation of the ranvatinib, the ranvatinib can be degraded quickly, the reported common stabilizer has no obvious effect on the degradation, and the genotoxic impurity B can be greatly increased after being placed at 60 ℃ for 10 days and exceeds the quality control limit (400 ppm) of the preparation.

Therefore, it is a challenge to provide a stable formulation of ranvatinib that has good dissolution characteristics.

On the other hand, the problems of low solubility of the varlitinib mesylate and the varlitinib mesylate are also present. To improve solubility, several schemes have been reported in the literature: CN109044977A provides a solid dispersion of varenib comprising varenib and a water soluble carrier material; the mass ratio of the Ranatinib to the water-soluble carrier material is 10: 1-1: 10.WO2013105895A1 provides a pharmaceutical composition comprising at least one protein kinase inhibitor and at least one stable, amorphous hybrid nanoparticle of a polymer stabilizing and matrix forming component; wherein the composition optionally further comprises at least one pharmaceutically acceptable solubilizer.

According to the report of an Int J Clin Pharmacol Ther.2015 Feb, 53 (2): 190-8, published by Ranvatinib raw research company (Wei material), levatinib mesylate capsules with different crystal form contents are prepared, and a human body PK test proves that the C crystal form content of the Ranvatinib mesylate in the preparation is less than 4 percent (the rest is amorphous) and the preparation with 15 percent (the rest is amorphous) crystal form content of the Ranvatinib mesylate in the preparation is bioequivalent. Based on this, the original preparation

The mesogenic lovatinib is also present predominantly in amorphous form.

The solid dispersion of lunvatinib prepared according to the exemplary embodiments of patents CN109044977A, WO2013105895A1 was subjected to dissolution test by two-step dissolution method simulating physiological conditions of human body, as same as the method

No improvement in dissolution is observed, nor are any reports of solid dispersions of ranvatinib

Comparative pharmacokinetic profile in vivo.

Therefore, the in vitro dissolution effect which is more excellent than that of the original preparation LENVIMA obtained by converting the mesylate C crystal form with poor solubility into an amorphous form through wet granulation cannot be obtained by the solid dispersion technology, the dissolution behaviors in two-step dissolution media simulating the physiological conditions of a human body are consistent or are not obviously improved, and the expected in vivo effect cannot be obtained by the solid dispersion solution.

According to the U.S. Lenvima FDA Clinical Pharmacology and Biopharmaceutical Review, 24mg of patients orally administered once a day, 68% of patients had to adjust their dose because side effects were not tolerated and 15% had to stop their dosing because of side effects; while the most common side effects are hypertension, urine protein, nausea, vomiting, diarrhea; the probability of side effects occurring is significantly higher when 24mg per day and 14mg per day are taken.

Therefore, how to use less medicine to take the dose to achieve the same treatment effect as the original high-dose group, reduce the side effect related to the dose, improve the tolerance of patients, overcome batch-to-batch in-vitro dissolution difference and in-vivo high variation caused by the existing process of the original research, and develop a pharmaceutical composition with stable quality, safety, effectiveness, better tolerance and obvious clinical advantages has great challenge.

Disclosure of Invention

In view of the above, the invention provides a novel pharmaceutical composition with good stability and a molecular level of ranvatinib for solving the problems of instability, easy degradation, poor batch reproducibility, high variation in vivo and the like of the existing marketed product preparation; it is an object of the present invention to provide a pharmaceutical composition which can achieve the same therapeutic effect as the original marketed product levnmima by administering a lower dose of 40% to 50% of the composition, and which significantly reduces the side effects associated with the dose administered; it is another object of the present invention to provide pharmaceutical compositions of the molecular level of ranvatinib that have lower intra-and inter-individual variability in the organism, reduce nephrotoxicity and neurotoxicity caused by sudden increase in plasma exposure of the drug or ineffectiveness caused by sudden decrease in plasma exposure, and improve the safety of administration to patients.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a pharmaceutical composition, which comprises a molecular level composition of the ranvatinib, wherein the molecular level composition of the ranvatinib contains:

1) Active ingredients: (ii) varlitinib or a pharmaceutically acceptable salt or solvate thereof;

2) A stabilizer;

3) A polymeric carrier;

the pharmaceutical composition is placed at 60 ℃ for 10 days, and the genotoxic impurity B is less than 400ppm.

In some embodiments of the invention, the pharmaceutical composition has a pharmacokinetic AUC _0-t Compared with the original preparation

The improvement is at least 40%. Corresponding to the existing marketed drugs

The specific dosage or specification can be reduced by more than 40 percent。

The variability is reduced, preferably CV is less than or equal to 30%.

In some embodiments of the invention, the stabilizer is selected from at least one of tromethamine, meglumine or sodium lauryl sulfate.

In some embodiments of the present invention, the polymeric carrier is at least one selected from hypromellose, hyprolose, copovidone, hypromellose phthalate, povidone, hypromellose acetate succinate, hydroxyethyl cellulose, and acrylic resin.

In some embodiments of the present invention, the polymeric carrier is at least one selected from hypromellose, copovidone, hypromellose phthalate, hypromellose acetate succinate, acrylic resin, and povidone.

In some embodiments of the invention, the pharmaceutically acceptable salt thereof is selected from at least one of the hydrochloride, hydrobromide, p-toluenesulfonate, methanesulfonate, sulfate or ethanesulfonate of ranvatinib, preferably of ranvatinib mesylate.

In some embodiments of the invention, the solvate of the ranvatinib or the pharmaceutically acceptable salt thereof is a hydrate, a dimethylsulfoxide, or an acetate.

In some embodiments of the present invention, the weight ratio of the active ingredient, the stabilizer and the polymeric carrier is 1 (0.05-0.75) to (0.5-10), preferably 1 (0.05-0.6) to (1-5), and more preferably 1 (0.1-0.6) to (1-3).

In some embodiments of the invention, the pharmaceutical composition comprises the following scheme:

(1) The stabilizer is tromethamine, and the high molecular carrier is hydroxypropyl methylcellulose acetate succinate;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active ingredient, the stabilizer and the polymer carrier is 1 (0.05-0.75) to (0.5-10), preferably 1 (0.05-0.4) to (1-5), more preferably 1 (0.075-0.3) to (1-2), and further preferably 1 (0.1-0.3) to (1-2);

or (2) the stabilizer is meglumine, and the high molecular carrier is hydroxypropyl methylcellulose acetate succinate;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

or (3) the stabilizer is sodium dodecyl sulfate, and the high molecular carrier is hydroxypropyl methylcellulose;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active ingredient to the stabilizer to the macromolecular carrier is 1 (0.075-0.5) to 1-5), preferably 1 (0.15-0.5) to 1-3, more preferably 1 (0.15-0.25) to 1-2;

or (4) the stabilizer is sodium dodecyl sulfate, and the polymer carrier is copovidone;

the active ingredient is rivastigmine and/or rivastigmine mesylate, preferably rivastigmine;

the weight ratio of the active ingredient, the stabilizer and the polymer carrier is 1 (0.1-0.75) to (1-5), preferably 1 (0.4-0.75) to (2-3), more preferably 1 (0.4-0.6) to (2-3);

or (5) the stabilizer is sodium dodecyl sulfate, and the polymer carrier is a copolymer of ethyl acrylate-methyl methacrylate and chlorinated trimethylamine-based ethyl methacrylate;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active ingredient to the stabilizer to the polymer carrier is 1 (0.1-0.5) to 1-5, preferably 1 (0.2-0.5) to 2-3, and more preferably 1 (0.2-0.3) to 3.

Or (6) the stabilizer is sodium dodecyl sulfate, and the polymer carrier is povidone;

the weight ratio of the active ingredient to the stabilizer to the polymer carrier is 1 (0.05-0.75) to 1-10, preferably 1 (0.2-0.5) to 2-3, and more preferably 1 (0.2-0.3) to 3.

In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient selected from at least one of a filler, a disintegrant, a binder, a lubricant, a flavoring agent, and a suspending agent.

In some embodiments of the present invention, the pharmaceutical composition is in the form of a capsule, a tablet, a granule, a suspension, preferably a capsule, a tablet, more preferably a tablet.

On the basis of the above research, the present invention also provides a cosolvent for dissolving the ranvatinib or the pharmaceutically acceptable salt or solvate thereof, the cosolvent comprising a halogenated methane and an alcohol.

In some embodiments of the invention, the alcohol is preferably methanol and/or ethanol.

In some embodiments of the invention, the methyl halide is preferably methylene chloride.

In some embodiments of the invention, the ratio of methyl halide to alcohol is 10.

In some embodiments of the invention, the cosolvent comprises the following scheme:

(1) The latent solvent comprises dichloromethane and methanol;

the ratio of dichloromethane to methanol is 10;

or (2) the cosolvent comprises dichloromethane and ethanol;

the ratio of dichloromethane to ethanol is 10 to 10, preferably 10.

In addition, the present invention provides a method for increasing the solubility of the rivastigmine or a pharmaceutically acceptable salt or solvate thereof using the cosolvent.

On the basis of the research, the invention also provides a preparation method of the molecular level composition of the ranvatinib, which comprises the steps of dissolving the active ingredient, the stabilizer and the high molecular carrier in an organic solvent, and carrying out spray drying to obtain the solid dispersing agent.

In some embodiments of the invention, the organic solvent is the latent solvent.

The invention also provides application of the pharmaceutical composition or the molecular level composition of the ranvatinib prepared by the preparation method in preparation of a medicine for treating or preventing cancer/tumor. In some embodiments of the invention, the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, gastric cancer, or lung cancer.

The invention also provides a method for treating or preventing cancer/tumor, and a molecular level composition of the ranvatinib, which is prepared by using the pharmaceutical composition or the preparation method. In some embodiments of the invention, the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, gastric cancer, or lung cancer.

The invention provides a novel Lovatinib molecular level composition with good stability, which can obviously improve the bioavailability in vivo. The invention also provides a method for treating or preventing cancer/tumor, and a molecular level composition of the ranvatinib, which is prepared by using the pharmaceutical composition or the preparation method.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.

FIG. 1 shows the decomposition mechanism of the decomposition under humidified, heated storage conditions when Rankine or its salt is formulated into a pharmaceutical composition;

FIG. 2 shows the degradation pathway of Ranvatinib;

FIG. 3 shows a compound of formula (I): DSC of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide;

FIG. 4 shows a compound of formula (I): TGA of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide;

FIG. 5 shows a compound of formula (I): XRPD of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide;

FIG. 6 shows a compound of formula (I): IR of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide;

FIG. 7 shows a DSC of a sample of comparative example 1 from which the peak of lenvatinib at 234 ℃ disappeared, indicating the formation of a molecular level composition;

FIG. 8 shows a DSC of a sample of comparative example 3 from which the peak of Rankine at 234 ℃ disappears, indicating the formation of a composition at the molecular level;

FIG. 9 shows a DSC of a sample of comparative example 4 from which the peak of Rankine at 234 ℃ disappears, indicating the formation of a composition at the molecular level;

FIG. 10 shows a DSC of a physical mixture of Rankine, HPMCAS, tromethamine;

FIG. 11 shows a DSC of a sample of example 8 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 12 shows a DSC of a sample of example 14 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 13 shows a DSC of a physical mixture of Ranvatinib, HPMC K15M, SDS;

FIG. 14 shows a DSC of a sample of example 19 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 15 shows a DSC of a sample of example 22 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 16 DSC chart of physical mixture of Lolvatinib, copovidone VA64, SDS;

FIG. 17 shows a DSC of a sample of example 29 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 18 shows a DSC of a sample of example 30 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 19 shows the formula,

DSC profile of SDS physical mixture;

FIG. 20 shows a DSC of a sample of example 35 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 21 shows a DSC of a sample of example 38 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 22 shows a DSC chart of a physical mixture of Lonicenib, povidone, SDS;

FIG. 23 shows a DSC of a sample of example 43 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 24 shows a DSC of a sample of example 49 from which the peak of lenvatinib at 234 ℃ disappears, indicating the formation of a molecular level composition;

FIG. 25 shows a DSC of a sample of example 50 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 26 shows a DSC of a sample of example 51 showing the disappearance of the peak of Rankine at 234℃, indicating the formation of a composition at the molecular level;

FIG. 27 shows a DSC of a sample of example 52 showing the disappearance of the peak of lenvatinib at 234 ℃ indicating the formation of a molecular level composition;

FIG. 28 shows the original preparation

The molecular level composition preparation and the original preparation have no obvious difference in dissolution according to a graph of simulated gastric fluid and simulated intestinal fluid dissolution in the examples and the comparative examples;

FIG. 29 shows the original preparation

The dissolution curve of phosphate buffer solution with pH6.8 and HCl + of comparative example 28-32.1M shows that the molecular level composition preparation has no obvious difference from the original preparation;

figure 30 shows the original preparation

The dissolution curve of the phosphate buffer solution with pH6.8 and HCl + of 58 to 63.0.1M of the examples shows that the molecular level composition has no obvious difference in the dissolution ratio with the original preparation;

FIG. 31 shows the original preparation

The dissolution curve of the phosphate buffer solution of comparative example 33 and examples 64-66.1M HCl + pH6.8 shows that the molecular level composition preparation has no obvious difference from the original preparation in the dissolution ratio;

FIG. 32 shows the original preparation

The dissolution curve of the phosphate buffer solution of comparative example 34 and examples 67-69, 0.1M HCl + pH6.8 shows that the molecular level composition preparation has no obvious difference from the original preparation in the dissolution ratio;

FIG. 33 shows the original preparation

The dissolution curve of phosphate buffer solution with pH6.8 of 70-74.1M HCl + is shown, and the molecular level composition preparation has no obvious difference from the original preparation in the dissolution ratio;

figure 34 shows the original preparation

The dissolution curve of phosphate buffer solution with pH6.8 of 75-80.1M HCl + is shown, and the molecular level composition preparation has no obvious difference from the original preparation in the dissolution ratio.

Detailed Description

The invention discloses a pharmaceutical composition containing Rivatinib and a preparation method and application thereof, and a person skilled in the art can realize the purpose by appropriately improving process parameters by referring to the content. It is specifically noted that all such substitutions and modifications will be apparent to those skilled in the art and are intended to be included herein. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The invention provides a novel pharmaceutical composition with good stability and molecular level of Rankine, aiming at solving the problems of instability and easy degradation of Rankine, poor batch reproducibility, high variation in vivo and the like in the existing preparation of the composition with molecular level of Rankine; an object of the present invention is to provide a pharmaceutical composition which can achieve the same efficacy as the original marketed product levima by administering a lower dose of 40% to 50% of the composition, and which significantly reduces the side effects associated with the administered dose; it is another object of the present invention to provide pharmaceutical compositions of the molecular level of ranvatinib that have lower intra-and inter-individual variability in the organism, reduce nephrotoxicity and neurotoxicity caused by sudden increase in plasma exposure of the drug or ineffectiveness caused by sudden decrease in plasma exposure, and improve the safety of administration to patients.

To this end, the present invention provides in a first aspect a pharmaceutical composition comprising a molecular level composition of varenib comprising:

2) A stabilizer;

3) A polymer carrier, wherein the polymer carrier is a polymer,

wherein the stabilizer is at least one selected from tromethamine, meglumine and sodium dodecyl sulfate.

The invention also provides a low-dose ranvatinib composition, which comprises the molecular level composition, and the dosage form of the low-dose ranvatinib composition can be capsules, tablets, granules and suspensions, preferably capsules and tablets, and more preferably tablets.

By preparing a molecular level composition having a low dose such that it exhibits a similar or increased AUC in an organism as the original formulation of LENVIMA or an imitation thereof; administration at doses lower than usual or conventional doses may also reduce side effects.

As used herein, the term "low dose" refers to a therapeutically effective dose of ranvatinib (or a pharmaceutically acceptable salt or solvate thereof) that is less than the conventional or customary dose required to produce an equivalent or greater therapeutic effect.

The ranvatinib (or a pharmaceutically acceptable salt or solvate thereof) may be administered at least once daily in a dose range of about 1mg to about 30mg. Preferably, the administration of lenvatinib (or a pharmaceutically acceptable salt or solvate thereof) is at least once daily in a dose range of about 1mg to about 20mg. Preferably, the administration of lenvatinib (or a pharmaceutically acceptable salt or solvate thereof) is at least once daily in a dose range of about 1mg to about 15mg.

In some embodiments of the present invention, the polymeric carrier is selected from at least one of hypromellose, hyprolose, copovidone, hypromellose phthalate, povidone, hypromellose acetate succinate, hydroxyethyl cellulose, acrylic resin.

In some preferred embodiments of the invention, the polymeric carrier is selected from Hypromellose (HPMC), copovidone (VA 64), hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), ethyl acrylate-methyl methacrylate, and chloromethylmethacrylate copolymer

At least one of povidone.

In other embodiments of the present invention, the pharmaceutically acceptable salt of ranvatinib is selected from at least one of a hydrochloride, hydrobromide, p-toluenesulfonate, methanesulfonate, sulfate or ethanesulfonate of ranvatinib.

In other further preferred embodiments of the invention, the pharmaceutically acceptable salt of ranvatinib is ranvatinib mesylate.

In other embodiments of the present invention, the weight ratio of the active ingredient, the stabilizer, and the polymeric carrier is 1.

In other preferred embodiments of the present invention, the weight ratio of the active ingredient, the stabilizer, and the polymeric carrier is 1.

In other more preferred embodiments of the present invention, the weight ratio of the active ingredient, the stabilizer, and the polymeric carrier is 1.

In some embodiments of the present invention, the active ingredient is rivastigmine and/or rivastigmine mesylate, preferably rivastigmine, the stabilizer is tromethamine, the polymeric carrier is hypromellose acetate succinate, and the weight ratio of the active ingredient, the stabilizer, and the polymeric carrier is 1.

In some embodiments of the present invention, the weight ratio of the active ingredient, the stabilizer, and the polymeric carrier is 1.

In other embodiments of the present invention, the weight ratio of the active ingredient, stabilizer, polymeric carrier is 1.

In other preferred embodiments of the present invention, the weight ratio of the active ingredient, the stabilizer and the polymeric carrier is 1.

In some embodiments of the present invention, the active ingredient is ranvatinib and/or ranvatinib mesylate, preferably ranvatinib, the stabilizer is meglumine, the polymeric carrier is hypromellose acetate succinate, and the weight ratio of the active ingredient, the stabilizer and the polymeric carrier is 1.

In some embodiments of the present invention, the active ingredient is ranvatinib and/or ranvatinib mesylate, preferably ranvatinib, the stabilizer is sodium lauryl sulfate, the polymeric carrier is hypromellose, and the weight ratio of the active ingredient to the stabilizer to the polymeric carrier is 1.

In some embodiments of the present invention, the active ingredient is ranvatinib and/or ranvatinib mesylate, preferably, ranvatinib, the stabilizer is sodium lauryl sulfate, the polymeric carrier is copovidone, and the weight ratio of the active ingredient to the stabilizer to the polymeric carrier is 1.

In some embodiments of the present invention, the active ingredient is rivastigmine and/or rivastigmine mesylate, preferably rivastigmine, the stabilizer is sodium lauryl sulfate, the polymeric carrier is a copolymer of ethyl acrylate-methyl methacrylate and trimethylammoniumchloride methacrylate, and the weight ratio of the active ingredient, the stabilizer, and the polymeric carrier is 1.

In some preferred embodiments of the present invention, the weight ratio of the active ingredient, the stabilizer and the polymeric carrier is 1.

In some embodiments of the present invention, the active ingredient is ranvatinib and/or ranvatinib mesylate, preferably ranvatinib, the stabilizer is sodium lauryl sulfate, the polymeric carrier is povidone, and the weight ratio of the active ingredient to the stabilizer to the polymeric carrier is 1.

In some embodiments of the present invention, the pharmaceutical composition is in the form of a capsule, tablet, granule, suspension, preferably a capsule, tablet, more preferably a tablet.

For the preparation of a dosage form for patient use, the composition may also contain suitable excipients, such as fillers, disintegrants, binders, lubricants, glidants, etc., one or more of which may be added as required for the dosage form. Examples of the filler include starch, microcrystalline cellulose, pregelatinized starch, maltitol, sorbitol, trehalose, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, and lactose. Examples of the disintegrant include dry starch, pregelatinized starch, croscarmellose sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, and crospovidone. Examples of the binder include hydroxypropyl cellulose, hypromellose, povidone, sodium carboxymethyl cellulose, starch slurry, and gum arabic. Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol, and glyceryl behenate. Examples of the glidant include silicon dioxide, talc, glyceryl behenate and the like.

In a second aspect, the present invention provides a cosolvent for dissolving ranvatinib or a pharmaceutically acceptable salt thereof or a solvate thereof, said cosolvent comprising a ratio of methyl halide to alcohol of 10.

In some preferred embodiments of the invention, the cosolvent comprises dichloromethane and methanol in a ratio of 10.

In other preferred embodiments of the present invention, the cosolvent comprises dichloromethane and ethanol in a ratio of 10.

The third aspect of the invention provides a preparation method of a molecular level composition of rivastigmine, comprising dissolving the active ingredient, the stabilizer and the polymeric carrier in an organic solvent, and spray-drying to obtain a solid dispersant, wherein the organic solvent is the latent solvent of the second aspect.

Preferably, 0-100% of the stabilizer is dissolved in the mixed solvent, then the carrier, the active ingredient and the rest of the stabilizer are added for dissolution, and spray drying is carried out to obtain the molecular level composition. More preferably, 0-50% of the stabilizer is dissolved in the mixed solvent, then the carrier is added for dissolution, then the active ingredient and the rest of the stabilizer are added for dissolution, and spray drying is carried out to obtain the molecular level composition. If necessary, the residual solvent may be further removed by drying under reduced pressure.

In some embodiments of the invention, the composition at the molecular level of ranvatinib is mixed with fillers, disintegrants, binders and the like, granulated, sized, blended together, tableted or filled into capsules. Or mixing the composition at the molecular level of Rankine with filler, disintegrant, binder, etc., and directly tabletting or encapsulating.

The fourth aspect of the invention provides the use of a molecular level composition of ranvatinib in the preparation of a medicament for the treatment or prevention of cancer/tumor, wherein the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, gastric cancer, lung cancer, but is not limited to the above.

The experimental procedures in the following examples are conventional, unless otherwise specified. Raw material medicines, reagents, kits and experimental instruments used for the experiment can be purchased from the market without special instructions.

FIGS. 3 to 7 show the DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), XRPD (X-ray powder diffraction) and IR (infrared spectroscopic analysis) results of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide (Ranvatinib), respectively.

The invention is further illustrated by the following examples:

experimental example 1 Lunvatinib-dissolving solvent screening

Weighing the bulk drug (API) of the Rankine, adding an organic solvent, heating in a water bath at 50 ℃, and shaking for 30min to dissolve the bulk drug.

TABLE 1 Single organic solvent screening

From the above results, it is understood that three solvents, N-methylpyrrolidone, dimethylsulfoxide and N, N-dimethylformamide, have high solubility, but these three solvents have high boiling points and are not suitable for use as solvents in spray drying. Furthermore, the solubility of lenvatinib is very low when dichloromethane, methanol or ethanol is used alone.

Table 2 mixed organic solvent screening (2

Based on the above results, we surprisingly found that the solubility of the dichloromethane and methanol mixed solvent and the dichloromethane and absolute ethanol mixed solvent to the rivastigmine is greatly improved, and the two mixed solvent systems are further screened in order to search for the optimal ratio.

TABLE 3 dichloromethane-methanol solvent System

From the above results, it is found that the dichloromethane-methanol mixed solvent has a large solubility when the ratio of the two is in the range of 10.

TABLE 4 dichloromethane-ethanol solvent System

From the above results, it is found that the dichloromethane/anhydrous ethanol mixed solvent has a large solubility when the ratio of the two is in the range of 10.

Experimental example 2 molecular level composition preparation and stability investigation

TABLE 5 comparative example molecular level composition recipe (g)

Comparative example	1	2	3	4	5
API	2.0	2.0	2.0	2.0	2.0
VA64	10.0	/	/	/	/
HPMCP(HP55)	/	3.0	/	/	/
HPMC(K100LV)	/	/	4.0	/	/
HPMCAS(HG)	/	/	/	2.0	/
EUDRAGIT	/	/	/	/	6.0

(RL100)

Note: comparative example 1 was prepared according to patent CN109044977A, example 5, and comparative example 2 was prepared according to patent WO2013105895A1, example 146, exchanging nilotinib for rivastigmine.

The preparation method comprises the following steps: adding a dichloromethane-methanol mixed solvent (3) into API for dissolving, adding a polymer carrier for dissolving, performing spray drying by adopting a Yamaduo spray drying machine set, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 deg.C under reduced pressure for 24 hr until the water content is less than 2%.

Taking a proper amount of the molecular level composition prepared in the table 5, sieving the molecular level composition and the stabilizer by a 80-mesh sieve for 8 times, mixing the mixture, putting the mixture into a penicillin bottle, sealing the penicillin bottle by a rolling cover, and inspecting the mixture for 10 days at the temperature of 60 ℃. Genotoxic impurity B (ZZ-B) is detected by UPLC method, and total impurities are detected by HPLC method.

TABLE 6 results of stabilizer screening for different molecular level compositions

As can be seen from the above table, the conventional stabilizers disclosed in the patent literature all have no significant effect on the composition at the molecular level of Rankine, and the genotoxic impurity B is greater than 400ppm when the composition is left at 60 ℃ for 10 days.

Examples 1, 2, comparative examples 6 to 12: preparation of different-prescription molecular level composition with HPMCAS as carrier and stability investigation

TABLE 7 molecular level composition recipe (g)

The preparation method comprises the following steps: adding a dichloromethane-methanol mixed solvent (3) into API for dissolving, adding a stabilizer for dissolving, adding a polymer carrier for dissolving, performing spray drying by adopting a Yamaduo spray drying machine set, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 4h. And (3) putting a small amount of dried spray-dried powder into a penicillin bottle, sealing the penicillin bottle by a rolling cover, and inspecting the penicillin bottle at the temperature of 60 ℃ for 10 days. The genotoxic impurity B is detected by a UPLC method, and the total impurities are detected by an HPLC method.

Table 8 HPMCAS vector formulation stability results

According to the results, the fact that the addition of tromethamine or meglumine in the formula has a remarkable effect on stability is surprisingly found for the composition at the molecular level of the ranvatinib, the toxic impurity B of the gene is less than 400ppm after 10 days of investigation at the temperature of 60 ℃, and other stabilizers have no remarkable effect.

Examples 3 to 14: molecular level composition using HPMCAS as carrier, tromethamine and meglumine optimal dosage screening method

TABLE 9 molecular level composition recipe (g)

The preparation method comprises the following steps: adding a dichloromethane-methanol mixed solvent (3) into API to dissolve, adding a stabilizer to dissolve, adding a polymer carrier to dissolve, performing spray drying by adopting a Yamaduo spray drying unit, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 4h. And (3) putting a small amount of dried spray-dried powder into a penicillin bottle, sealing the penicillin bottle by a rolling cover, and inspecting the penicillin bottle at the temperature of 60 ℃ for 10 days. The genotoxic impurity B is detected by UPLC method, and the total impurity is detected by HPLC method.

TABLE 10 HPMCAS vector prescription stability results (API 2.0g + HPMCAS 2.0 g)

From the above results, it is found that the addition of tromethamine (Tris) in the formulation has a certain effect on stability, and the effect is better when the amount of API: tris is 1. Meglumine (Mglm) is added in the formula, so that a certain effect is achieved on stability, the effect is better when the dosage of API (Mglm) is 1.

The stabilizer is still effective when the active ingredient is changed into the mesylate.

Example 15, comparative examples 13-17: preparation and stability investigation of different-prescription molecular level composition with HPMC (hydroxy propyl methyl cellulose) as carrier

TABLE 11 molecular level composition recipe (g)

Table 12 HPMC vehicle formulation stability results

According to the results, the inventor surprisingly found that sodium dodecyl sulfate added in the formula has a remarkable effect on stability for the ranvatinib molecular level composition taking HPMC as a carrier, and other stabilizers (including tromethamine and meglumine which have a remarkable effect on HPMCAS carrier) have no remarkable effect.

Examples 16 to 22: molecular level composition sodium dodecyl sulfate optimum dosage screening of HPMC carrier

TABLE 13 molecular level composition recipe (g)

Examples	API	HPMC(K15M)	Sodium dodecyl sulfate
Example 16	2.0	2.0	0.10
Example 17	2.0	2.0	0.20
Example 18	2.0	2.0	0.30
Example 19	2.0	2.0	0.40
Example 20	2.0	2.0	0.60
Example 21	2.0	2.0	0.80
Example 22	2.0	2.0	1.00

The preparation method comprises the following steps: adding a dichloromethane-methanol mixed solvent (3) into API for dissolving, adding a stabilizer for dissolving, adding a polymer carrier for dissolving, performing spray drying by adopting a Yamaduo spray drying machine set, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 4h. And (3) placing a small amount of dried spray-dried powder into a penicillin bottle, rolling a cover, sealing, and placing at 60 ℃ for 10 days. The genotoxic impurity B is detected by a UPLC method, and the total impurities are detected by an HPLC method.

TABLE 14 HPMC carrier recipe stability results (API 2.0g + HPMC 2.0g)

From the above results, sodium Dodecyl Sulfate (SDS) is added to the formulation, and the effect is preferable when the amount of API SDS is 1.

Example 23, comparative examples 18 to 22: preparation of different-prescription molecular level composition taking VA64 as carrier and stability investigation

TABLE 15 molecular level composition recipe (g)

The preparation method comprises the following steps: adding a dichloromethane-methanol mixed solvent (3) into API to dissolve, adding a stabilizer to dissolve, adding a polymer carrier to dissolve, performing spray drying by adopting a Yamaduo spray drying unit, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 4h. And (3) placing a small amount of dried spray-dried powder into a penicillin bottle, rolling a cover, sealing, and placing at 60 ℃ for 10 days. The genotoxic impurity B is detected by UPLC method, and the total impurity is detected by HPLC method.

TABLE 16 VA64 vector formulation stability results

According to the results, the inventors surprisingly found that the addition of sodium dodecyl sulfate has a certain effect on the stability of the composition at the molecular level of the ranvatinib with VA64 as a carrier, and other stabilizers have no obvious effect.

Examples 24 to 30: molecular level composition sodium dodecyl sulfate optimal dosage screening using VA64 as carrier

TABLE 17 molecular level composition prescription (g)

Examples	API	VA64	Sodium dodecyl sulfate
Example 24	2.0	4.0	0.20
Example 25	2.0	4.0	0.40
Example 26	2.0	4.0	0.50
Example 27	2.0	4.0	0.80
Example 28	2.0	4.0	1.00
Example 29	2.0	4.0	1.20
Example 30	2.0	4.0	1.50

The preparation method comprises the following steps: adding a dichloromethane-methanol mixed solvent (3) into API for dissolving, adding a stabilizer for dissolving, adding a polymer carrier for dissolving, performing spray drying by adopting a Yamaduo spray drying machine set, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 4h. And (3) putting a small amount of dried spray-dried powder into a penicillin bottle, sealing the penicillin bottle by a rolling cover, and inspecting the penicillin bottle at the temperature of 60 ℃ for 10 days. The genotoxic impurity B is detected by UPLC method, and the total impurity is detected by HPLC method.

TABLE 18 VA64 Carrier prescription stability results (API 2.0g + VA64.0g)

From the above results, it is found that the effect is preferable when the amount of Sodium Dodecyl Sulfate (SDS) added to the formulation is 1.

Example 31, comparative examples 23-26:

different prescriptionsMolecular level composition preparation

TABLE 19 molecular level composition recipe (g)

Examples/comparative examples	Comparative example 23	Comparative example 24	Example 31	Comparative example 25	Comparative example 26
API	2.0	2.0	2.0	2.0	2.0
RL100	6.0	6.0	6.0	6.0	6.0
Tromethamine	0.30	/	/	/	/
Meglumine	/	0.30	/	/	/

Sodium dodecyl sulfate	/	/	0.30	/	/
Diethylamine	/	/	/	0.30	/
Triethanolamine	/	/	/	/	0.30

TABLE 20 RL100 Carrier formulation stability results

According to the results, the inventors surprisingly found that the addition of sodium dodecyl sulfate has a certain effect on the stability of the composition at the molecular level of the lunvatinib with RL100 as a carrier, and other stabilizers have no obvious effect.

Examples 32 to 38: RL100 vector molecular level composition sodium dodecyl sulfate optimum dosage screening

TABLE 21 molecular level composition recipe (g)

Examples	API	RL100	Sodium dodecyl sulfate
Example 32	2.0	6.0	0.10
Example 33	2.0	6.0	0.20
Example 34	2.0	6.0	0.30
Example 35	2.0	6.0	0.40

Example 36	2.0	6.0	0.60
Example 37	2.0	6.0	0.80
Example 38	2.0	6.0	1.00

The preparation method comprises the following steps: adding a dichloromethane-methanol mixed solvent (3) into API to dissolve, adding a stabilizer to dissolve, adding a polymer carrier to dissolve, performing spray drying by adopting a Yamaduo spray drying unit, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 4h. And (3) putting a small amount of dried spray-dried powder into a penicillin bottle, sealing the penicillin bottle by a rolling cover, and inspecting the penicillin bottle at the temperature of 60 ℃ for 10 days. The genotoxic impurity B is detected by a UPLC method, and the total impurities are detected by an HPLC method.

TABLE 22 RL100 Carrier recipe stability results (API 2.0g + RL100.0g)

Examples 39 to 30: preparation of molecular level composition using polyvidone as carrier

TABLE 23 Povidone Carrier molecular level composition recipe (g)

Table 24 povidone vehicle formulation stability results

According to the results, the generation of ZZ-B impurity can be improved by adding Sodium Dodecyl Sulfate (SDS) in the formula of the molecular level composition using povidone as a carrier, and the effect is better when the amount of API is 1.10-0.75.

Examples 49-57 preparation of compositions at the molecular level and stability Studies

TABLE 25 molecular level composition prescription (g)

Examples 49-51 preparation method: adding a dichloromethane-methanol mixed solvent (3) into an API and a stabilizer for dissolving, adding a polymer carrier for dissolving, performing spray drying by adopting a Yamaduo spray drying unit, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder for 6h at 40 ℃ under reduced pressure.

Examples 52-54 methods of preparation: adding a stabilizer into a dichloromethane-methanol mixed solvent (3) for dissolving, adding API for dissolving, adding a polymer carrier for dissolving, performing spray drying by adopting a Yamaduo spray drying unit, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 6h.

Examples 55-57 methods of preparation: adding a dichloromethane-methanol mixed solvent (3) into an API, a stabilizer and a carrier for dissolving, performing spray drying by adopting a Yamaduo spray drying unit, wherein the air inlet temperature is 100 ℃, the liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and collecting the obtained spray-dried powder. Drying the spray-dried powder at 40 ℃ under reduced pressure for 6h.

And (3) putting a small amount of the prepared molecular level composition into a penicillin bottle, sealing by rolling a cover, and inspecting at the temperature of 60 ℃ for 10 days. The genotoxic impurity B is detected by a UPLC method, and the total impurities are detected by an HPLC method.

TABLE 26 stability results for compositions at the molecular level for different formulations

According to the results, the molecular level compositions prepared by the above formula have better stability. Comparative examples 28 to 34, examples 58 to 80: tablet preparation

Table 27 tablet formulation (250 tablets/batch)

The preparation process of the tablet comprises the following steps: weighing the materials according to the above table, sieving with 50 mesh sieve for 8 times, mixing, single-punch tabletting machine (Chinese medicine Longli DP 30A), shallow concave punch with diameter of 10mm, and tabletting.

Effect example 1 two-step dissolution test simulating physiological conditions of human body

(1) Simulated gastric fluid + simulated intestinal fluid dissolution test

Simulated gastric fluid: 10g of NaCl, 0.2g of sodium taurocholate, 0.075g of lecithin and 0.5g of pepsin, adding purified water until 9.5L of the mixture is dissolved, and adjusting the pH to 1.60 by using 0.1M HCL;

regulating liquid: 13.44g of sodium taurocholate, 1.14g of lecithin, 17.752g of maleic acid and 24g of NaOH, and purified water is added until 4L of the mixture is dissolved;

simulating intestinal juice: 187ml of simulated gastric fluid and 63ml of conditioning fluid are added to obtain simulated intestinal fluid with pH of about 6.5.

Dissolution method and results:

paddle, 100rpm,37 ℃, cuvette method.

187ml of simulated gastric juice is added into the dissolution cup for dissolution detection, the sampling time points are 10 min, 15min and 30min, 63ml of regulating fluid (37 ℃) is added into the dissolution cup after 30min of sampling and fluid infusion, the dissolution is regulated to be simulated intestinal juice, and the dissolution is continued for 3 hours, and the sampling time points are 35 min, 60 min, 120 min and 180min (note: the time includes the time in the simulated gastric juice). The sample is filtered by a filter membrane with the aperture of 0.45 micron, and is diluted by 0.1M hydrochloric acid solution (to prevent the main drug from being separated out in the detection process) and then sent to an analysis liquid phase for detection.

Table 28 simulated gastric fluid + simulated intestinal fluid two-step dissolution study

From the above results, it was found that the original drug preparation

The dissolution in simulated gastric fluid reaches 100% in 15min, no obvious precipitation is generated after the simulated gastric fluid is adjusted to be simulated intestinal fluid, the dissolution is not obviously reduced, and no obvious reduction is generated after 3 h. Comparative and example formulation samples of each pair dissolve the original formulation

The ratio was not significantly different.

Thus, the original preparation was obtained

The composition has excellent dissolution performance in simulated gastric fluid of 187ml and simulated intestinal fluid of 250ml, and the molecular level composition preparation does not show advantages in two-step dissolution simulating physiological conditions of a human body.

(2) 0.1M hydrochloric acid solution + pH6.8 phosphate buffer solution dissolution test

Considering that surfactant such as lecithin and sodium taurocholate is added into simulated gastric fluid and simulated intestinal fluid, in order to further examine molecular level composition preparation and original preparation

The two-step dissolution investigation was performed using more severe dissolution conditions (no surfactant added).

The dissolution method comprises the following steps: 37 ℃ paddle method, 100rpm, small cup method.

187ml of 0.1mol hydrochloric acid solution is added into the dissolution cup for dissolution detection, the sampling time points are 10, 15 and 30min, 63ml of 0.2M sodium phosphate solution (37 ℃) is added into the dissolution cup after 30min sampling and liquid supplementing, the pH value is adjusted to 6.8 phosphate buffer solution, the dissolution is continued for 3 hours, and the sampling time points are 35, 60, 120 and 180min (note: the time points include the time in the 0.1M hydrochloric acid solution). The sample is filtered by a filter membrane with the aperture of 0.45 micron, and is diluted by adding 0.1M hydrochloric acid solution (to prevent the main drug from being separated out in the detection process) for high performance liquid chromatography detection.

Table 29 two-step dissolution study in 0.1M HCl + pH6.8 phosphate buffer

From the above results, it was found that the original drug preparation

The dissolution in 0.1M hydrochloric acid solution for 15min reaches 100%, no obvious precipitation exists after the pH value is adjusted to be 6.8 phosphate buffer solution, the dissolution is not obviously reduced, and no obvious reduction exists after 3 h. Formulation samples dissolution of the same original formulation in each comparative example and example

The ratio was not significantly different.

Thus, the original preparation was obtained

The solid dispersion has excellent dissolution performance in 0.1M hydrochloric acid solution as low as 187ml and phosphate buffer solution with pH of 6.8 as 250ml, and the solid dispersion preparation does not show advantages in two-step dissolution simulating physiological conditions of human body. Based on this result, it is expected that the formulations of the molecular level compositions should not differ too significantly from the original formulations in vivo.

Effect example 2 Biggee pharmacokinetic study (Single dose)

Animals: the result of a beagle dog is that,

route and frequency of administration: single gavage oral administration, animals were fasted for 10-14 hours prior to dosing, and were given feed 4 hours after dosing, with free access to feed for the remainder of the experiment.

Administration dose: 4mg (in lenvatinib).

Group and animals per group: total 10 beagle dogs, 1 dog per group, 10 cycles of cross-dosing, 3 days at the end of the elution phase per cycle, and the next cycle of dosing.

Blood collection: pre-dose (0 h), post-dose 0.5h,1h,1.5h,2h,3h,4h,6h,8h,12h and 24h. Blood is collected by jugular venipuncture at 1 mL/time point, heparin sodium is anticoagulated, and the blood is placed on ice after collection.

Centrifugation conditions: 2200 g/min, 10 min, 2-8 ℃; stored in a refrigerator at-80 ℃ before analysis.

Biological analysis and detection: LC-MS/MS analysis of prototype drugs.

Data processing: phoenix WinNonlin calculated pharmacokinetic parameters (including Tmax, T) _1/2 、Cmax、AUC _0-t )。

Table 30 beagle pharmacokinetic results (n = 10)

Based on the above results, we have surprisingly found that comparative examples (formulations prepared from comparative examples 1 and 13 molecular level composition formulations) are the same as the original formulation

Compared with the prior art, the preparation has no obvious improvement on the bioavailability, and the same preparation in the examples

The ratio is improved to a different extent.

At the same time, comparative example and original preparation

Of the cells, we surprisingly found that the examples had less in vivo variability.

On one hand, the preparation has high bioavailability, so that the administration dosage can be greatly reduced, the low-dosage prescription administration can be realized, and the side effect can be reduced; on the other hand, adverse reactions may also be reduced due to lower in vivo variability.

The pharmaceutical composition containing the molecular level of the ranvatinib, the preparation method and the application thereof provided by the invention are described in detail above. The principles and embodiments of the present invention have been described herein using specific examples, which are set forth only to help understand the method and its core ideas of the present invention. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, it is possible to make various improvements and modifications to the present invention, and those improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

A pharmaceutical composition comprising rivastigmine or a pharmaceutically acceptable salt or solvate thereof;

pharmacokinetic AUC of the pharmaceutical composition _0-t Compared with the original preparation
The improvement is at least 40 to 50 percent.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition reduces side effects associated with the administered dose.
The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition has a low intra-and inter-individual variability in an organism.
The pharmaceutical composition of claim 3, wherein the pharmaceutical composition has a pharmacokinetic AUC _0-t Compared with the original preparation
The variability is reduced, preferably CV is less than or equal to 30%.
The pharmaceutical composition of any one of claims 1 to 4, wherein nephrotoxicity and neurotoxicity caused by sudden increase of exposure of the drug in plasma or ineffectiveness caused by sudden decrease of exposure of plasma are reduced, and the safety of administration to patients is improved.
The pharmaceutical composition according to any one of claims 1 to 5, comprising a molecular-level pharmaceutical composition of lenvatinib containing:

1) Active ingredients: (ii) varlitinib or a pharmaceutically acceptable salt or solvate thereof;

2) A stabilizer;

3) A polymeric carrier;

the pharmaceutical composition is placed at 60 ℃ for 10 days, and the genotoxic impurity B is less than 400ppm.
The pharmaceutical composition of any one of claims 1 to 6, wherein the stabilizer is selected from at least one of tromethamine, meglumine, or sodium lauryl sulfate.
The pharmaceutical composition according to any one of claims 1 to 7, wherein the polymeric carrier is selected from at least one of hypromellose, hyprolose, copovidone, hypromellose phthalate, povidone, hypromellose acetate succinate, hydroxyethyl cellulose, and acrylic resin.
The pharmaceutical composition according to any one of claims 1 to 8, wherein the polymeric carrier is selected from at least one of hypromellose, copovidone, hypromellose phthalate, hypromellose acetate succinate, acrylic resin, povidone.
Pharmaceutical composition according to any one of claims 1 to 9, characterized in that the pharmaceutically acceptable salt thereof is selected from at least one of the hydrochloride, hydrobromide, p-toluenesulfonate, methanesulfonate, sulfate or ethanesulfonate salts of rivastigmine, preferably of methane sulfonate.
The pharmaceutical composition according to any one of claims 1 to 10, wherein the solvate of the lenvatinib or the pharmaceutically acceptable salt thereof is a hydrate, a dimethylsulfoxide or an acetic acid compound.
The pharmaceutical composition according to any one of claims 1 to 11, wherein the weight ratio of the active ingredient, the stabilizer and the polymeric carrier is 1:0.05-0.75:0.5-10, preferably 1:0.05-0.6:1-5, and more preferably 1:0.1-0.6:1-3.
The pharmaceutical composition according to any one of claims 1 to 12, characterized by comprising the following scheme:

(1) The stabilizer is tromethamine, and the high molecular carrier is hydroxypropyl methylcellulose acetate succinate;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active ingredient, the stabilizer and the polymer carrier is 1:0.05-0.75:0.5-10, preferably 1:0.05-0.4:1-5, more preferably 1:0.075-0.3:1-2, and further preferably 1:0.1-0.3: 1-2;

or (2) the stabilizer is meglumine, and the high molecular carrier is hydroxypropyl methylcellulose acetate succinate;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active ingredient, the stabilizer and the polymer carrier is 1:0.05-0.75:0.5-10, preferably 1:0.05-0.4:1-5, more preferably 1:0.075-0.3:1-2, and further preferably 1:0.1-0.3: 1-2;

or (3) the stabilizer is sodium dodecyl sulfate, and the high-molecular carrier is hydroxypropyl methylcellulose;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active ingredient to the stabilizer to the macromolecular carrier is 1:0.075-0.5:1-5, preferably 1:0.15-0.5:1-3, and more preferably 1:0.15-0.25: 1-2;

or (4) the stabilizer is sodium dodecyl sulfate, and the polymer carrier is copovidone;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active ingredient, the stabilizer and the polymer carrier is 1:0.1-0.75:1-5, preferably 1:0.4-0.75:2-3, and more preferably 1:0.4-0.6: 2-3;

or (5) the stabilizer is sodium dodecyl sulfate, and the polymer carrier is a copolymer of ethyl acrylate-methyl methacrylate and chlorinated trimethylamine-based ethyl methacrylate;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active component, the stabilizer and the polymer carrier is 1:0.1-0.5:1-5, preferably 1:0.2-0.5:2-3, and more preferably 1:0.2-0.3: 3;

or (6) the stabilizer is sodium dodecyl sulfate, and the polymer carrier is povidone;

the active ingredient is varenib and/or varenib mesylate, preferably varenib;

the weight ratio of the active component, the stabilizer and the polymer carrier is 1:0.05-0.75: 1-10; preferably 1:0.2-0.75:2-5, more preferably 1:0.4-0.6: 2-4; most preferably 1:0.6:3.
The pharmaceutical composition according to any one of claims 1 to 13, further comprising a pharmaceutically acceptable excipient selected from at least one of a filler, a disintegrant, a binder, a lubricant, a flavoring agent, and a suspending agent.
The pharmaceutical composition according to any one of claims 1 to 14, wherein the pharmaceutical composition is in the form of capsules, tablets, granules, suspensions, preferably capsules, tablets, more preferably tablets.
A cosolvent that solubilizes ranvatinib or a pharmaceutically acceptable salt thereof or a solvate thereof, said cosolvent comprising a halomethane and an alcohol.
Latent solvent according to claim 16, characterized in that the alcohol is preferably methanol and/or ethanol.
Latent solvent according to claim 17, characterised in that the halogenated methane is preferably dichloromethane.
Latent solvent according to any of claims 16 to 18, characterised in that the ratio of methyl halide to alcohol is 10:2-10:10, preferably 10:2-10:5, more preferably 10:3-10:5.
Latent solvent according to any of claims 16 to 19, characterized by the fact that it comprises the following scheme:

(1) The latent solvent comprises dichloromethane and methanol;

the ratio of the dichloromethane to the methanol is 10:2-10:10, preferably 10:3-10: 5;

or (2) the cosolvent comprises dichloromethane and ethanol;

the ratio of the dichloromethane to the ethanol is 10:3-10:10, preferably 10:4-10:5.
A method for increasing the solubility of ranvatinib or a pharmaceutically acceptable salt or solvate thereof, wherein the cosolvent of any one of claims 16 to 20 is used.
A method for preparing a pharmaceutical composition of varenib at a molecular level, comprising dissolving the active ingredient, the stabilizer and the polymeric carrier in the pharmaceutical composition of any one of claims 6 to 15 in an organic solvent, and spray-drying to obtain the pharmaceutical composition at a molecular level.
A process according to claim 22, wherein the organic solvent is a latent solvent according to any one of claims 16 to 20.
Use of the pharmaceutical composition of any one of claims 1 to 15 or of the pharmaceutical composition of the molecular level of ranvatinib prepared by the preparation of any one of claims 16 to 20 for the preparation of a medicament for the treatment or prevention of cancer/tumor.
The use of claim 24, wherein the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, gastric cancer or lung cancer.
A method for treating or preventing cancer/tumor, wherein a pharmaceutical composition of any one of claims 1 to 15 or a pharmaceutical composition of the molecular level of ranvatinib prepared by the preparation method of any one of claims 16 to 20 is used.
The method of claim 26, wherein the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, gastric cancer, or lung cancer.