Apatinib mesylate tablet and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and provides an apatinib mesylate tablet and a preparation method thereof. The apatinib mesylate tablet prepared by the present invention effectively improves the dissolution of the tablet by adding powdered hydroxylated soybean lecithin and meglumine. The tablet preparation process is simple, and the tablet product quality is stable.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an apatinib mesylate tablet and a preparation method thereof. Background Art

[0002] Apatinib mesylate, chemical name is N-[4-(1-cyanocyclopentyl)phenyl]-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide mesylate (C 25 H 27 N5O4S, Mw = 493.58), is a new type of anti-tumor drug of the tyrosine kinase vascular endothelial growth factor receptor VEGFR-2 inhibitor class, which selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (KDR). In 2014, apatinib mesylate was approved for the treatment of advanced gastric cancer and was launched in China. The molecular structure of apatinib mesylate is shown below:

[0003]

[0004] The trade name of apatinib mesylate is Aitan. Aitan is an oral tablet containing 250mg, 375mg or 425mg of apatinib. The recommended clinical dose is 850mg each time, once a day. The clinical toxicity of apatinib mesylate manifests as liver toxicity. Clinical studies have observed that taking apatinib can cause transient increases in transaminases or total bilirubin. The in vivo pharmacokinetic data of apatinib mesylate showed that after a single oral fasting dose of 250mg, 500mg and 750mg to healthy subjects, it was absorbed rapidly in the body, and the average peak time of the plasma concentration of the prototype drug was about 1.7 to 2.3h; it was eliminated slowly, with an average elimination half-life of 7.9 to 9.4h. In the 250mg and 500mg dose groups, the plasma exposure of the prototype drug was proportional to the dose, and the exposure of the prototype drug in the 750mg dose group did not increase further.

[0005] The acidity coefficient (pKa) of apatinib is 11.93±0.70. Apatinib mesylate is unstable in water and easily dissociates, making apatinib free. Apatinib mesylate is slightly soluble in pH 2.0 phosphate buffer and almost insoluble in pH 4.0, 6.0, and 8.0 phosphate buffers. Apatinib is a BCS II class weak alkaline drug (pKa = 4.72; LogP = 4.51 (GastroPlus prediction); MW = 493.58 (apatinib mesylate), 397.48 (apatinib base)), which is an orally bioavailable small molecule inhibitor. Class II drugs in the Biologics Classification System (BCS) have good permeability and poor solubility. For these drugs, the solubility is poor and the absorption of the drug in vivo is limited.

[0006] CN102048737A discloses an oral pharmaceutical composition comprising erlotinib or its salt and apatinib or its salt, wherein the pharmaceutical composition is a tablet, a capsule, etc., and the preparation method is a wet granulation method or a dry granulation method, and the inactive ingredients of the pharmaceutical composition include excipients selected from lubricants, binders, diluents, disintegrants, wetting agents, preservatives, etc. In the embodiment, the pharmaceutical composition comprises apatinib mesylate / apatinib maleate, erlotinib hydrochloride, microcrystalline cellulose, starch slurry, and magnesium stearate as components.

[0007] CN108354902A discloses an apatinib polymer micelle, which is composed of apatinib as the main drug and an amphiphilic polymer material as a carrier, and is one or two of the amphiphilic polymer materials polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyglycolic acid (PEG-PLGA), polyethylene glycol-vitamin E succinate (TPGS), and polyethylene glycol-polycaprolactone (PEG-PCL). The obtained apatinib polymer micelle has low side effects, high biocompatibility, and a simple and feasible preparation process. However, the preparation process of the micelle has poor stability.

[0008] CN109381436A discloses an oral pharmaceutical composition comprising apatinib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The excipient comprises cross-linked sodium carboxymethyl cellulose. The pharmaceutical composition has the characteristics of good dissolution, good prescription reproducibility, and low content of related substances. The dissolution is 92.2% in 20 minutes and 99.5% in 45 minutes.

[0009] CN109394685A relates to a pharmaceutical composition comprising N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridinecarboxamide having a particle size D90 less than about 10 μm and a preparation method thereof. A nano preparation is used to improve the individual differences of a drug in different patients, and it is found that the active ingredient of the present invention exists in its free base form, and the use of the free base form of the active ingredient is completely different from the methanesulfonate of the active ingredient in the prior art. The inventors were surprised to find that when the methanesulfonate of the active ingredient is used as the active ingredient, the methanesulfonate of the active ingredient in some patients may be converted into a form that cannot be absorbed due to the different pH values ​​in the gastrointestinal tract of the patients taking the drug, thereby causing very obvious individual differences between different patients. After the present invention uses the free base form of the active ingredient, the individual differences between patients taking the drug are greatly improved. And a solid dispersion preparation technology is disclosed, but the dissolution effect is very unsatisfactory.

[0010] CN110063946A discloses a preparation method and application of chitosan sodium alginate microspheres encapsulating apatinib. The microspheres of the present invention can promote the absorption of drugs in the intestines; improve the absorption and utilization rate of drugs, reduce the oral intake of drugs, and reduce the side effects of drugs. Within 1 to 4 hours of oral administration, the drug microspheres stay in the stomach and release less; about 5 hours after taking the drug, the drug microspheres enter the intestinal environment and begin to release in large quantities, with the highest peak of drug release at 8 to 9 hours; at this time, the drug is basically completely released and combines with intestinal epithelial cells to exert the drug's therapeutic effect.

[0011] CN111150718A discloses a PLGA / poloxamer nanoparticles encapsulating apatinib and a preparation method thereof and application in melanoma treatment. The beneficial effects achieved are as follows: (1) Data prove that PLGA / poloxamer407 nanoparticles are suitable carriers for apatinib treatment; (2) The PLGA / poloxamer nanoparticles encapsulating apatinib prepared by the present invention have a good sustained release effect; (3) At the same time point, the intracellular drug concentration in the Apa / pNPs treatment group will be higher than that in the bare drug group, inducing cytotoxicity more quickly; (4) The use of Apa / pNPs for B16 tumor cells has a more obvious therapeutic effect, and there is no obvious sign of inflammation or redness of the tumor or surrounding tissue.

[0012] CN112891349A discloses a pharmaceutical composition comprising apatinib and hydroxypropyl methylcellulose and / or copolyvidone. Sedimentation inhibitors can prolong the supersaturation state and may last long enough to improve bioavailability. The bioavailability of apatinib is improved by sedimentation inhibitors such as polymers, surfactants and cyclodextrins.

[0013] CN115715764A discloses an apatinib oral patch and a preparation method thereof. The oral patch can prolong the retention time of the drug in the oral mucosa by its own viscosity, and the drug is continuously and slowly released, and enters the blood circulation through the oral mucosa, sublingual blood vessels, oral swallowing and other pathways, plays a local or systemic therapeutic role, improves the bioavailability of the drug, and achieves a better therapeutic effect. Therefore, the oral patch is designed to have an adhesion time of more than 3 hours, and the drug release amount must reach about 90% within 3 hours. However, the oral patch requires a retention time, and the drug is continuously and slowly released. The blood drug concentration achieved by the drug is difficult to guarantee.

[0014] CN115919741A discloses an apatinib anal suppository and a preparation method thereof. The apatinib anal suppository described in the invention is a non-gastrointestinal administration method, which can reduce the toxic side effects of the drug on the liver, reduce the dosage and cost of the drug, improve the stability of the drug, and improve the bioavailability of the drug, providing a new administration route for patients with advanced gastric cancer.

[0015] From the current existing technology, various technologies are used to improve the bioavailability of apatinib. However, the marketed product is a tablet. Only by maximizing the solubility of apatinib during in vivo exposure can the bioavailability of the compound during in vivo exposure be improved. Summary of the invention

[0016] In view of the problems existing in the prior art, the present invention provides an apatinib mesylate tablet and a preparation method thereof. The present invention has the advantages of simple preparation process, no need for micronization of apatinib mesylate, stable quality, high solubility, etc. and is suitable for industrial production.

[0017] In order to solve the problem of poor solubility of apatinib mesylate, the inventor tried to prepare solid dispersions by solvent method, but conventional solvents such as methanol and ethanol have poor solubility for apatinib mesylate, and need to be dissolved and used in combination with dichloromethane, but it is difficult to remove, and the solvent residue is easy to exceed the standard. When preparing solid dispersions by melting method, high temperature affects the stability of apatinib mesylate, and the operation process such as melting and crushing is cumbersome. And the dissolution effect of solid dispersion preparations analyzed by prior art is not ideal. In the process of process exploration, it was found that lecithin contributes to the absorption of apatinib mesylate. However, in the tablet dissolution test, lecithin has poor dispersibility and slow dissolution, which cannot achieve the desired effect. The inventor further screened and found that powdered hydroxylated soybean lecithin and meglumine can effectively improve the solubility of apatinib mesylate, and the tablet preparation process is smooth. The inventor further determined the dosage of each component through repeated experiments.

[0018] Specifically, the purpose of the present invention is achieved through the following technical solutions:

[0019] An apatinib mesylate tablet comprises apatinib mesylate, powdered hydroxylated soybean lecithin, meglumine and other pharmaceutically acceptable disintegrants and lubricants.

[0020] The mass ratio of apatinib mesylate to powdered hydroxylated soybean lecithin and meglumine is: 1:0.2-0.5:0.1-0.3; preferably 1:0.3:0.2.

[0021] The disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; sodium carboxymethyl starch is preferred.

[0022] The lubricant is selected from one or more of magnesium stearate, silicon dioxide and sodium stearate fumarate.

[0023] In a preferred embodiment, the apatinib mesylate tablets are composed of the following ingredients:

[0024]

[0025] In a preferred embodiment, the apatinib mesylate tablets are composed of the following ingredients:

[0026]

[0027] The tablets provided by the present invention can be thinly coated if necessary, and the coating agent film-forming material is selected from polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid resin, preferably polyvinyl alcohol. Preferably, Opadry II with polyvinyl alcohol as the film-forming material is used for coating, and the coating weight gain is 3.0%.

[0028] Another object of the present invention is to provide a method for preparing the above-mentioned apatinib mesylate tablets, which mainly comprises the following steps:

[0029] a) mixing apatinib mesylate, powdered hydroxylated soybean lecithin and meglumine, and then wet granulating, drying, granulating and homogenizing the mixture;

[0030] b) adding a disintegrant and a lubricant to the granules obtained in a) and mixing them uniformly;

[0031] c) The mixture obtained in b) is compressed into tablets to obtain the product; or further coated and dried to obtain the product.

[0032] Compared with the prior art, the present invention prepares apatinib mesylate tablets, and the dissolution of the tablets is effectively improved by adding powdered hydroxylated soybean lecithin and meglumine. Thus, the bioavailability of the drug is improved. At the same time, the coordinated effect of the two ensures the stability of the active ingredient. The tablet preparation process is simple, the apatinib mesylate raw material does not need to be micronized, and the tablet has a smooth and neat appearance and stable quality. DETAILED DESCRIPTION

[0033] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are provided only for illustrating the present invention, rather than limiting the present invention, and therefore, simple modifications of the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0034] Example 1

[0035]

[0036] 1000 pieces

[0037] Preparation process:

[0038] a) mixing apatinib mesylate, powdered hydroxylated soybean lecithin and meglumine, and then wet granulating, drying, granulating and homogenizing the mixture;

[0039] b) adding sodium carboxymethyl starch and magnesium stearate to the granules obtained in a) and mixing well;

[0040] c) The mixture obtained in b) is compressed into tablets to obtain the product.

[0041] Example 2

[0042]

[0043] 1000 pieces

[0044] Preparation process: Same as Example 1.

[0045] Example 3

[0046]

[0047]

[0048] 1000 pieces

[0049] Preparation process: Same as Example 1.

[0050] Example 4

[0051] Prescription dosage

[0052] Apatinib mesylate 500g

[0053] Powdered hydroxylated soybean lecithin 150g

[0054] Meglumine 150g

[0055] Sodium carboxymethyl starch 15g

[0056] Magnesium stearate 2g

[0057] 1000 pieces

[0058] Preparation process: Same as Example 1.

[0059] Example 5

[0060]

[0061] 1000 pieces

[0062] Preparation process: Same as Example 1.

[0063] Example 6

[0064]

[0065] 1000 pieces

[0066] Preparation process:

[0067] a) mixing apatinib mesylate, powdered hydroxylated soybean lecithin and meglumine uniformly;

[0068] b) adding crosslinked sodium carboxymethyl cellulose and magnesium stearate to the mixed powder obtained in a) and mixing well;

[0069] c) Compress the mixture obtained in b) into tablets to obtain the product.

[0070] Comparative Example 1

[0071]

[0072] 1000 pieces

[0073] Preparation process: Same as Example 1.

[0074] Comparative Example 2

[0075]

[0076] 1000 pieces

[0077] Preparation process: Same as Example 1.

[0078] Comparative Example 3

[0079]

[0080] 1000 pieces

[0081] Preparation process: Same as Example 1.

[0082] verify:

[0083] 1: Dissolution test

[0084] Dissolution conditions: Determined according to the dissolution and release method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Method 2). Dissolution medium and preparation:

[0085] 1) Simulated gastric fluid: Take 16.4 ml of dilute hydrochloric acid (equivalent to 3.84 ml of hydrochloric acid), add about 800 ml of water and 10 g of pepsin, shake well, dilute with water to 1000 ml, adjust pH to 1.5, and obtain the product.

[0086] 2) Use 900 ml of simulated full intestinal fluid FessIF (pH 6.0) solution as the medium.

[0087] Determination method: dissolution temperature: 37°C, rotation speed: 50rpm, sampling points: 5min, 10min, 20min, 30min. The dissolved sample solution is filtered through 0.45μm, and the filtrate is taken for HPLC analysis to determine the drug content and calculate the cumulative dissolution.

[0088] Dissolution test chromatographic conditions: 10mmol / L KH2PO4 (10% H3PO4 adjusted to pH 3.0) as mobile phase A, acetonitrile as mobile phase B, mobile phase A: mobile phase B = 60:40, flow rate 1.0mL / min, isocratic elution 10min, column temperature 30℃, detection wavelength 260nm, injection volume 10μl, chromatographic column Kromasil 100-5C18 (250×4.6mm, 5um). The dissolution amount of each tablet at each time point was calculated by the peak area according to the external standard method, and the dissolution of each group of samples was averaged. The dissolution results are shown in Table 1 below.

[0089] Table 1 Dissolution of tablets in various embodiments

[0090]

[0091] It can be seen from Table 1 that the tablets prepared in Examples 1-6 of the present invention all have good dissolution effects, which are better than commercially available preparations. Comparative Example 1 does not have the addition of meglumine, and the dissolution is relatively slow. Comparative Example 2 does not add hydroxylated soybean lecithin, and the dissolution is relatively worse. It can be seen that the surface activity of meglumine in the solution and the effect of hydroxylated soybean lecithin surfactant contribute to the dissolution of apatinib mesylate. Comparative Example 3 uses ordinary lecithin, and the dissolution effect of its preparation is much lower than the dissolution effect of using hydroxylated soybean lecithin.

[0092] 2: Stability test

[0093] According to the relevant methods in the general rules of the fourth volume of the Chinese Pharmacopoeia 2020, the content, related substances and dissolution of the samples after stability investigation were tested. The results are shown in Table 2.

[0094] Table 2 Stability test results

[0095] Stability test conditions: 40℃±2℃, 75%RH±5%, accelerated 6 months.

[0096]

[0097] Note: The simulated gastric fluid and simulated intestinal fluid in Table 2 are the simulated gastric fluid and simulated intestinal fluid in <1: Dissolution Test>.

[0098] As can be seen from Table 2, after stability testing, the tablets prepared by the present invention were tested at 40°C ± 2°C, 75% RH ± 5% for 6 months, and the content, related substances and dissolution effect of the samples were stable. The cumulative dissolution rate within 20 minutes in both simulated gastric fluid and simulated intestinal fluid was significantly improved compared with the prior art, thereby improving the bioavailability of the drug.

Claims

1. An apatinib mesylate tablet, characterized in that: It consists of apatinib mesylate, powdered hydroxylated soybean lecithin, meglumine and other pharmaceutically acceptable disintegrants and lubricants; The mass ratio of apatinib mesylate to powdered hydroxylated soybean lecithin and meglumine is: 1:0.2-0.5:0.1-0.3; The disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; The apatinib mesylate tablets are composed of the following ingredients: Apatinib mesylate 500 copies Powdered hydroxylated soybean lecithin 100-250 parts Meglumine 50-150 parts Disintegrant 12-16 parts 1-2 parts of lubricant.

2. The apatinib mesylate tablet according to claim 1, characterized in that: The mass ratio of apatinib mesylate to powdered hydroxylated soybean lecithin and meglumine is 1:0.3:0.

2.

3. The apatinib mesylate tablet according to claim 1, characterized in that: The disintegrant is sodium carboxymethyl starch.

4. The apatinib mesylate tablet according to claim 1, characterized in that: The lubricant is selected from one or more of magnesium stearate, silicon dioxide and sodium stearate fumarate.

5. The apatinib mesylate tablet according to claim 1, characterized in that: The apatinib mesylate tablets are composed of the following ingredients: Apatinib mesylate 500 copies Powdered hydroxylated soybean lecithin 150 parts Meglumine 100 parts 12-16 parts of sodium carboxymethyl starch 1-2 parts of magnesium stearate.

6. A method for preparing the apatinib mesylate tablet according to claim 1, characterized in that: The main steps include: a) mixing apatinib mesylate, powdered hydroxylated soybean lecithin and meglumine, and then wet granulating, drying, granulating and homogenizing the mixture; b) adding a disintegrant and a lubricant to the granules obtained in a) and mixing them uniformly; c) Compress the mixture obtained in b) into tablets to obtain the product.

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