A permeation pump controlled release tablet of tivozanib hydrochloride and a preparation method and application thereof

Abstract

The application provides a tivozanib hydrochloride osmotic pump controlled-release tablet, which is characterized in that the tablet comprises a tablet core, and the tablet core comprises 100 parts of tivozanib hydrochloride, 30-60 parts of a retarder, 40-80 parts of a disintegrant and / or an osmotic pressure promoter, 40-90 parts of a cosolvent and 8-15 parts of a pore-forming agent in terms of weight fraction. The tivozanib hydrochloride osmotic pump controlled-release tablet can realize zero-order release and has a 24-hour cumulative release degree of more than 96%, so that the bioavailability of tivozanib in vivo is improved, and the frequency or dosage of oral solid preparations of tivozanib is reduced.

Description

Technical Field

[0001] This invention relates to the field of sustained-release pharmaceutical technology, and in particular to a tevozaniol hydrochloride osmotic pump controlled-release tablet, its preparation method, and its application. Background Technology

[0002] Tevozarib is a targeted anti-tumor therapy drug, a novel multi-target anti-angiogenic inhibitor primarily used to treat renal cell carcinoma, showing good efficacy as first-line treatment for advanced renal cell carcinoma. The chemical name of tevozarib is N-{2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea. Its main targets are vascular endothelial growth factors (VEGFRs) 1, 2, and 3. By inhibiting these three VEGFR receptors, it exerts its therapeutic effect on patients with renal cell carcinoma. Recognized by the EMA as a rare disease drug for treating renal cell carcinoma, it is predicted to become a blockbuster drug upon its market launch. In March 2021, AVEO Oncology announced that the U.S. Food and Drug Administration (FDA) had approved Fotivda (brand name), an oral, next-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) who have received two or more prior lines of systemic therapy. AVEO launched Fotivda to the market. The recommended dose of Fotivda is 1.34 mg orally once daily, with or without food, in a 28-day cycle consisting of 21 days of treatment followed by a 7-day break, until disease progression or unacceptable toxicity. Tevozanib offers advantages over sorafenib: Tevozanib is a potent and highly selective inhibitor of VEGFR-1 / 2 / 3, designed to optimize blocking potential while minimizing off-target effects; and it has a much longer half-life than sorafenib, allowing for once-daily dosing. Chinese patent CN106822041A discloses an oral sustained-release microsphere of the novel anticancer drug Tivozanib and its preparation method. The oral sustained-release microsphere is composed of the following raw materials in parts by weight: 2-60 parts of Tivozanib drug, 10-90 parts of diluent, 1-25 parts of binder, 1-45 parts of sustained-release material, 0.5-10 parts of pore-forming agent, 0.5-10 parts of plasticizer, and 0.5-30 parts of anti-adhesion agent.

[0003] This sustained-release microgranule achieves its anti-cancer purpose through oral administration. However, although the drug formulation is taken once a day, the drug still has relatively high toxicity, and its release rate is relatively unstable and greatly affected by the gastrointestinal environment. Therefore, developing a sustained-release formulation of tevazanib is beneficial to improving the bioavailability of the drug and will have profound social significance and potential market value. Summary of the Invention

[0004] In view of this, the present invention proposes a tevozaniol hydrochloride osmotic pump controlled-release tablet, its preparation method and application, to solve the problems of high toxicity and unstable release rate of existing oral sustained-release microgranule drugs.

[0005] The technical solution of this invention is implemented as follows:

[0006] In a first aspect, the present invention provides a tevozaniol hydrochloride osmotic pump controlled-release tablet, comprising a tablet core, in parts by weight...

[0007] The chip core includes,

[0008] 100 parts of tivazanil hydrochloride

[0009] 30-60 parts of the inhibitor,

[0010] 40-80 parts of disintegrant and / or osmotic pressure enhancer,

[0011] 40-90 parts of co-solvent

[0012] 8-15 parts of pore-forming agent.

[0013] Tivorazanil hydrochloride is a multi-target tyrosine kinase inhibitor that selectively inhibits the activity of vascular endothelial growth factor receptor (VEGFR), blocking tumor angiogenesis and growth; it can inhibit tumor cell proliferation and reduce tumor volume; and it also has a long half-life, providing sustained anti-tumor effects. Using tivorazanil hydrochloride as the active ingredient, its formulation as an osmotic pump controlled-release tablet allows for control of the drug release rate through osmotic pump controlled-release technology, thereby achieving continuous and stable drug release and maintaining a certain drug concentration in the body. Compared to existing oral formulations, tevorazanil hydrochloride formulated as an osmotic pump controlled-release tablet reduces the frequency of drug administration, reduces peak drug concentration and fluctuations, while providing long-acting therapy, reducing the total drug dose, and thus reducing drug side effects and toxicity.

[0014] Based on the above technical solutions, preferably, the tablet core further includes one or more of a diluent, a binder, and a lubricant, wherein, by weight, the diluent is 20-65 parts, the binder is 15-30 parts, and the lubricant is 3-8 parts. The diluent adjusts the drug content to ensure that the drug dosage in each controlled-release tablet meets the standard; the binder is used to bond the various components in the tablet core, increasing the stability and mechanical strength of the controlled-release tablet; the lubricant is used to reduce adhesion and binding of the tablets during the preparation process, improving their flowability.

[0015] Based on the above technical solutions, preferably, the diluent includes one or more of compressible starch, lactose, cyclodextrin, and starch; the lubricant includes one or more of talc, magnesium stearate, micronized silica gel, and hydrogenated vegetable oil; and the binder includes one or more of hydroxypropyl methylcellulose, cyclodextrin, and lactose.

[0016] Based on the above technical solutions, preferably, the inhibitor includes one or more of polyethylene oxide, sodium alginate, carbomer, and mixed fatty acid glycerides; the cosolvent includes one or more of polyethylene glycol series and poloxamer series; and the porogen includes one or more of povidone, hydroxypropyl methylcellulose, polyethylene glycol 400, polyethylene glycol 200, xylitol, and sorbitol.

[0017] In this invention, the inhibitor is used to control the drug release rate and prolong the drug release time, thereby achieving the effect of osmotic pump controlled release; the solubilizer is used to improve the drug solubility, enabling the drug to dissolve better in the tablet, thereby achieving uniform drug distribution and release; the pore-forming agent is used to form a porous structure, increasing the porosity of the controlled-release tablet, thereby promoting drug release.

[0018] Based on the above technical solutions, preferably, the disintegrant includes one or more of sodium carboxymethyl cellulose, croscarmellose sodium, povidone series, and sodium carboxymethyl starch, and / or the osmotic pressure enhancer includes one or more of sodium carbonate, sodium sulfate, mannitol, lactose, and sucrose. The disintegrant is used to control the disintegration rate of the controlled-release tablet, promoting the gradual release of the drug; the osmotic pressure enhancer is used to increase the osmotic pressure inside the controlled-release tablet, promoting drug penetration and release.

[0019] Based on the above technical solutions, preferably, the method further includes coating, wherein the mass ratio of the coating to the core is 1.4 to 2.3:30.

[0020] Based on the above technical solutions, preferably, the coating comprises acetone, cellulose acetate and polyethylene glycol 1000, wherein the mass concentration of cellulose acetate is 4% to 8% and the mass concentration of polyethylene glycol 1000 is 0.5% to 1.2%.

[0021] In this invention, coating protects the drug in the tablet core from external environmental influences such as moisture, light, and temperature changes, thereby improving drug stability and shelf life. It also allows for controlled release via an osmotic pump. Furthermore, coating improves oral feasibility, reduces irritation and adverse reactions, and minimizes interactions between the drug and other components, thus reducing degradation and inactivation. A coating solution is prepared by dissolving cellulose acetate and polyethylene glycol 1000 in acetone. Acetone acts as a solvent to dissolve other components and form the coating layer. Cellulose acetate exhibits good film-forming properties and stability, while polyethylene glycol 1000 enhances the coating's flexibility and stability.

[0022] Based on the above technical solutions, preferably, the method further includes a drug release orifice with a diameter of 226–520 μm. By limiting the diameter of the drug release orifice, a smaller orifice diameter restricts the drug penetration rate, thereby reducing the drug release rate and helping to prolong the drug release time, enabling the drug to be continuously released into the body and maintaining a stable blood drug concentration. At the same time, a smaller orifice diameter can achieve more uniform and stable drug release, reduce sudden drug release and fluctuations, and improve the controllability and predictability of the drug.

[0023] Secondly, the present invention provides a method for preparing a tevozanil hydrochloride osmotic pump controlled-release tablet as described above, comprising the following steps:

[0024] S1. Mix tivazani hydrochloride with diluent, inhibitor, disintegrant and / or osmotic pressure promoter, solubilizer and pore-forming agent in proportion, sieve, mix evenly, add binder to make soft material, sieve to granulate, dry for 7-9 hours, add lubricant and press into core.

[0025] S2. Prepare the coating solution according to the composition and proportion of the coating solution, and use the coating solution to coat the tablet core. The flow rate of the coating solution is 0.4-0.56 ml / min, the coating temperature is 35-40℃, and the coating weight gain is 5%-11%. Then, use a laser to prepare drug release pores on the coated tablet to obtain tevozaniol hydrochloride osmotic pump controlled release tablets.

[0026] Thirdly, the present invention provides the application of the tevozaniol hydrochloride osmotic pump controlled-release tablet described above in the preparation of a drug for treating renal cell carcinoma, liver cancer, and pancreatic cancer.

[0027] The tevozaniol hydrochloride osmotic pump controlled-release tablet of the present invention, its preparation method, and its application have the following advantages over the prior art:

[0028] This invention prepares tevazanil hydrochloride into an osmotic pump controlled-release tablet, which achieves zero-order release with a cumulative release rate of >96% over 24 hours, thereby improving the bioavailability of tevazanil in vivo and reducing the frequency or dosage of oral solid dosage forms. Preparing it as an osmotic pump controlled-release tablet allows for control of the drug release rate using osmotic pump controlled-release technology, enabling continuous and stable drug release and maintaining a certain drug concentration in the body. Compared to existing oral formulations, preparing tevazanil hydrochloride into an osmotic pump controlled-release tablet reduces the frequency of drug administration, reduces peak drug concentration and fluctuations, while providing long-acting therapy, reducing the total drug dose, and thus lowering drug side effects and toxicity. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0030] Figure 1 This is a drug release curve diagram of Example 1 of the present invention;

[0031] Figure 2 This is a drug release curve diagram of Example 2 of the present invention;

[0032] Figure 3 This is a drug release curve diagram of Example 3 of the present invention;

[0033] Figure 4 This is a drug release curve diagram of Example 4 of the present invention;

[0034] Figure 5 This is a drug release curve diagram of Example 5 of the present invention;

[0035] Figure 6 This is a drug release curve diagram of Example 6 of the present invention. Detailed Implementation

[0036] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0037] To enable those skilled in the art to better understand the technical solution of this application, the technical solution of this application will be described in detail below with reference to specific embodiments. Unless otherwise specified, experimental conditions are generally as per conventional conditions or the conditions recommended by the reagent company. The reagents, consumables, etc., used in the following embodiments can be obtained commercially unless otherwise specified.

[0038] Example 1

[0039] This embodiment provides a tevozanil hydrochloride osmotic pump controlled-release tablet, the composition of which includes:

[0040]

[0041] The coating comprises acetone, cellulose acetate, and polyethylene glycol 1000, wherein the mass concentration of cellulose acetate is 5% and the mass concentration of polyethylene glycol 1000 is 0.8%.

[0042] Tevazani hydrochloride, polyethylene oxide (molecular weight 50,000), povidone, poloxamer, polyethylene glycol 400, and starch were mixed, passed through a 30-mesh sieve, and mixed evenly. Lactose was used as a binder to form a soft mass, which was granulated through a 30-mesh sieve and dried in an oven at 50℃ for 7-9 hours. The dried granules were then passed through a 30-mesh sieve to obtain dry granules. The obtained dry granules were then mixed with talc powder and pressed into tablet cores. Coating: Cellulose acetate and polyethylene glycol 1000 were dissolved in acetone, with a cellulose acetate mass concentration of 5% and a polyethylene glycol 1000 mass concentration of 0.8%, to prepare a coating solution. The tablet cores were coated in a coating pan at a flow rate of 0.5 ml / min and a coating temperature of 37℃, resulting in an 8% weight gain. A drug release hole with a diameter of 350 μm was then drilled on the coated tablet using a laser, yielding the tevozani hydrochloride osmotic pump controlled-release tablet.

[0043] Example 2

[0044] This embodiment provides a tevozanil hydrochloride osmotic pump controlled-release tablet, the composition of which includes:

[0045]

[0046]

[0047] The coating consists of acetone, cellulose acetate, and polyethylene glycol 1000, wherein the mass concentration of cellulose acetate is 8% and the mass concentration of polyethylene glycol 1000 is 1.2%.

[0048] Tevazani hydrochloride, polyethylene oxide (molecular weight 50,000), povidone, poloxamer, polyethylene glycol 400, and starch were mixed, passed through a 30-mesh sieve, and mixed evenly. Lactose was used as a binder to form a soft mass, which was granulated through a 30-mesh sieve and dried in an oven at 50℃ for 7-9 hours. The dried granules were then passed through a 30-mesh sieve to obtain dry granules. The obtained dry granules were then mixed with talc powder and pressed into tablet cores. Coating: Cellulose acetate and polyethylene glycol 1000 were dissolved in acetone, with a cellulose acetate mass concentration of 8% and a polyethylene glycol 1000 mass concentration of 1.2%, to prepare a coating solution. The tablet cores were coated in a coating pan at a flow rate of 0.4 ml / min and a coating temperature of 35℃, resulting in a 5% weight gain. A drug release pore with a diameter of 226 μm was then drilled on the coated tablet using a laser, yielding the tevozani hydrochloride osmotic pump controlled-release tablet.

[0049] Example 3

[0050] This embodiment provides a tevozanil hydrochloride osmotic pump controlled-release tablet, the composition of which includes:

[0051]

[0052] The coating comprises acetone, cellulose acetate, and polyethylene glycol 1000, wherein the mass concentration of cellulose acetate is 5% and the mass concentration of polyethylene glycol 1000 is 0.8%.

[0053] Tevazani hydrochloride, polyethylene oxide (molecular weight 50,000), povidone, poloxamer, polyethylene glycol 400, and starch were mixed, passed through a 30-mesh sieve, and mixed evenly. Lactose was used as a binder to form a soft mass, which was granulated through a 30-mesh sieve and dried in an oven at 50℃ for 7-9 hours. The dried granules were then passed through a 30-mesh sieve to obtain dry granules. The obtained dry granules were then mixed with talc powder and pressed into tablet cores. Coating: Cellulose acetate and polyethylene glycol 1000 were dissolved in acetone, with a cellulose acetate mass concentration of 5% and a polyethylene glycol 1000 mass concentration of 0.8%, to prepare a coating solution. The tablet cores were coated in a coating pan at a flow rate of 0.56 ml / min and a coating temperature of 40℃, resulting in a coating weight gain of 11%. A drug release hole with a diameter of 520 μm was then drilled on the coated tablet using a laser, yielding the tevazani hydrochloride osmotic pump controlled-release tablet.

[0054] Example 4

[0055] This embodiment provides a tevozanil hydrochloride osmotic pump controlled-release tablet, the composition of which includes:

[0056]

[0057] The coating comprises acetone, cellulose acetate, and polyethylene glycol 1000, wherein the mass concentration of cellulose acetate is 5% and the mass concentration of polyethylene glycol 1000 is 0.8%.

[0058] Tevazani hydrochloride, polyethylene oxide (molecular weight 50,000), povidone, poloxamer, polyethylene glycol 400, and starch were mixed, passed through a 30-mesh sieve, and mixed evenly. Lactose was used as a binder to form a soft mass, which was granulated through a 30-mesh sieve and dried in an oven at 50℃ for 7-9 hours. The dried granules were then passed through a 30-mesh sieve to obtain dry granules. The obtained dry granules were then mixed with talc powder and pressed into tablet cores. Coating: Cellulose acetate and polyethylene glycol 1000 were dissolved in acetone, with a cellulose acetate mass concentration of 5% and a polyethylene glycol 1000 mass concentration of 0.8%, to prepare a coating solution. The tablet cores were coated in a coating pan at a flow rate of 0.5 ml / min and a coating temperature of 37℃, resulting in a coating weight gain of 11%. A drug release hole with a diameter of 226 μm was then drilled on the coated tablet using a laser, yielding the tevozani hydrochloride osmotic pump controlled-release tablet.

[0059] Example 5

[0060] This embodiment provides a tevozaniol hydrochloride osmotic pump controlled-release tablet, which has the same composition and preparation steps as in Example 1, except that the diameter of the drug release pore is 520 μm.

[0061] Example 6

[0062] This embodiment provides a tevozanil hydrochloride osmotic pump controlled-release tablet, which has the same composition and preparation steps as in Example 1, except that the diameter of the drug release pore is 226 μm.

[0063] Release rate detection

[0064] Examples 1-6 were all determined according to Method I (rotating basket method) of the Chinese Pharmacopoeia Dissolution and Release Determination Method, using water as the medium. Samples were taken at 0h, 1h, 2h, 3h, 5h, 7h, 9h, 12h, 16h, 18h, and 24h, filtered, and used as test solutions. Separately, tevazaniol reference standard was accurately weighed, dissolved, and used as a reference solution. The cumulative release was calculated by high-performance liquid chromatography (HPLC).

[0065] High performance liquid chromatography conditions: Column: Welch Ultimate XB-C18 (5μm, 250*4.6mm); Instrument model: Fuli FL2200; Wavelength: 254nm; Mobile phase: Methanol:water (80:20); Injection volume: 20μl; Flow rate: 1ml / min.

[0066] Figure 1 The drug release curve of the tevozanil hydrochloride osmotic pump controlled-release tablets prepared in Example 1 is shown. The drug release curve conforms to the zero-order release, and the cumulative release rate after 24 hours is 98.1%. Figure 2 The drug release curve of the tevozanil hydrochloride osmotic pump controlled-release tablets prepared in Example 2 is shown. The drug release curve conforms to the zero-order release, and the cumulative release rate after 24 hours is 96.4%. Figure 3The drug release curve of the tevozanil hydrochloride osmotic pump controlled-release tablets prepared in Example 3 is shown. The drug release curve conforms to the zero-order release, and the cumulative release rate after 24 hours is 97.1%. Figure 4 The drug release curve of the tevozanil hydrochloride osmotic pump controlled-release tablets prepared in Example 4 is shown. The drug release curve conforms to the zero-order release, and the cumulative release rate after 24 hours is 98.6%. Figure 5 The drug release curve of the tevozanil hydrochloride osmotic pump controlled-release tablets prepared in Example 5 is shown. The drug release curve conforms to the zero-order release, and the cumulative release rate after 24 hours is 98.7%. Figure 6 The drug release curve of the tevozanil hydrochloride osmotic pump controlled-release tablet prepared in Example 6 is shown. The drug release curve conforms to zero-order release, and the cumulative release rate over 24 hours is 96.9%.

[0067] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A tevozaniol hydrochloride osmotic pump controlled-release tablet, characterized in that: By weight, the tablets include the tablet core and the coating. The tablet core is composed of the following substances: 100 parts of tivazanil hydrochloride, 30-60 parts of inhibitor, 40-80 parts of disintegrant, 40-90 parts of solubilizer, 8-15 parts of pore-forming agent, 20-65 parts of diluent, 15-30 parts of binder, and 3-8 parts of lubricant. The mass ratio of coating to tablet core is 1.4~2.3:30; the coating includes acetone, cellulose acetate and polyethylene glycol 1000, wherein the mass concentration of cellulose acetate is 4%~8% and the mass concentration of polyethylene glycol 1000 is 0.5%~1.2%; the diameter of the drug release pores of the controlled-release tablet is 226~520μm; The inhibitor is polyethylene oxide, the disintegrant is povidone, the solubilizer is poloxamer, the porogen is polyethylene glycol 400, the diluent is starch, the binder is lactose, and the lubricant is talc.

2. The method for preparing a tevozaniol hydrochloride osmotic pump controlled-release tablet as described in claim 1, characterized in that: Includes the following steps: S1. Mix tivazani hydrochloride with diluent, inhibitor, disintegrant, solubilizer and pore-forming agent in proportion, sieve, mix evenly, add binder to make soft material, sieve to granulate, dry for 7-9 hours, add lubricant and press into core. S2. Prepare the coating solution according to the composition and proportion of the coating solution, and use the coating solution to coat the tablet core. The flow rate of the coating solution is 0.4~0.56 ml / min, the coating temperature is 35~40℃, and the coating weight gain is 5%~11%. Then, use a laser to prepare drug release pores on the coated tablet to obtain tevozanil hydrochloride osmotic pump controlled release tablets.

3. The application of the tevozaniol hydrochloride osmotic pump controlled-release tablet as described in claim 1 in the preparation of a drug for treating renal cell carcinoma, liver cancer, and pancreatic cancer.

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