An aliskiren drug composition, a preparation method and application thereof

Abstract

The application provides an alisartan ester pharmaceutical composition with high loading capacity, good dissolution performance and good stability, which contains a carrier material of copolymerized povidone and crosslinked povidone and is prepared by using a hot melt extrusion process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and in particular, this invention relates to an alisartan ester pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Alisartan ester (CAS: 947331-05-7), chemically named 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-imidazol-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy]-methyl ester, is a novel angiotensin II receptor antagonist. Chinese patent CN200680000397.8 discloses the structural formula of the alisartan ester compound. Alisartan ester has low toxicity and a superior antihypertensive effect compared to similar products (such as losartan). It exerts its antihypertensive effect by metabolizing in vivo to produce an active metabolite (EXP3174). Alisartan ester is an ester derivative of EXP3174, and its solubility in water is low, making formulations obtained using conventional methods insufficient for clinical use.

[0003]

[0004] Chinese patent CN200880001668.0 discloses a series of formulations containing alisartan ester, among which Examples D1-D6 disclose an alisartan ester solid dispersion and its preparation method, which uses a fluidized bed top spray method to prepare the alisartan ester solid dispersion. This method is complex, and to avoid excessive organic solvent residue, a relatively long drying time is usually required, which is not the optimal process for preparing solid dispersions.

[0005] Chinese patents CN201510254020.6 and CN201510334498.X further optimized the formulation based on patent CN200880001668.0, providing two improved alisartan ester solid dispersions. However, their technical improvements did not involve changes to the preparation process. Therefore, this method still suffers from the drawbacks of the fluidized bed top spray method, which is complex and has a relatively long processing time.

[0006] Chinese patent CN201510287997.8 discloses a nano-suspension prepared by an effervescent method. Patent Example 8 discloses a method for preparing an alisartan ester nano-suspension containing povidone and sodium dodecyl sulfate (SDS). However, due to the properties of alisartan ester, the effervescent method for preparing nanoparticles results in certain quality fluctuations, making the process unstable and insufficient for industrial production. Furthermore, this method uses a large amount of pharmaceutical excipients (povidone, SDS, etc.), failing to achieve optimal combination of raw materials and excipients, resulting in a low drug loading per unit mass of internal phase particles, thus failing to achieve optimal formulation and process.

[0007] Chinese patent CN201610373232.0 discloses an alisartan ester pharmaceutical composition, which uses a grinding process to disperse alisartan ester into nano-sized particles in the pharmaceutical composition. However, this method fails to achieve good in vitro dissolution of alisartan ester. CN201610379945.8 discloses an alisartan ester solid dispersion prepared by a hot melt extrusion process. In this method, when the mass fraction of alisartan ester is 1%, the mass fraction of the carrier material is 0.8–2.5%, preferably 1–25%. This method uses a relatively large amount of binder.

[0008] CN202210060985.1 discloses a compound antihypertensive drug composition comprising the active ingredients alisartan medoxomil and / or its salts, indapamide and / or its salts. An example alisartan medoxomil monotherapy formulation contains 120 mg alisartan medoxomil, 58 mg copovidone, and 115 mg crospovidone, prepared using a fluidized bed process. This process has a long time to process solvent residue. Upon investigation, this formulation is not suitable for hot-melt extrusion processes, resulting in severe venting problems and discontinuous extruded particles.

[0009] Therefore, increasing the content of the active ingredient in the formulation while ensuring its stability and dissolution rate remains an unsolved technical problem in the prior art. This invention addresses the shortcomings of existing technologies by discovering a novel alisartan ester solid dispersion through extensive experimentation. This dispersion exhibits high drug loading, excellent dissolution performance, and good stability. Summary of the Invention

[0010] The purpose of this invention is to overcome the shortcomings of the prior art. Under the premise of ensuring the stability and dissolution of the formulation, the content of the active ingredient in the solid dispersion is increased by adjusting the type and proportion of the carrier material. As a result, a high-load alisartan ester solid dispersion has been discovered. The drug loading of the solid dispersion is higher than that of the prior art, and the drug composition containing the solid dispersion has the characteristics of good dissolution performance and good stability, which meets the requirements of clinical drug use.

[0011] As is well known in the art, solid dispersions are formulations that highly disperse active ingredients in the form of microcrystals, amorphous materials, or molecules within a carrier material, thereby improving drug dissolution. Drug loading, or drug concentration, refers to the amount of active ingredient loaded per unit mass of carrier in a solid dispersion. Generally, increasing the amount of carrier material in a solid dispersion helps improve drug dissolution; however, when the amount of carrier increases to a certain level, it will no longer significantly improve drug dissolution. Furthermore, excessively high carrier concentrations increase drug costs and the weight of the unit formulation. Typically, to achieve solubility enhancement, the mass ratio of active ingredient to carrier material in a solid dispersion is controlled between 1:5 and 20, but for specific drugs, there is still room for further improvement in the drug loading of solid dispersions.

[0012] Therefore, in the research on the preparation of solid dispersions, it is necessary to study the optimal combination and ratio of active drug and carrier material to promote drug dissolution while controlling the weight of the dosage form, thereby optimizing the clinical dosage and antihypertensive effect and improving medication adherence. However, obtaining solid dispersions with high dissolution and high drug loading is difficult. Regarding the selection of the ratio, excessively high drug loading corresponds to insufficient carrier usage, making it impossible for the active ingredient to be in a stable, highly dispersed state, thus failing to obtain a solid dispersion, resulting in substandard dissolution. In addition, the type of carrier material can also affect the dispersion effect of the active ingredient.

[0013] The above-mentioned beneficial effects of the solid dispersion of the present invention are achieved through the following technical means:

[0014] A pharmaceutical composition of alisartan ester, wherein the pharmaceutical composition contains alisartan ester, copovidone and cross-linked povidone as carrier materials, and is prepared by hot melt extrusion process, wherein the hot melt extrudate is a solid dispersion.

[0015] Specifically, the key technology of this invention lies in the carrier materials being copolyvinylpyrrolidone and cross-linked polyvinylpyrrolidone. Copolyvinylpyrrolidone (PVP / VA) is a water-soluble organic polymer compound, a linear copolymer of N-vinylpyrrolidone (NVP) and vinyl acetate (VA). Commonly available copolyvinylpyrrolidones include PVP-VA64, Kollidon VA64, and Plasdone S-630. Cross-linked polyvinylpyrrolidone is a water-insoluble synthetic cross-linked N-vinyl-2-pyrrolidone homopolymer.

[0016] More specifically, as a preferred embodiment of the present invention, when the mass fraction of alisartan ester is 1, the mass fraction of copovidone is 0.3-0.45.

[0017] Those skilled in the art typically use copovidone as a carrier material for solid dispersions and believe that a ratio of at least 0.8 is necessary for effective dissolution. For example, in prior art CN201610379945.8, when the mass fraction of alisartan medoxomil is 1, the mass fraction of the carrier material is 0.8–2.5, preferably 1–2. Ashland's guidelines for the use of povidone and copovidone Plasdone specify that the recommended amount of copovidone as a solid dispersion carrier is generally three times the amount of drug. However, the applicant has discovered through extensive research that for alisartan medoxomil, using a small amount of copovidone carrier material to prepare the solid dispersion can also achieve the desired dissolution effect, significantly reducing the amount of carrier material used and effectively controlling tablet weight. Furthermore, the applicant's research unexpectedly revealed that the optimal ratio of copovidone to the active pharmaceutical ingredient (API) for preparing hot-melt extruded granules is between 0.3:1 and 0.45:1. In the implementation cases, when the ratio was 0.5:1 or 0.625:1, the in vitro dissolution slowed down, resulting in non-compliance.

[0018] More specifically, as a preferred embodiment of the present invention, when the mass fraction of alisartan ester is 1, the mass fraction of crosslinked polyvinyl ketone is 0.3-0.45.

[0019] The selection of disintegrants is generally essential for achieving suitable dissolution effects in solid dispersions. Typically, the higher the amount of disintegrant, the better the dissolution effect. Furthermore, in fluidized bed solid dispersion processes, the applicant's preliminary research found that formulations containing copovidone require a similar amount of cross-linked povidone as a drug for alisartan medoxomil to achieve adequate disintegrant action. However, the applicant's research unexpectedly revealed that for preparing hot-melt extruded granules, a cross-linked povidone-to-active drug ratio between 0.3:1 and 0.45:1 is preferred. In the implemented case, when the ratio was 0.25:1, in vitro dissolution slowed down, resulting in non-compliance; when the ratio was 0.5:1, the extrusion process was unsuitable, leading to severe venting problems and discontinuous extruded granules.

[0020] As one technical solution of the present invention, it further includes a flow aid selected from talc, colloidal silica (fumed silica), or a combination thereof. When the mass fraction of alisartan ester is 1, the mass fraction of the flow aid is 0.005-0.01. This effectively ensures the uniform mixing and flowability of the solid dispersion.

[0021] Another object of the present invention is to provide a method for preparing an alisartan ester solid dispersion, wherein the alisartan ester solid dispersion is prepared by a hot melt extrusion process, and the extrusion temperature of the hot melt extrusion process is 160±10℃.

[0022] Another object of the present invention is to provide an alisartan ester pharmaceutical composition, said pharmaceutical composition being composed of the above-mentioned alisartan ester solid dispersion and pharmaceutical excipients.

[0023] As one technical solution of the present invention, the pharmaceutical excipients of the alisartan medoxomil pharmaceutical composition include one or a mixture of two or more of the following: disintegrant, binder, filler, flow aid, and lubricant.

[0024] As a preferred embodiment of the present invention, the disintegrant is one or more of the following: croscarmellose sodium, croscarmellose polyvinyl acetate, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, etc.

[0025] As a preferred embodiment of the present invention, the adhesive is one or a mixture of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, starch paste, and gelatin.

[0026] As a preferred embodiment of the present invention, the filler is one or more of the following: lactose, mannitol, dextrin, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium phosphate, and dicalcium phosphate.

[0027] As a preferred embodiment of the present invention, the flow aid is selected from one or more mixtures of talc powder and colloidal silica.

[0028] As a preferred embodiment of the present invention, the lubricant is one or a mixture of magnesium stearate, micronized silica gel, talc, and stearic acid.

[0029] As one technical solution of the present invention, the amounts of solid dispersion and newly added pharmaceutical excipients in the alisartan medoxomil pharmaceutical composition can be appropriately adjusted, for example: the mass ratio of disintegrant is 1:0.02-0.20; the mass ratio of solid dispersion to binder in the pharmaceutical composition is 1:0.01-0.05; the mass ratio of solid dispersion to filler in the pharmaceutical composition is 1:0.02-0.20; the mass ratio of solid dispersion to glidant in the pharmaceutical composition is 0.005-0.02; and the mass ratio of solid dispersion to lubricant in the pharmaceutical composition is 0.005-0.02.

[0030] This invention further provides a method for preparing alisartan ester solid dispersion by hot melt extrusion, the method comprising the following steps:

[0031] (1) Mix alisartan ester and excipients evenly to form a physical mixture;

[0032] (2) Add the physical mixture from step (1) to a hot melt extruder, and then melt and extrude the strip-shaped product;

[0033] (3) After cooling the strip-shaped product obtained in step (2), it is pulverized to obtain a solid dispersion containing alisartan ester drug.

[0034] The present invention further provides a method for preparing an alisartan ester pharmaceutical composition, the method comprising the following steps:

[0035] (4) The solid dispersion is mixed evenly with pharmaceutical excipients, compressed into tablets, and then coated with film to obtain alisartan ester pharmaceutical composition.

[0036] The alisartan medoxomil pharmaceutical composition of the present invention can be used for the treatment of hypertension and its complications. Preferably, the alisartan medoxomil pharmaceutical composition can be used for the treatment of mild, moderate, and severe essential hypertension. Hypertensive complications refer to conditions caused by hypertension, including: cardiac complications such as left ventricular hypertrophy, angina pectoris, myocardial infarction, and heart failure; stroke such as hemorrhagic stroke, ischemic stroke, and hypertensive encephalopathy; hypertensive kidney damage such as slowly progressive arteriolar nephrosclerosis, malignant arteriolar nephrosclerosis, and chronic renal failure; and ophthalmic diseases such as retinal arteriosclerosis and fundus changes.

[0037] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

[0038] 1. An alisartan ester solid dispersion is provided, which reduces the amount of binder and disintegrant used and effectively controls tablet weight;

[0039] 2. An alisartan ester pharmaceutical composition is provided, which contains the alisartan ester solid dispersion described in this invention and has the characteristics of good dissolution performance and good stability. Attached Figure Description

[0040] Figure 1 A schematic diagram of slow dissolution (30 min) using the experimental method of this invention;

[0041] Figure 2 A schematic diagram showing the smoothness of the extrudate using the experimental method of this invention;

[0042] Figure 3 A schematic diagram of XRPD diffraction of a solid dispersion containing crystalline material, using the experimental method of this invention. Detailed Implementation

[0043] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0044] The dissolution determination method of this invention:

[0045] Dissolution method: Paddle method (second method)

[0046] Speed: 50 rpm

[0047] Dissolution medium: pH 6.8 phosphate buffer

[0048] Temperature: 37.0±0.5℃

[0049] Sampling time: 30 min

[0050] Dissolution medium volume: 900ml

[0051] XRPD determination method:

[0052] X-ray powder diffraction (XRPD) was performed. The XRPD pattern was acquired using an X-ray powder diffraction analyzer manufactured by PANalytical. The scanning parameters are shown in the table below:

[0053] model Empyrean Optical path module BBHD Anode Material Cu Voltage, current 45kV, 40mA Diverging slit 1 / 4° Anti-scattering slit 1° Sola Slit 0.04 rad Scanning mode Continuous Scan range (°2Theta) 3-40 Scan time per step (s) 30.09 Scan step size (°2Theta) 0.026

[0054] Examples A1-A9

[0055]

[0056]

[0057] Preparation of solid dispersions:

[0058] (1) Alisartan ester and excipients PVP-VA64, crosslinked polyvinylpyrrolidone and colloidal silica are mixed evenly to form a physical mixture;

[0059] (2) Add the physical mixture from step (1) into a hot melt extruder (165°C), and melt and extrude the strip product;

[0060] (3) After cooling the strip-shaped product obtained in step (2), it is pulverized to obtain a solid dispersion containing alisartan ester drug.

[0061] in:

[0062] Formulations A3 (cross-linked povidone ratio of 0.28, <0.3%) and A9 (copovidone ratio of 0.47, >0.45%) both dissolve slowly. Figure 1 As shown;

[0063] Formula A6 (crosslinked polyvinyl chloride ratio of 0.47, >0.45) is unsuitable for extrusion processes, resulting in material leakage issues, such as... Figure 2 As shown;

[0064] Formula A7 (copovidone ratio 0.28, <0.3%) showed crystallization in XRPD analysis, such as... Figure 3 As shown;

[0065] Other preferred formulations exhibit good dissolution, are in an amorphous state, and have good stability.

[0066] Examples B1-B12

[0067] Internal prescription:

[0068]

[0069]

[0070] Additional prescription:

[0071]

[0072] preparation:

[0073] 1. Preparation of solid dispersions

[0074] (1) Alisartan ester and excipients PVP-VA64, crosslinked polyvinylpyrrolidone and colloidal silica are mixed evenly to form a physical mixture;

[0075] (2) Add the physical mixture from step (1) into a hot melt extruder (165°C), and melt and extrude the strip product;

[0076] (3) After cooling the strip-shaped product obtained in step (2), it is pulverized to obtain a solid dispersion containing alisartan ester drug.

[0077] 2. Preparation of pharmaceutical compositions

[0078] The solid dispersion is mixed evenly with the remaining materials, compressed into tablets, and then coated with a film to obtain the alisartan ester drug composition.

[0079] in:

[0080] Formulations B1 (cross-linked povidone ratio of 0.25, <0.3), B3 (copovidone ratio of 0.625, >0.45), and B4 (copovidone ratio of 0.5, >0.45) all dissolve slowly;

[0081] Formulas B2 and B7 (crosslinked polyvinyl chloride ratio of 0.5, >0.45) are not suitable for extrusion processes, resulting in severe venting problems and discontinuous extruded particles.

[0082] Preferred formulations such as B5, B6, and B8-B12 exhibit good disintegration and dissolution, good stability, and excellent in vivo exposure effects.

[0083] Comparative Example 1 -- CN201610379945.8 Example 4

[0084] prescription:

[0085]

[0086] Preparation of solid dispersions:

[0087] (1) Alisartan ester and excipients are mixed evenly to form a physical mixture;

[0088] (2) Set the extrusion temperature to 120℃. After the temperature stabilizes, add the physical mixture from step (1) to the hot melt extruder at a uniform speed and extrude the strip extrudate.

[0089] (3) After cooling the strip extrusion obtained in step (2), crush it through a 60-mesh sieve to obtain alisartan ester drug solid dispersion.

[0090] The drug composition prepared using the external formulations of Examples 1-12 has a slow disintegration rate. If a disintegrant is further added to the internal formulation, not only will the dissolution rate be slower, but the tablet weight will also increase significantly.

[0091] Comparative Example 2 -- CN202210060985.1 Example 3

[0092] prescription:

[0093]

[0094] The preparation process is the same as in Examples B1-B12.

[0095] The extrusion process for this formula is unsuitable, resulting in severe venting problems and discontinuous extruded particles.

[0096] Comparative Example 3

[0097] When using formulation 5, with a copovidone binder ratio of 0.2 (48 mg), this formulation has a dissolution problem.

[0098] Comparative Example 4

[0099] Long-term stability test of preferred embodiments of the present invention:

[0100]

[0101] As can be seen from the table above, the preferred formulation of the present invention has good dissolution stability.

[0102] Comparative Example 5

[0103] (1) Experimental materials

[0104] SD rats: male, 180-250g, purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0105] Reagents: DMSO (dimethyl sulfoxide) and HPMC are both commercially available.

[0106] Instrument: LC-MS / MS (SCIEX, TripleQuad5500+ triple quadrupole mass spectrometer).

[0107] (2) Experimental methods

[0108] Different formulations of alisartan ester solid dispersion powder were weighed and administered by gavage with 1% HPMC as solvent. Venous blood was collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h.

[0109] Accurately weigh a certain amount of EXP3174, dissolve it in DMSO to use as a stock solution, add blank plasma to prepare plasma samples of different concentrations, and establish a standard curve.

[0110] The aforementioned venous blood plasma was collected, and the EXP3174 concentration was analyzed by LC-MS / MS.

[0111] 3. Data Processing

[0112] After detecting the blood concentration of EXP3174 by LC-MS / MS, pharmacokinetic parameters were calculated using WinNonlin software and a non-compartmental model method.

[0113] The experimental results are as follows:

[0114]

[0115] As can be seen from the table above, the preferred formulation of the present invention exhibits better in vivo exposure.

[0116] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. An alisartan medoxomil pharmaceutical composition, characterized in that, The pharmaceutical composition contains alisartan ester, copovidone, and crospovidone, and is prepared by hot melt extrusion, wherein the hot melt extrudate is a solid dispersion; wherein, when the mass fraction of alisartan ester is 1, the mass fractions of copovidone and crospovidone are both 0.3-0.

45.

2. The alisartan medoxomil pharmaceutical composition according to claim 1, characterized in that, It further contains a flow aid selected from talc, colloidal silica, or a combination thereof.

3. The alisartan medoxomil pharmaceutical composition according to claim 2, characterized in that, The mass fraction of the gliding agent is 0.005-0.

01.

4. The alisartan medoxomil pharmaceutical composition according to any one of claims 1-3, characterized in that, It further includes one or more of the following: disintegrants, binders, fillers, and lubricants.

5. The alisartan medoxomil pharmaceutical composition according to claim 4, characterized in that, The disintegrant is one or a mixture of croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, and pregelatinized starch; And / or the adhesive is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, starch paste, and gelatin; And / or the filler is one or more of lactose, mannitol, dextrin, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium phosphate, and dicalcium phosphate; And / or the lubricant is one or more of magnesium stearate, micronized silica gel, talc, and stearic acid.

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