Velciguat sustained release tablet and preparation method thereof

Abstract

The invention discloses a Vilciguat sustained-release tablet which comprises the following raw materials: Vilciguat particles and a sustained-release material, and the Vilciguat particles are obtained by granulating a Vilciguat aqueous solution with the pH value of 2-6 and a filler. The invention also discloses a preparation method of the Vilciguat sustained-release tablet, which comprises the following steps: uniformly mixing the raw materials of the Vilciguat sustained-release tablet, granulating, and tabletting to obtain the Vilciguat sustained-release tablet. According to the invention, through mutual cooperation of the raw materials and a specific process, the influence of intestinal environment and diet on dissolution and efficacy of the viriciguat can be avoided, the problems of repeated dissolution, precipitation and re-dissolution of the viriciguat in intestinal tracts are avoided, the dissolution effect is improved, and the viriciguat can play a more stable and longer curative effect; in addition, through mutual cooperation of the raw materials and a specific process, the Velciguat sustained release tablet has good stability.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a vericiguat sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] Vericiguat is the first soluble guanylate cyclase (sGC) stimulator for heart failure treatment, which is a new type of oral sGC stimulator that can directly bind and stimulate sGC or can synergize with endogenous NO to increase the sensitivity of sGC to endogenous NO in the case of relatively insufficient NO generation in heart failure patients, so as to increase the synthesis of cyclic guanosine monophosphate (cGMP), thereby relaxing smooth muscle and dilating blood vessels, improving cardiovascular structure and function, and playing a role in anti-inflammation and anti-myocardial fibrosis.

[0003] At present, the vericiguat tablet marketed in China is the one of Bayer Company, with the trade name of Ventrivix ® , which is a common immediate-release tablet, 1 time / day. Ventrivix ® After a single oral administration after taking high-fat, high-calorie food, t max (maximum) is prolonged from 1h to 4h after administration when fasting, and the inter-individual variability of the pharmacokinetic parameters is reduced. Compared with the administration when fasting, the AUC and C max max of the administration after taking food are increased by 19-40%. The same dietary effect is also found when administered after taking low-fat, high-carbohydrate food, with a peak time of about 1-2.5h and a half-life of 18-22h.

[0004] The original research vericiguat tablet marketed is a conventional release dosage form, which disintegrates and dissolves rapidly in the human body, but is absorbed in the small intestine. Due to the high pH in the intestinal environment and the small solubility of vericiguat, a large amount of dissolved drug is precipitated in the intestine, thereby affecting absorption and increasing the difference between different human bodies; at the same time, it also causes significant changes in pharmacokinetics before and after taking food, thereby affecting the therapeutic effect. SUMMARY

[0005] Based on the technical problems existing in the background art, the present application provides a vericiguat sustained-release tablet and a preparation method thereof. The present application can avoid the influence of the intestinal environment and diet on the dissolution and efficacy of vericiguat by the mutual cooperation of each raw material and specific process, avoid the problem of repeated dissolution-precipitation-redissolution of vericiguat in the intestine, improve the dissolution effect, and make vericiguat play a more stable and longer lasting efficacy; and the present application makes the vericiguat sustained-release tablet have good stability by the mutual cooperation of each raw material and specific process.

[0006] The application provides a sustained-release vinitriptil tablet, which comprises vinitriptil particles and a sustained-release material.

[0007] Preferably, the solute of the vinitriptil aqueous solution comprises vinitriptil, an acidic substance and a binder.

[0008] Preferably, the acidic substance adjusts the pH of the vinitriptil aqueous solution to 2-6, more preferably to 3-5.

[0009] Preferably, the acidic substance is at least one of tartaric acid and citric acid.

[0010] Preferably, the binder is at least one of hydroxypropyl cellulose and hypromellose; when the binder is hydroxypropyl cellulose, the viscosity is 10-50 mPa·s, and when the binder is hypromellose, the viscosity is 3-10 mPa·s.

[0011] The application uses an acidic substance as a pH regulator to adjust the pH of the vinitriptil aqueous solution, and the acidic substance and the vinitriptil raw material are uniformly dispersed in the solution, and then the vinitriptil particles are obtained by granulation of the binder and the filler; in the vinitriptil particles, the acidic substance can be distributed on the surface of the vinitriptil raw material; on the one hand, the stability of vinitriptil in the sustained-release tablet can be improved, and on the other hand, the pH value of the intestinal environment is relatively high, the acidic substance can reduce the pH value of the microenvironment around vinitriptil, accelerate the dissolution rate of vinitriptil, and can avoid the problem of repeated dissolution-precipitation-redissolution of vinitriptil from gastric juice to intestinal tract, reduce the influence of intestinal environment and diet on the dissolution and efficacy of vinitriptil, and thus maintain the stability of the efficacy of vinitriptil. And the use of the sustained-release material can have a certain barrier effect on intestinal juice, which can further maintain the pH value of the microenvironment around vinitriptil, accelerate the dissolution rate of vinitriptil, and after the dissolution of vinitriptil, the vinitriptil can be dissolved from the channels in the sustained-release tablet, further reducing the influence of intestinal environment and diet on the dissolution and efficacy of vinitriptil.

[0012] Preferably, in the vinitriptil aqueous solution, the mass fraction of vinitriptil is 10-20 wt%.

[0013] Preferably, the weight ratio of vinitriptil to the binder is 2-4:1.

[0014] Preferably, the filler is at least one of microcrystalline cellulose, lactose and mannitol.

[0015] Preferably, the weight ratio of vinitriptil to the filler is 1:8-9.

[0016] Preferably, the sustained-release material is at least one of hypromellose, glyceryl behenate and sodium carboxymethyl cellulose.

[0017] The viscosity of the hydroxypropyl methyl cellulose as the sustained-release material is 3000-100000 mPa·s; the viscosity of the sodium carboxymethyl cellulose as the sustained-release material is 2000-8000 mPa·s.

[0018] Preferably, the sustained-release material is a mixture of hydroxypropyl methyl cellulose and glyceryl behenate.

[0019] Preferably, the weight ratio of the hydroxypropyl methyl cellulose and the glyceryl behenate is 3-5:1.

[0020] Preferably, the weight ratio of the vericiguat and the sustained-release material is 1:13-14.

[0021] Preferably, the raw material further comprises a lubricant.

[0022] Preferably, the lubricant is at least one of stearic acid and sodium stearyl fumarate.

[0023] Preferably, the weight ratio of the vericiguat and the lubricant is 1:0.2-0.4.

[0024] The present application can further improve the stability of the vericiguat sustained-release tablet by selecting suitable types of sustained-release material, binder, acidic substance, filler, and lubricant.

[0025] Preferably, the raw material further comprises a coating material.

[0026] Preferably, the weight ratio of the vericiguat and the coating material is 1:0.5-0.8.

[0027] The coating material can be a mixture of polyvinyl alcohol, polyethylene glycol, talc, and yellow iron oxide or a commercial film coating premix such as Opadry®. ® and the like.

[0028] Preferably, the vericiguat aqueous solution is fluidized bed granulated with the filler to obtain vericiguat granules.

[0029] The specific steps of the fluidized bed granulation are as follows: the vericiguat aqueous solution is sprayed into the fluidized bed containing the filler to perform one-step granulation, and then dried to obtain vericiguat granules.

[0030] The moisture content of the vericiguat granules is ≤3.0 wt%, the particle size of the vericiguat granules is 80-250 μm, and the particle size of the vericiguat raw material is 8-20 μm.

[0031] In the vericiguat sustained-release tablet, the content of the vericiguat can be 4-4.4 wt%.

[0032] The application further provides a preparation method of the above-mentioned venglustat sustained-release tablet, which comprises the following steps: uniformly mixing raw materials of the venglustat sustained-release tablet, granulating, and tabletting to obtain the venglustat sustained-release tablet.

[0033] After the tabletting, the tablet weight can be 345-365 mg, and the hardness of the tablet is greater than or equal to 100 N.

[0034] Preferably, when the venglustat sustained-release tablet further comprises a coating material, after the tabletting, the coating material is used for coating treatment to obtain the venglustat sustained-release tablet.

[0035] The coating treatment with the coating material can further improve the stability of the venglustat sustained-release tablet.

[0036] The venglustat sustained-release tablet prepared by the application can avoid the influence of the intestinal environment and diet on the dissolution and efficacy of venglustat, improve the dissolution effect, and make venglustat play a more stable and longer lasting effect. The venglustat sustained-release tablet can reduce the influence of food, reduce the difference in the human body, maintain a stable blood drug concentration, and prolong the half-life period through slow release. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 The figure is a microscopic photograph of the venglustat granules. DETAILED DESCRIPTION

[0038] In the following, the technical solutions of the application are described in detail through specific embodiments, but it should be made clear that these embodiments are only used for illustration, and are not used to explain the scope of the application.

[0039] Examples 1-6 According to the formula in Table 1, the venglustat sustained-release tablets are respectively prepared.

[0040] Table 1: Formulas of Examples 1-6

[0041] The preparation method of the above-mentioned venglustat sustained-release tablet is the same, which comprises the following steps: The venglustat, the binder hydroxypropyl cellulose and purified water are stirred and dissolved, and the acidic substance tartaric acid is added to adjust the pH to obtain a venglustat aqueous solution with a mass fraction of 15 wt%; then the whole venglustat aqueous solution is sprayed into the filler microcrystalline cellulose in a fluidized bed to granulate in one step, and the venglustat granules with a water content of less than or equal to 3.0 wt% and a particle size of 80-250 μm are obtained; a typical microscopic photograph of the venglustat granules is as follows:Figure 1 As shown; Add sustained-release materials (hydroxypropyl methylcellulose and glyceryl behenate) to the velixicat granules and mix for 10 minutes; then add the lubricant stearic acid and mix for 5 minutes to obtain intermediate granules; compress the intermediate granules into tablets using a rotary tablet press, controlling the tablet weight to 355 mg ± 10 mg and the hardness to ≥ 100 N, to obtain uncoated tablets; coat with 15 wt% of the film-coating premix, Opadryl. ® The above-mentioned tablets were coated with an aqueous solution to obtain veliximab sustained-release tablets.

[0042] The veliximab sustained-release tablets prepared in Examples 1-6 were used to investigate their cumulative dissolution in simulated gastric fluid (hydrochloric acid aqueous solution with pH=2), and compared with the original drug, Viagra. ® The results of the comparison are shown in Table 2.

[0043] Table 2. Dissolution results of Viliciguat sustained-release tablets in simulated gastric fluid in Examples 1-6

[0044] As can be seen from Table 2: the original drug, Viagra... ® The drug was completely released within 15 minutes, while Examples 1-6 significantly prolonged the drug release process, releasing about 85% at 3 hours and almost completely at 6 hours.

[0045] Then, the veliximab sustained-release tablets prepared in Examples 1-6 were used to investigate their cumulative dissolution in simulated intestinal fluid (phosphate buffer at pH 6.8), and compared with the original drug, Viagra. ® The results of the comparison are shown in Table 3.

[0046] Table 3. Dissolution results of Viliciguat sustained-release tablets in simulated intestinal fluid in Examples 1-6

[0047] As shown in Table 3, in Examples 1-5, when the pH of the velicitracin aqueous solution was adjusted to 2-6 with tartaric acid, it achieved a sustained-release effect in simulated intestinal fluid without velicitracin precipitation. However, in Example 6, when the pH was adjusted to 6.5, velicitracin could not be completely dissolved in simulated intestinal fluid, and the original drug, Vicocel, was not completely dissolved. ®Vilixibat cannot be completely dissolved in simulated intestinal fluid either. The gastric emptying time of a human body in a fasting state is about 30 min, and the gastric emptying time after a meal is prolonged to about 2 h; by slowing down the release of the drug, the amount of vilixibat released in the stomach is reduced (by about 30-55 wt% of the total amount), thereby reducing the precipitation of vilixibat in the small intestine due to the increase in the environmental pH, and selecting a suitable pH can further reduce the precipitation of vilixibat in the small intestine due to the increase in the environmental pH, avoiding the problem of repeated dissolution-precipitation-redissolution of the drug from gastric juice to the intestinal tract, and avoiding affecting drug absorption and efficacy.

[0048] Examples 7-15 Vilixibat sustained-release tablets were prepared according to the formulations in Table 4, respectively.

[0049] Table 4 Formulations of Examples 7-15

[0050] The preparation methods of Examples 7-15 were the same as those of Example 2, wherein it was found that the tablet hardness of Examples 14-15 was 40-80 N, which was significantly lower than that of the other examples, and the difference between the tablets was large.

[0051] The vilixibat sustained-release tablets prepared in Examples 7-15 were taken to investigate their cumulative dissolution in simulated intestinal fluid (pH 6.8 phosphate buffer), and the results are shown in Table 5.

[0052] Table 5 Dissolution results of vilixibat sustained-release tablets of Examples 7-15 in simulated intestinal fluid

[0053] As can be seen from Table 5, vilixibat in samples of Examples 9-11 cannot be completely dissolved; vilixibat in samples of Examples 12-13 can be completely dissolved, but the sustained-release effect is not good, and can only be maintained for about 2 h; and because the filler in Examples 14-15 is not suitable, the tablet hardness is not good during tabletting, thereby causing the dissolution to change and the difference between individuals to become large. Therefore, suitable acidic substances, sustained-release materials, and fillers need to be selected to cooperate with each other in order to obtain good sustained-release effect and avoid the incomplete dissolution of vilixibat in intestinal fluid.

[0054] Comparative Example 1 A preparation method of a vilixibat sustained-release tablet, comprising the following steps: By weight, 15 parts of veliciguanide, 5 parts of tartaric acid, 5 parts of hydroxypropyl cellulose, and 125 parts of microcrystalline cellulose were mixed for 10 minutes. Then, 160 parts of hydroxypropyl methylcellulose and 40 parts of behenicol glyceryl ester were added and mixed for 10 minutes. Finally, 5 parts of stearic acid were added and mixed for 5 minutes. The mixture was then compressed into tablets using a rotary tablet press, with the tablet weight controlled at 355 mg ± 10 mg and the hardness ≥ 60 N, to obtain unprocessed tablets. The tablets were coated with 15 wt% of the film-coating premix, Opadryl. ® The above-mentioned tablets were coated with an aqueous solution to obtain veliximab sustained-release tablets.

[0055] The cumulative dissolution of the sustained-release tablets of Comparative Example 1 in simulated intestinal fluid (phosphate buffer at pH 6.8) was examined and compared with that of Example 2. The results are shown in Table 6.

[0056] Table 6. Dissolution results of Vericigulet sustained-release tablets in simulated intestinal fluid (Comparative Example 1)

[0057] As shown in Table 6, the sample in Comparative Example 1 was completely released within 3 hours, and its sustained-release effect was not as good as that in Example 2. This indicates that the present invention can obtain tablets with sustained-release effect using a suitable process, and that veliciguat can be completely dissolved in simulated intestinal fluid.

[0058] Accelerated testing was conducted on the sustained-release tablets, veliciguat granules, uncoated tablets, and the active pharmaceutical ingredient veliciguat from Example 2 (stored at 40°C and 75% RH for 6 months), and compared with the original drug, Viagra. ® The comparison results are shown in Table 7-8.

[0059] Table 7. Accelerated experimental results of velixigua granules and velixigua active pharmaceutical ingredient in Example 2.

[0060] Table 8. Accelerated experimental results of virixigazine tablets, sustained-release tablets, and the original drug in Example 2.

[0061] As shown in Tables 7-8, Vilixigua granules have better stability than the raw material; the sustained-release tablets have good stability, superior to the original drug Vilixigua. ® The sustained-release tablets and plain tablets differ in moisture content, but their content and impurities are similar. The veliximab sustained-release tablets described in this invention exhibit good stability.

[0062] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A sustained release tablet of velusetrag, characterized in that, The raw materials include: vericiguat granules, a sustained-release material, wherein a vericiguat aqueous solution with pH=2-6 is granulated with a filler to obtain the vericiguat granules.

2. The riluzole sustained release tablet according to claim 1, wherein The solute of the vericiguat aqueous solution includes: vericiguat, an acidic substance, and a binder; preferably, the acidic substance adjusts the pH of the vericiguat aqueous solution to be 2-6.

3. The riluzole sustained release tablet according to claim 3, wherein the tablet is prepared by the process comprising the steps of: The acidic substance is at least one of tartaric acid and citric acid; preferably, the binder is at least one of hydroxypropyl cellulose and hypromellose; preferably, the mass fraction of vericiguat in the vericiguat aqueous solution is 10-20wt%; preferably, the weight ratio of vericiguat to the binder is 2-4:

1.

4. The sustained release tablet according to any one of claims 1 to 3, wherein The filler is at least one of microcrystalline cellulose, lactose, and mannitol; preferably, the weight ratio of vericiguat to the filler is 1:8-9.

5. The veliximab sustained-release tablet according to any one of claims 1-4, characterized in that, The sustained-release material is at least one of hypromellose, glyceryl behenate, and sodium carboxymethyl cellulose; preferably, the sustained-release material is a mixture of hypromellose and glyceryl behenate; preferably, the weight ratio of hypromellose to glyceryl behenate is 3-5:1; preferably, the weight ratio of vericiguat to the sustained-release material is 1:13-14.

6. The sustained release tablet according to any one of claims 1-5, wherein, The raw materials further include a lubricant; preferably, the lubricant is at least one of stearic acid and sodium stearyl fumarate; preferably, the weight ratio of vericiguat to the lubricant is 1:0.2-0.

4.

7. The sustained release tablet according to any one of claims 1-6, wherein, The raw materials further include a coating material; preferably, the weight ratio of vericiguat to the coating material is 1:0.5-0.

8.

8. The sustained release tablet according to any one of claims 1-7, wherein, The vericiguat aqueous solution is fluidized bed granulated with the filler to obtain the vericiguat granules.

9. A process for the preparation of a sustained release tablet of vedursigil according to any one of claims 1-8, characterized in that, The method includes the following steps: mixing and granulating the raw materials of the vericiguat sustained-release tablets to obtain the vericiguat sustained-release tablets.

10. The method of claim 9, wherein the extended release tablet of omalizumab is prepared by, When the vericiguat sustained-release tablets further include a coating material, after tabletting, the coating material is used for coating treatment to obtain the vericiguat sustained-release tablets.

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