Preparation composition for treating angina pectoris and preparation method thereof

Abstract

The present invention provides a preparation composition for treating angina pectoris and a preparation method thereof, comprising a sustained-release skeleton tablet core and a membrane-controlled coating layer wrapped on the surface of the sustained-release skeleton tablet core; the sustained-release skeleton tablet core comprises a main drug, a filler, a skeleton sustained-release material, an adhesive, a stabilizer and a lubricant; the membrane-controlled coating layer comprises a sustained-release coating material, a pore-forming agent and an anti-adhesive agent. The present invention adopts a wet granulation process to prepare the sustained-release skeleton tablet core and the membrane-controlled coating layer wrapped on the surface of the sustained-release skeleton tablet core. By combining skeleton sustained-release technology and membrane controlled-release technology, it is possible to coat the surface with a sustained-release coating to improve the influence of environmental water, heat and oxygen; the prepared preparation composition can treat chronic angina pectoris, delay the release of ranolazine in the body, prolong the half-life in the body, improve drug stability, improve the pharmacokinetic properties of the drug in the body, reduce the toxic and side effects of the drug, and thus improve its bioavailability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a preparation composition for treating angina pectoris and a preparation method thereof. Background Art

[0002] Angina pectoris is a common type of coronary heart disease.

[0003] Currently, the common treatment for angina pectoris is to take nitroglycerin sublingually during an attack. When recurring, anti-anginal drugs such as b - Blockers, Ca 2+ Channel blockers and long-acting nitrates. These drugs all reduce the work of the heart by slowing down the heart rate, lowering blood pressure or weakening the heart's pumping function. However, most patients with angina pectoris have congestive heart failure, chronic lung disease or diabetes, which further damages the already weakened heart function. Some drugs also increase blood flow to the heart by dilating the coronary arteries. The use of the above three types of anti-anginal drugs can only relieve the symptoms of angina pectoris. Most patients taking the above drugs will experience adverse reactions such as fatigue, headache, cold limbs, edema and impotence.

[0004] Ranolazine was originally developed by Gilead and is the first drug approved by the FDA to treat chronic angina in ten years. It was approved for marketing in the United States in 2006. The original research adopted skeleton sustained-release technology, and the surface coating is ordinary film coating. The coating material comes from Colorcon, brand Opadry Il Yellow 33G92721. Ranolazine has a brand-new mechanism of action. It is used in combination with other anti-anginal drugs. It is a piperazine derivative that reduces myocardial oxygen demand by changing the energy metabolism of the myocardium. The characteristic of its action is to inhibit fatty acid β-oxidation, thereby activating pyruvate dehydrogenase and increasing glucose oxidation, because glucose oxidation can produce more energy per unit of oxygen than fatty acid oxidation, so it can make the heart do more work, play an anti-ischemic and anti-anginal effect, and have no effect on hemodynamics. It does not produce the additive effect of "lower heart rate and lower blood pressure", thereby avoiding further damage to heart function.

[0005] Clinical data show that ranolazine can be used as a monotherapy or as an adjuvant drug for other anti-anginal treatments; for chronic stable angina, it can relieve symptoms and improve exercise tolerance. Unlike existing anti-anginal drugs, ranolazine is a partial fatty acid oxidase inhibitor that has no effect on heart rate and blood pressure. It can effectively relieve angina without changing other kinetic parameters of the drug, thus improving the quality of life of patients with angina.

[0006] Based on the efficacy of ranolazine, domestic researchers have studied its dosage form, striving to give patients with angina pectoris more choices, specifically: CN101637442A discloses a ranolazine oral sustained-release preparation, including ranolazine, sustained-release skeleton material, filler, adhesive and lubricant, and hydroxypropyl methylcellulose phthalate and methylcellulose are used as sustained-release skeleton materials of the sustained-release preparation. CN103565767B discloses a ranolazine sustained-release tablet core, a coated tablet and a preparation method thereof, wherein the core includes ranolazine, skeleton material, enteric material and lubricant, etc., and the coated tablet is composed of a ranolazine sustained-release tablet core plus a coating layer; the prepared ranolazine sustained-release tablet, after oral administration, the drug is continuously and steadily released in the body, and is less affected by changes in the pH value in the body, thereby maintaining the effective concentration of ranolazine in plasma and reducing concentration fluctuations, thereby better exerting the efficacy. CN104758265B relates to a ranolazine sustained-release tablet pharmaceutical composition and a preparation method thereof. The sustained-release tablet is prepared by using a mixed skeleton material with a specific content range composed of a pH-dependent adhesive, a pH-independent adhesive, microcrystalline cellulose, etc., so that the final drug release of the sustained-release preparation is smoother and more complete.

[0007] Based on the existing skeleton sustained-release technology of ranolazine, the surface coating is ordinary coating, and ordinary film coating is generally a layer of ordinary film containing hydroxypropyl methylcellulose or lactose on the surface of the plain tablet, which is greatly affected by environmental water, heat, oxygen, etc. Therefore, it is necessary to study ranolazine preparations to develop more new preparations to meet the needs of the public. Summary of the invention

[0008] To achieve the purpose of the invention, the present invention provides a preparation composition for treating angina pectoris and a preparation method thereof, wherein a sustained-release coating is coated on the surface by combining skeleton sustained-release technology and membrane controlled-release technology to improve the influence of environmental water, heat and oxygen; and the sustained-release coating is an inert dense membrane that is not easily soluble in gastric acid and intestinal fluid, and a pore-forming agent on the membrane surface that can pass through the aqueous solution dissolves to form pores, so that the dense sustained-release membrane layer becomes a semipermeable membrane, thereby facilitating dissolution; the release of ranolazine in vivo can be delayed, the half-life in vivo can be prolonged, the drug stability can be improved, the pharmacokinetic properties of the drug in vivo can be improved, the toxic and side effects of the drug can be reduced, and the bioavailability thereof can be improved.

[0009] To achieve the above object, the technical solution of the present invention is as follows:

[0010] In one aspect, the present invention provides a preparation composition for treating angina pectoris, comprising a sustained-release skeleton tablet core and a membrane-controlled coating layer coated on the surface of the sustained-release skeleton tablet core.

[0011] Furthermore, the sustained-release skeleton tablet core comprises a main drug, a filler, a skeleton sustained-release material, an adhesive, a stabilizer and a lubricant.

[0012] Furthermore, the membrane-controlled coating layer includes a sustained-release coating material, a pore-forming agent and an anti-adhesive agent.

[0013] Furthermore, the sustained-release skeleton tablet core comprises, by weight, 500 parts of a main drug, 60-150 parts of a filler, 40-100 parts of a skeleton sustained-release material, 10-25 parts of a binder, 2-5 parts of a stabilizer, and 5-20 parts of a lubricant.

[0014] Furthermore, the filler is 60, 65, 70, 75, 80, 90, 100, 120, 140, 150 parts; the skeleton sustained-release material is 40, 50, 60, 70, 80, 90, 100 parts; the adhesive is 10, 15, 20, 25 parts; the stabilizer is 2, 2.5, 3, 3.5, 4, 4.5 or 5 parts; the lubricant is 5, 10, 15 or 20 parts.

[0015] Furthermore, the membrane-controlled coating layer comprises, by weight, 10 to 30 parts of a sustained-release coating material, 2 to 10 parts of a pore-forming agent, and 0.1 to 1.5 parts of an anti-adhesive agent. Furthermore, the sustained-release coating material is 10, 15, 20, 25 or 30 parts; the pore-forming agent is 2, 4, 6, 8 or 10 parts; and the anti-adhesive agent is 0.1, 0.5, 1 or 1.5 parts.

[0016] Furthermore, the sustained-release skeleton tablet core comprises, by weight, 500 parts of a main drug, 68 to 127.5 parts of a filler, 40.8 to 72.75 parts of a skeleton sustained-release material, 10.8 to 20.25 parts of a binder, 2.4 to 4.5 parts of a stabilizer, and 8 to 15 parts of a lubricant.

[0017] Furthermore, the membrane-controlled coating layer comprises, by weight, 12.5 to 25 parts of a sustained-release coating material, 4.2 to 8.0 parts of a pore-forming agent, and 0.5 to 1.3 parts of an anti-adhesive agent.

[0018] Furthermore, the sustained-release skeleton tablet core comprises, by weight, 500 parts of a main drug, 85 parts of a filler, 48.5 parts of a skeleton sustained-release material, 13.5 parts of a binder, 3 parts of a stabilizer and 10 parts of a lubricant.

[0019] Furthermore, the membrane-controlled coating layer comprises, by weight, 18 parts of sustained-release coating material, 6 parts of pore-forming agent and 1 part of anti-sticking agent.

[0020] Furthermore, the main drug is a drug for treating angina pectoris, such as ranolazine or a pharmaceutically acceptable salt thereof.

[0021] Furthermore, the filler includes, but is not limited to, one or more mixtures of microcrystalline cellulose (e.g., type 102), silicified microcrystalline cellulose, pregelatinized starch, partially pregelatinized starch, corn starch, lactose, and sucrose. Microcrystalline cellulose, type 102, is preferred.

[0022] Furthermore, the skeleton sustained-release material includes, but is not limited to, one or more mixtures of insoluble materials (such as ethyl cellulose, polyacrylic acid resin, polyethylene, soluble materials beeswax, synthetic wax, butyl stearate), methacrylic acid copolymer (model L100-55 (Methacrylic Acid Copolymer, Type C)), hydrophilic gel material (such as hydroxypropyl methylcellulose, carboxymethyl cellulose, carbomer), etc. Preferably, it is methacrylic acid copolymer, model L100-55 (Methacrylic Acid Copolymer, Type C).

[0023] Further, the binder includes but is not limited to one or more mixtures of hypromellose and povidone, for example, hypromellose of different viscosities, which may be METHOCEL ® E5, K3 LV, VLV, F4 LV, F5 LV, A15 LV, and PHARMACOAT ® 603, 645, 606 and 615, etc. METHOCEL is preferred ® E5.

[0024] Furthermore, the stabilizer includes but is not limited to one or more mixtures of sodium hydroxide, potassium hydroxide and sodium bicarbonate, etc. Sodium hydroxide is preferred.

[0025] Furthermore, the lubricant includes but is not limited to one or more mixtures of colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, talc, etc. Preferably, magnesium stearate is used.

[0026] Furthermore, the sustained-release coating material includes, but is not limited to, one or more mixtures of ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, methacrylic acid copolymer, etc. Preferably, ethyl cellulose is used.

[0027] Furthermore, the porogen includes, but is not limited to, one or more mixtures of polyethylene glycol (such as PEG400, PEG600), hydroxypropyl cellulose, povidone, polyvinyl pyrrolidone, talc, etc. PEG 400 is preferred.

[0028] Furthermore, the anti-adhesive agent includes, but is not limited to, talc (e.g., 1250 mesh), magnesium stearate, hydrogenated vegetable oil, waxes, phthalates, or a mixture thereof, preferably talc with a mesh of 1250 mesh.

[0029] Furthermore, in the membrane-controlled coating layer, the weight ratio of the sustained-release coating material, the pore-forming agent and the anti-adhesive agent is (57.5-82.8): (19.2-27.6): (3.2-4.6).

[0030] On the other hand, the present invention provides a method for preparing a preparation composition for treating angina pectoris, the specific steps of which are as follows: preparing a sustained-release skeleton tablet core by a wet granulation process and attaching / spraying a film-controlled coating layer on the surface of the sustained-release skeleton tablet core.

[0031] Furthermore, the preparation process of the sustained-release matrix tablet core is as follows:

[0032] S1 premixing: put the main drug, filler, sustained-release matrix material and stabilizer into a wet granulation pot, and stir to obtain a mixture;

[0033] S2 wet granulation: spray the binder aqueous solution into the mixture under stirring, and then continue granulation to obtain wet granules;

[0034] S3 tablet core preparation: The wet granules are dried, sized, mixed with a lubricant and compressed into sustained-release matrix tablet cores.

[0035] Furthermore, in the S1 premixing, the stirring speed is 100-150 rpm, the granulating knife speed is 1800-2600 rpm, and the mixing is performed for 15-20 minutes.

[0036] Furthermore, the adhesive aqueous solution preparation process is: the adhesive is prepared into a clear solution with a concentration of 3% to 6% with purified water.

[0037] Furthermore, the specific process of S2 wet granulation is as follows: adjust the spray pressure to 0.3~0.5MPa, add the binder by spraying at a stirring speed of 100~180rpm and a granulator speed of 1800~2600rpm, and control the addition time to 4~6 min. After the binder is added, stop stirring and shearing, record the binder addition time, and observe the state of the particles; after spraying, continue granulation for 1~2min; after granulation, unload and observe whether there is material adhering to the pot body and the stirring paddle; pass the wet particles through a 10-mesh sieve for wet granulation.

[0038] Furthermore, in the S3 tablet core making process, the drying process is as follows: start the fluidized bed, preheat the bed, stop preheating when the bed is preheated to 45°C, set the inlet air temperature to 50°C~70°C, dry the wet particles, and adjust the air volume to 1000~2000 m³ / h according to the boiling state of the material; record each parameter every 15 minutes; during the drying process, use an online sampler to take 3 consecutive samples and mix them into 1 portion, measure the drying loss of the material, stop drying when the drying loss is less than 2.0%, close the fluidized bed, and discharge the material.

[0039] Furthermore, in the S3 tablet core making process, the granulation process is: the dried granules are granulated using a granulator, the aperture of the stainless steel sieve is 1.0 mm, the granulation speed is 300-900 rpm, and the granulation condition is carefully observed during the granulation process.

[0040] Furthermore, in the S3 tablet core preparation process, the dry granules obtained by granulation and the lubricant are added to the hopper mixer, and the mixing speed is set at 10-15 rpm and the mixing time is 3-5 min to obtain the total mixture; the total mixture is tableted using an elliptical punch with a long diameter of 17 mm and a tablet weight in the range of 95%-105% of the theoretical tablet weight. The hardness is controlled in the range of 200-250N during the tableting process.

[0041] Furthermore, the preparation process of the membrane-controlled coating layer is as follows:

[0042] Step A: preparing a sustained-release coating solution by taking a sustained-release coating material, a pore-forming agent and an anti-adhesive agent;

[0043] Step B: coating the sustained-release matrix tablet core with a sustained-release coating solution to obtain a formulation composition.

[0044] Furthermore, the preparation process of the sustained-release coating solution is as follows: taking the sustained-release coating material, the pore-forming agent and the anti-adhesive agent and dissolving them in an ethanol aqueous solution (anhydrous ethanol: water = 80:20 w / w) to prepare a sustained-release coating solution.

[0045] Furthermore, the specific conditions of the coating treatment are: air inlet speed 45~55°C, tablet bed temperature 32~38°C, peristaltic pump speed 3~12rpm, atomization pressure: 0.2~0.4MPa, coating weight gain: 2%~4%.

[0046] In another aspect, the present invention provides a use of the preparation composition of the present invention in preparing a pharmaceutical composition for treating angina pectoris.

[0047] Beneficial effects:

[0048] In order to solve the problem of sudden release of the main drug, the present invention wraps a membrane-controlled coating layer on the surface of a sustained-release skeleton tablet core containing the main drug, the membrane-controlled coating layer protects the sustained-release skeleton tablet core, delays the collapse speed of the sustained-release skeleton tablet core, and slows down the release speed of the tablet core itself; in the membrane-controlled coating layer, the porogen forms holes under the action of water, so that osmotic pressure is formed inside and outside the coating layer, and under the action of the osmotic pressure, the main drug is slowly released; the slow release of the sustained-release skeleton tablet core cooperates with the slow controlled release of the membrane-controlled coating layer, and the combined synergistic effect effectively forms an effective controlled release of the main drug.

[0049] In order to avoid the collapse of the sustained-release matrix during the release process, microcrystalline cellulose type 102, METHOCEL ® The combination of E5 hydroxypropyl methylcellulose, methacrylic acid copolymer L100-55, magnesium stearate and sodium hydroxide has a slow overall release rate and is not easy to collapse.

[0050] In order to improve the stability of the coating layer, a combination of ethyl cellulose + PEG400 + talcum powder is selected to increase the overall toughness and make it less likely to break.

[0051] The present invention adopts a wet granulation process to prepare a skeleton-type plain tablet containing the main drug, and performs membrane-controlled coating on the surface to prepare a skeleton-membrane-controlled combined sustained-release preparation. While enhancing the drug's ability to cope with the effects of environmental water, heat, and oxygen, the purpose of slow release of the drug combined with the skeleton-membrane-controlled combination is achieved, and a dissolution behavior similar to that of a reference preparation can be achieved.

[0052] This method is simple to operate and has good application prospects, and provides a way of thinking and strategy for the in-depth utilization of drugs for the treatment of angina pectoris. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 Comparison chart of dissolution curves of the preparation composition (plain tablets, coated tablets) prepared in the present invention and the reference preparation (pH 1.2, 4.0, 6.8, water).

[0054] Figure 2 This is a scanning electron micrograph of the cross section of the reference preparation (without coating).

[0055] Figure 3 This is a scanning electron micrograph of the cross section of the preparation composition (plain tablet) prepared in Example 1 of the present invention.

[0056] Figure 4 This is a graph showing the blood drug concentration of the preparation composition (plain tablets, coated tablets) prepared in Example 1 of the present invention and the reference preparation in beagle dogs.

[0057] In the figure, dissolution is dissolution rate; time is time; plasma concentration is blood concentration. DETAILED DESCRIPTION

[0058] As described in the background technology section, the existing ranolazine is a simple skeleton-type sustained-release preparation. Therefore, the research on sustained-release preparations combining skeleton and membrane control is very meaningful, which can fill the gap in the research of ranolazine membrane control agents. The preparation composition can delay the release of ranolazine in vivo, improve drug stability, prolong the half-life in vivo, improve the pharmacokinetic properties of the drug in vivo, reduce the toxic and side effects of the drug, and thus improve its bioavailability.

[0059] In order to develop a sustained-release preparation combining a ranolazine skeleton and membrane control, the design idea of ​​the present invention is: a wet granulation process is used to prepare a skeleton-type plain tablet containing the main drug, and a membrane-controlled coating is performed on the surface to prepare a sustained-release preparation combining a skeleton and membrane control, thereby achieving the purpose of slow drug release.

[0060] The preparation composition of the present invention comprises the following steps:

[0061] (1) Premixing: Add the main drug, filler, skeleton material and stabilizer into the wet granulation pot in sequence, stir at 100-150 rpm, granulator at 1800-2600 rpm, and mix for 15 min.

[0062] (2) Wet granulation: The prescribed amount of binder is prepared into a clear solution with a concentration of 3%~6% with purified water. The spray pressure is adjusted (0.3~0.5MPa). The binder is added by spraying at a stirring speed of 100~180rpm and a granulator speed of 1800~2600rpm. The addition time is controlled at about 4~6 minutes. After the binder is added, stirring and shearing are stopped. The binder addition time is recorded and the state of the particles is observed. After spraying is completed, granulation is continued for 1~2 minutes. After granulation is completed, the material is unloaded and the pot and stirring paddle are observed to see if there is any material adhering.

[0063] (3) Wet granulation: The wet granules are passed through a 10-mesh sieve for wet granulation.

[0064] (4) Drying: Turn on the fluidized bed and preheat the bed. Stop preheating when the temperature reaches 45°C. Set the air inlet temperature to 50°C~70°C. Adjust the air volume (1000~2000 m³ / h) according to the boiling state of the material and dry it. Record each parameter every 15 minutes. During the drying process, use an online sampler to take 3 consecutive samples and mix them into 1 portion. Measure the material loss on drying. When the loss on drying is less than 2.0%, stop drying, close the fluidized bed, and discharge the material.

[0065] (5) Dry granulation: The dried granules are granulated using a granulator. The aperture of the stainless steel sieve is 1.0 mm and the granulation speed is 300-900 rpm. Pay attention to the condition of the granules during the granulation process.

[0066] (6) Total mixing: Add the whole dry granules and magnesium stearate into the hopper mixer, set the mixing speed to 10-15 rpm, and the mixing time to 3-5 min.

[0067] (7) Tablet pressing: Use an elliptical punch with a long diameter of 17 mm and press the tablets at a weight of 95% to 105% of the theoretical tablet weight. During the tablet pressing process, the hardness is controlled in the range of 200 to 250 N.

[0068] (8) Coating: dissolving the sustained-release coating material, pore-forming agent and anti-adhesive agent in an ethanol aqueous solution (anhydrous ethanol: water = 80:20 w / w) to prepare a sustained-release coating solution; coating the plain tablets prepared in step (7) with the sustained-release coating solution to prepare a preparation composition. The specific conditions for the coating treatment are: air inlet speed of 45-55°C, tablet bed temperature of 32-38°C, peristaltic pump speed of 3-12 rpm, atomization pressure of 0.2-0.4 MPa, and coating weight gain of 2%-4%.

[0069] In the present invention, methacrylic acid copolymer is used as the main skeleton sustained-release material, and ethyl cellulose is used as the main membrane-controlled sustained-release material to further control and adjust the drug release to obtain a better sustained-release effect. In this step, the alternative sustained-release materials are: cellulose acetate, acrylic resins (such as Eudragit RS30D, E30D, L30D, L / S, RL / RS, Retard, etc.) or mixed sustained-release film coating materials of different models and different proportions as mentioned above.

[0070] like Figure 1 As shown in the figure, the dissolution curve comparison of the plain tablet, coated tablet and reference preparation prepared by the present invention shows that the dissolution behavior of the coated tablet prepared by the present invention is more consistent with the zero-order release of constant release, while the dissolution of the plain tablet is obviously faster, which shows that the membrane-controlled coating layer not only protects the tablet core but also delays the collapse speed of the tablet core. Compared with the reference, not only the dissolution curve is consistent with the reference, but also the release is slightly slower than the reference, and the end point is consistent.

[0071] In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below in conjunction with specific embodiments.

[0072] The experimental materials used in the examples of the present invention but not specifically described are all conventional experimental materials in the art and can be purchased through commercial channels.

[0073] Example 1

[0074] (1) Premixing: Add the main drug, filler, skeleton material and stabilizer into the wet granulation pot in sequence, stir at 100 rpm, granulator at 1800 rpm, and mix for 15 minutes;

[0075] (2) Wet granulation: The prescribed amount of binder is prepared into a clear solution with a concentration of 3% with purified water. The spray pressure (0.35 MPa) is adjusted. The binder is added by spraying at a stirring speed of 100 rpm and a granulator speed of 2000 rpm. The addition time is controlled to be about 5 min. After the binder is added, stirring and shearing are stopped. The binder addition time is recorded and the state of the particles is observed. After spraying is completed, granulation is continued for 1 min. After granulation is completed, the material is unloaded and the pot and stirring paddle are observed to see if there is any material adhering.

[0076] (3) Wet granulation: The wet granules are passed through a 10-mesh sieve for wet granulation.

[0077] (4) Drying: Turn on the fluidized bed and preheat the bed. Stop preheating when the temperature reaches 45°C. Set the air inlet temperature to 55°C. Adjust the air volume (1500 m³ / h) according to the boiling state of the material and dry it. Record each parameter every 15 minutes. During the drying process, use an online sampler to take 3 consecutive samples and mix them into 1 portion. Measure the material loss on drying. When the loss on drying is less than 2.0%, stop drying, turn off the fluidized bed, and discharge the material.

[0078] (5) Dry granulation: The dried granules are granulated using a granulator. The aperture of the stainless steel sieve is 1.0 mm and the granulation speed is 300 rpm. During the granulation process, pay attention to the condition of the granules.

[0079] (6) Total mixing: Add the whole dried granules and magnesium stearate into the hopper mixer and set the mixing speed to 10 rpm and the mixing time to 3 min.

[0080] (7) Tablet pressing: Use an elliptical punch with a long diameter of 17 mm and press the tablets at a weight of 95% to 105% of the theoretical tablet weight. During the tablet pressing process, the hardness is controlled in the range of 200 to 250 N.

[0081] (8) Coating: dissolving the sustained-release coating material, pore-forming agent and anti-adhesive agent in an ethanol aqueous solution (anhydrous ethanol: water = 80:20 w / w) to prepare a sustained-release coating solution; coating the plain tablets prepared in step (7) with the sustained-release coating solution to prepare a preparation composition. The specific conditions for the coating treatment are: air inlet speed of 50°C, tablet bed temperature of 35°C, peristaltic pump speed of 6rpm, atomization pressure of 0.25±0.05MPa, and coating weight gain of 2.7%.

[0082] Embodiment 2:

[0083] (1) Premixing: Add the main drug, filler, skeleton material and stabilizer into the wet granulation pot in sequence, stir at 120 rpm, granulator at 2000 rpm, and mix for 15 minutes;

[0084] (2) Wet granulation: The prescribed amount of binder is prepared into a clear solution with a concentration of 4% with purified water. The spray pressure (0.5 MPa) is adjusted. The binder is added by spraying at a stirring speed of 150 rpm and a granulator speed of 2200 rpm. The addition time is controlled to be about 6 min. After the binder is added, stirring and shearing are stopped. The binder addition time is recorded and the state of the particles is observed. After spraying is completed, granulation is continued for 2 min. After granulation is completed, the material is unloaded and the pot and stirring paddle are observed to see if there is any material adhering.

[0085] (3) Wet granulation: The wet granules are passed through a 10-mesh sieve for wet granulation.

[0086] (4) Drying: Turn on the fluidized bed and preheat the bed. Stop preheating when the temperature reaches 45°C. Set the air inlet temperature to 70°C. Adjust the air volume (2000 m³ / h) according to the boiling state of the material and dry it. Record each parameter every 15 minutes. During the drying process, use an online sampler to take 3 consecutive samples and mix them into 1 portion. Measure the material loss on drying. When the loss on drying is less than 2.0%, stop drying, close the fluidized bed, and discharge the material.

[0087] (5) Dry granulation: The dried granules are granulated using a granulator. The aperture of the stainless steel sieve is 1.0 mm and the granulation speed is 600 rpm. During the granulation process, pay attention to the condition of the granules.

[0088] (6) Total mixing: Add the whole dried granules and magnesium stearate into the hopper mixer and set the mixing speed to 10 rpm and the mixing time to 4 min.

[0089] (7) Tablet pressing: Use an elliptical punch with a long diameter of 17 mm and press the tablets at a weight of 95% to 105% of the theoretical tablet weight. During the tablet pressing process, the hardness is controlled in the range of 200 to 250 N.

[0090] (8) Coating: dissolving the sustained-release coating material, pore-forming agent and anti-adhesive agent in an ethanol aqueous solution (anhydrous ethanol: water = 80:20 w / w) to prepare a sustained-release coating solution; coating the plain tablets prepared in step (7) with the sustained-release coating solution to prepare a preparation composition. The specific conditions for the coating treatment are: air inlet speed of 45°C, tablet bed temperature of 38°C, peristaltic pump speed of 6rpm, atomization pressure of 0.4MPa, and coating weight gain of 3%.

[0091] Comparative Example 1

[0092] Ranolazine bilayer sustained-release tablets were prepared with reference to Example 1 of CN112438955A.

[0093] From the dissolution data recorded in Table 2 of the specification of patent CN112438955A, the single-layer skeleton sustained release of Example 1 of the patent cannot achieve the sustained release behavior of the original research, and there is a sudden release behavior. The solution is to change the original single-layer tablet through the process, and prepare it into a double-layer sustained release tablet by adding a regulating layer, thereby solving the problem of poor sustained release effect of the single-layer tablet and achieving the same release behavior as the reference preparation within 12 hours. Figure 1 As shown, the homemade preparation prepared by the present application is still a single-layer tablet, without increasing the process difficulty. By combining membrane control and skeleton, the release behavior is regulated in two phases. The dissolution of the skeleton tablet does not show sudden release, and the overall dissolution behavior is slightly faster than the reference dissolution. The release rate of the sustained-release coated tablet is significantly slowed down. Compared with the reference preparation, the dissolution behavior of the sustained-release coated tablet prepared by the present application shows a nearly linear release behavior, forming a constant-rate release, which is close to controlled release. It can be seen that the coated tablet prepared by the present application has a more stable overall release rate than the double-layer sustained-release regulated tablet prepared in Example 1 of patent CN112438955A, and the dissolution behavior is more in line with the zero-order release of constant release, which is more in line with the expectation of sustained-release effect than the reference preparation.

[0094] Test Example 1: Dissolution Test

[0095] The QC medium dissolution conditions of the reference product (granules) in FDA Dissolution Methods are shown in Table 3 below:

[0096] The dissolution test was carried out on the preparation composition prepared by the present invention. The medium selected by the present invention was: pH 1.2, pH 4.0, pH 6.8, and water. The stirring method was: paddle method, the rotation speed was: 50 rpm, the medium volume was: 900 ml, and the sampling points were set to: 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h.

[0097] The dissolution curves of the skeleton tablets and the membrane-controlled coated tablets of the preparation composition prepared in Example 1 are as follows: Figure 1 As shown. The results show that in different media, the release behavior of the preparation composition prepared by the present invention is closer to the zero-order or Higuchi release model under the condition of not changing the dissolution amount. Compared with the original research, it has a more stable and sustained release behavior. It can be seen that the release behavior of the preparation composition prepared by the present invention has reached or even exceeded the reference preparation. It can be seen that the preparation composition prepared by the present application has a stable process and can play a good role in sustained release. The release within 24 hours is stable, and there is no sudden release and difficult dissolution. The half-life of the active ingredient in the body can be extended and the bioavailability can be improved. The pharmacokinetic data of beagle dogs have been verified.

[0098] like Figure 2~Figure 3 By comparing the cross-sections of the skeleton sustained-release tablet core prepared in Example 1 and the tablet core of the original reference preparation after stripping the ordinary coating, it can be seen that the prescription and preparation process of Example 1 of the present invention are different from those of the reference preparation, but the cross-sectional view shows that the effects are basically the same, and it can be seen that the release behaviors of the two in vivo are the same.

[0099] Test Example 2: Animal Test

[0100] In vivo pharmacokinetic tests were performed on the reference preparation (RLD), the ranolazine matrix sustained-release tablets (RMT) prepared in Example 1, and the ranolazine matrix sustained-release coated tablets (RCT). The in vivo pharmacokinetic tests were used to further illustrate the content of the implementation example, mainly to illustrate the in vivo pharmacokinetic parameters and relative bioavailability.

[0101] Experimental animals: 2 healthy Beagle dogs, half male and half female (6 times), weighing 8±0.5kg, fasted for 12h before the experiment, but given drinking water, and administered at a dose of 500mg / dog, blood was collected from the forelimb vein. Plasma was obtained at 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, and 72h after administration.

[0102] Blood sample processing method: Beagle dog whole blood (including anticoagulant) was allowed to stand for 10-15 minutes, centrifuged at 5000rpm (or 2000g), the upper plasma was aspirated, 500μL of plasma was taken, and 50μL of internal standard (100μg / mL lidocaine solution) was accurately added. 100μL of 0.25M Na2CO3 buffer solution (pH8.0) was added, mixed evenly, 3mL of anhydrous ether and acetonitrile mixture (1:1) was added, vortexed for 5min, and centrifuged at 3500rpm for 5min. After standing, the organic layer was aspirated and placed in a glass centrifuge tube, and evaporated with nitrogen in a 40℃ water bath. The residue was dissolved with 200μL of mobile phase, vortexed for 1min, centrifuged for 10min (8000rpm), 40μL of supernatant was aspirated for injection, and HPLC was used for detection.

[0103] Chromatographic conditions: Chromatographic column: Diamonsil C18 column, 4.6mm×250mm, 5mm; mobile phase: acetonitrile: 7mmol / L ammonium acetate: 3.5mmol / L acetic acid (containing 0.1% triethylamine) = 50:25:25 (V:V:V); detection wavelength: 230nm; flow rate: 1.0mL / min; column temperature: 30℃; injection volume: 40μL.

[0104] The results are shown in Table 4:

[0105] As can be seen from Table 4, the half-life of the ranolazine skeleton sustained-release coated tablets (RCT) prepared in Example 1 of the present application is significantly longer than that of the reference preparation (RLD), and the AUC (0→72) It is also higher than the reference preparation, improving bioavailability.

[0106] 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 principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation composition for treating angina pectoris, characterized in that: It comprises a sustained-release skeleton tablet core and a membrane-controlled coating layer wrapped on the surface of the sustained-release skeleton tablet core; The sustained-release skeleton tablet core comprises, by weight, 500 parts of a main drug, 68 to 127.5 parts of a filler, 40.8 to 72.75 parts of a skeleton sustained-release material, 10.8 to 20.25 parts of a binder, 2.4 to 4.5 parts of a stabilizer, and 8 to 15 parts of a lubricant; The membrane-controlled coating layer comprises, by weight, 12.5 to 25 parts of a sustained-release coating material, 4.2 to 8.0 parts of a pore-forming agent, and 0.5 to 1.3 parts of an anti-adhesive agent; The main drug is ranolazine or a pharmaceutically acceptable salt thereof; the filler is microcrystalline cellulose; the skeleton sustained-release material is methacrylic acid copolymer; the binder is hypromellose; the stabilizer is sodium hydroxide; the lubricant is magnesium stearate; the sustained-release coating material is ethyl cellulose; the pore-forming agent is polyethylene glycol; and the anti-adhesive agent is talc. The microcrystalline cellulose model is 102; The methacrylic acid copolymer model is L100-55; The hypromellose is selected from METHOCEL ® E5; The polyethylene glycol is selected from PEG400.

2. The preparation composition according to claim 1, characterized in that: The sustained-release skeleton tablet core comprises, by weight, 500 parts of the main drug, 85 parts of the filler, 48.5 parts of the skeleton sustained-release material, 13.5 parts of the binder, 3 parts of the stabilizer and 10 parts of the lubricant; The membrane-controlled coating layer comprises, by weight, 18 parts of sustained-release coating material, 6 parts of pore-forming agent and 1 part of anti-adhesive agent.

3. The preparation composition according to claim 1, characterized in that: The mesh number of the talc powder is 1250 meshes.

4. A method for preparing the formulation composition according to claim 1, characterized in that: A wet granulation process is used to prepare a sustained-release skeleton tablet core and a film-controlled coating layer is attached to the surface of the sustained-release skeleton tablet core; The preparation process of the sustained-release matrix tablet core is as follows: S1 premixing: put the main drug, filler, sustained-release matrix material and stabilizer into a wet granulation pot, and stir to obtain a mixture; S2 wet granulation: spray the binder aqueous solution into the mixture under stirring, and then continue granulation to obtain wet granules; S3 tablet core preparation: the wet granules are dried, granulated, mixed with a lubricant, and then tableted to prepare a sustained-release matrix tablet core; The preparation process of the membrane-controlled coating layer is as follows: Step A: preparing a sustained-release coating solution by taking a sustained-release coating material, a pore-forming agent and an anti-adhesive agent; Step B: coating the sustained-release matrix tablet core with a sustained-release coating solution to obtain a formulation composition.

5. The preparation method according to claim 4, characterized in that: In S1 premixing, the stirring speed is 100-150 rpm, the granulating knife speed is 1800-2600 rpm, and the mixing is performed for 15-20 minutes; The preparation process of the adhesive aqueous solution is as follows: the adhesive is prepared into a clear solution with a concentration of 3% to 6% with purified water.

6. The preparation method according to claim 4, characterized in that: The specific process of S2 wet granulation is as follows: adjust the spray pressure to 0.3~0.5MPa, add the binder by spraying at a stirring speed of 100~180rpm and a granulator speed of 1800~2600rpm, and control the addition time to 4~6 min. After the binder spraying is completed, continue granulation for 1~2 min; after the granulation is completed, unload the material and pass the wet granules through a 10-mesh screen for wet granulation.

7. The preparation method according to claim 4, characterized in that: In the S3 tablet core making process, the drying process is as follows: start the fluidized bed, preheat the bed, stop preheating when the preheating reaches 45°C, set the air inlet temperature to 50°C~70°C, dry the wet particles, and adjust the air volume to 1000~2000 m³ / h according to the boiling state of the material; record each parameter every 15 minutes; stop drying when the drying loss is less than 2.0%, close the fluidized bed, and discharge the material; The granulation process is as follows: the dried granules are granulated using a granulator, the aperture of the stainless steel sieve is 1.0 mm, and the granulation speed is 300-900 rpm; The dry granules obtained by granulation and the lubricant are added to a hopper mixer, and the mixing speed is set at 10-15 rpm and the mixing time is 3-5 min to obtain a total mixture. The total mixture is tableted using an elliptical punch with a long diameter of 17 mm and a tablet weight in the range of 95%-105% of the theoretical tablet weight. The hardness is controlled in the range of 200-250N during the tableting process.

8. The preparation method according to claim 4, characterized in that: The preparation process of the sustained-release coating solution is as follows: taking the sustained-release coating material, the pore-forming agent and the anti-adhesive agent and dissolving them in an ethanol aqueous solution to prepare a sustained-release coating solution; The specific conditions of the coating treatment are: air inlet speed 45~55°C, tablet bed temperature 32~38°C, peristaltic pump speed 3~12rpm, atomization pressure: 0.2~0.4MPa, coating weight gain: 2%~4%.

9. Use of the preparation composition according to claim 1 in preparing a pharmaceutical composition for treating angina pectoris.

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