CN115671077A - Compound pellet capsule for preventing cardiovascular and cerebrovascular diseases and preparation method thereof - Google Patents
Compound pellet capsule for preventing cardiovascular and cerebrovascular diseases and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases and a preparation method thereof, wherein the compound pellet capsule is prepared by adding a lubricant into an aspirin pellet and an atorvastatin ramipril pellet according to a proportion, mixing the mixture, filling the capsule, taking the aspirin pellet as a preparation unit I, taking the atorvastatin calcium ramipril pellet as a preparation unit II, taking a blank pellet core as a core, firstly coating an atorvastatin calcium medicine-containing layer, coating an isolation layer, then coating a ramipril layer, and finally coating a light-shielding moisture-proof layer for four layers, thereby respectively forming an atorvastatin calcium layer, an isolation layer, a ramipril layer and a light-shielding moisture-proof layer from inside to outside, wherein each capsule contains 25 to 180mg of aspirin, 2.5 to 40mg of atorvastatin, 2 to 20mg of ramipril, the aspirin pellet is an enteric pellet, and the atorvastatin ramipril pellet is a quick-release pellet.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases and a preparation method thereof.
Background
The' 2020 summary of China cardiovascular health and disease report shows that cardiovascular death is the leading cause of total death of urban and rural residents, 3.30 million patients suffering from cardiovascular diseases are calculated, including 1300 million cerebral apoplexy, 1139 million coronary heart disease and 2.45 million hypertension, and the cardiovascular diseases bring new and serious challenges to human beings. Common risk factors for cardiovascular diseases include hypertension, dyslipidemia, diabetes, metabolic syndrome, sleep disorders, and the like, presenting diverse causes of morbidity.
Cardiovascular and cerebrovascular diseases, such as myocardial infarction and cerebral infarction, have the same pathological basis: in blood, low-density lipoprotein cholesterol (LDL-C) at an elevated concentration may be deposited in the wall of blood vessels of important sites such as heart and brain, and gradually form atherosclerotic plaques. After plaque erosion or rupture in the blood vessel, coagulation cascade may be further induced, and finally a large amount of blood platelets aggregate together to form a mass, thereby forming thrombus. If the thrombus is left untreated, the thrombus mass is likely to continue to grow until it completely occludes the blood vessel, causing cardiovascular disease (stroke, angina, etc.).
Statins lower total cholesterol and low density lipoprotein cholesterol (LDL-C) and prevent cardiovascular and cerebrovascular diseases, and data of the American food and drug administration shows that atorvastatin calcium is better than other statins in safety in terms of the report rate of adverse events of kidney and muscle. Although the aspirin has been on the market for hundreds of years, the aspirin is the antiplatelet medicament which is most widely applied in the first-level and second-level prevention and treatment of atherosclerosis at present clinically. Ramipril is the only anti-hypertensive drug of the pril class approved for reducing the risk of myocardial infarction, stroke and cardiovascular death.
Three drugs (aspirin, atorvastatin calcium and ramipril) are commonly used for the prevention and maintenance treatment of cardiovascular and cerebrovascular diseases. The results of the SECURE study show that: compared with the combined treatment of medicines, the fixed compound preparation can reduce the medicine withdrawal rate, further improve the compliance and continuity of the medicine treatment, and improve the single standard-reaching rate of blood pressure, blood fat and blood sugar. The combination formulation containing aspirin, atorvastatin, and ramipril reduces the recurrence of clinically relevant cardiovascular events in patients after myocardial infarction compared to the single administration of these drugs. The drug Trinomia used in the study was a compound preparation containing aspirin (100 mg), ramipril (2.5, 5 or 10 mg) and atorvastatin (20 or 40 mg). The preparation form of the preparation comprises two aspirin quick-release coating tablets, one or two atorvastatin calcium quick-release coating tablets and one ramipril quick-release coating tablet which are filled in a gelatin capsule.
The aspirin used in the compound preparation is a quick-release coated tablet, while the aspirin commonly used in China is an enteric-coated tablet. Compared with enteric-coated tablets, the immediate-release aspirin tablets have a high risk of gastrorrhagia. Moreover, the compound preparation is a multi-piece filled capsule, and a special capsule filling machine is required, so the manufacturing cost and efficiency of the corresponding preparation are not high. In addition, the Trinomia capsule is large in size and is not easy to swallow.
Disclosure of Invention
The invention aims to provide a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases and a preparation method thereof. The atorvastatin calcium and the ramipril are released quickly, and are prepared into one preparation unit in order to reasonably utilize the preparation space and increase the production efficiency.
Atorvastatin calcium is sensitive to light, temperature, humidity and carbon dioxide, and is easy to degrade under an acidic condition, and the main degradation route is that hydroxyl at the beta position and carboxyl at the epsilon position form lactone. Ramipril is a mildly acidic drug that is sensitive to high temperatures, humidity, light and pressure. During the process of preparing atorvastatin ramipril pellets, it is found that atorvastatin is incompatible with ramipril, atorvastatin calcium is seriously degraded under an acidic condition, and ramipril is easily degraded under an alkaline condition.
In order to solve the problems, atorvastatin calcium and ramipril are respectively designed in different coating layers, and an isolating layer is designed between the atorvastatin calcium coating layer and the ramipril coating layer, so that the problem of incompatibility of two raw material medicines is solved, and the stability of the atorvastatin calcium and the ramipril in the preparation process can be ensured by preparing coating solutions with different pH values in the process of preparing corresponding coating solutions.
The current commercial products suffer from the following disadvantages: 1. aspirin gastric solubility stimulant; 2. the multi-piece filling efficiency is low and the cost is high; 3. it is bulky and not easy to swallow. The following problems exist in the preparation process of the compound pellet: 1. atorvastatin calcium and ramipril are incompatible; 2. in the coating process, the raw materials in the coating liquid are unstable; 3. layering occurs during mixing of pellets of different sizes, resulting in inaccurate dosing.
Based on the above object, the present invention provides the following solutions:
a compound micropill capsule for preventing cardiovascular and cerebrovascular diseases is prepared from aspirin micropill and atorvastatin ramipril micropill through proportionally mixing them with lubricant, filling in capsules,
1. aspirin is designed into an independent preparation unit I (aspirin enteric-coated solution)Pellets), atorvastatin calcium and ramipril were prepared as another formulation unit ii (atorvastatin calcium ramipril pellets). The diameter of the pellets of the two units is similar, and the diameter of the preparation unit I and the diameter of the preparation unit II (D) 50 ) The ratio is 0.5 to 2, preferably 1.0, and the diameter of both formulation units is 0.40 to 1.20mm, preferably 0.50 to 1.00mm.
2. In the preparation unit II, a sucrose pill core is taken as a core, four layers of coatings are carried out, namely an atorvastatin calcium layer, an isolating layer, a ramipril layer and a shading and moisture-proof layer from inside to outside.
The invention aims to provide preparation of a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases, wherein the compound pellet capsule comprises an aspirin enteric-coated pellet and an atorvastatin calcium ramipril pellet. Each capsule contains 25-180 mg of aspirin, 2.5-40 mg of atorvastatin and 2-20 mg of ramipril. Preferably, each capsule contains 100mg of aspirin, 5/10/20/40mg of atorvastatin and 2.5/5/10mg of ramipril.
The aspirin pellet provided by the invention is an enteric-coated pellet, and the atorvastatin ramipril pellet is a quick-release pellet.
The compound pellet capsule is prepared by adding lubricant into an aspirin enteric-coated pellet and an atorvastatin ramipril pellet according to a proportion, mixing and filling the mixture into a capsule. The lubricant is common lubricants such as talcum powder, silicon dioxide, insect wax and the like, and the capsule is common capsules such as gelatin capsule, starch capsule, hydroxypropyl methylcellulose capsule and the like.
The atorvastatin ramipril pellet provided by the invention is based on a blank pellet core, and is firstly coated with an atorvastatin calcium drug-containing layer, an isolation layer is coated, then coated with a ramipril layer, and finally coated with a shading and moisture-proof layer.
The blank pellet core is mainly used as a coated seed core, and the seed core is selected from a sucrose pellet core, a microcrystalline cellulose pellet core, a starch pellet core, a mannitol pellet core, a silicon dioxide pellet core, a starch sucrose pellet core and the like, preferably a sucrose pellet core and a microcrystalline cellulose pellet core, and most preferably a sucrose pellet core. The grain diameter of the selected pill core is 0.1 mm-0.80 mm, preferably 0.250mm-0.355mm.
The atorvastatin calcium drug-containing layer coating solution consists of atorvastatin calcium, an adhesive, a wetting agent, a pH regulator and a solvent. The atorvastatin calcium is atorvastatin calcium trihydrate, the adhesive is selected from common adhesives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and polyvinyl alcohol, the wetting agent is a common wetting agent such as polysorbate 80, polysorbate 60, polyethylene glycol 6000, xanthan gum, soybean lecithin and triethyl citrate, the pH regulator is a common pH regulator such as dilute hydrochloric acid, calcium carbonate, dilute sodium hydroxide solution, sodium carbonate solution or sodium bicarbonate solution, preferably calcium carbonate, and the solvent is selected from common solvents such as purified water and ethanol. The mass ratio of the atorvastatin calcium to the adhesive to the wetting agent to the pH regulator is (5-20) to (6.7) to (22-40) to (0.9).
The coating solution for the isolation layer of the atorvastatin ramipril pellet consists of an adhesive, an anti-sticking agent and a solvent, wherein the adhesive is selected from common adhesives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol and the like, the anti-sticking agent is common anti-sticking agents such as talcum powder, magnesium stearate, glyceryl monostearate, kaolin, silicon dioxide and the like, and the solvent is selected from common solvents such as purified water, ethanol and the like. The mass ratio of the adhesive to the anti-sticking agent is 1:5-6, and the weight of the isolation layer is preferably increased by 5% -60%.
The ramipril drug-containing layer coating liquid consists of ramipril, an adhesive, an anti-sticking agent, a pH regulator and a solvent. The adhesive is selected from common adhesives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, polyvinyl alcohol and the like, the anti-sticking agent is common anti-sticking agents such as talcum powder, magnesium stearate, glyceryl monostearate, kaolin, silicon dioxide and the like, the pH regulator is common pH regulators such as dilute hydrochloric acid, calcium carbonate, dilute sodium hydroxide solution, sodium carbonate solution or sodium bicarbonate solution and the like, and the solvent is selected from common solvents such as purified water, ethanol and the like. The mass ratio of the ramipril, the adhesive and the antisticking agent is (2.5-10) to (8) (12-20).
In the technical scheme of the specification, the preparation method of the atorvastatin ramipril pellet comprises the following steps:
(1) Coating the atorvastatin calcium containing layer: firstly, grinding atorvastatin calcium by using a grinder until the D90 is less than or equal to 0.01mm, adding an adhesive and a wetting agent into a solvent, stirring the mixture to dissolve the mixture, adding the ground atorvastatin calcium and a pH regulator into the mixed solution of the adhesive and the wetting agent, uniformly stirring the mixture, passing the mixture through a 60-mesh screen for later use, adding a blank pellet core into a fluidized bed, and coating the atorvastatin calcium containing layer by using the fluidized bed to obtain atorvastatin calcium pellets;
(2) Coating an isolation layer: adding a binder into a solvent, stirring for dissolving, adding an anti-sticking agent, uniformly stirring to obtain an isolation layer coating solution for later use, adding the atorvastatin calcium pellet into a fluidized bed, and performing isolation layer coating by using the fluidized bed; (3) coating the ramipril medicament-containing layer: adding the adhesive into a solvent for dissolving, adjusting the pH to be less than or equal to 3.0 by using a pH regulator, and adding ramipril for dissolving for later use; adding an anti-sticking agent into hot water with the temperature of 60-80 ℃, homogenizing by using a homogenizer, cooling to room temperature, then adding into a ramipril solution, uniformly stirring for later use, adding isolated layer pellets into a fluidized bed, and coating a ramipril drug-containing layer by using the fluidized bed;
(4) And (3) coating a shading and moisture-proof layer: adding Opadry coating powder into purified water, stirring, adding ramipril pellets into a fluidized bed, and performing light-shading and moisture-proof layer coating by using the fluidized bed. The mass ratio of Opadry coating powder to purified water is 1:5. The weight of the shading and moisture-proof layer coating is increased by 5-20%.
The aspirin enteric-coated pellet provided by the invention takes aspirin raw material drug or an aspirin pellet core as a drug-containing pellet core, with or without an isolation layer, and then is coated with an enteric-coated layer.
The raw material of the aspirin raw material medicine provided by the invention has the particle size of 0.20-1.00 mm, preferably 0.355-0.850 mm, and the major diameter/minor diameter is less than or equal to 2.5.
The aspirin pill core provided by the invention is composed of aspirin, a disintegrating agent, a filling agent, an adhesive and a solvent, and is prepared by preparing a soft material through wet granulation and then performing an extrusion rounding process; wherein the filler is selected from common fillers such as starch, lactose, mannitol, etc.; the disintegrating agent is selected from microcrystalline cellulose, wherein the binder is selected from conventional binders such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crosslinked polyvinylpyrrolidone; wherein the solvent is selected from purified water, ethanol or mixture thereof. The aspirin used for extrusion and spheronization is a crushed raw material medicine, and the particle size D90 of the aspirin is less than or equal to 0.15mm.
The aspirin enteric-coated pellet provided by the invention comprises an isolating layer coating component, a plasticizer and a solvent, wherein the adhesive is selected from common adhesives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cross-linked polyvinylpyrrolidone and the like, the plasticizer is selected from one or more of polyethylene glycol, polyvinyl alcohol, povidone, talcum powder, kaolin and magnesium stearate, the solvent is selected from common solvents such as purified water, ethanol or a mixture of the purified water and the ethanol, and the weight of the isolating layer is preferably increased by 5-60%; the enteric coating component consists of a film forming agent, a plasticizer, an anti-sticking agent, a wetting agent and a solvent, wherein the film forming agent is methacrylic acid copolymer, the wetting agent is selected from one or two of sodium dodecyl sulfate and polysorbate 80, the plasticizer is selected from one or more of citrate, triacetin and triethyl citrate, and the weight of the enteric layer is preferably increased by 10-50%.
In a specific formula of the aspirin pill core, a disintegrating agent is microcrystalline cellulose, a filling agent is corn starch, an adhesive is hydroxypropyl cellulose, and a solvent is 70% ethanol; in the isolation layer, the adhesive is hydroxypropyl methylcellulose, the plasticizer is polyethylene glycol 6000, and the solvent is purified water; in the enteric layer, the film forming agent is methacrylic acid copolymer L30D, the plasticizer is triethyl citrate, the anti-sticking agent is glyceryl monostearate and distearate, the wetting agent is polysorbate 80, and the solvent is purified water.
The preparation method of the aspirin enteric-coated pellet in the scheme comprises the following steps:
(1) Preparation of aspirin pill cores: firstly, aspirin is crushed to D90 of less than or equal to 0.15mm by a crusher, the crushed aspirin, hydroxypropyl cellulose, corn starch and microcrystalline cellulose are added into wet granulation, 70% ethanol solution is sprayed to prepare soft materials, the aspirin soft materials are poured into an extruder to extrude strips, then the strips are added into a rounding machine to be rounded, and finally, the obtained aspirin pill cores are dried by a fluidized bed or an oven, and the water content is controlled to be less than or equal to 3%;
(2) Coating an aspirin isolated layer: adding hypromellose and polyethylene glycol into purified water to obtain coating solution, spray-coating with fluidized bed,
(3) Coating an aspirin enteric layer:
preparing a glyceryl monostearate and glyceryl distearate suspension: adding Tween 80, triethyl citrate and glyceryl monostearate into hot water at the temperature of between 60 and 80 ℃, and homogenizing by using a homogenizer for later use;
preparing enteric solution: adding the glyceryl monostearate and distearate suspension into a methacrylic acid copolymer L30D, and uniformly stirring for later use;
adding the separated layer micro-pills into a fluidized bed, and coating the enteric layer by using the fluidized bed.
In the technical scheme of the specification, the preparation method of the compound pellet capsule comprises the following steps:
(1) Adding the aspirin enteric-coated pellets, the atorvastatin ramipril pellets and the talcum powder into a mixer, and uniformly mixing.
(2) Filling the mixed pellets into gelatin capsules.
According to the invention, atorvastatin calcium and ramipril are prepared into one preparation unit, so that the preparation space is saved, and the medicine taking and swallowing are facilitated. An isolation layer is designed between the atorvastatin calcium layer and the drug-containing layer, so that the problem of incompatibility of two drugs is effectively solved, and the stable corresponding coating liquid with the prescription can be respectively designed. And the ramipril layer is coated with a shading and moisture-proof layer, so that the stability of the product is further improved.
The invention designs the preparation skillfully, and prepares the atorvastatin calcium ramipril compound preparation by using a pellet coating technology, so that the side effect is reduced, the production cost is reduced, the production efficiency is increased, and the capsule shell is broken off under the condition of inconvenient taking, and the content pellets are taken directly.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1: preparation of aspirin enteric-coated pellet (I)
| Name of material | Prescription/mg | Function of |
| Aspirin bulk drug (0.355 mm-0.850 mm) | 100.00 | Active ingredient |
| Youteqi L30D-55 (30% solid content) | 50.00 | Film forming agent |
| Talcum powder | 8.00 | Anti-sticking agent |
| Citric acid triethyl ester | 1.50 | Plasticizer |
| Purified water | 87.50 | Solvent(s) |
| Total of | 124.5 | / |
Screening raw material medicines: using 45-mesh and 20-mesh screens to screen aspirin raw material medicines of Huayin city Qianyiao pharmaceutical industry Co., ltd, and using 45-mesh to 20-mesh raw material medicines to carry out enteric coating.
Preparing a coating solution: adding the triethyl citrate and the talcum powder with the prescription dose into purified water, and homogenizing for 4 times and 3min each time by using a homogenizer at the rotating speed of 10000 rpm. Adding the Eudragit L30D-55 aqueous dispersion just before use, stirring uniformly, filtering with 40 mesh sieve to obtain coating solution, and continuously stirring during spraying operation.
Enteric coating (target coating weight gain 24.5%): the inlet air temperature is set to be 60 ℃, the frequency of a fan is set to be 25Hz, and the fluidized bed is preheated. Stopping the machine when the temperature of the material reaches 30 ℃, adding the screened aspirin, and spraying the coating liquid when the temperature of the material reaches 32 ℃. The coating parameters are as follows: the frequency of the fan is 25-30 Hz, the temperature of the materials is 28-32 ℃, the temperature of the inlet air is 40-60 ℃, the pump speed is 1-3 rpm, and the atomization pressure is 1.5bar. After spraying liquid, setting the air inlet temperature at 30 ℃, drying for 30min, and stopping discharging. Thereafter, the pellets were sieved using 35 mesh (0.5 mm) and 14 mesh (1.0 mm) screens, and pellets between 35 mesh and 14 mesh were taken for subsequent manufacturing procedures.
Example 2: preparation of aspirin enteric-coated pellet (II)
Preparation of aspirin pill cores: firstly, crushing aspirin twice by using a hammer mill (the rotating speed is 6000rpm, the aperture of a screen mesh is 0.5 mm) until the D90 is less than or equal to 0.15mm, adding the crushed aspirin, the corn starch, the microcrystalline cellulose and the hydroxypropyl cellulose into wet granulation, and spraying 70% ethanol solution to prepare a soft material. Pouring an aspirin soft material into an extruder to extrude a strip-shaped object, then adding the strip-shaped object into a rounding machine to round, and finally drying the obtained aspirin pill core in a fluidized bed, wherein the air inlet temperature is set to be 60 ℃, the air inlet frequency is set to be 25-30 Hz, and the drying is carried out until the water content is less than or equal to 3.0%;
coating an aspirin isolated layer: adding hydroxypropyl methylcellulose and polyethylene glycol into purified water, stirring and dissolving to obtain coating solution for the isolation layer. Coating is sprayed on the bottom of a fluidized bed, the air inlet temperature is set to be 60 ℃, the frequency of a fan is set to be 25Hz, and the fluidized bed is preheated. Stopping the machine when the temperature of the materials reaches 36 ℃, adding the aspirin pill core, and spraying the coating liquid of the isolating layer when the temperature of the materials reaches 36 ℃. The coating parameters are as follows: the frequency of the fan is 25-30 Hz, the temperature of the materials is 36-42 ℃, the temperature of the inlet air is 50-60 ℃, the pump speed is 3rpm, and the atomization pressure is 1.5bar. After spraying liquid, setting the air inlet temperature to be 40 ℃, drying for 30min, and stopping discharging.
Coating an aspirin enteric layer: (1) preparing a glyceryl monostearate and glyceryl distearate suspension: adding polysorbate 80, triethyl citrate and glyceryl monostearate into hot purified water at the temperature of 60-80 ℃, homogenizing for 4 times and 3min each time by using a homogenizer at the rotation speed of 10000rpm, then adding the mixture into the purified water while the mixture is hot, and cooling to 30 ℃ to obtain glyceryl monostearate suspension for later use. (2) Preparing an enteric solution: the glyceryl monostearate suspension was added to the Eudragit L30D-55, stirred until use, and sieved through a 60 mesh screen before use. Adding the isolated layer pellet into fluidized bed, preheating to material temperature above 30 deg.C, and spraying into coating solution. In the coating process, the air inlet temperature is controlled, the material temperature is controlled to be 32-38 ℃, and the air inlet quantity is controlled to control the pellets to keep a better fluidized state. After coating was completed, the coating was dried for 2 hours using an oven set at a drying temperature of 40 ℃. Thereafter, the pellets were sieved using 35 mesh (0.5 mm) and 14 mesh (1.0 mm) screens, and pellets between 35 mesh and 14 mesh were taken for subsequent manufacturing procedures.
Example 3: preparation of atorvastatin ramipril pellet
Coating the atorvastatin calcium containing layer: adding hydroxypropyl methylcellulose and polysorbate 80 into purified water, stirring to dissolve, adding atorvastatin calcium trihydrate (D90 is less than or equal to 0.01 mm) and calcium carbonate (D90 is less than or equal to 0.02 mm) into a mixed solvent of the hydroxypropyl methylcellulose and the polysorbate 80, stirring uniformly, and sieving with a 60-mesh sieve to obtain the atorvastatin calcium drug-containing layer coating solution for later use. Adding the sucrose pellet core into a fluidized bed, preheating to the material temperature of over 36 ℃, and spraying coating liquid of the atorvastatin calcium drug-containing layer. Setting the air inlet temperature to be 45-65 ℃, the air inlet frequency to be 25-30 Hz, controlling the material temperature to be 40-46 ℃, the pump speed to be 3rpm and the atomization pressure to be 1.5bar.
Coating the isolating layer pellets: adding hydroxypropyl cellulose into purified water, stirring for dissolving, adding magnesium stearate and pulvis Talci, and stirring to obtain coating solution for isolation layer. Adding the atorvastatin calcium drug-containing pellets into a fluidized bed, preheating the material at a temperature of over 36 ℃, and starting spraying the isolation layer coating liquid. Setting the air inlet frequency to be 30Hz, controlling the air inlet temperature to be 45-65 ℃, controlling the material temperature to be 38-42 ℃, controlling the pump speed to be 3rpm, and controlling the atomization pressure to be 1.5bar. After spraying, stopping heating, cooling the material to below 30 ℃, and discharging.
Coating the ramipril drug-containing layer: adding hydroxypropyl methylcellulose into purified water, dissolving and cleaning, adjusting pH to be less than or equal to 3.0 by using 0.1mol/L dilute hydrochloric acid or 0.1mol/L dilute sodium hydroxide solution, and adding ramipril to dissolve and clean for later use. Adding glyceryl monostearate and distearate into hot purified water of 60-80 ℃, homogenizing for 4 times and 3min each time by using a homogenizer at the rotation speed of 10000rpm, then cooling to 30 ℃, then adding into ramipril solution, and uniformly stirring for later use. Adding the isolated layer pellets into a fluidized bed, and coating the ramipril drug-containing layer by using the fluidized bed. Setting the air inlet frequency to be 30Hz, controlling the air inlet temperature to be 45-65 ℃, controlling the material temperature to be 38-42 ℃, controlling the pump speed to be 3rpm, and controlling the atomization pressure to be 1.5bar. After spraying liquid, stopping heating, reducing the temperature of the materials to below 30 ℃, and discharging.
And (3) coating a shading and moisture-proof layer: adding Opadry coating powder into purified water, and stirring uniformly. The ramipril pellets are added into a fluidized bed and the fluidized bed is used for shading and moisture-proof layer coating. Setting the air inlet frequency to be 30Hz, controlling the air inlet temperature to be 45-65 ℃, controlling the material temperature to be 38-42 ℃, controlling the pump speed to be 3rpm, and controlling the atomization pressure to be 1.5bar. After spraying, stopping heating, cooling the material to below 30 ℃, and discharging. Thereafter, the pellets were sieved using 35 mesh (0.5 mm) and 14 mesh (1.0 mm) screens, and pellets between 35 mesh and 14 mesh were taken for subsequent manufacturing procedures.
Example 4: preparation of atorvastatin and ramipril compound capsule containing aspirin
The aspirin enteric-coated pellets, the atorvastatin ramipril pellets and the talcum powder which is 1 percent of the total filling amount of the capsule in the embodiments 1 to 3 are respectively taken and evenly mixed by a three-dimensional mixer, the mixing frequency is 30Hz, and after the mixing for 20min, the mixture is filled into No. 1, no. 2 or No. 0 gelatin capsules.
Example 5: stability of ramipril coating solution under different pH conditions
Adding 4g of hydroxypropyl methylcellulose into 75g of purified water, dissolving and cleaning, adjusting pH to 1.2, 3.0, 4.5 and 6.8 by using 0.1mol/L dilute hydrochloric acid or 0.1mol/L dilute sodium hydroxide solution, adding 5g of ramipril, dissolving and cleaning, standing for 4h, and detecting related substances by using a liquid chromatography.
As can be seen from the above table, when the pH of the coating solution is greater than 3.0, the degradation of ramipril as the main component is severe, so the pH of the coating solution should be controlled not to be greater than 3.0 during the coating process.
Example 6: stability of atorvastatin calcium coating liquid at different times
Adding 3.35g of hydroxypropyl methylcellulose and 0.45g of polysorbate 80 into 104.20g of purified water, stirring for dissolving, adding 5.42g of atorvastatin calcium trihydrate (D90 is less than or equal to 0.01 mm) and 16.83g of calcium carbonate (D90 is less than or equal to 0.02 mm) into the adhesive, stirring uniformly, and sieving with a 60-mesh sieve for later use.
As can be seen from the table above, the prepared atorvastatin calcium coating liquid has good stability of the raw material medicine within 72 hours, and can be used for coating the pellets.
Example 7: dissolution detection of aspirin atorvastatin ramipril compound capsule
Dissolution test of aspirin
An instrument device: pulp process
Dissolution medium and volume: 0.1mol/L hydrochloric acid solution, 900ml
pH6.8 phosphate buffer, 900ml
Rotating speed: 50 revolutions per minute
Dissolution testing of atorvastatin
An instrument device: pulp process
Dissolution medium and volume: 900ml of water
pH6.8 phosphate buffer, 900ml
Rotating speed: 50 revolutions per minute
Dissolution testing of ramipril
An instrument device: pulp process
Dissolution medium and volume: 900ml of water
pH6.8 phosphate buffer, 900ml
Rotating speed: 50 revolutions per minute
According to the three tables, the compound capsule of the aspirin atorvastatin ramipril prepared by the application comprises the following components: 1. aspirin is not dissolved out under acidic condition, can be completely released under the condition of pH6.8, and can realize delayed release of aspirin to protect gastric mucosa. 2. The atorvastatin and the ramipril have high dissolution rates in different media and can be quickly released so as to achieve the aim of exerting the drug effect in a short time.
Example 8: stability test data of atorvastatin ramipril compound capsule aspirin the stability test of sample 4 was performed for 10 days at high temperature (60 ℃), the content and the change of related substances were examined, and the examination results are shown in the following table.
From the above table, the self-made sample has good stability and stable quality.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (8)
1. A compound pellet capsule for preventing cardiovascular and cerebrovascular diseases is characterized in that after an aspirin pellet and an atorvastatin ramipril pellet are proportionally added with a lubricant and mixed, the capsule is filled, the aspirin pellet is taken as a preparation unit I, the atorvastatin calcium ramipril pellet is taken as a preparation unit II, and the diameters (D) of the preparation unit I and the preparation unit II are respectively equal 50 ) The ratio is 0.5 to 2, the diameters of the two preparation units are 0.40 to 1.20mm, the atorvastatin calcium ramipril pellet takes a blank pellet core as a core, the atorvastatin ramipril pellet takes the blank pellet core as a base, an atorvastatin calcium drug-containing layer coating is firstly carried out, an isolating layer is coated, a ramipril layer coating is then carried out, and finally a light-shading and moisture-proof layer coating is carried out for four layers of coating, so that an atorvastatin calcium layer, the isolating layer, a ramipril layer and a light-shading and moisture-proof layer are respectively formed from inside to outside, wherein each capsule comprises 25 to 180mg of aspirin, 2.5 to 40mg of atorvastatin, 2 to 20mg of ramipril, the aspirin pellet is an enteric-coated pellet, and the atorvastatin ramipril pellet is a quick-release pellet; the aspirin enteric-coated pellet takes aspirin raw material drug or an aspirin pellet core as a drug-containing pellet core, contains or does not contain an isolation layer, and then is coated with an enteric-coated layer.
2. The compound pellet capsule for preventing cardiovascular and cerebrovascular diseases according to claim 1, wherein the diameters D of the preparation unit I and the preparation unit II are 50 The ratio is 1.0, and the diameters of the two preparation units are both 0.50 to 1.00mm; each capsule contains 100mg of aspirin, 5mg or 10mg or 20mg or 40mg of atorvastatin and 2.5mg or 5mg or 10mg of ramipril.
3. The preparation method of the compound pellet capsule for preventing cardiovascular and cerebrovascular diseases according to claim 1 or 2, characterized by comprising the following steps:
(1) Adding the aspirin enteric-coated pellets, the atorvastatin ramipril pellets and the lubricant into a mixer, and uniformly mixing;
(2) And filling the mixed pellets into a capsule, wherein the lubricant is one or a mixture of more than two of talcum powder, silicon dioxide and Chinese wax in any proportion, and the capsule is one of a gelatin capsule, a starch capsule and a hydroxypropyl methylcellulose capsule.
4. The preparation method of the compound pellet capsule for preventing cardiovascular and cerebrovascular diseases according to claim 3, wherein the atorvastatin ramipril pellet is obtained by the following process:
(1) Coating the atorvastatin calcium containing layer: firstly, grinding atorvastatin calcium by using a grinder until the D90 is less than or equal to 0.01mm, adding an adhesive and a wetting agent into a solvent, stirring the mixture to dissolve the mixture, adding the ground atorvastatin calcium and a pH regulator into the mixed solution of the adhesive and the wetting agent, uniformly stirring the mixture, passing the mixture through a 60-mesh screen for later use, adding a blank pellet core into a fluidized bed, and coating the atorvastatin calcium containing layer by using the fluidized bed to obtain atorvastatin calcium pellets;
(2) Coating with an isolating layer: adding an adhesive into a solvent, stirring for dissolving, adding an anti-sticking agent, uniformly stirring to obtain an isolation layer coating solution for later use, adding the atorvastatin calcium pellet into a fluidized bed, and performing isolation layer coating by using the fluidized bed;
(3) Coating the ramipril drug-containing layer: adding the adhesive into a solvent for dissolving, adjusting the pH to be less than or equal to 3.0 by using a pH regulator, and adding ramipril for dissolving for later use; adding an anti-sticking agent into hot water of 60 to 80 ℃, homogenizing by using a homogenizer, cooling to room temperature, then adding into a ramipril solution, uniformly stirring for later use, adding the isolated layer pellets into a fluidized bed, and coating a ramipril drug-containing layer by using the fluidized bed;
(4) And (3) coating a shading and moisture-proof layer: adding Opadry coating powder into purified water, stirring uniformly, adding ramipril pellets into a fluidized bed, and carrying out light-shading and moisture-proof layer coating by using the fluidized bed.
5. The method for preparing a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases according to claim 4, wherein in the step (1), the blank pellet core is selected from a sucrose pellet core, a microcrystalline cellulose pellet core, a starch pellet core, a mannitol pellet core, a silicon dioxide pellet core or a starch sucrose pellet core, and the particle size of the blank pellet core is 0.1mm to 0.80mm; the atorvastatin calcium is atorvastatin calcium trihydrate, the adhesive is one or a mixture of more than two of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and polyvinyl alcohol in any proportion, the wetting agent is one or a mixture of more than two of polysorbate 80, polysorbate 60, polyethylene glycol 6000, xanthan gum, soybean lecithin and triethyl citrate in any proportion, the pH regulator is dilute hydrochloric acid, calcium carbonate, a dilute sodium hydroxide solution, a sodium carbonate solution or a sodium bicarbonate solution, and the solvent is one or a mixture of two of purified water and ethanol in any proportion.
6. The method for preparing a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases according to claim 4, wherein in the step (2), the binder is one or a mixture of two or more of hydroxypropyl cellulose, hypromellose, povidone and polyvinyl alcohol in any proportion, the anti-sticking agent is one or a mixture of two or more of talcum powder, magnesium stearate, glyceryl monostearate, kaolin and silicon dioxide in any proportion, the solvent is one or a mixture of two or more of purified water and ethanol in any proportion, and the weight of the coating of the isolation layer is increased by 5-60% of the mass of the atorvastatin calcium pellet.
7. The method for preparing a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases according to claim 4, wherein in step (3), the binder is one or a mixture of two or more of hydroxypropyl cellulose, hypromellose, povidone and polyvinyl alcohol in any proportion, the anti-sticking agent is one or a mixture of two or more of talc, magnesium stearate, glyceryl monostearate, kaolin and silicon dioxide in any proportion, the pH regulator is one or a mixture of two or more of dilute hydrochloric acid, calcium carbonate, dilute sodium hydroxide solution, sodium carbonate solution or sodium bicarbonate solution in any proportion, and the solvent is one or a mixture of two or more of purified water and ethanol in any proportion.
8. The method for preparing a compound pellet capsule for preventing cardiovascular and cerebrovascular diseases according to claim 4, wherein in the step (4), the weight of the shading and moisture-proof layer coating is increased by 5-20%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211446239.2A CN115671077A (en) | 2022-11-18 | 2022-11-18 | Compound pellet capsule for preventing cardiovascular and cerebrovascular diseases and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008069546A1 (en) * | 2006-12-07 | 2008-06-12 | Boryung Pharmaceutical Co., Ltd | Oral administrative preparation for treating cardiovascular system disease |
| CN101980701A (en) * | 2008-03-28 | 2011-02-23 | 菲尔若国际公司 | Capsule for the prevention of cardiovascular diseases |
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2022
- 2022-11-18 CN CN202211446239.2A patent/CN115671077A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008069546A1 (en) * | 2006-12-07 | 2008-06-12 | Boryung Pharmaceutical Co., Ltd | Oral administrative preparation for treating cardiovascular system disease |
| CN101980701A (en) * | 2008-03-28 | 2011-02-23 | 菲尔若国际公司 | Capsule for the prevention of cardiovascular diseases |
Non-Patent Citations (1)
| Title |
|---|
| JUAN TAMARGO, ET AL.: "The Fuster-CNIC-Ferrer Cardiovascular Polypill: a polypill for secondary cardiovascular prevention", INTERNATIONAL JOURNAL OF CARDIOLOGY, vol. 201, no. 1, pages 15 - 22 * |
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