Medicine composite packaging preparation as well as preparation method and application thereof

Abstract

The invention provides a medicine composite packaging preparation as well as a preparation method and application thereof, and relates to the technical field of medicines. The composite packaging preparation comprises an aspirin enteric-coated tablet and a rivaroxaban tablet, the aspirin enteric-coated tablet comprises a tablet core, a sustained-release layer and a protective layer, the tablet core is prepared from aspirin and D-isoleucine; the rivaroxaban tablet comprises rivaroxaban, polacrilin potassium, mannitol, polyethylene glycol, an adhesive and a lubricant. The invention also provides an application of the composite packaging preparation in preparation of drugs for treating thrombotic diseases, the composite packaging preparation has extremely high stability and higher bioavailability, and the drugs are stably released in vivo and have good curative effects.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composite packaging preparation and a preparation method and application thereof. Background Art

[0002] Aspirin, also known as acetylsalicylic acid (ASA), is a non-steroidal anti-inflammatory drug first synthesized by Charles Gerhardt in 1853 and first marketed by Bayer in 1899. It has a wide range of pharmacological effects, including anti-inflammatory, anti-rheumatic, analgesic, antipyretic, and platelet aggregation inhibition. Small doses of aspirin (less than 300 mg per day) inhibit platelet aggregation by inhibiting platelet cyclooxygenase and reducing prostaglandins, and can prevent cardiovascular diseases. Clinically, aspirin has been shown to play an important role in preventing thrombotic diseases, including cerebral thrombosis, coronary heart disease, myocardial infarction, previous or recurrent myocardial infarction, ischemic stroke, transient ischemic attack, unstable angina, and postoperative thrombosis and thrombotic occlusion.

[0003] Rivaroxaban is a highly selective, dose-dependent new oral anticoagulant that interrupts the intrinsic and extrinsic pathways of the coagulation cascade by directly inhibiting factor Xa, inhibiting the generation of thrombin and thrombosis. Rivaroxaban was developed by Bayer Pharmaceuticals of Germany and was approved for marketing by the European Union on September 30, 2008. It was first approved for the treatment of patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism. Two new indications for rivaroxaban tablets have been approved by the CFDA, namely the treatment and prevention of deep vein thrombosis and prevention of pulmonary embolism, and stroke prevention in patients with atrial fibrillation. In November 2018, the U.S. FDA approved Bayer's rivaroxaban tablets (Xarelto) 2.5mg for combined administration with aspirin (ASA) for patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD) to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction and stroke). Rivaroxaban is currently the only non-vitamin K antagonist oral anticoagulant approved for use in combination with aspirin in the above-mentioned CAD and PAD patients to reduce the risk of major cardiovascular events.

[0004] Rivaroxaban plus low-dose aspirin can be used to treat patients with coronary artery disease who are at high risk of subsequent events (including peripheral arterial disease, recurrent myocardial infarction, diabetes or chronic kidney disease requiring medication) and who have a history of myocardial infarction and have a high risk of ischemic events and a low risk of bleeding.

[0005] Patent CN 112451531 B discloses a compound pharmaceutical preparation of aspirin and rivaroxaban and a preparation method thereof. The compound preparation is formed by filling capsules with aspirin microtablets and rivaroxaban microtablets. Wherein, aspirin is enteric-coated and released, and rivaroxaban is sustained-release, which is used for the treatment of related diseases such as thrombolysis and prevention of thrombosis. The aspirin microtablet is an enteric-coated tablet with a specification of 25-100 mg / tablet, and each capsule is filled with 1-4 tablets. The rivaroxaban sustained-release microtablet has a specification of 1.25-20 mg / tablet, and each capsule is filled with 1-8 tablets. The microtablets of two drugs and two release mechanisms are filled in the same capsule using microtablet capsule filling technology to make rivaroxaban aspirin capsules. This patent tested the dissolution performance and bioavailability of aspirin and rivaroxaban. The maximum blood concentration of rivaroxaban was low, and the bioavailability was about 97% of the reference preparation. The AUC0-t of aspirin was 91.99%. The disintegration time and stability of the compound preparation were not examined.

[0006] Since aspirin is unstable, it is easily hydrolyzed into salicylic acid and acetic acid, the latter of which can make the preparation have a strong vinegar taste. The former is more irritating to the gastrointestinal tract than aspirin, has certain toxic and side effects on the human body, and can cause irritation and damage to the digestive tract. The excipients have a greater impact on the content of aspirin enteric-coated tablets and the content of free salicylic acid. Improper use will accelerate the hydrolysis of aspirin, resulting in excessive free salicylic acid and unstable products. The bioavailability is affected by dosage form factors, such as disintegration time, dissolution rate, etc. How to improve its stability and bioavailability and better exert its efficacy is the research focus of researchers in this field.

[0007] Based on this, the researchers of the present invention provide a composite packaged preparation of aspirin and rivaroxaban and a preparation method thereof. The composite packaged preparation is obtained by combining and packaging aspirin enteric-coated tablets (specification 100 mg) and rivaroxaban tablets (specification 2.5 mg) in proportion. By optimizing the preparation process and excipients, a combined preparation with high stability, high bioavailability and good efficacy is obtained. Summary of the invention

[0008] In view of the above problems, the present invention provides a composite packaged preparation of aspirin and rivaroxaban, comprising enteric-coated aspirin tablets and rivaroxaban tablets. On the one hand, the efficacy of the enteric-coated aspirin tablets and rivaroxaban tablets is improved by optimizing the formula and process of the enteric-coated aspirin tablets and rivaroxaban tablets, and on the other hand, the preparation is convenient for taking and the phenomenon of missed doses is reduced.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] In one aspect, the present invention provides a composite package preparation of aspirin and rivaroxaban, characterized in that the composite package preparation comprises enteric-coated aspirin tablets and rivaroxaban tablets;

[0011] The enteric-coated aspirin tablets comprise a tablet core, a sustained-release layer and a protective layer; the tablet core of the enteric-coated aspirin tablets comprises aspirin and D-isoleucine; the mass ratio of aspirin to D-isoleucine is 1:0.8-1.5;

[0012] The rivaroxaban tablets include rivaroxaban, polacrilin potassium, mannitol, polyethylene glycol, an adhesive and a lubricant; the mass ratio of the rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol is 1:0.6-0.85:5.5-7.2:2.0-3.2.

[0013] Preferably, the mass ratio of the enteric-coated aspirin tablets to the rivaroxaban tablets is 18-22:1; preferably, the mass ratio of the enteric-coated aspirin tablets to the rivaroxaban tablets is 20:1.

[0014] Preferably, the specification of the enteric-coated aspirin tablets is 50 mg / tablet or 100 mg / tablet; more preferably, the specification of the enteric-coated aspirin tablets is 100 mg / tablet. The specification is the mass of aspirin contained in each enteric-coated aspirin tablet.

[0015] Preferably, the specification of the rivaroxaban tablets is 2.5 mg / tablet or 5 mg / tablet, and further preferably, the specification of the rivaroxaban tablets is 2.5 mg / tablet. The specification is the mass of rivaroxaban contained in each rivaroxaban tablet.

[0016] Preferably, the composite packaged preparation packages enteric-coated aspirin tablets with a specification of 100 mg / tablet and rivaroxaban tablets with a specification of 2.5 mg / tablet together in a ratio of 1:2.

[0017] Preferably, the composite package preparation of the present invention comprises enteric-coated aspirin tablets, wherein the enteric-coated aspirin tablets comprise a tablet core, a sustained-release layer and a protective layer;

[0018] Preferably, the mass ratio of aspirin to D-isoleucine in the core of the enteric-coated aspirin tablets is 1:0.8-1.5, more preferably 1:1-1.3, and more preferably 1:1.2.

[0019] Preferably, the sustained-release layer of the enteric-coated aspirin tablets comprises a sustained-release material, a plasticizer and a lubricant;

[0020] Preferably, the sustained-release material is selected from at least one of hydroxypropyl methylcellulose phthalate, alginate, guar gum, Eudragit L100-55, Eudragit L30D-55, cellulose acetate phthalate, and hydroxypropyl methylcellulose acetate; further preferably, the sustained-release material is selected from at least one of hydroxypropyl methylcellulose phthalate, alginate, and Eudragit L100-55; more preferably, the sustained-release material is selected from at least one of hydroxypropyl methylcellulose phthalate and alginate; most preferably, the sustained-release material is hydroxypropyl methylcellulose phthalate and alginate;

[0021] Preferably, the mass ratio of hydroxypropyl methylcellulose phthalate to alginate is 1:0.4-0.6; further preferably, the mass ratio of hydroxypropyl methylcellulose phthalate to alginate is 1:0.5-0.6; more preferably, the mass ratio of hydroxypropyl methylcellulose phthalate to alginate is 1:0.55.

[0022] Preferably, the plasticizer is selected from at least one of dibutyl sebacate, polyethylene glycol, xylitol, lactitol, mannitol, glycerol, soluble starch, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, citrate, and triacetin; further preferably, the plasticizer can be selected from at least one of dibutyl sebacate, polyethylene glycol, xylitol, lactitol, soluble starch, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, alginic acid, citrate, and triacetin; more preferably, the plasticizer can be dibutyl sebacate;

[0023] Preferably, the lubricant is selected from at least one of poloxamer, soybean lecithin, magnesium stearate, silicon dioxide, peppermint oil, and fennel oil; further preferably, the lubricant is selected from at least one of poloxamer and soybean lecithin; more preferably, the lubricant is poloxamer.

[0024] Preferably, the protective layer of the enteric-coated aspirin tablets comprises a stabilizer, a lubricant and a disintegrant;

[0025] Preferably, the stabilizer is selected from at least one of tert-butylhydroquinone, butylated hydroxytoluene, ascorbic acid, gallic acid, tocopherol, and ethylenediaminetetraacetic acid; further preferably, the stabilizer is selected from at least one of tert-butylhydroquinone, butylated hydroxytoluene, ascorbic acid, and tocopherol; more preferably, the stabilizer is tert-butylhydroquinone.

[0026] Preferably, the lubricant is selected from at least one of poloxamer, soybean lecithin, magnesium stearate, silicon dioxide, peppermint oil, and fennel oil; further preferably, the lubricant is selected from at least one of poloxamer and soybean lecithin; more preferably, the lubricant is soybean lecithin.

[0027] Preferably, the mass ratio of poloxamer to soybean lecithin is 0.8-1.1:1; further preferably, the mass ratio of poloxamer to soybean lecithin is 0.8-1:1; more preferably, the mass ratio of poloxamer to soybean lecithin is 0.9:1.

[0028] Preferably, the disintegrant is selected from at least one of mannitol, hydroxypropyl cellulose, corn starch, bentonite, sodium alginate, guar gum and xanthan gum; further preferably, the disintegrant is selected from at least one of mannitol and hydroxypropyl cellulose; more preferably, the disintegrant is mannitol and hydroxypropyl cellulose.

[0029] Preferably, the mass ratio of mannitol to hydroxypropyl cellulose is 0.3-0.7:1; further preferably, the mass ratio of mannitol to hydroxypropyl cellulose is 0.4-0.5:1; more preferably, the mass ratio of mannitol to hydroxypropyl cellulose is 0.42:1.

[0030] Preferably, the enteric-coated aspirin tablets comprise the following components in parts by mass:

[0031] 1) Tablet core: 6-6.5 parts of aspirin, 7.2-7.8 parts of D-isoleucine;

[0032] 2) Sustained-release layer: 25-26 parts of hydroxypropyl methylcellulose phthalate, 14-14.5 parts of alginate, 32-37 parts of dibutyl sebacate, and 0.4-0.5 parts of poloxamer;

[0033] 3) Protective layer: 0.9-1.1 parts of tert-butylhydroquinone, 0.5-0.55 parts of soybean lecithin, 9-11 parts of mannitol, and 23-25 ​​parts of hydroxypropyl cellulose.

[0034] Further preferably, the enteric-coated aspirin tablets comprise the following components in parts by mass:

[0035] 1) Tablet core: 6.25 parts of aspirin and 7.50 parts of D-isoleucine;

[0036] 2) Sustained-release layer: 25.80 parts of hydroxypropyl methylcellulose phthalate, 14.19 parts of alginate, 35 parts of dibutyl sebacate, and 0.47 parts of poloxamer;

[0037] 3) Protective layer: 1 part of tert-butylhydroquinone, 0.53 parts of soybean lecithin, 10.17 parts of mannitol, and 24.2 parts of hydroxypropyl cellulose.

[0038] Preferably, the composite packaged preparation of the present invention comprises rivaroxaban tablets, wherein the rivaroxaban tablets comprise rivaroxaban, polacrilin potassium, mannitol, polyethylene glycol, an adhesive and a lubricant;

[0039] Preferably, the mass ratio of rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol is 1:0.6-0.8:6.0-7.0:2.2-3.0; further preferably, the mass ratio of rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol is 1:0.77:6.14:2.69.

[0040] Preferably, the binder of the rivaroxaban tablets is selected from at least one of carboxymethylcellulose calcium, glyceryl monostearate, carbomer, lactose, polyethylene glycol, and methylcellulose; further preferably, the binder of the rivaroxaban tablets is selected from at least one of carboxymethylcellulose calcium and glyceryl monostearate; more preferably, the binder of the rivaroxaban tablets is carboxymethylcellulose calcium and glyceryl monostearate.

[0041] Preferably, the mass ratio of the carboxymethylcellulose calcium to glyceryl monostearate is 1-3:3-5, and more preferably, the mass ratio of the carboxymethylcellulose calcium to glyceryl monostearate is 2:3.5.

[0042] Preferably, the lubricant of the rivaroxaban tablets is selected from at least one of polyoxyethylene fatty acid esters, poloxamer, soybean lecithin, magnesium stearate, silicon dioxide, peppermint oil, and fennel oil; further preferably, the lubricant of the rivaroxaban tablets is polyoxyethylene fatty acid esters.

[0043] Preferably, the rivaroxaban tablets comprise the following components by mass fraction:

[0044] 4-4.5 parts of rivaroxaban, 3-3.5 parts of polacrilin potassium, 25-26 parts of mannitol, 11-11.5 parts of polyethylene glycol, 2-3 parts of carboxymethylcellulose calcium, 4-5 parts of glyceryl monostearate and 0.9-1.1 parts of polyoxyethylene fatty acid ester.

[0045] Further preferably, the rivaroxaban tablets comprise the following components by mass fraction:

[0046] 4.17 parts of rivaroxaban, 3.21 parts of polacrilin potassium, 25.58 parts of mannitol, 11.21 parts of polyethylene glycol, 2.67 parts of carboxymethylcellulose calcium, 4.66 parts of glyceryl monostearate and 1 part of polyoxyethylene fatty acid ester.

[0047] On the other hand, the present invention provides a method for preparing a composite packaged preparation of aspirin and rivaroxaban, the preparation method comprising the following steps:

[0048] Enteric-coated aspirin tablets and rivaroxaban tablets were prepared separately, and the enteric-coated aspirin tablets and rivaroxaban tablets were packaged together in a ratio of 1:2.

[0049] Preferably, the method for preparing the enteric-coated aspirin tablets comprises the following steps:

[0050] S1: grind aspirin and D-isoleucine, sieve, and tablet press to obtain granules 1;

[0051] S2: Mix the sustained-release material, plasticizer, lubricant of the sustained-release layer and solvent at 20-25° C. for 20-40 min to prepare a coating solution, add granules 1 into a fluidized bed, preheat, add the coating solution and perform spray coating to obtain granules 2;

[0052] S3: Mix the stabilizer, disintegrant, lubricant of the protective layer and solvent at 30-40°C for 20-40 minutes to prepare a coating solution, add the granules 2 into the fluidized bed, preheat, and add the coating solution for spray coating.

[0053] Preferably, the method for preparing rivaroxaban tablets comprises the following steps:

[0054] S1: rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol are crushed, sieved, mixed, and tableted to obtain granules 1;

[0055] S2: Granule 1, binder and lubricant were mixed at 20-30°C for 20-40 min to prepare granules.

[0056] Further preferably, the preparation method of rivaroxaban tablets comprises the following steps:

[0057] S1: rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol are crushed, passed through a 50-80 mesh sieve, mixed evenly, placed on a rotary tablet press, and compressed using a shallow concave round punch with a diameter of 5-8 mm to obtain granules 1;

[0058] S2: Granule 1, binder and lubricant were mixed in a high-speed shear mixing granulator at 25°C for 30 min, granulated by a granulator with a screen diameter of 0.8-1.0 mm, and placed on a rotary tablet press with a tablet diameter of 4.0 mm-6.0 mm to obtain rivaroxaban tablets with a specification of 2.5 mg / tablet and a hardness of 45-85N.

[0059] In yet another aspect, the present invention provides an application of a composite packaged preparation of aspirin and rivaroxaban in the preparation of a drug for treating thrombotic diseases.

[0060] Preferably, the arterial disease includes coronary artery disease (CAD) and peripheral arterial disease (PAD).

[0061] Preferably, the use includes treatment of adult patients with coronary artery disease (CAD) at high risk of ischemic events to reduce the risk of major cardiovascular events, such as cardiovascular death, myocardial infarction and stroke; treatment of adult patients with peripheral arterial disease (PAD), such as patients who have recently undergone lower limb revascularization due to symptomatic peripheral arterial disease (PAD), to reduce the risk of major thrombotic events, such as myocardial infarction, ischemic stroke, acute limb ischemia and major amputation due to vascular disease.

[0062] Compared with the prior art, the present invention has the following beneficial effects:

[0063] 1. In the composite package preparation of aspirin and rivaroxaban provided by the present invention, for enteric-coated aspirin tablets, first, aspirin and D-isoleucine are mixed in a specific ratio to prepare a tablet core. On the one hand, D-isoleucine resists the irritation of aspirin to the gastrointestinal tract and reduces the side effects; on the other hand, the absorbability of aspirin is improved, the efficacy is improved, and the bioavailability is improved;

[0064] Secondly, by using hydroxypropyl methylcellulose phthalate, alginate and dibutyl sebacate in a specific ratio, the drug is released stably, the efficacy is improved, and the bioavailability is enhanced;

[0065] Furthermore, the researchers of the present invention have found through experiments that the combination of hydroxypropyl methylcellulose phthalate, poloxamer and tert-butylhydroquinone in a specific ratio has a synergistic effect on improving the stability of aspirin.

[0066] 2. For enteric-coated aspirin tablets, the three-layer structure of tablet core, sustained-release layer and protective layer and the corresponding preparation process improve the stability of aspirin on the one hand; on the other hand, the drug is released stably, the efficacy is improved, and the bioavailability is improved.

[0067] 3. For rivaroxaban tablets, by optimizing the excipients, a specific ratio of polacrilin potassium, mannitol and polyethylene glycol is used as the filling material, a specific ratio of carboxymethylcellulose calcium and glyceryl monostearate is used as a binder, and polyoxyethylene fatty acid ester is used as a lubricant; this specific formula significantly improves the efficacy and bioavailability, and also improves stability.

[0068] 4. The enteric-coated aspirin tablets and rivaroxaban tablets prepared by the present invention have extremely high stability, higher bioavailability, and are released smoothly in the body, with better therapeutic effects.

[0069] 5. The present invention packages enteric-coated aspirin tablets and rivaroxaban tablets together, which is more convenient for patients to take and reduces the risk of missing a dose. DETAILED DESCRIPTION

[0070] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0071] Example 1

[0072] 1) Preparation of enteric-coated aspirin tablets:

[0073] Prescription of enteric-coated aspirin tablets: calculated by weight

[0074] Tablet core: 6.25 parts of aspirin, 7.50 parts of D-isoleucine;

[0075] Sustained-release layer: 25.80 parts of hydroxypropyl methylcellulose phthalate, 14.19 parts of alginate, 35 parts of dibutyl sebacate, and 0.47 parts of poloxamer;

[0076] Protective layer: 1 part of tert-butylhydroquinone, 0.53 parts of soybean lecithin, 10.17 parts of mannitol, and 24.2 parts of hydroxypropyl cellulose.

[0077] Preparation method:

[0078] S1: Take aspirin and D-isoleucine, grind them, pass them through an 80-mesh sieve, put them in a rotary tablet press, and use a shallow concave round punch with a diameter of 6 mm to tablet to obtain granules 1;

[0079] S2: Mix hydroxypropyl methylcellulose phthalate, alginate, dibutyl sebacate and poloxamer evenly, add 60% ethanol solution by volume, ultrasonicate at 20°C for 30 min to prepare coating solution, add particle 1 into the fluidized bed, preheat at 25-55°C, add coating solution, set the inlet air temperature to 65±5°C, and the inlet air volume to 600±100m 3 , atomization pressure 0.1-0.2 bar; material temperature is controlled at 35-45°C, and liquid spray coating is performed to obtain granules 2;

[0080] S3: Mix tert-butylhydroquinone, soybean lecithin, mannitol and hydroxypropyl cellulose evenly, add 70% ethanol solution by volume, ultrasonicate at 20°C for 30 min to prepare coating solution, add particle 2 into the fluidized bed, preheat at 25-40°C, add coating solution, set the air inlet temperature to 65±5°C, and the air volume to 600±100m 3 , atomization pressure 0.1-0.2bar; the material temperature is controlled at 35-45°C, and liquid spray coating is performed to obtain granules 2. The granulator is used for granulation, and the sieve diameter of the granulator is 1.0mm. The granulator is placed on a rotary tablet press, and the tablet diameter is 4.5mm-5.5mm. Enteric-coated aspirin tablets with a specification of 100mg / tablet are obtained, and the hardness is 50-80N.

[0081] 2) Preparation of Rivaroxaban Tablets:

[0082] Rivaroxaban prescription: by weight

[0083] 4.17 parts of rivaroxaban, 3.21 parts of polacrilin potassium, 25.58 parts of mannitol, 11.21 parts of polyethylene glycol, 2.67 parts of carboxymethylcellulose calcium, 4.66 parts of glyceryl monostearate and 1 part of polyoxyethylene fatty acid ester.

[0084] Preparation method:

[0085] S1: rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol were crushed, passed through a 60-mesh sieve, mixed evenly, placed on a rotary tablet press, and tableted using a shallow concave round punch with a diameter of 6 mm to obtain granules 1;

[0086] S2: Granule 1, carboxymethylcellulose calcium, glyceryl monostearate and polyoxyethylene fatty acid ester were mixed in a high-speed shear mixing granulator at 25°C for 30 min, and granulated in a granulator with a screen diameter of 1.0 mm. The granulators were placed on a rotary tablet press with a tablet diameter of 4.5 mm-5.5 mm to obtain rivaroxaban tablets with a specification of 2.5 mg / tablet and a hardness of 50-80 N.

[0087] 3) Preparation of aspirin and rivaroxaban composite packaging preparation:

[0088] The enteric-coated aspirin tablets prepared by the above method and rivaroxaban tablets are packaged together in a ratio of 1:2 to obtain a composite packaged preparation.

[0089] Example 2

[0090] Adjust the prescription of enteric-coated aspirin tablets to:

[0091] Tablet core: 6 parts of aspirin, 7.8 parts of D-isoleucine;

[0092] Sustained-release layer: 25 parts of hydroxypropyl methylcellulose phthalate, 14.5 parts of alginate, 32 parts of dibutyl sebacate, and 0.5 parts of poloxamer;

[0093] Protective layer: 0.9 parts of tert-butylhydroquinone, 0.55 parts of soybean lecithin, 11 parts of mannitol, and 23 parts of hydroxypropyl cellulose.

[0094] The rest is the same as Example 1.

[0095] Example 3

[0096] Adjust the prescription of enteric-coated aspirin tablets to:

[0097] Tablet core: 6.5 parts of aspirin, 7.2 parts of D-isoleucine;

[0098] Sustained-release layer: 26 parts of hydroxypropyl methylcellulose phthalate, 14 parts of alginate, 37 parts of dibutyl sebacate, and 0.4 parts of poloxamer;

[0099] Protective layer: 1.1 parts of tert-butylhydroquinone, 0.5 parts of soybean lecithin, 9 parts of mannitol, and 25 parts of hydroxypropyl cellulose.

[0100] The rest is the same as Example 1.

[0101] Example 4

[0102] The prescription of Rivaroxaban tablets was adjusted as follows:

[0103] 4 parts of rivaroxaban, 3.5 parts of polacrilin potassium, 26 parts of mannitol, 11 parts of polyethylene glycol, 3 parts of carboxymethylcellulose calcium, 4 parts of glyceryl monostearate, and 0.9 parts of polyoxyethylene fatty acid ester.

[0104] The rest is the same as Example 1.

[0105] Example 5

[0106] The prescription of Rivaroxaban tablets was adjusted as follows:

[0107] 4.5 parts of rivaroxaban, 3 parts of polacrilin potassium, 25 parts of mannitol and 11.5 parts of polyethylene glycol, 2 parts of carboxymethylcellulose calcium, 5 parts of glyceryl monostearate, and 1.1 parts of polyoxyethylene fatty acid ester.

[0108] The rest is the same as Example 1.

[0109] Comparative Example 1

[0110] Compared with Example 1, only the core of the enteric-coated aspirin tablets was changed to 6.25 parts of aspirin and 7.50 parts of starch;

[0111] The rest is the same as Example 1.

[0112] Comparative Example 2

[0113] Compared with Example 1, only the sustained-release layer of enteric-coated aspirin tablets was changed to: 46.35 parts of hydroxypropyl methylcellulose phthalate, 3.64 parts of alginate, 25 parts of dibutyl sebacate, and 0.47 parts of poloxamer;

[0114] The rest is the same as Example 1.

[0115] Comparative Example 3

[0116] Compared with Example 1, only the alginate in the sustained-release layer of the enteric-coated aspirin tablets was replaced with hydroxypropyl methylcellulose phthalate of equal mass, and the rest was the same as Example 1.

[0117] Comparative Example 4

[0118] Compared with Example 1, only the hydroxypropyl methylcellulose phthalate in the sustained-release layer of the enteric-coated aspirin tablets was replaced with alginate of equal mass, and the rest was the same as Example 1.

[0119] Comparative Example 5

[0120] Compared with Example 1, only the proportions of hydroxypropyl methylcellulose phthalate, poloxamer and tert-butylhydroquinone in the enteric-coated aspirin tablets were changed to 18.5 parts of hydroxypropyl methylcellulose phthalate, 4.77 parts of poloxamer and 4 parts of tert-butylhydroquinone, and the rest were the same as Example 1.

[0121] Comparative Example 6

[0122] Compared with Example 1, only the preparation method of enteric-coated aspirin tablets is changed to the method of Example 5 of Chinese patent CN 112451531B.

[0123] Total mixing: put aspirin, D-isoleucine, mannitol and hydroxypropyl cellulose into a three-dimensional mixer with a mixing speed of 30 Hz and a mixing time of 10 min.

[0124] Tablet compression: 6.0mm shallow concave punch, tablet weight 120mg, hardness range 2-4kgf.

[0125] Coating: Add dibutyl sebacate, mannitol, hydroxypropyl cellulose, poloxamer, soybean lecithin to purified water, stir for 30 minutes, add hydroxypropyl methylcellulose phthalate and alginate to prepare a coating solution with a solid content of 15% (w / w, solid content of dibutyl sebacate, mannitol, hydroxypropyl cellulose, poloxamer, soybean lecithin, hydroxypropyl methylcellulose phthalate, alginate, the same below), stir for 40 minutes, and set aside. The inlet air temperature is 35-55°C, the tablet bed temperature is 28-32°C, and the coating weight gain is 13-17%.

[0126] The rest is the same as Example 1.

[0127] Comparative Example 7

[0128] All raw materials for preparing aspirin are uniformly mixed and placed on a rotary tablet press, with a tablet diameter of 4.5 mm-5.5 mm to obtain enteric-coated aspirin tablets with a specification of 100 mg / tablet and a hardness of 50-80N.

[0129] The rest is the same as Example 1.

[0130] Comparative Example 8

[0131] Compared with Example 1, only the proportions of polacrilin potassium, mannitol and polyethylene glycol in the rivaroxaban tablets were changed to 7.8 parts of polacrilin potassium, 12.5 parts of mannitol and 19.69 parts of polyethylene glycol; the rest were the same as Example 1.

[0132] Comparative Example 9

[0133] Compared with Example 1, only the carboxymethylcellulose calcium in the rivaroxaban tablets was replaced with glyceryl monostearate of equal mass. The rest was the same as Example 1.

[0134] Comparative Example 10

[0135] Compared with Example 1, only the glyceryl monostearate in the rivaroxaban tablets was replaced with carboxymethylcellulose calcium of equal mass. The rest was the same as Example 1.

[0136] Comparative Example 11

[0137] Only the preparation method of rivaroxaban tablets was changed to the method of Example 1 of Chinese patent CN 112451531 B.

[0138] Granulation: Add the other materials of the plain tablets except polyoxyethylene fatty acid ester into the wet granulator, with the stirring paddle speed of 300rpm and the cutting knife of 500rpm, and mix for 5min; with the stirring paddle speed of 200rpm and the cutting knife of 500rpm, spray purified water in by atomization, and add it in about 7min; with the stirring paddle speed of 250rpm and the cutting knife of 1200rpm, granulate for 2min; discharging, the granulator screen is 3×3mm, the rotation speed is 400rpm, and wet granulation is performed; add the wet granules into the fluidized bed, with the air intake of 60℃ and the air volume of 30Hz, and dry. When the material temperature reaches 40℃, sample and measure the moisture content. When the moisture content is less than 2.0%, stop heating, cool and discharge; the granulator screen has a diameter of 1.0mm, the rotation speed is 400rpm, and dry granulation is performed.

[0139] Total mixing: put the particles and polyoxyethylene fatty acid ester into a three-dimensional mixer with a mixing speed of 30 Hz and a mixing time of 10 min.

[0140] Tablet compression: 5.0mm shallow concave punch, tablet weight 70mg, hardness range 4-6kgf.

[0141] The rest is the same as Example 1.

[0142] Comparative Example 12

[0143] All the raw materials of rivaroxaban are mixed evenly and placed on a rotary tablet press, with a tablet diameter of 4.5 mm-5.5 mm, to obtain rivaroxaban tablets with a specification of 2.5 mg / tablet and a hardness of 50-80N.

[0144] The rest is the same as Example 1.

[0145] The yields of the preparations prepared in the above embodiments and comparative examples are shown in Table 1.

[0146] Table 1. Yields of Examples 1-5 and Comparative Examples 1-12

[0147] Comparative Example Yield of enteric-coated aspirin tablets / % Rivaroxaban Tablets Yield / % Example 1 99.9 99.8 Example 2 99.7 99.5 Example 3 99.8 99.7 Example 4 99.7 99.6 Example 5 99.6 99.8 Comparative Example 1 99.5 99.6 Comparative Example 2 99.6 99.7 Comparative Example 3 99.4 99.3 Comparative Example 4 99.5 99.2 Comparative Example 5 99.8 99.7 Comparative Example 6 95.7 96.1 Comparative Example 7 91.2 92.8 Comparative Example 8 99.2 99.1 Comparative Example 9 99.2 99.5 Comparative Example 10 99.7 99.2 Comparative Example 11 94.5 95.2 Comparative Example 12 90.8 90.5

[0148] Except that Comparative Examples 7 and 12 adopt the preparation process of direct tableting by mixing raw materials, and Comparative Examples 6 and 11 adopt the preparation process of Chinese patent CN 112451531 B, which leads to a significant decrease in tablet yield, the yields of the remaining embodiments and comparative examples are good.

[0149] Test Example 1

[0150] Stability study of drug preparations:

[0151] The pharmaceutical preparations continuously prepared in Examples 1-5 and Comparative Examples 1-12 were respectively subjected to routine tests and stability studies. The results of the routine tests are shown in Table 2. The content determination methods of aspirin and rivaroxaban refer to Part II of the 2010 edition of the Pharmacopoeia of the People's Republic of China. The chromatographic conditions are as follows: the chromatographic column is Diamonsil C 18 Column (250mm×4.6mm, 5μm); mobile phase is methanol-20mmol / L potassium dihydrogen phosphate buffer solution (35:65, phosphoric acid adjusted to pH 3.0); flow rate 1.0mL / min; detection wavelength 280nm; injection volume 10μl. The drug preparation was sealed and packaged in aluminum foil bags and then vacuumed. It was placed in an environment with a temperature of (40±2)℃ and a relative humidity of (75±5)% for 6 months. Samples were taken at the end of 1, 3, and 6 months for investigation and compared with the initial values. The results are shown in Table 2.

[0152] Table 2. Stability results

[0153]

[0154] As shown in Table 2, the prepared enteric-coated aspirin tablets and rivaroxaban tablets of Example 1-5 have good stability. Comparative Examples 1-7 change the raw materials, proportions and processes in the preparation process of enteric-coated aspirin tablets, and their stability decreases. Especially, Comparative Example 5 changes the proportions of hydroxypropyl methylcellulose phthalate, poloxamer and tertiary butylhydroquinone, and the stability of enteric-coated aspirin tablets decreases significantly. Comparative Examples 6-7 change the preparation process of enteric-coated aspirin tablets, and their stability also decreases significantly. Comparative Examples 8-12 change the raw materials, proportions and processes in the preparation process of rivaroxaban tablets, resulting in a significant decrease in their stability compared with Example 1. It is illustrated that the specific raw materials and their proportions in the technical solution of the present invention, and the optimized preparation process have a significant effect on improving the stability of enteric-coated aspirin tablets and rivaroxaban tablets.

[0155] Test Example 2

[0156] Study on the bioavailability of enteric-coated aspirin tablets

[0157] Experimental animals: 78 healthy Wistar rats, half male and half female, weighing 200 g ± 10 g. They were fed for 7 days and fasted but not watered for 12 hours before the experiment.

[0158] Experimental drugs: Enteric-coated aspirin tablets prepared in Examples 1-5 and Comparative Examples 8-14, and Enteric-coated aspirin tablets produced by Bayer.

[0159] Experimental animals The experimental animals were randomly divided into 13 groups, 6 in each group, half male and half female. They were respectively embodiment group 1-5, comparative example group 1-7 and control group. Embodiment 1-5 was given the samples prepared in embodiment 1-5, comparative example group 1-7 was given the samples prepared in comparative example 1-7, and the control group was given Bayer enteric-coated aspirin tablets. When administering, the enteric-coated aspirin tablets were crushed into a suspension of appropriate concentration for gavage. The dosage of rats was 30 mg / kg. After the rats were anesthetized with ether, 0.3 mL of blood was taken from the fundus vein at 0.5 h, 1 h, 1.5 h, 1.75 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h, respectively, and placed in a centrifuge tube containing sodium heparin, centrifuged at 3000 rpm for 10 min, and the upper plasma was placed in a cryopreservation tube, stored at -70 ° C, and tested.

[0160] Determination method: High performance liquid chromatography (HPLC) was used to detect the content of aspirin in rat plasma.

[0161] Accurately measure 200 μL of rat plasma sample and place it in a centrifuge tube. Add 20 μL of internal standard benzoic acid solution (100 μg / mL) and 1 mL of methanol in sequence. Vortex for 30 seconds, centrifuge at 10,000 rpm for 10 minutes, take the supernatant, and centrifuge at 10,000 rpm for 10 minutes. Inject 20 μL

[0162] The experimental results are shown in Table 3.

[0163] Table 3. Bioavailability test results of enteric-coated aspirin tablets

[0164]

[0165]

[0166] From the data in Table 3, it can be seen that the AUC0-t of Example Groups 1-5 is basically consistent with that of the control group, while the Comparative Example Groups 1-7 are significantly worse than that of the Example group, indicating that the technical solution of the present invention significantly improves the bioavailability of enteric-coated aspirin tablets.

[0167] Test Example 3

[0168] Study on the bioavailability of rivaroxaban tablets

[0169] Experimental animals: 78 healthy Wistar rats, half male and half female, weighing 200 g ± 10 g. They were fed for 7 days and fasted but not watered for 12 hours before the experiment.

[0170] Experimental drugs: Rivaroxaban tablets prepared in Examples 1-5 and Comparative Examples 8-12, and Bayer Rivaroxaban tablets.

[0171] Experimental animals The experimental animals were randomly divided into 13 groups, 6 in each group, half male and half female. They are respectively embodiment group 1-5, comparative example group 8-14 and control group. Example 1-5 was given to obtain samples respectively, comparative example group 8-14 was given to obtain samples respectively, and the control group was given Bayer Rivaroxaban tablets. During administration, Rivaroxaban tablets were crushed and made into a suitable concentration suspension for gavage. The dosage of rats was 3mg / kg. 0.3mL of blood was taken from the fundus vein after anesthesia of rats with ether at 0.5h, 1h, 1.5h, 1.75h, 2h, 3h, 4h, 6h, 8h, and 12h, respectively, and placed in a centrifuge tube containing sodium heparin, centrifuged at 3000rpm for 10min, and the upper plasma was placed in a cryopreservation tube, stored at -20°C, to be tested.

[0172] Determination method: High performance liquid chromatography (HPLC) was used to detect the content of rivaroxaban in rat plasma.

[0173] Accurately measure 200 μL of rat plasma sample and place it in a centrifuge tube. Add 20 μL of internal standard benzoic acid solution (100 μg / mL) and 1 mL of methanol in sequence. Vortex for 30 seconds, centrifuge at 10,000 rpm for 10 minutes, take the supernatant, and centrifuge at 10,000 rpm for 10 minutes. Inject 20 μL

[0174] The experimental results are shown in Table 4.

[0175] Table 4. Results of the bioavailability test of rivaroxaban tablets

[0176] Group <![CDATA[T max (h)]]> <![CDATA[C max (of mL) -1 )]]> <![CDATA[AUC 0-t (ng·h·mL) -1 )]]> Example Group 1 0.57±0.08 458.0±4.5 1627.5±11.2 Example Group 2 0.56±0.02 450.9±0.2 1598.4±34.8 Example Group 3 0.56±0.05 451.4±2.3 1611.9±15.7 Example Group 4 0.57±0.01 450.2±1.7 1608.5±28.6 Example Group 5 0.56±0.04 449.6±5.8 1601.2±24.1 Comparative Example Group 8 0.38±0.07 358.2±3.5 1156.3±37.5 Comparative Example Group 9 0.40±0.08 342.5±8.2 1126.8±24.1 Comparative Example Group 10 0.40±0.03 350.1±4.9 1140.3±16.4 Comparative Example Group 11 0.39±0.12 329.6±9.5 1195.4±10.7 Comparative Example Group 12 0.37±0.09 345.7±2.1 1088.1±46.5 Control group 0.50±0.01 412.1±1.2 1512.5±23.5

[0177] From the data in Table 4, it can be seen that the AUC0-t of Example Groups 1-5 is basically consistent with that of the Control Group, while the Comparative Example Groups 8-12 are significantly worse than that of the Example Group, indicating that the technical solution of the present invention significantly improves the bioavailability of rivaroxaban tablets.

[0178] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A composite packaging preparation of a drug, characterized in that: The composite packaged preparation comprises enteric-coated aspirin tablets and rivaroxaban tablets; The enteric-coated aspirin tablets comprise a tablet core, a sustained-release layer and a protective layer; the tablet core of the enteric-coated aspirin tablets comprises aspirin and D-isoleucine; the mass ratio of aspirin to D-isoleucine is 1:0.8-1.5; The rivaroxaban tablets include rivaroxaban, polacrilin potassium, mannitol, polyethylene glycol, an adhesive and a lubricant; the mass ratio of the rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol is 1:0.6-0.85:5.5-7.2:2.0-3.

2.

2. The composite packaging preparation according to claim 1, characterized in that: The mass ratio of the enteric-coated aspirin tablets to the rivaroxaban tablets is 18-22:

1.

3. The composite packaging preparation according to claim 1, characterized in that: The sustained-release layer of the enteric-coated aspirin tablets comprises a sustained-release material, a plasticizer and a lubricant; The protective layer of the enteric-coated aspirin tablets comprises a stabilizer, a lubricant and a disintegrant; The sustained-release material is selected from at least one of hydroxypropyl methylcellulose phthalate, alginate, guar gum, Eudragit L100-55, Eudragit L30D-55, cellulose acetate phthalate, and hydroxypropyl methylcellulose acetate; The plasticizer is selected from at least one of dibutyl sebacate, polyethylene glycol, xylitol, lactitol, mannitol, glycerol, soluble starch, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, citrate, and triacetin; The lubricant of the sustained-release layer is selected from at least one of poloxamer, soybean lecithin, magnesium stearate, silicon dioxide, peppermint oil, and fennel oil; The stabilizer is selected from at least one of tertiary butylhydroquinone, butylated hydroxytoluene, ascorbic acid, gallic acid, tocopherol, and ethylenediaminetetraacetic acid; The lubricant of the protective layer is selected from at least one of poloxamer, soybean lecithin, magnesium stearate, silicon dioxide, peppermint oil, and fennel oil; The disintegrant is selected from at least one of mannitol, hydroxypropyl cellulose, corn starch, bentonite, sodium alginate, guar gum and xanthan gum.

4. The composite packaging preparation according to claim 3, characterized in that: The sustained-release material is hydroxypropyl methylcellulose phthalate and alginate; the mass ratio of hydroxypropyl methylcellulose phthalate to alginate is 1:0.4-0.6; The plasticizer is dibutyl sebacate; The lubricant of the sustained-release layer is poloxamer; The stabilizer is tert-butylhydroquinone; The lubricant of the protective layer is poloxamer; The disintegrants are mannitol and hydroxypropyl cellulose; The mass ratio of poloxamer to soybean lecithin is 0.8-1.1:1; The mass ratio of mannitol to hydroxypropyl cellulose is 0.3-0.7:

1.

5. The composite packaging preparation according to claim 1, characterized in that: The binder of the rivaroxaban tablets is selected from at least one of carboxymethylcellulose calcium, glyceryl monostearate, carbomer, lactose, polyethylene glycol, and methylcellulose; The lubricant of the rivaroxaban tablets is selected from at least one of polyoxyethylene fatty acid esters, poloxamer, soybean lecithin, magnesium stearate, silicon dioxide, peppermint oil, and fennel oil.

6. The composite packaging preparation according to claim 1, characterized in that: The binder of the rivaroxaban tablet is carboxymethylcellulose calcium and glyceryl monostearate; the mass ratio of the carboxymethylcellulose calcium and glyceryl monostearate is 1-3:3-4; the lubricant of the rivaroxaban tablet is polyoxyethylene fatty acid ester.

7. A method for preparing the composite packaging preparation according to any one of claims 1 to 6, comprising the following steps: Enteric-coated aspirin tablets and rivaroxaban tablets are prepared separately; and the enteric-coated aspirin tablets and rivaroxaban tablets are packaged together in a ratio of 1:

2.

8. The preparation method according to claim 7, characterized in that: The preparation method of the enteric-coated aspirin tablets comprises the following steps: S1: grind aspirin and D-isoleucine, sieve, and tablet press to obtain granules 1; S2: Mix the sustained-release material, plasticizer, lubricant of the sustained-release layer and solvent at 20-25° C. for 20-40 min to prepare a coating solution, add granules 1 into a fluidized bed, preheat, add the coating solution and perform spray coating to obtain granules 2; S3: Mix the stabilizer, disintegrant, lubricant of the protective layer and solvent at 30-40°C for 20-40 minutes to prepare a coating solution, add the granules 2 into the fluidized bed, preheat, and add the coating solution for spray coating.

9. The preparation method according to claim 7, characterized in that: The preparation method of the rivaroxaban tablets comprises the following steps: S1: rivaroxaban, polacrilin potassium, mannitol and polyethylene glycol are crushed, sieved, mixed, and tableted to obtain granules 1; S2: Granule 1, binder and lubricant were mixed at 20-30°C for 20-40 min to prepare granules.

10. Use of the composite packaging preparation according to any one of claims 1 to 6 in preparing drugs for treating thrombotic diseases.

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