A pharmaceutical composite packaging preparation and its preparation method and application

Abstract

The present invention provides a pharmaceutical composite packaging preparation, a preparation method, and an application thereof, relating to the field of pharmaceutical technology. The composite packaging preparation includes enteric-coated aspirin tablets and rivaroxaban tablets; the enteric-coated aspirin tablets include a tablet core, a sustained-release layer, and a protective layer; the tablet core is composed of aspirin and D-isoleucine; and the rivaroxaban tablets include rivaroxaban, polacrilin potassium, mannitol, polyethylene glycol, an adhesive, and a lubricant. The present invention also provides the use of the composite packaging preparation in preparing a drug for treating thrombotic diseases, which has extremely high stability and higher bioavailability, and the drug is steadily released in vivo with good efficacy.

Description

Technical Field

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

[0002] Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug first synthesized by Charles Gerhardt in 1853 and marketed by Bayer in 1899. It has a wide range of pharmacological actions, including anti-inflammatory, anti-rheumatic, analgesic, antipyretic, and platelet aggregation inhibition. Low-dose aspirin (up to 300 mg per day) inhibits platelet cyclooxygenase and reduces prostaglandins, thereby inhibiting platelet aggregation and preventing cardiovascular disease. Clinically, aspirin has been shown to play an important role in preventing thrombotic disorders, 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 novel oral anticoagulant that interrupts both the intrinsic and extrinsic pathways of the coagulation cascade by directly inhibiting factor Xa, thereby inhibiting thrombin generation and thrombus formation. Developed by Bayer Pharmaceuticals of Germany, Rivaroxaban received marketing authorization in the European Union on September 30, 2008. It was initially approved for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery. Two new indications for Rivaroxaban tablets have also been approved by the China Food and Drug Administration (CFDA): treatment and prevention of deep vein thrombosis and pulmonary embolism, and stroke prevention in patients with atrial fibrillation. In November 2018, the US FDA approved Bayer's Rivaroxaban tablets (Xarelto) 2.5 mg for combination with aspirin (ASA) for the reduction of the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with chronic coronary artery disease (CAD) or peripheral arterial disease (PAD). 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 mellitus requiring medication, or chronic kidney disease) and who have a history of myocardial infarction and a high risk of ischemic events but a low risk of bleeding.

[0005] Patent CN 112451531 B discloses a kind of aspirin and rivaroxaban compound pharmaceutical preparation and 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 and released, and is used for the treatment of related diseases such as thrombolysis and prevention of thrombosis.The aspirin microtablet is enteric-coated tablet with a specification of 25-100mg / tablet, and each capsule is filled with 1-4 tablets.The rivaroxaban sustained-release microtablet has a specification of 1.25-20mg / tablet, and each capsule is filled with 1-8 tablets.Microtablet capsule filling technology is utilized to fill two kinds of drugs and two kinds of microtablets with two release mechanisms into the same capsule 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 its 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] Aspirin is unstable and easily hydrolyzes into salicylic acid and acetic acid, the latter of which can impart a strong vinegary flavor to the formulation. The former, on the other hand, is more irritating to the gastrointestinal tract than aspirin and has certain toxic side effects on the human body, potentially causing digestive tract irritation and damage. Excipients significantly impact the content of enteric-coated aspirin tablets and the free salicylic acid content. Improper use can accelerate the hydrolysis of aspirin, leading to excessive free salicylic acid and unstable products. Bioavailability is affected by dosage form factors, such as disintegration time and dissolution rate. Improving stability and bioavailability to better maximize drug efficacy is a key research priority for 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 combination preparation with high stability, high bioavailability and good efficacy is obtained. Summary of the Invention

[0008] In response to 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. On the other hand, the preparation is convenient for administration and the phenomenon of missed doses is reduced.

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

[0010] In one aspect, the present invention provides a composite packaged preparation of aspirin and rivaroxaban, characterized in that the composite packaged 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 in a ratio of 1:2.

[0017] Preferably, the composite packaged 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 tablet is 1:0.8-1.5, more preferably 1:1-1.3, and even 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 acetin; 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 acetin; 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 anise 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 anise 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 the poloxamer to soybean lecithin is 0.8-1.1:1; further preferably, the mass ratio of the poloxamer to soybean lecithin is 0.8-1:1; more preferably, the mass ratio of the 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, 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, which 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 carboxymethylcellulose calcium to glyceryl monostearate is 1-3:3-5, and more preferably, the mass ratio of 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:

[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:

[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] In another aspect, 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: aspirin and D-isoleucine were crushed, sieved, and tableted 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 minutes to prepare a coating solution. Add Granules 1 to a fluidized bed, preheat, and add the coating solution for 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 preparation method of rivaroxaban tablets comprises the following steps:

[0054] S1: rivaroxaban, polacrilin potassium, mannitol, and polyethylene glycol are crushed, sieved, mixed, and tableted to obtain Granule 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: Grind rivaroxaban, polacrilin potassium, mannitol, and polyethylene glycol, pass through a 50-80 mesh sieve, mix well, place on a rotary tablet press, and compress using a shallow concave round punch with a diameter of 5-8 mm to obtain Granule 1;

[0058] S2: Granules 1, binder and lubricant were mixed in a high-speed shear mixing granulator at 25°C for 30 min, granulated on 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 45-85 N.

[0059] In another aspect, the present invention provides a use of a composite packaged preparation of aspirin and rivaroxaban in preparing a medicament 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; and 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 packaged 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 side effects; on the other hand, it improves the absorption of aspirin, improves the efficacy, and improves the bioavailability;

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

[0065] Furthermore, the researchers of the present invention have found through experiments that a specific ratio of combination of hydroxypropyl methylcellulose phthalate, poloxamer, and tert-butylhydroquinone 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, on the one hand, improve the stability of aspirin; on the other hand, the drug is released stably, the efficacy is improved, and the bioavailability is increased.

[0067] 3. For rivaroxaban tablets, by optimizing excipients, a specific ratio of polacrilin potassium, mannitol, and polyethylene glycol is used as the filler, a specific ratio of carboxymethylcellulose calcium and glyceryl monostearate is used as the binder, and polyoxyethylene fatty acid ester is used as the 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, making it more convenient for patients to take the tablets and reducing the risk of missed doses. 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 illustrated below in conjunction with specific embodiment, but the following embodiment is only a preferred embodiment of the present invention, not all. Based on the embodiment in the embodiment, other embodiments obtained by those skilled in the art without making creative work all fall within 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 source is not specifically limited. The technology and scientific terms used in the embodiment have the meaning 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] Aspirin enteric-coated tablets prescription: according to mass parts

[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: Aspirin and D-isoleucine were ground, passed through an 80-mesh sieve, placed on a rotary tablet press, and compressed using a 6-mm diameter shallow concave round punch to obtain Granule 1;

[0079] S2: Mix hydroxypropyl methylcellulose phthalate, alginate, dibutyl sebacate, and poloxamer evenly, add 60% ethanol solution by volume, and ultrasonicate at 20°C for 30 minutes to prepare a coating solution. Add particles 1 to the fluidized bed, preheat at 25-55°C, add the 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 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, and ultrasonicate at 20°C for 30 minutes to prepare a coating solution. Add particles 2 to the fluidized bed, preheat at 25-40°C, add the 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; the material temperature is controlled at 35-45°C, and liquid coating is carried out to obtain granules 2, which are sized by a granulator with a screen diameter of 1.0 mm. The granulators are 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 50-80 N.

[0081] 2) Preparation of Rivaroxaban Tablets:

[0082] Rivaroxaban prescription: calculated 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: Grind rivaroxaban, polacrilin potassium, mannitol, and polyethylene glycol, pass through a 60-mesh sieve, mix well, place on a rotary tablet press, and compress using a 6 mm diameter shallow concave round punch to obtain Granule 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 using a granulator with a screen diameter of 1.0 mm. The granules were placed on a rotary tablet press with a tablet diameter of 4.5 mm to 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] Adjust the prescription of Rivaroxaban tablets to:

[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 part of polyoxyethylene fatty acid ester.

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

[0105] Example 5

[0106] Adjust the prescription of Rivaroxaban tablets to:

[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 tablet 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 the 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 in Example 1.

[0121] Comparative Example 6

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

[0123] Total mixing: Place aspirin, D-isoleucine, mannitol, and hydroxypropyl cellulose into a three-dimensional mixer at a mixing speed of 30 Hz for 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, and soybean lecithin to purified water and stir for 30 minutes. Then add hydroxypropyl methylcellulose phthalate and alginate to prepare a coating solution with a solids content of 15% (w / w, solids content of dibutyl sebacate, mannitol, hydroxypropyl cellulose, poloxamer, soybean lecithin, hydroxypropyl methylcellulose phthalate, and alginate, the same below). Stir for 40 minutes and set aside. Maintain an inlet air temperature of 35-55°C and a tablet bed temperature of 28-32°C. 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. The tablet diameter is 4.5mm-5.5mm, and aspirin enteric-coated tablets with a specification of 100mg / tablet and a hardness of 50-80N are obtained.

[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 in 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 in Example 1.

[0134] Comparative Example 10

[0135] Compared with Example 1, only the glyceryl monostearate in the rivaroxaban tablets was replaced with an equal mass of carboxymethylcellulose calcium. The rest was the same as in 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, stir at a paddle speed of 300 rpm, cutter at 500 rpm, and mix for 5 minutes; stir at a paddle speed of 200 rpm, cutter at 500 rpm, spray purified water into the granulator by atomization, and add it for about 7 minutes; stir at a paddle speed of 250 rpm, cutter at 1200 rpm, and granulate for 2 minutes; discharge, granulate with a 3×3 mm screen in the granulator, rotate at 400 rpm, and wet granulate; add the wet granules into the fluidized bed, inlet air at 60°C, air volume at 30 Hz, and dry. When the material temperature reaches 40°C, take a sample to measure the moisture content. When the moisture content is less than 2.0%, stop heating, cool and discharge; granulate with a 1.0 mm screen in the granulator, rotate at 400 rpm, and dry granulate.

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

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

[0145] The yields of the preparations prepared in the above examples 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 adopted the preparation process of direct tableting by mixing raw materials, and Comparative Examples 6 and 11 were prepared by the preparation process of Chinese patent CN 112451531 B, which resulted in a significant decrease in tablet yield, the yields of the remaining examples and comparative examples were good.

[0149] Test Example 1

[0150] Stability study of pharmaceutical preparations:

[0151] The pharmaceutical preparations prepared continuously in Examples 1-5 and Comparative Examples 1-12 were 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 were based on Part II of the 2010 edition of the Pharmacopoeia of the People's Republic of China. The chromatographic conditions were as follows: the chromatographic column was Diamonsil C 18 The column was 250 mm × 4.6 mm, 5 μm. The mobile phase consisted of methanol and 20 mmol / L potassium dihydrogen phosphate buffer (35:65, with phosphoric acid adjusted to pH 3.0). The flow rate was 1.0 mL / min, the detection wavelength was 280 nm, and the injection volume was 10 μl. The drug preparation was sealed in aluminum foil bags, vacuum-treated, and placed in an environment with a temperature of (40 ± 2)°C and a relative humidity of (75 ± 5)% for 6 months. Samples were collected at the end of the first, third, and sixth month and compared with the initial values. The results are shown in Table 2.

[0152] Table 2. Stability results

[0153]

[0154] As can be obtained from Table 2 data, the stability of enteric-coated aspirin tablets and rivaroxaban tablets prepared by embodiment 1-5 is good, comparative example 1-7 changes the raw material, proportioning and process in the process for preparing enteric-coated aspirin tablets, and its stability decreases, especially comparative example 5, changes the proportion of hydroxypropyl methylcellulose phthalate, poloxamer, tertiary butylhydroquinone, and the stability of enteric-coated aspirin tablets significantly decreases; comparative example 6-7 changes the preparation process of enteric-coated aspirin tablets, and its stability also significantly decreases. Comparative example 8-12 changes the raw material, proportioning and process in the process for preparing enteric-coated aspirin tablets, causes its stability to significantly decrease compared with embodiment 1. Explain specific raw material and proportioning thereof in technical solution of the present invention, the optimized preparation technology has remarkable effect to 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, were fed for 7 days and fasted for 12 hours before the experiment.

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

[0159] Experimental animals were randomly divided into 13 groups, with 6 rats in each group, half male and half female. They were respectively Example Group 1-5, Comparative Example Group 1-7 and Control Group. Example 1-5 were given the samples prepared in Example 1-5, Comparative Example Group 1-7 were 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 to make a suspension of appropriate concentration for gavage. The dosage for rats was 30 mg / kg. After the rats were anesthetized with ether at 0.5h, 1h, 1.5h, 1.75h, 2h, 3h, 4h, 6h, 8h, and 12h, 0.3mL of blood was collected from the fundus vein, placed in a centrifuge tube containing sodium heparin, centrifuged at 3000rpm for 10min, and the upper layer of 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 AUC0-t of Comparative Example Groups 1-7 is 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, were fed for 7 days and fasted 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] 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 8-14 and control group. Example 1-5 was given to prepare samples of Example 1-5, comparative example group 8-14 was given to prepare samples of comparative example 8-14, and control group was given Bayer Rivaroxaban tablets. During administration, Rivaroxaban tablets were crushed and made into a suspension of appropriate concentration for gavage. The dosage of rats was 3mg / kg. At 0.5h, 1h, 1.5h, 1.75h, 2h, 3h, 4h, 6h, 8h, and 12h, 0.3mL of blood was collected from the fundus vein of rats after anesthesia with ether, 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. Bioavailability test results 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 AUC0-t of Comparative Example Groups 8-12 is 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 consists of enteric-coated aspirin tablets and rivaroxaban tablets; The enteric-coated aspirin tablets are composed of a tablet core, a sustained-release layer, and a protective layer; the tablet core of the enteric-coated aspirin tablets is composed of aspirin and D-isoleucine; the mass ratio of aspirin to D-isoleucine is 1:0.8-1.5; The sustained-release layer of the enteric-coated aspirin tablets is composed of a sustained-release material, a plasticizer and a lubricant; The sustained-release material is hydroxypropyl methylcellulose phthalate and alginate; the plasticizer is dibutyl sebacate; the lubricant of the sustained-release layer is poloxamer; The protective layer of the enteric-coated aspirin tablets is composed of a stabilizer, a lubricant, and a disintegrant; the stabilizer is tert-butylhydroquinone; the lubricant of the protective layer is poloxamer; and the disintegrant is mannitol and hydroxypropyl cellulose. The enteric-coated aspirin tablets are composed of the following components in parts by mass: 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; 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; The rivaroxaban tablets are composed of rivaroxaban, polacrilin potassium, mannitol, polyethylene glycol, a binder, and a lubricant; the mass ratio of rivaroxaban, polacrilin potassium, mannitol, and polyethylene glycol is 1:0.6-0.85:5.5-7.2:2.0-3.2; The binder of the rivaroxaban tablets is carboxymethylcellulose calcium and glyceryl monostearate; the lubricant of the rivaroxaban tablets is polyoxyethylene fatty acid ester; The preparation method of the enteric-coated aspirin tablets comprises the following steps: S1: aspirin and D-isoleucine were crushed, sieved, and tableted to obtain granules 1; S2: Mix the sustained-release material, plasticizer, and lubricant of the sustained-release layer with 60% ethanol solution at 20-25°C for 20-40 minutes to prepare a coating solution. Add Granules 1 into a fluidized bed, preheat, and add the coating solution for spray coating to obtain Granules 2. S3: Mix the stabilizer, disintegrant, and protective layer lubricant with 70% ethanol solution at 30-40°C for 20-40 minutes to prepare a coating solution. Add granules 2 to the fluidized bed, preheat, and add the coating solution for spray coating. 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 Granule 1; S2: Granule 1, binder and lubricant were mixed at 20-30°C for 20-40 min to prepare granules.

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 mass ratio of hydroxypropyl methylcellulose phthalate to alginate is 1:0.4-0.6; The mass ratio of poloxamer to soybean lecithin is 0.8-1.1:1; The mass ratio of the mannitol to the hydroxypropyl cellulose is 0.3-0.7:

1.

4. The composite packaging preparation according to claim 1, characterized in that The mass ratio of the carboxymethyl cellulose calcium to the glyceryl monostearate is 1-3:3-4.

5. A method for preparing the composite packaging formulation according to any one of claims 1 to 4, 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.

6. The preparation method according to claim 5, characterized in that The preparation method of the enteric-coated aspirin tablets comprises the following steps: S1: aspirin and D-isoleucine were crushed, sieved, and tableted 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 minutes to prepare a coating solution. Add Granules 1 to a fluidized bed, preheat, and add the coating solution for 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.

7. The preparation method according to claim 5, 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 Granule 1; S2: Granule 1, binder and lubricant were mixed at 20-30°C for 20-40 min to prepare granules.

8. Use of the composite packaged preparation according to any one of claims 1 to 4 in preparing drugs for treating thrombotic diseases.

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