Solid oral pharmaceutical composition

Abstract

A solid oral pharmaceutical composition, comprising: a first active ingredient, which is pitavastatin or a pharmaceutically acceptable salt thereof, and a second active ingredient, which is a pharmaceutically acceptable salt thereof; the second active ingredient is ezetimibe or a pharmaceutically acceptable salt of the ezetimibe; and at least one excipient comprising a diluent, a stabilizer, a disintegrating agent, an adhesive, a sweetener, a lubricant, a glidant, a perfume, a colorant or a combination thereof.

Description

[0001] This invention is a divisional application of the Chinese invention patent application with application number 202110086613.1, application date January 22, 2021, and invention name “Solid Oral Pharmaceutical Composition”. Technical Field

[0002] The present invention relates to a solid oral pharmaceutical composition, and in particular to a solid oral pharmaceutical composition comprising pitavastatin or its pharmaceutically acceptable salt and ezetimibe or its pharmaceutically acceptable salt in a single dosage form. Background Art

[0003] The so-called cardiovascular and cerebrovascular diseases include stroke, heart disease, hypertension and hyperlipidemia.

[0004] Hyperlipidemia is an important risk factor for cardiovascular disease. The accumulation of cholesterol and oxidized fat in the blood causes the pore size of blood vessels to become smaller. The heart must exert extra force to transport blood, which increases blood pressure and systolic pressure, increases pressure in surrounding blood vessels, leads to left ventricular hypertrophy, abnormally high blood pressure, and even the risk of atherosclerosis.

[0005] Bad living habits are an important factor in causing high blood lipids. Good and regular exercise habits can help increase the body's good cholesterol (high-density lipoprotein; HDL) and reduce blood cholesterol concentration. When blood lipid values ​​exceed the standard and cannot be achieved by diet and exercise alone, medication control is needed. Currently, pitavastatin or other statins are commonly used lipid-lowering drugs.

[0006] In recent years, in the clinical treatment of lowering blood lipids, it has been gradually found that the use of a single blood lipid-lowering drug may not be sufficient to achieve a satisfactory effect of controlling blood lipids. Therefore, there are studies on the combination of pitavastatin or other statins with ezetimibe in order to improve the treatment effect.

[0007] However, taking two drugs in different dosage forms is not only inconvenient for patients, but also prone to improper dosage control. In view of this, it is urgent to develop a single dosage form containing two drugs to solve the above problems and improve the treatment effect. Summary of the invention

[0008] The present invention provides a solid oral pharmaceutical composition, which comprises pitavastatin or its pharmaceutically acceptable salt and ezetimibe or its pharmaceutically acceptable salt in a single dosage form, for treating or preventing cardiovascular diseases (such as atherosclerosis) or related diseases.

[0009] The solid oral pharmaceutical composition of the present invention comprises: a first active ingredient, which is pitavastatin or a pharmaceutically acceptable salt thereof; a second active ingredient, which is ezetimibe or a pharmaceutically acceptable salt thereof; and at least one excipient, including a diluent, a stabilizer, a disintegrant, a sticking agent, a sweetener, a lubricant, a glidant, a flavor, a colorant or a combination thereof.

[0010] In the solid oral pharmaceutical composition of the present invention, a single dosage form includes pitavastatin or its pharmaceutically acceptable salt and ezetimibe or its pharmaceutically acceptable salt. Studies have shown that when the two drugs are used in combination, they are helpful in the treatment of patients with acute coronary heart disease (ACS); and compared with taking only pitavastatin calcium salt, they can effectively reduce low-density cholesterol (LDL) and total cholesterol (TC) in patients with acute coronary heart disease. In addition, studies have shown that compared with taking only statins, patients with acute coronary heart disease with dyslipidemia have lower levels of sitosterol; and an increase in sitosterol will increase the risk of coronary heart disease attacks in patients with coronary heart disease. In addition, studies have shown that when the two drugs are used in combination, renal failure can be effectively prevented in mice undergoing nephrectomy fed with high cholesterol; among them, ezetimibe can achieve kidney protection by inhibiting cholesterol absorption, while pitavastatin calcium salt can improve kidney damage by increasing NO production. In addition, studies have shown that taking ezetimibe 10 mg / day and pitavastatin calcium salt 2 mg / day can enhance the effect of reducing urine protein in patients with chronic kidney disease by reducing total cholesterol (TC) and triglycerides (TG).

[0011] However, when two drugs are taken in different dosage forms, it is not only inconvenient for patients to take the drugs, but also easy to have the problem of improper dosage control. In view of this, the solid oral pharmaceutical composition provided by the present invention provides a single solid oral dosage form, which can be used to take two drugs with appropriate dosages at one time, which is not only faster in drug preparation, but also more convenient for patients to take the drugs.

[0012] In the solid oral pharmaceutical composition of the present invention, the first active ingredient may be the calcium salt of pitavastatin; and the second active ingredient may be ezetimibe.

[0013] In the solid oral pharmaceutical composition of the present invention, the dosage of the first active ingredient may be between 0.5 mg and 5 mg, for example, about 2 mg.

[0014] In the solid oral pharmaceutical composition of the present invention, the dosage of the second active ingredient may be between 5 mg and 20 mg, for example, about 10 mg.

[0015] In the solid oral pharmaceutical composition of the present invention, the excipient may include a stabilizer, which may be magnesium oxide, magnesium aluminometasilicate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium carbonate, ammonium hydroxide, diethanolamine or a combination thereof. The aforementioned stabilizer is an alkaline stabilizer, which can effectively stabilize pitavastatin or its pharmaceutically acceptable salts, in particular, can effectively stabilize the calcium salt of pitavastatin.

[0016] In the solid oral pharmaceutical composition of the present invention, the excipient may include another stabilizer, which may be citric acid, acetic acid, tartaric acid, lactic acid, sodium phosphate monobasic or a combination thereof. The aforementioned stabilizer is an acidic stabilizer, which can effectively stabilize ezetimibe or its pharmaceutically acceptable salt, and in particular, can effectively stabilize ezetimibe.

[0017] The solid oral pharmaceutical composition of the present invention may be in a form commonly seen in the art, such as tablets, granules or capsules. When in tablets or granules, the tablets or granules may include a protective layer, and the material of the protective layer may be a polymer, such as polyvinyl pyrrolidone (povidone). In addition, the number of layers of the protective layer is not particularly limited, and may be a single layer or multiple layers.

[0018] In one embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition is a single-layer tablet, which includes the first active ingredient, the second active ingredient and excipients mentioned above. For example, the single-layer tablet includes 2 mg of calcium salt of pitavastatin, 10 mg of ezetimibe and appropriate excipients.

[0019] In another embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition is a double-layer tablet, wherein one layer comprises the aforementioned first active ingredient and excipients, and the other layer comprises the aforementioned second active ingredient and excipients. Here, the excipients in the two layers may be the same or different, depending on the design. For example, one layer comprises 2 mg of calcium salt of pitavastatin and appropriate excipients, and the other layer comprises 10 mg of ezetimibe and appropriate excipients.

[0020] In another embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition may be a capsule, wherein the aforementioned first active ingredient and the second active ingredient may be separately prepared into two independent tablets or granules, and then the two independent tablets or granules of appropriate doses are filled into one capsule.

[0021] In another embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition may be a capsule, wherein a first tablet and a second tablet are contained in the capsule. The first tablet may include the aforementioned first active ingredient and excipients, and the second tablet may include the aforementioned second active ingredient and excipients. Here, the excipients in the first tablet and the second tablet may be the same or different, depending on the design. For example, the first tablet may include 2 mg of the calcium salt of pitavastatin and a suitable excipient, and the second tablet may include 10 mg of ezetimibe and a suitable excipient.

[0022] In another embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition may be a capsule, wherein a first particle and a second particle are contained in the capsule. The first particle may include the aforementioned first active ingredient and excipients, and the second particle may include the aforementioned second active ingredient and excipients. Here, the excipients in the first particle and the second particle may be the same or different, depending on the design. For example, the first particle contained in the first capsule may include a calcium salt of pitavastatin with a total dose of about 2 mg and a suitable excipient; the second particle contained in the second capsule may include a total dose of about 10 mg of ezetimibe and a suitable excipient.

[0023] In one embodiment of the present invention, the first particles may be formed by directly granulating the first active ingredient and the excipient, and the second particles may be formed by directly granulating the second active ingredient and the excipient. Therefore, the first particles and the second particles may be particles without special structures.

[0024] In another embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition may be a capsule, wherein a first particle and a second particle are contained in the capsule. The first particle may be a particle having a core-shell structure, which may include: a first core; a first drug-containing layer disposed on the first core and including the aforementioned first active ingredient and excipient; and a first protective layer disposed on the first drug-containing layer and including a polymer. The first drug-containing layer covers the entire surface of the first core, and the first protective layer covers the entire surface of the first drug-containing layer. The first active ingredient may be a calcium salt of pitavastatin. The excipient may be the aforementioned alkaline stabilizer. In one embodiment of the present invention, the alkaline stabilizer used may be magnesium oxide; however, the present invention is not limited thereto and may be changed according to the design. In addition, the weight ratio of the calcium salt of pitavastatin to the alkaline stabilizer may be between 20:1 and 1:1, 15:1 and 2:1, 10:1 and 3:1, or 7:1 and 3:1.

[0025] In addition, the second particle may also be a particle with a core-shell structure, which may include: a second core; a second drug-containing layer, which is disposed on the second core and includes a second active ingredient and an excipient; and a second protective layer, which is disposed on the second drug-containing layer and includes a polymer. The second drug-containing layer covers the entire surface of the second core, and the second protective layer covers the entire surface of the second drug-containing layer. The second active ingredient may be ezetimibe. The excipient may be the aforementioned acidic stabilizer. In one embodiment of the present invention, the acidic stabilizer used may be citric acid; however, the present invention is not limited thereto and may be changed according to the design. In addition, the weight ratio of ezetimibe to the acidic stabilizer may be between 150:1 and 30:1, 120:1 and 50:1, 110:1 and 70:1, or 100:1 and 80:1.

[0026] The first core and the second core can be used as a carrier to carry the first drug-containing layer and the second drug-containing layer, respectively. Here, the first core or the second core can be a spherical particle (or pellet). For example, the first core or the second core can be a spheroid formed by sucrose and / or starch and / or microcrystalline cellulose; the size of the spheroid can be between 1700 μm and 250 μm, 1000 μm and 355 μm, or 850 μm and 500 μm.

[0027] In addition, the first protective layer and the second protective layer can protect the first core and the second core from being damaged by external stress, respectively. Here, the type of polymer used for the first protective layer or the second protective layer is not particularly limited, and for example, it can be polyvinyl pyrrolidone. In addition, based on the weight of the first protective layer or the second protective layer, the amount of polyvinyl pyrrolidone used can be between 1% and 50%, 5% and 30%, 10% and 25%, or 15% and 20%.

[0028] In another embodiment of the present invention, the aforementioned first particles and second particles without special structures can be used in combination with the aforementioned first particles and second particles with core-shell structures. For example, the first particles without special structures and the second particles with core-shell structures can be contained in a capsule at the same time; and vice versa.

[0029] In addition to providing the aforementioned solid oral pharmaceutical composition, the present invention also provides the use of the aforementioned solid oral pharmaceutical composition for treating or preventing cardiovascular diseases, such as atherosclerosis.

[0030] In addition, the present invention also provides a method for treating or preventing cardiovascular diseases, comprising: providing the solid oral pharmaceutical composition to a subject in need of treatment or prevention of cardiovascular diseases.

[0031] In the present invention, the term "treatment" refers to administering or applying a solid oral pharmaceutical composition to a subject to cure, improve, alleviate, alter, cure, improve, or affect a disease, symptom, or constitution. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is a schematic diagram of a solid oral pharmaceutical composition according to Example 1 of the present invention;

[0033] Figure 2 is a schematic diagram of a solid oral pharmaceutical composition according to Example 2 of the present invention;

[0034] Figure 3 is a schematic diagram of a solid oral pharmaceutical composition according to Example 3 of the present invention;

[0035] Figure 4 is a schematic diagram of a solid oral pharmaceutical composition according to Example 4 of the present invention;

[0036] Figure 5 is a schematic diagram of a solid oral pharmaceutical composition according to Example 5 of the present invention;

[0037] Figure 6 Schematic cross-sectional view of the first and second particles of Example 5 of the present invention.

[0038] [Description of Reference Numerals]

[0039] 10 tablets

[0040] 11 Calcium salt layer of Pitavastatin

[0041] 11a Pitavastatin calcium salt tablets

[0042] 11b Pitavastatin calcium salt granules

[0043] 11c Calcium salt microparticles of Pitavastatin

[0044] 12 Ezetimibe layer

[0045] 12a Ezetimibe tablets

[0046] 12b Ezetimibe Granules

[0047] 12c Ezetimibe Microparticles

[0048] 13 capsules

[0049] 21 cores

[0050] 22 drug-containing layer

[0051] 23 protection layers DETAILED DESCRIPTION

[0052] The following is an explanation of the implementation of the present invention through specific examples. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified and changed in various ways for different viewpoints and applications without departing from the spirit of the present invention. Unless otherwise specified herein, the singular forms "a", "an" and "the" used in the specification and the appended claims include one or more individuals.

[0053] It should be noted that, in this document, unless otherwise specified, “a” element is not limited to a single element, but may include one or more elements.

[0054] In addition, in this document, unless otherwise specified, ordinal numbers such as "first" and "second" are only used to distinguish multiple components with the same name, and do not indicate the existence of a hierarchy, level, execution order or process order between them. A "first" component and a "second" component may appear together in the same component, or appear in different components respectively. The presence of a component with a larger ordinal number does not necessarily indicate the presence of another component with a smaller ordinal number.

[0055] In this document, unless otherwise specified, the so-called feature A "or" or "and / or" (and / or) feature B means that A exists alone, B exists alone, or A and B exist at the same time; the so-called feature A "and" (and) or "and" (and) or "and" (and) feature B means that A and B exist at the same time; the so-called "include", "comprise", "have" and "contain" mean including but not limited to these.

[0056] In addition, in this document, unless otherwise specified, a numerical value may include a range of ±10% of the numerical value, in particular, a range of ±5% of the numerical value. Unless otherwise specified, a numerical range is composed of multiple sub-ranges defined by a lower endpoint, a lower quartile, a median, an upper quartile, and a higher endpoint.

[0057] The present invention will be described in more detail by way of examples, but these examples are not intended to limit the scope of protection of the present invention. Unless otherwise specified, in the following preparation examples, examples and comparative examples, the temperature is in degrees Celsius, and the parts and percentages are by weight. The relationship between parts by weight and parts by volume is like the relationship between kilograms and liters.

[0058] Dissolution methods and experiments

[0059] The medium used for the dissolution test was prepared according to the USP method and contained 0.1N HCl, pH 4.5 phosphate buffer solution, or pH 6.8 phosphate buffer solution. 0.3% polysorbate 80 (Tween 80) was added to the medium to aid in the dissolution of the active ingredient. The conditions for the dissolution test were as follows. The eluted samples were analyzed by HPLC.

[0060] Apparatus: USP apparatus II with sinker (Paddle Method)

[0061] Medium: 0.1N HCl, pH 4.5 phosphate buffer solution, or pH 6.8 phosphate buffer solution

[0062] Volume: 900 mL

[0063] Temperature: 37±0.5℃

[0064] Filter paper: 10 μm HDPE full flow filter tips

[0065] Sample volume: 10 mL

[0066] Time: 5, 10, 15, 20, 30, 45 minutes

[0067] Example 1: Single-layer tablet

[0068] Ingredients: calcium salt of pitavastatin (10 mg), ezetimibe (50 mg), lactose monohydrate (629 mg), microcrystalline cellulose (MCC) (308 mg), sodium lauryl sulfate (SLS) (10 mg), sodium starch glycolate (SSG) (90 mg), crospovidone (30 mg), magnesium stearate (8 mg), polyvinyl pyrrolidone (Povidone) (45 mg), 95% ethanol (18 mg), water (72 mg). Ethanol and water will be removed during the drying step.

[0069] Preparation steps

[0070] Place calcium salt of pitavastatin, ezetimibe, lactose, microcrystalline cellulose, sodium lauryl sulfate, sodium carboxymethyl starch and polyvinyl pyrrolidone in a suitable container respectively. Dissolve 45 mg of polyvinyl pyrrolidone in 18 mg of ethanol and 72 mg of water to prepare an adhesive solution.

[0071] The calcium salt of pitavastatin and ezetimibe were mixed with SLS, MCC and SSG sieved through a 30-mesh screen of a granulator, and then the mixture was rotated 100 times. The mixture was mixed with lactose. All materials were transferred to a granulator and mixed with a high shear mixer for 7 minutes at an impeller speed of 215 rpm.

[0072] After the aforementioned mixing step, the adhesive solution prepared above is added to the mixer and granulated. The chopper speed is 3400 rpm and the impeller speed is 215 rpm. The obtained wet granules are dried at 40 to 60°C. The dried granules are mixed with sieved cross-linked vinylpyrrolidone and magnesium stearate. Finally, the tablets are compressed by a rotary tablet press. The schematic diagram of the obtained tablet 10 is as shown in FIG. Figure 1 As shown, its weight is 300 mg + 15 mg per unit, and the hardness of the tablet is controlled between 8 and 11 kp. In addition, each tablet contains about 2 mg of calcium salt of pitavastatin and about 10 mg of ezetimibe.

[0073] The dissolution test was performed as described above, and the test results are shown in Tables 1 and 2 below.

[0074] Table 1

[0075]

[0076] Table 2

[0077]

[0078] Example 2: Double-layer tablet

[0079] The ingredients of the calcium salt layer of pitavastatin are: calcium salt of pitavastatin (24 mg), lactose monohydrate (732 mg), microcrystalline cellulose (732 mg), magnesium oxide (MgO) (96 mg), sodium carboxymethyl starch (192 mg), cross-linked vinblastine (76.8 mg), magnesium stearate (9.6 mg), polyvinyl pyrrolidone (57.6 mg), 95% ethanol (57.6 mg), and water (57.6 mg). Ethanol and water will be removed during the drying step.

[0080] Ingredients of the ezetimibe layer: ezetimibe (120 mg), lactose monohydrate (720 mg), microcrystalline cellulose (950.4 mg), sodium lauryl sulfate (24 mg), sodium starch glycolate (38.4 mg), magnesium stearate (9.6 mg), polyvinyl pyrrolidone (57.6 mg), 95% ethanol (57.6 mg) and water (57.6 mg). Ethanol and water will be removed during the drying step.

[0081] Preparation of Pitavastatin Calcium Salt Granules

[0082] Calcium salt of pitavastatin, lactose monohydrate, microcrystalline cellulose, magnesium oxide, sodium carboxymethyl starch, cross-linked vinblastine, magnesium stearate and polyvinyl pyrrolidone are placed in a suitable container respectively. 57.6 mg of polyvinyl pyrrolidone is dissolved in a solution of 57.6 mg of ethanol and 57.6 mg of water to prepare an adhesive solution.

[0083] Here, the preparation is carried out using the geometric dilution method. The calcium salt of pitavastatin is mixed with MgO, part of MCC and part of SSG, which have been sieved through a 30-mesh screen of a granulator. All materials are mixed by rotating 100 times with a drum mixer. The mixture is mixed with lactose sieved through a 30-mesh screen of a granulator. All materials are transferred to a granulator and mixed with a high shear mixer for 7 minutes at an impeller speed of 215 rpm.

[0084] Next, granulation was performed, with the chopper speed at 3400 rpm and the impeller speed at 215 rpm. The adhesive solution prepared above was added to the granulator within 2 minutes and stirred for 3 minutes with a vertical mixer. The obtained wet granules were dried at 50°C until the water content in the granules was less than 2.0%; here, the IR moisture analyzer was used to dry at 105°C for 15 minutes and measure the water loss.

[0085] After drying, the dried granules were mixed with the remaining MCC, the remaining SSC and crosin, and mixed 300 times with a barrel mixer. Then, the mixed granules were mixed with magnesium stearate 60 times with a barrel mixer for lubrication.

[0086] Preparation of Ezetimibe Granules

[0087] Separately place ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, sodium carboxymethyl starch, magnesium stearate and polyvinyl pyrrolidone in a suitable container. Dissolve 57 mg of polyvinyl pyrrolidone in a solution of 57 mg of ethanol and 57 mg of water to prepare an adhesive solution.

[0088] Ezetimibe was mixed with SLS, SSG and part of MCC sieved through a 30-mesh screen of a granulator, and all the materials were placed in a barrel mixer and rotated for 100 times. The mixture was mixed with lactose sieved through a 30-mesh screen of a granulator. All the materials were transferred to a granulator and mixed with a high shear mixer for 7 minutes at an impeller speed of 215 rpm.

[0089] Next, granulation was performed, with the chopper speed at 3400 rpm and the impeller speed at 215 rpm. The adhesive solution prepared above was added to the granulator within 2 minutes and stirred for 3 minutes with a vertical mixer. The obtained wet granules were dried at 50°C until the water content in the granules was less than 2.0%; here, the IR moisture analyzer was used to dry at 105°C for 15 minutes and measure the water loss.

[0090] After drying, the dried granules were mixed with the remaining MCC and mixed 300 times with a barrel mixer. Then, the mixed granules were mixed with magnesium stearate 60 times with a barrel mixer for a lubrication step.

[0091] The calcium salt granules of pitavastatin and ezetimibe granules obtained above are compressed into double-layer tablets using a double-sided rotary tablet press. The schematic diagram of the obtained tablets is shown in FIG. Figure 2 As shown, it comprises: a calcium salt layer of pitavastatin 11 and an ezetimibe layer 12. The weight of the double-layer tablet is 320 mg per unit. + 16 mg, the hardness of the tablet is controlled between 9 and 13 kp. In addition, each tablet contains about 2 mg of calcium salt of pitavastatin and about 10 mg of ezetimibe.

[0092] The dissolution test was performed as described above, and the test results are shown in Tables 3 and 4 below.

[0093] Table 3

[0094]

[0095] Table 4

[0096]

[0097] Example 3: Capsule containing two tablets

[0098] The ingredients of the calcium salt tablet of pitavastatin are: calcium salt of pitavastatin (10 mg), lactose monohydrate (454 mg), pregelatinized starch (54 mg), magnesium aluminum silicate (11 mg), magnesium stearate (3 mg), hydroxypropyl methylcellulose (HPMC) (9 mg), 95% ethanol (40 mg), and water (40 mg). Ethanol and water will be removed during the drying step.

[0099] The ingredients of ezetimibe tablets are: ezetimibe (50 mg), lactose monohydrate (190 mg), microcrystalline cellulose (190 mg), sodium lauryl sulfate (10 mg), pregelatinized starch (50 mg), magnesium stearate (3 mg), hydroxypropyl methylcellulose (8 mg), 95% ethanol (37 mg) and water (37 mg). Ethanol and water will be removed during the drying step.

[0100] The calcium salt particles of pitavastatin and ezetimibe particles were prepared in a similar manner to Example 2.

[0101] The obtained calcium salt granules of pitavastatin are compressed by a rotary tablet press to obtain a single-layer tablet having a weight of 120 mg per unit. + 6 mg, and the hardness of the tablet is controlled between 4 and 6 kp. In addition, the obtained ezetimibe granules are also pressed by a rotary tablet press to obtain a single-layer tablet with a weight of 100 mg per unit. + 5 mg, and the hardness of the tablet is controlled between 3 and 6 kp. Finally, the obtained calcium salt tablet of pitavastatin and ezetimibe tablet are placed in a gelatin capsule. The schematic diagram of the obtained capsule is shown in Figure 3 As shown, it includes: a calcium salt tablet of pitavastatin 11a, an ezetimibe tablet 12a and a capsule 13. In addition, each capsule contains about 2 mg of calcium salt of pitavastatin and about 10 mg of ezetimibe.

[0102] Example 4: Capsules containing different particles

[0103] The calcium salt particles of pitavastatin and ezetimibe particles obtained in Example 2 are directly placed in a gelatin capsule. The schematic diagram of the obtained capsule is as follows: Figure 4 As shown, it includes: a pitavastatin calcium salt particle 11b, an ezetimibe particle 12b and a capsule 13. In addition, each capsule contains about 2 mg of pitavastatin calcium salt and about 10 mg of ezetimibe.

[0104] Example 5: Capsules containing different microparticles

[0105] In this embodiment, the calcium salt particles of pitavastatin and the ezetimibe particles have the following characteristics: Figure 6 The structure of Figure 6 As shown, the active ingredient particles used in this embodiment include: a core 21; a drug-containing layer 22, which is disposed on the core 21 and covers all surfaces of the core 21; and a protective layer 23, which is disposed on the drug-containing layer 22 and covers all surfaces of the drug-containing layer 22. In this embodiment, the core 21 is a round particle; and the drug-containing layer 22 is a layer containing calcium salt of pitavastatin or ezetimibe.

[0106] Preparation of Pitavastatin Calcium Salt Microparticles

[0107] Drug-containing layer: The calcium salt of pitavastatin (9 mg) is evenly dispersed in an aqueous solution containing mannitol (24 mg), polyvinyl pyrrolidone (8 mg), magnesium oxide (2 mg), and sodium dodecyl sulfate (2 mg), and stirred and homogenized until the suspension is free of lumps.

[0108] Protective layer: Mix mannitol (47 mg), polyvinyl pyrrolidone (15 mg), talc (27 mg) and yellow iron oxide (0.5 mg) in water.

[0109] Use fluidized bed equipment to coat particles. After adding sugar balls (round particles made of sucrose) to the preheated equipment, wait until the product temperature is above 35°C, and use the prepared drug-containing layer suspension to start the drug-containing layer coating operation. In the subsequent coating process of particles, the inlet air temperature and inlet air volume are used to adjust the product temperature to no more than 60°C. After the drug-containing layer coating operation is completed, the protective layer suspension is used to coat the protective layer, and the previous coating operation is continued until the protective layer suspension is exhausted. After the coated particles are dried, the calcium salt particles containing 2 mg of pitavastatin are filled into a capsule.

[0110] Preparation of ezetimibe microparticles

[0111] Drug-containing layer: Disperse ezetimibe (36 mg) evenly in an aqueous solution containing mannitol (80 mg), polyvinyl pyrrolidone (27 mg), anhydrous citric acid (0.4 mg), and sodium lauryl sulfate (0.4 mg), and stir and homogenize until the suspension is free of lumps.

[0112] Protective layer: Mix mannitol (38 mg), polyvinyl pyrrolidone (13 mg), talc (15 mg) and sodium lauryl sulfate (7 mg) in water.

[0113] Use fluidized bed equipment to coat round particles (sugar balls). After adding sugar balls to the preheated equipment, wait until the product temperature is greater than 35°C, and use the prepared drug-containing layer suspension to start the drug-containing layer coating operation. In the subsequent coating microparticle process, the inlet air temperature and inlet air volume are used to adjust the product temperature to not exceed 60°C. After the drug-containing layer coating operation is completed, the prepared protective layer suspension is used to coat the protective layer, and the previous coating operation is continued until the protective layer suspension is exhausted. After the coated microparticles are dried, the 10 mg ezetimibe microparticles are filled into the capsules filled with 2 mg pitavastatin calcium salt particles.

[0114] The composition of the calcium salt particles of pitavastatin and ezetimibe particles in a gelatin capsule obtained in this example is shown in the schematic diagram as follows: Figure 5 As shown, it comprises: a pitavastatin calcium salt particle 11c, an ezetimibe particle 12c and a capsule 13. In addition, each capsule contains about 2 mg of pitavastatin calcium salt and about 10 mg of ezetimibe.

[0115] The dissolution test was performed as described above. In this embodiment, there are three types of media for the dissolution test, namely, a medium containing 0.1 N HCl and 0.3% Tween 80, a medium containing a pH 4.5 phosphate buffer solution and 0.3% Tween 80, and a medium containing a pH 6.8 phosphate buffer solution and 0.3% Tween 80. The test results are shown in Tables 5 to 7 below.

[0116] Table 5

[0117]

[0118] Table 6

[0119]

[0120] Table 7

[0121]

[0122] Stability test of the calcium salt of pitavastatin

[0123] The calcium salt of pitavastatin is relatively unstable; therefore, the present invention stabilizes the calcium salt of pitavastatin by adding an alkaline stabilizer (here, magnesium oxide). The tablet was used as a comparative sample in the experiment, and its composition is shown in Example 1.

[0124] Here, the samples were placed in an aluminum foil blister package (Alu-alu blister) and placed in an environment of 55°C and 75%RH; the results are shown in Table 8 below.

[0125] Table 8

[0126]

[0127] Note: Drug content (%) = (drug content of stable sample / drug content of initial sample) x 100%

[0128] Stability test of ezetimibe

[0129] Here, the stability of ezetimibe microparticles with an acidic stabilizer (here, citric acid) was also measured, and the capsule dosage form of Example 5 was used as a comparative sample in this test. The capsules containing ezetimibe microparticles were placed at 40°C and 75% RH, and 55°C and 75% RH, and detected using a high-performance liquid chromatograph (Waters Alliance HPLC system) under UV245nm spectrum, and the content of impurities was analyzed using a liquid chromatography column (Hypersil Gold C18). The prescription and its results are shown in Table 9 below.

[0130] Table 9

[0131]

[0132] Note: Product impurity specifications: Maximum impurity- NMT0.2% and total impurity- NMT1.0%

[0133] *As the citric acid content increases, the amount of mannitol in the formulation decreases to maintain the total weight per unit.

[0134] Stability test of the combined dosage form of pitavastatin calcium salt and ezetimibe

[0135] The composite dosage form of the calcium salt of pitavastatin and ezetimibe prepared in Example 5 of the present invention was placed in an aluminum foil blister package and placed in an environment of 25°C and 60% RH for a long time test, and the stability of the drug content (Assay) and impurities (Impurities) per unit of the calcium salt of pitavastatin and ezetimibe were measured. The results are shown in Tables 10 and 11 below.

[0136] Table 10

[0137]

[0138] Table 11

[0139]

[0140] The above experiments confirm that the solid oral pharmaceutical composition provided by the present invention has excellent stability by adding a suitable stabilizer.

[0141] Although the present invention has been described through a number of embodiments, it should be understood that many other possible modifications and variations may be made without departing from the spirit of the present invention and the scope of protection claimed by the claims.

Claims

1. A solid oral pharmaceutical composition comprising: A first active ingredient, which is a calcium salt of pitavastatin; A second active ingredient is ezetimibe or a pharmaceutically acceptable salt thereof; an alkaline stabilizer, wherein the alkaline stabilizer is magnesium oxide, magnesium aluminum silicate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium carbonate, ammonium hydroxide, ethylene glycol amine or a combination thereof; an acidic stabilizer, wherein the acidic stabilizer is citric acid, acetic acid, tartaric acid, lactic acid, sodium dihydrogen phosphate or a combination thereof; and At least one excipient, including a diluent, a disintegrant, a binder, a sweetener, a lubricant, a glidant, a flavor, a colorant, or a combination thereof; The solid oral pharmaceutical composition is a capsule, wherein the capsule comprises a first particle and a second particle, and the first particle comprises:

1. The first core; a first drug-containing layer disposed on the first core and comprising the first active ingredient, the alkaline stabilizer and the excipient; and a first protective layer, disposed on the first drug-containing layer and comprising a first polymer; The second particles include:

1. Second core; a second drug-containing layer disposed on the second core and comprising the second active ingredient, the acidic stabilizer and the excipient; and A second protective layer is disposed on the second drug-containing layer and includes a second polymer.

2. The solid oral pharmaceutical composition according to claim 1, wherein the second active ingredient is ezetimibe.

3. The solid oral pharmaceutical composition as claimed in claim 1, wherein the dosage of the first active ingredient is between 0.5 mg and 5 mg.

4. The solid oral pharmaceutical composition according to claim 1, wherein the dosage of the second active ingredient is between 5 mg and 20 mg. The solid oral pharmaceutical composition according to claim 1 , wherein the first polymer is polyvinyl pyrrolidone. The solid oral pharmaceutical composition according to claim 1 , wherein the alkaline stabilizer is magnesium oxide. The solid oral pharmaceutical composition according to claim 1 , wherein the second polymer is polyvinyl pyrrolidone.

8. The solid oral pharmaceutical composition according to claim 1, wherein the acidic stabilizer is citric acid.

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