CN114073701A

CN114073701A - Solid oral pharmaceutical composition

Info

Publication number: CN114073701A
Application number: CN202110086613.1A
Authority: CN
Inventors: 陈建宇; 黄大伟; 斯梅克
Original assignee: Orient Pharma Co Ltd
Current assignee: Orient Pharma Co Ltd
Priority date: 2020-08-13
Filing date: 2021-01-22
Publication date: 2022-02-22
Also published as: TWI760067B; TW202206071A

Abstract

A solid oral pharmaceutical composition comprising: a first active ingredient which is pitavastatin or a pharmaceutically acceptable salt thereof; a second active ingredient which is ezetimibe (ezetimibe) or a pharmaceutically acceptable salt thereof; and at least one excipient including diluents, stabilizers, disintegrants, binders, sweeteners, lubricants, glidants, flavors, colorants, or combinations thereof.

Description

Solid oral pharmaceutical composition

Technical Field

The invention relates to a solid oral pharmaceutical composition, in particular to a solid oral pharmaceutical composition which simultaneously comprises pitavastatin or pharmaceutically acceptable salts thereof and ezetimibe or pharmaceutically acceptable salts thereof in a single dosage form.

Background

The cardiovascular and cerebrovascular diseases include apoplexy, heart disease, hypertension and hyperlipidemia.

Hyperlipidemia is an important risk factor for cardiovascular diseases, and due to accumulation of cholesterol and oxidized fat in blood, the diameter of blood vessels is reduced, and the heart must add extra force to transport blood, so that the blood pressure is increased, the systolic pressure is increased, the peripheral blood vessel pressure is increased, the left ventricle is enlarged, the blood pressure is abnormally increased, and even atherosclerosis is caused.

Poor living habits are important factors causing hyperlipidemia, good regular exercise habits are helpful for increasing good cholesterol (high density lipoprotein; HDL) in the body and reducing the concentration of cholesterol in blood, and when the blood lipid value exceeds the standard and cannot achieve the treatment goal by diet and exercise alone, drug control is required. At present, pitavastatin or other statin drugs are commonly used hypolipidemic drugs.

In recent years, in clinical treatment of blood fat reduction, it is gradually found that only a single blood fat reducing drug is not enough to achieve a satisfactory effect of controlling blood fat. Therefore, there have been studies on the use of pitavastatin or other statin drugs in combination with ezetimibe in order to improve the therapeutic effect.

However, the two drugs are taken in different dosage forms, which is not only inconvenient for patients to take, but also prone to the problem of improper dosage control. In view of the above, there is a need to develop a single dosage form containing two drugs simultaneously to solve the above problems and improve the therapeutic effect.

Disclosure of Invention

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

The solid oral pharmaceutical composition of the present invention comprises: a first active ingredient which is pivalatine 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 diluents, stabilizers, disintegrants, binders, sweeteners, lubricants, glidants, flavors, colorants, or combinations thereof.

In the solid oral pharmaceutical composition of the present invention, a single dosage form comprises both pivastatin or a pharmaceutically acceptable salt thereof and ezetimibe or a pharmaceutically acceptable salt thereof. Research has shown that when two drugs are used together, they are helpful for treating patients with acute coronary heart disease (ACS); and can effectively reduce low density cholesterol (LDL) and Total Cholesterol (TC) of patients with acute coronary heart disease compared with the case of taking only calcium pitavastatin. In addition, studies have indicated that patients with dyslipidemia acute coronary disease have lower amounts of sitosterol than patients taking statin drugs alone; while an increased amount of sitosterol may result in an increased risk of coronary heart disease episodes in patients with coronary heart disease. In addition, there have been studies that have shown that when two drugs are used in combination, renal failure in mice fed with high cholesterol nephrotomy can be effectively prevented; among them, ezetimibe can achieve renal protection effects by inhibiting cholesterol absorption, while atorvastatin calcium can improve renal injury by increasing NO production. In addition, it is shown that when ezetimibe is taken at 10 mg/day and atorvastatin calcium at 2 mg/day, the effect of decreasing urinary protein in patients with chronic renal disease can be improved by decreasing Total Cholesterol (TC) and Triglyceride (TG).

However, when two drugs are taken separately in different dosage forms, it is not only inconvenient for patients to take the drugs, but also easy to control the dosage improperly. In view of the above, the solid oral pharmaceutical composition provided by the present invention provides a single solid oral dosage form, which can be used to administer two drugs with appropriate dosage at a time, and not only can the dosage be more rapidly adjusted, but also the convenience of taking the drug by the patient can be improved.

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

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

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

In the solid oral pharmaceutical composition of the present invention, the excipient may include a stabilizer, which may be magnesium oxide (magnesium oxide), magnesium aluminum silicate (magnesium aluminate silicate), potassium hydroxide (potassium hydroxide), sodium bicarbonate (sodium bicarbonate), sodium carbonate (sodium carbonate), sodium hydroxide (sodium hydroxide), calcium carbonate (calcium carbonate), ammonium hydroxide (ammonium hydroxide), glycol amine (diethanolamine), or a combination thereof. The stabilizer is an alkaline stabilizer effective for stabilizing atorvastatin or a pharmaceutically acceptable salt thereof, particularly a calcium salt of atorvastatin.

In the solid oral pharmaceutical composition of the present invention, the excipient may comprise another stabilizer, which may be citric acid (citric acid), acetic acid (acetic acid), tartaric acid (tartaric acid), lactic acid (lactic acid), sodium dihydrogen phosphate (sodium phosphate monobasic), or a combination thereof. The stabilizer is an acidic stabilizer which is effective in stabilizing ezetimibe or a pharmaceutically acceptable salt thereof, and particularly effective in stabilizing ezetimibe.

The solid oral pharmaceutical composition of the present invention may be in the form of tablets, granules or capsules. When in the form of tablets or granules, the tablets or granules may include a protective layer of a polymer such as: polyvinylpyrrolidone (povidone). In addition, the number of the protective layers is not particularly limited, and may be a single layer or a plurality of protective layers.

In one embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition is a single layer tablet comprising the first active ingredient, the second active ingredient and the excipients described above. For example, a single layer tablet includes 2mg of the calcium salt of pitavastatin, 10mg of ezetimibe and a suitable excipient.

In another embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition is a bilayer tablet, wherein one layer comprises the first active ingredient and excipients as described above, and the other layer comprises the second active ingredient and excipients as described above. Here, the excipients in the two layers may be the same or different, depending on the design. For example, one layer comprises 2mg of the calcium salt of atorvastatin and suitable excipients, and the other layer comprises 10mg of ezetimibe and suitable excipients.

In another embodiment of the present invention, the dosage form of the solid oral pharmaceutical composition can be a capsule, wherein the first active ingredient and the second active ingredient can be separately prepared into two separate tablets or granules, and the two separate tablets or granules with appropriate dosage are filled into a capsule.

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. Wherein the first tablet may comprise the first active ingredient and excipients described above and the second tablet may comprise the second active ingredient and excipients described above. Here, the excipients in the first and second tablets may be the same or different, depending on the design. For example, a first tablet may include 2mg of the calcium salt of atorvastatin and suitable excipients, while a second tablet may include 10mg of ezetimibe and suitable excipients.

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

In one embodiment of the present invention, the first granules may be formed by direct granulation of the first active ingredient and the excipient, and the first granules may be formed by direct granulation of the second active ingredient and the excipient. Therefore, the first particles and the second particles may be particles having no particular structure.

In another embodiment of the present invention, the solid oral pharmaceutical composition can be in the form of 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, and may include: a first core; a first drug-containing layer disposed on the first core and comprising the first active ingredient and the excipient; and a first protective layer disposed on the first drug-containing layer and comprising a polymer. The first medicine-containing layer covers the whole surface of the first core, and the first protective layer covers the whole surface of the first medicine-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; the present invention is not limited thereto and may be changed according to design. Furthermore, the weight ratio of the calcium salt of pitavastatin to the alkaline stabilizing agent may be between 20: 1 to 1: 1, 15: 1 to 2: 1, 10: 1 to 3: 1, or 7: 1 to 3: 1.

In addition, the second particle may also be a particle having a core-shell structure, which may include: a second core; a second drug-containing layer disposed on the second core and comprising a second active ingredient and an excipient; and a second protective layer disposed on the second drug-containing layer and comprising a polymer. Wherein 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 an acidic stabilizer as described previously. In one embodiment of the present invention, the acidic stabilizer used may be citric acid; the present invention is not limited thereto and may be changed according to design. Furthermore, the weight ratio of ezetimibe to the acidic stabilizer may be between 150: 1 to 30: 1, 120: 1 to 50: 1, 110: 1 to 70: 1, or 100: 1 to 80: 1.

Wherein, the first core and the second core can be respectively used as a carrier to bear the first medicine-containing layer and the second medicine-containing layer. The first core or the second core may be a pellet. For example, the first core or the second core may be spheroids formed from sucrose and/or starch and/or microcrystalline cellulose; the spheroid size may be 1700 μm to 250 μm, 1000 μm to 355 μm, or 850 μm to 500 μm.

In addition, the first protection layer and the second protection layer can respectively protect the first core and the second core from being damaged by external stress. Here, the kind of the polymer used for the first protective layer or the second protective layer is not particularly limited, and for example, polyvinylpyrrolidone may be used. In addition, the polyvinylpyrrolidone may be used in an amount of 1% to 50%, 5% to 30%, 10% to 25%, or 15% to 20% based on the weight of the first protective layer or the second protective layer.

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

The present invention provides, in addition to the aforementioned solid oral pharmaceutical composition, the use of the aforementioned solid oral pharmaceutical composition for the treatment or prevention of cardiovascular diseases, such as atherosclerosis congee.

In addition, the present invention provides a method for treating or preventing cardiovascular disease, comprising: providing the solid oral pharmaceutical composition to a desired host. The subject in need thereof is a subject in need of treatment or prevention of cardiovascular disease.

In the present invention, for "treating" is meant to refer to the administration or application of a solid oral pharmaceutical composition to an individual to achieve a cure, amelioration, slowing, alteration, cure, improvement, or effect on the disease, condition, or constitution.

Drawings

FIG. 1 is a schematic view of a solid oral pharmaceutical composition according to example 1 of the present invention;

FIG. 2 is a schematic view of a solid oral pharmaceutical composition according to example 2 of the present invention;

FIG. 3 is a schematic view of a solid oral pharmaceutical composition according to example 3 of the present invention;

FIG. 4 is a schematic view of a solid oral pharmaceutical composition according to example 4 of the present invention;

FIG. 5 is a schematic view of a solid oral pharmaceutical composition according to example 5 of the present invention;

FIG. 6 is a schematic cross-sectional view of first and second particles of example 5 of the present invention.

[ description of reference ]

10 troche

11 layer of calcium salt of pitavastatin

11a calcium salt of pitavastatin

11b calcium salt particles of pitavastatin

11c microparticles of calcium salt of pitavastatin

12 ezetimibe layer

12a ezetimibe ingot

12b ezetimibe granules

12c fine particles of ezetimibe

13 capsules

21 core

22 medicated layer

23 protective layer

Detailed Description

The following embodiments of the present invention are described by way of examples, and other advantages and effects of the present invention will be readily apparent to those skilled in the art from the disclosure herein. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include one or more of the individual unless the context clearly dictates otherwise.

It should be noted that, unless otherwise specified herein, the inclusion of "a" or "an" element is not limited to inclusion of a single such element, but rather may include one or more such elements.

In addition, unless otherwise specified, the ordinal numbers "first", "second", etc., are used herein to distinguish between elements having the same name and do not denote any order, hierarchy, order of execution, or order of processing. A "first" element and a "second" element may be present together in the same component or separately in different components. The presence of an element having a higher ordinal number does not necessarily indicate the presence of another element having a lower ordinal number.

In this context, unless otherwise specified, the term "or" and/or "the term" means that the term "A" or "and" the term "B" alone or in combination with the term "A" and/or "B" alone or in combination with the term "B"; by the features A "and" (and) or "and" (and) feature B, it is meant that A and B are present simultaneously; the terms "comprising," "including," "having," "containing," and "containing" are intended to be inclusive and not limiting.

In addition, a numerical value herein may encompass a range of ± 10% of the numerical value, and particularly a range of ± 5% of the numerical value, unless otherwise specified. Unless otherwise specified, a range of values is made up of a plurality of subranges defined by a lesser endpoint number, a lesser quartile number, a median number, a greater quartile number, and a greater endpoint number.

The present invention will be described more specifically with reference to examples, which are not intended to limit the scope of the present invention. In the following preparations, examples and comparative examples, temperatures are given in degrees centigrade and parts and percentages are by weight, unless otherwise indicated. Parts by weight relate to parts by volume as kilograms relate to liters.

Dissolution method and experiment

The medium used for the dissolution test, which was formulated according to the USP method, contained 0.1N HCl, a phosphate buffer solution at pH 4.5 or a phosphate buffer solution at pH 6.8. Polysorbate 80 (Tween 80) at 0.3% was added to the medium to aid in the dissolution of the active ingredient. The conditions of the dissolution test are as follows. The eluted samples were analyzed by HPLC.

The instrument comprises the following steps: USP appaatus II with sinkers (Paddle Method)

Medium: 0.1N HCl, phosphate buffer solution of pH 4.5 or phosphate buffer solution of pH 6.8

Volume: 900mL

Temperature: 37 +/-0.5 DEG C

Filter paper: 10 μm HDPE full speed filter tips

Sample volume: 10mL

Time: 5. 10, 15, 20, 30, 45 minutes

Example 1: single layer lozenge

The components: atorvastatin calcium salt (10mg), ezetimibe (50mg), Lactose monohydrate (629mg), microcrystalline cellulose (MCC) (308mg), Sodium Lauryl Sulfate (Sodium Lauryl Sulfate; SLS) (10mg), Sodium carboxymethyl Starch (Sodium Starch Glycolate; SSG) (90 mg), Crospovidone (30mg), Magnesium Stearate (Magnesium Stearate) (8mg), polyvinylpyrrolidone (Povidone) (45mg), 95% ethanol (18mg), water (72 mg). Wherein the ethanol and water are removed in a drying step.

Preparation procedure

Separately, the calcium salt of pitavastatin, ezetimibe, lactose, microcrystalline cellulose, sodium lauryl sulfate, sodium carboxymethyl starch and polyvinylpyrrolidone are placed in a suitable container. 45mg of polyvinylpyrrolidone was dissolved in 18mg of ethanol and 72mg of water to prepare an adhesive solution.

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 blended with lactose. All materials were transferred to a granulator and mixed with a high shear mixer for 7 minutes at 215rpm impeller (impelleter).

After the foregoing mixing step, the previously prepared adhesive solution was added to a mixer and granulated, with the chopper (chopper) rotating at 3400rpm and the impeller rotating at 215 rpm. The resulting wet granules are dried at 40 to 60 ℃. The dried granules are mixed with sieved crospovidone and magnesium stearate. Finally, the pastilles 10 obtained were pastilles having a weight of 300mg +15mg per unit and a hardness controlled between 8 and 11kp, as shown schematically in figure 1, were pastilles pressed in a rotary pastiller. Furthermore, the calcium salt of pitavastatin was about 2mg and the ezetimibe content was about 10mg per tablet.

The results of the above-described dissolution test were shown in tables 1 and 2 below.

TABLE 1

TABLE 2

Example 2: double-layer pastille

Composition of calcium salt layer of pitavastatin: calcium salt of pitavastatin (24mg), lactose monohydrate (732mg), microcrystalline cellulose (732mg), Magnesium Oxide (MgO) (96mg), sodium carboxymethyl starch (192mg), crospovidone (76.8mg), Magnesium stearate (9.6mg), polyvinylpyrrolidone (57.6mg), 95% ethanol (57.6mg), and water (57.6 mg). Wherein the ethanol and water are removed in a drying step.

Composition of the ezetimibe layer: ezetimibe (120mg), lactose monohydrate (720mg), microcrystalline cellulose (950.4mg), sodium lauryl sulfate (24mg), sodium carboxymethyl starch (38.4 mg), magnesium stearate (9.6mg), polyvinylpyrrolidone (57.6mg), 95% ethanol (57.6mg), and water (57.6 mg). Wherein the ethanol and water are removed in a drying step.

Preparation of granules of the calcium salt of pitavastatin

Separately, the calcium salt of pitavastatin, lactose monohydrate, microcrystalline cellulose, magnesium oxide, sodium carboxymethyl starch, crospovidone, magnesium stearate and polyvinylpyrrolidone are placed in a suitable container. 57.6mg of polyvinylpyrrolidone was dissolved in a solution of 57.6mg of ethanol and 57.6mg of water to prepare a viscous solution.

Here, the preparation was carried out using the geometric dilution method. The calcium salt of pitavastatin was mixed with MgO, a portion of MCC and a portion of SSG sieved through a 30 mesh screen of a granulator. All materials were mixed 100 times with a cylinder mixer. The mixture was mixed with lactose which was sieved through a 30 mesh screen of a granulator. All materials were transferred to a granulator and mixed with a high shear mixer for 7 minutes at 215rpm impeller speed.

Subsequently, granulation was carried out at a chopper speed of 3400rpm and an impeller speed of 215 rpm. The previously prepared adhesive solution was added to the pelletizer over 2 minutes and stirred with a vertical stirrer for 3 minutes. Drying the obtained wet granules at 50 ℃ until the water content in the granules is less than 2.0%; here, it was dried at 105 ℃ for 15 minutes with an IR moisture analyzer and its water loss was measured.

After drying, the dried granules were mixed with the remaining MCC, the remaining SSC and the cross-linked vessone and mixed 300 times in a barrel mixer. Then, the blended granules were mixed with magnesium stearate in a barrel mixer 60 times to perform a lubricating step.

Preparation of ezetimibe granules

The ezetimibe, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, sodium carboxymethyl starch, magnesium stearate and polyvinylpyrrolidone are placed in a suitable container respectively. 57mg of polyvinylpyrrolidone was dissolved in a solution of 57mg of ethanol and 57mg of water to prepare a viscous solution.

Ezetimibe was mixed with SLS, SSG and part of MCC sieved through a 30 mesh screen of a granulator, and all materials were placed in a tumbler mixer for 100 times of rotary mixing. The mixture was mixed with lactose which was sieved through a 30 mesh screen of a granulator. All materials were transferred to a granulator and mixed with a high shear mixer for 7 minutes at 215rpm impeller speed.

After drying, the dried granules were mixed with the remaining MCC and mixed 300 times in a barrel mixer. Then, the blended granules were mixed with magnesium stearate in a barrel mixer 60 times to perform a lubricating step.

The above obtained calcium salt particles of pitavastatin and ezetimibe particles are pastilled in a double layer tablet by a double-side rotary pastillator, and the schematic diagram of the obtained tablet is shown in fig. 2, which comprises: a calcium salt layer 11 of pitavastatin and an ezetimibe layer 12. The weight of the bi-layer troche is 320mg +/-16 mg per unit, and the hardness of the troche is controlled between 9 and 13 kp. In addition, the calcium salt of pitavastatin per lozenge was about 2mg and the ezetimibe content was about 10 mg.

The results of the above-described dissolution test are shown in tables 3 and 4 below.

TABLE 3

TABLE 4

Example 3: capsule comprising two pastilles

Composition of the calcium salt lozenges of pitavastatin: calcium salt of pitavastatin (10mg), lactose monohydrate (454mg), Pregelatinized Starch (54mg), magnesium aluminum silicate (11mg), magnesium stearate (3mg), Hydroxypropylmethylcellulose (HPMC) (9mg), 95% ethanol (40mg), water (40 mg). Wherein the ethanol and water are removed in a drying step.

Ingredients of the ezetimibe tablet: ezetimibe (50mg), lactose monohydrate (190mg), microcrystalline cellulose (190mg), sodium lauryl sulfate (10mg), pregelatinized starch (50mg), magnesium stearate (3mg), hydroxypropyl methylcellulose (8mg), 95% ethanol (37mg), and water (37 mg). Wherein the ethanol and water are removed in a drying step.

The calcium salt granules of pitavastatin and ezetimibe granules were prepared in a similar manner to example 2.

The obtained granules of the calcium salt of pitavastatin are subjected to tabletting by a rotary tablet machine to obtain a single layer tablet having a weight of 120mg + -6 mg per unit and a hardness of 4 to 6 kp. Furthermore, the ezetimibe granules obtained are also pastilled in a rotary pastiller to obtain a mono-layer tablet with a weight of 100mg + -5 mg per unit and a hardness of 3 to 6 kp. Finally, the tablets of the calcium salt of pitavastatin and the tablets of ezetimibe are placed in gelatin capsules, the schematic representation of the resulting capsules being shown in figure 3 and comprising: an ingot of the calcium salt of atorvastatin 11a, an ezetimibe ingot 12a and a capsule 13. The weight of the bi-layer troche is 320mg +/-16 mg per unit, and the hardness of the troche is controlled between 9 and 13 kp. Furthermore, each capsule had a content of the calcium salt of pivalastatin of about 2mg and a content of ezetimibe of about 10 mg.

Example 4: capsules containing different particles

The calcium salt granules of pitavastatin obtained in example 2 and the ezetimibe granules were directly placed in gelatin capsules, and the schematic diagram of the obtained capsules is shown in fig. 4 and comprises: a granule 11b of the calcium salt of atorvastatin, a granule 12b of ezetimibe and a capsule 13. Furthermore, the amount of the calcium salt of pitavastatin per capsule was about 2mg and the amount of ezetimibe was about 10 mg.

Example 5: capsule containing different microparticles

In this example, the fine particles of the calcium salt of pitavastatin and the fine particles of ezetimibe each have the structure shown in fig. 6. As shown in fig. 6, the active ingredient fine particles used in this example include: a core 21; a drug-containing layer 22 disposed on the core 21 and covering all surfaces of the core 21; and a protective layer 23 disposed on the drug-containing layer 22 and covering all surfaces of the drug-containing layer 22. In the present embodiment, the core 21 is a round pellet; and drug-containing layer 22 is a layer comprising the calcium salt of pitavastatin or ezetimibe.

Preparation of microparticles of calcium salt of pitavastatin

A medicine-containing layer: the calcium salt of pitavastatin (9mg) was uniformly dispersed in an aqueous solution containing Mannitol (Mannitol) (24mg), polyvinylpyrrolidone (8mg), magnesium oxide (2mg), sodium lauryl sulfate (2mg), stirred and homogenized until the suspension was free of lumps.

Protective layer: mannitol (47mg), polyvinylpyrrolidone (15mg), Talc (Talc) (27mg), and yellow iron oxide (0.5mg) were mixed in water to homogeneity.

Coating the particles by using fluidized bed equipment, adding sugar balls (round granules with cane sugar as a raw material) into the preheated equipment, and starting coating operation of the medicine-containing layer by using the prepared medicine-containing layer suspension liquid when the product temperature is higher than 35 ℃. In the subsequent particle coating process, the product temperature is adjusted and controlled to be not more than 60 ℃ by utilizing the air inlet temperature and the air inlet amount. After finishing the coating operation of the medicine-containing layer, the prepared protective layer suspension liquid is used for coating the protective layer, and the previous coating operation is continued until the protective layer suspension liquid is exhausted. After drying the coated microparticles, microparticles containing 2mg of the calcium salt of pitavastatin were filled in a capsule.

Preparation of fine particles of ezetimibe

A medicine-containing layer: ezetimibe (36mg) was uniformly dispersed in an aqueous solution containing mannitol (80mg), polyvinylpyrrolidone (27mg), Anhydrous Citric Acid (Anhydrous Citric Acid) (0.4mg), and sodium lauryl sulfate (0.4mg), stirred and homogenized until the suspension became free of lumps.

Protective layer: mannitol (38mg), polyvinylpyrrolidone (13mg), talc (15mg) and sodium lauryl sulfate (7mg) were mixed in water to homogeneity.

Coating round granules (sugar spheres) by using fluidized bed equipment, adding preheated equipment into the sugar spheres, and starting coating operation of a medicine-containing layer by using prepared medicine-containing layer suspension liquid when the temperature of a product is higher than 35 ℃. In the subsequent particle coating process, the product temperature is adjusted and controlled not to exceed 60 ℃ by utilizing the air inlet temperature and the air inlet quantity. And after finishing the coating operation of the medicine-containing layer, using the prepared protective layer suspension liquid to perform the coating operation of the protective layer, and continuing the previous coating operation until the protective layer suspension liquid is exhausted. After drying the coated microparticles, the capsules containing 10mg of ezetimibe microparticles were filled with 2mg of atorvastatin calcium salt granules.

The composition of fine particles of calcium salt of pitavastatin and fine particles of ezetimibe in gelatin capsules obtained in this example is shown in fig. 5, and comprises: a fine particle 11c of a calcium salt of atorvastatin, a fine particle 11c of ezetimibe, and a capsule 13. Furthermore, each capsule had a content of the calcium salt of pivalastatin of about 2mg and a content of ezetimibe of about 10 mg.

Detection was performed by the aforementioned dissolution test. In this example, there are three media for the dissolution test, namely, a medium containing 0.1N HCl and 0.3% Tween 80, a medium containing a phosphate buffer solution of pH 4.5 and 0.3% Tween 80, and a medium containing a phosphate buffer solution of pH 6.8 and 0.3% Tween 80. The test results are shown in tables 5 to 7 below, respectively.

TABLE 5

TABLE 6

TABLE 7

Stability testing of the calcium salt of pitavastatin

The calcium salt of atorvastatin is relatively unstable; thus, the present invention stabilizes the calcium salt of pitavastatin by adding an alkaline stabilizing agent (here, magnesium oxide). The test was conducted using tablets as comparison samples, the composition of which is shown in example 1.

Here, the sample was placed in an aluminum foil blister pack (Alu-Alu holder) and placed in an environment of 55 ℃ and 75% RH; the results are shown in Table 8 below.

TABLE 8

Note: drug content (%) - (drug content of diazepam sample/drug content of initial sample) x 100%

Stability test of ezetimibe

Here, the stability of the ezetimibe microparticles with the acidic stabilizer (here, citric acid) was also measured, and this test used the capsule dosage form of example 5 as a comparison sample. Capsules containing ezetimibe particles were placed at 40 ℃ and 75% RH, and 55 ℃ and 75% RH, and analyzed for impurity content using a liquid chromatography column (Hypersil Gold C18) with high performance liquid chromatography (Waters Alliance HPLC system) under UV 245nm spectroscopy. The recipe and the results are shown in Table 9 below.

TABLE 9

Remarking: specification of product impurities: maximum impurity-NMT 0.2% and total impurity-NMT 1.0%

As citric acid content increased, mannitol within the formula decreased relatively to maintain per unit total weight.

Stability testing of a Complex formulation of the calcium salt of atorvastatin and Ezetimibe

The formulation of the calcium salt of pitavastatin and ezetimibe prepared in example 5 of the present invention was packaged in an aluminum foil blister, and tested in an environment of 25 ℃ and 60% RH for a long time, and the content per unit of drug (Assay) and the stability of Impurities (Impurities) of the calcium salt of pitavastatin and ezetimibe were measured. The results are shown in tables 10 and 11 below.

Watch 10

TABLE 11

The above experiments prove that the solid oral pharmaceutical composition provided by the invention has excellent stability by adding a proper stabilizer.

Although the present invention has been described by way of examples, it is to be understood that many other modifications and variations are possible without departing from the spirit of the invention and the scope of the claims.

Claims

1. A solid oral pharmaceutical composition comprising:

a first active ingredient which is pitavastatin or a pharmaceutically acceptable salt thereof;

a second active ingredient which is ezetimibe (ezetimibe) or a pharmaceutically acceptable salt thereof; and

at least one excipient including diluents, stabilizers, disintegrants, binders, sweeteners, lubricants, glidants, flavors, colorants, or combinations thereof.

2. The solid, oral pharmaceutical composition of claim 1, wherein the first active ingredient is a calcium salt of pitavastatin.

3. The solid oral pharmaceutical composition of claim 1, wherein the second active ingredient is ezetimibe.

4. The solid oral pharmaceutical composition of claim 1, wherein the dose of the first active ingredient is between 0.5mg to 5 mg.

5. The solid oral pharmaceutical composition of claim 1, wherein the dose of the second active ingredient is between 5mg to 20 mg.

6. The solid oral pharmaceutical composition of claim 1, wherein the excipient comprises a stabilizer, and the stabilizer is magnesium oxide (magnesium oxide), magnesium aluminum silicate (magnesium aluminate silicate), potassium hydroxide (potassium hydroxide), sodium bicarbonate (sodium bicarbonate), sodium carbonate (sodium carbonate), sodium hydroxide (sodium hydroxide), calcium carbonate (calcium carbonate), ammonium hydroxide (ammonium hydroxide), glycol amine (diethanolamine), or a combination thereof.

7. The solid oral pharmaceutical composition of claim 1, wherein the excipient comprises a stabilizer, and the stabilizer is citric acid (citric acid), acetic acid (acetic acid), tartaric acid (tartaric acid), lactic acid (lactic acid), sodium dihydrogen phosphate (sodium phosphate monobasic), or a combination thereof.

8. The solid, oral pharmaceutical composition of claim 1, which is a lozenge.

9. The solid oral pharmaceutical composition of claim 8, which is a single-layer tablet comprising the first active ingredient, the second active ingredient and the excipient.

10. The solid oral pharmaceutical composition of claim 8, which is a bi-layer tablet, and one layer of the bi-layer tablet comprises the first active ingredient and the excipient, and the other layer of the bi-layer tablet comprises the second active ingredient and the excipient.

11. The solid oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first tablet comprising the first active ingredient and the excipient and a second tablet comprising the second active ingredient and the excipient.

12. The solid, oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first granule and a second granule, the first granule comprising the first active ingredient and the excipient, and the second granule comprising the second active ingredient and the excipient.

13. The solid oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first particle and a second particle, the first particle comprising

A first core;

a first drug-containing layer disposed on the first core and comprising the first active ingredient and the excipient; and

a first protective layer disposed on the first drug-containing layer and comprising a polymer.

14. The solid, oral pharmaceutical composition of claim 13, wherein the polymer is polyvinylpyrrolidone (povidone).

15. The solid oral pharmaceutical composition of claim 13, wherein the excipient is a stabilizer, and the stabilizer is magnesium oxide, magnesium aluminum silicate, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, calcium carbonate, ammonium hydroxide, glycol amine, or a combination thereof.

16. The solid, oral pharmaceutical composition of claim 15, wherein the stabilizer is magnesium oxide.

17. The solid oral pharmaceutical composition of claim 1, which is a capsule, wherein the capsule comprises a first particle and a second particle, the second particle comprising

A second core;

a second drug-containing layer disposed on the second core and comprising the second active ingredient and the excipient; and

a second protective layer disposed on the second drug-containing layer and comprising a polymer.

18. The solid, oral pharmaceutical composition of claim 17, wherein the polymer is polyvinylpyrrolidone.

19. The solid oral pharmaceutical composition of claim 17, wherein the excipient is a stabilizer, and the stabilizer is citric acid, acetic acid, tartaric acid, lactic acid, sodium dihydrogen phosphate, or a combination thereof.

20. The solid, oral pharmaceutical composition of claim 19, wherein the stabilizer is citric acid.