JP2017210455A - Ezetimibe-containing pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an improved ezetimibe-containing pharmaceutical composition having excellent elution properties.SOLUTION: A pharmaceutical composition contains ezetimibe as an activator, and at least one binder selected from the group consisting of povidone, hydroxypropyl cellulose and polyvinyl alcohol. The binder is preferably hydroxypropyl cellulose or polyvinyl alcohol.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition comprising ezetimibe. More particularly, it relates to a pharmaceutical composition comprising ezetimibe with good dissolution characteristics.

で表され、小腸でのコレステロールの吸収を選択的に阻害し、肝臓のコレステロール含量を低下させ、血中コレステロールを低下させると考えられており、高コレステロール血症、家族性高コレステロール血症、ホモ接合体性シトステロール血症などに効果を有する高脂血症治療剤として、「ゼチーア（登録商標）錠１０ｍｇ」の名称で販売されている。 Ezetimibe (chemical name: (3R, 4S) -1- (4-fluorophenyl) -3-[(3S) -3- (4-fluorophenyl) -3-hydroxypropyl] which is one of sterol absorption inhibitors -4- (4-hydroxyphenyl) azetidin-2-one) has the formula (I):

It is thought to selectively inhibit the absorption of cholesterol in the small intestine, lowering the cholesterol content of the liver and lowering blood cholesterol, hypercholesterolemia, familial hypercholesterolemia, homo As a therapeutic agent for hyperlipidemia having an effect on zygotic sitosterolemia and the like, it is marketed under the name of “Zetia (registered trademark) 10 mg”.

  Patent Document 1 discloses that a hydroxy-substituted azetidinone containing ezetimibe reduces serum cholesterol levels and is useful for the treatment of atherosclerosis, and the combined use with a cholesterol biosynthesis inhibitor. Patent Document 2 describes a method for treating sitosterolemia using a hydroxy-substituted azetidinone containing ezetimibe as a sterol absorption inhibitor.

Japanese National Patent Publication No. 8-509989 JP-T-2004-532186

  However, Patent Document 1 describes only two formulation examples, and there is room for further improvement in order to obtain good dissolution characteristics. Further, Patent Document 2 does not clearly describe a preparation example using ezetimibe, and there is room for study.

  Then, this invention makes it a subject to provide the further ezetimibe containing pharmaceutical composition which has a favorable elution characteristic.

  The present inventors have found that good elution characteristics can be obtained by using a specific binder in the ezetimibe-containing pharmaceutical composition, and have further studied and completed the present invention.

That is, the present invention
[1] A pharmaceutical composition comprising ezetimibe as an active drug and at least one binder selected from the group consisting of povidone, hydroxypropylcellulose, and polyvinyl alcohol,
[2] The pharmaceutical composition according to the above [1], wherein the binder is hydroxypropylcellulose or polyvinyl alcohol,
[3] The pharmaceutical composition according to the above [1] or [2], further comprising an anionic surfactant,
[4] The pharmaceutical composition according to the above [3], wherein the anionic surfactant is sodium lauryl sulfate,
[5] The active drug has a d ₅₀ of 0.1 to 20 μm, preferably 2 to 5 μm, more preferably 2.5 to 4 μm, and a d ₉₀ of 0.5 to 30 μm, preferably 5 to 13 μm, more preferably 5 The pharmaceutical composition according to any one of [1] to [4] above having a particle size distribution of ˜8 μm, and [6] any one of [1] to [5] above, wherein the dosage form of the pharmaceutical composition is a tablet. It relates to the pharmaceutical composition as described above.

  According to the present invention, by using at least one binder selected from the group consisting of popidone, hydroxypropylcellulose and polyvinyl alcohol, an ezetimibe-containing pharmaceutical composition having good dissolution characteristics can be obtained.

It is a graph which shows the elution characteristic of ezetimibe in a tablet. 2 is a graph showing the dissolution stability of ezetimibe in the tablet obtained in Example 1. FIG. 3 is a graph showing the dissolution stability of ezetimibe in the tablet obtained in Example 2. 4 is a graph showing the dissolution stability of ezetimibe in the tablet obtained in Example 3.

  The present invention is characterized in that in a pharmaceutical composition containing ezetimibe as an active ingredient, at least one selected from the group consisting of povidone, hydroxypropylcellulose and polyvinyl alcohol is contained as a binder. Thereby, an ezetimibe-containing pharmaceutical composition having good dissolution characteristics can be obtained.

  The active drug in the present invention is ezetimibe or a pharmaceutically acceptable salt thereof, and has an action of inhibiting the absorption of cholesterol in the small intestine as a small intestinal cholesterol transporter inhibitor.

The particle size distribution of ezetimibe, the effect of the present invention is easily exhibited more, from the viewpoint of more excellent dissolution characteristics can be obtained, it is preferable that d ₅₀ of a 0.1 to 20 [mu] m, more preferably 2~5μm , more preferably from 2.5～4Myuemu, preferably d ₉₀ is 0.5 to 30 m, more preferably from 5～13Myuemu, further preferably 5～8Myuemu. The particle size distribution is a value determined on a volume basis by a laser diffraction / scattering method (dry measurement method) assuming that the particles are spherical.

  The amount of the active drug in the pharmaceutical composition of the present invention is, for example, preferably 5 to 20 mg as ezetimibe, and more preferably 10 mg.

  The binder used in the present invention is at least one selected from the group consisting of povidone, hydroxypropylcellulose, and polyvinyl alcohol, and is used to obtain a good dissolution property of ezetimibe. These may be used alone or in combination of two or more. Of these, hydroxypropyl cellulose and polyvinyl alcohol are preferable because not only elution characteristics but also better elution stability can be obtained.

  The content of the binder in the pharmaceutical composition of the present invention varies depending on the type of the binder used and is not particularly limited, but is usually preferably 1% by mass or more and more preferably 3% by mass or more. If the content of the binder is less than 1% by mass, sufficient tablet strength tends to be difficult to obtain, and sufficient dissolution property tends to be difficult to obtain. The content of the binder in the pharmaceutical composition of the present invention is preferably 10% by mass or less, and more preferably 5% by mass or less. When the content of the binder exceeds 10% by mass, the content of other additives such as disintegrants is relatively decreased, and the elution property tends to decrease and stability (increased active drug related substances). There is a tendency to influence.

  The pharmaceutical composition of the present invention contains an active drug, ezetimibe or a pharmaceutically acceptable salt thereof, povidone, hydroxypropylcellulose, and a binder that is at least one selected from the group consisting of polyvinyl alcohol. Additives commonly used in this field such as a form, a disintegrant, a lubricant, a surfactant, a sweetener, a fragrance, a stabilizer, and a fluidizing agent can be included.

  The excipient is not particularly limited, and examples thereof include celluloses (crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose) and the like) and derivatives thereof, starch (corn starch, potato starch, Wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch, etc. and derivatives thereof, sugar (glucose, lactose, sucrose, purified sucrose, powdered sugar, trehalose, dextran, dextrin, etc.), sugar alcohol (D-mannitol, xylitol) , Sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (magnesium aluminate metasilicate, synthetic hydrotalcite), anhydrous calcium phosphate, precipitated carbonic acid Calcium, calcium silicate, calcium hydrogen hydrate phosphoric acid, inorganic salts such as sodium hydrogen carbonate. Of these, celluloses such as crystalline cellulose, and sugars such as lactose and lactose hydrate are preferable. An excipient | filler may be used independently and may be used in mixture of 2 or more types.

  The content in the pharmaceutical composition when an excipient is used varies depending on the type of excipient used and is not particularly limited, but is usually preferably 60% by mass or more, and preferably 70% by mass or more. More preferred.

  The disintegrant is not particularly limited, but for example, crospovidone, sodium carboxy starch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, synthetic silicic acid Examples thereof include aluminum crystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose, croscarmellose sodium, carboxymethylcellulose calcium, carmellose, and hydroxypropyl starch. Of these, croscarmellose sodium is preferred because of its rapid disintegration. A disintegrating agent may be used independently and may mix and use 2 or more types.

  The content in the pharmaceutical composition when using a disintegrant varies depending on the type of disintegrant used and is not particularly limited, but is usually preferably 5% by mass or more, more preferably 7% by mass or more. . The content of the disintegrant in the pharmaceutical composition is preferably 10% by mass or less, and more preferably 8% by mass or less.

  The lubricant is not particularly limited. For example, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester. And talc. Of these, magnesium stearate is preferred because of its high lubricity. These may be used alone or in combination of two or more.

  The content in the pharmaceutical composition when a lubricant is used varies depending on the type of lubricant used and is not particularly limited, but is usually preferably 1% by mass or more, and preferably 3% by mass or less. preferable.

  The surfactant is not particularly limited. For example, benzalkonium chloride, benzethonium chloride, polyoxyethylene (40) monostearate (polyoxyl 40 stearate), sorbitan sesquioleate (sorbitan sesquioleate) , Polyoxyethylene (20) sorbitan monooleate (polysorbate 80), glyceryl monostearate (glyceryl monostearate), sodium lauryl sulfate, polyoxyethylene lauryl ether (lauromacrogol) and the like. Among these, sodium lauryl sulfate, which is an anionic surfactant, is particularly preferable from the viewpoint that better elution characteristics can be obtained. These may be used alone or in combination of two or more.

  The content in the pharmaceutical composition when a surfactant is used varies depending on the type of surfactant used and is not particularly limited, but is usually preferably 1% by mass or more, and preferably 3% by mass or less. preferable.

  Additives such as sweeteners, fragrances, stabilizers and fluidizing agents are not particularly limited, and those commonly used in the technical field are used, and the addition in the pharmaceutical composition is also used. A person skilled in the art can appropriately set according to the kind of the agent.

  The pharmaceutical composition of the present invention is useful as a small intestinal cholesterol transporter inhibitor for the treatment of hypercholesterolemia, familial hypercholesterolemia, and homozygous sitosterolemia.

  The dosage of the pharmaceutical composition of the present invention varies depending on the age, body weight, administration route, etc., and is, for example, 10 mg as ezetimibe per day for an adult.

  The administration route of the pharmaceutical composition of the present invention is preferably enteral administration, particularly oral administration, from the mechanism of action of ezetimibe.

  The dosage form of the pharmaceutical composition of the present invention is preferably a tablet, and may be a coated tablet such as a sugar-coated tablet or a film-coated tablet with a functional polymer.

  The pharmaceutical composition of this invention can be manufactured by a well-known method in the formulation field | area. For example, in the case of a tablet, an active drug, in particular ezetimibe, is put in a fluid bed granulator together with an excipient and a disintegrant, and fluid bed granulation is performed using a granulation liquid containing a binder and a surfactant. Dry and granulate. It can be manufactured by mixing the obtained granules with other additives such as excipients, disintegrants, lubricants, sweeteners, fragrances and the like, and then tableting. The tableting method is not particularly limited. For example, using a tableting die, a tableting upper punch and a lower punch, a hydraulic hand press, a single-shot tableting machine, a rotary tableting machine, etc. Or the like can be used. Tableting may be performed so that the resulting tablet has an appropriate hardness. The tableting pressure is appropriately adjusted according to the tableting method, the device used for tableting, the size of the tablet, the type of pharmaceutical ingredient, and the like.

  The tablets thus obtained can be further processed using conventional techniques. Appropriate coatings common in the art can be applied without affecting the dissolution characteristics of the final formulation. As the coating agent, hypromellose, macrogol and the like can be used. In addition, coloring agents such as titanium oxide and iron sesquioxide, and brighteners such as carnauba wax can be appropriately added to the coating agent. It can also be a sugar-coated tablet.

  The shape of the tablet thus obtained is not particularly limited, and can be, for example, a disk shape, a donut shape, a polygonal plate shape, a spherical shape, an elliptical shape, a caplet shape, or the like. The size is preferably small. For example, in the case of a caplet shape, the major axis is preferably about 8 to 9 mm, the minor axis is preferably 4 to 5 mm, and a secant can be inserted. The mass is preferably about 80 to 100 mg.

  EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not intended to be limited to these Examples.

Details of the reagents used in the examples are described below.
Lactose hydrate: JP XVI
Crystalline cellulose: JP XVI
Hydroxypropylcellulose: JP XVI
Polyvinyl alcohol: Medicinal regulations Povidone: JP XVI
Alpha starch: Medicinal supplement croscarmellose sodium: JP XVI
Sodium lauryl sulfate: JP XVI
Magnesium stearate: JP XVI

  In the above, JP XVI represents the 16th revised Japanese Pharmacopoeia, and supplementary regulations represent Pharmaceutical Additive Standard 2003 and its supplements.

Test Example 1: Particle size distribution measurement The particle size distribution of ezetimibe crushed with a jet mill (hereinafter, the same one was used in all examples and comparative examples) was measured by laser diffraction / scattering particle size distribution in a dry measurement method. The volume was measured with an apparatus (Partica LA-950 manufactured by Horiba, Ltd., dispersion solvent: ethanol, sample refractive index 1.60). The results are shown in Table 1.

Average particle diameter = Σ {q (J) × X (J)} ÷ Σ {q (J)}
J: Particle size division number q (J): Frequency distribution value (%)
X (J): representative diameter in the J-th particle size range (μm)

Examples 1 to 3 and Comparative Example 1
Caplet tablets were produced according to the composition in Table 2. First, the binder in Table 2 was added to an aqueous solution of sodium lauryl sulfate to obtain a granulated liquid. Next, ezetimibe, lactose hydrate, and croscarmellose sodium were mixed to obtain a granulated nucleus. The fluidization of the fluidized bed granulator was started, and the granulated liquid was sprayed while fluidizing the resulting granulated nuclei to obtain a fluidized bed granulated product. The obtained granulated product was sieved with a 850 μm sieve to obtain sized granules.

  Crystalline cellulose, the remaining sodium croscarmellose, and magnesium stearate are added to and mixed with the obtained granulated granules, and the mixture is put into a tableting machine (major axis: 8.1 mm, minor axis: 4.1 mm) for tableting. Caplet tablets were obtained.

Test Example 2: Measurement of dissolution characteristics Dissolution tests were conducted on ezetimibe tablets (n = 3) obtained in each of Examples and Comparative Examples. In the dissolution test, in accordance with the Japanese Pharmacopoeia dissolution test method, the dissolution solution (trade name: NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.) was used as the dissolution test solution second solution (pH 6.8) of the Japanese Pharmacopoeia. ) Using a paddle method using a test solution in which 0.1% polysorbate 80 was added. The test conditions were an elution solvent volume of 900 ml, a temperature of 37 ± 0.5 ° C., and a paddle speed of 50 rpm. The results are shown in FIG.

  From FIG. 1, it can be seen that the pharmaceutical composition of the present invention using a specific binder has improved dissolution properties compared to Comparative Example 1.

Test Example 3: Measurement of dissolution stability The tablets of ezetimibe obtained in each Example and Comparative Example were packaged immediately after production (n = 3) and PTP packaging material (polypropylene single layer), 60 ° C., humidity After storage for 1 week under the condition of 75% RH (n = 3), elution characteristics were measured in the same manner as in Test Example 2. The results are shown in FIGS.

  2 and 3, in Example 1 using hydroxypropylcellulose as a binder and Example 2 using polyvinyl alcohol, no decrease in dissolution was observed under severe environments, and good dissolution stability was exhibited. I understand that. Further, Example 3 using povidone as a binder showed the most excellent elution characteristics in the elution rate immediately after production, but the elution rate was lowered by storage under severe conditions. From this, it can be considered that in Example 3, the stability of the active ingredient is lower than in Examples 1 and 2 under severe conditions.

Test Example 4: Measurement of dissolution stability Immediately after production, the tablets obtained in Examples 1 and 2 were stored in a thermostat at 60 ° C. and humidity 75% RH. The stability (amount of related substances) of the tablets at the start of storage (n = 3), 1 week after storage (n = 3) and 2 weeks after storage was measured. The results are shown in Table 3.

Concentrations of ezetimibe related substances were measured by the liquid chromatograph method under the following conditions in accordance with the 16th revised Japanese Pharmacopoeia.
Test conditions:
Detector: UV absorptiometer (measurement wavelength: 232 nm)
Column: A stainless steel tube having an inner diameter of 3.9 mm and a length of 15 cm was filled with 5 μm of octylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 30 ° C. Mobile phase: 20 mM KH ₂ PO ₄ / CH ₃ CN (1/1)
Flow rate: 1.0 mL / min Area measurement range: 7 minutes after sample injection Injection volume: 50 μL
Diluent: 0.05M Hydrochloric acid: acetonitrile mixture (1: 1)

  In all the examples, the average amount of the related substances was 0.02% or less and the total amount of the related substances was 0.1% or less in the storage period of 2 weeks, and very good results were obtained.

Claims (6)

A pharmaceutical composition comprising ezetimibe as an active drug and at least one binder selected from the group consisting of povidone, hydroxypropylcellulose and polyvinyl alcohol. The pharmaceutical composition according to claim 1, wherein the binder is hydroxypropyl cellulose or polyvinyl alcohol. The pharmaceutical composition according to claim 1 or 2, comprising an anionic surfactant. The pharmaceutical composition according to claim 3, wherein the anionic surfactant is sodium lauryl sulfate. Active drug, d ₅₀ is 0.1 to 20 [mu] m, the pharmaceutical composition according to any one of claims 1 to 4, d ₉₀ have a particle size distribution of 0.5 to 30 m. The pharmaceutical composition according to any one of claims 1 to 5, wherein the dosage form of the pharmaceutical composition is a tablet.

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