KR20200137243A - Process for preparation of pharmaceutical combination containing ezetimibe and rosuvastatin - Google Patents

Abstract

The present invention relates to a method for manufacturing a complex containing rosuvastatin and ezetimibe which exhibits an effect of treating hyperlipidemia, wherein the method has advantages of being easy for mass production, reducing production cost, improving the quality by securing content uniformity, and providing the complex with excellent stability during storage and distribution compared to an existing manufacturing method.

Description

Process for preparation of pharmaceutical combination containing ezetimibe and rosuvastatin}

The present invention relates to a novel method for preparing a combination drug comprising rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe. Specifically, the manufacturing method comprises the steps of mixing a first active ingredient, a second active ingredient, and an additive in a blender; And tableting the mixture. Since the manufacturing method of the present invention does not use a solvent and does not include the process of compression molding and crushing assembly to dry granulation, it is possible to shorten the process time, facilitate mass production, and reduce production cost. . In particular, there is an effect of improving the quality through securing content uniformity and providing a combination agent with excellent stability during storage and distribution.

In general, cholesterol related to dyslipidemia binds to proteins in the blood and is divided into low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. About 70% of cholesterol is synthesized by the liver and 30% is absorbed by food. Therefore, various methods are used for the treatment of dyslipidemia. Among them, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are the most effective drugs for inhibition of synthesis in the liver. It is known as, and is used as a primary treatment.

However, if the dose of HMG-CoA reductase inhibitor is increased, the risk of side effects may also increase, so if the HMG-CoA reductase inhibitor alone is insufficient to sufficiently lower blood cholesterol, it is recommended to additionally administer drugs of other mechanisms. Is considered. For example, in addition to HMG-CoA reductase inhibitor drugs for inhibiting cholesterol synthesis in the liver, many studies and developments have been conducted on drug combinations for inhibiting cholesterol absorption from food. In particular, research on the drug combination of Rosuvastatin and Ezetimibe, which is known as the most ideal HMG-CoA reductase inhibitor in terms of effects and side effects, has been actively studied.

However, when the rosuvastatin component and the ezetimibe component are formulated into a single combination, formulation is difficult due to differences in physicochemical properties between the components. Rosuvastatin has the property of being easily decomposed by heat and humidity, and in order to manufacture it into tablets, it is preferable to manufacture it through a direct pressing method or a dry granulation method rather than a wet granulation method including a solvent and a drying process. Since V is a poorly soluble material, it is necessary to adjust the size of its particles (less than 10um) to show an appropriate dissolution rate, but ezetimibe composed of a low particle size is not suitable for molding into tablets due to poor fluidity and compressibility. It has a problem and requires a separate granulation process, but it is known that granules suitable for tablet production can be formed when manufactured through a wet granulation process.

In the case of the currently sold rosuvastatin and ezetimibe combination products, they are commercialized and sold through a wet granulation or dry granulation process, and an oral combination formulation containing ezetimibe and rosuvastatin and its manufacturing method are disclosed. Korean Patent Registration No. 10-1834559 discloses a manufacturing method using a wet granulation method, and Korean Patent Publication No. 10-2016-0000762 discloses a wet granulation method using a fluidized bed granulator.

However, when using the wet granulation or dry granulation method, it takes a long time to manufacture because it has to go through several processes, and rosuvastatin, an active ingredient weak to heat and humidity, may be decomposed during the manufacturing process.

Korean Patent Registration No. 10-1834559 Republic of Korea Patent Publication No. 10-2016-0000762

Accordingly, the present inventors have studied to solve the above problems, and when using a combination of specific excipients among pharmaceutically acceptable additives, the method of directly tableting without using a solvent or making granules (direct hitting method) The present invention was completed by confirming that it was possible to prepare a combination drug that can secure an effect equivalent to that obtained by taking each single drug.

The present invention aims to provide a novel method for preparing a combination drug comprising rosuvastatin or a pharmaceutically acceptable salt thereof and ezetimibe, and the use of a solvent or granulation by combining two specific excipients It is a specific challenge to provide a manufacturing method in which the time required for the process and productivity are improved compared to the known manufacturing method, which enables the manufacture of a composite agent including two active ingredients having different physicochemical properties without a process.

Further, the present invention has another problem of providing excellent quality tablets with no residual risk of organic solvents used during the manufacturing process and significantly reduced generation of related substances even during long-term storage.

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention comprises the steps of mixing rosuvastatin or a pharmaceutically acceptable salt thereof, ezetimibe, and additives inside a blender; And it discloses a method for producing a composite for oral administration comprising the step of tableting the mixture.

The additives are excipients, disintegrants and lubricants.

In the above preparation method, rosuvastatin or a pharmaceutically acceptable salt thereof is 1 to 5 wt (%), ezetimibe or a pharmaceutically acceptable salt thereof is 1 to 5 wt (%), and excipients It may be 70 to 83 weight (%), disintegrant 12 to 15 weight (%), lubricant may be 2 to 5 weight (%).

The excipient is a combination of corn starch and partially pregelatinized corn starch, and may be included in an amount of 20 to 25 weight (%) based on the total weight of the formulation.

The excipient is lactose, starch, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate or carboxymethyl cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, crospovidone, and one selected from the group consisting of povidone or It may further include two or more.

The lubricant may be glyceryl behenate, and may further include one or two or more selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, talc, colloidal silicon dioxide, and light anhydrous silicic acid. I can.

In the above manufacturing method, a solvent is not used in the mixing step, and a step of compression molding and crushing assembly to dry granulation is not included.

In another aspect, the present invention discloses an oral composite preparation prepared by the above manufacturing method.

The oral composite formulation is characterized in that the related substances fall to less than 0.5% of the initial composite formulation at the time of 1 month after storage under severe conditions of 40°C and 75% relative humidity.

The manufacturing method according to the present invention does not require special equipment for manufacturing two or more active ingredients having different physicochemical properties into a multi-layered tablet, and it is possible to shorten the process time because it does not undergo granulation compression, milling, screening, etc. , Mass production is easy and production cost can be reduced. In particular, there is an advantage of improving quality through securing content uniformity and providing a combination agent with excellent stability during storage and distribution.

In the case of the wet granulation or dry granulation method, which is a conventionally known method for manufacturing a combination of rosuvastatin and ezetimibe, it takes a long time for the manufacturing process due to various processes or requires a separate facility to manufacture a multilayer tablet. It is based on the fact that when two types of excipients are used in combination, the two active ingredients can be prepared as a single combination by using a separate device or by a direct compression method of mixing and tableting the two ingredients without making granules.

According to the present invention, the manufacturing method comprises the steps of mixing a first active ingredient, a second active ingredient, and an additive in a blender; And tableting the mixture, and the production method of the present invention does not use a solvent, and does not include a process of dry granulation by compression molding and crushing assembly.

The first active ingredient rosuvastatin is rosuvastatin free base or a pharmaceutically acceptable acid addition salt thereof (hereinafter, unless otherwise indicated in the specification, rosuvastatin free base or a pharmaceutically acceptable salt thereof) May be included, for example, calcium salt, magnesium salt, strontium salt, and the like, of which calcium salt is most preferred.

The second active ingredient, ezetimibe, is known to exist in the form of a polymorphic form, and International Publication No. WO 2005/062897 also discloses a method for preparing ezetimibe amorphous form.

The additive includes at least one of an excipient, a disintegrant, and a lubricant.

The excipient is a combination of corn starch (eg, ^StarCap® 1500) and partially pregelatinized corn starch (eg, ^Starch® 1500), and may be included in an amount of 20 to 25% by weight based on the total weight of the formulation.

The excipient is lactose, starch, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate or carboxymethyl cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, crospovidone, and one selected from the group consisting of povidone or Two or more types may be additionally included, and the present invention is not limited thereto, and those applicable to excipients known in the art may be used without limitation. Preferably, Prosolve (Provolv ^® ), Prosolve Easy Top, Rudipress ^® or a combination thereof may be further included. The corn starch and partially pregelatinized corn starch and additional excipients may be included in an amount of 70 to 83% by weight based on the total weight of the formulation.

The disintegrant may be one or two or more selected from crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), or corn starch. Preferably, it is L-HPC, crospovidone, or a combination thereof, and may be included in an amount of 12 to 15% by weight based on the total weight of the total formulation.

The lubricant may be glyceryl behenate, and one or two or more selected from magnesium stearate, stearic acid, sodium stearyl fumarate, talc, colloidal silicon dioxide, or light anhydrous silicic acid may be additionally included. The lubricant may be included in 2 to 5 weight (%) based on the total weight of the formulation.

In addition to the excipients, disintegrants, and lubricants of the present invention, binders, colorants, sweeteners, and the like may be further included.

The binder is selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, and the like, and any combination thereof, and may further include pharmaceutically acceptable ingredients.

The colorant may include at least one selected from titanium oxide, iron sulfate, or pigments recommended by FD&C.

The sweetener may include at least one selected from sucralose, sucrose, dextrose, exaggeration, glucose, liquid glucose, or maltose.

Hereinafter, it will be described in detail by examples to aid in understanding of the present invention. However, the following examples are only illustrative of the present invention, and the content of the present invention should not be construed as being limited to the following examples.

Example 1. Test on the basis for setting the amount of raw material drug: Rosuvastatin , With ezetimibe The interaction of additives and Check compatibility

<Test method>

After confirming the initial content by mixing rosuvastatin calcium (main ingredient 1), ezetimibe (main ingredient 2) and the additives shown in Table 1 below, the main ingredient was subjected to an accelerated test (temperature 45°C, humidity 75%, period 1 month). The interaction and compatibility between the and additives were confirmed.

additive Initial content test (%) Content test after accelerated test (%) standard result
Main ingredient 1 result
Main ingredient 2 Judgment standard result
Main ingredient 1 result
Main ingredient 2 Judgment Microcrystalline cellulose 95~105 100.2 100.0 fitness 95~105 99.9 99.8 fitness Prosolve Easy Top 95~105 99.8 99.9 fitness 95~105 99.6 99.3 fitness Prosolve 95~105 100.2 99.8 fitness 95~105 99.9 99.5 fitness Rudy Press 95~105 99.4 100.8 fitness 95~105 99.4 100.2 fitness Low-substituted hydroxypropyl cellulose 95~105 100.2 100.1 fitness 95~105 99.8 99.7 fitness Lactose hydrate 95~105 100.5 99.9 fitness 95~105 99.9 99.7 fitness Crospovidone 95~105 99.7 99.8 fitness 95~105 99.7 99.3 fitness Croscarmellose Sodium 95~105 99.9 99.7 fitness 95~105 97.5 99.3 fitness Aerosil 95~105 100.2 100.1 fitness 95~105 100.1 99.5 fitness Sodium starch glycolate 95~105 100.5 100.2 fitness 95~105 100.1 99.4 fitness Star Cap 1500 95~105 100.1 100.2 fitness 95~105 99.9 99.8 fitness Starch 1500 95~105 99.7 100.7 fitness 95~105 99.8 100.0 fitness Hydroxypropylcellulose 95~105 100.5 99.8 fitness 95~105 99.8 99.8 fitness Mannitol 95~105 100.3 99.9 fitness 95~105 99.7 99.7 fitness Magnesium stearate 95~105 99.7 100.2 fitness 95~105 98.9 98.9 fitness Glyceryl behenate 95~105 99.6 100.1 fitness 95~105 99.6 99.3 fitness Stearic acid 95~105 100.1 100.3 fitness 95~105 98.9 99.1 fitness Stearate fumarate 95~105 99.8 100.6 fitness 95~105 99.6 99.2 fitness

* ProsolveGTOP is a brand name for a mixture of microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and sodium stearyl fumarate.

* Prosolve is a brand name for a mixture of microcrystalline cellulose and colloidal silicon dioxide.

* Rudipress is a trade name for a mixture of lactose, crospovidone and povidone

* Starch 1500 is a brand name for partially pregelatinized corn starch, and StarCap 1500 is a brand name for a mixture of corn starch and starch 1500

Example 2. Manufacture of composite formulation by mixer

According to the composition of Table 2 below, the main component and other additives were mixed with a mixer and then tableted, and the fluidity test, hardness test, friability test, disintegration test, and dissolution test were each tested, and the results are shown in Table 3.

Raw material name Formulation 1 Formulation 2 Formulation 3 Formulation 4 Formulation 5 Formulation 6 Formulation 7 Formulation 8 chief ingredient Rosuvastatin Calcium 20.8 20.8 20.8 20.8 20.8 10.4 10.4 5.2 Ezetimibe 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Excipient Star Cap 1500 50.0 - - 90 - 20 25 20 Excipient Starch 1500 40.0 - - - 90 25 20 25 Excipient Mannitol - 73 - - - - - - Excipient Lactose hydrate - 90 90 - - - - - Excipient Microcrystalline cellulose - 60 - - - - - - Excipient Prosolve - 100 - - - - - Excipient Prosolve Easy Top 73.0 - 73 73 73 36.5 36.5 36.5 Excipient Rudy Press 160.0 - 160 160 160 80 80 80 Disintegrant Sodium starch glycolate - 22 - - - - Disintegrant Croscarmellose Sodium - 40 - - - - - Disintegrant Low-substituted hydroxypropyl cellulose 40.0 - 40 40 40 20 20 20 Disintegrant Crospovidone 22.0 - 22 22 22 11 11 11 Lubricant Magnesium stearate 4.2 - 4.2 4.2 4.2 2.1 2.1 2.1 Lubricant Glyceryl behenate 10.0 10.0 10.0 10.0 10.0 5 5 5 Lubricant Stearic acid - 4.2 - - - - - -

<Test result>

Friction: 40 tablets, 100 rotations 0.5% or less

Fluidity: angle of repose below 43℃

Hardness: 5kp or more

Disintegration: within 2 minutes

Dissolution: 85% or more within 15 minutes

Friction Test Hardness test Fluidity test Disintegration test Dissolution test Formulation 1 fitness fitness fitness fitness fitness Formulation 2 fitness fitness fitness incongruity fitness Formulation 3 fitness fitness incongruity fitness fitness Formulation 4 fitness fitness fitness incongruity fitness Formulation 5 fitness fitness incongruity incongruity fitness Formulation 6 fitness fitness fitness fitness fitness Formulation 7 fitness fitness fitness fitness fitness Formulation 8 fitness fitness fitness fitness fitness

As shown in Table 3, it was confirmed that the formulations 1 and 6 to 7 of the present invention containing both Starcap ^® 1500 and Starch ^® 1500 as excipients showed suitable results in all items. Star excipients cap ^® 1500 and Formulation 2 and 3 that do not include all of the starch ^® 1500 as well as the case of the star preparations 4 and 5, including a cap ^® 1500 or only Starch ^® 1500 also showed an improper result in some of the items. This means that it is necessary to include both StarCap ^® 1500 and Starch ^® 1500 as excipients to prepare a formulation suitable for fluidity and uniformity.

Example 3 . Coating of complex formulations

The coating process shown in Table 4 below was performed using the formulation of Table 3 using an HPMC-based coating agent (Opadry) provided by Colorcon Korea.

Rosuba, Ezetimibe
Complex formulation Coating agent (coating amount) Formulation 1 Opadry Pink (03B54445)
15mg Formulation 2 Formulation 3 Formulation 4 Formulation 5 Formulation 6 Opadry Pink (03B640058)
8mg Formulation 7 Formulation 8 Opadry Pink (03B620025)
8mg

Test example 1. Content uniformity test

The content uniformity test was conducted according to the content uniformity clause of the general test methods of the Korean Pharmacopoeia for the composite formulation prepared in Example 2, and as a result, the determination value (the smaller the value is, the better the product quality is generally guaranteed at 15 or less Possible) is shown in Table 5 below.

Rosuba, Ezetimibe
Complex formulation Content uniformity
exam Formulation 1 4.2 Formulation 2 Production impossible Formulation 3 9.9 (production instability) Formulation 4 9.3 (production instability) Formulation 5 9.5 (production instability) Formulation 6 5.2 Formulation 7 4.6 Formulation 8 5.1

As shown in Table 5, in the case of formulations 2 and 3 that do not contain both StarCap ^® 1500 and Starch ^® 1500 as excipients, and formulations 4 and 5 containing only one type, the content uniformity of each tablet is not satisfied. Production was impossible or unstable. This means that StarCap ^® 1500 and Starch ^® 1500 must be used simultaneously.

Table 5 with the results shown eje thymidine beuwa of poorly soluble drugs is generally a separate solvent or mothayeo not the drug evenly distributed case be produced by direct tabeop without granulation process, tablets difficult to satisfy the specific content uniformity star excipients cap ^® By using 1500 and Starch ^® 1500, it was confirmed that the content uniformity can be satisfied even though it is manufactured by direct pressing. This means that in the case of the direct pressing process, no drug loss occurred during the mixing process of the drug and the additive or the tableting process.

Test example 2. Related substances exam

After the composite formulation prepared in Example 3 was packaged with Alu-Alu, a test was performed to measure total related substances under long-term and accelerated conditions, and the results are shown in Tables 6 and 7, respectively.

<Test conditions for ezetimibe>

Progress detector: UV absorbance photometer (measurement wavelength: 231 nm) according to the USP process

Column: Phenimenex Luna Phenyl Hexyl

Flow rate: 1.0ml/min

Column temperature: 45℃

Analysis time: 120 minutes

Related substances in long-term conditions Initial 6 months 24 months Formulation 1 Not detected 0.05 0.17 Formulation 6 Not detected 0.06 0.22 Formulation 7 Not detected 0.02 0.19 Formulation 8 Not detected 0.04 0.17 Commercially available 0.06 0.13 0.42 Formulation 1 (bottle packaging) Not detected 0.08 0.19

As shown in Table 6, the formulations 1 and 6 to 8 of the present invention prepared by a manufacturing method that does not use a solvent and does not include a granulation process are related substances compared to commercial products containing the granulation process at the time of 24 months. It was confirmed that the amount of occurrence of is remarkably low.

Related substances under accelerated conditions Initial 6 months Formulation 1 Not detected 0.20 Formulation 6 Not detected 0.27 Formulation 7 Not detected 0.23 Formulation 8 Not detected 0.25 Commercially available 0.06 0.47 Formulation 1 (bottle packaging) Not detected 0.21

In addition, as shown in Table 7, it was confirmed that the amount of related substances was significantly lower than that of commercial products at the time of 6 months after storage under accelerated conditions of 40°C and 75% relative humidity. This is a concern for convention, so commercially available products are sold in special packaging (Alu-Alu) due to stability issues, but the manufacturing method of the present invention improves the stability during manufacturing and is packaged in bottle packaging that is convenient to take and carry. Means this is possible.

Since the manufacturing method according to the present invention can provide a combination drug containing rosuvastatin and ezetimibe that exhibits a therapeutic effect on hyperlipidemia, it can be used as a method for manufacturing pharmaceuticals in the pharmaceutical industry and medical fields.

Claims (11)

Mixing rosuvastatin or a pharmaceutically acceptable salt thereof, ezetimibe, and additives in a blender; And
Method for producing a composite for oral administration comprising the step of tableting the mixture The method of claim 1, wherein the additive is an excipient, a disintegrant and a lubricant. The method of claim 2, wherein rosuvastatin or a pharmaceutically acceptable salt thereof is 1 to 5 weight (%), and ezetimibe or a pharmaceutically acceptable salt thereof is 1 to 5 weight (%) with respect to the total weight of the formulation. , Excipient 70 to 83 weight (%), disintegrant 12 to 15 weight (%), lubricant 2 to 5 weight (%) preparation method for oral composite The method of claim 2 or 3, wherein the excipient is a combination of corn starch and partially pregelatinized corn starch, and is contained in an amount of 20 to 25% by weight based on the total weight of the formulation. The method of claim 4, wherein the excipient is lactose, starch, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate or carboxymethyl cellulose, colloidal silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, crospovidone and povidone. Method for preparing an oral composite formulation further comprising one or two or more selected from the group The method of claim 2 or 3, wherein the lubricant is glyceryl behenate. The oral composite agent of claim 6, wherein the lubricant further comprises one or more selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, talc, colloidal silicon dioxide, and light anhydrous silicic acid. Manufacturing method The method of claim 1, wherein a solvent is not used in the mixing step. The method of claim 1, which does not include compression molding and crushing assembly to dry granulation. An oral combination preparation prepared according to any one of claims 1 or 9 The oral combination preparation according to claim 10, wherein the related substance falls to less than 0.5% of the initial combination preparation at a time of 1 month after storage under accelerated conditions of 40°C and 75% relative humidity.