KR102501636B1 - Tablet for oral administration comprising fenofibric acid and method for manufacturing same - Google Patents

Abstract

The present invention relates to an oral tablet containing fenofibric acid, and more particularly, the tablet of the present invention includes mixture granules containing fenofibric acid or a pharmaceutically acceptable salt thereof as an active ingredient, calcium silicate, and a sustained-release controlling agent, so that it is possible to exhibit excellent quality without capping or laminating, protect active ingredients and calcium silicate from gastric acid by inhibiting the initial release of active ingredients, and thus finally improve bioavailability.

Description

Oral tablet containing fenofibric acid and method for manufacturing the same {Tablet for oral administration comprising fenofibric acid and method for manufacturing same}

The present invention relates to an oral tablet containing fenofibric acid and a method for preparing the same.

The present invention relates to an oral double-layer tablet containing fenofibric acid and pravastatin sodium and a method for preparing the same.

Fenofibrate, one of the fibrate drugs, is used as a treatment for hyperlipidemias, hypercholesterolemias, and hypertriglyceridemias. Fenofibrate is metabolized into fenofibric acid (chemical name: 2-[4-(4-lorobenzoyl)phenoxy]-2-methyl propanoic acid), a major metabolite in vivo. Fenofibric acid promotes the catabolism of VLDL (Very low-density lipoprotein) and triglyceride by activating lipoprotein lipase by activating PPARs (Peroxisome proliferator-activated receptors). In addition, it inhibits fatty acid synthesis in the liver by inhibiting the activity of acetyl-CoA carboxylase. Fenofibrate and fenofibric acid have problems in that they are poorly soluble in water and show lower solubility in the acidic environment of the stomach. In addition, the bioavailability of fenofibrate and fenofibric acid may vary depending on whether food is ingested. In particular, fenofibrate is absorbed in the digestive tract when fat-soluble food is ingested, which is inconvenient that it should be described as a usage after eating. In addition, fenofibric acid exhibits higher solubility in high pH regions such as the small intestine. Accordingly, a number of studies have been conducted to prepare a fenofibrate/fenofibric acid formulation having improved solubility and bioavailability.

On the other hand, Pravastatin sodium (1-naphthaleneheptanoid acid) is a therapeutic agent for dyslipidemia (eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia), It inhibits the synthesis of cholesterol by competitively inhibiting HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme that acts in the cholesterol synthesis rate control step. Pravastatin sodium increases the expression of low-density lipoprotein-cholesterol (LDL-C) receptors to maintain cellular cholesterol homeostasis when blood cholesterol levels are lowered, and very low-density lipoprotein-cholesterol (very low density) It reduces the production of lipoprotein-Cholesterol (VLDL-C) and LDL-C. At the same time, it has the effect of increasing high-density lipoprotein-cholesterol (HDL-C) levels. Accordingly, pravastatin sodium and HMG-CoA inhibitors (statin drugs) are widely used as primary treatments for dyslipidemia. Both fibrates (fenofibric acid, fenofibrate, or gemfibrozil) and statins increase the risk of myopathy (e.g., rhabdomyolysis), and the combination of the two increases the risk of myopathy; Higher doses of statins also increase this risk. In particular, since gemfibrozil among fibrate-based drugs has a function of inhibiting CYP enzymes, it is known that the risk of myopathy is greatest when used in combination with statin drugs that use CYP enzymes as the main metabolic pathway. However, combination therapy of fibrate-based drugs and statin-based drugs is very effective in reducing cholesterol and triglyceride levels in patients with complex dyslipidemia whose LDL-C levels are not normalized by using each drug alone. Treatment options can be provided. In particular, among statin drugs, pravastatin sodium is a drug that is hardly metabolized by CYP enzymes and is not affected by the CYP enzyme inhibitory action of fibrate drugs. Therefore, if the fibrate-based drug and the release time are controlled, it is expected that side effects can be minimized and effective treatment of dyslipidemia can be obtained when the drug is used in combination. Accordingly, the applicant of the present invention developed a two-layer composite tablet in which the bioavailability of fenofibric acid was improved while reducing the risk of myopathy caused by the combined use of a statin drug and fenofibric acid.

Korean Patent Publication No. 2007-0119700

An object of the present invention is to provide an oral tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof.

An object of the present invention is to provide an oral double-layer composite tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof, and pravastatin sodium.

An object of the present invention is to provide a method for preparing an oral tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof.

An object of the present invention is to provide a method for preparing an oral double-layer complex tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof, and pravastatin sodium.

1. An oral tablet comprising granules of a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate and a sustained-release controlling agent.

2. In the above 1, the sustained-release controlling agent is polyethylene oxide, polyethylene glycol, ammonio methacrylate copolymer, ethyl acrylate·methyl methacrylate copolymer, methacrylic acid copolymer and amino methacrylate At least one selected from the group consisting of, tablets for oral use.

3. The oral tablet according to 1 above, wherein the sustained-release controlling agent is at least one of an ammonio methacrylate copolymer and a methacrylic acid copolymer.

4. In the above 1, the sustained-release controlling agent is an ammonio methacrylate copolymer and a methacrylic acid copolymer, and the weight ratio of the methacrylate copolymer and the methacrylic acid copolymer is 0.5: 1 to 2: 1 phosphorus, tablets for oral use.

5. The oral tablet according to 1 above, wherein the tablet further comprises at least one selected from the group consisting of a disintegrant, a diluent, a lubricant and a stabilizer.

6. The oral tablet according to 1 above, wherein the calcium silicate is contained in an amount of 0.3 to 1 part by weight based on 1 part by weight of the fenofibric acid or a pharmaceutically acceptable salt thereof.

7. The oral tablet according to 1 above, wherein the sustained-release controlling agent is contained in an amount of 0.05 to 0.4 parts by weight based on 1 part by weight of the fenofibric acid or a pharmaceutically acceptable salt thereof.

8. The oral tablet according to 1 above, wherein the granules of the mixture are prepared by wet granulation.

9. The oral tablet according to 1 above, wherein the tablet is prepared by mixing at least one selected from the group consisting of a disintegrant, a diluent, a lubricant and a stabilizer with the granules of the mixture and then tableting.

10. Sustained-release layer comprising granules of a first mixture comprising fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate and a sustained-release controlling agent; and

A composite tablet for oral use comprising: an immediate release layer comprising granules of a second mixture containing pravastatin sodium and at least one alkalizing agent selected from the group consisting of calcium silicate and magnesium oxide.

11. The method of 10 above, wherein at least one of the sustained-release layer or the fast-release layer further comprises at least one selected from the group consisting of a disintegrant, a diluent, a lubricant, and a stabilizer, oral composite tablet.

12. The method of 10 above, wherein the second mixture granules included in the sokbang layer are polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, dextrin, gelatin, methylcellulose, hydroxycellulose, hydroxyl A composite tablet for oral use further comprising at least one binder selected from the group consisting of hydroxymethyl cellulose and polyvinyl alcohol.

13. The combination tablet for oral use according to 10 above, wherein the alkalizer is contained in an amount of 0.5 to 2 parts by weight based on 1 part by weight of the pravastatin sodium.

14. The composite tablet for oral use according to 10 above, wherein at least one of the granules of the first mixture or the granules of the second mixture is prepared by a wet granulation method.

15. The method of 10 above, wherein the tablet further mixes at least one selected from the group consisting of a disintegrant, a diluent, a lubricant, and a stabilizer with the granules of the first mixture to prepare a first post-mixture, and in the granules of the second mixture preparing a second post-mixture by further mixing at least one selected from the group consisting of a disintegrant, a diluent, a lubricant, and a stabilizer; and

A tablet for oral use prepared by a method comprising: tableting the first post-mixture as a first layer and the second post-mixture as a second layer.

16. Adding a sustained-release controlling agent to a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate to obtain mixture granules; and

Method for producing a tablet for oral use, comprising: mixing at least one selected from the group consisting of a disintegrant, a diluent, a lubricant and a stabilizer with the granules of the mixture and then tableting.

17. The method for preparing an oral tablet according to 16 above, wherein the granules of the mixture are obtained by sieving through a sieve having a size of 12 to 55 mesh.

18. Adding a sustained-release controlling agent to a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate to obtain granules of the first mixture;

obtaining second mixture granules by adding C1 to C4 lower alcohol to a mixture containing at least one alkalizing agent selected from the group consisting of pravastatin sodium and calcium silicate or magnesium oxide;

A first post-mixture is prepared by mixing at least one selected from the group consisting of a disintegrant, a diluent, a lubricant, and a stabilizer with the granules of the first mixture, and a disintegrant, a diluent, a lubricant, and a stabilizer are mixed with the granules of the second mixture. preparing a second post-mixture by further mixing at least one selected from the group; and

A method for manufacturing an oral tablet comprising the step of tableting the first post-mixture as a first layer and the second post-mixture as a second layer.

19. The method for preparing an oral tablet according to 18 above, wherein the granules of the first mixture are obtained by sifting through a sieve having a size of 12 to 55 mesh.

The oral tablet containing fenofibric acid of the present invention includes granules of a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof as an active ingredient, calcium silicate, and a sustained-release controlling agent, so that capping or laminating ( It can exhibit excellent quality without laminating, and it is possible to increase the bioavailability of pharmacologically active ingredients by suppressing the initial release of pharmacologically active ingredients and alkalizing agents to prevent functional loss of calcium silicate in the gastric acid environment.

The method for preparing an oral tablet of the present invention is to prepare granules of a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate, and a sustained-release controlling agent, and then, as a subsequent step, a disintegrant, a diluent, and a lubricant for the granules By further mixing at least one selected from the group consisting of an agent and a stabilizer to prepare a post-mixture and tableting it, it exhibits excellent tableting properties (eg, buffering action against tableting pressure, prevention of sticking of granules to the tableting machine) in the tableting process. Tablets of excellent quality can be manufactured, and tablets with improved bioavailability of active ingredients can be manufactured by effectively suppressing the initial release of an alkalizing agent and pharmacologically active ingredients in a gastrointestinal environment or a low pH environment.

In addition, the manufacturing method of the oral tablet of the present invention is a pharmacologically active ingredient, fenofibric acid or a pharmaceutically acceptable salt thereof, and calcium silicate in the granule manufacturing step before performing the tableting process, by mixing a sustained-release controlling agent, thereby forming a separate binder. Even if not added, the pharmacologically active ingredient and calcium silicate are better dispersed so that the pharmacologically active ingredient can be well encapsulated in the porous structure of calcium silicate, so that it can show a buffering effect against tableting pressure in the subsequent tableting process, and is manufactured through the tableting process. It is possible to effectively suppress the rapid release of pharmacologically active ingredients from the tablets, thereby protecting the active ingredients and calcium silicate from gastric acid, and finally improving the bioavailability of the pharmacologically active ingredients.

The combined tablet for oral use of the present invention includes granules of a mixture containing an active ingredient, fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate, and a sustained-release controlling agent in a sustained-release layer, and is effective without the sustained-release controlling agent in an immediate-release layer. By including the components pravastatin sodium, calcium silicate and/or magnesium oxide, the release rate of the two active ingredients is different, ultimately reducing side effects caused by drug use of fenofibric acid or a pharmaceutically acceptable salt thereof and pravastatin sodium. And at the same time, it can exhibit excellent dyslipidemia treatment effect.

1 is a schematic diagram of one form of an oral tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof.
Figure 2 is a schematic diagram of several forms of oral complex tablets containing fenofibric acid or a pharmaceutically acceptable salt thereof, and pravastin sodium.
Figure 3 shows the dissolution test results of a single tablet of fenofibric acid.
Figure 4 shows the results of the disintegration test of a single tablet of sustained-release granules of fenofibric acid.
Figure 5 shows the dissolution test results of a single tablet of sustained-release granules of fenofibric acid.
6 is a result showing the dissolution pattern by converting the maximum dissolution rate of a single tablet of sustained-release granules of fenofibric acid to 100%.
Figure 7 shows the dissolution test results of a single tablet of sustained-release granules of fenofibric acid.
8 shows the dissolution test results of a single tablet of pravastatin sodium.
9 shows a photograph of a double-layer tablet of fenofibric acid and pravastatin sodium according to an embodiment.
10 shows the dissolution test results of fenofibric acid and pravastatin sodium in double-layer tablets.
Figure 11 shows the dissolution test results of pravastatin sodium in a double-layer tablet of fenofibric acid and pravastatin sodium.

Hereinafter, the present invention will be described.

The present invention provides an oral tablet containing granules of a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate and a sustained-release controlling agent.

The oral tablet of the present invention is a granular formulation, and by including the pharmacologically active ingredient in the form of granules, the initial release of the pharmacologically active ingredient can be more effectively suppressed and high stability can be exhibited.

1 is a schematic diagram of a form according to an embodiment of an oral tablet of the present invention. Figure 1 is shown to explain the release mechanism of the granules and pharmacologically active ingredients contained in the oral tablet of the present invention, the oral tablet of the present invention is not limited to the form of Figure 1.

The oral tablet (100) of the present invention includes at least one granule (101) of the mixture. In the oral tablet 100 of the present invention, the pharmacologically active ingredient may be released when the mixture granules 101 are exposed after the post-mix region 103 surrounding the mixture granules 101 disintegrates first.

The mixture granules may be granules containing a pharmacologically active ingredient, fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate, and a sustained-release controlling agent. For example, the mixture granules may be in the form of a mixture of a pharmacologically active ingredient, calcium silicate, a sustained-release controlling agent, and other ingredients.

The mixture granules are obtained by adding and mixing a sustained-release controlling agent to a mixture containing the pharmacologically active ingredient and calcium silicate and then granulating the mixture, and can maintain the sustained-release properties of the granules even when tableting pressure is applied in a subsequent step.

On the other hand, in the case of coated granules in which granules are formed with a mixture containing a pharmacologically active ingredient and calcium silicate and the surface thereof is coated with the sustained-release modifier, the sustained-release modifier coating may be broken when tableting pressure is applied to the coated granules in a subsequent step. Therefore, a problem in which sustained-release properties cannot be maintained may occur.

Mixture granules may be prepared according to a conventional granulation method using fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate and a sustained-release controlling agent.

For example, the granules of the mixture may be granulated by mixing fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate, adding a sustained-release controlling agent to obtain wet granules, and then drying them. At this time, the sustained-release control agent may be dissolved in C1 to C4 alcohol.

The mixture granules may be prepared by a wet granulation method.

According to the present invention, by preparing mixture granules by wet granulation and then adding pharmacologically acceptable additives to tablets, it is possible to reduce compression problems and efficiently produce tablets.

The mixture granules may have a particle diameter of 0.3 mm or more, for example, 0.3 mm to 5.0 mm, 0.4 mm to 4.5 mm, 0.5 mm to 4.0 mm, 0.6 mm to 3.5 mm, 0.7 mm to 3.0 mm, 0.8 mm to 2.5 mm. , or may be 0.8 mm to 2.0 mm, but is not limited thereto.

The particle diameter is determined according to the mesh size. When the particle diameter of the granules of the mixture is within the above range, the microencapsulated granules are not damaged during tableting, and the pharmacologically active ingredient can be reproducibly released from the granules.

The mixture granule may be included in 35% to 70% by weight, 40 to 65% by weight, 45 to 60% by weight, or 50 to 55% by weight based on the total weight of the oral tablet, but is not limited thereto.

The oral tablet of the present invention includes mixture granules, so it can exhibit excellent quality without capping or laminating, and by suppressing the initial release of pharmacologically active ingredients to protect pharmacologically active ingredients and calcium silicate from an environment with low pH, improving bioavailability. can be raised

A pharmaceutically acceptable additive (for example, a disintegrant, diluent, lubricant or stabilizer) may be mixed with the granules of the mixture obtained as described above, followed by tableting to prepare a tablet. Specifically, the oral tablet of the present invention may be obtained by mixing at least one selected from the group consisting of a disintegrant, a diluent, a lubricant, and a stabilizer with the granules of the mixture, and then tableting the mixture.

Fenofibric acid or a pharmaceutically acceptable salt thereof is a pharmacologically active ingredient contained in oral tablets and is a metabolite of fenofibrate. Fenofibric acid has improved water solubility than fenofibrate, so it has high drug bioavailability and has the advantage of being less affected by food in absorption. Accordingly, the oral tablet and oral composite tablet of the present invention can be taken regardless of food or drink.

The term "pharmaceutically acceptable" means that a compound or composition exhibits properties that do not cause serious irritation to an object, cell, tissue, etc. to which it is administered and do not impair the biological activity and physical properties of the compound.

The term "pharmaceutically acceptable salt" refers to a salt prepared using a specific compound according to the present invention with a relatively non-toxic acid or base. A pharmaceutically acceptable salt may be, for example, an acid addition salt or a metal salt.

Fenofibric acid is prescribed for patients with hypertriglyceridemia, primary hypercholesterolemia, or mixed dyslipidemia. It can reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides and apolipoprotein B and increase high-density lipoprotein cholesterol (HDL-C).

Fenofibric acid and its pharmaceutically acceptable salts may be contained in 90 mg to 155 mg, 95 mg to 150 mg, 100 mg to 145 mg, 105 mg to 140 mg, or 110 mg to 135 mg per unit tablet. Since the oral tablet according to the present invention exhibits excellent bioavailability, it can exhibit a high therapeutic effect even with a small amount compared to a unit tablet, and can also reduce side effects.

By including calcium silicate, the tablet for oral use of the present invention can improve the stability and solubility of the manufactured tablet to enhance the bioavailability of active ingredients, and can exhibit excellent tableting effect in the tablet manufacturing process. This effect may be an excellent effect due to the combination of fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate.

Specifically, since calcium silicate has a porous structure, it can effectively encapsulate the pharmacologically active ingredient, fenofibric acid or a pharmaceutically acceptable salt thereof, using a small amount of fenofibric acid or a pharmaceutically acceptable salt thereof. A tablet containing a high content of fenofibric acid or a pharmaceutically acceptable salt thereof can be prepared. In addition, the tablet of the present invention contains calcium silicate having a porous structure, so that the pharmacologically active ingredient can be effectively encapsulated in the porous structure of calcium silicate, and the initial release of the pharmacologically active ingredient is effectively suppressed compared to the case of using only a sustained-release controlling agent. It can be.

In addition, since calcium silicate has a porous structure, it can exhibit a flexible buffering action against tableting pressure in the tableting process after granule production, and calcium silicate has excellent fluidity and compressibility, so it can play a role as a lubricant, resulting in problems in tableting. (e.g., capping and laminating) can be reduced and tablets can be compressed effectively.

Calcium silicate can create an alkaline microenvironment near the pharmacologically active ingredient when it is exposed to the body, and prevents the rapid rise of the total pH of the gastrointestinal tract where the active ingredient exists, thereby improving the stability of the active ingredient and the bioavailability of the drug. Utilization can be improved. In addition, calcium silicate can increase the solubility of fenofibric acid in the digestive tract, and ultimately improve the convenience of taking medication by increasing the solubility of drugs without food intake.

Calcium silicate may be included in 0.1 to 2 parts by weight, 0.2 to 1.5 parts by weight, 0.3 to 1 part by weight, or 0.4 to 0.9 parts by weight based on 1 part by weight of fenofibric acid or a pharmaceutically acceptable salt thereof. When calcium silicate is contained in less than the above range, it is difficult to form sustained-release granules, and when calcium silicate is contained in excess of the above range, the effect of improving solubility is not great, resulting in poor economic feasibility and increasing the size of the tablet, making it difficult to manufacture a double-layer tablet. Medication convenience may be reduced.

Sustained release modifier refers to a substance used to control the release of pharmacologically active ingredients in vivo. Sustained-release control agents can prolong the pharmacological activity of an active ingredient by lowering the initial release (burst release) of the active ingredient upon dissolution in the small intestine and slowly releasing the drug.

The oral tablet of the present invention can suppress the initial release of the active ingredient because it contains porous calcium silicate, but can more effectively suppress the initial release of the active ingredient if it further includes a sustained-release control agent.

The oral tablet of the present invention contains a sustained-release controlling agent, so that the pharmacologically active ingredient and calcium silicate are well mixed without adding a separate binder so that the pharmacologically active ingredient can be well encapsulated in the porous structure of calcium silicate in the subsequent tableting process. It can show a buffering effect on tableting pressure. In addition, the oral tablet of the present invention can protect the active ingredient from gastric acid by effectively suppressing the initial release of the pharmacologically active ingredient from the tablet manufactured through the tableting process by including a sustained-release controlling agent, and ultimately inhibits absorption in the small intestine. Maximizing the bioavailability of pharmacologically active ingredients can be improved.

According to one embodiment, the oral tablet of the present invention was induced to dissolve in 750 ml of artificial gastric juice (pH 1.2, USP) at 75 rpm for 2 hours according to the second method (paddle method) of the dissolution test of the Korean Pharmacopoeia (KP), In addition, when elution is induced in 1000 ml of artificial intestinal fluid (pH 6.8, USP) at 75 rpm for 4 hours, the pharmacologically active ingredient fenofibric acid or its pharmaceutically acceptable salt is 80% within 4 hours after 2 hours. % or more may be eluted.

Sustained-release controlling agent serves as a binder that uniformly connects 'fenofibric acid or its pharmaceutically acceptable salt' and 'calcium silicate' to each other in the preparation of granules of the mixture, and when exposed to the living body, the fine alkaline environment around fenofibric acid It is possible to increase the stability of the active ingredient by forming a.

The sustained-release controlling agent may be at least one selected from the group consisting of polyethylene oxide, polyethylene glycol, and Eudragit.

Eudragit is an ammonio methacrylate copolymer (Eudragit RS series, Eudragit RL series), ethyl acrylate/methyl methacrylate copolymer (Eudragit NE series), and methacrylic acid copolymer (Eudragit NE series). It may be at least one selected from the group consisting of GIT L series, Eudragit S series) and amino methacrylate (Eudragit E series). Specifically, Eudragit RS is an ethyl methacrylate·trimethylammoniumethyl methacrylate chloride copolymer.

The ammonio methacrylate copolymer may be trade names Eudragit RS, Eudragit RL. For example, it may be Eudragit RS PO or Eudragit RL PO in powder form, it may be Eudragit RL100 or Eudragit RS 100, and Eudragit RL30D or Eudragit RS 30D in the form of a 30% aqueous dispersion. It may be, but is not limited thereto.

The methacrylic acid copolymer may be a copolymer of methacrylic acid and methyl methacrylate. For example, the methacrylic acid copolymer is trade name Eudragit S-100 (Eudragit S-100), Eudragit L-100 (Eudragit L-100) or Eudragit L-100-55 ), but is not limited thereto. Specifically, Eudragit L is a methacrylic acid·methyl methacrylate copolymer (methacrylic acid·methyl methacrylate copolymer).

The sustained-release controlling agent may be at least one of a methacrylate copolymer and a methacrylic acid copolymer.

The sustained-release controlling agent may be an ammonio methacrylate copolymer and a methacrylic acid copolymer, wherein the weight ratio of the ammonio methacrylate copolymer and the methacrylic acid copolymer is 0.1:1 to 10:1, 0.2:1 to 8:1, 0.3:1 to 6:1, 0.4:1 to 4:1, 0.5:1 to 2:1, or 0.8:1 to 1.5:1. According to one embodiment, the sustained-release controlling agent may be an ammonio methacrylate copolymer and a methacrylic acid copolymer, wherein the weight ratio of the ammonio methacrylate copolymer and the methacrylic acid copolymer may be 1:1. there is.

According to one embodiment, the oral tablet of the present invention may contain Eudragit RS 100 as a sustained-release control agent.

According to one embodiment, the oral tablet of the present invention may contain Eudragit RS 100 and Eudragit-L 100 as a sustained-release controlling agent. Tablets containing both Eudragit RS 100 and Eudragit-L 100 as sustained-release modifiers may not show a phenomenon of aggregation of granules during disintegration. On the other hand, even when only Eudragit RS 100 is included as a sustained-release controlling agent, the tablet disintegrates in the in vivo environment, but during the disintegration process, granules may clump together to form a cake. In this case, bioavailability may be lowered because sufficient release (100% release) may not occur in the administered drug.

The sustained-release controlling agent may be dissolved in water or C1 to C4 lower alcohol.

Sustained-release controlling agent may be included in 0.01 to 0.6 parts by weight, 0.02 to 0.5 parts by weight, 0.05 to 0.4 parts by weight or 0.1 to 0.25 parts by weight based on 1 part by weight of fenofibric acid or a pharmaceutically acceptable salt thereof. If the sustained-release control agent is included in an amount less than 0.01 parts by weight, it may be difficult to control the initial burst release, and if it is used in an amount greater than 0.6 parts by weight, the granules become very hard and all active ingredients are effective in vivo within 6 hours. There is a possibility that it may not be released.

The oral tablet of the present invention may further contain pharmaceutically acceptable additives. The pharmaceutically acceptable additive may be at least one selected from the group consisting of a disintegrant, a diluent, a lubricant and a stabilizer.

Disintegrants, diluents, lubricants and stabilizers can be applied without limitation as long as they are known in the art.

Disintegrants include croscarmellose sodium, sodium starch glycolate, CMC-Ca (carboxymethyl cellulose-Ca), crospovidone, alginic acid, polyvinylpyrrolidone, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxyl It may be at least one selected from the group consisting of propyl cellulose and combinations thereof.

The oral tablet of the present invention may be a sustained-release single tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient.

The oral tablet of the present invention may be uncoated or coated.

In addition, the present invention is a sustained-release layer comprising a first mixture granules containing fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate and a sustained-release controlling agent; and

Provided is an oral tablet comprising a sok-release layer comprising granules of a second mixture containing pravastatin sodium and at least one alkalizing agent selected from the group consisting of calcium silicate and magnesium oxide. The tablet is a combination tablet containing two pharmacologically active ingredients.

Figure 2 is a schematic diagram of the form according to an embodiment of the oral composite tablet of the present invention. Figure 2 is a schematic diagram for explaining the sustained-release layer, the fast-release layer, and the granules included in each layer included in the oral composite tablet of the present invention, and the oral composite tablet of the present invention is not limited to the form disclosed in FIG. 2 no.

The oral composite tablet of the present invention may be a multi-layer composite tablet (200 or 300) in which the slow-release layer (210 or 310) and the fast-release layer (230 or 330) are laminated. For example, the oral composite tablet of the present invention may be a two-layer composite tablet 300 in which the slow-release layer 310 and the fast-release layer 330 are laminated. For another example, the oral complex tablet of the present invention may be a nucleated complex tablet 200 in which the sustained-release layer 210 is located in the core and the immediate-release layer 230 surrounds the core (see FIG. 2). ).

The sustained-release layer (210 or 310) of the oral composite tablet (200 or 300) of the present invention includes at least one agent containing a pharmacologically active ingredient, fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate, and a sustained-release controlling agent. 1 contains the mixture granules (101).

The immediate-release layer (230 or 330) of the oral composite tablet (200 or 300) of the present invention includes at least one second mixture granule (201) containing pharmacologically active ingredient pravastatin sodium and calcium silicate and/or magnesium oxide do.

In the oral composite tablet (200 or 300) of the present invention, after the release of pravastatin sodium from the second mixture granules (201) included in the immediate-release layer (230 or 330), the first tablet included in the sustained-release layer (210 or 310) Fenofibric acid or a pharmaceutically acceptable salt thereof may be released from the mixture granules 101.

The term “combined tablet” may refer to a tablet comprising two or more active ingredients present in a single dosage unit.

The complementary action and/or synergistic mechanism of action between a statin drug such as pravastatin sodium and a fenofibrate drug (e.g., fenofibric acid) is known. The effect of increasing HDL-C is more excellent. Accordingly, some clinicians already prescribe statin-based drugs and fenofibrate-based drugs in combination to patients. However, concomitant administration of each separate drug complicates the patient's regimen, increases the risk of mistake or omission in drug intake, and has disadvantages in that it is difficult to provide accurate control of the pharmacokinetics of the active substance. In addition, fibrates and statins can cause muscle side effects (e.g., myopathy) and in the worst case can cause fatal rhabdomyolysis. Higher doses may further increase the risk of developing myopathy. Therefore, it is important to develop a formulation that includes both statin-based drugs and fenofibrate-based drugs to provide excellent therapeutic effects to dyslipidemia-related patients while reducing the risk of side effects such as myopathy.

The oral composite tablet of the present invention is granulated after adding a sustained-release modifier to a fenofibrate-based drug and included in the sustained-release layer, and is granulated without adding the sustained-release modulator to a statin drug and included in the immediate-release layer, thereby exhibiting two pharmacological activities By setting the release characteristics of the ingredients independently, the time to reach the peak blood concentration (Tmax) is formed at different time points, minimizing drug side effects due to combined use, and increasing the patient's convenience by reducing the number of medications taken.

Specifically, pravastatin sodium contained in the immediate-release layer of the oral complex tablet of the present invention is initially released and absorbed in the gastrointestinal environment with low pH, and fenofibric acid contained in the sustained-release layer is slowly eluted and absorbed in the small intestine environment with high pH. can

The immediate-release layer of the complex tablet for oral use of the present invention may not contain the sustained-release controlling agent included in the sustained-release layer. In the combination tablet for oral use of the present invention, the release of the pharmacologically active ingredient of each layer can be controlled by the immediate-release layer not containing a sustained-release controlling agent and the sustained-release layer containing a sustained-release controlling agent.

Among the oral complex tablets of the present invention, pravastatin sodium, a pharmacologically active ingredient in the immediate-release layer, is released from the gastrointestinal region within 2 hours after administration into the body, and fenofibric acid or a pharmaceutically acceptable salt thereof, a pharmacologically active ingredient in the slow-release layer, is released in the body. It can be released in the small intestine after 2 hours of administration.

According to one embodiment, according to the Korean Pharmacopoeia (KP) dissolution test method 2 (paddle method), the oral complex tablet of the present invention was induced to dissolve in 750 ml of artificial gastric juice (pH 1.2, USP) at 75 rpm for 2 hours, and then , In addition, when elution is induced in 1000 ml of artificial intestinal fluid (pH 6.8, USP) at 75 rpm for 4 hours, pravastatin sodium, the pharmacologically active ingredient of the immediate-release layer, can be eluted by more than 80% within 2 hours, and the pharmacological activity of the sustained-release layer 80% or more of fenofibric acid or a pharmaceutically acceptable salt thereof, which is a component, can be eluted within 6 hours after 2 hours have elapsed.

The granules of the first mixture may be granules containing fenofibric acid or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, calcium silicate, and a sustained-release controlling agent.

The granules of the second mixture may be granules containing the pharmacologically active ingredient pravastatin sodium and calcium silicate and/or magnesium oxide.

The first mixture granules and the second mixture granules may be prepared according to conventional granulation methods.

For example, granules of the second mixture may be granulated by mixing pravastatin sodium with calcium silicate and/or magnesium oxide, adding a binding solution to obtain wet granules, and then drying the granules. At this time, the binding solution may be C1 to C4 alcohol.

At least one of the granules of the first mixture and the granules of the second mixture may be prepared by a wet granulation method. The composite tablet for oral use of the present invention may be manufactured by a wet granulation method. A combination of pravastatin sodium and a specific alkalizing agent can be applied to the wet granulation method to reduce tableting problems and efficiently produce tablets.

The granules of the first mixture may have a particle diameter of 0.3 mm or more, for example, 0.3 mm to 5.0 mm, 0.4 mm to 4.5 mm, 0.5 mm to 4.0 mm, 0.6 mm to 3.5 mm, 0.7 mm to 3.0 mm, 0.8 mm to 2.5 mm. mm, or 0.8 mm to 2.0 mm, but is not limited thereto.

The granules of the first mixture may be included in an amount of 35% to 70% by weight, 40 to 65% by weight, 45 to 60% by weight, or 50 to 55% by weight based on the total weight of the oral tablet, but is not limited thereto.

The composite tablet for oral use is prepared by further mixing a pharmaceutically acceptable additive (eg, a disintegrant, diluent, lubricant or stabilizer) with the granules of the first mixture to prepare a first post-mixture, and the second mixture It may be prepared by further mixing pharmaceutically acceptable additives with granules to prepare a second post-mixture, and then tableting the first post-mixture as a first layer and the second post-mixture as a second layer. . In this case, the additives added to the granules of the first mixture and the additives added to the granules of the second mixture may be the same or different.

Fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate and the sustained-release regulator have been described above, and detailed descriptions thereof will be omitted.

Pravastatin sodium is a pharmacologically active ingredient included in the fast-release layer of the oral composite tablet of the present invention, and selectively acts on the rate-limiting step of cholesterol biosynthesis by inhibiting HMG Co-A reductase. Pravastatin sodium can lower circulating total plasma cholesterol levels by upregulating hepatic LDL receptors, inducing LDL metabolism and elimination. It can also reduce VLDL-C, triglycerides and apolipoprotein B and increase HDL-C levels.

Pravastatin sodium may be included at 5 mg to 60 mg, 5 mg to 50 mg, 5 mg to 45 mg, or 5 mg to 40 mg per unit tablet. Since the combination tablet for oral use according to the present invention exhibits excellent bioavailability, it can exhibit a high therapeutic effect even with a small amount compared to a unit tablet, and can also reduce side effects.

The sustained-release layer of the complex tablet for oral use of the present invention contains calcium silicate, thereby improving the stability and solubility of the manufactured tablet, thereby enhancing the bioavailability of the active ingredient, and exhibiting an excellent tableting effect in the tablet manufacturing process. can

The sok-release layer of the oral composite tablet of the present invention may contain an alkalizing agent.

The alkalizing agent included in the fast-release layer may be at least one selected from the group consisting of calcium silicate, magnesium oxide, and mixtures thereof.

The alkalizing agent included in the sok-release layer can maintain the stability of the active ingredient, pravastatin sodium. Pravastatin sodium has instability in which the compound reacts easily to form other decomposition products at neutral to acidic pH due to the excessive substitution potential of the hydroxy group and the presence of a double bond. This decomposition can also be accelerated by heat, light and moisture. When the alkalinizing agent of the fast-release layer includes calcium silicate, the tableting effect may be more excellent in the tablet manufacturing process.

In the fast-release layer, the alkalizing agent may be included in an amount of 0.5 to 3 parts by weight, 0.5 to 2.5 parts by weight, 0.5 to 2 parts by weight, or 1.5 to 2 parts by weight based on 1 part by weight of pravastatin sodium. When the alkalizing agent is included in less than the above range, the stability of the tablet may deteriorate, and when the alkalizing agent is included in excess of the above range, the difference in stability maintenance effect is insignificant, resulting in low economic feasibility.

The sok-release layer of the composite tablet for oral use of the present invention may further include a binder.

The binder included in the fast-release layer is not limited as long as it serves to uniformly connect sodium pravastatin and the alkalizing agent. For example, the binder is at least selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, dextrin, gelatin, methylcellulose, hydroxycellulose, hydroxymethylcellulose and polyvinyl alcohol. can be one

The sustained-release layer or fast-release layer of the complex tablet for oral use of the present invention may further include at least one selected from the group consisting of a pharmaceutically acceptable disintegrant, diluent, lubricant, and stabilizer. Disintegrants, diluents, lubricants and stabilizers can be applied without limitation as long as they are known in the art.

The composite tablet for oral use of the present invention is sufficient as long as it includes a sustained-release layer and an immediate-release layer, and the form is not limited.

In the oral composite tablet of the present invention, at least a portion of the surface of the immediate-release layer may be in contact with at least a portion of the surface of the sustained-release layer.

The composite tablet for oral use of the present invention may be a multi-layer composite tablet in which the slow-release layer and the fast-release layer are laminated. For example, the oral composite tablet of the present invention may be a two-layer composite tablet 300 in which the slow-release layer 310 and the fast-release layer 330 are laminated. For another example, the oral complex tablet of the present invention may be a nucleated complex tablet 200 in which the sustained-release layer 210 is located in the core and the immediate-release layer 230 surrounds the core (see FIG. 2). ).

The oral composite tablet of the present invention may be uncoated or coated.

The oral tablet or combined oral tablet of the present invention described above can be used as a drug for treating dyslipidemia. For example, dyslipidemia may be hypercholesterolemia (type IIa), a combination of hypercholesterolemia and hypertriglyceridemia (type IIb), and hypertriglyceridemia (type IV), but is not limited thereto.

The term "dyslipidemia" may refer to a state in which lipid components such as triglycerides, LDL cholesterol, phospholipids, and free fatty acids in the blood are increased or HDL cholesterol is decreased. The dyslipidemia may be, for example, at least one selected from the group consisting of hyperlipidemia, hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia.

In addition, the present invention provides a method for preparing an oral tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof.

The method for preparing an oral tablet of the present invention comprises the steps of adding a sustained-release controlling agent to a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate, followed by obtaining granules of the mixture; and

It may include; mixing the granules of the mixture with a pharmaceutically acceptable additive and then tableting.

In the method for manufacturing oral tablets of the present invention, after preparing granules, additives are further mixed with the granules in a subsequent step to prepare a post-mixture and tableting the resulting mixture, thereby providing excellent tableting properties (eg, buffering action against tableting pressure) in the tableting process. .

The mixture granules may be prepared according to a conventional granulation method, for example, may be prepared by a wet granulation method.

For example, the step of obtaining the mixture granules may include obtaining wet granules after adding a sustained-release controlling agent to a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate. In addition, the step of obtaining the mixture granules may further include drying the obtained wet granules.

The sustained-release controlling agent may be dissolved in water or C1 to C4 lower alcohol.

In the method for manufacturing oral tablets of the present invention, by mixing the sustained-release controlling agent before the tableting process, the pharmacologically active ingredient and calcium silicate are well mixed without adding a separate binder, so that the pharmacologically active ingredient is well encapsulated in the porous structure of calcium silicate. can make it possible

The mixture granules may be obtained by sieving.

For example, the obtained wet granules or dry granules can be extruded through a sieve.

The size of the sieve for extruding the wet granules or the dry granules may be the same or different, for example, the sieve used to obtain the extruded granules may be of a larger size than the sieve for extruding the dry granules.

12 to 55 mesh, 12 to 40 mesh, 12 to 30 mesh, 12 to 20 mesh, 13 mesh, 14 mesh, 15 mesh, 16 mesh, 17 mesh, 18 mesh, 19 mesh, 20 mesh, 25 mesh, 30 mesh mesh, 35 mesh, 40 mesh, 45 mesh, 50 mesh or 55 mesh size, but is not limited thereto. The sieve may have a size of 12 to 55 mesh, 15 to 55 mesh, 20 to 55 mesh, 25 to 55 mesh, 30 to 55 mesh, or 35 to 50 mesh, but is not limited thereto.

If the size of the mesh is too large, the size of the granules increases, so the disintegrant, diluent, lubricant, stabilizer, etc. added by mixing cannot be uniformly mixed with the granules. If the size of the mesh is too small, the surface area of the granules increases, As the contact area with water is widened, the release delay effect of the active ingredient may be lowered.

The pharmaceutically acceptable additive may be at least one selected from the group consisting of a disintegrant, a diluent, a lubricant and a stabilizer.

Fenofibric acid or a pharmaceutically acceptable salt thereof, calcium silicate, sustained-release controlling agent, mixture granules, disintegrating agent, diluent, lubricant and stabilizer have been described above, so detailed descriptions thereof will be omitted.

In addition, the present invention provides a method for preparing an oral complex tablet containing fenofibric acid or a pharmaceutically acceptable salt thereof and pravastatin sodium.

The method for preparing a complex tablet for oral use of the present invention comprises the steps of adding a sustained-release controlling agent to a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate to obtain granules of the first mixture;

obtaining second mixture granules by adding C1 to C4 lower alcohol to a mixture containing at least one alkalizing agent selected from the group consisting of pravastatin sodium and calcium silicate or magnesium oxide;

preparing a first post-mix by mixing the granules of the first mixture with a pharmaceutically acceptable additive, and further mixing a pharmaceutically acceptable additive with the granules of the second mixture to prepare a second post-mix; and

and tableting the first post-mixture as a first layer and the second post-mixture as a second layer.

In the step of obtaining the granules of the second mixture, the mixture may further include a binder. The binder may be in powder form.

The binder is at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, dextrin, gelatin, methylcellulose, hydroxycellulose, hydroxymethylcellulose and polyvinyl alcohol It may be, but is not limited thereto.

Adding a binder solution (eg, water or C1 to C4 lower alcohol) to a mixture containing at least one alkalizing agent selected from the group consisting of pravastatin sodium and calcium silicate or magnesium oxide

The first mixture granules and the second mixture granules may be prepared according to conventional granulation methods. At least one of the granules of the first mixture and the granules of the second mixture may be prepared by a wet granulation method.

For example, the step of obtaining the granules of the first mixture may include obtaining first wet granules by adding a sustained-release controlling agent to a mixture containing fenofibric acid or a pharmaceutically acceptable salt thereof and calcium silicate. . In addition, the obtaining of the first mixture granules may further include drying the obtained first wet granules. The sustained-release controlling agent may be dissolved in water or C1 to C4 lower alcohol.

For example, the step of obtaining the second mixture granules is a binder solution (eg, water or C1 to C4 lower alcohol) in a mixture containing pravastatin sodium and at least one alkalizing agent selected from the group consisting of calcium silicate or magnesium oxide. It may include obtaining a second wet granulation by adding. In addition, the step of obtaining the second mixture granules may further include drying the obtained second wet granules.

In the step of obtaining granules of the second mixture, a sustained-release controlling agent may not be added.

The granules of the first mixture and/or the granules of the second mixture may be obtained by sieving. For example, the first and/or second wet granules or the first and/or second dry granules may be extruded through a sieve.

The granules of the first mixture and the granules of the second mixture may be extruded through sieves of the same size or different sizes. For example, the size of the sieve for extruding the granules of the first mixture may be larger than the size of the sieve for extruding the granules of the second mixture.

The size of the sieve through which the first and/or second wet granules or the first and/or second dry granules are extruded may be the same or different.

12 to 55 mesh, 12 to 40 mesh, 12 to 30 mesh, 12 to 20 mesh, 13 mesh, 14 mesh, 15 mesh, 16 mesh, 17 mesh, 18 mesh, 19 mesh, 20 mesh, 25 mesh, 30 mesh mesh, 35 mesh, 40 mesh, 45 mesh, 50 mesh or 55 mesh size, but is not limited thereto. The sieve may have a size of 12 to 55 mesh, 15 to 55 mesh, 20 to 55 mesh, 25 to 55 mesh, 30 to 55 mesh, or 35 to 50 mesh, but is not limited thereto.

The pharmaceutically acceptable additive may be at least one selected from the group consisting of a disintegrant, a diluent, a lubricant and a stabilizer. Additives added to the granules of the first mixture and the granules of the second mixture may be the same or different.

Fenofibric acid or a pharmaceutically acceptable salt thereof, pravastatin sodium, calcium silicate, magnesium oxide, sustained-release control agent, mixture granules, disintegrant, diluent, lubricant, and stabilizer have been described above, and therefore, detailed descriptions thereof are omitted.

Using the production method of the present invention, a complex formulation containing both active ingredients can be prepared with a simpler process.

Specifically, the manufacturing method of the present invention includes calcium silicate and a sustained-release controlling agent in the granules of the first mixture, and includes at least one of calcium silicate or magnesium oxide without including the sustained-release agent in the granules of the second mixture, tableting Complex tablets can be efficiently manufactured with fewer obstacles.

Hereinafter, examples will be described in detail to explain the present invention in detail. However, the following examples are only for exemplifying the present invention, and the scope of the present invention is not limited by the following examples.

1. Solubility test of fenofibrate, fenofibric acid and choline fenofibrate

A 1.5ml EP tube was filled with distilled water, pH 1.2 gastric juice (USP) or pH 6.8 simulated intestinal fluid (USP), respectively, and then fenofibrate, fenofibric acid, and choline fenofibrate were added to the precipitation point, and then mixed for 72 hours. After filtering the mixture with a 0.45um filter, each solubility was measured by HPLC analysis, and the analysis method referred to the 'Fenofibrate' section of USP (United States Pharmacopeia) (see Table 1 below, unit ppm).

Fenofibrate Fenofibric acid choline fenofibrate Distilled water 0 17.3 over 1000 pH 1.2 artificial gastric juice 0 9.2 over 1000 pH 6.8 simulated intestinal fluid 12.5 over 1000 over 1000

From the results of Table 1, it was found that the solubility increased in the order of fenofibrate < fenofibric acid < cholinefenofibrate. In the case of fenofibrate, it was confirmed that it was hardly soluble in water due to its very poor solubility, and in the case of fenofibric acid, its solubility was low at pH 1.2, but it was confirmed that it was well soluble at 1000 ppm or more at pH 6.8. It was confirmed that all choline fenofibrate had a solubility of 1000 ppm or more and was well dissolved regardless of conditions. In subsequent experiments, fenofibric acid, which has a particularly high solubility in simulated intestinal fluid, was used.

2. Preparation and dissolution test of fenofibric acid sustained-release granular single tablet

2-1. Preparation of single tablet of fenofibric acid sustained-release granules

에서 10분 건조하여 건조과립을 수득하였다.Calcium silicate, an alkalizing agent, was mixed with fenofibric acid, followed by bag mixing to obtain a fenofibric acid/alkalizing agent mixture. Separately, a release controlling agent (Eudragit, PEO, etc.) was added to ethanol and dissolved while stirring. To the fenofibric acid/alkalizing agent mixture, 1 ml of the slow-release modifier dissolved in ethanol was added and granulated. Wet granules were prepared by granulating and sizing the water granules. Specifically, the granules were obtained by sieving the granules with a 14 mesh, and the granules were sieved at 60

dried for 10 minutes to obtain dry granules.

Wet granules were prepared by sieving the dry granules with a 14 mesh. Microcrystalline cellulose and a disintegrant were mixed with the obtained wet granules, and magnesium stearate was added as a lubricant to lubricate them, and then tableted using a circular punch with a diameter of 10 mm using a China Zp10 rotary tablet press machine with a hardness of 9 kgf, to include the granules. A single tablet (Preparation Example 1-4) was prepared. Components and weights for each preparation example are shown in Table 2 below. The hardness of the tablet was measured with COPLEY's TBF 1000.

Ingredients (Unit: mg/T) Preparation Example 1 Preparation Example 2 Preparation Example 3 Production Example 4 Fenofibric acid
(Fenofibric acid) 135 135 135 135 calcium silicate 65 65 65 115 Sustained release modifier Eudragit RS 100 10 20 20 25 HPMC 10 - - - PEO 10 2 0.5 1.25 post-mixing agent Kollidon K-30 lactose hydrate - - - - microcrystalline cellulose 50 50 50 37.5 Magnesium Stearate 5 5 5 5 Sodium starch glycolate 30 30 30 37.5 Calcium silicate / phenofibric acid
weight ratio 0.48 0.48 0.48 0.85 Calcium silicate / slow-release control agent
weight ratio 0.22 0.16 0.15 0.19 total amount 315 337 335.5 356.25

2-2. Fenofibric acid sustained-release granule single tablet dissolution test

With respect to the tablets of Preparation Examples 1 to 4, a dissolution test was conducted by applying the second method (paddle method) of the Korean Pharmacopoeia. The dissolution test method was designed considering the retention time of 1 to 2 hours in the stomach. Specifically, after dissolution in 750 ml of artificial gastric fluid (pH 1.2, USP) at 75 rpm for 2 hours, a dissolution test was performed in artificial intestinal fluid (pH 6.8, USP) for 4 hours. As a control drug, commercially available phenoside capsules (Hanmi Pharmaceutical) were purchased and used as Comparative Example 1.

As a result, in all of Preparation Examples 1 to 4, no dissolution was observed in the acidic stomach at pH 1.2, and dissolution started in an artificial intestinal environment 2 hours after the start of dissolution (see FIG. 3).

3. Effect according to the type of sustained-release regulator of single tablet of fenofibric acid sustained-release granules

3-1. Preparation of single tablet of fenofibric acid sustained-release granules

Same as 2-1 above, but the components (especially the type of sustained-release control agent) and weight are different for each preparation example, and the final tablet is tableted with a hardness of 9kgf (kP) and 11kgf as the target, and a single tablet containing granules ( Preparation Examples 11-14) were prepared. Components and weights for each preparation example are shown in Table 3 below. The hardness of the tablet was measured with COPLEY's TBF 1000.

Ingredients (Unit: mg/T) Preparation Example 11 Production Example 12 Preparation Example 13 Production Example 14 Hardness 9 kgf 11 kgf 9 kgf 11 kgf Fenofibric acid
(Fenofibric acid) 135 135 135 135 calcium silicate 65 65 65 65 Sustained release modifier Eudragit RS 100 20 20 10 10 Eudragit L 100 - - 10 10 PEO One One One One post-mixing agent Magnesium Stearate 5 5 5 5 lactose hydrate 45 45 45 45 microcrystalline cellulose 45 45 45 45 Sodium starch glycolate 35 35 35 35 total amount 351 351 351 351

3-2. Results of disintegration test of single tablet of sustained-release granules of fenofibric acid

With respect to the tablets of Preparation Examples 11 to 14, a disintegration test was conducted in artificial gastric juice (pH 1.2, USP). Specifically, LabFine. After putting the tablet in the tester using Inc's Disintegration tester DIT-200, the tester was moved up and down for 30 minutes at 37.5°C to the extent that the tester was submerged to the surface.

As a result, Preparation Examples 11 and 12 were disintegrated, but cakes in which granules were clumped during the disintegration process appeared, whereas in Preparation Examples 13 and 14, all tablets were disintegrated without a phenomenon of granules clumping during the disintegration process (Table 4 below and see FIG. 4).

Time put into USP 1 liquid Preparation Example 11 Production Example 12 Preparation Example 13 Production Example 14 immediately after input Tablet form Slightly crumbly tablet form
slightly broken Tablet form Slightly crumbly Tablet form Slightly crumbly 1 min Disintegrated but in tablet form disintegrated
Visible in tablet form disintegrated more than half disintegrated more than half 3 minutes Granules are all disintegrated, but cake with granules clumped together Granules are all disintegrated, but cake with granules clumped together little lump present little lump present 5 minutes Granules are all disintegrated, but cake with granules clumped together Granules are all disintegrated, but cake with granules clumped together disintegration complete disintegration complete 7 minutes 10 minutes 20 minutes 30 minutes final result all disintegrated all disintegrated

3-3. Result of dissolution test of single tablet of fenofibric acid sustained-release granules

With respect to the tablets of Preparation Examples 11 to 14, a dissolution test was conducted by applying the second method (paddle method) of the Korean Pharmacopoeia. The specific method is described in '2-2. It is the same as that described in 'Dissolution test of a single tablet of sustained-release granules of fenofibric acid'. As a control drug, commercially available phenoside capsules (Hanmi Pharmaceutical) were purchased and used as Comparative Example 1. As a result, in all of Preparation Examples 11 to 14, dissolution was not observed in the acidic stomach at pH 1.2, and dissolution started in an artificial intestinal environment 2 hours after the start of dissolution (see FIG. 5). Through the content uniformity test results, it was confirmed that in the case of Preparation Examples 13 and 14 groups, the dissolution rate was as much as the excess of the content during tableting. On the other hand, the dissolution pattern was compared by converting the maximum dissolution rate of Preparation Examples 11 to 14 and Comparative Example 1 into 100%, and the overall dissolution pattern was slightly higher than that of Comparative Example 1, but it was confirmed that there was no significant difference (see FIG. 6).

In addition, in order to confirm the reproducibility of the mixed formulation of the sustained-release controlling agent and to confirm the dissolution pattern of the tablet with reduced granule size, the same as in Preparation Example 13 or 14 of 3-1 above, but tableting the final tablet with a hardness of 10 kgf. Then, a single tablet containing granules (Preparation Example 15-16) was prepared using a sieve size of 18 or 20 mesh. Specific components, contents and characteristics of Preparation Examples 15-16 are listed in Table 5 below. Then, the dissolution rate was confirmed by applying the second method (paddle method) of the Korean Pharmacopoeia. As a result, it was confirmed that the dissolution pattern of Preparation Examples 15-16 was similar to that of the control drug (Comparative Example 1) (see FIG. 7).

Ingredients (Unit: mg/T) Production Example 15 Production Example 16 Hardness 10 kgf 10 kgf sieve size 18 mesh 20 mesh Fenofibric acid
(Fenofibric acid) 135 135 calcium silicate 65 65 Sustained release modifier Eudragit RS 100 10 10 Eudragit L 100 10 10 PEO One One post-mixing agent Magnesium Stearate 5 5 lactose hydrate 45 45 microcrystalline cellulose 45 45 Sodium starch glycolate 35 35 total amount 351 351

3-4. Fenofibric acid sustained-release granule single tablet wear test result

The friability test was performed on the tablets of Preparation Examples 11 and 12. The test conditions were performed under conditions of 25 rpm and 100 revolutions. The test was conducted on about 6.5 g of tablets according to Table 6 of the 11th revision of the Korean Pharmacopoeia using COPLEY's FRV 2000 device, and the difference in tablet weight should be less than 1% for tablets before and after the test. As a result of the friability test, as shown in Table 6 below, the weight difference between the tablets before and after the test was less than 1%, and the tablets manufactured according to the known friability test suitability criteria were determined to be suitable.

Preparation Example 11 Production Example 12 weight before test 6.579g 6.652g weight after test 6.567g 6.628g Masondo 0.18% 0.36% Test result fitness fitness

4. Preparation and dissolution test of pravastatin sodium single tablet

4-1. Preparation of single tablet of pravastatin sodium

1) Manufacture by wet granulation method

에서 15분 건조하여 건조과립을 수득하였다. 건조과립을 14mesh로 sieving하여 습식 과립을 제조하였다. 수득한 습식과립에 붕해제, 희석제, 활택제 등을 혼합한 후, China Zp10 rotary tablet press machine으로 직경 10mm 원형 펀치를 이용하였고 경도 9kgf을 목표로 타정하여 과립을 포함하는 단일정(제조예 7-8)을 제조하였다.An alkalizer (calcium silicate or magnesium oxide) and a diluent were mixed with pravastatin sodium and bag-mixed to obtain a pravastatin sodium/alkalizer mixture. Water granulation was performed while adding 1 ml of ethanol as a binding solution to the pravastatin sodium/alkalizing agent mixture. Wet granules were prepared by granulating and sizing the water granules. Specifically, the granules were obtained by sieving the water granules with 12 mesh, and the granules were 60

dried for 15 minutes to obtain dry granules. Wet granules were prepared by sieving the dry granules with a 14 mesh. After mixing a disintegrant, diluent, lubricant, etc. with the obtained wet granules, a circular punch with a diameter of 10 mm was used with a China Zp10 rotary tablet press machine, and a single tablet containing granules was obtained by tableting with a target hardness of 9 kgf (Preparation Example 7- 8) was prepared.

2) Manufacturing by direct compression method

A mixture was obtained by mixing pravastatin sodium with an alkalizing agent (calcium silicate or magnesium oxide), a disintegrant, a diluent, a lubricant, and the like. This mixture was tableted with a China Zp10 rotary tablet press machine using a round punch with a diameter of 10 mm, aiming at a hardness of 9 kgf, to prepare a single tablet (Preparation Example 5-6). Component weights for each preparation example are shown in Table 7 below.

Ingredients (Unit: mg/T) Preparation Example 5 Preparation Example 6 Preparation Example 7 Preparation Example 8 Granule manufacturing method direct hit method wet granulation Pravastatin Sodium 40 40 40 40 alkalizing agent calcium silicate - 80 magnesium oxide 80 80 80 - binder L-HPC 5 - 20 Crospovidone 10 - lactose hydrate - - - 25 microcrystalline cellulose 50 50 50 25 Magnesium Stearate 4 4 4 4 Sodium starch glycolate - 20 30 30 Alkalizing agent/pravastatin sodium weight ratio 2 2 2 2 total amount 189 194 194 224

Tablets manufactured by the wet granulation method (Preparation Examples 7 and 8) showed reduced compression difficulties such as capping and laminating compared to tablets manufactured by the direct compression method (Preparation Examples 5 and 6). It can be seen that the flowability was improved through the wet granulation method, and as a result, the compression blockage was reduced.

4-2. Dissolution test for single tablet of pravastatin sodium

With respect to the tablets of Preparation Examples 5 to 8, a dissolution test was conducted by applying the second method (paddle method) of the Korean Pharmacopoeia. Specifically, elution was performed at 75 rpm in 750 ml of artificial gastric juice (pH 1.2, USP) for 1 hour. As a control drug, a commercially available mevaro parental tablet (HK Inoen) was purchased and used as Comparative Example 2.

As a result, it was confirmed that at least 80% of the active ingredient was rapidly dissolved within 15 minutes, similar to Comparative Example 2 (see FIG. 8).

5. Preparation and dissolution test of fenofibric acid and pravastatin sodium double-layer tablet

5-1. Preparation of fenofibric acid and pravastatin sodium bi-layer tablet

에서 10분 건조하여 건조과립을 수득하였다. 건조과립을 18mesh로 sieving하였다. 수득한 과립에 미세결정 셀룰로오스와 붕해제를 혼합하고, 스테아린산마그네슘을 활택제로 첨가하여 후혼합물을 수득하였다.Calcium silicate, an alkalizing agent, was mixed with fenofibric acid, followed by bag mixing to obtain a fenofibric acid/alkalizing agent mixture. Separately, a release controlling agent (Eudragit, PEO, etc.) was added to ethanol and dissolved while stirring. To the fenofibric acid/alkalizing agent mixture, 1 ml of the slow-release control agent dissolved in ethanol was added and granulated. Wet granules were prepared by granulating and sizing the water granules. Specifically, the granules were obtained by sieving the water granules with 18 mesh, and the granules were sieved at 60

dried for 10 minutes to obtain dry granules. The dried granules were sieving with 18 mesh. Microcrystalline cellulose and a disintegrant were mixed with the obtained granules, and magnesium stearate was added as a lubricant to obtain a post-mixture.

에서 15분 건조하여 건조과립을 수득하였다. 건조과립을 18mesh로 sieving하였다. 수득한 과립에 붕해제, 희석제, 활택제 등을 혼합하여 후혼합물을 수득하였다.In addition, pravastatin sodium was mixed with an alkalizing agent (calcium silicate or magnesium oxide) and a binding agent, followed by bag mixing to obtain a pravastatin sodium/alkalizing agent mixture. Water granulation was performed while adding 1 ml of ethanol as a binding solution to the pravastatin sodium/alkalizing agent mixture. Wet granules were prepared by granulating and sizing the water granules. Specifically, the granules were obtained by sieving the water granules with 18 mesh, and the granules were sieved at 60

dried for 15 minutes to obtain dry granules. The dried granules were sieving with 18 mesh. A post-mixture was obtained by mixing a disintegrant, a diluent, a lubricant, and the like with the obtained granules.

The post-mixture containing the granules containing fenofibric acid finally obtained through the above method is used as the first layer, and the post-mixture containing the granules containing pravastatin sodium is used as the second layer, and then a rectangular shape is formed using a Flexitab machine. A double tablet was prepared. A rectangular punch was used with a major axis of 14.00mm and a minor axis of 8.00mm, and tableting was performed at a fill up of 6.3-7.8mm and a main pressure of 8-10kN, targeting a tablet hardness of 11kgf to 14kgf to prepare a double-layer tablet of fenofibric acid and sodium pravastatin. (Preparation Examples 9-10) (see FIG. 9).

Component weights for each preparation example are shown in Table 8 below.

Ingredients (Unit: mg/T) Production Example 9 Production Example 10 Fenofibric acid
Western layer Fenofibric acid 135 135 calcium silicate 65 115 Sustained release modifier Eudragit 20 25 HPMC - - PEO One 1.25 lactose hydrate microcrystalline cellulose 30 37.5 Magnesium Stearate 5 5 Sodium starch glycolate 30 37.5 Pravastatin Sodium
immediate release layer Pravastatin Sodium 40 40 alkalizing agent calcium silicate 30 30 magnesium oxide 40 40 binder L-HPC - 20 lactose hydrate - 25 microcrystalline cellulose 50 25 Magnesium Stearate 4 4 Sodium starch glycolate 30 30

5-2. Dissolution test of fenofibric acid and pravastatin sodium double-layer tablets

Regarding the tablets of Preparation Examples 9 and 10, '2-2. The dissolution test was conducted in the same manner as the dissolution test of the single tablet of fenofibric acid sustained-release granules. As a result, fenofibric acid was not eluted in the gastric environment at low pH 1.2, but rapidly eluted in the intestinal environment at pH 6.8. On the other hand, pravastatin exhibited a dissolution rate of 80% or more of the active ingredient within the initial 15 minutes (see FIGS. 10 and 11).

100: oral tablet
101, 201: mixture granules
103: post-mixture area
200, 300: multi-layer composite tablet
210, 310: Western layer
230, 330: immediate release layer

Claims (19)

Mixture granules containing fenofibric acid, calcium silicate and a sustained-release controlling agent; and a disintegrant;
The disintegrant is contained outside the granules of the mixture, oral tablet.
The method according to claim 1, wherein the sustained-release controlling agent is a group consisting of polyethylene oxide, polyethylene glycol, ammonio methacrylate copolymer, ethyl acrylate·methyl methacrylate copolymer, methacrylic acid copolymer and amino methacrylate At least one selected from, oral tablet.
The oral tablet according to claim 1, wherein the sustained-release controlling agent is at least one of an ammonio methacrylate copolymer and a methacrylic acid copolymer.
The method according to claim 1, wherein the sustained-release controlling agent is an ammonio methacrylate copolymer and a methacrylic acid copolymer, and the weight ratio of the ammonio methacrylate copolymer and the methacrylic acid copolymer is 0.5:1 to 2:1 phosphorus, tablets for oral use.
The oral tablet according to claim 1, further comprising at least one selected from the group consisting of a diluent, a lubricant and a stabilizer outside the granules of the mixture.
The method according to claim 1, wherein the calcium silicate is contained in 0.3 to 1 part by weight based on 1 part by weight of the fenofibric acid, oral tablet.
The method according to claim 1, wherein the sustained-release control agent is contained in 0.05 to 0.4 parts by weight based on 1 part by weight of the fenofibric acid, oral tablet.
The method according to claim 1, wherein the disintegrant is croscarmellose sodium, sodium starch glycolate, CMCa (carboxymethyl cellulose-Ca), crospovidone, alginic acid, polyvinylpyrrolidone, corn starch, microcrystalline cellulose, hydroxypropyl methyl At least one tablet for oral use selected from the group consisting of cellulose and hydroxypropyl cellulose.
The method according to claim 1, wherein the tablet is prepared by mixing a composition containing a disintegrant with the granules of the mixture to obtain a post-mixture; and
Tablets for oral use prepared by a method comprising: tableting the mixture obtained in the above step.
delete delete delete delete delete delete Obtaining mixture granules by adding a sustained-release controlling agent to a mixture containing fenofibric acid and calcium silicate; and
preparing a post-mixture by mixing the granules of the mixture with a composition including a disintegrant; and
A method for producing a tablet for oral use, comprising: tableting the mixture obtained in the step of preparing the mixture after the preparation.
The method of claim 16, wherein the granules of the mixture are obtained by sifting through a sieve having a size of 12 to 55 mesh.
delete delete

Images