KR20100022626A - Risedronate-containing hard capsule using formation of nanoparticle - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation containing risedronate is provided to rapidly release risedronate and to improve absorption of the risedronate through digestive tract. CONSTITUTION: A risedronate hard capsule contains 2.5-10 weight% of risedronate or its pharmaceutically acceptable salt, polyethylene-polypropylene-polyethylene copolymer, lauroyl polyoxylglyceride or mixture thereof, surfactant, co-surfactant, and water. The surfactant is polysorbate having HLB value of 8-16. The co-surfactant is polyethyleneglycol.

Description

Risedronate-containing hard capsule using formation of nanoparticles

The present invention relates to risedronate-containing pharmaceutical formulations, wherein the rise of risedronate is improved, bioabsorption is improved, and risedronate containing minimized side effects of risedronate by reducing direct contact between the gastrointestinal mucosa and risedronate. It relates to pharmaceutical preparations.

Bisphosphonate-based drugs used for osteoporosis show low absorption and low bioavailability due to their very high water solubility. Among the bisphosphonate-based drugs, risedronate exhibits a faster absorption than other bisphosphonate drugs (Tmax is about 1 hour), with absorption occurring mainly in the upper part of the gastrointestinal tract. Risedronate is a drug with a relatively high dietary effect, which can reduce absorption by up to 55% compared to fasting. The risedronate also exhibits an average absorption rate of about 0.63% due to its low bioavailability, and it is inconvenient to maintain a correct posture for 30 minutes or more after taking the drug to increase the absorption rate. For example, lying down or in an incorrect position may delay the absorption of the drug. In addition, there are side effects such as vomiting, gastrointestinal disorders, and digestive tract disorders caused by reflux of gastric acid, which are inherent side effects of the drug.

As a method for improving the absorption rate of risedronate or bisphosphonate, Korean Patent Application Publication No. 10-2007-0111551 includes risedronate and a chelating agent, and performs release delay of risedronate and chelating agent. By introducing the release time of risedronate through means to introduce a system that is released in the upper intestine, the absorption site of risedronate, such a system is introduced to show a uniform absorption regardless of the food intake. However, these formulations have the disadvantage of using excess chelating material for chelating risedronate.

Also, Korean Patent Application Publication No. 10-2007-0121759 discloses the steps of mixing a nanoparticulate bisphosphonate, one or more surface stabilizers, sodium caprylate, and a chelating agent such as EDTA or EGTA, followed by pH of the drug particles. Nanoparticulate bisphosphonate compositions comprising coating with a sensitive coating material are introduced. However, this method has a disadvantage in that the manufacturing method is complicated and the manufacturing cost is high.

In addition, in order to improve oral absorption of bisphosphonate-based drugs, Korean Patent Application No. 10-2005-0008711 is selected from bisphosphonate-based drugs having ionization in vivo and high water solubility that do not pass through the biolipid membrane and have a bioavailability of less than 10%. A pharmaceutical composition comprising at least one active substance and at least one selected from biocompatible water-soluble chitosan as an essential component is introduced. This method is to improve the absorption method by combining the cationic of the chitosan used as a water-soluble polymer and the negative ion of the bisphosphonate or by reducing the polarity by a physical force method.

In addition, US Patent Publication No. 2003/0091623 discloses a prior art for increasing oral absorption by adding an absorption accelerator including fatty acid to an active material including bisphosphonates. The patent introduces a medium chain fatty acid triglyceride (medium chain triglyceride) as an absorption promoting agent, but since fatty acids and medium fatty acid triglycerides must be used in very large amounts, it is difficult to commercialize the product, and also dispersed in the gastrointestinal As such, it is difficult to expect an improvement in absorption.

In addition, European Patent Application No. 88-4628 discloses a pharmaceutical composition for oral administration based on bisphosphonates and containing an appropriate amount of sodium laurylsulfate. It is not a suitable method to increase the gastrointestinal absorption of the alendronate as a triggering material.

Therefore, the technical problem to be achieved by the present invention is the rapid elution of risedronate, it is possible to improve the digestive tract absorption of risedronate by forming riserate-containing lipid lipid particles of a certain size, the risedronate is directly with the gut mucosa To minimize the contact with the drug to reduce the side effects of risedronate gastrointestinal disorders, reflux esophagitis and the like to provide a pharmaceutical formulation.

In order to achieve the above technical problem, the present invention is an active ingredient risedronate or a pharmaceutically acceptable salt thereof; Polyethylene-polypropylene-polyethylene copolymers, lauroyl polyoxylglycerides or mixtures thereof that serve as lipids to enclose the drug as drug carriers to form particles; A surfactant for stably dispersing the lipid role component and risedronate, which is an active ingredient, and forming nanoparticles in an aqueous solution; Cosurfactants to facilitate dispersion of the lipid component and the surfactant; And water for improving solubility and dispersibility, and more preferably, providing a lipid nanostructure-containing hard capsule formulation of risedronate in which such a composition is filled using a liquid hard capsule charger. do.

As a method of supporting the liquid or semi-solid contents in the form of pharmaceutical engineering, there is a method of solidifying the liquid or semi-solid components by a method such as adsorption, drying, etc. to prepare them as tablets, or to support them in soft capsules or hard capsules. However, the manufacture of tablets by solidifying the liquid components is difficult in reality, such as tableting disorders occur when the content of the liquid components is high, in order to prepare a soft capsule to soften the film of the soft capsule in the contents (polyethylene glycol, Propylene glycol) and the like, there is a problem that there should be no substance to be cured (metal salt, aldehyde, ester, etc.). In addition, when the thickness of the coating is increased to improve the stability of the soft capsule, the dissolution time of the coating may delay the release of the drug. That is, in the case of certain soft capsules, it takes about 10 minutes to completely dissolve in purified water, and thus a lag time may appear during elution. Due to this problem, the use of soft capsules is not easy for drugs that need to express rapid efficacy. On the contrary, the hard capsules exhibit rapid solubility in the majority of solutions compared to the soft capsules, and may also have the advantages that the soft capsules can have, which is advantageous over the soft capsule formulations for risedronate preparations according to the present invention.

Risedronate is strongly anionic in the process of dissolving and dissociating by the body fluid, and the polarity of the gastrointestinal permeability is inferior. Therefore, if nanoparticles containing risedronate are formed in an aqueous solution, ie, inclusion of risedronate into the nanoparticle, the polarity of the drug is canceled, and these particles increase the permeability of the mucosa. The digestive tract mucosa permeability of nanoparticles is affected by the size of the particles. Importantly judged in the present invention, the size of the particles is preferably 500 nm or less, and more preferably 100 nm or less in terms of increase in absorption rate.

In the composition according to the invention, the content of risedronate is preferably 2.5-10% by weight. If the content of risedronate is less than 2.5% by weight, the amount of the effective drug is so small that the volume of the composition containing the usual risedronate dose is too large to fill in the hard capsules, and when the content exceeds 10% by weight, the present invention There is a fear that risedronate precipitates from the particles formed by the interaction between the components.

As the polyethylene-polypropylene-polyethylene copolymer, poloxamer ™ may be used, but is not limited thereto. In addition, lauroyl polyoxylglyceride may be used as GELUCIRE ™ (lauroyl macrogol-32 glycerides), but is not limited thereto, and more preferably, gelucer 44/14 may be used. have. Zeluser 44/14 is a mixture of mono and di-fatty acid esters of mono-, di- and triglycerides and polyethylene glycols. These two components are relatively water soluble and have an advantage in the present invention having a hydrophilic-lipophilic balance (HLB) value of 14 or more.

These two components serve as lipids that form particles by surrounding risedronate as drug delivery agents, and their content is preferably 20-50% by weight. When the amount of the lipid role component is less than 20% by weight, it is difficult to form nanoparticles, and when the amount of the lipid role is greater than 50% by weight, the size of the nanoparticles may be so large that absorption of the digestive tract of the lipid particles may be difficult.

Surfactants included in the composition of the present invention include polysorbate (polyoxyethylene sorbitan fatty acid ester) having an HLB value of 8-16, polyethylene glycol fatty phase glyceride, polyoxyethylene castor oil derivative (cremopoo), and the like. Among these surfactants, polysorbate is preferred, and polysorbate 80 (twin 80 or polyoxyethylene (20) sorbitan monooleate) is more preferred.

The content of such surfactant is preferably 10-25% by weight based on the total weight of the composition. If the amount of the surfactant is less than 10% by weight, it is difficult to form nanoparticles due to the lack of surfactant activity, and when used in excess of 25% by weight, the size of the nanoparticles becomes so large that absorption of the active ingredient risedronate particles may be inhibited. There is concern.

As the cosurfactant included in the composition of the present invention, polyethylene glycol, propylene glycol, glycerin, and the like may be used. Among these surfactants, polyethylene glycol is preferable, and polyethylene glycol 300-600 is more preferable.

The content of such cosurfactant is preferably 10-40% by weight based on the total weight of the composition. If the content of the co-surfactant component is less than 10% by weight, it is not easy to dissolve risedronate, and when used in excess of 40% by weight, nanoparticles may not be formed well.

The content of the water included in the composition of the present invention is preferably 2.5-7.5% by weight, more preferably 2.5-5% by weight based on the total weight of the composition. As the content of water included in the present invention increases, softening of the hard capsules may occur, thereby lowering stability.

The invention also relates to (S1) risedronate or a pharmaceutically acceptable salt thereof; Polyethylene-polypropylene-polyethylene copolymers, lauroyl polyoxylglycerides or mixtures thereof; And heating the water (preferably about 50-90 ° C., more preferably 70 ° C.) to dissolve risedronate or a pharmaceutically acceptable salt thereof; (S2) sequentially mixing and cooling the surfactant and the co-surfactant (preferably about 45-65 ° C., preferably about 55 ° C.); And (S3) provides a method for producing a riseronate-containing hard capsule formulation comprising the step of filling the hard capsule with a liquid hard capsule filling machine (for example, Lidcap ™) made liquid composition.

Because risedronate has the best solubility in water, solubility tends to decrease when other ingredients are added. It is also useful to prevent the precipitation of risedronate particles by embedding risedronate on a polymer network by first mixing polyethylene-polypropylene-polyethylene copolymer or lauroyl polyoxylglyceride with water and risedronate. Such a manufacturing method may, for example, produce a more stable system than when all the components are mixed at once.

The risedronate hard capsules prepared according to the preparation method of the present invention can rapidly elute the effective drug, and can form nanoparticles of a constant size that can promote risedronate absorption into the digestive tract regardless of the eluate.

The average size of the particles formed when the composition according to the invention is dispersed in an aqueous solution is about 100-500 nm.

The risedronate-containing preparation according to the present invention has a rapid dissolution of risedronate, which is a main component, can form risedronate-containing lipid particles of a certain size, thereby improving absorption of digestive tract of risedronate, and risedronate is a digestive tract. It is isolated from the outside environment and improves the stability of risedronate. In addition, the risedronate-containing preparation according to the present invention may minimize direct contact between the gastrointestinal mucosa and risedronate, and thus, side effects such as gastrointestinal disorders and reflux esophagitis, which are drug side effects, may be minimized.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Example 1>

Risedronate-containing hard capsules were prepared as shown in Table 1. 5.83% by weight of risedronate sodium was added to 5% by weight of distilled water and 40% by weight of Ploxamer 407, and heated to 70 ° C. Then, 15% by weight of Tween 80 and 34.17% by weight of polyethylene glycol 400 were added and stirred for 1 hour. Thereafter, the mixture was cooled to 55 ° C and charged using a liquid hard capsule charger.

Ingredient Name Usage (g) weight% Risedronate sodium 35 5.83 poloxamer 407 180 30.00 polyethylene glycol 400 205 34.17 Tween 80 150 25.00 Water 30  5.00 sum 600 100 Average size of particles: 500 nm (Add about 1 g to 100 mL of purified water at 37 ° C, and stir to measure particles)

<Example 2-4>

According to the ingredients and contents of Table 2 below, risedronate-containing hard capsules were prepared in a similar manner as in Example 1.

Ingredient Name Example 2 (% by weight) Example 3 (% by weight) Example 4 (% by weight) Risedronate sodium 5.83 5.83 5.83 poloxamer 407 35.00 40 45 polyethylene glycol 400 34.17 34.17 34.17 Tween 80 20.00 15.00 10.00 Water 5.00  5.00 5.00 sum 100 100 100

<Examples 5 and 6>

According to the ingredients and contents of Table 3 below, risedronate-containing hard capsules were prepared in a similar manner as in Example 1.

Ingredient Name Example 5 (% by weight) Example 6 (% by weight) Risedronate sodium 5.83 5.83 poloxamer 188 30.00 40.00 polyethylene glycol 300 34.17 34.17 Tween 80 25.00 15.00 Water 5.00  5.00 sum 100 100

<Example 7-9>

Prepared in the same manner as in Example 1, using GELUCIRE ™ 44/14 instead of poloxamer. Their components and contents are shown in Table 4 below.

Ingredient Name Example 7 (% by weight) Example 8 (% by weight) Example 9 (% by weight) Risedronate sodium 5.83 5.83 5.83 Gelucire 44/14 35.00 40.00 45.00 polyethylene glycol 400 34.17 34.17 34.17 Tween 80 20.00 15.00 10.00 Water 5.00  5.00 5.00 sum 100 100 100

Experimental Example 1 Dissolution Test

The dissolution test of the control capsule (Actonel ™ 35 mg, tablet, Sanofiabentis), a commercially available formulation containing risedronate and hard capsules of Examples 5 and 8 of the present invention, was performed. Purified water was used as the dissolution medium, and was tested according to the Korean Pharmacopoeia Dissolution Test Method 2 (paddle method), and the rotational speed of the paddle was 50 rpm. The results are shown in FIG.

As shown in Figure 1, risedronate-containing hard capsule formulation according to the present invention can be seen that the dissolution rate is improved than the conventional commercial formulation.

<Experiment 2> Size measurement of risedronate-containing particles

In order to preliminarily evaluate the bioavailability of risedronate, the size of risedronate-containing particles formed upon in vivo administration was measured. 1 g of each of the compositions of Examples 5 and 8 according to the present invention was added to 100 mL of 37 ° C purified water and stirred at 50 rpm for about 15 minutes, and then the size of risedronate-containing particles formed in purified water was measured. The results are shown in FIGS. 2 (Example 5) and 3 (Example 8), respectively.

As shown in Figures 2 and 3, the average particle diameter of risedronate-containing particles formed from the composition of Example 5 was about 98 nm, and the average particle diameter of risedronate-containing particles formed from the composition of Example 8 was about 560 nm. . It is believed that risedronate containing particles of this size may promote digestive tract absorption of risedronate.

FIG. 1 shows the dissolution test results of a control tablet (Actonel ™ 35 mg, Sanofiaventis), which is a commercially available tablet containing risedronate and hard capsules of Examples 5 and 8, which are embodiments of the present invention.

Figure 2 is a result of measuring the size of the particles formed when administering Example 5, an embodiment of the present invention.

Figure 3 is a result of measuring the size of the particles formed when the administration of Example 8 according to the present invention.

Claims (8)

Risedronate or a pharmaceutically acceptable salt thereof; Polyethylene-polypropylene-polyethylene copolymers, lauroyl polyoxylglycerides or mixtures thereof; Surfactants; Cosurfactants; And risedronate hard capsule formulation comprising a composition comprising water. The risedronate hard capsule formulation according to claim 1, wherein the risedronate content is 2.5-10% by weight based on the total weight of the composition. The method of claim 1, wherein the content of the polyethylene-polypropylene-polyethylene copolymer, lauroyl polyoxylglyceride or a mixture thereof is risedronate hard capsule formulation, characterized in that 20-50% by weight relative to the total weight of the composition. . 2. The risedronate hard capsule formulation of claim 1, wherein the surfactant is a polysorbate having an HLB value of 8-16. 5. The risedronate hard capsule formulation according to claim 1 or 4, wherein the amount of the surfactant is 10-25 wt% based on the total weight of the composition. According to claim 1, wherein the co-surfactant is risedronate hard capsule formulation, characterized in that the polyethylene glycol. 7. The risedronate hard capsule formulation according to claim 1 or 6, wherein the content of the co-surfactant is 10-40 wt% based on the total weight of the composition. The risedronate hard capsule formulation according to claim 1, wherein the water content is 2.5-7.5 wt% based on the total weight of the composition.

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