KR20130094086A - Oral formulation comprising lansoprazole and the preparation method thereof - Google Patents

Abstract

PURPOSE: An oral formulation containing lansoprazole is provided to improve an elution property at pH 5.5 without the loss of activity, caused by gastric acid and to effectively transfer lansoprazole into body through oral administration. CONSTITUTION: An oral formulation containing lansoprazole as an active ingredient. The oral formulation comprises: a spherical core containing lansoprazole as an active ingredient and has a central value of 90-1000 micrometers; an intermediate layer which is formed on the spherical core and contains a pharmaceutically acceptable inactive excipient; and a granule with an enteric coating layer. [Reference numerals] (AA) Ransoprazole 30mg capsule pH 5.5; (BB,EE,HH) Example 1; (CC,FF,II) Comparative example 1; (DD) Ransoprazole 30mg capsule pH 6.0; (GG) Ransoprazole 30mg capsule pH 6.8

Description

[0001] The present invention relates to oral preparations containing lansoprazole and methods for preparing the same,

The present invention relates to an oral preparation containing lansoprazole, which is unstable and poorly soluble in acid, and a method for preparing the same, wherein lansoprazole is effectively administered orally Which can be delivered into the body, and a preparation method thereof.

Lansoprazole is a benzimidazole derivative compound, and has an excellent effect on gastric ulcer, duodenal ulcer and gastroesophageal reflux disease by inhibiting gastric acid secretion by inactivating a proton pump involved in gastric acid production. In the United States, it was approved by the FDA in May 1995, and in Korea since December 1995, it is marketed under the name Lanston.

On the other hand, lansoprazole is very water-insoluble and very unstable to acid, which is easily decomposed in gastric juice, which is an acidic solution. In addition, since the pH affects the stability of lansoprazole in an aqueous solution, the half life of lansoprazole is only 30 minutes at 25 ° C and pH 5, and the half life is only 18 hours at pH 7. As such, when lansoprazole is orally administered, it is easily decomposed in a gastric juice of pH 1.2, failing to exhibit the desired pharmacological effect. Thus, formulations coated with enteric coatings are required to prevent rapid degradation in acidic gastric juices during oral administration and to reach the small intestine, the drug absorption site (Kinoshita et al., 2002).

However, even if the gastric acid hydrolysis attack is avoided in enteric-coated formulations, since lansoprazole is also poorly soluble in water and is poorly soluble in water, lansoprazole is a site that should be rapidly eluted and absorbed to exhibit a pharmacological effect (Sohn et al., 1997; Pearce et al., 1996), the bioavailability is low and it is effective for oral administration. The delivery of lansoprazole is limited.

Therefore, in order to effectively deliver lansoprazole through oral administration, it is required to formulate an improved dissolution property at the upper part of the small intestine while minimizing the loss of activity due to stomach acid by enteric coating.

On the other hand, enteric coated formulations can be roughly classified into single formulations and multi-particle formulations. Most intestinal formulations are single formulations of small size and easy to manufacture. However, since a single tablet formulation is affected by the intestinal mobile complex (IMC), the active ingredient may have a negative impact on absorption in the digestive tract. On the other hand, the multiparticulate formulation has been studied in the drug delivery system in recent years because of its low rate of stomach uptake and low individual variation compared to single tablet formulations and little effect of food ingestion. Therefore, it is desirable to develop a multi-particle formulation in which a weak drug such as lansoprazole and a weak acid drug is coated with a long-acting agent.

Korean Patent Publication No. 1996-0005138 discloses a method for producing spherical granules by using a centrifugal fluidized-bed coating granulator (CF granulator) capable of obtaining spherical granules and narrow granule size distributions. That is, spherical granules obtained by coating an inert seed nucleus composed of an inactive material such as nonpara rails, crystalline cellulose and crystalline vitamin C, which do not contain drugs, with a drug such as lansoprazole and a spray powder containing hydroxypropylcellulose with low substitution . Since the spherical granules obtained by using the CF granule of the above-mentioned 1996-0005138 use an inert seed nucleus and the drug is coated on the surface of the seed nucleus, the production method of covering the nucleus containing an active drug such as lansoprazole There is a problem that a manufacturing step is complicated and a manufacturing time is long. CF granulators are also very expensive. On the other hand, the above-mentioned 1996-0005138 only discloses the hardness and disintegration of spherical granules, and there is no mention of the dissolution effect of lansoprazole in the small intestine. Korean Patent No. 10-535228 discloses that lansoprazole is dissolved or dispersed in an oil or a fatty acid and an emulsifying agent is added to a swelling liquid in which a hydrophilic polymer compound containing an alkaline agent is dissolved and an additive is added thereto to prepare an emulsion, Discloses a hard capsule preparation in which hard gelatine capsules are packed with lansoprazole-containing pellets obtained by forming a film by spraying, lyophilizing it to prepare pellets, and film-coating and intestinal coating the pellets. However, there is a disadvantage in that the drug is decomposed in the solution during the coating of the drug layer, resulting in poor manufacturing stability, and the manufacturing steps thereof are numerous and complicated. Korean Patent No. 10-877649 also discloses that lanthanoprazole The same drug and an inert excipient are coated to obtain an active layer, spherical granules covering the intermediate layer containing an inert excipient are obtained on the active layer, and the spherical granules are mixed with a pressing excipient to obtain a plurality of units, The formulation is disclosed. However, this method is also complicated in the manufacturing steps. Therefore, there is a need for a lansoprazole-containing oral preparation capable of effectively delivering lansoprazole by oral administration and having excellent elution in the small intestine, and a method capable of producing the lansoprazole by a simple and economical process.

Korean Patent Publication No. 1996-0005138 Korean Patent No. 10-535228 Korean Patent No. 10-877649

The present invention provides a lansoprazole-containing oral preparation capable of effectively dissolving lansoprazole in the body by oral administration, without the loss of activity due to gastric acid, and improving the intramuscular dissolution characteristics, and a method for economically and rapidly producing the lansoprazole-containing oral preparation.

In order to achieve the above object,

The present invention relates to a spherical core containing lansoprazole as an active ingredient and having a median particle size of 90 占 퐉 or more and less than 1000 占 퐉, preferably 250 占 퐉 to 850 占 퐉; An intermediate layer formed on said spherical core, said intermediate layer comprising a pharmaceutically acceptable inert excipient; And granules having an intestinal crotch shell layer for the intestinal epidermis. Preferably the spherical core is extruded.

The present invention also provides a method for preparing an oral preparation containing lansoprazole as described above,

1) lansoprazole and a pharmaceutically acceptable carrier mixture are passed through an extruder having a sieving diameter of less than 1 mm and then spheronized with a sieving machine to obtain a median particle size of 90 占 퐉 m or more and less than 1,000 占 퐉, preferably 250 占 퐉 to 850 占 퐉 Forming a spherical core;

2) coating a solution of a pharmaceutically acceptable inert excipient onto the spherical core to form an intermediate layer; And

3) coating a solution containing an enteric coating polymer on the intermediate layer to form an enteric coated layer.

Hereinafter, the present invention will be described in more detail.

1. Oral preparation containing lansoprazole of the present invention

The lansoprazole-containing oral preparation of the present invention comprises an extruded spherical core containing lansoprazole as an active ingredient and having a median particle size of 90 占 퐉 or more and less than 1000 占 퐉, preferably 250 占 퐉 to 850 占 퐉; An intermediate layer formed on said spherical core, said intermediate layer comprising a pharmaceutically acceptable inert excipient; And a granule having an intestinal crotch layer for intestinal absorption of the intermediate layer.

The oral preparation of the present invention has the advantage that the spherical particles containing lansoprazole as the active ingredient have a median value of the particle range of the specific range, and thus the lansoprazole dissolution characteristics and bioavailability at pH 5.5 are improved, As shown in FIG.

The spherical core contains lansoprazole as an active ingredient and may include pharmaceutically acceptable carriers such as an alkalizing agent, a disintegrant, an excipient, a binder, a surfactant, and the like. Lansoprazole is generally present in an amount of 0.5% to 25% (w / w) based on the total weight of the spherical core.

The alkalizing agent can be used to increase the acid stability of lansoprazole, and examples thereof include alkali metal or alkaline earth metal carbonates such as calcium carbonate, magnesium carbonate, sodium carbonate, sodium hydrogen carbonate and the like, alkali metals such as calcium hydroxide and sodium hydroxide, Hydroxides of earth metals, magnesium oxide and the like can be used. Preferably, magnesium carbonate is used.

Surfactants can be used for improving dispersibility and mixing of lansoprazole and an alkalizing agent to improve acid stability and storage stability and to improve rapid disintegration and dissolution. For example, a copolymer composed of polyoxypropylene and polyoxyethylene ( Poloxamers and derivatives thereof), various polysorbates (twin types), reaction products of natural or hydrogenated vegetable oils with ethylene glycol (crepolm), but are not limited thereto. Tween 80, Poloxamers 188, 237, 338 and 407 are preferred.

The disintegrant may be used for increasing the dispersibility of lansoprazole to improve rapid disintegration and elution. For example, the disintegrant may be selected from corn starch, microcrystalline cellulose, calcium carboxymethylcellulose, lactose, mannitol, crospovidone, low substituted hydroxypropylcellulose and the like One or more types of disintegrants may be used, but not limited thereto, and calcium carboxymethylcellulose can be preferably used in view of improvement in disintegration and elution.

As the binding agent, hydroxypropyl cellulose, polyvinyl pyrrolidone, methyl cellulose, polyvinyl alcohol, starch and the like can be used. In addition, lubricants such as talc and magnesium stearate, antioxidants and the like may be added as needed.

These spherical cores are manufactured using the extrusion molding method used for the manufacture of spherical granules and the equipment used for extrusion molding. The spherical granules produced by the extrusion molding have a very low loss of drug due to wear during the coating process because the prepared core is hard. Extrusion methods used in the manufacture of spherical granules and equipment used in extrusion are described in detail in the following references, which are incorporated herein by reference: [1] DC Hicks, HL Freese, Extrusion and spheronizing equipment, in: I. [2] KE Fielden, JM Newton, Extrusion and extruders, in: J. Swarbrick, JC Boylan (eds.), Ghebre-Sellassie (ed.), Pharmaceutical Pelletization Technology, Marcel Dekker, New York, 1989, pp. 71-84. ), Encyclopaedia of Pharmaceutical Technology 5, Marcel Dekker, New York, 1992. pp. 422-431. [3] L. Baert, D. Fanara, P. De Baets, JP Remon, Instrumentation of a gravity feed extruder and the influence (1991) 7455749. [4] L. Baert, D. Fanara, JP Remon, D. Massart, Correlation of extrusion forces, raw materials, J. Pharm. and Sphere characteristics, J. Pharm. Pharmacol. 44 (1992) 6766678. [5] PJ Harrison, JM Newton, RC Rowe, Flow defects in wet Powder mass extrusion, J. Pharm. Pharmacol. 37 (1985) 81-83. [6] L. Hellen, M. Ritala, J. Ylirusi, P. Palmroos, E. Kristoffersson, Process variables of the radial screen extruder. Part I, Pharm. Tech. Int. 4 (1992) 50-60. [7] L. Hellen, J. Yliriusi, E. Muttonen, E. Kristoffersson, Process variables of the radial screen extruder. Part II. Size and size distribution, Pharm. Tech. Int. 5 (1993) 44-53. [8] G.A. Hileman, S.R. Goskoda, A.J. Spalitto, SM. Upadrashta, A factorial approach to high dose product development by an extrusion / spheronization process, Drug Dev. Ind. Pharm. 19 (1993) 4833491. [9] R.D. Shah, M. Kabadi, D.G. Pope, L.L. Augsburger, Physicomechanical characterization of the extrusion-spheronization process. I. Instrumentation of the extruder, Pharm. Res. II (1994) 3555360. [10] C. Vervaet, L. Baert, P.A. Risha, J.P. Remon, the influence of the extrusion screen on pellet quality using an instrumented basket extruder, Int. J. Pharm. 107 (1994) 29-39. [11] C. Vervaet, J.P. Remon, Influence of impeller design, method of screen perforation and perforation geometry on the quality of pellets made by extrusion-spheronization, Int. J. Pharm. 133 (1996) 29-37).

The spherical core containing the lansoprazole as an active ingredient is extruded at a median particle size of from 90 탆 to less than 1000 탆, preferably from 250 탆 to 850 탆, and has a median value of particle diameters in the above range. The dissolution rate is high and the dissolved lansoprazole is prevented from being precipitated by recrystallization, so that the dissolution property is good and thus the oral absorption rate through the small intestine is high. The median particle size is determined using the apple method, which is well known in the art for the particle size measurement of powdered particles. For example, according to the method described in "General Chapters and Assays - Physical Test and Determinations", USPTO PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING, a series of standards were used to aply sample powder, To measure the particle size distribution, from which the median of the particle size distribution can be calculated.

The intermediate layer formed on the spherical core protects the lansoprazole insecure in an acidic environment from direct contact with a weakly acidic enteric base agent to ensure the stability of the preparation and induces rapid dissolution of the enteric base agent in the upper part of the small intestine, It is used to create an environment that can be absorbed. Such an intermediate layer is used as a pharmaceutically acceptable inactive excipient which is used for coating for thin film coating, and includes, for example, sugar such as starch and sucrose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, methyl Cellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinylacetyldiethylaminoacetate, and the like can be used alone or in combination, and in particular, a cellulose-based disintegrant, more preferably a low-substituted hydroxypropylcellulose (L -HPC), and the substitution degree is 5 to 50% (w / w), more preferably 20 to 35% (w / w). The ratio of these intermediate layers is 5% to 50% (w / w) of the spherical core. If it is less than 5%, separation with the enteric substrate is not sufficient, and when it is 50% or more, elution and absorption of lansoprazole may be lowered. More preferably, the ratio of the intermediate layer is 5% to 15% (w / w) of the total weight of the core.

The intermediate layer is coated by using a conventional technique such as a fan coating method, a spray coating method or a fluidized bed coating method by using a soluble base or a dissolved or dispersed base in water and / or a suitable organic solvent to form an enteric coating layer. The nutrient-based base agents used are hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), methacrylic acid and methacrylic acid methyl ester copolymer (trade name: Eudragit) , Other enteric coating materials and plasticizers can be used. Especially, Eudragit L30D-55 and L100-55 which are soluble in the upper part of the small intestine are preferable. The proportion of the enteric coated layer is 20% to 200% (w / w) of the spherical core coated with the intermediate layer. If it is less than 20%, stomach acid-induced destruction can not be effectively blocked in gastric juice. If it is above 200%, dissolution of lanthanoprazole in the upper part of the small intestine is lowered due to incomplete dissolution of enteric agent.

As described above, the spherical granule of the present invention is a spherical core containing lansoprazole as an active ingredient and having a median particle size of 90 占 퐉 or more and 1000 占 퐉 or less, preferably 250 占 퐉 to 850 占 퐉; An intermediate layer formed on said spherical core, said intermediate layer comprising a pharmaceutically acceptable inert excipient; The intermediate layer has an intestinal epithelium for enteric application, and is orally administered by filling the capsule in a predetermined amount or in a tablet form.

The lansoprazole-containing oral preparations of the present invention exhibit particularly improved elution properties at a particular pH, i.e., pH 5.5. Thus, the uptake rate at the upper part of the small intestine including the duodenum is remarkably improved to increase the bioavailability, and lansoprazole can be effectively delivered to the body by oral administration. For example, the oral preparation of the present invention is characterized in that 60% or more of lansoprazole is eluted in a pH 5.5 eluate in the elution test according to the Korean Pharmacopoeia or the paddle method described in the United States Pharmacopoeia, and the elution rate is lowered even after 6 hours I can not see. On the other hand, the comparative preparation exhibited a relatively low elution pattern in the pH 5.5 eluate as compared with the preparation of the present invention, and lansoprazole was recrystallized and precipitated with time. As a result of measuring the bioavailability of the preparation of the present invention and the (comparative) preparation of the comparative example on the basis of the comparative preparation as a marketed product, the formulation of the present invention showed the same bioavailability as the comparative preparation which is a commercial preparation, Indicating bioavailability that did not meet the control formulation.

From this, it can be seen that the preparations according to the invention exhibit improved dissolution properties, especially at pH 5.5, resulting in a significant increase in uptake at the upper small intestine, resulting in a bioavailability equal to or higher than that of the reference preparation. In the upper part of the small intestine containing the duodenum showing the physiological pH, the preparation of the present invention is considered to be a result of the lansoprazole being eluted well and the lansoprazole being absorbed in a relatively stable state without decomposition or precipitation.

2. Preparation of Oral Formulations Containing Lansoprazole of the Present Invention

The process of the present invention

1) lansoprazole and a pharmaceutically acceptable carrier mixture are passed through an extruder having a shed diameter of less than 1 mm and then spheronized with a spheringizer to obtain a median particle size of 90 탆 or more and less than 1000 탆, preferably 250 탆 to 850 탆 Forming a spherical core;

2) coating a solution of a pharmaceutically acceptable inert excipient onto the spherical core to form an intermediate layer; And

3) coating a solution containing an enteric coating polymer on the intermediate layer to form an enteric coated layer.

Specifically, a mixture containing lansoprazole as an active ingredient is passed through an extruder having a sieving diameter of less than 1 mm to form granules, which are then spheronized with a sphero liner to obtain a median particle size distribution of 90 탆 or more and less than 1000 탆, To 850 占 퐉. At this time, the diameter of the extruder sieve is preferably 0.1 mm or more and less than 1 mm, more preferably 0.1 to 0.9 mm, more preferably 0.3 to 0.8 mm, and most preferably 0.6 mm. When the diameter of the sieved portion of the extruder is 1 mm or more, the spherical granules obtained by sphering the spherical granules after passing through the sieves have a median particle size distribution of the core of 1000 m or more, especially at pH 5.5, The lansoprazole is recrystallized and precipitated, and the dissolution characteristics deteriorate, and thus the oral absorption rate through the upper part of the small intestine is lowered. When the diameter of the extruder sieve is less than 0.1 mm, excessive heat is generated in the manufacture of the spherical core, and the elution characteristics of lansoprazole are also undesirable in the spherical core produced.

The extruder or sparnery used in the process of the present invention is an extrusion (injection) molding equipment used for making spherical granules. As described above, by using various coating techniques and equipments commonly used in the field of pharmaceutical preparations, An intermediate layer and an enteric coated layer can be formed.

The process of the present invention is a process for producing spherical granules through spheronization of extruded granules prepared by passing extruded granules having a certain size or less than 1 mm through a sieving machine. There is no activity loss due to stomach acid and elution characteristics Can be improved, and lansoprazole oral preparations with ease of controlled release can be prepared. Further, since the core is hardened because it is produced by extrusion molding, drug loss due to abrasion which may occur in the coating process is very small, and the production yield is high. Since the core itself contains an active ingredient, a number of coating steps are not necessary. Therefore, the total weight of the finished product is small, and manufacturing cost is reduced and manufacturing cost is reduced compared to the conventional manufacturing method in which a drug is coated on an inert core .

Hereinafter, the present invention will be described in more detail by way of examples. However, the following embodiments are for illustrating and illustrating the present invention, and the present invention is not limited by the embodiments.

As described above, the oral preparation of the present invention shows particularly improved elution characteristics at pH 5.5, thereby minimizing the elution and elution deviations, and improving the bioavailability by improving the uptake rate at the upper part of the small intestine. Thus, To deliver lansoprazole into the body. In addition, the preparation method of the present invention can provide a lansoprazole-containing oral preparation in which the final preparation is small in a short preparation time and a simple process, and the controlled release of lansoprazole is easy to control.

Fig. 1 shows the particle size distributions of the formulation of Example 1 of the present invention and the formulation of Comparative Example 1 in comparison.
FIG. 2 shows dissolution profiles using the eluate of pH 5.5, pH 6.0 and pH 6.8 for the preparation of Example 1 of the present invention and the preparation of Comparative Example 1, respectively.
FIG. 3 shows the in vivo dynamics of oral administration of the formulation of Example 1 of the present invention and the control preparation.

≪ Example 1 >

The components listed in Table 1 were well mixed in the ratios described, the mixture was kneaded by adding water, passed through an extrusion granulator (Fuji Paudal Co., Ltd., sieve size 0.6 mm) .Ltd., 1000 rpm, 90 seconds) to produce spherical cores. The obtained spherical core was dried at 45 ° C in a high-speed drier and dried until the loss on drying reached 3.0% or less (105 ° C, 20 minutes). The spherical core produced exhibited a median particle size distribution of 500 mu m (measured by the method described in USP - General Tests and Determinations - Physical Test and Determinations - Particle Size Distribution Estimation by Analytical Sieving).

Lansoprazole 30 mg Magnesium carbonate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg Carboxymethyl Cellulose Calcium 10 mg Lactose 26 mg Hydroxypropylcellulose 10 mg Poloxamer 188 4 mg Purified water 95 mg

The resulting spherical core was placed in a fluidized-bed separator and an intermediate layer was formed by spraying a solution of the composition described in the following table at a rate of 50 ml / min under controlled conditions of inlet air at 65 ° C and a material temperature of 40 ° C .

Corn starch 5.25 mg Low substituted hydroxypropylcellulose 5.25 mg saccharose 9.50 mg Purified water 70.00 mg

The spherical core with the intermediate layer was placed in a fluidized-bed separator and sprayed with a solution of the composition shown in the following table at a rate of 50 ml / min under controlled conditions of inlet air at 55 ° C and a material temperature of 30 ° C, .

Talc 15.00 mg Titanium oxide 4.94 mg Triethyl ethoxide 4.94 mg Polysorbate 80 2.23 mg Eudragit L30D-55 166.30 mg Purified water 165.00 mg

0.5 mg of talc and 0.5 mg of hard anhydrous silicic acid were added to 297 mg of the granules containing the enteric coated layer and then the enteric granules obtained in an amount of 298 mg per hard capsule were filled in a capsule filling machine to prepare capsules.

<Example 2>

The components listed in Table 4 were well mixed in the ratios described, the mixture was kneaded by adding water, passed through an extrusion granulator (Fuji Paudal Co., Ltd., sieve size 0.8 mm) .Ltd., 1000 rpm, 90 seconds) to produce spherical cores. The obtained spherical core was dried at 45 ° C in a high-speed drier and dried until the loss on drying reached 3.0% or less (105 ° C, 20 minutes). The spherical core produced exhibited a median value of the particle size distribution of 850 mu m (measured by the method described in the General Chapters and Assays - Physical Test and Determinations - U.S. Pharmacopoeia).

Lansoprazole 30 mg Magnesium carbonate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg Carboxymethyl Cellulose Calcium 10 mg Lactose 26 mg Hydroxypropylcellulose 10 mg Poloxamer 188 4 mg Purified water 95 mg

The resulting spherical core was placed in a fluidized-bed separator and an intermediate layer was formed by spraying a solution of the composition described in the following table at a rate of 50 ml / min under controlled conditions of inlet air at 65 ° C and a material temperature of 40 ° C .

Corn starch 5.25 mg Low substituted hydroxypropylcellulose 5.25 mg saccharose 9.50 mg Purified water 70.00 mg

The spherical core with the intermediate layer was placed in a fluidized-bed separator and sprayed with a solution of the composition shown in the following table at a rate of 50 ml / min under controlled conditions of inlet air at 55 ° C and a material temperature of 30 ° C, .

Talc 15.00 mg Titanium oxide 4.94 mg Triethyl ethoxide 4.94 mg Polysorbate 80 2.23 mg Eudragit L30D-55 166.30 mg Purified water 165.00 mg

0.5 mg of talc and 0.5 mg of hard anhydrous silicic acid were added to 297 mg of the granules containing the enteric coated layer and then the enteric granules obtained in an amount of 298 mg per hard capsule were filled in a capsule filling machine to prepare capsules.

<Example 3>

The ingredients listed in Table 7 below were mixed well in the ratios described, the mixture was kneaded by adding water, passed through an extrusion granulator (Fuji Paudal Co., Ltd., sieve size 0.3 mm) .Ltd., 1000 rpm, 90 seconds) to produce spherical cores. The obtained spherical core was dried at 45 ° C in a high-speed drier and dried until the loss on drying reached 3.0% or less (105 ° C, 20 minutes). The spherical core produced exhibited a median value of particle size distribution of 250 mu m (measured by the method described in the General Chapters and Assays - Physical Test and Determinations - 786 US Pat.

Lansoprazole 30 mg Magnesium carbonate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg Carboxymethyl Cellulose Calcium 10 mg Lactose 26 mg Hydroxypropylcellulose 10 mg Poloxamer 188 4 mg Purified water 95 mg

The resulting spherical core was placed in a fluidized-bed separator and an intermediate layer was formed by spraying a solution of the composition described in the following table at a rate of 50 ml / min under controlled conditions of inlet air at 65 ° C and a material temperature of 40 ° C .

Corn starch 5.25 mg Low substituted hydroxypropylcellulose 5.25 mg saccharose 9.50 mg Purified water 70.00 mg

The spherical core with the intermediate layer was placed in a fluidized-bed separator and sprayed with a solution of the composition shown in the following table at a rate of 50 ml / min under controlled conditions of inlet air at 55 ° C and a material temperature of 30 ° C, .

Talc 19.286 mg Titanium oxide 6.351 mg Triethyl ethoxide 6.351 mg Polysorbate 80 2.867 mg Eudragit L30D-55 213.813 mg Purified water 212.143 mg

1.0 mg of talc and 1.0 mg of hard anhydrous silicic acid were added to 319.00 mg of the granules having the enteric coated layer and then the enteric granules obtained in an amount of 321.00 mg per hard capsule were filled in a capsule filling machine to prepare capsules.

&Lt; Comparative Example 1 &

A spherical core was prepared by the method described in Example 1, except that an extrusion granulator having a sieve size of 1 mm was passed through the outer core, and an intermediate layer and an intestinal coating layer were coated thereon to prepare capsules. The obtained spherical core showed a median particle distribution of 1,000 mu m. The particle size of the spherical core of the obtained comparative example was measured by the method described in General Chapters and Assays - Physical Test and Determinations - PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING, The distribution is shown in Fig. 1 in comparison with Example 1.

&Lt; Control Example 1 &

The following experiment was conducted using a lansoprazole oral preparation (Lanston (trade name), Cheil Pharmaceutical Co., Ltd., Korea), which is a gastric ulcer treatment agent mainly composed of lansoprazole, which is commercially available on the market.

<Experimental Example 1>

The change in the dissolution profile according to the pH of the preparation example 1 according to the present invention was observed in comparison with the comparative example 1.

Example 1 and Comparative Example 1 of the present invention were tested according to the comparative dissolution test method of the Korean Pharmaceutical Affairs Agency's Equivalence Test Administration Regulations. Specifically, a pH 5.5 acetate buffer solution of the US Pharmacopoeia, a pH 6.0 and a pH 6.8 phosphate buffer solution of the drug equivalency test management regulation were used as an eluent, and the eluate was rotated at 50 rpm for 6 hours. A predetermined amount of the eluted solution was filtered, The amount of lansoprazol dissolved by UV analysis at 285 nm was measured and is shown in Fig.

As can be seen from FIG. 2, about 70% or more of lansoprazole was eluted within 30 minutes from the start of the elution test at pH 5.5 in Example 1 of the present invention, whereas in Comparative Example 1, only about 50% of lansoprazole was eluted , And the stability of the preparation of the present invention at pH 5.5 was 80%, even after about 6 hours, while the dissolution rate of lansoprazole was lowered after 1 hour in the comparative preparation, which was very unstable. The instability of this dissolution was thought to be due to recrystallization of lansoprazole dissolved out. On the other hand, at pH 6.0 and pH 6.8, which are used for evaluating the intestinal motility of a general enteric preparation, the formulation of Example 1 of the present invention and the composition of Comparative Example 1 were not significantly different from each other. From this, it can be seen that the preparations of the present invention exhibit very different dissolution profiles at a specific pH, that is, at a pH of 5.5.

<Experimental Example 2>

The preparations of Examples 1, 2 and 3 according to the present invention, the preparations of Comparative Example 1 and the control preparations were tested according to the comparative dissolution test method of the Pharmaceutical Equivalency Test Management Regulations of Korea Food & Drug Administration. In order to confirm the solubility in the upper intestinal environment including the duodenum, a pH 5.5 acetate buffer solution of US Pharmacopoeia was used as an eluent. The eluate was rotated at 50 rpm and a certain amount of the eluted solution was filtered and analyzed by UV at 285 nm to elute The amount of lansoprazole was measured and shown in Table 10. As can be seen from Table 10, the lanthanoprazole of Examples 1, 2 and 3 of the present invention eluted more than 60% of lansoprazole within 30 minutes from the start of the elution test at pH 5.5, whereas the preparation of Comparative Example 1 contained less than about 50% And the difference can be known.

Dissolution rate 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes Example 3 3.48% 15.41% 36.16% 76.57% 81.98% Example 1 1.17% 20.19% 42.27% 70.23% 77.62% Example 2 2.59% 10.14% 21.20% 63.65% 73.35% Comparative Example 1 0.64% 4.26% 17.37% 50.00% 60.02% Control Example 1 0.61% 2.28% 8.42% 52.34% 68.99%

As can be seen from the above table, the preparations of the present invention were prepared by dissolving 60% or more of lansoprazole within 30 minutes at pH 5.5 and remarkably improving the dissolution characteristics of lansoprazole, It can be confirmed that the dissolution rate is higher than that of the control preparation which is a commercial product.

<Experimental Example 3>

A bioequivalence test was performed on Control 1 to confirm the bioavailability of the Example 1 formulation of the present invention and the Comparative Example 1 formulation. The formulation of Example 1 and the formulation of Comparative Example 1 were each an average of these values using six formulations. The test method was 2X2 cross-over test for healthy adult applicants according to the Korea Food & Drug Administration's (KFDA) Notice on Biological Equivalence (Korea Food and Drug Administration Notice No. 2009-184). (AUC) and maximum blood concentration (Cmax) obtained by measuring the blood concentration of each subject were statistically examined. The results of Example 1 and Comparative Example 1 were compared with those of Control 1 The bioequivalence with the preparation is evaluated and shown in Table 11 and FIG.

Biological equivalence criteria Example 1 Comparative Example 1 AUC log 0.8 to log 1.25 log 0.9501 to log 1.1521 log 0.8792 ~ log 1.2052 Cmax log 0.8 to log 1.25 log 0.8773 to log 1.1259 log 0.7297 to log 1.0755

The bioequivalence test standard required by the Korea Food and Drug Administration is 90% confidence interval of log mean value difference between log 0.8 and log 1.25 when Aorta and Cmax are log transformed and statistically processed. As can be seen from the above table and the results of FIG. 4, the preparation of Example 1 of the present invention exhibited values in the range of log 0.9501 to log 1.1521 and log 0.8773 to log 1.1259, respectively, with respect to AUC and Cmax of the control drug, , While the preparation of Comparative Example 1 exhibited a Cmax in the range of log 0.7297 to log 1.0755, which was out of the above range, which was below the bioavailability of the reference drug.

As can be seen from the above results, the preparations of the present invention show particularly improved elution characteristics at a specific pH of 5.5, so that the elution lowering and the elution deviation are minimized, the absorption is improved at the upper small intestine and the bioavailability is increased, It can be confirmed that lansoprazole can be delivered into the body by oral administration.

Claims (14)

A spherical core containing lansoprazole as an active ingredient and having a median particle size of 90 µm or more and less than 1000 µm; An intermediate layer formed on said spherical core, said intermediate layer comprising a pharmaceutically acceptable inert excipient; A granular preparation containing lansoprazole comprising granules having an intestinal crotch layer as an intermediate layer. The oral preparation of claim 1, wherein the median particle distribution of the spherical core is 250 μm to 850 μm. The oral preparation of claim 1, wherein the spherical core is extruded. The oral preparation according to claim 1, wherein the content of lansoprazole in the spherical core is 0.5% to 25% (w / w). The oral preparation according to claim 1, wherein the spherical core further comprises carboxymethylcellulose calcium as an excipient. The oral preparation according to claim 1, wherein the intermediate layer of the pharmaceutically acceptable inert excipient is 20% to 35% (w / w) low substituted hydroxypropyl cellulose. The oral preparation according to claim 1, wherein the ratio of the intermediate layer is 5% to 50% (w / w) of the spherical core. The use according to claim 1, wherein the enteric coating layer is formed from hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP) and methacrylic acid and methacrylic acid methylester copolymer An oral preparation coated with at least one enteric polymer selected. 9. The oral preparation according to claim 8, which is coated with a methacrylic acid and methacrylic acid methyl ester copolymer. The oral preparation according to claim 1, wherein the ratio of enteric coated layer is 20% to 200% (w / w) of the spherical core coated with the intermediate layer. The oral preparation according to claim 1, wherein 60% or more of lansoprazole is eluted at 30 minutes in a pH 5.5 eluate in the elution test according to the paddle method described in Korean Pharmacopoeia. 1) passing the lansoprazole and the pharmaceutically acceptable carrier mixture through an extruder having a body diameter of less than 1 mm and then spheronizing to form a spherical core having a median particle size of at least 90 μm and less than 1000 μm;
2) coating a pharmaceutically acceptable inert excipient solution onto the spherical core to form an intermediate layer; And
And 3) coating a solution containing an enteric coating polymer on the intermediate layer to form an enteric coated layer. The method according to claim 12, wherein the diameter of the body of the extruder is 0.1 mm or more and less than 1 mm. The method according to claim 12, wherein the diameter of the body of the extruder is 0.3 mm to 0.8 mm.

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