WO2013122413A1

WO2013122413A1 - Oral formulation comprising lansoprazole and the preparation method thereof

Info

Publication number: WO2013122413A1
Application number: PCT/KR2013/001189
Authority: WO
Inventors: Hee Chul Chang; Bok Ki Kang; Jung Soo Kim
Original assignee: Daewoong Pharmaceutical Co., Ltd.
Priority date: 2012-02-15
Filing date: 2013-02-15
Publication date: 2013-08-22
Also published as: CN109939084A; KR101390647B1; PH12014501822A1; KR20130094086A; PH12014501822B1; CN104114157A

Abstract

An acid-unstable, insoluble lansoprazole-containing oral formulation, and a method of preparing the same are provided. The lansoprazole-containing oral formulation is resistant to activity loss caused by gastric juice, has improved dissolution characteristics, and thus ensures effective delivery of lansoprazole into the body through oral administration.

Description

ORAL FORMULATION COMPRISING LANSOPRAZOLE AND THE PREPARATION METHOD THEREOF

The present invention relates to an acid-unstable, insoluble lansoprazole-containing oral formulation, and a method of preparing the same, and more particularly, to a lansoprazole-containing oral formulation that is resistant to activity loss caused by gastric acid, and has improved release characteristics at pH 5.5 and may be effectively delivered into the body via oral administration, and a method of preparing the same.

Lansoprazole as a benzimidazole derivative compound inhibits the secretion of gastric acid by inhibiting a proton pump involved in the production of gastric acid, and thus has a strong therapeutic effect against stomach and duodenal ulcer, and gastroesophageal reflux disease. It was approved for market release by the US Food and Drug Administration (FDA) in May 1995, and has been sold under the trademark of Lanston from December 1995 in Korea.

Lansoprazole is poorly water-soluble, and is very unstable to an acid, and thus liable to decompose in acidic gastric juice. The pH affects lansoprazole's stability in an aqueous solution. A half-life of lansoprazole is merely about 30 minutes at 25℃ and pH 5, and is about 18 hours at pH 7. When orally administered, lansoprazole is liable to decompose in the gastric juice condition of pH 1.2, and thus may not provide desired pharmacological effects. Accordingly, lansoprazole needs to be prepared as an enteric-coated formulation to prevent from rapid decomposition by acidic gastric juice when orally administrated to reach the small intestine through which drug absorption occurs.

However, even though protected from hydrolysis by gastric acid by being formulated as an enteric-coated formulation, lansoprazole may not be smoothly released and absorbed in an upper small intestine absorption site due to poor water solubility, and thus shows significant variations in absorption between individual organisms when orally administered. Thus, an enteric-coated formulation of lansoprazole may have low bioavailability of lansoprazole, which limits effective delivery into the body via oral administration.

For effective delivery of lansoprazole into the body via oral administration, there is a demand for an enteric-coated formulation with a reduction in activity loss caused by gastric juice and with improved release characteristics in the upper small intestine.

Enteric-coated formulations may be roughly classified into a single formulation or multi-granule formulation. Most enteric-coated formulations are prepared as a single formulation like a tablet that is small and convenient to prepare. However, the single tablet formulation is vulnerable to Interdigestive migrating motor complex (IMMC), and thus may have a negative effect on absorption of its active component. Meanwhile, the multi-granule formulation has less variation in stomach emptying rate or absorption between individuals, as compared with the single tablet formulation, , and is nearly never influenced by food intake, and thus recently has been researched much in conjunction with drug delivery systems. Accordingly, such an enteric-coated multi-granule formulation is suitable for an acid-liable, poorly-soluble drug, such as lansoprazole.

Korean Patent Publication No. 1996-0005138 discloses a method for preparing spherical granules with a centrifugal fluidized-bed coating-granulator (CF granulator) suitable for the preparation of spherical granules with a narrow size distribution. That is, it is directed to spherical granules prepared by coating an inactive seed core consisting of an inactive material, such as nonpareils, crystalline cellulose, or crystalline vitamin C, containing no drug, with spraying powder containing a drug, such as lansoprazole, and low substituted hydroxypropylcellose. For the preparing of the spherical granules of Korean Patent Publication No. 1996-0005138 using a CF granulator, which further involves coating a surface of the inactive seed core with the drug, as compared with the process of coating a core containing an active drug, such as lansoprazole, the preparation process is more complicated and time-consuming. The CF granulator is very expensive. Korean Patent Publication No. 1996-0005138 mentions about hardness and disintegration of the spherical granules, but not effective release in the small intestine.

Korean Patent No. 10-535228 discloses hard capsules prepared by filling hard gelatin capsules with lansoprazole-containing pellets obtained by dissolving or dispersing lansoprazole in oil or fatty acid; adding the lansoprazole solution to a solution of a swollen hydrophilic polymer compound-contained solution, an emulsifying agent, and an alkalifying agent; adding additives to the solution to obtain an emulsion; injecting the emulsion into an aqueous calcium chloride solution to coat films on particles in the emulsion; freeze-drying the resulting product to produce pellets; and forming a film and an enteric coating layer on the pellet; and filling the resulting pellet in a hard gelatin capsule. However, the preparation process is unstable for the drug component, since the coating of the drug component in the solution may decompose the drug component, and the overall process is so complicated.

Korean Patent No. 10-877649 discloses tableted pharmaceutical dosage forms covered with an enteric coating, which are prepared by coating a spherical inert core consisting of, such as sacchalose, with a drug, such as lansoprazole, and an inert excipient to form an active layer, coating the active layer with an intermediate layer containing an inert excipient to obtain spherical granules, mixing the spherical granules with compression excipient to obtain a plurality of units, and enteric-coating the plurality of units. The preparation method of Korean Patent No. 10-535228 is also very complicated.

Therefore, there is a demand for a lansoprazole-containing oral formulation that is capable ofdelivering lansoprazole into the body via oral administration and has good release characteristics in the small intestine, and a simple, economical preparation process therefor.

(Patent Document 1) Korean Patent Publication No. 1996-0005138

(Patent Document 2) Korean Patent No. 10-535228

(Patent Document 3) Korean Patent No. 10-877649

The present invention provides a lansoprazole-containing oral formulation that is resistant to activity loss caused by gastric juice, has improved intestinal release characteristics, and thus ensures effective delivery of lansoprazole into the body via oral administration, and an economical, rapid method of preparing the same.

According to an aspect of the present invention, there is provided a lansoprazole-containing oral formulation comprising granules having: spherical cores containing lansoprazole as an active component and having a median value in particle size distribution of from about 90㎛ or greater to about less than 1000㎛, and in some embodiments, from about 250㎛ to about 850㎛; an intermediate layer on the spherical cores and containing a pharmaceutically acceptable inert excipient; and an enteric coating layer coating the intermediate layer. The spherical cores may be obtained by extrusion molding.

According to another aspect of the present invention, there is provided a method of preparing the lansoprazole-containing oral formulation, the method including:

a) passing a mixture of lansoprazole and a pharmaceutically acceptable excipient through an extruder having a die diameter less about 1 mm and spheronizing the resulting product using a spheronizer to obtain spherical cores having a median value in particle size distribution of from about 90㎛ or greater and to less than 1000㎛, and in some embodiments, from about 250㎛ to about 850㎛;

b) coating the spherical cores with a solution of pharmaceutically acceptable inert excipient to form an intermediate layer on the spherical cores; and

c) coating the intermediate layer with a solution of an enteric coating polymer to form an enteric coating layer on the intermediate layer.

Hereinafter, embodiments of the present invention will be described in greater detail.

1. Lansoprazole-containing oral formulations according to embodiments

According to embodiments, the lansoprazole-containing oral formulation comprising granules having: spherical cores containing lansoprazole as an active component and having a median value in particle size distribution of from about 90㎛ or greater to about less than 1000㎛, and in some embodiments, from about 250㎛ to about 850㎛, the spherical cores shaped by extrusion molding; an intermediate layer on the spherical cores and containing a pharmaceutically acceptable inert excipient; and an enteric coating layer coating the intermediate layer.

In the lansoprazole-containing oral formulation, the spherical particles containing lansoprazole as an active component may have a median value in particle size distribution within the above-described ranges, and thus lansoprazole release characteristics and bioavailability at pH 5.5 may be improved, enabling effective delivery of lansoprazole into the body via oral administration.

The spherical cores including lansoprazole as an active component may include a common pharmaceutically acceptable carrier, such as an alkalifying agent, a disintegrant, an excipient, a binder, or a surfactant. An amount of lansoprazole may be from about 0.5% to about 25% (w/w) based on a total weight of the spherical cores.

The alkalifying agent may be used to improved stability of lansoprazole in acid. Non-limiting examples of the alkalifying agent are carbonates of alkali metal or alkali earth metal, including calcium carbonate, magnesium carbonate, sodium carbonate, or sodium hydrogen carbonate; hydroxides of alkali metal or alkali earth metal, including calcium hydroxide or sodium hydroxide; and magnesium oxide. For example, magnesium carbonate may be used as the alkalifying agent.

The surfactant may improve dispersion characteristics and miscibility of lansoprazole with the alkalifying agent, and accordingly improve stability to acid and storage stability of lansoprazole. The surfactant may facilitate disintegration and improve release characteristics of lansoprazole. Non-limiting examples of the surfactant are a polyoxypropylene-polyoxyethylene copolymer (Poloxamer and derivatives thereof), a variety of polysorbates (Tweens), and reaction products of natural or hydrogenated vegetable oil with ethylene glycol(cremophor). For example, the surfactant may be Tween 80, Poloxamer 188, 237, 338, or 407.

The disintegrant may improve dispersibility of lansoprazole, and thus facilitate disintegration and improve release characteristics of lansoprazole. The disintegrant may be at least one selected from the group consisting of corn starch, microcrystalline cellulose, calcium carboxymethyl cellulose, lactose, mannitol, crospovidone, and low substituted hydroxypropyl cellulose. For example, calcium carboxymethyl cellulose may be used as the disintegrant, in view of improving disintegration and release characteristics of lansoprazole.

Non-limiting examples of the binder are hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinylalcohol, and starch. If required, other additives, for example, a glidant, such as talc or magnesium stearate, or an antioxidant may be further added.

The spherical cores may be prepared by extrusion molding for preparing spherical granules with an equipment used for extrusion molding. The spherical cores prepared through extrusion molding are hard enough to be resistant against damage during coating processes to have a reduced drug loss. Extrusion molding methods and an equipment therefor for use in preparing spherical cores are disclosed in the following documents, which are incorporated herein by reference: [1] D.C. Hicks, H.L. Freese, Extrusion and spheronizing equipment, in: I. Ghebre-Sellassie (Ed.), Pharmaceutical Pelletization Technology, Marcel Dekker, New York, 1989, pp. 71-84. [2] K.E. Fielden, J.M. Newton, Extrusion and extruders, in: J.Swarbrick, J.C. Boylan (Eds.), Encyclopaedia of Pharmaceutical Technology 5, Marcel Dekker, New York, 1992. pp. 422-431. [3] L. Baert, D. Fanara, P. De Baets, J.P. Remon, Instrumentation of a gravity feed extruder and the influence of the composition of binary and ternary mixtures on the extrusion forces, J. Pharm. Pharmacol. 43 (1991) 7455749. [4] L. Baert, D. Fanara, J.P. Remon, D. Massart, Correlation of extrusion forces, raw materials and sphere characteristics, J. Pharm. Pharmacol. 44 (1992) 6766678.[5] P.J. Harrison, J.M. Newton, R.C. Rowe, Flow defects in wet powder mass extrusion, J. Pharm. Pharmacol. 37 (1985) 81-83. [6] L. Hellen, M. Ritala, J. Yliruusi. P. Palmroos, E. Kristoffersson, Process variables of the radial screen extruder. Part I, Pharm. Tech. Int. 4 (1992) 50-60. [7] L. Hellen, J. Yliruusi, 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. [l0] 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 cores including lansoprazole as an active component may have a median value in particle size distribution of from about 90㎛ or greater to less than 1000㎛, and in some embodiments, from about 250㎛ to 850㎛, the spherical cores shaped by extrusion molding. When the median value in particle size distribution of the spherical cores is within these ranges, a dissolution rate of lansoprazole may be high at pH 5.5, and the released lansoprazole may have improved solubility, not likely to precipitate via recrystallization, and thus have high absorption rate in an upper small intestine region with oral administration. The median value in particle size distribution may be measured using sieving method well-known as a diameter measurement method of powders and granules. For example, according to a method described in the U.S. Pharmacopeia (General chapters and Assays - Physical Test and Determinations - <786> PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING), a powder sample may be sieved using a series of standard sieves, followed by weighing the remaining particles on each sieve to obtain a particle size distribution, and calculating a median value in the particle size distribution.

In the lansoprazole-containing oral formulation, the intermediate layer on the spherical cores may protect acid-unstable lansoprazole not to directly contact the enteric coating material, which is usually weakly acidic, to ensure stability of the formulation, and may induce rapid dissolution of the enteric coating material in the upper small intestine to create conditions for facilitating dissolution and absorption of the lansoprazole. The intermediate layer may include a pharmaceutically acceptable inert excipient that may be used for thin film coating. Non-limiting examples of the pharmaceutically acceptable inert excipient are starch, sugars, such as sucrose, polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, hydroxypropylcellulose, methylcellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylacetyl diethyl aminoacetate, which may be used alone or in a combination thereof. For example, the pharmaceutically acceptable inactive excipient may be a cellulose-based disintegrant, and in some embodiments, a low- substituted hydroxypropyl cellulose (L-HPC) with a degree of substitution of about 5% to 50% (w/w), for example, about 20% to 35% (w/w). A ratio of the intermediate layer to the spherical cores may be from about 5% to about 50 %(w/w). If the ratio of the intermediate layer to the spherical cores is lower than 5%, the intermediate layer may not be sufficiently separated from the enteric coating layer. If the ratio of the intermediate layer to the spherical cores is higher than 50%, the dissolution and absorption of lansoprazole may become lower. In some embodiments, the ratio of the intermediate layer to the spherical cores may be from about 5% to about 15% (w/w) based on a total weight of the spherical cores.

The intermediate layer may be coated using a solution or dispersion of an enteric coating material dissolved or dispersed in water and/or an appropriate organic solvent, and an appropriate common technology, such as pan coating, spray coating, or fluidized bed coating, to form the enteric coating layer on the intermediate layer. Non-limiting examples of the enteric coating material are hydroxypropyl methylcellulose phthalate(HPMCP), hydroxypropyl methylcellulose acetate succinate(HPMCAS), cellulose acetate phthalate (CAP), and a methacrylic acid- methacrylic acid methylester copolymer (Product name: Eudragit). Other enteric coating materials, a plasticizer, and the like may also be used. In some embodiments, the enteric coating material may be Eudragit L30D-55, or L100-55 that are dissoluble in the upper small intestine. A ratio of the enteric coating layer to the spherical cores with the intermediate layer may be from about 20% to about 200% (w/w). When the ratio of the enteric coating layer to the spherical cores with the intermediate layer is less than 20%, damage by gastric juice may not be effectively blocked. When the ratio of the enteric coating layer to the spherical cores with the intermediate layer is greater than 200%), the dissolution and absorption of lansoprazole in the upper small intestine may become lower due to incomplete dissolution of the enteric coating material.

In some embodiments, the lansoprazole-containing spherical granules described above, i.e.,, which includes: spherical cores containing lansoprazole as an active component and having a median value in particle size distribution of from about 90㎛ or greater to about less than 1000㎛, and in some embodiments, from about 250㎛ to about 850㎛; an intermediate layer on the spherical cores and containing a pharmaceutically acceptable inactive excipient; and an enteric coating layer coating the intermediate layer, may be filled in capsules or formulated as tablets for oral administration.

According to the embodiments, the lansoprazole-containing oral formulation may have improved dissolution characteristics at pH 5.5, so that absorption rate in the duodenal and upper small intestine may be significantly improved, consequently resulting in improved bioavailability and effective delivery of lansoprazole into the body via oral administration. For example, the lansoprazole-containing oral formulation may about 60% or greater of lansoprazole at pH 5.5 in 30 minutes from the beginning of a dissolution test, as measured by a paddle dissolution test described in the Korea Pharmacopeia or the USP, without a reduction in dissolution rate even after 6 hours. Meanwhile, a formulation prepared as a comparative example exhibited a relatively slow release behavior in a pH 5.5 dissolution media, as compared with the lansoprazole-containing oral formulations according to the embodiments of the present invention, and led to recrystallization and precipitation of lansoprazole over time. Furthermore, as a result of a bioavailability measurement with the lansoprazole-containing oral formulation according to the present invention, the formulation as the comparative example, and a commercially available reference formulation, the lansoprazole-containing oral formulation according to the present invention was found to have an equivalent bioavailability to the commercially available reference formulation, while the formulation as the comparative example had a lower bioavailability than the commercially available reference formulation.

According to embodiments of the present invention, the lansoprazole-containing oral formulation exhibits improved release characteristics, in particular, at pH 5.5, as described above, and accordingly have a significantly increased absorption rate at the upper small intestine, and thus have equivalent or higher bioavailability as compared with a reference formulation. This improved bioavailability of the lansoprazole-containing oral formulation is attributed to the improved dissolution and absorption of lansoprazole from the lansoprazole-containing oral formulation in the duodenal and upper small intestine having a physiological pH of about 5.5 at which, not decomposed or precipitate, lansoprazole may remain relatively stable.

2. Preparation of lansoprazole-containing oral formulation according to embodiments

According to an embodiment of the present invention, a method of preparing a lansoprazole-containing oral formulation includes:

a) passing a mixture of lansoprazole and a pharmaceutically acceptable excipent through an extruder having a die diameter less about 1 mm and spheronizing a resulting product using a spheronizer to obtain spherical cores having a median value in particle size distribution of from about 90㎛ or greater and to less than 1000㎛, and in some embodiments, from about 250㎛ to about 850㎛;

b) coating the spherical cores with a solution of pharmaceutically acceptable inactive excipient to form an intermediate layer on the spherical cores; and

c) coating the intermediate layer with a solution of an enteric coating polymer to form an enteric coating layer on the intermediate.

In particular, the mixture of lansoprazole as an active component and the a pharmaceutically acceptable excipient may be passed through an extruder having a die diameter of less than 1mm to form granules, which may then be subjected to spheronization using a spheronizer to obtain spherical cores having a median value in particle size distribution of from about 90㎛ or greater to less than 1000㎛, and in some embodiments, from about 250㎛ to about 850㎛. For example, the extruder's die diameter may be from about 0.1 mm or greater to less than 1 mm, and in some embodiments, from about 0.1 mm to about 0.9 mm, and in some other embodiments, from about 0.3 mm to about 0.8 mm, and in still other embodiments, about 0.6 mm. When the extruder's die diameter is greater than 1 mm, the spherical cores obtained through spheronization following extrusion may have a median value in particle size distribution of 1000㎛ or greater, which consequently may lead to a lower dissolution rate at pH 5.5 and poor dissolution characteristics causing precipitation of lansoprazole through recrystallization over time, so that an absorption rate of the orally administered lansoprazole in the upper small intestine may become low. When the extruder's die diameter is less than 0.1 mm, excess heat may be generated during the preparation of the spherical cores, which may deteriorate dissolution characteristics of lansoprazole from the spherical cores.

The extruder or spheronizer used in the preparation of the lansoprazole-containing oral formulation may be a common extrusion molding equipment. The intermediate layer and the enteric coating layer may be formed using any common coating technology and equipment available in the pharmaceutical preparations field.

According to an embodiment of the present invention, the method of preparing a lansoprazole-containing oral formulation involves passing the mixture through an extruder die having a constant diameter of less than 1 mm to obtain granules, and spheronizing the granules using a spheronizer to obtain spherical cores. The lansoprazole-containing oral formulation obtained using the method may be resistant to activity loss by gastric acid, and have improved, controllable release characteristics in the small intestine. Since prepared through extrusion molding, the spherical cores may be hard enough to be resistant against friction loss of drug which may happen during coating processes, and result in a high yield in the preparation. Furthermore, since the spherical cores contain an active component, multiple complicated coating processes as used in conventional methods to coat an inactive core with an active drug component may be unnecessary, so that a total weight of the final formulation prepared according to the method of the present invention may be small. In addition, the overall preparation method according to the embodiments of the present invention is simple, and lowers manufacturing coats compared to the conventional methods..

Hereinafter, one or more embodiments of the present invention will be described in detail with reference to the following examples. However, these examples are not intended to limit the purpose and scope of the one or more embodiments of the present invention.

As described above, according to the one or more embodiments of the present invention, the lansoprazole-containing oral formulation exhibits distinct improvement in dissolution characteristics at pH 5.5 with reduction or deviation of dissolution rate minimized, and improved absorption in the upper small intestine, and thus has improved bioavailability. Thus, the lansoprazole-containing oral formulation may effectively deliver lansoprazole into the body through oral administration. The preparation method takes less time, is relatively simple, and may form a final lansoprazole-containing oral formulation that is small in size and have easily controllable dissolution characteristics.

FIG. 1 is a comparative graph of particle size distribution of formulations of Example 1 and Comparative Example 1;

FIG. 2 illustrates comparative graphs illustrating dissolution behaviors of the formulations of Example 1 and Comparative Example 1 at pH 5.5, pH 6.0, and pH 6.8 mediums; and

FIG. 3 illustrates pharmacokinetic behavior in the body of the orally administered formulations of Example 1 and reference formulation.

The components of Table 1 below were mixed together in the ratio identified in Table 1, followed by adding water to the mixture to obtain a slurry, which was then passed through an extrusion granulator (Fuji Paudal Co.Ltd., die diameter; 0.6 mm), and immediately shaped using a spheronizer to obtain spherical cores. The spherical cores were dried using a high-speed dryer at about 45℃ to a weight loss of about 3.0% or less by drying (at 105℃, for 20 minutes). A median value of the particle size distribution of the spherical cores were about 500㎛ (measured using a method described in the U.S. Pharmacopeia (USP) - General chapters and Assays - Physical Test and Determinations - <786> PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING).

Table 1

After the obtained spherical cores were put in a fluidized-bed coater, a solution with the composition of Table 2 below at about 40℃ was sprayed at a rate of 50 ml/min while supplying 65℃-air to form an intermediate layer on the spherical cores.

Table 2

After the spherical cores with the intermediate layer were put in a fluidized-bed coater, a solution with the composition of Table 3 below at about 30℃ was sprayed at a rate of 50 ml/min while supplying 65℃-air, to form an enteric coating layer.

Table 3

0.5 mg of talc and 0.5 mg of light anhydrous silicic acid were added to 297 mg of the granules with the enteric coating layer prepared above to obtain a mixture, which was then filled in hard capsules in 298 mg per capsule using a capsule filling machine to prepare capsules.

The components of Table 1 below were mixed together in the ratio identified in Table 4 below, followed by adding water to the mixture to obtain a slurry, which was then passed through an extrusion granulator (Fuji Paudal Co.Ltd., die size; 0.8 mm), and immediately shaped using a spheronizer to obtain spherical cores. The spherical cores were dried using a high-speed dryer at about 45℃ to a weight loss of about 3.0% or less by drying (at 105℃, for 20 minutes). A median value of the particle size distribution of the spherical cores were about 850㎛ (measured using a method described in the U.S. Pharmacopeia (USP) - General chapters and Assays - Physical Test and Determinations - <786> PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING).

Table 4

After the obtained spherical cores were put in a fluidized-bed coater, a solution with the composition of Table 5 below at about 40℃ was sprayed at a rate of 50 ml/min while supplying 65℃-air to form an intermediate layer on the spherical cores.

Table 5

After the spherical cores with the intermediate layer were put in a fluidized-bed coater, a solution with the composition of Table 6 below at about 30℃ was sprayed at a rate of 50 ml/min while supplying 65℃-air, to form an enteric coating layer.

Table 6

0.5 mg of talc, and 0.5 mg of light anhydrous silicic acid were added to 297 mg of the granules with the enteric coating layer prepared above to obtain a mixture, which was then filled in hard capsules in 298 mg per capsule using a capsule filling machine to prepare capsules.

The components of Table 7 below were mixed together in the ratio identified in Table 7 below, followed by adding water to the mixture to obtain a slurry, which was then passed through an extrusion granulator (Fuji Paudal Co.Ltd., die size; 0.3 mm), and immediately shaped using a spheronizer to obtain spherical cores. The spherical cores were dried using a high-speed dryer at about 45℃ to a weight loss of about 3.0% or less by drying (at 105℃, for 20 minutes). A median value of the particle size distribution of the spherical cores were about 250㎛ (measured using a method described in the U.S. Pharmacopeia (USP) - General chapters and Assays - Physical Test and Determinations - <786> PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING).

Table 7

After the obtained spherical cores were put in a fluidized-bed coater, a solution with the composition of Table 8 below at about 40℃ was sprayed at a rate of 50 ml/min while supplying 65℃-air to form an intermediate layer on the spherical cores.

Table 8

After the spherical cores with the intermediate layer were put in a fluidized-bed coater, a solution with the composition of Table 9 below at about 30℃ was sprayed at a rate of 50 ml/min while supplying 65℃-air, to form an enteric coating layer.

Table 9

1.0 mg of talc and 0.5 mg of light anhydrous silicic acid were added to 319.00 mg of the granules with the enteric coating layer prepared above to obtain a mixture, which was then filled in hard capsules in 298 mg per capsule using a capsule filling machine to prepare capsules.

< Comparative Example 1 >

Spherical cores were prepared, followed by being coated with an intermediate layer and an enteric coating layer, and filled in capsules, in the same manner as in Example 1, except that an extrusion granulator with a die size of about 1 mm was used. A median value of the particle size distribution of the spherical cores were about 1,000㎛. The particle sizes of the spherical cores of Comparative Example 1 were measured in the same manner as in the above-described example using a method described in the U.S. Pharmacopeia (USP) - General chapters and Assays - Physical Test and Determinations - <786> PARTICLE SIZE DISTRIBUTION ESTIMATION BY ANALYTICAL SIEVING. The results are shown in FIG. 1 for comparison with Example 1.

< Reference Example 1>

A lansoprazole oral formulation (commercially available with the trademark of Lanston, JEIL PHARMACEUTICAL CO., LTD, KOREA) as a stomach ulcer treatment drug containing lansoprazole as a main component was used as a reference formulation in the following experimental examples.

< Experimental Example 1>

A dissolution pattern of the formulation of Example 1 with respect to pH was observed relative to the formulation of Comparative Example 1.

The formulations of Example 1 and Comparative Example 1 were subjected to a comparative dissolution rate test of the pharmaceutical equivalence test management regulations by Korea Food & Drug Administration (KFDA). in particular, a pH 5.5 acetate buffer from the USP, and pH 6.0 and pH 6.8 phosphate buffers from the KDFA's pharmaceutical equivalence test management regulations were used as dissolution media. Each formulation was dissolved in the dissolution medium at about 50 rpm for about 6 hours. An amount of each of the resulting dissolution solutions was filtered and then analyzed using UV at about 286 nm to measure an amount of dissolved lansoprazole. The results are shown in FIG. 2.

Referring to FIG. 2, the formulation of Example 1 was found to dissolve about 70% or greater lansoprazole at pH 5.5 within 30 minutes, while the formulation of Comparative Example 1 dissolved only about 50% of lansoprazole in the same condition. The formulation of Example 1 dissolved about 80% of lansoprazole even after 6 hours, indicating stable dissolution at pH 5.5, while the dissolution rate of lansoprazole from the formulation of Comparative Example 1 was reduced after 1 hour, indicating unstable dissolution at pH 5.5. This unstable dissolution of lansoprazole is attributed to recrystallization and precipitation of the dissolved lansoprazole. Intestinal behaviors of the formulation of Example 1 and Comparative Example 1 were similar to each other at pH 6.0 and pH 6.8 at which intestinal behaviors of general enteric formulations are evaluated. The formulation of Example1 was found to have distinct dissolution behaviors at pH 5.5.

< Experimental Example 2>

The formulations of Examples 1, 2, and 3, Comparative Example 1, and Reference Example 1 were subjected to a comparative dissolution rate test of the pharmaceutical equivalence test management regulations by Korea Food & Drug Administration (KFDA). To identify solubility in duodenal and upper intestinal conditions, a pH 5.5 acetate buffer according to the USP was used as a dissolution medium. Each formulation was dissolved in the dissolution medium at about 50 rpm. An amount of the resulting dissolution solution was filtered and then analyzed using UV at about 285 nm to measure an amount of dissolved lansoprazole. The results are shown in Table 10 below.

Referring to Table 10, the formulations of Examples 1, 2, and 3 were found to dissolve about 60% or greater of lansoprazole at pH 5.5 within 30 minutes from the beginning of the dissolution test, while the formulation of Comparative Example 1 dissolved only about less than 50% of lansoprazole.

Table 10

Referring to Table 10, the formulations of Examples 1, 2, and 3 were found to dissolve about 60% or greater of lansoprazole at pH 5.5 within 30 minutes from the beginning of the dissolution test, indicating a significant improvement in dissolution characteristics of lansoprazole known be poorly soluble in the acid condition, as compared with the formulation of Reference Example 1 as a commercial formulation that require expensive equipment for preparation.

< Experimental Example 3>

To identify bioavailability of the formulations of Example 1 and Comparative Example 1, a biological equivalence test was performed with the formulation of Reference Example 1. The bioavailability of each of the formulations of Example 1 and Comparative Example 1 was measured as an average from six samples for each formulation. The bioequivalence test was performed on healthy adult volunteers in 2X2 crossover design, according to the bioequivalence test guidelines (KFDA Notification No. 2009-184) by KFDA. The concentration of lansoprazole in blood of each subject was measured to plot a blood concentration versus time curve. Bioavailability parameters, including the area under the curve (AUC) of blood concentration versus time curve and a maximum concentration in blood (Cmax), were statistically considered to evaluate the bioequivalence of the formulation of Example 1 and the formulation of Comparative Example 1 to the formulation of Reference Example 1. The results are shown in Table 11 and FIG. 3.

Table 11

According to the bioequivalence standard by KFDA, when AUC and Cmax as parameters for estimating bioavailability are log-transformed and statistically processed, difference of log-transformed mean values between a test formulation and a reference formulation, should be each from log 0.8 to log 1.25, at a 90% confidence interval. Referring to Table 11 and FIG. 4, AUC and Cmax of the formulation of Example 1 to those of the reference formulation were found to be from log 0.9501 to log 1.1521, and be from log 0.8773 to log 1.1259, respectively, indicating as having equivalent bioavailability as the reference formulation. Meanwhile, Cmax of the formulation of Comparative Example 1 to those of the reference formulation was found to be from log 0.7297 to log 1.0755, which is out of the standard, indicating as having lower bioavailability than the reference formulation.

As is understood from the above results, according to the one or more embodiments of the present invention, the lansoprazole-containing oral formulation exhibits distinct improvement in release characteristics at pH 5.5 with reduction or deviation of dissolution rate minimized, and improved absorption in the upper small intestine, and thus has improved bioavailability. Thus, the lansoprazole-containing oral formulation may effectively deliver lansoprazole into the body through oral administration.

Claims

A lansoprazole-containing oral formulation comprising granules having spherical cores containing lansoprazole as an active component and having a median value in particle size distribution of from about 90㎛ or greater to about less than 1000㎛; an intermediate layer on the spherical cores and containing a pharmaceutically acceptable inert excipient; and an enteric coating layer coating the intermediate layer.
The lansoprazole-containing oral formulation of claim 1, wherein the median value in particle size distribution of the spherical cores is from about 250㎛ to about 850㎛.
The lansoprazole-containing oral formulation of claim 1 or 2, wherein the spherical cores are obtained by extrusion molding.
The lansoprazole-containing oral formulation of claim 1, wherein the spherical cores each comprises about 0.5% to about 25%(w/w) of lansoprazole.
The lansoprazole-containing oral formulation of claim 1, wherein the spherical core further comprises calcium carboxymethyl cellulose as excipient.
The lansoprazole-containing oral formulation of claim 1, wherein the pharmaceutically acceptable inert excipient in the intermediate layer is from about 20% to about 35% (w/w) of low-substituted hydroxypropyl cellulose.
The lansoprazole-containing oral formulation of claim 1, wherein a ratio of the intermediate layer to spherical cores is from about 5% to about 50% (w/w).
The lansoprazole-containing oral formulation of claim 1, wherein the enteric coating layer is formed of at least one enteric polymer selected from the group consisting of hydroxymethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), and a methacrylic acid and methacrylic acid methyl ester copolymer.
The lansoprazole-containing oral formulation of claim 8, wherein the enteric coating layer is formed of a methacrylic acid and methacrylic acid methyl ester copolymer.
The lansoprazole-containing oral formulation of claim 1, wherein a ratio of the enteric coating layer to the spherical cores with intermediate layer is from about 20% to about 200% (w/w).
The lansoprazole-containing oral formulation of claim 1, wherein about 60% or greater of the lansoprazole is dissoluble at pH 5.5 dissolution medium within about 30 minutes as measured by dissolution test with the paddle method according to the Korea Pharmacopeia.
A method of preparing a lansoprazole-containing oral formulation, the method comprising:

a) passing a mixture of lansoprazole and a pharmaceutically acceptable excipent through an extruder having a die diameter less about 1 mm and spheronizing the resulting product using a spheronizer to obtain spherical cores having a median value in particle size distribution of from about 90㎛ or greater and to less than 1000㎛;

b) coating the spherical cores with a solution of pharmaceutically acceptable inert excipient to form an intermediate layer on the spherical cores; and

c) coating the intermediate layer with a solution of an enteric coating polymer to form an enteric coating layer on the intermediate layer.
The method of claim 12, wherein the extruder has a die diameter of from about 0.1 mm or greater to less than 1 mm.
The method of claim 12, wherein the extruder has a die diameter of from about 0.3 mm or greater to about 0.8 mm.