CONTROLLED RELEASE FORMULATION COMPRISING
BENZIMIDAZOLE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF WITH INCREASED STABILITY AND METHOD FOR PREPARING THE SAME
Technical Field
The present invention relates to a controlled release formulation with increased stability comprising benzimidazole derivatives or pharmaceutically acceptable salts thereof as active ingredients, and a method for preparing the same.
Background Art
Benzimidazole derivatives are H+, K+-ATPase inhibitors and exhibit antiulcerogenic activity. Examples of the benzimidazole derivatives include lansoprazole (2-[[[3-methyl-4(2,2,2-trifluoroethoxy)-2- pyridyl]methyl]sulfinyl]benzimidazole) and currently used omeprazole (5-methoxy-3,5- dimethyl-2-pyridinyl)methyl)sulfinyl)-lH-benzimidazole), etc. These compounds are used to treat gastric and duodenal ulcer. The benzimidazole derivatives such as lansoprazole, omeprazole, etc., exhibit low water solubility, but very high solubility in aqueous alkaline solutions with ions bearing negative charges. The benzimidazole derivatives are unstable in aqueous solutions, and in particular more unstable as the pH decreases.
Accordingly, in order to prevent the benzimidazole derivatives from coming into contact with gastric acid, it is required to coat the benzimidazole derivatives with an enteric coating material, etc., during formulation of the benzimidazole derivatives.
Since conventional enteric coating materials, however, are acidic, there still exist the
above-mentioned problem. To solve this problem, an alkaline material is inserted into a central core to increase pH, or a neutral or alkaline coating process is first carried out, followed by enteric coating process.
For example, Losec™ (Astra Pharma. Inc.) is prepared by a method comprising introducing an inorganic alkalizing agent as a stabilizer to form a core, coating the core with a water soluble subcoating layer, and forming an enteric coating on the subcoating layer. However, the method requires high accuracy in the coating processes to stabilize active ingredients therein. Further, since a large amount of sodium is used,' the method is unsuitable for patients such as hypertensives, who are allowed limited in dietary sodium intakes. Furthermore, since the alkalizing agent may damage the enteric coating, there is a problem of inadequate long-term stability.
Korean Patent Publication Nos. 91-4579 and 87-1005 disclose a salt such as NaHPO4 as an alkalizing agent. According to both patents, since anions damaging to the stability of active ingredients are supplied together with the alkalizing agent, the stability of active ingredients may be deteriorated.
In order to solve the above-mentioned problems of conventional controlled release formulations, the present inventor has conducted intensive research to develop a novel formulation which can stabilize active ingredients uniformly contained therein and completely release the active ingredients, and as a result, accomplished the present invention.
Disclosure of the Invention
Therefore, it is an object of the present invention is to provide a formulation for oral administration which is stable even in aqueous and acidic environments, greatly decreases loss of active ingredients occurring during preparation of the formulation, and has uniform content of active ingredients therein.
It is another object of the present invention is to provide a method for preparing the formulation for oral administration.
In accordance with one aspect of the present invention, there is provided a controlled release formulation with increased stability, comprising: a pellet including a benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a cationic polymer; and at least one coating layer selected from an intermediate coating layer, a moisture-resistant coating layer and an enteric coating layer as an outer layer surrounding the pellet. In accordance with another aspect of the present invention, there is provided a method for preparing a controlled release formulation with increased stability, comprising the steps of: extruding a blend of a benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient and a cationic polymer to form a filament; molding the filament into a pellet; and forming at least one coating layer selected from an intermediate coating layer, a moisture-resistant coating layer and an enteric coating layer as an outer layer surrounding the pellet.
The active ingredient includes benzimidazole derivatives and pharmaceutically acceptable salts thereof. These compounds function as proton pump inhibitors and their effects are highly pH-dependent. Examples of the benzimidazole-based compounds include those called generic names such as lansoprazole, omeprazole, pantoprazole, rabeprazole, etc.
The term 'blend' as used herein refers to a composition prior to molding into a pellet, and the blend may be a mixture including various auxiliary ingredients so as to have an appropriate strength and ductility suitable for extrusion into a filament. The strength and ductility suitable for extrusion into a filament are specifically obtained from
experimental and empirical approaches. For example, when extruding the blend at an extrusion force of 1000-4000N, the cohesive force of the blend is preferably 3.0-45N.
The cationic polymer included in the blend is adsorbed to -SO groups, which promote the degradation of the benzimidazole-based compounds in aqueous environments, thereby electrostatically stabilizing the active ingredient. Further, the cationic polymer functions as a structural barrier to electrostatically stabilize the active ingredient in acidic environments.
As the cationic polymer, at least one polymer selected from water-soluble chitosan, oligochitosan, glucosamine and cationic polysaccharides may be used. Other ingredients which can be included in the blend include alkalizing agents, surfactants, excipients, etc.
The alkalizing agents can be added in an effective amount to maintain optimum pH required for the stability of the active ingredient. Since the active ingredient is unstable in acid environments, the use of the alkalizing agent is limited when the environment is neutral or alkaline. The alkalizing agent is selected from the group consisting of magnesium oxide, sodium hydrogen phosphate, potassium hydrogen phosphate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, aluminum phosphate, calcium phosphate, sodium phosphate, potassium phosphate, aluminum citrate, calcium citrate, sodium citrate, potassium citrate, arginine, lysine, histidine, eglumine, meglumine and mixtures thereof.
So long as the surfactant is pharmaceutically acceptable and serves to dissolve and elute the active ingredient, any compounds may be used as the surfactant. Examples of the surfactant include ionic and non-ionic surfactants, e.g., sodium lauryl sulfate, Polysolvates, triethanolamine stearate, alkyl sulfonic acid salts, alkylaryl sulfonic acid salts, sorbitan esters, Pluronics, etc. The amount of the surfactant added
varies according to the elution conditions of the active ingredient, but preferably is within the range of from 0.5 to 100% by weight, based on the weight of the active ingredient.
Examples of the excipient usable for the formation of the blend in the present invention include microcrystalline cellulose, cellulose powder, low-substituted hydroxypropyl cellulose, cellulose acetate, sodium crosscarmellose, calcium phosphate, calcium sulfate, corn starch, lactose, mannitol, sorbitol, polyvinyl pyrrolidone, talc, dextrate, dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, hydroxypropylmethyl cellulose, ethyl cellulose, gelatin, guar gum, xanthan gum, acrylic polymers and copolymers, and mixtures thereof.
Brief Description of the Drawings
The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
Fig. 1 is a schematic diagram showing a structure of an extrusion molder used in Examples of the present invention;
Fig. 2a is a perspective view showing a pelletizer usable in the present invention;
Fig. 2b is a left side view showing a pelletizer usable in the present invention; Fig. 2c is a cross-sectional view of Fig. 2b, taken along line A-A; Fig. 3 is a graph showing the amounts of active ingredients contained in controlled release formulations according to various Examples of the present invention; and
Fig. 4 is a graph showing the results of an elution test on a formulation according to the present invention.
Best Mode for Carrying Out the Invention
Hereinafter, a process for preparing a blend and a molding process into a pellet will be explained in more detail with reference to the accompanying drawings. First, an active ingredient, an alkalizing agent, a surfactant, etc., are suspended in an appropriate solvent, preferably water, ethanol or a mixture thereof. A solution of a cationic polymer is mixed with the suspension, and then an excipient is added to the mixture to prepare a blend having a desired strength and ductility.
Fig. 1 is a schematic diagram showing a structure of an extrusion molder used in Examples of the present invention.
An extrusion molding process is carried out by a hydraulic extrusion molder 1.
The hydraulic extrusion molder 1 has a plurality of holes 2 having a constant inner diameter and formed at the bottom of the extrusion molder 1. A blend having an appropriate strength and ductility is added to the extrusion molder 1 to form long- cylindrical filaments.
Figs. 2a and 2b are a perspective view and a left side view showing a pelletizer usable in the present invention, respectively. Fig. 2c is a cross-sectional view of Fig. 2b, taken along line A-A.
The pelletizer has a pair of molding rollers (upper and lower molding rollers) 4 and 5 for molding the filaments into circular rings (pellets). The respective molding rollers have a plurality of semicircular grooves 6 having a constant inner diameter and formed perpendicularly to rotation axes of the molding rollers, along the surface of the molding rollers. A plurality of protrusions 7 for cutting an extruded material are serially formed between the respective semicircular grooves 6. The upper and lower molding rollers 4 and 5 rotate in a counter direction so that the semicircular grooves formed on the upper molding roller 4 are adapted to contact with those formed on the lower molding roller 5, and the protrusions formed on the upper molding roller 4 are
adapted to contact with those formed on the lower molding roller 5. The long- cylindrical filament 3 is placed at the contact surface between the molding rollers 4 and 5 in a direction parallel to the rotation axes of the molding rollers. The long-cylindrical filament is rotated by the molding rollers rotating at different rates, cut by the protrusions 7 formed on the molding rollers, and compressed by the semicircular grooves to mold into rings having a constant inner diameter.
The size of the molded pellets is determined by controlling the inner diameter of the plurality of holes 2 formed at the bottom of the extrusion molder or the size of the semicircular grooves 6 between the protrusions formed on the molding rollers of the pelletizer.
In the present invention, the final size of the pellet is preferably in the range of about l~5mm, and more preferably about 1.5~2.5mm.
At least one coating layer selected from an intermediate coating layer, a moisture-resistant coating layer and an enteric coating layer is formed on the pellet. As a material capable of forming the coating layer, methylcellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, polyoxyethyleneglycolcellulose, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, celluloseacetate phthalate, chitosan, alginic acid, galactomannose, tragant, shellac, agar, arabic gum, guar gum, xanthan gum, polyacrylic copolymer, methacrylic copolymer, polyvinylacetate phthalate, polyethylene oxide, polypropylene oxide, other enteric film-forming polymers known in the art or a mixture thereof may be used, but is not particularly limited to these compounds.
The coating layer-forming material is dissolved or diluted in an organic solvent such as an alcohol, acetone and methylene chloride, or a mixed solvent with water, but the solvent usable in the present invention is not particularly limited thereto. The amount of the material added depends on the viscosity of solution, but is commonly within 1.5-30% by weight.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are given for the purpose of illustration and are not to be construed as limiting the scope of the invention.
<Examples 1 and 2>
Water-soluble chitosan (average molecular weight: 200,000), polymerized from glucosamine bearing positive charges, was dissolved in an appropriate amount of distilled water (molar equivalent amount corresponding to 30mg of lansoprazole), and the resulting solution was added to an aqueous solution of lansoprazole, SLS (surfactant) and sodium hydrogen phosphate (Na2HPO4) (alkalizing agent), in accordance with amounts of the respective ingredients shown in Table 1 below. At this time, the chitosan electrostatically stabilizes lansoprazole bearing negative charges, thereby exhibiting an excellent stability of the lansoprazole in aqueous solutions. Thereafter, the solution thus obtained was subjected to sonication for an adequate time. Microcrystalline cellulose (Avicel PHI 02), low-substituted hydroxypropyl cellulose (L-HPC) and mannitol were mixed with each other, in accordance with amounts of the respective ingredients shown in Table 1 below, and then the mixture was blended with the first solution to obtain blends.
The respective blends thus obtained were charged into an extrusion molder having a plurality of holes (inner diameter: 2.00mm), and molded into long-cylindrical filaments. The filaments were molded into pellets using a pelletizer. The pellets were dried in a cool and ventilating shady place for 1-2 days. After drying, the pellets were coated with a coating solution containing 4% by weight of hydroxypropylmethylcellulose (HPMC) dissolved in distilled water in a coating pan, and then coated with a coating solution containing 12% by weight of hydroxypropylmethylcellulose phthalate (HPMCP) dissolved in a mixture of acetone, ethanol and cetyl alcohol to form an enteric coating layer on the pellets.
Table 1
<Examples 3~8>
Blends were obtained in the same manner as in Examples 1 and 2, except that the amounts of water-soluble chitosan (average molecular weight: ≤ 200,000 and ≤ 10,000) for promoting disintegration of a pellet containing lansoprazole, crosscarmellose (Ac-di-sol) as an excipient, microcrystalline cellulose (Avecel PHI 02),
low-substituted hydroxypropylcellulose (L-HPC) and mannitol were changed to those shown in Table 1.
The blends thus obtained were charged into an extrusion molder having a plurality of holes (inner diameter: 2.00mm), and molded into long-cylindrical filaments. The filaments were molded into pellets using a pelletizer. The pellets were dried in a cool and ventilating shady place for 1-2 days. After drying, the pellets were coated with a coating solution containing 4% by weight of hydroxypropylmethylcellulose (HPMC) dissolved in distilled water in a coating pan, and then coated with a coating solution containing 12% by weight of hydroxypropylmethylcellulose phthalate (HPMCP) dissolved in a mixture of acetone, ethanol and cetyl alcohol to form an enteric coating layer on the pellets.
Table 2
<Examples 9~12> lOmg of chitosan (average molecular weight ≤ 10,000) was dissolved in distilled water, and the resulting solution was added to a suspension of lansoprazole, Poloxamer F127 (surfactant) and meglumine (alkalizing agent) in distilled water, in
accordance with amounts of the respective ingredients shown in Table 3 below. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L-HPC) and mannitol as excipients were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same manner as in Examples 1-2.
Table 3
<Examples 13~14> lOmg of chitosan (average molecular weight ≤ 10,000) was dissolved in distilled water, and the resulting solution was added to a suspension of lansoprazole, Poloxamer F127 (surfactant) and meglumine (alkalizing agent) in distilled water, in accordance with amounts of the respective ingredients shown in Table 4 below. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L-HPC)
and mannitol as excipients were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same manner as in Examples 1-2.
Table 4
<Examples 15~16> lOmg of chitosan (average molecular weight ≤ 10,000) was dissolved in distilled water, and the resulting solution was added to a suspension of lansoprazole, Poloxamer F127 (surfactant) and meglumine (alkalizing agent) in distilled water, in accordance with amounts of the respective ingredients shown in Table 5 below. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L-HPC)
and mannitol as excipients were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same mamier as in Examples 1~2.
Table 5
<Examples 17~19> lOmg of chitosan (average molecular weight ≤ 10,000) was dissolved in distilled water, and the resulting solution was added to a suspension of lansoprazole, Poloxamer F127 (surfactant) and meglumine (alkalizing agent) in distilled water, in accordance with amounts of the respective ingredients shown in Table 6 below. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L-HPC)
and mannitol as excipients were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same manner as in Examples 1-2.
In Example 19, lOmg of chitosan (average molecular weight ≤ 10,000) was dissolved in distilled water, and the resulting solution was added to a suspension of Poloxamer F127 (surfactant) and meglumine (alkalizing agent) in distilled water. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L- HPC) and mannitol as excipients were added to obtain a blend.
The blend thus obtained was molded into pellets, and then the pellets were coated in the same manner as in Examples 1-2. Table 6
<Examρles 20~22> lOmg of chitosan (average molecular weight ≤ 10,000) was dissolved in distilled water, and the resulting solution was added to a suspension of lansoprazole, Poloxamer F127 (surfactant) and meglumine (alkalizing agent) in distilled water, in accordance with amounts of the respective ingredients shown in Table 7 below. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L-HPC) and mannitol as excipients were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same mamier as in Examples 1-2.
Table 7
<Examples 23~25>
30mg of lansoprazole, 2mg of Poloxama F127 and 24mg of meglumine were dissolved in a mixed solvent of distilled water and ethanol (1:1), and then the resulting solution was added to a solution of glucosamine in an appropriate amount of distilled water, in accordance with amounts of the respective ingredients shown in Table 8 below. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L-
HPC) and mannitol as excipients were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same manner as in Examples 1-2.
Table 8
<Examples 26-28>
30mg of lansoprazole, Poloxama F127 and meglumine were dissolved in a mixed solvent of distilled water and ethanol (1:1), in accordance with amounts of the respective ingredients shown in Table 9 below, and then the resulting solution was added to a solution containing 14mg of oligochitosan. To the mixture, crosscarmellose (Ac- di-sol), low-substituted hydroxypropylcellulose (L-HPC) and mannitol as excipients
were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same mamier as in Examples 1-2.
Table 9
<Examples 29~31>
30mg of lansoprazole, Poloxama F127 and meglumine were dissolved in a mixed solvent of distilled water and ethanol (1:1), and then the resulting solution was added to solutions containing different amounts of oligochitosan, in accordance with amounts of the respective ingredients shown in Table 10 below. To the mixture, crosscarmellose (Ac-di-sol), low-substituted hydroxypropylcellulose (L-HPC) and
mannitol as excipients were added to obtain blends.
The blends thus obtained were molded into pellets, and then the pellets were coated in the same manner as in Examples 1-2.
Table 10
Experimental Example 1> Measurement of Contents
20 capsules (corresponding to 0.6g of lansoprazole) of the pellets obtained from the above Examples were precisely weighed, and then mixed. Next, an amount corresponding to 30mg of lansoprazole was precisely separated from the mixture. 25mL of 0.25mol/L sodium hydroxide was added to the above separated mixture, and sonicated with shaking to dissolve them. 25.0mL of ethanol and about 150mL of
0.235mol/L sodium hydrogen phosphate were added thereto, and then subjected to sonication. 0.235mol/L sodium hydrogen phosphate was further added to the solution until the total volume was 250mL, and then filtered. 25.0mL of the filtrate was transferred to a lOOmL volumetric flask. 0.235mol/L sodium hydrogen phosphate was added to the flask until the total volume was 100ml, and then filtered. The filtrate was used as a sample solution.
Separately, 25mL of 0.25mol/L sodium hydroxide, 25.0mL of ethanol and about 150mL of 0.235mol/L sodium hydrogen phosphate were added to 30mg of a lansoprazole standard product, and then the resulting solution was subjected to sonication. 0.235mol/L sodium hydrogen phosphate was added thereto until the total volume was 250ml, and then filtered. 25mL of the filtrate was placed in a lOOmL volumetric flask, and 0.235mol/L sodium hydrogen phosphate was added thereto until the total volume was 100ml, and then filtered. The filtrate was used as a standard solution. 20μl of the test solution and 20μl of the standard solution were tested in accordance with the standard test method for liquid chromatography of the Korea Pharmacopedia under the following operating conditions.
[Operating conditions] Column: stainless steel column (inner diameter: 4.6mm, length: 15cm) filled with octadecylsilylated silica gel (particle size: 5 m)
Detector: UV absorbance spectrometer (wavelength: 270nm) Mobile phase: acetonitrile/O.lM KH2PO4 = 40/60 Flow rate: 1.0 mL/min, First, peak areas of lansoprazole (Ar and As) were obtained, and then the amounts of lansoprazole contained in pellets were calculated by the following equation: The amount of lansoprazole (mg)
= the amount of the lansoprazole standard product (mg) x (— '-)
4 in which At is a peak area of the sample obtained in Example, and As is a peak area of the standard product.
The results are shown in Fig. 3.
Experimental Example 2> Elution Experiment
A pellet containing 30mg of lansoprazole was precisely weighed. Elution test on the pellet was carried out using 900mL of an eluent containing a phosphate buffer (pH 6.8, Pharmacopedia) and 1% (w/v) Polysolvate 80 (Tween80) at lOOrpm for 30 minutes, in accordance with the second standard test method for elution of the Korea Pharmacopedia. lOmL of the eleunt was separated and then filtered. l.OmL of 0.25mol/L sodium hydroxide solution was added to 5.0mL of the filtrate. The resulting mixture was homogeneously mixed, and used as a sample solution.
Separately, 30mg of a lansoprazole standard product was precisely weighed, and dissolved in lO.OmL of ethanol. The eluent was added thereto until the total volume was lOOmL. 5.0mL of the resulting solution was separated. The eluent was further added thereto until the total volume was 50mL, and filtered. l.OmL of 0.25mol/L sodium hydroxide solution was added to 5.0mL of the filtrate. The resulting mixture was homogeneously mixed, and used as a sample solution. Elution efficiency of lansoprazole (C16H14F3N3O2S) per one pellet (%)
= At Ws 900 c As Wt 1000 in which Ws represents the amount of the lansoprazole standard product (mg), Wt represents the amount of lansoprazole contained in one pellet of sample (mg), and C represents the content of lansoprazole in the standard product (%).
As a result, it was observed that almost all effective ingredients were eluted.
Experimental Example 3> Stability test
After the pellets containing chitosan obtained in Example 31 were stored at various temperatures (25 °C , 37 °C, 50 °C) and relative humidities (66%, 0%) for 1 month, respectively, the contents of lansoprazole in the pellets were determined by high performance liquid chromatography. The results are shown in Table 11 below.
<Table ll>
As can be seen from Table 11, the formulation according to the present invention exhibits high stability even under severe conditions. Further, when the formulation according to the present invention was stored at a relatively low humidity, the stability was greatly increased. Accordingly, storing or circulating the formulation containing effective ingredients at room temperature, e.g., through PTP wrapping, prior to using the formulation in various industrial applications greatly contributes to the stability of the effective ingredients.
Industrial Applicability
As described above, the formulation according to the present invention electrostatically stabilizes benzimidazole derivatives or pharmaceutically acceptable
salts thereof, and thus exhibits excellent resistance to acidic and aqueous environments.
In addition, the method for preparing the formulation according to the present invention greatly decreases loss of active ingredients occurring during preparation of the formulation, and facilitates the preparation of formulation having uniform content of active ingredients.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.