KR20110029250A - Pharmaceutical composition containing proton pump inhibitor - Google Patents

Abstract

PURPOSE: A coated fine particle is provided to ensure acetic acid stability and to prevent reduction bioavailability based on gastric pH concentration. CONSTITUTION: A pharmaceutical composition contains omeprazol, lansoprazole, and alkaline salt thereof as a proton pump inhibitor or as an active ingredient. The pharmaceutical composition comprise: a sustained release layer and a pH-independent polymer which controls sustained release layer; an immediate release layer; and a polymeric enteric coating film.

Description

Pharmaceutical composition containing proton pump inhibitor

The present invention includes proton pump inhibitors (PPIs) such as benzimidazole compounds (e.g., lansoprazole, omeprazole, rabeprazole, pantoprazole, ilaprazole, etc.), ie, H +, K + -ATPase inhibitors. It relates to a new oral pharmaceutical composition.

PPI drugs have been widely used as a therapeutic agent for peptic ulcer because they have gastric acid secretion-inhibitory action, gastric acid mucosa-protective action, and the like.

However, these compounds have low stability and are unstable in humidity, temperature, light, acid and the like. Such compounds are particularly labile to acids, and the lower the pH of their aqueous solutions or suspensions, the more unstable they become. Therefore, when orally administered, these compounds may be degraded by gastric acid or the like, and thus may not be able to exhibit sufficient activity.

The present invention is a multi-layered drug release system prepared to secure stability against gastric acid after oral administration and to release rapid PPI drug from the upper duodenum to prompt release of the drug and at the same time to release the drug of PPI drug to sustained release. A pharmaceutical composition is designed for two or more different rates of drug release.

In formulations such as tablets, powders, microgranules, capsules and the like, the stability of these compounds may be lower than the stability of the compounds themselves due to the strong interaction with other components in the formulation. As a result, color change and degradation can be observed during manufacture and storage.

In pharmaceutical formulations containing such compounds as active ingredients, various attempts have been made to overcome the instability of the compounds. For example, tablets, granules or microgranules or salts thereof or their optically active forms containing core particles containing PPI as the active ingredient and in particular their release control films (enteric films) have been disclosed. Because of the enteric film, such preparations can prevent degradation of the active ingredient by gastric acid or the like.

On the other hand, PPI-based drugs are generally reported to have a significant effect on the bioavailability of oral administration according to the pH in the stomach depending on food or drug intake. In order to have less influence on the absorption rate of intragastric pH, a method of increasing the bioavailability by adjusting the release rate of the drug may be introduced.

Therefore, the present invention is to release the drug in the PPI properties oral administration to the stomach acid and to reduce the bioavailability according to the pH in the stomach is less than 85% within 30 minutes at the top of the duodenum or drug release for 12 hours Particles or tablets coated with a polymer that forms a drug release control film on the surface of the fine particles or tablets (Sustained release (SR)) as a core to form enteric skin to secure stability against gastric acid, or drugs The microparticles or tablets (sustained release) coated with a polymer that forms a drug release control film on the surface of the fine particles or tablets are slowly formed at the upper and lower portions of the duodenum at 85% or less within 30 minutes. Release the drug layer, which releases the drug rapidly (immediate release; IR). And / or a multiple drug delivery system prepared by producing a particulate having the characteristics of a multiple drug delivery system (MDDS) prepared by continuously coating and forming the same. It is to provide a protective coated fine particles to ensure the stability against gastric acid as a film forming enteric skin on the fine particles of MDDS).

PPI drugs according to the present invention are omeprazole and lansoprazole, its alkali salts, one of its single enantiomers or one of its enantiomers. The PPI drug contained in the sustained release drug layer may be the same or different drug as the PPI drug contained in the fast-release drug layer coated on the outer layer.

PPI, the active ingredient in the sustained-release portion, was used as a test solution for phosphate buffer solution of pH6.8 in the test method for enteric preparation in the dissolution test method of the Korean Pharmacopoeia. Elution rate of 85% or less is suitable for the sustained release regulations. Preferably it is 20 to 40% in 1 hour, 30 to 50% in 2 hours, 70 to 90% in 6 hours and 85% in 12 hours. It is characterized by showing.

It is characterized by dissolution rate of 85% or more within 30 minutes when PPI, the active ingredient in the immediate release part, is used in the same test method as the sustained release part drug layer.

The substance using the PPI of the present invention to exhibit sustained release is a pH-independent substance, which is a substrate for controlling the release rate of the drug by body fluids in the gastrointestinal tract of the body, and according to the change of pH in the body and the movement of the digestive tract. As a substrate which is characterized in that the release rate does not change, such a pH-independent substance contains at least one mixture from hydrophilic polymers and hydrophobic polymers, and particularly preferably hydrophobic polymers.

The above-mentioned hydrophobic polymer is a polymer which is insoluble in water, soluble in an organic solvent, and swelled by a body fluid in the body to form a matrix of the polymer during oral administration, thus acting as a drug release control membrane. In addition, the above-mentioned hydrophilic polymer is a polymer that can form a gel upon water absorption or can be dissolved in water to control the release rate of the drug with strong viscosity.

In the present invention, to control the release rate of the PPI can be used by adjusting the amount of hydrophobic polymer in the sustained-release drug layer and may be possible by using a mixture of hydrophilic polymer and hydrophobic polymer.

The hydrophilic polymers mentioned above are preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyethylene oxide, carboxymethylcellulose sodium, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer , A methyl methacrylate-ethyl acrylate copolymer and a vinyl acetate-polyvinylpyrrolidone polymer matrix.

The hydrophilic polymer mentioned above is preferably hydroxypropyl cellulose.

The above-mentioned hydrophobic polymer is a polymer composed of ethyl cellulose and polyvinylacetate, which may be used alone or in a suitable ratio.

The above-mentioned method for preparing the microparticles or tablets of the sustained-release drug layer uses a pharmaceutically acceptable method and is not particularly limited. In particular, the method for forming the microparticles containing granules may be prepared using a wet granulation method or a fluidized bed coating method or a centrifugal rotation coating method using a CF coating machine. Sustained release drug layer portions are tablets and particulates having a pH-independent drug release controlling membrane. As used herein, the "pH-independent drug release controlling membrane" generally refers to a coating which does not dissolve on its own and controls the release rate of PPI by diffusion through the pores produced in the coating itself or in the coating itself. The pH-independent drug release control membrane mentioned above is a release control membrane composed of a hydrophilic polymer and a hydrophobic polymer or a hydrophobic polymer and can control the release of the PPI drug stably without depending on the pH in the gastrointestinal tract of the body. There is no special courtship. As the pH-independent drug release controlling film, a film containing polyvinylacetate as a hydrophobic polymer is preferable, and hydroxypropylcellulose can be mixed with polyvinylacetate as a hydrophobic polymer as a hydrophilic polymer.

In preparing the microparticles containing the sustained-release drug layer, a core material may be used. For this purpose, a pharmaceutically acceptable inert material such as nonpareil may be used. Can be coated by a conventional manufacturing method to form a sustained release drug layer.

In other words, the sustained-release drug layer using the core may be prepared by spraying or distributing by using a flow coater, a centrifugal fluidized bed coater (CF-coater), and the like. Preferably, the above-mentioned coating liquid may prepare a sustained release drug layer by spraying a solution containing a binder or the like on the center of the inert carrier. The two manufacturing apparatuses mentioned above can be used separately and, if necessary, can be used in combination to make particulates.

On the other hand, when the core material is not used, PPI and water-soluble alkaline or non-aqueous alkaline materials and excipients such as lactose, white sugar, starch, microcrystalline cellulose and sugar alcohols may be used to prepare PPI-containing core particles. Binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, polyvinyl alcohol, macrogol, gelatin, pregelatinized starch and the like, carboxymethylcellulose calcium, cross Disintegrating agents such as sodium carboxymethyl cellulose, crospovidone, low-substituted hydroxypropyl cellulose, etc. as pharmaceutical additives, stirred granule materials, wet extruder granulators (e.g. extruders), granulation machines (e.g. marumerizers or core using pelletizer, fluidized bed coater, etc. It can get cut.

The core particle obtained above is about 100 micrometers-2 mm, Preferably it is 300 micrometers-1 mm.

On the surface of the sustained-release drug layer obtained as the core particles, a coating solution containing a pH-independent polymer was prepared according to a conventional pharmaceutical method, and then sprayed onto the surface of the core particle to form a film to slowly release the PPI drug. To produce a pH-independent, sustained release particulate that is adjusted to

By using the core material of the sustained-release drug layer obtained above, it is possible to prepare a rapid-release drug layer in which the release is rapidly released at the absorption site of the drug. In other words, the pharmacologically active substance used in the rapid release drug layer to prepare it may be a pharmacologically active substance such as PPI used in the sustained release drug layer or another substance. To this end, PPI or pharmacologically active substances and, if necessary, water-soluble alkaline or non-aqueous alkaline substances and excipients such as lactose, white sugar, starch, microcrystalline cellulose and sugar alcohols, are used, and hydroxypropyl cellulose, hydroxypropylmethyl Binders such as cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, macrogol, gelatin, pregelatinized starch, etc. Disintegrating agents such as oxypropyl cellulose can be obtained by coating the rapid release drug layer using a flow coater or a centrifugal fluidized bed coater (CF-coater) as a pharmaceutical additive.

Subsequently, the multiple drug delivery system pellets containing the sustained-release drug layer and the fast-release drug layer obtained above were finally used an enteric coating using an enteric polymer resistant to gastric acid using a conventional coating method. Form.

Materials for forming an enteric coating for this purpose are methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate. Solutions or dispersions of cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other suitable enteric coating polymers may be used alone or in combination.

Sustained release coatings and enteric coatings may contain pharmaceutically acceptable plasticizers to achieve the desired mechanical properties. Such plasticizers include, but are not limited to, for example, triacetin, dibutyl sebacate, macrogol, glycerol monoesters, polysorbates or other plasticizers. The amount of plasticizer is preferably optimized for each formulation for the encapsulating polymeric material to be selected, the plasticizer to be selected, and the amount thereof coated.

As described above, the microparticles are coated with an enteric polymer coating which contains a benzimidazole compound and simultaneously contains a rapid-release drug layer and a sustained-release drug layer to stably protect against gastric acid. Prepare a pharmaceutical composition.

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

The present invention has been described in more detail by presenting Preparation Examples, Examples, and Experimental Examples below, but the present invention is not limited thereto.

Preparation Example 1

① Preparation of core as sustained-release drug layer (microspheres coated with pharmacologically active substance)

   A drug containing suspension was prepared in the following composition.

    S-omeprazole Mg 30 g

    Polysorbate 80 0.75G

    Talc 3.75G

    HPMC 15c ps 7.5g

    260 g of ethanol

  HPMC was dissolved while stirring ethanol, and polysorbate 80, drug, and talc were stirred and dispersed. The prepared suspension containing the drug was sprayed on the gaseous substance Sugaspear 200G in a fluidized bed coater. The theoretical amount of the sustained release drug layer is 242G.

② Cover of slow release control film

   The drug release was controlled to the following composition to form a film showing sustained release.

   Collicoat SR30D 125.00G

     (Polyvinylpyrrolidone K30 3.37G)

     (Polyvinylacetate 33.75G)

     (Sodium Lauryl Sulfate 0.37G)

   Polyethylene Glycol 3.75G

   Purified Water 87.50 G

   Collicott SR30D was homogeneously dispersed and suspended with stirring purified water, and polyethylene glycol was dissolved and sprayed onto the core 242G of the sustained-release drug layer prepared above. The theoretical amount of the sustained-release drug microspheres coated with the prepared sustained release control film is 283.24G.

③ Preparation of multi-layered drug-release microspheres coated with rapid-release drug layer

   A drug containing suspension was prepared in the following composition.

    S-omeprazole Mg 10.0 g

    Polysorbate 80 0.25G

    Talc 1.25G

    HPMC 15c ps 2.50G

    Ethanol 90.0G

HPMC was dissolved while stirring ethanol, and polysorbate 80, drug, and talc were stirred and dispersed. The suspension prepared above was sprayed on a 283.24G sustained-release drug core with a sustained release control membrane in a fluidized bed coater. The theoretical amount of the prepared multilayer drug-release microspheres is 297.24G.

④ coating of enteric coating

   The enteric coating was coated with the following composition.

   Eascol EAB L55 76.6G

   Purified Water 90.0G

   The coating solution was prepared by homogeneously suspending Eascol EAB L55 while stirring purified water. Spray coating was performed on the multi-layered drug-release microsphere 297.24G coated with the above-release drug release layer as a core in a fluidized bed coater equipped with Worcester. The theoretical amount of the prepared enteric coated microspheres is 373.84G.

  In order to confirm the resistance of stomach enteric coated microspheres to gastric acid, artificial gastric juice of pH 1.2 was prepared according to the dissolution test method of the Korean Pharmacopoeia. The dissolution test was carried out for 2 hours at to observe the appearance of microspheres. There was no change in the appearance of microspheres after 2 hours of elution in gastric acid. The dissolution test was carried out with pH6.8 phosphate buffer solution according to the dissolution test method of the Korean Pharmacopoeia to evaluate the dissolution pattern over time, and the desired dissolution rate was obtained.

Claims (7)

Omeprazole, lansoprazole and its alkali salts as proton pump inhibitors Or in a formulation comprising an optical isomer of omeprazole, lansoprazole and an alkali salt thereof as an active ingredient, 1) containing a sustained release drug layer and a pH independent polymer controlling the release of the drug layer. 2) contains a rapid release drug layer 3) The outermost pharmaceutical composition, characterized in that to form a polymeric enteric coating film that is dissolved at pH 5.0 or more to suppress drug release to stomach acid. The enteric coating film dissolving at pH 5.5 or above is hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate air. A formulation containing one or two or more mixtures selected from the group consisting of copolymers, methacrylic acid-methyl acrylate-methyl methacrylate copolymers, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and shellac. The formulation of claim 1 wherein the pH independent polymer controlling the release of the drug layer uses polyvinyl acetate. The formulation according to claim 1, wherein the proton pump inhibitor (PPI) is omeprazole, lansoprazole or an optically active form thereof or a salt thereof. The formulation of claim 3 wherein the pH independent polymer controlling the release of the drug layer contains from 1.0 to 20.0 w / w% content. The formulation according to claim 1, wherein the proton pump inhibitor (PPI) contains 10 to 40% of the immediate release drug layer and 60 to 90% of the sustained release drug layer. The formulation according to claim 1, wherein the dissolution rate of the drug in pH 6.8 phosphate buffer is 20 to 40% at 1 hour, 30 to 50% at 2 hours, 70 to 90% at 6 hours and 85% at 12 hours.