WO2009038340A1 - Composition pharmaceutique d'extrait d'artemisia à système de délivrance de médicament gastro-rétentive, et formulation de libération prolongée orale l'utilisant - Google Patents

Composition pharmaceutique d'extrait d'artemisia à système de délivrance de médicament gastro-rétentive, et formulation de libération prolongée orale l'utilisant Download PDF

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Publication number
WO2009038340A1
WO2009038340A1 PCT/KR2008/005487 KR2008005487W WO2009038340A1 WO 2009038340 A1 WO2009038340 A1 WO 2009038340A1 KR 2008005487 W KR2008005487 W KR 2008005487W WO 2009038340 A1 WO2009038340 A1 WO 2009038340A1
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WIPO (PCT)
Prior art keywords
artemisia extract
formulation
artemisia
sustained
pharmaceutical composition
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PCT/KR2008/005487
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English (en)
Inventor
Moo-Hi Yoo
Jeong-Hoon Kim
Sun-Woo Jang
Bae-Chan Kim
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Dong-A Pharm.Co., Ltd.
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Application filed by Dong-A Pharm.Co., Ltd. filed Critical Dong-A Pharm.Co., Ltd.
Publication of WO2009038340A1 publication Critical patent/WO2009038340A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/282—Artemisia, e.g. wormwood or sagebrush
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a pharmaceutical composition including an Artemisia extract using a gastro-retentive drug delivery system (GRDDS), and an oral sustained-release formulation using the same.
  • GLDDS gastro-retentive drug delivery system
  • eupatilin extracted from Artermisia asiatica Nakai is used as an antitumor agent (WO 8803805), an antipsoriatic agent (WO 8803800), an anti-allergenic agent (JP 84155314) and an anti-aphthous ulcer agent (CA 2065496 AA).
  • Korean Patent Application No. 94-00147 discloses a medicinal use for treatment of a gastroesopageal disease using eupatilin extracted from Artermisia asiatica Nakai
  • Korean Patent Application No. 94-39337 discloses a use for treatment of gastroesopageal disease using jaceosidin separated from Artermisia asiatica Nakai
  • Korean Patent Application No. 96-28230 discloses that an
  • Artemisia extract including eupatilin and jaceosidin has an effect on inflammatory bowel diseases.
  • Korean Patent Application No. 2003-41628 discloses a method for extracting Artermisia asiatica Nakai having excellent effects on prevention or treatment of a gastrointestinal disease or an inflammatory bowel disease, compared to the conventional Artemisia extracts containing the noxious components, by selectively removing only noxious components while maintaining effective components of an Artemisia extract.
  • An Artemisia extract formulation has been known as a water-insoluble drug, but an immediate- release formulation is required to prevent or treat a gastrointestinal disease or an inflammatory bowel disease when it is administered with a sustained-release formulation.
  • Korean Patent Application No. 2004-23663 discloses an oral immediate-release formulation comprising an Artemisia extract, a water-soluble polymer as a carrier, and a solid dispersant
  • Korean Patent Application No. 2004-23664 discloses an immediate-release emulsion-concentrated composition comprising an Artemisia extract using a self-emulsifying drug delivery system, wherein the composition includes an Artemisia extract, an oil, a surfactant and a co-solvent at ratio of 1 :0.5 ⁇ 50:0.1-50:0. l ⁇ 50 % by weight.
  • the conventional herbal extract formulations including an Artemisia extract have been developed as an oral administration formulation, but have problems in that it is difficult to fill them in a capsule due to the characteristics such as strong hygroscopicity of a herbal extract, and density, fluidity and adhesive cohesiveness of raw materials although the herbal formulations are ground into powder. Therefore, the Artemisia extract have been used by grinding an extract into microgranules and filling the microgranules into a capsule, or used as capsule formulations using a large amount of a lubricant.
  • the Artemisia extract-containing formulation has problems in that biologically active substances are easily decomposed from a pharmacological administration form due to a variety of factors such as the kinds of aiding agents in the formulations, environmental factors (i.e. a preparation method of a wet granule, etc.) or storage environment factors (i.e. moisture, temperature, etc.) required for a formulation process, mechanical stresses according to the preparation method, etc.
  • environmental factors i.e. a preparation method of a wet granule, etc.
  • storage environment factors i.e. moisture, temperature, etc.
  • the present inventors have developed a tablet formulation that may solve the problems regarding the formulation process owing to the hygroscopicity, and density, fluidity and adhesive cohesiveness of raw materials, etc. by reducing a mass variation of the components and removing innate smells of herbal plants in a herbal formulation, especially an oral administration formulation containing an Artemisia extract. Then, the present inventors have filed an application as Korean Patent Application No. 200549830.
  • the oral formulation including an Artemisia extract is recommended to be administered three times a day with one pill being taken in every administration in the case of a formulation containing 60 mg of Artemisia 95% ethanol extract
  • a formulation containing 60 mg of Artemisia 95% ethanol extract In general, it has been reported that the medication compliance of patients gets better with the decrease in number of medications. Particularly, when the patients are out, or on duty, it is rather cumbersome for the patients to pack medicines that are taken after meals, and therefore it is possibly apprehended that the patients may take medicine twice a day since they omit the medication after the lunch meals. Also, it has been reported that medical supplies has undesired side effects in addition to the good effects. Therefore, the pharmaceutical companies have made ardent attempts to reduce these side effects. For this purpose, most of the pharmaceutical companies have already attempted to develop a sustained-release formulation that may reduce side effects by decreasing the maximum concentration of drug in blood while showing desired therapeutic effects through slow release of the drug, and a large number of the sustained-release formulations are on the
  • the Artemisia extract has two effects from a systemic absorption and a topical release. Therefore, it is possible to maximize the topical effects of the Artemisia asiatica Nakai and enhance the absorption of drug when the Artemisia extract will develop into sustained-release formulations using a gastro-retentive system that may retain the Artemisia extract in the stomach for an extended time.
  • Three technologies such as a floating system, an expansion system and a bioadhesive system have been widely known as the gastro-retentive drug delivery system.
  • the floating system is to retain a drug in the stomach and intestines for an extended time by using a property in which a formulation floats in the gastric juice since the density of the drug decreases due to the presence of bubbles generated by a foaming agent, and the expansion system is to retain a drug in the stomach and intestines for an extended time by expanding a formulation with an expandable polymer to prevent the formulation from passing through the pylorus.
  • the bioadhesive system is to retain a drug in the stomach and intestines for an extended time by employing an adhesive polymer to absorb the drug into the stomach walls.
  • the bioadhesive system runs short of consistency due to the difference in the amount, consistency and metabolic turnover of the viscous fluid between humans, and the drug absorbed in the gastric mucosa may be drained within an unexpectedly short time over the secretion of the gastric juice. Therefore, the gastro-retentive drug delivery system used to control the sustained release of the Artemisia extract is suitable when it is selected from the floating system and the expansion system.
  • the gastro-retentive drug delivery system using the above-mentioned floating system or expansion system is to allow a drug to flow out through pores when the drug in the formulation is dissolved in moisture while maintaining a constant shape of the formulation. In this case, the moisture flows in the formulation through the pores formed in a surface of the formulation.
  • the gastro-retentive drug delivery system has a problem in that a drug is not easily released from the formulation when the Artemisia extract including water-insoluble substances and having strong adhesion is used in the gastro-retentive drug delivery system using the conventional floating system and expansion system.
  • the present inventors have designed a novel release system of a drug by modifying conventional floating and expansion systems, and found that it is possible to improve topical reaction of a drug and enhance an absorption rate of the drug in an Artemisia extract-containing pharmaceutical composition and a sustained-release formulation using the same. Therefore, the present invention was completed on the basis of the above facts.
  • an object of the present invention is to provide a pharmaceutical composition capable of improving a topical reaction of an Artemisia extract and enhancing an absorption rate of the Artemisia extract with an increase of a gastro-retentive period of a drug including the Artemisia extract.
  • Another object of the present invention is to provide an oral sustained-release formulation using the pharmaceutical composition.
  • a pharmaceutical composition comprising an Artemisia extract using a gastro-retentive drug delivery system, comprising an expandable polymer, a foaming agent, a sustained-release polymer and a dissolution-aiding agent.
  • an oral sustained-release formulation using the pharmaceutical composition applies to a gastro-retentive drug delivery system obtained by modifying conventional floating and expansion systems.
  • the gastro-retentive drug delivery system includes a novel drug-release system in which some segments are steadily peeled off from an outer layer of a formulation while maintaining an expansion and floating state of the formulation for at least 12 hours, and a drug is released from the peeled segments.
  • the oral sustained-release formulation comprises an extract of Artemisia asiatica Nakai as an active substance, the Artermisia asiatica Nakai belonging to Compositae, sp.
  • the Artemisia extract may include 0.8-2.40 % by weight of eupatilin (CigHi ⁇ Oy, molecular weight: 344.31), based on 1 g of the Artemisia extract.
  • eupatilin CigHi ⁇ Oy, molecular weight: 344.31
  • a lower alcohol, particularly ethanol may be used as the extraction solvent, and the use of 95% ethanol is desirable.
  • the Artemisia extract is prepared into a viscous extract by stirring, extracting, cold-dipping and filtering the Artermisia asiatica Nakai in an extraction solvent of 95% ethanol, followed by concentrating the Artemisia extract at 78 ° C or below under a reduced pressure.
  • the Artemisia extract has an excellent effect to treat gastrointestinal diseases, gastritis and gastric ulcer, and its effective one-time dose is 60 mg and its total dose is 180 mg a day.
  • novel drug-release system is achieved by the use of the pharmaceutical composition comprising the Artemisia extract, an expandable polymer, a foaming agent, a sustained-release polymer and a dissolution-aiding agent.
  • the expandable polymer may include, but is not particularly limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, propyleneglycol alginate, polyvinyl alcohol, povidone, carbomer, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose trimelite, hydroxypropyl methylcellulose maleate, and xanthan gum.
  • hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomer and xanthan gum may be selected.
  • the expandable polymer functions to reduce a density of the formulation and control an initial immediate release of a drug since it rapidly expands when it comes in contact with an aqueous medium such as gastric juice, etc.
  • the foaming agent may be selected from the group consisting of, but is not particularly limited to, alkaline substances such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and the like.
  • alkaline substances such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and the like.
  • sodium carbonate, sodium bicarbonate and the like are desirable, and an alkalizing agent may be added to promote an acid-base neutralization reaction.
  • the foaming agent rapidly generates bubbles when it comes in direct contact with an aqueous medium such as gastric juice and the like, and retains or discharges the bubbles.
  • the foaming agent also functions to maintain a floating property of the formulation, and control the release of a drug through pores formed when the bubbles are removed.
  • the sustained-release polymer includes, but is not particularly limited to, Eudragit, a methacrylic acid copolymer, a methacrylic acid-acrylic acid ethyl ester copolymer, a dimethylaminoethyknethacrylate-methacrylic acid ester copolymer, etc.
  • Eudragit, a methacrylic acid-acrylic acid ethyl ester copolymer and the like may be selected.
  • the sustained-release polymer functions to peel segments from an outer layer of the formulation so as to facilitate the release of the Artemisia extract and simultaneously control the immediate release of the drug since the sustained-release polymer is water-insoluble and has adhesion.
  • the dissolution-aiding agent that may be used herein includes various surfactants such as pharmaceutically available cationic, anionic, non-ionic or amphoteric surfactants.
  • the dissolution-aiding agent used herein may include at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, a polyoxyethylene polyoxypropylene block copolymer, a polyoxyethylene polyoxypropylene copolymer, a reactant of natural or hydrogenated vegetable oil and ethylene glycol, dioctylsulfosuccinic acid sodium salt, lauryl sulfonic acid sodium salt, phospholipid, propylene glycol mono- or di-fatty acid ester, a trans-esterification reactant of natural vegetable oil triglyceride and polyalkylene polyol, mono-, di- or mono/di-glyceride, a mixture of propylene glycol mono- or di-fatty acid ester and mono-, di- or mono/di-glyceride, and derivatives thereof.
  • the surfactant used herein include one selected from the group consisting of a polyoxyethylene polyoxypropylene block copolymer, a reactant of natural or hydrogenated vegetable oil and ethylene glycol, polyoxyethylene sorbitan fatty acid ester, and a mixture of propylene glycol mono- or di-fatty acid ester and mono-, di- or mono/di-glyceride.
  • the pharmaceutical composition provided in the present invention is prepared by mixing the
  • Artemisia extract, the expandable polymer, the foaming agent, the sustained-release polymer and the dissolution-aiding agent at a weight ratio of 1 :0.1-20:0.1-20:0.1-20:0. l ⁇ 20 parts by weight, and preferably 1 :0.2 ⁇ 5:0.2 ⁇ 5:0.2 ⁇ 5:0.2 ⁇ 5 parts by weight.
  • the oral sustained-release formulation is a tablet, a granule, or a hard capsule.
  • the present invention provides a film-coating tablet formulation comprising a deoderant polymer in order to remove smells of a herbal formulation when the tablet formulation including an Artemisia extract is formulated into a tablet.
  • the used deoderant polymer includes, but is not particularly limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, propyleneglycol alginate, polyvinyl alcohol, povidone, carbomer, an Eudragit, methacrylic acid-acrylic acid ethyl ester copolymer, a dimethylaminoethylmethacrylate- methacrylic acid ester copolymer, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose trimelite, hydroxypropyl methylcellulose maleate, etc.
  • Eudragit a methacrylic acid copolymer, a methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethylmethacrylate-methacrylic acid ester copolymer, hydroxypropylmethylcellulose and the like are selectable.
  • the coating agent used herein is prepared as a film-coating tablet by using components and their contents as listed in the following.
  • coating agent A and coating agent B it to define the following compositions.
  • Coating agent A is a composition obtained by mixing 83.38 % by weight of a methacrylic acid copolymer, 6.65 % by weight of sodium lauryl sulfate, and 9.97 % by weight of stearic acid together.
  • Coating agent B is a composition obtained by mixing 51.72 % by weight of talc, 26.69 % by weight of titanium oxide, 15.96 % by weight of magnesium stearate, 1.15 % by weight of Blue 2 aluminum lake (tar pigment approved by the Korea Food & Drug Administration), and 4.48 % by weight of Yellow 203 aluminum lake (tar pigment approved by the Korea Food & Drug Administration) together.
  • the film-coating tablet according to one exemplary embodiment of the present invention is coated with a suitable amount of the coating agents A and B by using a conventional film-coating method.
  • the present invention is related to a film-coated tablet formulation that may remove patients' displeasures when the patients take herbal formulations since the use of the coating agents A and B prevents the innate smells of herbal plants from the herbal formulation.
  • the method for preparing a tablet according to one exemplary embodiment of the present invention includes the following steps, which are widely used in the art:
  • Poloxamer is mixed with the mixture of the viscous extracts of Steps (1) and (2), and the resulting mixture is dissolved in a solvent ethanol to prepare anArtermisia ethanol solution.
  • Calcium silicate, lactose, sodium bicarbonate, anhydrous citric acid and microcrystalline cellulose are mixed.
  • an excipient and a disintegrating agent may be further added to the resulting mixture.
  • Step (5) The ethanol solution prepared in Step (3) and the mixture prepared in Step (4) are combined together, dried, and ground into granules.
  • the granules prepared in Step (5) are mixed with an expandable polymer, a sustained-release polymer and a lubricant, and the resulting mixture is formulated into a tablet.
  • Step (6) The formulated tablet prepared in Step (6) is coated with the coating solution prepared in Step (7) to prepare a film-coating tablet.
  • the Artemisia extract comprises at least one of a pharmaceutically available excipient, a carrier and a diluent.
  • the used specific carrier, diluent or excipient may be changed according to the methods and objects to which the active component, Artemisia extract, applies.
  • the tablet formulation containing a herbal extract generally comprises substances such as a diluent, a lubricant, a disintegrating agent and mixtures thereof.
  • the pharmaceutical composition according to one exemplary embodiment of the present invention may include, but is not particularly limited to, any of components, such as an excipient, a disintegrating agent and a lubricant, that are widely used in the manufacture of the formulation in the pharmacological field.
  • the excipient comprises lactose, starch, lactose, mannitol, kaolin inorganic salt (i.e.
  • additives such as fatty acid or fatty alcohol that may be widely used to increase the solubility of the Artemisia extract and its absorption into the gastrointestines, enhance the release of a drug by dispersing and emulsifying the drug with water when the Artemisia extract is orally administered, and improve the bioavailability; sugars such as white sugar, malt ion taffy, purified white sugar, gelatin, sugar and taffy liquid; lubricants such as magnesium stearate, talc, and colloidal silicon dioxide; excipients such as microcrystalline cellulose, dibasic calcium phosphate, starch, and mannitol; disintegrating agents such as polypyrrolidone, sodium starch glycolate, crosspovidone, low-substituted hydroxypropyl cellulose,
  • the pharmaceutical composition comprising an Artemisia extract according to one exemplary embodiment of the present invention and the oral sustained-release formulation using the same may be useful to enhance a dissolution rate of the water-insoluble drug, Artemisia extract, using a gastro-retentive drug delivery system.
  • the sustained-release system including an Artemisia extract was established by controlling the in vivo absorption of the drug under the control of the release of the drug so that the drug can be slowly released in vivo, and the efficacy of the drug may be proven to be similar in the efficacy test using a beagle dog when the immediate-release formulation is administered twice a day, compared to when the immediate-release formulation is conventionally administered three time a day.
  • FIG. 2 shows results obtained by comparing concentrations of eupatilin in blood according to the change in time after the formulation of Experimental example 1 comprising 90 mg of eupatilin and the formulation of Comparative example 1 are orally administered into beagle dogs according to one exemplary embodiment of the present invention.
  • FIGS. 3 to 8 show endoscopic photographs taken from the placebo-administered groups when placebo is administered after the induction of gastric ulcer:
  • FIG. 3 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog right after the induction of gastric ulcer.
  • FIG. 4 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 3 day after the administration of placebo.
  • FIG. 5 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 6 day after the administration of placebo.
  • FIG. 6 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 9 day after the administration of placebo.
  • FIG. 7 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 12 day after the administration of placebo.
  • FIG. 8 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 15 day after the administration of placebo.
  • FIGS. 9 to 14 show endoscopic photographs taken from the Comparative formulation 2- administered groups when the formulation of Comparative example 2 is administered after the induction of gastric ulcer:
  • FIG. 9 is an endoscopic photograph taken right after the induction of gastric ulcer.
  • FIG. 10 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 3 day after the administration of the formulation of Comparative example 2.
  • FIG. 11 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 6 day after the administration of the formulation of Comparative example 2.
  • FIG. 12 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 9 day after the administration of the formulation of Comparative example 2.
  • FIG. 13 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 12 day after the administration of the formulation of Comparative example 2.
  • FIG. 14 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 15 day after the administration of the formulation of Comparative example 2.
  • FIGS. 15 to 20 show endoscopic photographs taken from the Example formulation 1 -administered groups when the formulation of Example 1 of the present invention is administered after the induction of gastric ulcer:
  • FIG. 15 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog right after the induction of gastric ulcer.
  • FIG. 16 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 3 days after the administration of the formulation of Example 1.
  • FIG. 17 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 6 days after the administration of the formulation of Example 1.
  • FIG. 18 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 9 days after the administration of the formulation of Example 1.
  • FIG. 19 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 12 days after the administration of the formulation of Example 1.
  • FIG. 20 is an endoscopic photograph showing Sites 1 and 2 in the stomach of the beagle dog 15 days after the administration of the formulation of Example 1.
  • FIG. 21 is an endoscopic photograph illustrating a distribution pattern of a drug in 4 lesional regions of the stomach of beagle dogs when the formulation of Example 1 of the present invention is administered into the beagle dogs.
  • an Artemisia extract and 70 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer.
  • 45 mg of calcium silicate, 32 mg of lactose, 36 mg of microcrystalline cellulose, 80 mg of sodium bicarbonate, 30 mg of anhydrous citric acid and 45 mg of crosspovidone were homogeneously mixed, and the Artemisia asiatica Nakai ethanol solution prepared thus was slowly added to the resulting mixture, and blended, dried at 40 ° C, and injected into an oscillator with an 18-mesh sieve to prepare a granule.
  • Oral formulation 2 including Artemisia extract 90 mg of an Artemisia extract and 70 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 45 mg of calcium silicate, 100 mg of microcrystalline cellulose, 40 mg of sodium bicarbonate, 15 mg of anhydrous citric acid and 30 mg of crosspovidone were homogeneously mixed, and the Artermisia asiatica Nakai ethanol solution prepared thus was slowly added to the resulting mixture, and blended, dried at 40 ° C, and injected into an oscillator with an 18-mesh sieve to prepare a granule.
  • hydroxypropylmethylcellulose 2910 40 mg of hydroxypropylmethylcellulose 2910, 80 mg of hydroxypropylmethylcellulose 2208, 50 mg of methacrylic acid copolymer, 50 mg of xanthan gum and 2 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, and formulated into a tablet.
  • a coating agent A and a coating agent B were prepared and mixed together at a suitable amount to prepare a coating composition. Then, the formulated tablet was coated with the coating composition using a conventional film-coating method.
  • a coating agent A and a coating agent B were prepared and mixed together at a suitable amount to prepare a coating composition. Then, the formulated tablet was coated with the coating composition using a conventional film-coating method.
  • an Artemisia extract and 80 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer.
  • 80 mg of calcium silicate, 100 mg of sodium bicarbonate, 50 mg of anhydrous citric acid and 60 mg of crosspovidone were homogeneously mixed, and the Artermisia asiatica Nakai ethanol solution prepared thus was slowly added to the resulting mixture, and blended, dried at 40 ° C, and injected into an oscillator with an 18-mesh sieve to prepare a granule.
  • a coating agent A and a coating agent B were prepared and mixed together at a suitable amount to prepare a coating composition. Then, the formulated tablet was coated with the coating composition using a conventional film-coating method.
  • an Artemisia extract and 70 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer.
  • 50 mg of calcium silicate, 30 mg of lactose, 40 mg of microcrystalline cellulose, 80 mg of sodium bicarbonate, 30 mg of anhydrous citric acid and 45 mg of crosspovidone were homogeneously mixed, and the Artermisia asiatica Nakai ethanol solution prepared thus was slowly added to the resulting mixture, and blended, dried at 40 ° C, and injected into an oscillator with an 18-mesh sieve to prepare a granule.
  • a coating agent A and a coating agent B were prepared and mixed together at a suitable amount to prepare a coating composition. Then, the formulated tablet was coated with the coating composition using a conventional film-coating method.
  • an Artemisia extract and 50 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer.
  • 40 mg of calcium silicate, 30 mg of lactose, 30 mg of microcrystalline cellulose, 50 mg of sodium bicarbonate, 15 mg of anhydrous citric acid and 35 mg of crosspovidone were homogeneously mixed, and the Artermisia asiatica Nakai ethanol solution prepared thus was slowly added to the resulting mixture, and blended, dried at 40 ° C, and injected into an oscillator with an 18-mesh sieve to prepare a granule.
  • an Artemisia extract and 30 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer.
  • 30 mg of light anhydrous silicic acid, 100 mg of lactose, 40 mg of sodium bicarbonate, 10 mg of anhydrous citric acid and 50 mg of crosspovidone were homogeneously mixed, and the Artermisia asiatica Naked ethanol solution prepared thus was slowly added to the resulting mixture, and blended, dried at 40 ° C, and injected into an oscillator with an 18-mesh sieve to prepare a granule.
  • an Artemisia extract and 10 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer.
  • 30 mg of light anhydrous silicic acid, 50 mg of microcrystalline cellulose, 30 mg of sodium bicarbonate, 10 mg of anhydrous citric acid and 20 mg of crosspovidone were homogeneously mixed, and the Artermisia asiatica Nakai ethanol solution prepared thus was slowly added to the resulting mixture, and blended, dried at 40 ° C , and injected into an oscillator with an 18-mesh sieve to prepare a granule.
  • a coating agent A and a coating agent B were prepared and mixed together at a suitable amount to prepare a coating composition. Then, the formulated tablet was coated with the coating composition using a conventional film-coating method.
  • an Artemisia extract and 70 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer, and dried under a vacuum condition using a dryer to obtain an Artermisia powder.
  • the Artermisia powder was added to the resulting mixture, and formulated into a tablet. Separately, a coating agent A and a coating agent B were prepared and mixed together at a suitable amount to prepare a coating composition. Then, the formulated tablet was coated with the coating composition using a conventional film-coating method.
  • a coating agent A and a coating agent B were prepared and mixed together at a suitable amount to prepare a coating composition. Then, the formulated tablet was coated with the coating composition using a conventional film-coating method.
  • coating agents A, B and C were prepared.
  • the coating agent A is a composition obtained by mixing 54.85 % by weight of hydroxypropyl methylcellulose, 22.86 % by weight of titanium oxide, 13.72% of ethylcellulose and 8.57 % by weight of diethylphthalate.
  • the coating agent B is a composition obtained by mixing 45.52 % by weight of polyvinyl alcohol, 22.30 % by weight of titanium oxide, 20.00 % by weight of talc, 5.00 % by weight of tartrazine aluminum lake (tar pigment approved by the Korea Food & Drug Administration), 3.
  • the coating agent C is a composition obtained by mixing 54.16 % by weight of carboxymethylcellulosesodiurn, 20.79 % by weight of maltodextrin, 16.95 % by weight of glucose, 6.10 % by weight of lecithin and 0.48 % by weight of sodium citrate.
  • Each of the prepared tablets was coated with a suitable amount of the coating agents A, B and C, respectively, using a conventional film-coating method.
  • Dissolution rates of the oral formulation including an Artemisia extract using the gastro-retentive drug delivery system according to one exemplary embodiment of the present invention and the oral formulation including an Artemisia extract without the use of the gastro-retentive drug delivery system were measured and compared with each other.
  • the experimental method was carried out, as follows.
  • Test samples were taken at points of stirring time: 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, and the Artemisia extracts were extracted from the test samples to measure contents of the Artemisia extracts.
  • the dissolution rate was measured by percentage using the Artemisia extract measured from the test sample when it is assumed that a content of the Artemisia extract in the oral formulation is 100.
  • Example 1 As shown in FIG. 1, it was revealed that the oral formulation (test formulation) prepared in Example 1 according to one exemplary embodiment of the present invention shows a dissolution rate of
  • the oral formulation according to one exemplary embodiment of the present invention has a sustained-release system in which a drug is slowly released in a buffer solution (pH-1.2). Also, it was seen that the oral formulation according to one exemplary embodiment of the present invention floats over an extruder within 5 minutes and maintains a floating state up to 12 hours when it is stirred, whereas the comparative formulation shows a pattern where the formulation is disintegrated within 5 minutes with the complete loss in the shape of the formulation.
  • the pharmaceutical composition according to one exemplary embodiment of the present invention and the oral sustained-release formulation using the same are suitable for the gastro-retentive drug delivery system, as seen from the results that the oral formulation floats over an extruder within 5 minutes and maintains a floating state for 5 minutes to 12 hours.
  • Example 1 When the oral formulation of Example 1 according to one exemplary embodiment of the present invention and the oral formulation prepared in Comparative example 1 were administered into dogs, concentrations of the oral formulations in blood were measured and compared with each other.
  • the experimental method was carried out, as follows.
  • a column is Hichrom RPB (250*4.6mm, grain size: 5 ⁇ m), an analysis wavelength is 350 nm, and a mobile phase is a mixture of 0.5% acetate buffer and acetonitrile (volume ratio: 50:50).
  • a flow rate of the mobile phase was ImU/ minutes, and an amount of the injected test sample was 100/ ⁇ Eupatilin was quantitified as an area ratio to the internal standard substance.
  • the maximum concentration, Cmax, of the formulation in blood is lower when the formulation (test formulation) prepared in Example 1 of the present invention is administered to the dogs than when the formulation (comparative formulation) prepared in Comparative example 1 is administered to the dogs.
  • the formulation according to one exemplary embodiment of the present invention has a 10 times-higher area under the curve (AUC) of blood concentration than the formulation prepared in Comparative example 1.
  • the pharmaceutical composition according to one exemplary embodiment of the present invention and the oral sustained-release formulation using the same last in blood for a longer time since the formulation prepared in Comparative example 1 has a blood concentration of 0 when it is administered to dogs, and the dogs were kept for 4 hours, but the formulation according to one exemplary embodiment of the present invention has a blood concentration of nearly 0 when it is administered to dogs, and the dogs were kept for 12 hours.
  • the gastro-retentive drug delivery system may successfully apply to the oral formulation according to 1he present invention. Therefore, the gastro-retentive drug delivery system may be used to prepare a formulation showing low toxicity and higher bioavailability, as well as a sustained release pattern.
  • Experimental example 3 Efficacy Test Gastric ulcer was experimentally induced in dogs, and the oral formulation of Example 1 of the present invention, the oral formulation prepared in Comparative example 2, and placebo were administered to the dogs. Then, the effect of the oral formulation of the present invention on the experimentally induced gastric ulcer was determined by evaluating a therapeutic effect of the oral formulation using endoscopy.
  • the experimental method was carried out, as follows.
  • Test dogs 9 clinically healthy female beagle dogs weighing 7-8 kg were used in this experiment. Test dogs were all put into a kennel 1 month before the experiment, and adapted to a new feeding environment, and their blood test, serum biochemistry, abdominal and thoracic radiography were carried out to confirm that they are healthy, and then used in this experiment.
  • the beagle dogs were fasted for 2 hours, and co-anesthetized with meditomidine and midazolam. Then, the stomach walls of the beagle dogs were thoroughly scanned using endoscope to confirm that their stomach walls are healthy and normal, and the stomach walls were damaged at the same size of 3 mm x 3 mm with an endoscopic biopsy forceps to induce the gastric ulcer. 3 damaged sites were selected from the gastric fundus of the stomach walls so as to facilitate the gastroscopy.
  • Example formulation 1 was orally administered twice a day at a dose corresponding to 90 mg of the Artemisia extract
  • Comparative example 2 was orally administered three times a day at a dose corresponding to 60 mg of the Artemisia extract
  • placebo that does not include the Artemisia extract was orally administered three times a day.
  • an endoscope with a diameter of 10 mm was used, and Olympus CLV-E was used as an endoscope power.
  • the endoscopy was carried out before and after the induction of the gastric ulcer, and at points of time of 3,
  • Example 1 and Comparative example 2 were obtained by determining gastroscopic grades of two sites (Site 1 and Site 2) of each population that are observed before the induction of the gastric ulcer, right after the induction of the gastric ulcer, and at points of time of 3, 6, 9, 12 and 15 days after the induction of the gastric ulcer using an endoscope.
  • the endoscopic results are listed in the following Table 1, and their gastroscopic photographs are shown in FIGS. 3 to 21. [Table 1 ]
  • the erosion is significantly reduced in size from the point of time of 12 days after the administration, and most of the ulcer regions tend to be healed into a scar shape from the point of time of 15 days after the administration.
  • the scars in each site are significantly reduced in size at the points of time of 12 and 15 days after the induction of the gastric ulcer in the case of the Example formulation 1 -administered group, compared to the Comparative formulation 2-administered group.
  • the oral formulation of Example 1 has an excellent effect to heat the gastric ulcer, compared to the placebo-administered group.
  • a dose of the administered effective component of Example 1 is identical to that of Comparative example 2 (180 mg/dog/day), but the number of the daily administrations is reduced to 2 doses, but the effect to heal the gastric ulcer is identical or superior to that of Comparative example 2 and the scars in the healed gastric tissues are small in size. From these results, it was seen that the oral formulation of Example 1 has the same daily dosage as that of Comparative example 2, but shows a good therapeutic effect since the oral formulation has an improved topical effect through the retention in the stomach although the number of the daily administrations is reduced.
  • the oral formulation according to one exemplary embodiment of the present invention shows a sustained release pattern due to the use of the gastro-retentive drug delivery system, the oral formulation has the same or more excellent effect to heal the gastric ulcer than the commercially available products of the conventional immediate- release formulations although the oral formulation is not administered three times a day but twice a day.

Abstract

L'invention concerne une composition pharmaceutique qui comprend un extrait d'Artermisia sp. (Artemisia asiatica, A. mongolica, A. princeps, A. argyi), à système de délivrance de médicament gastro-rétentive, et elle concerne aussi une formulation de libération prolongée orale utilisant ladite composition. Cette formulation à extrait d'Artemisia, selon une variante de l'invention donnée à titre d'exemple, peut être utile en vue d'augmenter un taux d'absorption de médicament dans le tractus gastro-intestinal car elle permet au médicament de se maintenir dans un état flottant à l'intérieur des sucs digestifs ou liquides corporels lorsque lorsqu'elle est administrée à l'être humain, ce qui améliore l'effet thérapeutique du médicament par le biais d'une libération lente renforçant une réaction topique de l'Artermisia asiatica Nakai alors que le médicament est retenu dans l'estomac et l'intestin pendant une durée prolongée.
PCT/KR2008/005487 2007-09-21 2008-09-17 Composition pharmaceutique d'extrait d'artemisia à système de délivrance de médicament gastro-rétentive, et formulation de libération prolongée orale l'utilisant WO2009038340A1 (fr)

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WO2012085018A1 (fr) * 2010-12-21 2012-06-28 Mepha Gmbh Composition pharmaceutique contenant des principes actifs végétaux
KR20190075872A (ko) * 2011-07-26 2019-07-01 지엘팜텍주식회사 가금류의 생산성 개선을 위한 사료 조성물
US11124425B2 (en) 2014-12-22 2021-09-21 Solvay Sa Alkali metal bicarbonate particles with increased dissolution time

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WO2015174684A1 (fr) * 2014-05-14 2015-11-19 동아에스티 주식회사 Préparation à libération prolongée de rétention gastrique à libération contrôlée
KR101964799B1 (ko) 2014-07-17 2019-04-02 동아에스티 주식회사 서방성 정제의 제조방법
KR101779513B1 (ko) * 2015-06-24 2017-09-19 대원제약주식회사 애엽의 이소프로판올 추출물을 포함하는 약제학적 조성물

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KR20050098441A (ko) * 2004-04-07 2005-10-12 동아제약주식회사 애엽추출물의 속효성 에멀젼 농축조성물 및 이를 함유하는 애엽추출물의 속효성 경구용 제제
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WO2012085018A1 (fr) * 2010-12-21 2012-06-28 Mepha Gmbh Composition pharmaceutique contenant des principes actifs végétaux
KR20190075872A (ko) * 2011-07-26 2019-07-01 지엘팜텍주식회사 가금류의 생산성 개선을 위한 사료 조성물
KR102258773B1 (ko) 2011-07-26 2021-06-01 지엘팜텍주식회사 가금류의 생산성 개선을 위한 사료 조성물
US11124425B2 (en) 2014-12-22 2021-09-21 Solvay Sa Alkali metal bicarbonate particles with increased dissolution time

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