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WO2009038340A1 - Pharmaceutical composition of artemisia extract using gastro-retentive drug delivery system and its oral sustained release formulation - Google Patents

Pharmaceutical composition of artemisia extract using gastro-retentive drug delivery system and its oral sustained release formulation 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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WO
WIPO (PCT)
Prior art keywords
artemisia extract
formulation
artemisia
sustained
pharmaceutical composition
Prior art date
Application number
PCT/KR2008/005487
Other languages
French (fr)
Inventor
Moo-Hi Yoo
Jeong-Hoon Kim
Sun-Woo Jang
Bae-Chan Kim
Original Assignee
Dong-A Pharm.Co., Ltd.
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Publication date
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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/en

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Classifications

    • 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.

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Abstract

There is provided a pharmaceutical composition comprising an extract of Artermisia sp. (Artemisia asiatica, A. mongolica, A. princeps, A. argyi) using a gastro-retentive drug delivery system (GRDDS), and an oral sustained-release formulation using the same. The oral sustained-release formulation comprising an Artemisia extract according to one exemplary embodiment of the present invention may be useful to enhance an absorption rate of a drug in the gastrointestines by allowing the drug to maintain a floating state in the digestive juice or body fluid when the oral sustained-release formulation is administered into a human body, and to improve a therapeutic effect of the drug by slowly releasing the drug to increase a topical reaction of Artermisia asiatica Nakai while retaining the drug in the stomach and intestines for an extended time.

Description

[DESCRIPTION]
[Invention Title]
PHARMACEUTICAL COMPOSITION OF ARTEMISIA EXTRACT USING GASTRO- RETENΉVE DRUG DELIVERY SYSTEM AND ITS ORAL SUSTAINED RELEASE FORMULATION
[Technical Field]
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.
[Background Art]
It has been known that Artemisia asiatica, A. mongolica, A. princeps, A. argyi is a perennial plant belonging to Compositae sp., and its extract has an effect to extend the blood coagulation (The Pharmaceutical Society Of Korea, 28(2): 69-77, 1984). Also, it has been also known that flavone extracted from Artermisia asiatica Nakai has an anti-cancer activity (Chem. Pharm. Bull. 32(2): 723; 1984), an effect on inhibition of blood platelet aggregation (Zhonggiio Zhongyao Zazhi, 17(6): 353, 1992), and an antifungal activity (J of Chemical Ecology, 19(11), 1993), as well as having effects on allergic and inflammatory treatments by helping a defense system of a host through the anti-complementary activity {Chem. Pharm. Bull 33(5): 2028-2034, 1985), and antihypertensive and sedative activities (Indian J. Med Res. 60, 1972). In addition, it has been known that 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, and Korean Patent Application No. 96-28230 discloses that an
Artemisia extract including eupatilin and jaceosidin has an effect on inflammatory bowel diseases. Also, 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. Accordingly, 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, and 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.
Also, 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.
However, the conventional herbal extract formulations have problems on process of filling an
Artemisia extract into a capsule several times, not once, and have problems in that patients are inconvenient to take medicine since the final herbal products has their own smells owing to the characteristics of the herbal formulations. Also, 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.
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 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 market.
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. Also, 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. However, 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.
However, 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. However, 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 above-mentioned systems have problems in that it is difficult to apply Artemisia asiatica Naked to the simple gastro-retentive drug delivery system since they show their effects in applying to the water-soluble substances having no adhesion. Therefore, there has been a demand for an Artemisia extract-containing oral sustained-release formulation that can solve the problem regarding the sustained release of the Artemisia extract that is water- insoluble and has a strong adhesion.
Accordingly, 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.
[Disclosure] [Technical Problem]
Accordingly, the present invention is designed to solve such drawbacks of the prior art, and therefore 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.
Also, another object of the present invention is to provide an oral sustained-release formulation using the pharmaceutical composition.
[Technical Solution]
According to an aspect of the present invention, there is provided 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.
According to another aspect of the present invention, there is provided an oral sustained-release formulation using the pharmaceutical composition. The oral sustained-release formulation according to one exemplary embodiment of the present invention applies to a gastro-retentive drug delivery system obtained by modifying conventional floating and expansion systems. In this case, 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.
Hereinafter, exemplary embodiments of the present invention will be described in more detail.
The oral sustained-release formulation according to one exemplary embodiment of the present invention 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 (CigHiόOy, molecular weight: 344.31), based on 1 g of the Artemisia extract. In this case, 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.
It has been known that 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.
The novel drug-release system according to one exemplary embodiment of the present invention 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.
In accordance to the present invention, 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. Preferably, 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.
In accordance to the present invention, 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. Preferably, 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. In this case, 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.
In accordance to the present invention, 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. Preferably, 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. Also, in accordance to the present invention, the dissolution-aiding agent that may be used herein includes various surfactants such as pharmaceutically available cationic, anionic, non-ionic or amphoteric surfactants. More particularly, 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. Preferably, 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.
In accordance to the present invention, the oral sustained-release formulation is a tablet, a granule, or a hard capsule. Particularly, 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. Preferably, 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.
In accordance to the present invention, 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:
(I) A herbal drug is coarsely dried, stirred in an extraction solvent for a suitable period, extracted, cold-dipped, filtered and concentrated to prepare a viscous extract. (2) The remnant of the herbal drug was treated in the same manner as Step (1) to prepare a viscous extract, and the prepared viscous extract is mixed with the viscous extract of Step (1).
(3) 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. (4) Calcium silicate, lactose, sodium bicarbonate, anhydrous citric acid and microcrystalline cellulose are mixed. In this case, an excipient and a disintegrating agent may be further added to the resulting mixture.
(5) The ethanol solution prepared in Step (3) and the mixture prepared in Step (4) are combined together, dried, and ground into granules. (6) 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.
(T) Suitable amounts of the coating agents are taken and mixed with ethanol and water to prepare a coating solution.
(8) The formulated tablet prepared in Step (6) is coated with the coating solution prepared in Step (7) to prepare a film-coating tablet.
In general, 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. In this case, the excipient comprises lactose, starch, lactose, mannitol, kaolin inorganic salt (i.e. sodium chloride), powdered sugar and powdered cellulose derivatives, and may further comprises substances that are pharmacologically used in general within the scope at which they do not adversely affect the effects of medicine, for example, 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, and calcium carboxymethylcellulose; antioxidant agents for preventing the formulation from being oxidized; a flavoring agent, a preservative agent, an aromatic agent, a sweetening agent, a dye, a pH control agent and a viscosity control agent. In this case, the above-listed components are preferably added at an amount at which they may be used on the basis of the content of the Artemisia extract.
[Advantageous Effects] As described above, 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. In accordance with the present invention, 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. [Description of Drawings]
FIG. 1 shows results obtained by comparing dissolution rates of a formulation of Experimental example 1 comprising 90 mg of an Artemisia extract dissolved in a buffer solution (pH=1.2) and a formulation of Comparative example 1 according to one exemplary embodiment of the present invention. 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.
[Best Mode]
Hereinafter, the present invention will be described in more detail referring to the exemplary embodiments of the present invention. However, it should be understood that the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention.
<ExampIe 1> Oral formulation 1 including Artetnisia 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, 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. 30 mg of carbomer 934P, 20 mg of hydroxypropylmethylcellulose 2910, 60 mg of hydroxypropylmethylcellulose 2208, 80 mg of methacrylic acid copolymer and 2 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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.
<ExampIe 2> 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. 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. 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.
<Example 3> Oral formulation 3 including Artemisia extract
90 mg of an Artemisia extract and 20 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 45 mg of calcium silicate, 80 mg of lactose, 120 mg of sodium bicarbonate, 50 mg of anhydrous citric acid and 80 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. 50 mg of carbomer 934P, 100 mg of hydroxypropylmethylcellulose 2208, 50 mg of methacrylic acid copolymer, 50 mg of hydroxypropylcellulose and 2 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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.
<Example 4> Oral formulation 4 indudingArtemisia extract
90 mg of an Artemisia extract and 80 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 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. 50 mg of carbomer 934P, 50 mg of methacrylic acid copolymer, 50 mg of hydroxypropylcellulose, 50 mg of ethylcellulose and 2 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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.
<Example 5> Oral formulation 5 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, 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. 50 mg of carbomer 97 IG, 25 mg of hydroxypropylmethylcellulose 2910, 65 mg of hydroxypropylmethylcellulose 2208, 80 mg of methacrylic acid copolymer and 2 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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.
<Example 6> Oral formulation 6 inύnάmgΛrtemisia extract
90 mg of an Artemisia extract and 50 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 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. 20 mg of carbomer 97 IG, 70 mg of hydroxypropylmethylcellulose 2208, 50 mg of methacrylic acid copolymer and 2 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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.
<Example 7> Oral formulation 7 inchidingArtemisia extract
90 mg of an Artemisia extract and 30 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 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. 10 mg of carbomer 934P, 10 mg of hydroxypropylmethylcellulose 2910, 20 mg of hydroxypropylmethylcellulose 2208, 20 mg of methacrylic acid copolymer and 1 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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.
<Example 8> Oral formulation 8 indudingArtemisia extract
90 mg of an Artemisia extract and 10 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 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. 50 mg of carbomer 971G, 100 mg of methacrylic acid copolymer, 50 mg of xanthan gum and 3 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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.
<Example 9> Oral formulation 9 includingArtemisia extract
90 mg of 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. Separately, 40 mg of calcium silicate, 30 mg of lactose, 30 mg of microcrystaUine cellulose, 50 mg of sodium bicarbonate, 10 mg of anhydrous citric acid, 30 mg of crosspovidone, 20 mg of carbomer 934P, 10 mg of hydroxypropylmethylcellulose 2910, 20 mg of hydroxypropylmethylcellulose 2208, 10 mg of methacrylic acid copolymer, 10 mg of xanthan gum and 2 mg of light anhydrous silicic acid were added, and homogeneously mixed. 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.
<Example 10> Oral formulation 10 includingArtemisia extract
90 mg of an Artemisia extract and 50 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 35 mg of calcium silicate, 38 mg of lactose, 25 mg of microcrystalline cellulose, 50 mg of sodium bicarbonate, 10 mg of anhydrous citric acid, 40 mg of crosspovidone, 15 mg of carbomer 97 IG, 50 mg of hydroxypropylmethylcellulose 2910, 10 mg of hydroxypropylmethylcellulose 2208, 20 mg of methacrylic acid copolymer and 1 mg of light anhydrous silicic acid were homogeneously mixed together, and the prepared Artermisia ethanol solution was slowly added to the resulting mixture, blended, and injected into a pelletizer with an 18-mesh sieve to prepare a pellet. 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. <Example 11> Oral formulation 11 including Artemisia extract
90 mg of an Artemisia extract and 40 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 35 mg of calcium silicate, 35 mg of lactose, 35 mg of microcrystalline cellulose, 20 mg of sodium bicarbonate, 5 mg of anhydrous citric acid, 20 mg of crosspovidone, 10 mg of carbomer 971G, 10 mg of hydroxypropylmethylcellulose 2910, 20 mg of hydroxypropylmethylcellulose 2208, 15 mg of methacrylic acid copolymer and 2 mg of light anhydrous silicic acid were homogeneously mixed together, and the prepared Artermisia ethanol solution was slowly added to the resulting mixture, blended, and injected into a pelletizer with an 18-mesh sieve to prepare a pellet. 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.
<ExampIe 12> Oral formulation 12 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, 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 together, and the prepared Artermisia ethanol solution was slowly added to the resulting mixture, blended, dried at 40 °C , and injected into a roller compacter with a 24-mesh sieve to prepare a granule having 80 mesh or more. 30 mg of carbomer 934P, 20 mg of hydroxypropylmethylcellulose 2910, 60 mg of hydroxypropylmethylcellulose 2208, 80 mg of methacrylic acid copolymer and 2 mg of light anhydrous silicic acid were added to the prepared granule, homogeneously mixed, 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 compositioα Then, the formulated tablet was coated with the coating composition using a conventional film-coating method. <Comparative example 1>
8 kg of lactose and 4 kg of corn starch were put into a high-speed mixer, and homogeneously mixed together. The resulting mixture was mixed with the 3 kg of the Artemisia extract prepared in the same manner as in Example 1 , blended in a blending machine, and then collected with a 20-mesh sieve. The collected mixture was dried at 60 °C with hot wind, and sieved with the 20-mesh sieve to obtain a granule. The prepared granule was filled into an automatic capsule filling machine to prepare a capsule formulation including 90 mg of an. Artemisia extract.
^Comparative example 2> 60 mg of an Artemisia extract and 5 mg of a polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, 20 mg of calcium silicate, 100 mg of microcrystalline cellulose, 133 mg of lactose and 5 mg of croscarmellose sodium were homogeneously mixed together, and the prepared Artermisia ethanol solution was slowly added to the resulting mixture, blended, dried at 40 °C , and injected into an oscillator with an 18-mesh sieve to prepare a granule. Suitable amounts of magnesium stearate and talc were added to the prepared granule, homogeneously mixed, and formulated into a tablet Separately, 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. 00 % by weight of Brilliant Blue FCF aluminum lake (tar pigment approved by the Korea Food & Drug Administration), 2.00 % by weight of lecithin, 1.70 % by weight of Indigocarmine aluminum lake (tar pigment approved by the Korea Food & Drug Administration) and 0.48 % by weight of xanthan gum. And 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. <Experimental example 1> Comparison Test of Dissolution Rate
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.
Amounts of test samples corresponding to 90 mg of the Artemisia extract were taken from the oral formulations including an Artemisia extract prepared in Example 1 and Comparative example 1, and their dissolution rates were compared in a buffer solution (pH=1.2) (a paddle method in the Korean Pharmacopoeia, 50 rpm). 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. The dissolution rates measured at pH=l .2 are shown in FIG. 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
20% or more at the point of stirring time of 1 hour, a dissolution rate of 35% or more at the point of stirring time of 4 hours, and a dissolution rate of 80% or more at the point of stirring time of 12 hours. On the contrary, it was seen that the oral formulation (comparative formulation) prepared in Comparative example
1 has a very higher initial dissolution rate than the oral formulation prepared in Example 1, and shows a dissolution rate of 30% or more at the point of stirring time of 1 hour but its dissolution rate are not increased after the point of stirring time of 1 hour. Therefore, it was revealed that 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.
Therefore, it was revealed that 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.
<Experimental example 2> Comparison Test of Concentration in Blood
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.
10 male dogs weighing 15±5 kg were purchased, adapted for approximately 1~2 weeks, and then used in this experiment. The dogs were fasted except for water so that they cannot be fed with any food for
24 hours before the experiment. Then, amounts of test samples corresponding to 90 mg of the Artemisia extract were taken from the oral formulations comprising the composition including an Artemisia extract prepared in Example 1 and Comparative example 1, and orally administered to the dogs. Then, approximately 3 ml of venous blood was collected from the veins of the dog forelegs at points of time of 5, 10, 20 and 30 minutes, and I5 2, 4, 6, 8, 10 and 12 hours. The collected bloods were stored at -200C until they are used for analysis. The content of eupatilin in blood was quantitified using HPLC. First, 100 μl of blood was put into a microtube, and 100 μl of an acetate buflFer and 20 μi of β-glucuronidase were added to the microtube, reacted at 37°C for 2 hours. 100 μl of biochainin A as an internal standard substance and 1.5 ml of ether were added to the resulting reaction solution, and then voltexed for 2 minutes. The reaction solution was centrifuged at a rotary speed of 12,000 rpm for 2 minutes, and a supernatant was separated, and evaporated under a nitrogen gas condition. 130 μl of a mobile phase was added to the resulting pellet, and voltexed for 1 minute. 100 μlt of the mobile phase was injected into HPLC. The analysis conditions: a column is Hichrom RPB (250*4.6mm, grain size: 5 μm), 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/Λ Eupatilin was quantitified as an area ratio to the internal standard substance.
The results are shown in FIG. 2.
As shown in FIG. 2, it was revealed that 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. Also, 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. In addition, it was seen that 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.
Therefore, it was shown that 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.
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.
The experimental groups were divided into an Example formulation 1 -administered group according to the present invention, a Comparative formulation 2-administered group and a placebo- administered group, and each group was administered to 3 beagle dogs. The oral formulation of Example 1 was orally administered twice a day at a dose corresponding to 90 mg of the Artemisia extract, the oral formulation of Comparative example 2 was orally administered three times a day at a dose corresponding to 60 mg of the Artemisia extract, and the placebo that does not include the Artemisia extract was orally administered three times a day.
Figure imgf000026_0001
In order to perform gastroscopy to determine a therapeutic effect on the gastric ulcer, 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,
6, 9, 12 and 15 days after the induction of the gastric ulcer, and the test animals were fasted for 12 hours, and used for the endoscopy.
3 sites of the gastric ulcer that are induced per population were evaluated with 6 grades from 0 to 5. The grade evaluation standard is listed as follows.
Figure imgf000026_0002
The endoscopic results in 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 ]
Endoscopy * (Induction of gastric ulcer)
Group Population Site
Before Right after 3 Day 6 Day 9 Day 12 Day XS Day rI-U
1 0 5 4 4 4 3 3
No.l 2 0 5 4 4 4 3 3
3 0 5 4 4 3 3 2
1 0 5 4 4 4 4 3
No.2
Group 1 2 0 5 4 4 4 4 4
3 0 5 4 4 4 4 4
1 0 5 4 4 4 3 3
No.3 2 0 5 4 4 4 4 3
3 0 5 4 4 4 4 3
Total 0 45 36 36 35 32 28
1 0 5 4 3 3 2 1
No.l 2 0 5 4 4 3 2 2
3 0 5 4 3 2 1 1
1 0 5 4 3 3 2 2
No.2 2 4 4
Group2 0 5 3 2 2
3 0 5 4 4 3 2 2
1 0 5 4 3 3 2 1
No.3 2 0 5 4 3 2 2 1
3 0 5 4 3 2 2 1
Total 0 45 36 30 24 17 13
1 0 5 4 4 3 2 2
No.l 2 0 5 4 3 2 2 1
3 0 5 4 3 2 1 1
1 0 5 4 4 3 2 2
No.2 ?, 0 5 4 3 2 2 2
Group3
3 0 5 4 4 3 2 1
1 0 5 4 4 3 2 2
No.3 2 0 5 4 3 2 2 1
3 0 5 4 3 2 1 1
Total 0 45 36 31 22 16 13
* See Grade Evaluation Standard for Treatment of Gastric Ulcer
From the gastroscopic results as listed in Table 1 and shown in FIGS. 3 to 20, it was revealed that a state of the ulcer lasts in each site up to 12 days after the induction of the gastric ulcer, then tends to be healed into an erosive shape at the point of time of 15 days in the case of the placebo-administered group, and hemorrhages are observed in some populations of the placebo-administered group. In the case of the Example formulation 1 and Comparative formulation 2-administered groups, ulcer regions in each site tend to be healed into an erosive shape from the point of time of 6 days after the induction of the gastric ulcer, and the erosion is reduced in size from the point of time of 9 days after the induction of the gastric ulcer. Also, 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. In particular, it was seen that 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.
As one noticeable fact from Hie endoscopy, it was observed that a large amount of white powder that is considered to be a drug is homogeneously distributed over the stomach walls in the Example formulation 1 -administered group, compared to the placebo-administered group and the Comparative formulation 2-administered group. These results are shown in FIG.21.
From the above-mentioned experimental results, it was revealed that, like the oral formulation of Comparative example 2, the oral formulation of Example 1 has an excellent effect to heat the gastric ulcer, compared to the placebo-administered group. In particular, 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.
From the above-mentioned experiments, it was confirmed that, since 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.

Claims

[CLAIMS] [Claim 1]
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.
[Claim 2]
The pharmaceutical composition comprising an Artemisia extract according to claim 1, wherein the expandable polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxyme&ylcellulose calcium, propyleneglycol alginate, polyvinyl alcohol, povidone, carbomer, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose trimelite, hydroxypropyl methylcellulose maleate, and xanthan gum.
[Claim 3]
The pharmaceutical composition comprising an. Artemisia extract according to claim 1, wherein the foaming agent is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.
[Claim 4]
The pharmaceutical composition comprising an Artemisia extract according to claim 1, wherein the sustained-release polymer is selected from the group consisting of Eudragit, a methacrylic acid copolymer, a methacrylic acid-acrylic acid ethyl ester copolymer, and a dimethylaminoethylmethacrylate- methacrylic acid ester copolymer.
[Claim 5]
The pharmaceutical composition comprising an Artemisia extract according to claim 1, wherein the dissolution-aiding agent is 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.
[Claim 6]
The pharmaceutical composition comprising an Artemisia extract according to claim 1, wherein the expandable polymer, the foaming agent, the sustained-release polymer and the dissolution-aiding agent are mixed at a weight ratio of l:0.1~20:0.1~20:0.1~20:0.1~20 parts by weight, based on 1 parts by weight of the Artemisia extract.
[Claim 7]
The pharmaceutical composition comprising an Artemisia extract according to claim 6, wherein the expandable polymer, the foaming agent, the sustained-release polymer and the dissolution-aiding agent are mixed at a weight ratio of 1 :0.2~5:0.2~5:0.2~5:0.2~5 parts by weight, based on 1 parts by weight of the Artemisia extract.
[Claim 8]
An oral sustained-release formulation 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.
[Claim 9]
The oral sustained-release formulation comprising an Artemisia extract according to claim 8, wherein the oral formulation is selected from the group consisting of a tablet, a granule and a hard capsule.
[Claim 10]
A method for preparing an Artemisia extract-containing film-coating tablet, the method comprising: dissolving an Artemisia extract and poloxamer in 95% ethanol to prepare an Artemisia ethanol solution; mixing the Artermisia ethanol solution with calcium silicate, microcrysalline cellulose, sodium bicarbonate, anhydrous citric acid and a pharmaceutically available excipient to prepare a granule; mixing the granule with an expandable polymer and a sustained-release polymer lubricant to formulate the mixture into a tablet; film-coating the formulated tablet with a coating agent.
[Claim 11]
The method for preparing an Artemisia extract-containing film-coating tablet according to claim 10, wherein the Artemisia extract is a viscous extracted with 95% ethanol.
[Claim 12]
The method for preparing an Artemisia extract-containing film-coating tablet according to claim 10, wherein the Artemisia extract includes 0.8-2.40 % by weight of eupatilin (C18H16O7, molecular weight: 344.31), based on 1 g of the Artemisia extract.
PCT/KR2008/005487 2007-09-21 2008-09-17 Pharmaceutical composition of artemisia extract using gastro-retentive drug delivery system and its oral sustained release formulation WO2009038340A1 (en)

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KR20190075872A (en) * 2011-07-26 2019-07-01 지엘팜텍주식회사 An animal feed form with poultry productivity improvement
KR102258773B1 (en) 2011-07-26 2021-06-01 지엘팜텍주식회사 An animal feed form with poultry productivity improvement
EP3037388A1 (en) * 2014-12-22 2016-06-29 Solvay SA Alkali metal bicarbonate particles with increased dissolution time
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US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers

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