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WO2009154396A2 - Préparation à libération prolongée renfermant un extrait de médicament brut servant à prévenir l’humidification et permettant une libération prolongée - Google Patents

Préparation à libération prolongée renfermant un extrait de médicament brut servant à prévenir l’humidification et permettant une libération prolongée Download PDF

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Publication number
WO2009154396A2
WO2009154396A2 PCT/KR2009/003228 KR2009003228W WO2009154396A2 WO 2009154396 A2 WO2009154396 A2 WO 2009154396A2 KR 2009003228 W KR2009003228 W KR 2009003228W WO 2009154396 A2 WO2009154396 A2 WO 2009154396A2
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Prior art keywords
extract
composition
dried
cellulose
crude drug
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Ceased
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PCT/KR2009/003228
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English (en)
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WO2009154396A3 (fr
Inventor
Hee-Joo Kil
Jung-Sik Lee
Je-Kyo Jeong
Gyo-Cheol Gu
Seon-Hwa Jung
Ji-Eun Kim
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PHARMAPEX CO Ltd
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PHARMAPEX CO Ltd
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Priority claimed from KR1020090053084A external-priority patent/KR20090131256A/ko
Application filed by PHARMAPEX CO Ltd filed Critical PHARMAPEX CO Ltd
Priority to CN2009800004796A priority Critical patent/CN101896168A/zh
Publication of WO2009154396A2 publication Critical patent/WO2009154396A2/fr
Publication of WO2009154396A3 publication Critical patent/WO2009154396A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation

Definitions

  • the present invention relates to a sustained releasing preparation comprising a crude drug extract for the moisturizing prevention and controlled release, specifically, the sustained releasing preparation comprising a crude drug extract of Salvia miltiorrhiza Bunge (Salviae Radix), Panax notoginseng Burk (Notoginseng Radix), borneolum etc, and water insoluble macro-molecule and/or sustained releasing carrier.
  • the sustained releasing preparation comprising a crude drug extract of Salvia miltiorrhiza Bunge (Salviae Radix), Panax notoginseng Burk (Notoginseng Radix), borneolum etc, and water insoluble macro-molecule and/or sustained releasing carrier.
  • the conventional preparation methods of natural product medicine for example, the method comprising the step of simple drying the natural product originated from animal, plant, minerals etc as a form of the natural form itself, chopped or pulverized form; and then extracting the same according to the conventional extraction methods such as boiling with water or spirits, have several disadvantages such as inconvenience to dosing, long-period preparation etc till now.
  • Korean Patent Publication No. 10-2007-0118020 discloses the preparation method of the granule and pill preparation comprising ginseng extract using by fluid-bed coater, specifically, HPMC, corn starch or dextrin as a seed.
  • Salviae Radix is a radix part of Salvia mitiorrhiza Bunge, a perennial herb belong to Labiatae genus, and it has been reported to contain lipophilic compounds such as tanshinone I, IIA, IIB, dihydrotanshinone, cryptotanshinone, neotanshinone A, B, C etc; hydrophilic compounds such as 3,4-dihydroxypheny lactic acid (Danshensu), procatechuic aldehyde, slavianolic acid B, ferulic acid, phenolic compounds etc (Luo H.W, et al, pigments from Salvia mitiorrhiza, phytochemistry, 24(4), pp815-817, 1985; Kang H.S. et al., Antioxidant effect of Salvia mitiorrhiza, Arch. Pharm. Res., 20(5), pp496-500, 1977).
  • lipophilic compounds such as tanshinone I, IIA, IIB, dihydrot
  • Notoginseng Radix is a radix part of Panax notoginseng (Burk.) F. H. Chen, a perennial herb belonged to Araliaceae, and it has been reported to contain 60 kinds of ginsenosides such as ginsenoside Rb1, Rh1, Rg1, notoginsenoside R1, R2, Fa, Fc etc, polyacetylene compounds, sesquiterpene compounds, phenolic acid, sterols, amino acid and polysaccharides (Wang C-Z et al., Phytochemical and Analytical studies of Panax notoginseng (Burk.) F. H. Chen. J. Nat. Med ., 60, pp97-105, 2006; Komakine N et al., New Dammarane type saponin from roots of Panax notoginseng, J. Nat. Med ., pp.135-137, 2006).
  • ginsenosides such as ginsenoside Rb1, Rh1, Rg1,
  • Borneolum is a white crystal prepared by performing the resin exuded from Dryobalanops aromatica belong to Diterocarpaceae genus and is reported to contain d-borneol, cinelol, L-camphor etc (Oh, K.S. et al, Pharmacological Research 42(6), pp559-564, 2000).
  • the natural product medicine mainly comprising crude drugs has been known to show various disadvantages such as easily stickiness caused by moisturization in the air, irregular releasing rate in blood resulting in frequent dosing etc till now.
  • sustained releasing preparation comprising a crude drug extract
  • the present inventors has been endeavored to develop a sustained releasing preparation comprising a crude drug extract showing potent preventing effect on moisturization and controlled release during all the day, specifically, the sustained releasing preparation comprising a crude drug extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, borneolum etc, by applying the drug delivery system having applied to only Western drug thereto, and finally, the present inventors have found a sustained releasing preparation comprising a crude drug extract showing potent preventing effect on moisturization and controlled release during all the day.
  • the object of the present invention is to provide a sustained releasing preparation comprising a crude drug extract for preventing effect on moisturization and controlled release for all the day.
  • a sustained releasing preparation comprising a crude drug extract for moisturizing prevention and controlled release for all the day.
  • the present invention provides an oral sustained releasing composition
  • an oral sustained releasing composition comprising (a) a dried granule composition, (b) a dried extract of crude drug, and (c) a sustained releasing carrier.
  • the above-mentioned dried granule composition is prepared by mixing (1) a dried extract of crude drug with (2) a slow releasing base including an water insoluble macromolecule; and performing the mixture to spray drying; wherein said crude drug is at least one selected from the group consisting of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, and borneolum, the extract of Dioscorea nipponica , the extract of Glycyrrhiza uralenesis, the extract of Paeonia albiflora, Paeonia lactiflora, Paeonia japonica, the rhizoma extract of Pueraria thunbergiana , the root extract of Angelica Koreana , the rhizoma extract of Zingiber officinale , the cortex extract of Cinnamomum cassia, the seed extract of Trichosanthes kirilowii , the leaf extract of Agastache rugosa , the fruit peel extract of Citrus
  • Water insoluble macromolecule defined herein is at least one selected from the group consisting of hydroxyl propyl cellulose such as hydroxyl propyl methyl cellulose 2910; methacrylic acid macromolecule and the ester thereof such as Eudragit RS 12.5, RS 100, RS PO, RS 30D, RL 12.5, RL 100, RL PO, RL 30D, NE 30D etc; lactose, cellulose acetate, Floxamer such as F127, F69 etc; ethyl cellulose, povidone; polyethylene oxide, polyamide, silicone and their derivatives etc.
  • the above-described dried granule composition is prepared by a spray drying method using by fluid-bed granular or spray dryer etc.
  • the present invention provides a sustained releasing composition mixed (a) the dried granule composition, with (b) the dried extract of crude drug with a mixed ratio ranging from 1: 0.1 ⁇ 5.0 (w/w) in the composition; a sustained releasing composition mixed (a) the dried granule composition, with (c) sustained releasing carrier with a mixed ratio ranging from 1: 0.1 ⁇ 20 (w/w) in the composition; a sustained releasing composition mixed (a) the dried granule composition, (b) the dried extract of crude drug, with (c) sustained releasing carrier with a mixed ratio ranging from 1: 0.01 ⁇ 10: 0.1 ⁇ 20 (w/w) in the composition.
  • dried extract of crude drug comprise the extract of simple crude drug originated from nature such as animal, plant, minerals etc and the combination thereof prepared by extracting the crude drug according to the well-known extraction methods by the person skilled in the art; in particular, for example, the dried extract of mixed crude drugs consisting of Salvia miltiorrhiza Bunge and Panax notoginseng Burk, and borneolum powder, preferably, with the mixture ratio of 1: 0.1 ⁇ 10: 0.1 ⁇ 3.0 (w/w), more preferably, with the mixture ratio of 1: 0.1 ⁇ 2: 0.1 ⁇ 3.0 (w/w); the extract of yam, a root or rhizome of Dioscorea genus plants such as Dioscorea nipponica, Dioscorea bulbifera, Dioscorea batatas, Dioscorea quinqueloba etc; wherein “extract”comprises the extract which is soluble in the solvent consisting of water, C1-C4 lower alky
  • a dried extract of crude drug defined herein means the dried powder prepared by well-known drying method in the art such as hot-wind drying method, freeze drying method, spray drying method, air oven drying method, vacuum oven drying method etc.
  • C1-C4 lower alkyl alcohol such
  • the dried granule composition defined herein comprise for example, the dried granule powder prepared by a spray drying method using by fluid-bed coater or spray dryer etc.
  • the present invention provides with a method for preparing a dried granule composition by the process comprising the steps of:
  • the present invention provides with a method for preparing a sustained releasing composition by the process comprising the steps of: mixing (a) the dried granule composition prepared in above-mention, (b) the dried extract of crude drugs as set forth in above-mention, and (c) a sustained releasing carrier together with the appropriate mixed ratio, and/or if necessary, further adding (d) a pharmaceutically acceptable additive thereto; and formulating into the purposed sustained releasing composition.
  • sustained releasing carrier comprises, for example, carboxymethyl cellulose, hydroxypropyl methyl cellulose, xanthan gum, povidone, sodium alginate, cabopol, polyethylene oxide, gelatin, starch, dextran sulfate, chitosan, hydroxyethyl cellulose, hydroxyl propyl cellulose, methyl cellulose, methacrylate polymer, and their ester such as Eudragit RS 12.5, RS 100, RS PO, RS 30D, RL 12.5, RL 100, RL PO, RL 30D, NE 30D etc, arabinogalactan gum, polyacrylate, polyvinyl alcohol, Arabia gum, locust bean gum, guar gum, cyclodextrin, gellan gum, Karaya gum, casein, tara gum, tamarind gum, tragacanth gum, pectin, glucomannan, ghatti gum, furcelleran, pullulan, carrageen
  • the sustained releasing oral composition comprising crude extracts as an active ingredient of the present invention shows 24-hours routinely releasing effect of drug, and could allow the rapid reach to initial therapeutic region as well as maintain the drug concentration within therapeutic region during 24 hours in blood by dint of adopting both active ingredient in the form of the sprayed dried powder and the dried powder of extract simultaneously.
  • the term “dried extract of crude drug”used herein comprise dried extract of simple crude drug of which extract is derived from the extraction of simple crude drug individually, for example, an extract of Dioscorea nipponica, and the extract of mixed crude drug of which extract is derived from the extraction of multiple crude drugs simultaneously, for example, the extract of mixed crude drugs consisting of Salvia miltiorrhiza Bunge , Panax notoginseng Burk , and borneolum , both of which are called as “extract”herein.
  • the “extract”soluble in solvent consisting of water, C1-C4 lower alkyl alcohol such as methanol, and ethanol etc and the mixture thereof are preferable in the present invention.
  • exemplary extract defined herein is the extract of mixed crude drugs consisting of (a) Salvia miltiorrhiza Bunge, (b) Panax notoginseng Burk, and (c) borneolum, preferably, wherein the mixed ratio of (a) Salvia miltiorrhiza Bunge, and (b) Panax notoginseng Burk ranges from 1: 0.1 ⁇ 10 (w/w), more preferably, 1: 0.1 ⁇ 2 (w/w).
  • the method of preparing inventive composition is mixing each component with each other of which 50 ⁇ 120 (w/w), preferably, 70 ⁇ 90 (w/w) (a) Salvia miltiorrhiza Bunge; 5 ⁇ 50 (w/w), preferably, 10 ⁇ 30 (w/w) (b) Panax notoginseng Burk; and 0.1 ⁇ 3 (w/w), preferably, 0.5 ⁇ 1.5 (w/w) (c) borneolum based on the dried weight of each component to prepared the inventive composition.
  • the present invention also provides the method for preparing “the dried extract of crude drug”comprising the steps;
  • the term “spray-dried granule composition”used herein comprise, for example, (a) a dried extract of crude drug and (b) water-insoluble polymers such as hydroxypropylcellulose, Eudragit RS 100 and the combination thereof.
  • the composition may be prepared by mixing (a) a dried extract of crude drug with (b) water-insoluble polymers with the mixed ratio ranging 1: 0.1 ⁇ 10 (w/w), preferably, 1: 0.7 ⁇ 2 (w/w); dissolving the mixture in an appropriate amount of mixture solution consisting of water, ethanol and acetone; and subjecting to spray drying using by fluid-bed granular to obtain inventive dried granule of the present invention.
  • the inventive granule of the present invention shows several advantages, for example, it allows sustained releasing property although a little amount of sustained releasing carrier is used in preparing sustained releasing oral preparation since the extract is enveloped with or attached to the water-insoluble polymer, as well as it plays important roles in improving several problems in the preparation designing and stability insurance which may frequently be occurred by the moisturization caused by crude drug extract.
  • the mixed ratio of the (a) crude extract and (b) hydroxyl propyl cellulose ranges 1: 0.1 ⁇ 10 (w/w), more preferably, 1: 0.7 ⁇ 2 (w/w) in order to exerting maximum effect on the moisturization prevention and sustained releasing activity.
  • the mixed ratio of the (a) crude extract and (b) Eudragit RS 100 ranges 1: 0.1 ⁇ 10 (w/w), more preferably, 1: 0.7 ⁇ 2 (w/w) and that of (a) crude extract, (b) hydroxyl propyl cellulose and (b) Eudragit RS 100 ranges 1: 0.1 ⁇ 5: 0.1 ⁇ 5 (w/w), more preferably, 1: 0.3 ⁇ 5: 0.3 ⁇ 5 (w/w), in order to exerting maximum effect on the moisturization prevention and sustained releasing activity.
  • Exemplary components used in the preparation of inventive dried granule of the present invention comprise lactose, cellulose acetate, poloxamer (F127, F68), ethyl cellulose, povidone, hydroxypropyl methyl cellulose 2910, polyethylene oxide, Eudragit etc, and other pharmaceutically acceptable water-insoluble polymers and sustained releasing base soluble in water, ethanol or acetone.
  • sustained releasing carrier comprise, for example, at least one selected from the group consisting of hydroxyl propyl methyl cellulose, xanthan gum, povidone, sodium alginate, and cabopol, which plays a key role as a matrix of the crude extract which is easily soluble in water or ethanol as well as plays a key role in maintaining the regular releasing for 24 hours by dint of the its sustained releasing effect through rapid Gel-hydration effect with water in dosing.
  • each carrier i.e., hydroxyl propyl methyl cellulose, xanthan gum, povidone, sodium alginate, and cabopol
  • the combinations therewith i.e., (2) the combination with hydroxyl propyl methyl cellulose and xanthan gum with the mixed ratio ranging 1:0.1 ⁇ 10 (w/w), more preferably, 1:0.1 ⁇ 0.5 (w/w) (3) the combination with hydroxyl propyl methyl cellulose and povidone with the mixed ratio ranging 1:0.1 ⁇ 10 (w/w), more preferably, 1:0.1 ⁇ 0.5 (w/w)
  • the combination with hydroxyl propyl methyl cellulose and sodium alginate with the mixed ratio ranging 1:0.1 ⁇ 20 (w/w), more preferably, 1:0.1 ⁇ 4 (w/w) (5) the combination with hydroxyl
  • sustained releasing carriers for example, hydroxyl propyl methyl cellulose (4000cps ⁇ 100,000cps), povidone (M.W. 10,000 ⁇ M. W. 3,000,000), locust bean gum, xanthan gum, guar gum, cabopol, polyethylene oxide (M.W. 10,000 ⁇ M. W.
  • sodium bicarbonate sodium bicarbonate, carnauba wax, polyvinyl acetate, sodium alginate, the mixture of povidone and polyvinyl acetate, Eudragits and the like as well as the other pharmaceutically acceptable sustained releasing base may be used herein, which allow dual effects, i.e., rapid reach to therapeutic region in a few hours by dint of rapid dissolution of crude extract; and the long-lasting maintenance of drug concentration in therapeutic region.
  • the inventive composition is prepared by mixing (a) the extract of mixed crude drugs consisting of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, and borneolum, with the dried granule comprising the same prepared by spray-drying method, wherein the mixed ratio of (a) the extract of mixed crude drugs, and (b) the dried granule composition comprising the same, ranging from 0.1 ⁇ 5: 1 (w/w), more preferably, 0.1 ⁇ 1: 1 (w/w) is preferred to obtain more faster releasing sustained releasing oral composition at initial stage.
  • the extract of mixed crude drugs consisting of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, and borneolum
  • the extract of Dioscorea nipponica the extract of Glycyrrhiza uralenesis
  • the extract of Paeonia albiflora, Paeonia lactiflora, Paeonia japonica etc may be used herein.
  • At least one crude drug extract(s) selected from the group of: the rhizoma extract of Pueraria thunbergiana , the root extract of Angelica Koreana , the rhizoma extract of Zingiber officinale , the cortex extract of Cinnamomum cassia, the seed extract of Trichosanthes kirilowii , the leaf extract of Agastache rugosa , the fruit peel extract of Citrus unshinu , the flower extract of Lonicera japonica , the root extract of Platycodon grandiflorum , the root extract of Angelica sinensis , the seed extract of Zizyphus jujube , the rhizoma extract of Erigeron Canadensis , the rhizoma extract of Liriope platyphylla , the seed extract of Hordeum vulgare , the root extract of Paeonia suffruticosa , the root
  • the present invention provides an oral sustained releasing composition
  • an oral sustained releasing composition comprising (a) the dried granule composition, (b) the dried extract of crude drug, (c) sustained releasing carrier, and (d) a pharmaceutically acceptable additive.
  • a pharmaceutically acceptable additive comprises at least one additives selected from the group of a binder, a lubricant, a disintegrating agent, coloring agent, a sweetener, a flavoring agent, a stabilizer, a diluting agent and so on.
  • Exemplary binders which may be used herein comprises at least one selected from polyvinyl pyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose, hydroxyl propyl methyl cellulose, dextrin, gelatin, methyl cellulose, hydroxyl cellulose, hydroxyl methyl cellulose, polyvinyl alcohol, pre-gelatinized starch, and Arabia gum.
  • Exemplary disintegrating agents which may be used herein comprises at least one selected from sodium starch glycolate, Crospovidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyl propyl methyl cellulose, polyvinyl pyrrolidone, starch, calcium carboxymethyl cellulose and the combination thereof.
  • Exemplary lubricants which may be used herein comprises at least one selected from magnesium stearate, talc, stearic acid, light anhydrous silicate and the combination thereof.
  • Exemplary coloring agents which may be used herein comprises at least one selected from titanium dioxide, ferrous oxide, magnesium carbonate, calcium sulfuric acid, magnesium oxide, aluminium lake, such as blue No.1, red No. 40, yellow No 203 and the combination thereof.
  • Exemplary conservatives which may be used herein comprises at least one selected from benzoic acid, methyl paraben, propyl paraben and the combination thereof.
  • additives well-known in the art such as a sweetener, a flavoring agent, a stabilizer, a diluting agent and so on, may be further added if necessary.
  • the present invention also provides a method for preparing a sustained releasing composition by the process comprising the steps of: mixing (a) aformentioned dried granule composition, (b) the dried extract of crude drugs, and (c) a sustained releasing carrier together with the appropriate mixed ratio, if necessary, further adding (d) a pharmaceutically acceptable additive thereto; and formulating into purposed sustained releasing composition, preferably, oral sustained releasing composition, which does not intend to limit thereto herein.
  • inventive composition of the present invention may be used to prepare various oral sustained releasing composition, for example, tablet, as well as powder, granule, capsule, pill and the like, which is well-known in the art.
  • the sustained releasing preparation comprising a crude drug extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, borneolum etc, which shows 24-hours routinely releasing effect of drug, and reach to initial therapeutic region rapidly well as maintain the drug concentration within therapeutic region during 24 hours in blood. Therefore, the present invention can be used as the sustained releasing oral composition.
  • Fig. 1 presents the releasing test result of inventive sustained releasing composition disclosed in Experimental Example 2-1.
  • the supernatant was collected by removing the precipitate from the solution, concentrated and dried at 60°C with hot-wind spraying method to obtain 170g of dried extract of mixed crude drugs consisting of Salvia miltiorrhiza Bunge and Panax notoginseng Burk.
  • 170g of the extract prepared in 1-1 was mixed with dried power of borneolum thoroughly to obtain inventive extract of mixed crude drugs consisting of (a) Salvia miltiorrhiza Bunge, (b) Panax notoginseng Burk, and (c) borneolum.
  • inventive composition as shown in Table 1, the dried extract of Salvia miltiorrhiza Bunge and Panax notoginseng Burk prepared in Reference Example were mixed together with the mixed ratio of 1: 0.2 (w/w %).
  • the mixed powder of crude drugs was further mixed with dried powder of borneolum together with the mixed ratio of 1: 0.01 (w/w %).
  • the mixture was mixed with hydroxyl propyl cellulose (HPC) and the mixture was dissolved in appropriate amount of mixture solution consisting of water, ethanol and acetone.
  • the solution was dried and formulated to 350g of dried granule composition using by fluid-bed granular (GPCG1, Glatt Inc, Germany).
  • the resulting granule composition comprise (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum (b) HPC showing a mixed ratio ranging 1: 0.5 ⁇ 1.5 (w/w) and the granule was sieved with mesh sieve (No. 30) to prepare inventive dried granules as shown in Table 1.
  • inventive composition as shown in Table 2, the dried mixture of the extract of Salvia miltiorrhiza Bunge and Panax notoginseng Burk prepared in Reference Example were mixed with Eudragit RS 100, and the granule composition comprising (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum (b) Eudragit RS 100 was prepared according to the procedure disclosed in Example 2-1.
  • inventive composition as shown in Table 3, the dried mixture of the extract of Salvia miltiorrhiza Bunge and Panax notoginseng Burk prepared in Reference Example was mixed with HPC and Eudragit RS 100, and the granule composition comprising (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum (b) HPC, and Eudragit RS 100 was prepared according to the procedure disclosed in Example 2-1.
  • inventive composition as shown in Table 4, the dried extract of Dioscorea nipponica prepared in Reference Example was mixed with HPC and Eudragit RS 100, and the granule composition comprising (a) the dried extract of Dioscorea nipponica , (b) HPC, and Eudragit RS 100 was prepared according to the procedure disclosed in Example 2-1.
  • Example 1 Sustained releasing composition
  • the granule composition comprising (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum and (b) HPC was prepared according to the procedure disclosed in Referance Example 2-1.
  • the granule composition was further mixed with (a′) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum and (c) a sustained releasing carrier in order to make the mixture with the mixed ratio of (e): (a′): (c)(1:0.01:0.1, w/w).
  • the mixture was dissolved in appropriate amount of mixture solution consisting of water, ethanol and acetone.
  • the solution was dried and formulated to 350g of dried granule using by fluid-bed granular (GPCG1, Glatt Inc, Germany).
  • the resulting granule was mixed and further formulated to a tablet.
  • composition comprising (e) the granule composition, (a′) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum (c) hydroxy propyl methyl cellulose 2208 (100,000cps), xanthan (d) microcrystalline cellulose, magnesium stearate, calcium carboxy methyl cellulose, sodium starch glycolate was formulated to granule and the granule was sieved with mesh sieve (No. 30) to prepare inventive tablet as shown in Table 5.
  • Table 7 Component Amount (w/w %) (e) granule composition (a) the mixture * 27.3 (b) Hydroxypropylcellulose(HPC) Mixed base (a′) the mixture * 10.6 (c) Hydroxypropylmethyl cellulose 2208 27.8 Cabopol 7.6 (d)** Microcrystalline cellulose 12.6 Magnesium stearate 1.5 Sodium starch glycolate 12.6 Total 100 100 *: (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum **: (d): additive
  • Table 8 Component Amount (w/w %) (e) granule composition (a) the mixture * 27 (b) Hydroxypropylcellulose(HPC) Mixed base (a′) the mixture * 10 (c) Hydroxypropylmethyl cellulose 2208 37 (d)** Microcrystalline cellulose 10 Magnesium stearate 1.5 Calcium carboxy methyl cellulose 14 Total 100 100 *: (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum **: (d): additive
  • Table 12 Component Amount (w/w %) (e) granule composition (a) the mixture * 44.6 (b) Eudragit RS100 Mixed base (a′) the mixture * 30 (c) Hydroxypropylmethyl cellulose 2208 15 (d)** Microcrystalline cellulose 4 Magnesium stearate 0.4 Sodium starch glycolate 6 Total 100 100 *: (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum **: (d): additive
  • Table 14 Component Amount (w/w %) (e) granule composition (a) the mixture * 39 (b) Eudragit RS100 (b) HPC Mixed base (a ′)the mixture * 9.8 (c) Hydroxypropylmethyl cellulose 2208 24.4 (d)** Microcrystalline cellulose 14.6 Magnesium stearate 1.2 Calcium caroxymethyl cellulose 7.3 Sodium starch glycolate 3.7 Total 100 100 *: (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum **: (d): additive
  • test groups had been kept on store at room temperature and the reduced weight of the groups was determined by using an apparatus (MB45, OHUS Co.).
  • each dissolution solution was collected at regular intervals, i.e., 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours and filtered with 0.45 microlitermeter of syringe filter to use as a test sample.
  • New dissolution solution was supplemented to the dissolution tester apparatus after collecting the dissolution solution.
  • the inventive sustained releasing tablet comprising an inventive dried granule composition and a crude extract, showed rapidly releasing pattern at initial stage and then routinely releasing pattern for 24 hours whereas the comparative sustained releasing tablet comprising only a crude extract, showed rapidly releasing pattern at initial stage, as shown in Fig. 1.
  • the sustained releasing tablet comprising a dried granule prepared by using HPC and dried crude extract showed various releasing patterns according to various factors, i.e., the sort of sustained releasing carrier, disintegrating agent, lubricator etc, as shown in Table 24.
  • Example 1-8 The dissolution test on the inventive sustained releasing tablet disclosed in Example 1-8 was performed according to the procedure disclosed in Experimental Example 2-1.
  • the sustained releasing tablet comprising dried granule prepared by using Eudragit RS 100, showed favorable releasing pattern i.e., 46% in 5 hours, 78% in 12 hours, and 94% in 24 hours, as shown in Table 24.
  • the releasing pattern of the sustained releasing tablet comprising dried granule prepared by using HPC and Eudragit RS 100, with various conditions, i.e., the different amout of sustained releasing carrier and bases was shown in Table 24.
  • the sustained releasing tablet comprising dried granule prepared by using HPC and Eudragit RS 100 as water insoluble macromolecules, and various amount of sodium alginate as a additive, showed favorable releasing pattern i.e., 64% in case the tablet disclosed in Example 1-12, 74% in case the tablet disclosed in Example 1-13, and 76% in case the tablet disclosed in Example 1-14, in 12 hours, respectively, as shown in Table 25.
  • Example 1-16 The dissolution test on the inventive sustained releasing tablet disclosed in Example 1-16 was performed according to the procedure disclosed in Experimental Example 2-1.
  • the sustained releasing tablet comprising dried granule comprising an extract of Dioscorea nipponica, HPC and Eduragit RS 100, and sustained releasing carrier with an additive, showed favorable releasing pattern i.e., 48% in 5 hours, 79% in 12 hours and 99% in 24 hours, as shown in Table 25.
  • the inventive sustained releasing preparation comprising crude drug extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, borneolum etc, showed potent preventing effect on moisturization and controlled release during all the day, which is useful in the preparation of oral sustained releasing composition.

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Abstract

L’invention concerne une préparation à libération prolongée renfermant un extrait de médicament brut servant à prévenir l’humidification et permettant une libération prolongée, et en particulier une préparation à libération prolongée renfermant un extrait de médicament brut de Salvia miltiorrhiza Bunge, Panax notoginseng Burk, borneolum, etc., ainsi qu’une macromolécule insoluble dans l’eau et/ou un vecteur à libération prolongée présentant un effet de libération régulière de médicament sur 24 heures, et pouvant permettre d’atteindre rapidement la région thérapeutique initiale ainsi que de maintenir la concentration du médicament à l’intérieur de ladite région thérapeutique durant 24 heures dans le sang.
PCT/KR2009/003228 2008-06-17 2009-06-16 Préparation à libération prolongée renfermant un extrait de médicament brut servant à prévenir l’humidification et permettant une libération prolongée Ceased WO2009154396A2 (fr)

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CN2009800004796A CN101896168A (zh) 2008-06-17 2009-06-16 用于阻止水分增加并控制释放的包含生药提取物的缓释制剂

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KR10-2008-0056664 2008-06-17
KR20080056664 2008-06-17
KR1020090053084A KR20090131256A (ko) 2008-06-17 2009-06-15 함습 억제 및 방출속도 조절을 위한 생약추출물 함유 서방성 제제
KR10-2009-0053084 2009-06-15

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ITMI20091970A1 (it) * 2009-11-11 2011-05-12 Velleja Res Srl Formulazioni comprendenti acido carnosico, o derivati estrattivi che lo contengano, per il trattamento e la prevenzione dell'ipertrigliceridemia
WO2011143844A1 (fr) * 2010-05-21 2011-11-24 深圳市齐旺投资有限公司 Composition de médecine chinoise traditionnelle pour traiter l'infection du sous-type de virus de la grippe a et procédé de préparation de celle-ci
CN102657719A (zh) * 2012-04-27 2012-09-12 中国人民解放军第三七一医院 一种治疗高血脂的中药制剂
CN109602653A (zh) * 2018-12-17 2019-04-12 广州市白云区研美化妆品厂 具有美白功效的组合物、化妆品、精华液及其制备方法
CN112120970A (zh) * 2020-09-29 2020-12-25 上海相宜本草化妆品股份有限公司 精油组合物、其制备方法及用途
CN114470508A (zh) * 2022-01-26 2022-05-13 中原工学院 一种具有药物缓释作用的理疗盐枕材料、制备方法和应用
CN115501156A (zh) * 2022-09-28 2022-12-23 福建片仔癀化妆品有限公司 一种具有美白舒缓功效的化妆品原料组合物及其评价体系
CN120242134A (zh) * 2025-04-09 2025-07-04 海南觅蜜健康科技有限公司 一种抑菌养护水凝胶及其制备方法与应用

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KR19980066045A (ko) * 1997-01-18 1998-10-15 이영호 부형제가 함유되지 않은 생약의 순수엑스건조분말 및 그의 제조방법
GB0102342D0 (en) * 2001-01-30 2001-03-14 Smithkline Beecham Plc Pharmaceutical formulation
US20040006072A1 (en) * 2002-06-25 2004-01-08 Franz Robert M. Sustained-release alprazolam composition

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ITMI20091970A1 (it) * 2009-11-11 2011-05-12 Velleja Res Srl Formulazioni comprendenti acido carnosico, o derivati estrattivi che lo contengano, per il trattamento e la prevenzione dell'ipertrigliceridemia
WO2011143844A1 (fr) * 2010-05-21 2011-11-24 深圳市齐旺投资有限公司 Composition de médecine chinoise traditionnelle pour traiter l'infection du sous-type de virus de la grippe a et procédé de préparation de celle-ci
CN102657719A (zh) * 2012-04-27 2012-09-12 中国人民解放军第三七一医院 一种治疗高血脂的中药制剂
CN109602653A (zh) * 2018-12-17 2019-04-12 广州市白云区研美化妆品厂 具有美白功效的组合物、化妆品、精华液及其制备方法
CN109602653B (zh) * 2018-12-17 2022-01-11 广州市白云区研美化妆品厂 具有美白功效的组合物、化妆品、精华液及其制备方法
CN112120970A (zh) * 2020-09-29 2020-12-25 上海相宜本草化妆品股份有限公司 精油组合物、其制备方法及用途
CN112120970B (zh) * 2020-09-29 2023-02-03 上海相宜本草化妆品股份有限公司 一种具有促渗作用的中草药精油组合物、其制备方法及用途
CN114470508A (zh) * 2022-01-26 2022-05-13 中原工学院 一种具有药物缓释作用的理疗盐枕材料、制备方法和应用
CN114470508B (zh) * 2022-01-26 2023-07-21 中原工学院 一种具有药物缓释作用的理疗盐枕材料、制备方法和应用
CN115501156A (zh) * 2022-09-28 2022-12-23 福建片仔癀化妆品有限公司 一种具有美白舒缓功效的化妆品原料组合物及其评价体系
CN115501156B (zh) * 2022-09-28 2023-12-29 福建片仔癀化妆品有限公司 一种具有美白舒缓功效的化妆品原料组合物及其评价体系
CN120242134A (zh) * 2025-04-09 2025-07-04 海南觅蜜健康科技有限公司 一种抑菌养护水凝胶及其制备方法与应用

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