WO2009154396A2 - Sustained releasing preparation comprising a crude drug extract for preventing moisturization and controlled release - Google Patents

Abstract

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, Panax notoginseng Burk, borneolum etc, and water insoluble macro-molecule and/or sustained releasing carrier, which shows 24-hours routinely releasing effect of drug, and could allow the rapid reach to initial therapeutic region well as maintain the drug concentration within therapeutic region during 24 hours in blood.

Description

SUSTAINED RELEASING PREPARATION COMPRISING A CRUDE DRUG EXTRACT FOR PREVENTING MOISTURIZATION AND CONTROLLED RELEASE

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.

Generally, there has been reported that 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.

There have been several attempts to solve the problems occurring in the preparation of natural product medicine containing crude drug, for example, the development to the form of powder, granule, pills, extract and tablet designed to quantification recently.

For example, 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.

However, there still has been needed to develop useful preparation comprising crude drug extract in dosing, which can be orally administrated once a day till now.

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).

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).

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).

However, 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.

Furthermore, there has been not reported or disclosed on the sustained releasing preparation comprising a crude drug extract, in any of above cited literatures, the disclosures of which are incorporated herein by reference.

Accordingly, 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.

Accordingly, it is an object of the present invention to provide a sustained releasing preparation comprising a crude drug extract for moisturizing prevention and controlled release for all the day.

In a preferred embodiment, the present invention provides an oral sustained releasing composition comprising (a) a dried granule composition, (b) a dried extract of crude drug, and (c) a sustained releasing carrier.

Specifically, 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 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 extract of Inula helenium, the herb extract of Mentha arvensis, the rhizoma extract of Pinellia ternate, the root extract of Ledebouriella seseloides, the white powder of Poria cocos, the root extract of Panax ginseng, the rhizoma extract of Paeonia japonica, the root extract of Angelica dahurica, the rhizome extract of Atractylodes macrocephala, the rhizome extract of Curcuma zedoaria, the fructus extract of Amomum xanthioides, the fructus extract of Crataegus pinnatifida, the rhizome extract of Sparganium stoloniferum, the rhizome extract of Rehmannia glutinosa, the powder of gypsum, the root extract of Asarum sieboldii, the seed extract of Perilla frutescens, the rhizoma extract of Cimifuga foetida, the root extract of Bupleurum falcatum, the fructus extract of Forsythia koreana, the fructus extract of Schisandra chinensis, the fructus extract of Arctium lappa, the rhizome extract of Curcuma aromatica, the herb extract of Artemisia capillaries, the root extract of Angelica decursiva, the fructus extract of Poncitrus trifoliata, the rhizoma extract of Anemarrhena asphodeloides, the fructus extract of Citrus aurantium, the rhizome extract of Atractylodes japonica, the rhizome extract of Cnidium officinale, the rhizome extract of Gastrodia elata, the fructus peel extract of Citrus unshiu, the root extract of Allium fistulosum, the fructus extract of Amomum villosum, the fructus extract of Gardenia jasminoides, the rhizome extract of Alisma plantago-aquatica, the seed extract of Prunus armeniaca var ansu, the rhizome extract of Cyperus rotundus, the herb extract of Schizonepeta tenuifolia var japonica, the root extract of Scutellaria baicalensis, the root extract of Astragalus membranaceus, the rhizome extract of Coptis chinensis, and the cortex extract of Phellodendron amurense., preferably, at least one selected from the group consisting of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, and borneolum, the extract of Dioscorea nipponica.

The term, “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.

Specifically, the above-described dried granule composition is prepared by a spray drying method using by fluid-bed granular or spray dryer etc.

Specifically, 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.

The term “dried extract of crude drug” defined herein 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 alkyl alcohol such as methanol, and ethanol etc and the mixture thereof, preferably, water.

The term, “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.

The term, “water insoluble macromolecule” defined herein used as a slow releasing base comprise for example, 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, in particular, at least one macromolecule disclosed in the literature (Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, 1986), wherein the slow releasing base is insoluble in simple water however, soluble in other solvents for example, C1-C4 lower alkyl alcohol such as methanol, ethanol, butanol etc, acetone and the like or the combination with water.

The term, “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:

(a)mixing (1) Salvia miltiorrhiza Bunge, with (2) Panax notoginseng Burk, with the appropriate mixed ratio and extracting the mixture with water, C1-C4 lower alkyl alcohol such as methanol, ethanol etc, or the mixture thereof to concentrate at 1^st step;

(b)Centrifuging the concentrates obtained at 1^st step to remove the precipitate at 2^nd step;

(c)Concentrating the precipitate obtained at 2^nd step in vaccuo at 3^rd step;

(d)Adding an organic solvent such as ethanol etc to the concentrate obtained at 3^rd step to be left alone at 4^th step;

(e)Filtering the residue obtained at 5^th step and removing the remaining organic solvent from the extract in vaccuo at 6^th step;

(f) Concentrating the extract of water layer obtained in 6^th step and drying the extract to obtain the dried extract of crude drugs (1) and (2);

(g) mixing the dried extract of crude drugs (1) and (2) with dried powder of borneolum (3) with the appropriate mixed ratio;

(h) mixing the dried extract of crude drug with (4) water insoluble macromolecule selected from the group consisitng of hydroxypropyl methyl cellulose 2910, Eudragit etc and other pharmaceutically acceptable water-insoluble polymers, such as lactose, cellulose acetate, poloxamer (F127, F68), ethyl cellulose, povidone, polyethylene oxide, polyamide and silicone with the appropriate mixed ratio,

(i)dissolving the mixture in water, C1-C4 lower alkyl alcohol such as methanol, ethanol etc, or the mixture thereof;

(j) subjecting to spray drying method using by fluid-bed granular or spray dryer etc; and forming granule by granulate machine to obtain final dried granule composition.

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.

The term “sustained releasing carrier” defined herein 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, carrageenan, glucosamine, and their derivatives, in particular, a pharmaceutically acceptable carrier showing the slow releasing effect on the drug release disclosed in the literature (Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, 1986), preferably, at least one selected from the group consisting of hydroxyl propyl methyl cellulose, xanthan gum, povidone, sodium alginate, and cabopol.

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.

In detail, each component of the composition and the mechanism of the present invention are explained as follows:

A. Active Ingredient

As an active ingredient in the present composition, 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. Preferably, 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.

Specifically, 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). In a preferred embodiment, 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.

As an exemplary method for preparing inventive extract of the present invention, the present invention also provides the method for preparing “the dried extract of crude drug”comprising the steps;

(a)Mixing (1) Salvia miltiorrhiza Bunge, with (2) Panax notoginseng Burk, with the appropriate mixed ratio and extracting the mixture with water, C1-C4 lower alkyl alcohol such as methanol, ethanol etc, or the mixture thereof to concentrate at 1^st step;

(b)Centrifuging the concentrates obtained at 1^st step to remove the precipitate at 2^nd step;

(c)Concentrating the supernatant obtained at 2^nd step in vaccuo at 3^rd step;

(d)Adding an organic solvent such as ethanol etc to the concentrate obtained at 3^rd step to be left alone at 4^th step;

(e)Filtering the residue obtained at 5^th step and removing the remaining organic solvent from the extract in water layer at 6^th step;

(f) Concentrating the extract of water layer obtained in 6^th step and drying the extract to obtain the dried extract of crude drugs (1) and (2);

(g) mixing the dried extract of crude drugs (1) and (2) with dried powder of borneolum (3) with the appropriate mixed ratio to afford dried crude drug extract of the present invention.

B. Spray-dried granule

As an important component in the present composition, 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. Preferably, 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.

In case of adopting the aforementioned two components of the dried granule, it is preferred that 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. Additionally, it is preferred that 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.

C. Sustained releasing carriers

As an other important component in the present composition, the term “sustained releasing carrier”used herein 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.

In case of using the above-mentioned five carriers, (1) 5~70 (w/w %), more preferably, 10~40 (w/w %) each carrier, i.e., hydroxyl propyl methyl cellulose, xanthan gum, povidone, sodium alginate, and cabopol, of the composition is preferably used; and 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) (4) 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 propyl methyl cellulose and cabopol with the mixed ratio ranging 1:0.1~10 (w/w), more preferably, 1:0.1~0.5 (w/w) (6) the combination with hydroxyl propyl methyl cellulose, xanthan gum and sodium alginate with the mixed ratio ranging 1: 0.1~10 :0.1~10 (w/w), more preferably, 1: 0.1~0.5: 0.1~0.5 (w/w) are used herein.

As exemplary specific components which can be used as such 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. 3,000,000), 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.

In a preferred embodiment of the present invention, 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.

In an alternative active ingredients, for example, 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, and the extract of Paeonia albiflora, Paeonia lactiflora, Paeonia japonica etc may be used herein.

Besides the extract of the above-described crude drugs, 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 extract of Inula helenium, the herb extract of Mentha arvensis, the rhizoma extract of Pinellia ternate, the root extract of Ledebouriella seseloides, the white powder of Poria cocos, the root extract of Panax ginseng, the rhizoma extract of Paeonia japonica, the root extract of Angelica dahurica, the rhizome extract of Atractylodes macrocephala, the rhizome extract of Curcuma zedoaria, the fructus extract of Amomum xanthioides, the fructus extract of Crataegus pinnatifida, the rhizome extract of Sparganium stoloniferum, the rhizome extract of Rehmannia glutinosa, the powder of gypsum, the root extract of Asarum sieboldii, the seed extract of Perilla frutescens, the rhizoma extract of Cimifuga foetida, the root extract of Bupleurum falcatum, the fructus extract of Forsythia koreana, the fructus extract of Schisandra chinensis, the fructus extract of Arctium lappa, the rhizome extract of Curcuma aromatica, the herb extract of Artemisia capillaries, the root extract of Angelica decursiva, the fructus extract of Poncitrus trifoliata, the rhizoma extract of Anemarrhena asphodeloides, the fructus extract of Citrus aurantium, the rhizome extract of Atractylodes japonica, the rhizome extract of Cnidium officinale, the rhizome extract of Gastrodia elata, the fructus peel extract of Citrus unshiu, the root extract of Allium fistulosum, the fructus extract of Amomum villosum, the fructus extract of Gardenia jasminoides, the rhizome extract of Alisma plantago-aquatica, the seed extract of Prunus armeniaca var ansu, the rhizome extract of Cyperus rotundus, the herb extract of Schizonepeta tenuifolia var japonica, the root extract of Scutellaria baicalensis, the root extract of Astragalus membranaceus, the rhizome extract of Coptis chinensis, the cortex extract of Phellodendron amurense, the cortex extract of Magnolia officinalis, and the extract of other pharmacologically active crude drugs, in particular, the extract thereof prepared by the extraction with water or organic solvent such as ethanol, may preferably, be used herein.

In the other preferred embodiment, the present invention provides 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.

Specifically, the term “a pharmaceutically acceptable additive”used herein 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.

Additionally, the other 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.

Accordingly, 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.

The 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.

The above and other objects and features of the present invention will become apparent from the following description, when taken in conjunction with the accompanying drawings, in which:

Fig. 1 presents the releasing test result of inventive sustained releasing composition disclosed in Experimental Example 2-1.

The following Examples and Experimental Examples are intended to further illustrate matrix type patch formulation of the present invention without limiting its scope.

Reference Example 1. Preparation of the extract of crude drugs

1-1. The extract of mixed crude drugs (1)

1400g of Salvia miltiorrhiza Bunge, and 274g of Panax notoginseng Burk, procured from Kyungdong market in Korea was washed, sliced and dried. 8.4kg of distilled water was added to the crude drug to extract at 105℃ for 2 hours using high-speed vaccum extraction apparatus (COSMOS 660, KyungSeo Electronics, Korea) and repeated twice. The extracted solution was concentrated with vaccuo and centrifuged to collect the supernatant layer. The supernatant layer was concentrated again, and the concentrate was added to ethanol solution to be left alone for more than 12 hours. The supernatant was collected by removing the precipitate from the solution, concentrated and dried at 60℃ with hot-wind spraying method to obtain 170g of dried extract of mixed crude drugs consisting of Salvia miltiorrhiza Bunge and Panax notoginseng Burk.

1-2. The extract of mixed crude drugs (2)

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.

1-3. The extract of Salvia miltiorrhiza Bunge(3)

1.4 kg of Salvia miltiorrhiza Bunge, procured from Kyungdong market in Korea was used to obtain 154g of the extract of Salvia miltiorrhiza Bunge, according to similar method to that disclosed in 1-1.

1-4. The extract of Panax notoginseng Burk(4)

274g of Panax notoginseng Burk, procured from Kyungdong market in Korea was used to obtain 30g of the extract of Panax notoginseng Burk, according to similar method to that disclosed in 1-1.

1-5. The extract of Dioscorea nipponica (5)

2000g of Dioscorea nipponica procured from Kyungdong market in Korea was washed, sliced and dried. 10kg of distilled water was added to the crude drug to extract at 105℃ for 2 hours using high-speed vaccum extraction apparatus (COSMOS 660, KyungSeo Electronics, Korea) and repeated twice. The supernatant layer was concentrated with vaccuo, and the concentrate was subjected to recrystallization with saturated ethanol solution. The supernatant was collected by removing the precipitate from the solution, concentrated and dried at 60℃ with hot-wind spraying method to obtain 224g of dried extract of Dioscorea nipponica.

Reference Example 2. dried granule composition

2-1. Mixture of crude drug extract and HPC (1)

To prepare 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.

Table 1

Component		Amount (w/w %)
		1:0.5	1:1	1:1.5
Granule	(a) the mixture *	66	50	34
	(b) HPC**	34	50	66
Total		100	100	100
*: (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum**: (b) hydroxyl propyl cellulose (HPC)

2-2. Mixture of crude drug extract and Eudragit RS 100 (2)

To prepare 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.

Table 2

Component		Amount (w/w %)
		1:0.5	1:1	1:1.5
Granule	(a) the mixture *	66	50	34
	(b) Eudragit RS	34	50	66
Total		100	100	100
*: (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum

2-3. Mixture of crude drug extract, HPC and Eudragit RS 100 (3)

To prepare 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.

Table 3

Component			Amount (w/w %)
			1:1:1
Granule	(a)	the mixture *	34
	(b)	HPC	33
		Eudragit RS	33
Total			100
*: (a) the mixture of crude drug consisting of the extract of Salvia miltiorrhiza Bunge, Panax notoginseng Burk and dried powder of borneolum

2-4. Mixture of crude drug extract, HPC and Eudragit RS 100 (4)

To prepare 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.

Table 4

Component			Amount (w/w %)
			1:1:1
Granule	(a)	the extract DN *	34
	(b)	HPC	33
		Eudragit RS	33
Total			100
*: (a) the extract D N: the extract of Dioscorea nipponica

Example 1. Sustained releasing composition

1-1. Sustained releasing composition (1)

To prepare inventive composition as shown in Table 5, 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. (e) 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.

The 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 5

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		27
	(b) Hydroxypropylcellulose(HPC)
Mixed base	(a′) the mixture *		10
	(c)	Hydroxypropylmethyl cellulose 2208	30
		xanthan	5
	(d)**	Microcrystalline cellulose	12
		Magnesium stearate	1.5
		Calcium carboxy methyl cellulose	10
		Sodium starch glycolate	3.7
Total	100	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

1-2. Sustained releasing composition (2)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (2) as shown in Table 6.

Table 6

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		27
	(b) Hydroxypropylcellulose(HPC)
Mixed base	(a′) the mixture *		10
	(c)	Hydroxypropylmethyl cellulose 2208	30
		xanthan	3.7
	(d)**	Microcrystalline cellulose	15
		Magnesium stearate	1.5
		Sodium starch glycolate	12
Total	100	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

1-3. Sustained releasing composition (3)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (3) as shown in Table 7.

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	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

1-4. Sustained releasing composition (4)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (4) as shown in Table 8.

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	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

1-5. Sustained releasing composition (5)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (5) as shown in Table 9.

Table 9

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		18.9
	(b) Hydroxypropylcellulose(HPC)
Mixed base	(a′) the mixture *		34.1
	(c)	Hydroxypropylmethyl cellulose 2208	22.7
	(d)**	Microcrystalline cellulose	7.6
		Magnesium stearate	1.5
		Sodium starch glycolate	15.9
Total	100	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

1-6. Sustained releasing composition (6)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (6) as shown in Table 10.

Table 10

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		26.5
	(b) Hydroxypropylcellulose(HPC)
Mixed base	(a ′)the mixture *		26.5
	(c)	Hydroxypropylmethyl cellulose 2208	22.7
	(d)**	Microcrystalline cellulose	7.6
		Magnesium stearate	1.5
		Sodium starch glycolate	15.2
Total	100	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

1-7. Sustained releasing composition (7)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (7) as shown in Table 11.

Table 11

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		34.1
	(b) Hydroxypropylcellulose(HPC)
Mixed base	(a′) the mixture *		18.9
	(c)	Hydroxypropylmethyl cellulose 2208	22.7
	(d)**	Microcrystalline cellulose	7.6
		Magnesium stearate	1.5
		Sodium starch glycolate	15.2
Total	100	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

1-8. Sustained releasing composition (8)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (8) as shown in Table 12.

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	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

1-9. Sustained releasing composition (9)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (9) as shown in Table 13.

Table 13

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		39
	(b) Eudragit RS100
	(b) HPC
Mixed base	(a′) the mixture *		9.7
	(c)	Hydroxypropylmethyl cellulose 2208	25.5
		xanthan	3.5
	(d)**	Microcrystalline cellulose	11.6
		Magnesium stearate	1.4
		Calcium caroxymethyl cellulose	7.0
		Sodium starch glycolate	2.3
Total	100	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

1-10. Sustained releasing composition (10)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (10) as shown in Table 14.

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	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

1-11. Sustained releasing composition (11)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (11) as shown in Table 15.

Table 15

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		36
	(b) Eudragit RS100
	(b) HPC
Mixed base	(a′) the mixture *		9
	(c)	Hydroxypropylmethyl cellulose 2208	24.4
		povidone	2.6
	(d)**	Microcrystalline cellulose	15
		Magnesium stearate	1.3
		Calcium caroxymethyl cellulose	7.7
		Sodium starch glycolate	4
Total	100	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

1-12. Sustained releasing composition (12)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (12) as shown in Table 16.

Table 16

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		38
	(b) Eudragit RS100
	(b) HPC
Mixed base	(a′) the mixture *		9.5
	(c)	Hydroxypropylmethyl cellulose 2208	30.8
		Sodium alginate	7.7
	(d)**	Magnesium stearate	1.18
		Eudragit S100	7.7
		Titanium oxide	5.13
Total	100	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

1-13. Sustained releasing composition (13)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (13) as shown in Table 17.

Table 17

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		37.5
	(b) Eudragit RS100
	(b) HPC
Mixed base	(a ′)the mixture *		9.4
	(c)	Hydroxypropylmethyl cellulose 2208	30.4
		Sodium alginate	5
	(d)**	Magnesium stearate	1.2
		Eudragit S100	7.6
		Titanium oxide	8.9
Total	100	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

1-14. Sustained releasing composition (14)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (14) as shown in Table 18.

Table 18

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		36.6
	(b) Eudragit RS100
	(b) HPC
Mixed base	(a ′)the mixture *		9.1
	(c)	Hydroxypropylmethyl cellulose 2208	29.7
		Sodium alginate	3.7
	(d)**	Magnesium stearate	1.1
		Eudragit S100	7.4
		Titanium oxide	12.4
Total	100	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

1-15. Sustained releasing composition (15)

Excepting that a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (15) as shown in Table 19.

Table 19

Component			Amount (w/w %)
(e) granule composition	(a) the mixture *		39
	(b) Eudragit RS100
	(b) HPC
Mixed base	(c)	Hydroxypropylmethyl cellulose 2208	22
	(d)**	Microcrystalline cellulose	7.5
		Magnesium stearate	1.5
		Sodium carboxymethyl cellulose	15
		Sodium starch glycolate	15
Total	100	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

1-16. Sustained releasing composition (16)

Excepting that the active ingredient was substituted with the extract of Dioscorea nipponica prepared in Reference Example 1-5 and a part of the composition was modified with other component, all the procedure was performed according the method disclosed in Example 1-1 to prepare inventive tablet preparation (16) as shown in Table 20.

Table 20

Component			Amount (w/w %)
(e) granule composition	(a) the extract of Dioscorea nipponica		39
	(b) Eudragit RS100
	(b) HPC
Mixed base	(a′)	the extract of Dioscorea nipponica	9.8
	(c)	Hydroxypropylmethyl cellulose 2208	24.4
	(d)**	Microcrystalline cellulose	14.6
		Magnesium stearate	1.2
		Sodium carboxymethyl cellulose	7.3
		Sodium starch glycolate	3.7
Total	100	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

Comparative Example 1

Excepting that the granule compositions prepared in Reference Examples 2-1 to 2-4 were not used in this experiment, all the procedure was performed according the method disclosed in Example 1-1 to prepare comparative tablet preparation (C1) as shown in Table 21.

Table 21

Component		Amount (w/w %)
(a) the mixture＊		39
(c) Hydroxypropylmethyl cellulose 2208		22
(d)**	Microcrystalline cellulose	7.5
	Magnesium stearate	1.5
	Sodium carboxymethyl cellulose	15
	Sodium starch glycolate	15
Total		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

Experimental Example 1. Determination of humidity

To compare the humidity of the inventive granule compositions prepared in Examples 2-1 to 2-3 with those of the extract of Salvia miltiorrhiza Bunge prepared in Reference Example 1-3, and the extract of Panax notoginseng Burk prepared in Reference Example 1-4, the 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.).

At the result as shown in Table 22, the humidity of the extract disclosed in Reference Examples was significantly decreased comparing with those of inventive granule compositions prepared in Examples.

Table 22

Days	Water content (%)
	Reference Example 1-3 & 1-4	Reference Example 2-1	ReferenceExample 2-2	ReferenceExample 2-3
1st	4.37	3.40	3.72	3.11
3rd	4.71	4.05	4.26	3.36
5th	5.63	4.22	4.41	3.54
7th	6.24	4.39	4.58	3.73
10th	6.91	4.43	4.71	3.90
15th	7.21	4.49	4.82	4.09
30th	7.43	4.55	4.98	4.14

Experimental Example 2. Dissolution test on sustained releasing composition

2-1. Analysis Procedure

To compare the dissolution rate of the inventive sustained releasing compositions prepared in Examples 1-10 and 1-15 with that of the comparative composition prepared in Comparative Example 1, the dissolution test on the samples was performed according to the regulation stipulated in K.P (general test method-dissolution test-the 2^nd method: paddle method) under the condition shown in Table 23.

2ml of 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 analysis was determined at the wavelength of 280 nm with flow rate of 1 ml/min using by HPLC (Water Inc.) running with mixture solvent of 1% acetic acid: MeOH (9:1) as a mobile phase.

Table 23

Apparatus	VK7025 (Varian Inc.)
Dissolution solution	Water
Temperature of dissolution solution	37℃
Amount of dissolution solution	900 ml
Spinning speed	50 rpm

At the result, 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.

2-2. Dissolution test of inventive sustained releasing composition (2)

The dissolution test on the inventive sustained releasing tablet disclosed in Examples 1-1 to 1-4 was performed according to the procedure disclosed in Experimental Example 2-1.

At the result, 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.

2-3. Dissolution test of inventive sustained releasing composition (3)

The dissolution test on the inventive sustained releasing tablet disclosed in Examples 1-5 to 1-7 was performed according to the procedure disclosed in Experimental Example 2-1.

At the result of the test determining comparison releasing patterns according to respective mixed ratio between an inventive granule and dried extract, there showed the releasing pattern with reduced releasing rate in accordance with the increased portion of the inventive granule, as shown in Table 24.

2-4. Dissolution test of inventive sustained releasing composition (4)

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.

At the result, 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.

2-5. Dissolution test of inventive sustained releasing composition (5)

The dissolution test on the inventive sustained releasing tablet disclosed in Examples 1-9 to 1-11 was performed according to the procedure disclosed in Experimental Example 2-1.

At the result, 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.

Table 24

Experimental Example 2-2 (releasing rate % /hour)
Hour	0 hr	0.5 hr	2 hr	4 hr	6 hr	8 hr	10 hr	12 hr	24 hr
CE* 1	0	20	46	76	86	90	93	95	99
E** 1-1	0	10	28	40	48	54	61	70	89
E 1-2	0	12	23	37	48	57	64	69	85
E 1-3	0	8	18	29	39	47	52	59	77
E 1-4	0	5	20	35	50	58	65	74	95
Experimental Example 2-3 (releasing rate % /hour)
Hour	0 hr	0.5 hr	1 hr	2 hr	4 hr	6 hr	8 hr	12 hr	24 hr
E 1-5	0	12	22	34	50	62	73	86	98
E 1-6	0	16	21	30	43	55	68	80	100
E 1-7	0	10	20	27	38	50	62	76	80
Experimental Example 2-4 (releasing rate % /hour)
Hour	0 hr	1 hr	3 hr	5 hr	7 hr	9 hr	12 hr	24 hr
E 1-8	0	17	37	46	57	66	78	94
Experimental Example 2-5 (releasing rate % /hour)
Hour	0 hr	1 hr	3 hr	5 hr	7 hr	9 hr	12 hr	24 hr
E 1-9	0	19	36	44	52	58	64	80
E 1-10	0	25	37	48	58	65	70	92
E 1-11	0	22	41	52	62	68	76	100
CE*: Comparative ExampleE**: Example

2-6. Dissolution test of inventive sustained releasing composition (6)

The dissolution test on the inventive sustained releasing tablet disclosed in Examples 1-12 to 1-14 was performed according to the procedure disclosed in Experimental Example 2-1.

At the result, 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.

2-7. Dissolution test of inventive sustained releasing composition (7)

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.

At the result, 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.

Table 25

Experimental Example 2-6 (releasing rate % /hour)
Hour	0 hr	1 hr	3 hr	5 hr	7 hr	9 hr	12 hr	24 hr
E 1-12	0	21	42	58	69	78	85	99
E 1-13	0	24	39	55	66	74	83	99
E 1-14	0	22	36	48	58	70	78	88
CE 1	0	30	62	83	88	93	95	99
Experimental Example 2-7 (releasing rate % /hour)
Hour	0 hr	1 hr	3 hr	5 hr	7 hr	9 hr	12 hr	24 hr
E 1-16	0	18	35	48	60	68	79	99
CE*: Comparative ExampleE**: Example

As mentioned above, 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.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modification and changes might be made to the invention by those skilled in the art which also fall within the scope of the invention as defined in the appended claims.

Claims (18)

1. An oral sustained releasing composition comprising (a) a dried granule composition, (b) a dried extract of crude drug, and (c) a sustained releasing carrier.
2. The composition of claims 1, 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 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 extract of Inula helenium, the herb extract of Mentha arvensis, the rhizoma extract of Pinellia ternate, the root extract of Ledebouriella seseloides, the white powder of Poria cocos, the root extract of Panax ginseng, the rhizoma extract of Paeonia japonica, the root extract of Angelica dahurica, the rhizome extract of Atractylodes macrocephala, the rhizome extract of Curcuma zedoaria, the fructus extract of Amomum xanthioides, the fructus extract of Crataegus pinnatifida, the rhizome extract of Sparganium stoloniferum, the rhizome extract of Rehmannia glutinosa, the powder of gypsum, the root extract of Asarum sieboldii, the seed extract of Perilla frutescens, the rhizoma extract of Cimifuga foetida, the root extract of Bupleurum falcatum, the fructus extract of Forsythia koreana, the fructus extract of Schisandra chinensis, the fructus extract of Arctium lappa, the rhizome extract of Curcuma aromatica, the herb extract of Artemisia capillaries, the root extract of Angelica decursiva, the fructus extract of Poncitrus trifoliata, the rhizoma extract of Anemarrhena asphodeloides, the fructus extract of Citrus aurantium, the rhizome extract of Atractylodes japonica, the rhizome extract of Cnidium officinale, the rhizome extract of Gastrodia elata, the fructus peel extract of Citrus unshiu, the root extract of Allium fistulosum, the fructus extract of Amomum villosum, the fructus extract of Gardenia jasminoides, the rhizome extract of Alisma plantago-aquatica, the seed extract of Prunus armeniaca var ansu, the rhizome extract of Cyperus rotundus, the herb extract of Schizonepeta tenuifolia var japonica, the root extract of Scutellaria baicalensis, the root extract of Astragalus membranaceus, the rhizome extract of Coptis chinensis, and the cortex extract of Phellodendron amurense.
3. The composition of claim 2, wherein said crude drug is at least one selected from the group consisting of Salvia miltiorrhiza Bunge, Panax notoginseng Burk, borneolum, and the extract of Dioscorea nipponica.
4. The composition of claim 1, wherein said dried granule composition is prepared by mixing (1) a dried extract of crude drug with (2) a slow releasing base including water insoluble macromolecule; and performing the mixture to spray drying.
5. The composition of claim 4, wherein said water insoluble macromolecule 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.
6. The composition of claim 1, wherein said dried granule composition is prepared by a spray drying method using by fluid-bed granular or spray dryer etc.
7. The composition of claim 1, wherein said sustained releasing carrier is at least one selected from the group consisting of carboxymethyl cellulose, hydroxypropyp 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, carrageenan, glucosamine, and their derivatives.
8. The composition of claim 1, wherein the mixed ratio of (b) the dried extract of crude drug, and (a) the dried granule composition is ranging from 0.1∼5: 1 (w/w) in the composition.
9. The composition of claim 1, wherein the mixed ratio of (a) the dried granule composition, and (c) sustained releasing carrier is ranging from 1: 0.1∼20 (w/w) in the composition.
10. The composition of claim 1, wherein the mixed ratio of (a) the dried granule composition of claim 1, (b) the dried extract of crude drug, and (c) sustained releasing carrier is ranging from 1: 0.01∼10: 0.1∼20 (w/w) in the composition.
11. An oral sustained releasing composition comprising (a) the dried granule composition, (b) a dried extract of crude drug, (c) sustained releasing carrier, and (d) a pharmaceutically acceptable additive.
12. The composition of claim 11, wherein said pharmaceutically acceptable additive is 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, and a diluting agent.
13. The composition of claim 12, wherein said binder is 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.
14. The composition of claim 12, wherein said disintegrating agents is 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.
15. The composition of claim 12, wherein said lubricant is at least one selected from magnesium stearate, talc, stearic acid, light anhydrous silicate and the combination thereof.
16. The composition of claim 12, wherein said conservative is at least one selected from benzoic acid, methyl paraben, propyl paraben and the combination thereof.
17. A method for preparing a dried granule composition by the process comprising the steps of:

    (a)mixing (1) Salvia miltiorrhiza Bunge, with (2) Panax notoginseng Burk, with the appropriate mixed ratio and extracting the mixture with water, C1-C4 lower alkyl alcohol such as methanol, ethanol etc, or the mixture thereof to concentrate at 1^st step;

    (b)Centrifuging the concentrates obtained at 1^st step to remove the precipitate at 2^nd step;

    (c)Concentrating the precipitate obtained at 2^nd step in vaccuo at 3^rd step;

    (d)Adding an organic solvent such as ethanol etc to the concentrate obtained at 3^rd step to be left alone at 4^th step;

    (e)Filtering the residue obtained at 5^th step and removing the remaining organic solvent from the extract in vaccuo at 6^th step;

    (f) Concentrating the extract of water layer obtained in 6^th step and drying the extract to obtain the dried extract of crude drugs (1) and (2);

    (g) mixing the dried extract of crude drugs (1) and (2) with dried powder of borneolum (3) with the appropriate mixed ratio;

    (h) mixing the dried extract of crude drug with (4) water insoluble macromolecule selected from the group consisitng of hydroxypropyl methyl cellulose 2910, Eudragit etc and other pharmaceutically acceptable water-insoluble polymers, such as lactose, cellulose acetate, poloxamer (F127, F68), ethyl cellulose, povidone, polyethylene oxide, polyamide and silicone with the appropriate mixed ratio,

    (i)dissolving the mixture in water, C1-C4 lower alkyl alcohol such as methanol, ethanol etc, or the mixture thereof;

    (j) subjecting to spray drying method using by fluid-bed coater or spray dryer etc; and forming granule by granulate machine to obtain final dried granule composition.
18. A method for preparing a sustained releasing composition by the process comprising the steps of: mixing (a) the dried granule composition prepared in claim 17, (b) the dried extract of crude drugs as set forth in claim 17, 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 the purposed sustained releasing composition.

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