WO2016208926A1 - Composition pharmaceutique comprenant un extrait d'artemisiae argyi folium dans l'isopropanol - Google Patents

Composition pharmaceutique comprenant un extrait d'artemisiae argyi folium dans l'isopropanol Download PDF

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WO2016208926A1
WO2016208926A1 PCT/KR2016/006536 KR2016006536W WO2016208926A1 WO 2016208926 A1 WO2016208926 A1 WO 2016208926A1 KR 2016006536 W KR2016006536 W KR 2016006536W WO 2016208926 A1 WO2016208926 A1 WO 2016208926A1
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pharmaceutical composition
minutes
extract
leaf
sodium
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PCT/KR2016/006536
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English (en)
Korean (ko)
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신용관
이종현
홍일기
임종재
박상욱
조상호
송세현
손세일
이홍우
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대원제약주식회사
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/282—Artemisia, e.g. wormwood or sagebrush
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates

Definitions

  • the present invention relates to a pharmaceutical composition containing the isopropanol extract of the leaf.
  • the present invention relates to a pharmaceutical composition which allows solubilization without using a surfactant in a pharmaceutical composition comprising the isopropanol extract of a leaf. More specifically, in the pharmaceutical composition comprising the isopropanol extract of the leaflet as an active ingredient, the combination of the specific polymer and the specific disintegrating agent, and when using a pH regulator, isopropanol extract of the leaflet without using a surfactant It relates to a pharmaceutical composition characterized in that it can be solubilized effectively.
  • the present invention relates to a unit dosage form for the treatment of gastrointestinal diseases, which contains 90 mg of isopropanol extract of the mesenchymal per unit dosage form and can be taken twice a day.
  • Mugwort (Artemisia mongolica, A. asiatica, A. princeps var. Orientalis, A. argyi, A. montana, etc.) is a perennial herb belonging to the Asteraceae family and has been used to treat tonic blood, gynecological diseases and diarrhea. Examples thereof include isocoumarin, coumarin, diterpenlactone, and the like.
  • the herbal medicine standard Korean herbal medicine
  • the leaves and young stems of the mugwort are referred to as Artemisiae argyi Herb.
  • leaf extracts contained flavonoids such as eupatillin and postiosidine, and even these single ingredients were known to have gastrointestinal protection and gastritis.
  • flavonoids such as eupatillin and postiosidine
  • these single ingredients were known to have gastrointestinal protection and gastritis.
  • the synergistic interaction of these components is thought to have the effect of treating gastrointestinal diseases. .
  • compositions using the leaf extract as an active ingredient are known, and pharmaceutical products containing the leaf extract as an active ingredient are commercially available, and these medicines use the leaf ethanol extract and leaf isopropanol extract of the leaf.
  • the content of the indicator component is often different depending on which solvent is extracted, and therefore, the therapeutic effect is also different.
  • the Ministry of Food and Drug Safety uses the ethanol extract of the leaf as an active ingredient. Even after receiving this permission, Phase III clinical trials will be conducted during the approval process of a drug containing the isopropanol extract of the young leaf.
  • Patent No. 127777 discloses that eupatilin, a flavonoid component included in the lobe, has a therapeutic effect on gastrointestinal diseases
  • Patent No. 181751 discloses that another component, postural osdine, is also effective in treating gastrointestinal diseases. .
  • Patent No. 181751 describes that the mugwort extract itself has an excellent anti- gastritising effect compared to the anti-gastritising effect of eupatillin or postiosidine purified from mugwort, and unknown substances in the extract increase the anti-gastritising effect.
  • Patent No. 1000951 indicates that mugwort contains blood coagulation inhibitor components, that is, coumarins.
  • dicoumarol components are included in the extraction process. The method is disclosed.
  • leaf extracts are known as poorly soluble drugs, and therefore suitable solubilization means are indispensable to formulate them. Accordingly, in Patent No. 1100942, the dissolution rate of the lobar extract in the gastrointestinal tract is about 40 to 50%, and the bioavailability is low due to low biomembrane permeability.
  • a delivery system (SMEDDS) is proposed, which essentially includes a surfactant.
  • Patent No. 909193 discloses a solubilizing means of the leaf extract in the same manner as the above patent, but also proposes the use of poloxamer, which is also a kind of surfactant.
  • the present inventors have a problem in that the surfactant adopted as a solubilizing means of the leaf extract in the conventional patent document, although it acts to solubilize the leaf extract, it stimulates the gastrointestinal mucosa (Contact Dermatitis. 1995 Oct; 33 (4 ): 217-25), especially considering that the indication of the leaf extract is the treatment of gastrointestinal diseases, when surfactant is used to solubilize the leaf extract, it is necessary to restore damaged gastric wall cells of gastrointestinal disease patients. It was found that it did not match the purpose of administration of the leaf extract. Thus, it was realized that the need to reduce the risk of accelerating gastric wall damage by solubilizing the leaf extract without using a surfactant.
  • Patent No. 1050015 discloses a pharmaceutical composition of larvae extract using a gastroretentive drug delivery system (GRT) and a sustained release oral formulation using the same, wherein the swellable polymer, the foaming agent, the sustained release polymer and Dissolution aids are used, and surfactants are used as dissolution aids.
  • GRT gastroretentive drug delivery system
  • a surfactant is used to solubilize and / or sustain the release of the leaf extract, but in a pharmaceutical product using the leaf extract as an active ingredient for the purpose of treating gastrointestinal diseases
  • a surfactant which may damage the gastrointestinal mucosa is not preferred.
  • the present inventors as a means for solubilizing the leaf extract, devotes to the study of a technique that does not use a surfactant, the combination of a specific polymer and a specific disintegrant as a pharmaceutical composition comprising a leaf extract, and a pH adjuster
  • the use of the present invention has led to the discovery that a solubilized pharmaceutical composition can be provided.
  • the present invention provides a pharmaceutical composition in which isopropanol extract of soybean leaves is solubilized without surfactants in order to reduce side effects that adversely affect the gastrointestinal tract of patients with gastrointestinal diseases such as damaging gastric wall cells. . More specifically, the problem is to provide a solubilized pharmaceutical composition by using a combination of isopropanol extract of a leaf, a specific polymer and a specific disintegrant, and a pH adjusting agent.
  • a pharmaceutical composition for the treatment of gastrointestinal diseases comprising the isopropanol extract of the leaves as an active ingredient
  • a pharmaceutical composition comprising a polymer material and a disintegrant is disclosed.
  • the pharmaceutical composition is characterized in that the polymeric material is HPC and the disintegrant is croscarmellose sodium.
  • composition comprising a pH adjusting agent.
  • a pharmaceutical composition characterized in that the elution of eupatin satisfies the following conditions.
  • the pharmaceutical composition exhibits a dissolution rate of eupatillin in pH 1.2 buffer added with 0.5% of sodium lauryl sulfate (SLS) at 5 to 45% at 15 minutes and at least 65% at 60 minutes.
  • SLS sodium lauryl sulfate
  • a unit dosage form for treating gastrointestinal diseases which contains 90 mg of isopropanol extract of a leaf per unit dosage form, can be taken twice a day.
  • the soybean isopropanol extract is solubilized to provide a pharmaceutical composition having high bioavailability and capable of being produced as a sustained release agent.
  • a surfactant can provide a pharmaceutical composition free of gastrointestinal disorders.
  • Example 1 is a graph showing the dissolution rate of Example 1 and Comparative Examples 3 to 7 of the present invention.
  • Figure 2 is a gastric motion picture of the first embodiment of the present invention.
  • 3 is a gastric behavior image photograph of a commercial preparation.
  • Figure 4 is a graph of the ethanol-induced gastritis treatment effect in the rat of Example 1 of the present invention.
  • Example 5 is a graph showing the effect of indomethacin-induced gastritis treatment in the rat of Example 1 of the present invention.
  • mixtures of compounds are not easy to define their physical and chemical properties. This is because, in the case of extracts extracted from natural products, it is very difficult to specify easily because each single component of the extract is a mixture of a number of single compounds having different physical and chemical properties. to be.
  • the leaf extract is known to have a better effect of gastrointestinal disease when the leaf extract is used as a whole than the gastrointestinal disease effect exhibited by eupatillin or postiosidine, which is known as an index component. It is reasonable to understand that the physicochemical properties of the leaf extracts are also greatly influenced by the unknown components because they are mutually influenced and the gastrointestinal disease effects are excellent.
  • both the ethanol extract of the leaf and the isopropanol extract of the leaf are both different therapeutic effects including the indicator component, and the optimal solubilization method will not be the same.
  • a pharmaceutical composition comprising isopropanol extract of a leaf of a young leaf is included in a combination of a specific polymer material and a specific disintegrant, and furthermore, a pH adjusting agent is included so that the solubilization can be obtained. Reached.
  • the means which the inventors derived for solubilizing the isopropanol extract of the young leaf is a combination of hydroxypropyl cellulose (HPC) as a polymer material and croscarmellose sodium as a disintegrant.
  • HPC hydroxypropyl cellulose
  • the HPC may include 0.01 to 0.2 parts by weight based on 1 part by weight of isopropanol extract of the leaves, and croscarmellose sodium may include 0.01 to 0.3 parts by weight based on 1 part by weight of isopropanol extract of the leaves.
  • disintegrants in oral solid preparations play a role in promoting disintegration of the formulation when administered in vivo, so it is difficult to predict that such disintegrants will affect the solubilizing ability.
  • the solubilization effect is increased by using HPC and disintegrant croscarmellose sodium in the granulation process, and in addition to HPC, other combinations other than croscarmellose sodium as disintegrant.
  • the composition may comprise a substance for adjusting the pH.
  • a pH adjuster By incorporating a pH adjuster into the present composition, the isopropanol extract of the leaves is solubilized, and further, sustained release can be achieved.
  • the pH adjusting agent calcium hydroxide, ethanolamine, potassium bicarbonate, potassium citrate, sodium bicarbonate, sodium hydroxide citrate, calcium silicate, sodium hydroxide, arginine, magnesium oxide, calcium carbonate, calcium phosphate, magnesium carbonate, magnesium hydroxide .
  • An alkalizing agent selected from the group consisting of magnesium silicate, magnesium aluminum hydroxide, sodium borate, and meglumine may be used, and in particular, an alkalizing agent selected from the group consisting of sodium hydrogen carbonate, magnesium oxide, meglumine and sodium carbonate may be used.
  • the amount of the pH adjusting agent may be suitably changed, but may include 0.1 to 1 part by weight based on 1 part by weight of the isopropanol extract of the leaf.
  • composition comprising the leaf extract of the present invention may include within 10 to 50% by weight of the isopropanol extract of the leaf on the basis of the total weight of the composition.
  • compositions of the present invention may generally comprise one or more pharmaceutically acceptable excipients, carriers or diluents.
  • tablet preparations containing herbal extracts include substances such as diluents, lubricants and mixtures thereof.
  • the present invention may contain excipients, glidants, and the like, which are conventionally used in the preparation of tablet formulations in the pharmaceutical field, and the excipients include lactose, starch, lactose, mannitol, powdered sugars and powdered cellulose derivatives. It is preferable to add a substance which is usually used pharmaceutically as an additive in a usual amount of use within a range that does not adversely affect the drug efficacy.
  • Comparative Example 1 was prepared by changing the ethanol extract in place of the isopropane extract of the leaf as an active ingredient in Example 1, Comparative Example 2 is the same as in Example 1 except adding poloxamer as a surfactant.
  • the solubility test was done about Example 1 and Comparative Examples 1-2.
  • the solubility test method was compared by measuring the solubility in one tablet of the Example and Comparative Example according to the solubility test method described in Korean Patent No. 1100942.
  • Solubility (%) is the relative comparison value based on the solubility of the comparative example 1.
  • Example 1 solubilization was possible by including a combination of HPC and croscarmellose sodium, but in the case of the ethanol extract of the young leaf, solubilization is possible even by including a combination of HPC and croscarmellose sodium. It was not achieved (comparative example 1), and surfactant was needed (comparative example 2).
  • isopropanol extracts of the leaves were dissolved in ethanol to form a binding solution.
  • 10 mg of calcium silicate, 48 mg of lactose monohydrate, 54 mg of microcrystalline cellulose, and 60 mg of sodium bicarbonate were added to form a granule.
  • 20 mg hypromellose was mixed and compressed to prepare uncoated tablets.
  • Film-coated tablets were prepared by coating uncoated tablets with a base containing HPMC.
  • isopropanol extracts from the leaves were dissolved in ethanol to form a binding solution.
  • the binding solution was mixed with 10 mg of calcium silicate, 48 mg of lactose monohydrate, 54 mg of microcrystalline cellulose, 60 mg of sodium bicarbonate, and 20 mg of croscarmellose sodium.
  • 20 mg hypromellose was mixed and then compressed into tablets to prepare uncoated tablets.
  • Film-coated tablets were prepared by coating uncoated tablets with a base containing HPMC.
  • isopropanol extracts of the leaves were dissolved in ethanol to form a binding solution.
  • 10 mg of calcium silicate, 48 mg of lactose monohydrate, 54 mg of microcrystalline cellulose, and 60 mg of sodium bicarbonate were added to form a granule.
  • 20 mg of hypromellose were mixed and compressed to prepare uncoated tablets.
  • Film-coated tablets were prepared by coating uncoated tablets with a base containing HPMC.
  • Example 1 The dissolution test of Example 1 and Comparative Examples 3 to 7 was carried out, the results are shown in Table 2.
  • the dissolution test was performed under the condition of 100 rpm of the Korean Pharmacopoeia paddle method in pH 1.2 buffer containing 0.5% of sodium lauryl sulfate (SLS), and the dissolution rate of eu Patillin was confirmed. (Unit:%)
  • Example 1 The dissolution test of Example 1 and Comparative Examples 8 to 10 was carried out, the results are shown in Table 3.
  • the dissolution test was performed under the condition of 100 rpm of the Korean Pharmacopoeia paddle method in pH 1.2 buffer containing 0.5% of sodium lauryl sulfate (SLS), and the dissolution rate of eu Patillin was confirmed. (Unit:%)
  • Example 1 0 24.4 47.1 72.0 89.6
  • Example 2 0 32.4 53.6 79.9 92.2
  • Example 3 0 26.7 42.8 68.2 86.9
  • Example 4 0 25.3 48.5 73.3 88.4 Comparative Example 8 0 8.8 20.3 34.2 40.1
  • Intra-gastric behavior was confirmed by oral administration of a commercially available formulation three times a day as an active ingredient of 60 mg of isopropanol extract of Example 1 and young leaf according to the present invention.
  • Example 1 After oral administration of Example 1 to the beagle dog, check whether swallowed and feed about 10 mL of water, and using the C-Arm (model name: Aroadis Vario, Simens co.) Equipment for 5 minutes, 10 minutes, 15 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 180 minutes
  • C-Arm model name: Aroadis Vario, Simens co.
  • Example 1 shows that the tablets remained in the stomach even after 120 minutes when the intragastric behavior was confirmed after oral administration of Example 1, but in the case of commercially available preparations in FIG. 4, no trace of the intragastric tablets remained after 10 minutes. Was observed. As a result, it can be seen that Example 1 according to the present invention remains longer than the commercially available three times a day formulation.
  • Example 1 The effect of Example 1 on gastric injury was evaluated through animal experiments.
  • Example 1 was administered after acute gastric injury was induced by ethanol administration to Sprague-Dawey Rat.
  • the experimental animals of this test were SPF rats and Crlj: CD (SD).
  • the experimental animals were purified for 7 days after acquisition, and the weights of the animals determined to be healthy during the acclimation period were distributed in a random manner to distribute the average weight as evenly as possible.
  • Example 1 and levamifeed treatment for gastritis
  • the appropriate amount was weighed and then suspended in 0.5% CMC.
  • Example 1 and 48 hours before levamifeed administration all animals were fasted and then pre-prepared ethanol was orally administered at a dose of 80 mg / kg.
  • animals were anesthetized with Zoletil 50 (VIRBAC, France) and xylazine (Rompun®, Bayer AG, Germany), and then opened and ligated the gastric pyloric region.
  • Example 1 and levamipid were orally administered.
  • the anesthesia was extracted with dieth ether, and the stomach was extracted, and the gastric mucosa surface was photographed with a digital camera.
  • the area of injury was analyzed using Image software (NIH, Bethesda, MD).
  • G1 normal treat with 90 mg / kg Example 1; G2: ethanol treated only; G3: ethanol + 100 mg / kg levamifeed; G4: ethanol + 90 mg / kg Example 1; G5: normal treat with 90 mg / kg Example 1; G6: ethanol treated only; G7: ethanol + 100 mg / kg levamifeed; G8: ethanol + 90 mg / kg Example 1.
  • G1-G4 gastric retention time 10 minutes; G5-G8 : gastric retention time 120 minutes.Data are expressed as mean ⁇ SEM.The number of animal used for each group was 15. * P ⁇ 0.05 vs the ethanol treated group (G2). # P ⁇ 0.05 vs the ethanol treated group (G6 & P ⁇ 0.05 vs levamifeed treated group (G3). $ P ⁇ 0.05 vs Example 1 treated group (G4).)
  • Example 1 In the experiment of gastric injury treatment effect with 70% ethanol, Example 1 was confirmed to improve the treatment effect of 26.1% at 120 minutes of stay than 10 minutes, and levamipid was 21.9% at 120 minutes of stay than 10 minutes of stay. The treatment effect was confirmed to be improved. Therefore, it can be seen that the treatment effect by the 120-minute stay of Example 1 is more improved than levamifeed.
  • Example 1 Acute Gastric Injury by Indomethacin Administration In the Sprague-Dawey Rat model, the effect of Example 1 on the gastric injury area was evaluated.
  • the experimental animals of this test were SPF rats and Crlj: CD (SD).
  • the experimental animals were purified for 7 days after acquisition, and the weights of the animals determined to be healthy during the acclimation period were distributed in a random manner to distribute the average weight as evenly as possible.
  • Example 1 For Example 1 and levamifeed, the titrations were weighed and then suspended in 0.5% CMC. Indomethacin, a gastrointestinal injury-causing substance, was diluted with sodium bicarbonate injection (8.4%), weighed in an appropriate amount, dissolved in an excipient, and orally administered. Experimental Example 1 and 48 hours before the administration of levamipid, all animals were fasted, and pre-prepared indomethacin was orally administered at a dose of 80 mg / kg. Animals were anesthetized with Zoletil 50 (VIRBAC, France) and xylazine (Rompun®, Bayer AG, Germany) 4 hours after indomethacin administration, and then opened and ligation of the gastric pyloric region.
  • Zoletil 50 VIRBAC, France
  • xylazine Rosun®, Bayer AG, Germany
  • Example 1 and levamipid were orally administered. 10 and 120 minutes after administration, the animals were anesthetized with dieth ether, and the stomach was extracted and the mucosal surface of the stomach was photographed with a digital camera. The area of injury was analyzed using Image software (NIH, Bethesda, MD).
  • G1 normal treat with 90 mg / kg Example 1; G2: indomethacin treated only; G3: indomethacin + 100 mg / kg levamifeed; G4: indomethacin + 90 mg / kg Example 1; G5: normal treat with 90 mg / kg Example 1; G6: indomethacin treated only; G7: indomethacin + 100 mg / kg levamifeed; G8: indomethacin + 90 mg / kg Example 1.G1-G4: gastric retention time 10 minutes; G5-G8 : gastric retention time 120 minutes.Data are expressed as mean ⁇ SEM. * P ⁇ 0.05 compared to indomethacin treated group (G2). # P ⁇ 0.05 compared to indomethacin treated group (G6). & P ⁇ 0.05 compared to Example 1 treated group (G4). $ P ⁇ 0.05 compared to levamifeed treated group (G7).)
  • Example 1 confirmed that the treatment effect was improved by 14.1% at 120 minutes stay than the 10 minutes stay, and levamipid was confirmed to be improved by 10 minutes and 120 minutes stay.
  • the therapeutic effect by the 120-minute stay in Example 1 is further improved than the levamifeed.
  • Example 1 Patients diagnosed with acute and chronic gastritis were evaluated for the therapeutic effect of tablets of Example 1 twice daily and once tablets. Subjects were 230 patients diagnosed with acute and chronic gastritis with more than one erosion, and received the tablets prepared according to Example 1 twice a day, twice a day for 2 weeks. Gastroscopy was evaluated by the same examiner and the same device for each subject. The analysis was performed on the efficacy of gastroscopy, cure rate of gastroscopy, effective rate of improvement of subjective symptoms, edema, redness, and bleeding effectiveness of gastroscopy.
  • the effective rate and cure rate in gastroscopy were evaluated according to the erosion number according to Table 6 below to calculate the improvement rate.
  • Classification according to subjective symptom frequency was calculated through the questionnaire survey according to the following Table 7 for the subjects with subjective symptoms before the test.
  • the effective rate of endoscopic examination in subjects whose erosion score improved by 50% or more after the administration of the study drug was 45.5% and the mean rate was significantly improved from 4.30 to 1.90. .
  • the cure rate was improved to 41.1%. 71.3% of subjects who had symptoms on subjective symptom questionnaire before the investigational drug administration had a reduction of 50% or more. In gastroscopy, 41.9% of the subjects who had edema were cured. 40.1% of the subjects who showed redness on gastroscopy showed improvement after administration of test drug, and 63.0% of those who showed bleeding finding.
  • Example 1 is considered to be a drug that can improve the ease of taking to the patient by reducing the number of administration while having a statistically significant efficacy of gastritis treatment when taking two weeks.

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Abstract

La présente invention concerne une composition pharmaceutique pour le traitement de maladies gastro-intestinales contenant un extrait d'Artemisiae argyi folium dans l'isopropanol utilisé comme principe actif, ladite composition pharmaceutique comprenant une substance polymère et un agent délitant et ayant une vitesse de dissolution spécifique.
PCT/KR2016/006536 2015-06-24 2016-06-20 Composition pharmaceutique comprenant un extrait d'artemisiae argyi folium dans l'isopropanol WO2016208926A1 (fr)

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KR20090031011A (ko) * 2007-09-21 2009-03-25 동아제약주식회사 위체류약물전달시스템을 이용한 애엽 추출물의 약학조성물및 이를 이용한 서방성 경구용 제제
KR100900725B1 (ko) * 2008-02-14 2009-06-05 지엘팜텍 주식회사 고함량의 유파틸린을 함유하는 쑥 추출물의 제조방법
KR100967832B1 (ko) * 2009-09-24 2010-07-07 김진하 애엽 추출물 및 연근 추출물을 유효성분으로 함유하는 항균 조성물
KR20140031131A (ko) * 2012-08-31 2014-03-12 주식회사 드림파마 애엽 추출물을 유효성분으로 포함하는 아토피 치료용 조성물

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