KR101326241B1 - Pharmaceutical Composition for improving anti pain Comprising Lonicerae Flos Extracts - Google Patents
Pharmaceutical Composition for improving anti pain Comprising Lonicerae Flos Extracts Download PDFInfo
- Publication number
- KR101326241B1 KR101326241B1 KR1020120011908A KR20120011908A KR101326241B1 KR 101326241 B1 KR101326241 B1 KR 101326241B1 KR 1020120011908 A KR1020120011908 A KR 1020120011908A KR 20120011908 A KR20120011908 A KR 20120011908A KR 101326241 B1 KR101326241 B1 KR 101326241B1
- Authority
- KR
- South Korea
- Prior art keywords
- gold
- extract
- water
- silver
- analgesic
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A61K2236/30—Extraction of the material
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- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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Abstract
본 발명은 진통 활성이 증진된 금은화 추출 정제물의 제조방법에 관한 것이다. 본 발명에 따른 금은화 추출물은 부작용 없이 진통 작용에 매우 효과적으로 사용될 수 있다.The present invention relates to a method for preparing a gold-silver extract purified with enhanced analgesic activity. The gold coin extract according to the present invention can be used very effectively for analgesic action without side effects.
Description
본 발명은 행동학적 지표인 말초성 통증 모델(Writhing test)을 이용하여 통증에 대해 금은화의 진통효과를 확인하고 진통효과가 검증된 금은화 추출 정제물의 제조방법에 대한 것이다.
The present invention relates to a method of preparing gold-silver extract extracted tablets confirmed the analgesic effect of gold and silver coins for pain by using the peripheral pain model (Writhing test) which is a behavioral indicator.
진통제란 동통을 제거하거나 경감시키는 목적으로 사용하는 의약품으로서 비마약성 진통제와 마약성 진통제로 구분된다.
Painkillers are drugs that are used to eliminate or alleviate pain and are divided into nonnarcotic and narcotic analgesics.
비마약성 진통제는 인체 내에서 프로스타글란딘 (Prostagladin)이라는 물질을 억제하여 통증의 역치를 상승시켜 진통 효과를 나타내는 약물이고, 진통효과 이외에 해열, 소염 효과도 나타나게 된다. 비마약성 진통제는 진통, 해열 작용을 나타내는 아세트아미노펜 (acetaminophen)과 인체 내의 다양한 프로스타글란딘 (Prostagladin)을 억제하여 진통, 해열, 소염 작용을 나타내는 비스테로이드성 소염진통제 (NSAID)로 나눌 수 있다.
Non-narcotic analgesics are drugs that suppress the prostaglandin (Prostagladin) in the human body to increase the threshold of pain, which has an analgesic effect, in addition to the analgesic effect is also an antipyretic, anti-inflammatory effect. Non-narcotic analgesics can be classified into acetaminophen, which exhibits analgesic and antipyretic effects, and nonsteroidal anti-inflammatory analgesic (NSAID), which has analgesic, antipyretic, and anti-inflammatory effects by inhibiting various prostagladins in the human body.
아세트아미노펜 (acetaminophen)은 미국 류마티스 학회의 지침에서 위장에 대한 부작용이 적기 때문에 염증을 동반하지 않는 골관절염 환자에게 우선적으로 사용하도록 권장되고 있다. 그러나 어린이 환자에 대한 안전지수(치사용량을 유효용량으로 나눈 값)가 크고, 위출혈, 혈소판 감소증, 오심, 구토, 식욕부진 등 부작용이 나타날 수 있다. FDA에 따르면, `타이레놀'로 잘 알려진 아세타미노펜 계열의 약은 과다 복용 시간을 손상시킬 수 있다고 한다.
Acetaminophen is recommended for use in patients with osteoarthritis who do not have inflammation because it has fewer side effects on the stomach in the guidelines of the American Rheumatology Society. However, the safety index (lethal dose divided by the effective dose) for children is large, and side effects such as gastric bleeding, thrombocytopenia, nausea, vomiting and anorexia may occur. According to the FDA, the acetaminophen family of drugs, known as tylenol, can damage overdose time.
비스테로이드성 소염진통제 (NSAID)는 소염작용이 있기 때문에 주로 염증을 동반한 관절염에 사용되며, 암이 뼈로 전이가 되는 경우에는 국소적으로 프로스타글란딘 (Prostagladin)이 많이 생기기 때문에 아세트아미노펜으로 효과가 없는 경우에 유효하게 사용될 수 있다. 하지만, NSAID는 위산으로부터 위장을 보호하는 물질의 분비를 억제하기 때문에 위염, 위출혈의 부작용이 발생할 가능성이 있어 신중하게 사용하도록 권장되고 있다. FDA에 따르면 아스피린, 이부프로펜, 나프록센, 디클로페낙 같은 비(非)스테로이드 소염진통제(NSAID)도 신장 장애, 위출혈, 위궤양 같은 부작용을 초래할 수 있다고 보고된 바 있다.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly used for inflammation-induced arthritis because they have anti-inflammatory effects.In case of cancer metastasis to bone, prostagladin is produced locally, so it is ineffective with acetaminophen. Can be used effectively. However, since NSAIDs inhibit the secretion of substances that protect the stomach from stomach acid, side effects of gastritis and gastric bleeding may occur. According to the FDA, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and diclofenac can also cause side effects such as kidney failure, gastric bleeding, and gastric ulcers.
또한, 디클로페낙(Diclofenac)은 항염, 진통 및 해열작용을 나타내는 cyclooxygenase inhibitor로 류마티스성 관절염과 골관절염과 같은 만성 염증 질환이나 급성 근골격계 통증 시 유효하고, 또한 신경통, 후진통, 월경 곤란증 등 수술 및 발치후의 진통, 소염에 쓰인다. 그러나 소화성 궤양, 위출혈 등의 소화기 증상, 호흡곤란, 혈압저하, 부종, 발진, 식욕부진, 구토, 오심 등 하부위장 장해 등 많은 부작용이 있다.
Diclofenac is a cyclooxygenase inhibitor that has anti-inflammatory, analgesic and antipyretic effects and is effective in chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis or acute musculoskeletal pain, and also pain relief after surgery and extraction such as neuralgia, backward pain and dysmenorrhea. Used for anti-inflammatory. However, there are many side effects such as digestive ulcers, digestive symptoms such as gastric bleeding, dyspnea, lowering blood pressure, edema, rashes, anorexia, vomiting, and nausea, such as nausea.
금은화(Lonicerae Flos)는 인동과(Caprifoliaceae)에 속하는 인동 덩굴(Lonicera japonica Thunb.)의 꽃으로, 맛은 달고, 기는 평하다. 성질은 약간 차다. 독을 없애는데 좋다. 그러므로 옹저, 종독, 창선, 양매창, 풍습의 사기로 인한 모든 독을 치료하는 요약이다. 독이 아직 완전히 성하지 않을 때에는 능히 그 독을 흩어낼 수 있고, 독이 이미 성한 때에는 터뜨릴 수 있다. 단, 그 성질이 완만하므로 용량을 배가시켜야한다. 꽃에는 루테올린, 이노시톨 약 1%가 함유되어 있으며, 이외에 사포닌, 탄닌, 이소클로로제닌산(isochlorogenic acid), 클로로제닌산(chlorogenic acid) 등을 함유(신민교, 정보섭, 도해 향약대사전, pp939-940, 1989; 최호영 외, 본초학, pp198)하는 것으로 알려져 있고, flavonoid 성분으로서는 luteolin, apigenin, luteolin-7-O-rhamnoglucoside, quercetin 등이 알려져 있다.
Lonicerae Flos is a flower of the Lonicera japonica Thunb. Belonging to the family Caprifoliaceae, which tastes sweet and is flat. The nature is a bit cold. Good to get rid of poison Therefore, it is a summary to cure all poisons caused by Onggi, bells, lances, spearheads, and customs. When the poison is not yet full, it can be scattered, and when the poison is already over, it can burst. However, since its properties are gentle, the capacity should be doubled. Flowers contain about 1% of luteolin and inositol, in addition to saponins, tannins, isochlorogenic acid, and chlorogenic acid (Shinmin Kyo, Yoo Seop, Doha Yakdae Dictionary, pp939-940 , 1989; Choi Ho-young et al., Herbology, pp198), and flavonoids include luteolin, apigenin, luteolin-7-O-rhamnoglucoside, quercetin, and the like.
금은화의 flavonoid 성분은 항염증작용[Lee, S.J., Son, K.H., Chang, H. W., Do, J.D., Jung, K.Y., Kang, S. S. and Kim, H.P.: Anti-inflammatory activity of naturally occurring flavones and flavonol glycosides. Arch.Pharm.Res.16,25(1993)] 및 항돌연변이작용 등이 보고되었으나 아직 그 작용기전에 관한 연구는 미진한 상태에 있다.
Gold and silver flavonoids have anti-inflammatory effects [Lee, SJ, Son, KH, Chang, HW, Do, JD, Jung, KY, Kang, SS and Kim, HP: Anti-inflammatory activity of naturally occurring flavones and flavonol glycosides. Arch.Pharm.Res. 16,25 (1993)] and antimutagenic activity, but studies on the mechanism of action are still insufficient.
따라서, 본 발명은 금은화 추출물의 진통 효과가 우수한 것임을 전임상 실험을 통하여 그 효능을 과학적으로 증명하고, 통증에 효과가 있는 제제를 제공하는데 있다.
Therefore, the present invention scientifically proves its efficacy through preclinical experiments that the analgesic effect of the sterling silver extract is excellent, and provides an agent effective in pain.
본 발명자들은 금은화 추출물의 진통 효과가 우수한 것을 전임상 실험을 통해 확인하였다. The present inventors confirmed that the analgesic effect of the gold and silver extract is excellent through preclinical experiments.
따라서, 본 발명은 진통 효과가 우수한 금은화 추출물을 함유하는 진통제 약학조성물의 제공과 이에 사용되는 금은화 추출물의 제조방법을 확립하는 데 그 목적이 있다.
Accordingly, an object of the present invention is to provide an analgesic pharmaceutical composition containing a gold silver extract excellent in analgesic effect and to establish a method for preparing a gold silver extract used therein.
상기 목적을 수행하기 위하여, 본 발명에서 진통 활성이 증진된 금은화 추출 정제물은 하기와 같이 제조될 수 있다.
In order to carry out the above object, the gold coins extract purified with improved analgesic activity in the present invention can be prepared as follows.
상세하게는, 본 발명은 금은화를 그 중량의 10 내지 20배(v/w)의 정제수를 포함한 물, C1 내지 C4의 저급 알콜 중의 어느 하나 또는 이들의 혼합용매로부터 선택되어진 용매를 가하여 1시간 내지 24시간 동안, 바람직하게는 3시간 내지 5시간 동안 열수추출, 냉침추출, 환류냉각추출 또는 초음파추출 중 어느 하나의 추출방법, 바람직하게는 환류냉각추출방법을 사용하여 1회 내지 5회 반복 추출하는 제 1단계; 상기 제 1단계에서 추출된 추출물을 일정량의 정제수로 용해시키고 동량의 유기용매인 노르말헥산, 에틸아세테이트, 클로로포름, 노르말 부탄올 등으로 순차적으로 극성을 올려 1회 내지 5회 분획한 후, 유기용매 가용부를 제거하는 제 2단계; 상기 제 2단계에서 제거 후 남은 수가용성 분획을 일정량의 정제수에 용해시켜, 그 중량의 10 내지 15배(w/w)의 HP-20, SP-850 수지 컬럼 등과 같은 미세다공 비이온 흡착제 수지 또는 C-18, C-8컬럼 등과 같은 역상 칼럼에 사용되는 수지에 흡착시켜 용출하는 제 3단계의 공정을 포함하는 제조공정으로 진통 활성이 증진된 금은화 추출 정제물을 제조하는 방법을 제공한다.
In detail, the present invention is added by adding a solvent selected from any one of water or a mixed solvent of C 1 to C 4 lower alcohol, water containing gold and silver, 10 to 20 times the weight (v / w) of purified water 1 Repeated 1 to 5 times using any one of hot water extraction, cold sewage extraction, reflux cooling extraction or ultrasonic extraction for hours to 24 hours, preferably 3 hours to 5 hours, preferably reflux cooling extraction method. Extracting the first step; After dissolving the extract extracted in the first step with a predetermined amount of purified water and sequentially raising the polarity with the same amount of organic solvents, such as normal hexane, ethyl acetate, chloroform, normal butanol and the like once to five times, the organic solvent soluble part A second step of removing; The water-soluble fraction remaining after the removal in the second step is dissolved in a predetermined amount of purified water, and a microporous nonionic adsorbent resin such as HP-20, SP-850 resin column, or the like having a weight of 10 to 15 times (w / w) or The present invention provides a method for producing a gold-silver extract purified product having improved analgesic activity by a manufacturing step including a third step of adsorbing and eluting a resin used in a reverse phase column such as C-18 and C-8 columns.
본 발명은 상기 제조방법으로 얻어지는 금은화 추출 정제물을 유효성분으로 함유하는 진통제 약학 조성물을 제공한다. 상기 제조방법으로 수득되는 금은화 추출 정제물은 독성이 적고 효과가 선택적이며 진통 활성이 탁월하게 증진됨을 특징으로 한다.
The present invention provides an analgesic pharmaceutical composition containing a goldsmith extract purified product obtained by the above production method as an active ingredient. The gold and silver extract extracted by the above production method is characterized by low toxicity, selective effect and excellent analgesic activity.
본 발명의 조성물은 조성물 총 중량에 대하여 상기 금은화 추출 정제물을 0.1 내지 50중량%로 포함한다. 그러나 상기와 같은 조성은 반드시 이에 한정되는 것은 아니고, 환자의 상태 및 질환의 종류 및 진행 정도에 따라 변할 수 있다.
The composition of the present invention comprises 0.1 to 50% by weight of the gold coin extract purified based on the total weight of the composition. However, the composition as described above is not necessarily limited thereto, and may vary according to the condition of the patient and the type and extent of the disease.
본 발명의 금은화 추출 정제물을 포함하는 조성물은 약학적 조성물의 제조에 통상적으로 사용하며 약학적으로 허용 가능한 담체, 부형제 및 희석제를 더 포함할 수 있다.
The composition comprising the sterling extract tablets of the present invention may further comprise pharmaceutically acceptable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
본 발명에 따른 추출물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될수 있으며, 추출물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜,올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.
Compositions comprising extracts according to the invention are formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterile injectable solutions, respectively, according to conventional methods. The carriers, excipients and diluents that may be used in the composition comprising the extract may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin , Calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
본 발명의 금은화 추출물은 독성이 적고 효과가 선택적이며 진통 활성이 탁월하여 진통 효과가 우수하고 안전한 진통제 약학 조성물로 매우 유용하게 이용될 수 있어, 통증을 느끼는 환자에 대해 상기 약재의 이용을 통하여 통증 완화효과를 기대할 수 있다.
Gold silver extract of the present invention has a low toxicity, selective effect and excellent analgesic activity, excellent analgesic effect and can be very useful as a safe analgesic pharmaceutical composition, pain relief through the use of the medicine for patients suffering pain You can expect the effect.
<실시예 1. 금은화 물 추출물의 제조>
Example 1 Preparation of Gold Coin Water Extract
금은화 2.0kg를 정제수 20L로 3 내지 5시간 동안 3회 환류 추출하여 물 추출엑스 460g(수율: 21.0%)을 얻었으며, 이 물 추출엑스 460g을 4.6L의 정제수로 용해시킨 후, 동량의 유기 용매인 노르말헥산, 에틸아세테이트, 클로로포름 및 노르말부탄올로 순차적으로 극성을 올려 각각 3회 분획하여 유기용매에 용해되는 물질을 제거하였다. 남은 수가용성 분획 300g을 정제수 9L로 용해시킨 후, 미세다공 비이온 흡착제 수지(HP-20 resin) 3.0kg을 넣고 실온에서 4시간 동안 교반하여 흡착시켰으며, 흡착물을 감압 여과하여 최종 200g의 추출 정제물(수율: 10.0%)을 수득하였다.
2.0 kg of gold and silver coins were extracted by refluxing three times with 20 L of purified water for 3 to 5 hours to obtain 460 g of water extract (yield: 21.0%). After dissolving 460 g of this water extract with 4.6 L of purified water, the same amount of organic solvent was used. Increasing the polarity sequentially with phosphorus normal hexane, ethyl acetate, chloroform and normal butanol three times each to remove the material dissolved in the organic solvent. After dissolving the remaining 300 g of the water-soluble fraction in 9 L of purified water, 3.0 kg of microporous non-ionic adsorbent resin (HP-20 resin) was added thereto, stirred at room temperature for 4 hours, and the adsorbate was filtered under reduced pressure to extract 200 g of the final product. Purified product (yield: 10.0%) was obtained.
<실시예 2. 금은화 에탄올 추출물의 제조>
Example 2 Preparation of Gold Coin Ethanol Extract
금은화 2.0 kg를 30% 에탄올 20L로 3 내지 5시간 동안 3회 환류 추출하여 30% 에탄올 추출엑스 450g(수율: 22.5%)을 수득하였고, 30% 에탄올 추출엑스를 4.5L의 정제수로 용해시킨 후, 동량의 유기용매인 노르말헥산, 에틸아세테이트, 클로로포름, 노르말부탄올로 순차적으로 극성을 올려 각각 3회 분획하여 유기용매에 용해되는 물질을 제거하였다. 남은 수가용성 분획 280g을 정제수 8.4L로 용해시킨 후, 미세다공 비이온 흡착제 수지(HP-20 resin) 2.8kg을 넣고 실온에서 4시간 동안 교반하여 흡착시켰으며, 흡착물을 감압여과하여 최종185g(수율: 9.25%)의 추출 정제물을 수득하였다.
2.0 kg of gold and silver coins were extracted by refluxing 3 times with 20 L of 30% ethanol for 3 to 5 hours to obtain 450 g of 30% ethanol extract (yield: 22.5%), and after dissolving 30% ethanol extract with 4.5 L of purified water, The same amount of the organic solvent, normal hexane, ethyl acetate, chloroform, and normal butanol were sequentially raised to three times to remove the substance dissolved in the organic solvent. After dissolving 280 g of the remaining water-soluble fraction in 8.4 L of purified water, 2.8 kg of microporous non-ionic adsorbent resin (HP-20 resin) was added thereto, and the mixture was stirred at room temperature for 4 hours, followed by adsorption under reduced pressure, followed by 185 g ( Yield: 9.25%) of the extract was obtained.
본 발명은 상기한 제법으로 얻어진 금은화 추출물을 함유한다. 본 발명의 추출물은 독성 및 부작용은 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다.
This invention contains the gold-silver coin extract obtained by the above-mentioned manufacturing method. Since the extract of the present invention has little toxicity and side effects, it can be used safely even when taken for a long time for the purpose of prevention.
<실시예 3> 실험동물의 사육
Example 3 Breeding of Experimental Animals
시험동물은 오리엔트로부터 SD계 랫트와 ICR 마우스를 공급 받아 온도 23±1℃, 상대습도 55×15% 및 300-500 룩스(Lux)의 조도로 12시간 간격으로 명암이 조절되는 동물 사육실에서 일주일 이상 순화시킨 후 육안적 증상을 관찰하여 정상적인 동물만을 실험에 사용하였으며, 실험동물용 고형사료(주, 삼양사) 및 물은 자유롭게 섭취시켰으며, 실험 24시간 전에 절식시켜 사용하였다.
The test animals received SD rats and ICR mice from the orient, and at least 1 week in the animal breeding room where the brightness was controlled every 12 hours with a temperature of 23 ± 1 ° C, a relative humidity of 55 × 15%, and an illumination of 300-500 Lux. After acclimatization, only the normal animals were used for the experiment by observing gross symptoms, and the solid feed (Samyangsa) and water for the experimental animals were freely ingested, and fasted 24 hours before the experiment.
<실시예 4> 시험물질의 조제 및 투여
Example 4 Preparation and Administration of Test Substance
시험 물질을 각각 체중 100g당 1㎖의 용량으로 (1㎖/100g b.wt.) 경구투여 바늘(sonde)을 사용하여 경구로 강제 투여하였다. 투여 부피는 투여 당일에 측정된 체중에 따라 산출하였고, 대조군은 D.W 용액만 투여하였다(1㎖/100g b.wt.). 양성대조군은 디클로페낙를 사용하였으며 각각 실험 모델에 적합한 용량으로 saline에 녹인 후 경구로 투여하였다 (1㎖/100g b.wt.).
The test substances were forced orally using oral needles (sonde) at a dose of 1 ml per 100 g of body weight (1 ml / 100 g b.wt.), respectively. Dosing volume was calculated according to body weight measured on the day of dosing and control group was administered only DW solution (1 mL / 100 g b.wt.). The positive control group was diclofenac, which was dissolved orally administered in saline at a dose suitable for each experimental model (1 ml / 100 g b.wt.).
<실험예 1. 진통 효능 평가 실험: 핫 플레이트 테스트 (Hot plate test)>
Experimental Example 1. Analgesic Efficacy Evaluation Experiment: Hot plate test
시험 전 12시간을 절식시킨 25-28g의 ICR계 웅성 마우스를 사용하였으며, 동통반응은 55℃로 유지되는 핫 플레이트(Ugo Basile, Italy)에 조심스럽게 올려 놓고 핫 플레이트 위에 접촉할 때부터 뛰어오를 때까지의 시간(sec)을 측정한 것을 지표로 열감에 의한 동통 반응을 측정하였다(Wolfe G, MacDonald AD.; J. Pharmacol. Exp. Ther., 80, pp300-307, 1944). 시험물질은 시험 30분 전에 경구로 투여하였고, 양성 대조물질로는 디클로페낙(25 mg/kg 체중)을 사용하였다. 대조군의 반응시간을 100% 대비하여 억제율로 표시하였다.
25-28 g of ICR male mice were fasted 12 hours before the test, and the pain response was carefully placed on a hot plate (Ugo Basile, Italy) maintained at 55 ° C and jumped from touching the hot plate. The pain response due to the sensation was measured by measuring the time to sec (Wolfe G, MacDonald AD .; J. Pharmacol. Exp. Ther., 80, pp 300-307, 1944). The test substance was administered orally 30 minutes before the test, and diclofenac (25 mg / kg body weight) was used as a positive control. The reaction time of the control group was expressed as the inhibition rate compared to 100%.
각 수치는 시험군당 N=10 마우스에 대한 평균ㅁ표준편차로 나타낸 것임, Each figure is the mean standard deviation for N = 10 mice per test group.
***: 대조군에 대해 유의적으로 상이함(P<0.001)
***: significantly different for the control group (P <0.001)
실험 결과, 상기 표 1에서 나타낸 바와 같이 본 발명의 금은화 물, 에탄올 추출물은 아세트산으로 유도된 뒤틀림 현상의 횟수를 유의적으로 억제하였으며, 진통 억제율의 상승정도는 약 80%로 소염진통제인 디클로페낙과 유사한 정도로 억제시켜, 진통효과가 우수함을 확인할 수 있었다.
As a result, as shown in Table 1, the gold and silver ethanol extract of the present invention significantly inhibited the number of times of warping phenomenon induced by acetic acid, and the increase in analgesic inhibition rate was about 80%, similar to that of diclofenac, an anti-inflammatory analgesic. The degree of inhibition was confirmed, and the analgesic effect was confirmed to be excellent.
<실험예 2: Formalin test>
Experimental Example 2: Formalin test
시험 전 18시간을 절식 시킨 130~200g의 SD rat에 시험 물질을 sc 투여하고 20분이 경과한 후 5% formalin을 오른쪽 뒷발에 plantal 부위에 sc 투여하였다. 양성 대조군은 디클로페낙을 사용하였다. Formalin 20ul를 주사하고 즉시 투명한 rat 용 cage에 넣고 5분 동안 주사부위에 licking response를 관찰하였다. 통증억제율(A)은 다음의 식에 따라 계산 하였다.
The test material was administered to 130-200 g of SD rats that were fasted 18 hours before the test, and 20 minutes later, 5% formalin was administered to the plantal site in the right hind paw. A positive control was diclofenac. Formalin 20ul was injected and immediately placed in a transparent rat cage for 5 minutes to observe the licking response at the injection site. Pain inhibition rate (A) was calculated according to the following equation.
A(%) = 100 - (T1 * 100 / T2), T1은 약물을 투여한 군의 licking time이고 T2는 대조군의 licking time을 나타낸 것이다.
A (%) = 100-(T1 * 100 / T2), where T1 is the licking time of the drug group and T2 is the licking time of the control group.
각 수치는 시험군당 N=10 랫트에 대한 평균±표준편차로 나타낸 것임, Each value is expressed as mean ± standard deviation for N = 10 rats per test group.
***: 대조군에 대해 유의적으로 상이함(P<0.001)
***: significantly different for the control group (P <0.001)
실험 결과, 상기 표 2에서 나타낸 바와 같이 본 발명의 금은화 물, 에탄올 추출물은 포르말린을 투여한 뒷발에 licking time을 유의적으로 억제하였으며, 진통 억제율의 상승정도는 약 79%로 소염진통제인 디클로페낙과 유사한 정도로 억제시켜, 진통효과가 우수함을 확인할 수 있었다.
As a result, as shown in Table 2, the gold and silver water of the present invention, ethanol extract significantly inhibited the licking time in the hind paw after administration of formalin, and the increase in analgesic inhibition rate was about 79%, similar to that of diclofenac, an anti-inflammatory analgesic. The degree of inhibition was confirmed, and the analgesic effect was confirmed to be excellent.
<실험예 3: Writhing Test>
Experimental Example 3: Writhing Test
시험 전 하룻밤을 절식 시킨 100~200g의 SD rat에 실험 물질을 투여한 후 일정시간(경구투여인 경우 30분)후에 0.7% acetic acid를 복강투여하였다. 0.7% acetic acid 투여 5분 후에 10분 동안 writhing syndrome 발생횟수를 측정하였다. 양성 대조군은 디클로페낙을 사용하였다.
After the test material was administered to 100-200 g of SD rats that were fasted overnight before the test, 0.7% acetic acid was intraperitoneally administered after a certain time (30 minutes in the case of oral administration). The frequency of writhing syndrome was measured for 10 minutes after 0.7 minutes of 0.7% acetic acid administration. A positive control was diclofenac.
각 수치는 시험군당 N=10 랫트에 대한 평균±표준편차로 나타낸 것임, Each value is expressed as mean ± standard deviation for N = 10 rats per test group.
***: 대조군에 대해 유의적으로 상이함(P<0.001)
***: significantly different for the control group (P <0.001)
실험 결과, 상기 표 3에서 나타낸 바와 같이 본 발명의 금은화 물, 에탄올 추출물은 0.7% acetic acid 복강 투여 후 5분후부터 writhing 횟수가 유의적으로 증가하였으며, 진통 억제율의 상승정도는 약 70%로 소염진통제인 디클로페낙과 유사한 정도로 억제시켜, 진통효과가 우수함을 확인할 수 있었다.
As a result, as shown in Table 3, the gold and silver ethanol extract of the present invention significantly increased writhing frequency from 5 minutes after 0.7% acetic acid intraperitoneal administration, and the increase in analgesic suppression rate was about 70%. It was confirmed that the analgesic effect was excellent by suppressing it to a similar degree as in diclofenac.
<실험예 4: 랫트에 대한 급성경구투여 독성실험>
Experimental Example 4: Acute Oral Administration of Rats
6주령의 특정병원부재 (SPF) SD계 암수 랫트를 사용하여 2개의 금은화 추출물에 대한 급성독성실험을 실시하였다. 실험군의 구성은 군당 암수 각각 5 마리씩의 동물에 대하여 본 발명의 2개의 금은화 추출물을 1g/㎏, 2g/㎏ 및 5g/㎏의 용량군으로 하였으며, 시험물질은 5% HPMC(hydroxypropylmethyl cellulose) 용액에 현탁하여 1회 경구투여 하였다. 시험물질 투여 후 동물의 폐사여부, 임상증상, 체중변화를 관찰하고 혈액학적 검사와 혈액 생화학적 검사를 실시하였으며, 부검하여 육안으로 복강장기와 흉강장기의 이상여부를 관찰하였다. 그 결과, 시험물질을 투여한 모든 동물에서 특기할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학 검사, 부검소견 등에서도 독성변화는 관찰되지 않았다. 또한, 본 발명의 금은화 추출물을 투여한 실험군과 투여하지 않은 대조군의 현미경적 소견을 비교한 결과, 간장, 비장, 신장, 뇌, 피부, 생식기계, 위장, 대장, 심장, 폐장 등 실질 장기 등에서 본 발명의 금은화 추출물이 독성을 나타내지 않는 것으로 확인되었다. 이상의 결과 실험된 본 발명의 금은화 추출물은 모두 랫트에서 5g/㎏까지 독성변화를 나타내지 않는 안전한 물질로 판단되었다.Acute toxicity test was performed on two gold and silver coin extracts in 6-week-old SPF SD male and female rats. The experimental group consisted of two gold and silver coins extracts of the present invention in dose groups of 1 g / kg, 2 g / kg and 5 g / kg for 5 male and female animals per group, and the test substance was added to 5% HPMC (hydroxypropylmethyl cellulose) solution. Suspended and administered once orally. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed, and hematological and blood biochemical tests were performed. Necropsy was performed to visually observe the abdominal and thoracic organ abnormalities. As a result, no significant clinical symptoms or dead animals were noted in all animals treated with the test substance, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings. In addition, as a result of comparing the microscopic findings of the experimental group and the non-administered control group to which the gold-silver coin extract of the present invention was administered, the present invention was found in real organs such as liver, spleen, kidney, brain, skin, reproductive system, stomach, large intestine, heart and lung. Was found to be nontoxic. As a result, all of the tested silver coin extract of the present invention was determined to be a safe substance that does not show a toxicity change in rats up to 5 g / kg.
Claims (4)
상기 제 1단계에서 추출된 추출물을 일정량의 정제수로 용해시키고 동량의 유기용매인 노르말 헥산, 에틸아세테이트, 클로로포름, 노르말 부탄올로 순차적으로 극성을 올려 각각 1회 내지 5회 분획한 후, 유기용매 가용부를 제거하는 제 2단계; 및
상기 제 2단계에서 제거 후 남은 수가용성 분획을 일정량의 정제수에 용해시켜, 그 중량의 10 내지 15배(w/w)의 미세다공 비이온 흡착제 수지 또는 역상 칼럼에 사용되는 수지에 흡착시켜 용출하는 제 3단계의 공정을 포함하는 것을 특징으로 하는 진통 활성이 증진된 금은화 추출 정제물의 제조방법.Gold and silver coins were extracted from hot water for 1 to 24 hours by adding a solvent selected from water containing 10 to 20 times (v / w) purified water, any one of C 1 to C 4 lower alcohols or a mixed solvent thereof. A first step of extracting one to five repetitions using any one of cold extraction, reflux cooling extraction, and ultrasonic extraction;
After dissolving the extract extracted in the first step with a predetermined amount of purified water and sequentially raising the polarity with the same amount of organic solvents normal hexane, ethyl acetate, chloroform, normal butanol, and fractionated once to five times, the organic solvent soluble part A second step of removing; And
The water-soluble fraction remaining after the removal in the second step is dissolved in a predetermined amount of purified water, eluted by adsorbing to a 10 to 15 times (w / w) microporous nonionic adsorbent resin or a resin used in a reverse phase column of the weight. A method for producing a gold-silver extract purified product, characterized in that it comprises a third step process.
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