KR100242546B1 - Antialzheimer active composition - Google Patents

Abstract

The present invention relates to an anti-dementia active composition comprising a lower alcohol extract of detoxified riches such as aspirations, and a butanol fraction, an alkaloid-containing fraction and at least one component selected from neoline as an active ingredient, and a method for producing the same. According to the present invention there is provided a useful new pharmaceutical composition which exhibits an excellent effect in the prevention and treatment of dementia.

Description

Anti-dementia active composition and preparation method thereof

1 is a graph measured by measuring the passive learning ability of the dementia-induced dementia-induced anti-dementia activity of the total methanol extract and the butanol fraction and alkaloid fraction of the aspirator, where the indicated value is the average of experimental animals. Retention time ± standard deviation, relative to each experimental group 15 dogs, the significance for the scopolamine control is *: p <0.05, **: p <0.01.

FIG. 2 is a graph measuring the anti-dementia activity of neoline by measuring passive learning ability of mice dementia-induced dementia, where the indicated values are relative to the mean dwell time ± standard deviation of experimental animals. Each experimental group consisted of 15 animals, and the significance for the scopolamine control group was *: p <0.05, **: p <0.01.

FIG. 3 is a graph showing the activity of neoolein recovering prominently by recovering active learning ability in mice dementia-induced with scopolamine, wherein the indicated values are the average number of reactions of the animals + standard deviation, The experimental group consisted of 15 animals.

FIG. 4 is a graph showing that neoline, which improves memory and learning ability of mice dementia-induced with dementia, has an activity of improving learning ability even in normal mice without dementia. Is the average number of responses ± standard deviation of the animals. Each group consists of 15 animals.

The present invention relates to an anti-dementia active composition and a method for producing the same. More specifically, the present invention provides an anti-dementia active composition comprising as an active ingredient a lower alcohol extract of a detoxified (detoxified or detoxified), and a butanol fraction, an alkaloid-containing fraction, at least one component selected from neoline, and It relates to a manufacturing method.

Alzheimer's disease is known to be the major cause of dementia, which has recently emerged as a social problem. Alzheimer's disease patients cause abnormalities in almost all nerves, including cholinergic, adrenergic, GABA and glutamate nerves, and the loss of cholinergic nerves is known to be most serious. In order to restore or improve cholinergic abnormalities, research on the development of therapeutic agents for Alzheimer's disease is being actively conducted (Smith CM Alzheimer's Disease.In Neurotransmitters, Drugs and Disease (eds Webster, RA and Jordan. CC), Blackwell Scientific) Publ. Co., London, p. 428 (1989); Lang, W. and Henke, H. Cholinergic receptor binding and auto-radiography in brains of non-neurological and senile dementia of Alzheimer-type patients. Brain Res ., 267: 271 (1983). The development of a cure for Alzheimer's disease has been advanced as the method of artificially manipulating a condition similar to Alzheimer's disease by inducing abnormalities in the cholinergic nervous system by administering scopolamine to experimental animals (Flood, J.). and Cherkin, A. Scopolamine effects on memory retention in mice, Behav. Neural. Biol. 45: 169-184 (1986)). The administration of scopolamine in rats showed symptoms similar to those in Alzheimer's disease, such as degeneration of cholinergic neurons and loss of memory, including deficiencies in learning, learning, immediate response, and working memory. Smith, 1988; Giacobini, E. and Cuadra, G. (1994) Second and third generation cholin-esterase inhibitors: from preclinical studies to clinical efficacy.In Alzheimer's Disease: Therapeutic Strategies (Giacobini, E. and Becker, R. ed. Birkauser.Boston, pp. 155-171; Ben-Barak, J. and Dudai, Y. (1980) Scopolamin induced an increase in muscarinic receptor level in rat hippocampus, Brain Res ., 193: 309-313). These symptoms are Pizo, an acetylcholinesterase (AChE) inhibitor that maintains the concentration of acetylcholine in the cell by inhibiting the degradation of arecoline and oxotremorine or acetylcholine, which are agonists of cholinergic nerves. It was alleviated by the administration of physostigmine and the like. Indeed, tacrine, an AChE inhibitor, is used in clinical practice, but issues such as hepatotoxicity, short half-life and low bioavailability have been raised (Antuono, PG (1995) Effectiveness and Safety of Velnacrine for the Treatment of Alzheimers-Disease- . A Double-Blind, Placebo- Controlled Study Arch Int Med, 155:... 1766-1772; Siegfried, K. (1995) The Efficacy of Cholinergic Drugs in Patients with Alzheimers Disease - Focus on the Aminoacridines Human Psychopharmacology, Clin. Exp . 10: 89-96) Research is actively underway to find new alternatives.

The present inventors found that the total methanol extract of rich man had significant antidementia activity while searching for dementia activity in natural products to find a substance having new antidementia activity.

The rich have long been used in the private sector for the purpose of strong heart, fever, soothing, analgesia, metabolic promotion and hyperactivity, and have been used as a medicine for dementia in oriental medicine (相 賀 澈 夫, (1985). The Institute of Technology Publishers, pp. 1482-1487), attempted to isolate substances that enhance memory and learning ability from the rich. In the rich, the main ingredient is aconitine (Honino, H., Takahashi, M., Konno, C., Hashimoto, I. and Namiki, T. (1983) Subacute and subchronic toxicity of Aconitum roots and mesaconitine, Shoyakugaku Zasshi 37: 1-9), hypaconitine (Hikino, H., Takahashi, M., Konno, Co., Hashimoto, I. and Namiki, T. (1983) Subacute and subchronic toxicity of Aconitum roots and mesaconitine , Shoyakugaku Zasshi 37: 1-9) and mesaconitine (Hikino, H. Takata, H., Fujiwara, M., Konno, C. and Ohuchi, K. (1982) Mechnism of inhibitory action of mesaconitine in acute inflammations, Eur. J. Pharmacol . 28: 65-71. Other alkaloids (Konno, C., Murayama, M., Suigiyama, K., Murakami, M., Takahashi, M. and Hikino, H. (1985) Isolation and hypoglycemic activity of aconitans, Planta med 51: 160-161; Kitagawa, I., Chem ZL, Yoshihara, M. and Yoshigawa, M. (1984) Chemical studies on crude drug processing.II.Aconiti Tuber (1) .On the constituents of Chuan-wu, the dried tuber of Aconitum carmichaeli Debx.Yakugaku Zasshi 104: 848-857; Hikino, H., Takahashi, M., Konno, C., Hashimoto, I. and Namiki, T. (1983) Subacute and subchronic toxicity of Aconitum roots and mesaconitine, Shoyakugaku Zasshi 37:. 1-9; Pelletier, SW, Mody, such as NV and Varughese, KI (1982) Fuziline, a new alkaloids from chinese drug Fuzi (Aconitum carmichaeli Debx) Heterocycles 17-19) with simple amines of (Konno, C., Shirasaka, M. and Hikino, H. (1979) Cardioactive principle of Aconitum carmichaeli roots, Planta Med . 35: 150-155) Various substances have been isolated and reported. Among the pharmacological effects of the rich, pharmacological effects on the nervous system have been reported to affect inadequate or cholinergic neurons (Yu, SP And Kloot, WV (1990) Non-quantal acetylcholoine release at mouse neuromuscular junction: effects of elevated quantal release). and aconitine. Neurosci. Lett . 117: 111-116).

There are many kinds of Aconitum plants belonging to the rich, similar to the group of components, such as Baekbuja (白 附子), Jinbeom (秦 梵), Ciao (草烏) in Korea, and similar uses, All of them are toxic and used after various processing. Such processing is called numerical value. According to this numerical method, salt rich man (鹽 附子: soaked in rich juice and salt water and dried), roster (明 附 塊: peel off the rich man, split vertically, soak in hot water and dry) , Peeled slices (淡 附 片: peeled and sliced into thin slices and soaked in boiling water and dried), abuja (split in two vertically grilled or steamed) (Hyundeok Ryong (1989), modern pharmacist, Hakchang , Pp. 268-271).

The rich man was highly toxic by the main components, aconitine, mesaconitine, hypaconitine, etc., and the acute toxicity test in mice showed that LD50 was 0.22, 0.27, 0.50mg / kg. Fairly large (Hikino, H., Takahashi, M., Konno, C., Hashimoto, I. and Namiki, T. (1983) Pharmaceutical studies on Aconitum roots.Part 13, Structure of hokbusine A and B, diterpene alkaloids of Aconitum carmichaeli roots from Japan, I. Nat. Prod. 46: 178-82). In the case of the rich, the acetyl or benzoyl group is lost in the diterpene nucleus, or lipo-alkaloid is formed, and the existing alkaloid is converted into a weakly toxic alkaloid, which reduces the content of the relatively toxic alkaloid. Toxicity in the rich is greatly reduced (Kitagawa, I., Chem ZL, Yoshihara, M. and Yoshigawa, M. (1984) Chemical studies on crude drug processing.II.Aconiti Tuber (1) .On the constituents of Chuan- wu, the dried tuber of Aconitum carmichaeli Debx.Yakugaku Zasshi 104: 848-857). When the acetyl group is separated from the aconitines, benzoyl aconitine is produced, and when the benzoyl group is separated there, aconine is produced. In addition, the aconitines are converted into a pyro-type structure in which the acetyl group of the 8th carbon falls and the hydroxyl group of the 15th carbon is a keto-form when heated near the melting point. LD ₅₀ levels of mice showed that benzoylmesaconine was about 1/150 more toxic than mesaconitine, mesaconine was about 1/500 toxic, and pyromesaconitine was mesaconi. About 1/200 of tin and pyromesaconine are about 1/300 toxic. Their toxicity is gradually weakened in the order of mesaconitin> benzoyl mesaconin>pyromesaconitin>mesaconin> pyromesaconin.

Neolin is a relatively toxic tatalazamine-based alkaloid that has pharmacological effects stronger than toxicity because it has a nucleus in which acetyl or benzoyl groups, which are toxic functional groups, are toxic.

As shown above, the extract of rich man who does not have any level is very toxic and cannot be used as a medicine in clinical practice. However, the rich man extract which reduced its toxicity through heat treatment or salt treatment including aspiration can be effectively used in clinical practice. have. In addition, as a composition of anti-dementia activity, neoline may exhibit effective activity as well as itself as a component of the total extract of the numerically rich.

Accordingly, it is an object of the present invention to provide a composition for the prevention and treatment of dementia, which comprises a lower alcohol extract of detoxified rich, butanol fraction thereof, an alkaloid-containing fraction, and at least one component selected from neoline as an active ingredient.

It is another object of the present invention to mix the lower alcohol extract of detoxified rich, butanol fraction, alkaloid containing fraction and one or more components selected from neoline with one or more components selected from conventional excipients, adjuvants, diluents, etc. It provides a method for preparing a composition for the prevention and treatment of dementia by formulating in the form of a conventional formulation in an academically acceptable method.

Hereinafter, the present invention will be described in detail.

In order to provide a composition of the present invention, to obtain a crude extract by extracting abuja and the like detoxified by a low alcohol, such as methanol, ethanol, and the like to determine which of the various components of the rich shows an effective pharmacological action Fractionation and identification were carried out according to the scheme of finding a compound that actually shows pharmacological action.

Scheme 1: Extraction and Fraction of Active Ingredients from Aspirations

Scheme 2: Isolation of Neoline from Fractions B and C

When the present invention is described schematically with reference to the above scheme, first, aspiration detoxification of a rich man is extracted with methanol, and the extract is concentrated under reduced pressure to obtain a methanol extract. The methanol extract is suspended in water and fractionated with methylene chloride to obtain a methylene chloride fraction and a water fraction. The water fraction is further fractionated with n-butanol to obtain an n-butanol fraction and a water residue. The n-butanol fraction was fractionated with ethyl acetate with pH adjustment, and fraction A of fraction 4 at pH 4, fraction B at fraction 7, fraction C at fraction 11 and fraction D at fraction 13 were obtained. Get

Fraction B and Fraction C, which is a double alkaloid containing fraction, were combined and subjected to silica gel column chromatography to obtain Fr. 1, Fr. 2 (6.5 g), Fr. 3, Fr 4, Fr 5, Fr. 6, Fr. 7, Fr. 8, Fr. 9 and Fr. 10, and Fr. 2 (6.5 g) was purified by silica gel column chromatography. 11, Fr. 12, Fr. 13, Fr. 14 (4 g), Fr. 15 and Fr. 16, Fr. 14 (4 g) was again purified by silica gel column chromatography. 17, Fr. 18, Fr. 19 (1 g) and Fr. Get 20 Fr. The substance isolated at 19 was identified as neoline.

Next, the present invention will be described in more detail with examples and experimental examples.

Experimental Animals-ICR-based female mice (25-30g) were supplied from Seoul National University Animal Breeding Farm and were bred in the Laboratory Animal Laboratory, Seoul National University. The environment of the experimental animal room was maintained at 22 ± 5 ℃ and the lighting time was fixed from 7 am to 7 pm, and the feed was 23.2% crude protein, 4.0% crude fat, 60% crude fiber, 10.0% crude ash, crude calcium Solid feeds (Seoul, Samyang) containing 0.6% and 0.4% of joins were used.

EXAMPLE

1. Reagents and Materials:

The rich ( Aconitum carmichaeli ) was grown in a herbal medicine garden affiliated with Seoul National University College of Pharmacy and harvested in December 1994. The black bean and Wongamcho were purchased from Kyungdong Market Herbal Medicines and used by Emeritus Professor Seoul National University. All reagents used in the study were from Sigma, St. Louis, Mo., USA.

2. Preparation, Extraction and Fraction of Aspirations:

After washing the rich 47kg in running water to remove the soil, divided into 4 large pieces, 8kg black soybean and 14kg of persimmon vinegar soaked for 2 hours in decoction of black bean persimmon for 2 hours. The detox was picked up, steamed for 2 hours, then chopped and dried quickly when hot to obtain 14 kg of aspirations. Aspirator 14 kg was extracted 6 times with methanol at room temperature for 2 hours using an ultrasonic apparatus, and concentrated under reduced pressure to obtain methanol x 1.8 kg (Scheme 1). Abubu X (1.8 kg) was suspended in distilled water, and then fractionated according to the polarity of the solvent to obtain a methylene chloride (CH ₂ Cl ₂ ) fraction (20 g) and a water fraction (1.75 kg). The fraction was n-butanol - - a fraction again n-butanol to give a 330g fraction.

3. Isolation of Compound 1:

Butanol fraction (330g) was adjusted to pH 4 with 1N HCl, extracted with ethyl acetate, fraction A (25g) was adjusted to pH 7 with NH ₄ OH, and extracted with ethyl acetate and fraction B (10g). The fraction C (65 g) was adjusted to pH 11 using NH ₄ OH and NaOH, and the fraction D (1 g) was adjusted to pH 13 using NaOH (Scheme 1). Fractions B and C (75 g), which were fractions containing double alkaloids, were repeatedly subjected to silica gel column chromatography and recrystallized with a mixed solvent of n -hexane-ethyl acetate to obtain 1 g of compound 1 as colorless acicular crystals (Scheme 2).

4. Structure Determination of Compound 1:

Colorless acicular crystal, EIMS (m / z) 437 [M +], molecular weight: C ₂₅ H ₃₉ NO ₆

IR (KBr) 3260 cm ^-1 (OH group),

¹ H-NMR (CDCl ₃ , 400 MHz) δ 0.98 (3H, t, N-CH ₂ CH ₃ ), δ3.19 (3H, s, OCH ₃ ), 3.28 (3H, t, OCH ₃ ), 3.50 ( 3H, s, OCH ₃ ),

¹³ C NMR (CDCl ₃ , 100 MHz) δ 72.3 (C1), 29.5 (C2), 29.9 (C3), 38.2 (C4), 44.9 (C5), 83.3 (C6), 52.3 (C7), 74.3 (C8) , 48.3 (C9), 40.7 (C10), 49.6 (C11), 29.8 (C12), 44.3 (C13), 75.9 (C14), 42.7 (C15), 82.3 (C16), 63.6 (C17), 80.3 (C18) , 57.2 (C19), 48.2 (N-CH ₂ -CH ₃ ), 13.0 (N-CH ₂ -CH ₃ ), 57.8 (C6 '), 56.3 (C16'), 59.1 (C18 ')

(화합물 Ⅰ)

(Compound I)

Based on the above spectral data, compound 1 was estimated as neoline, and the literature values (Kitagawa, I., Chem ZL, Yoshihara, M. and Yoshigawa, M. (1984) on crude drug processing.II.Aconiti Tuber (1) .On the constituents of Chuan-wu, the dried tuber of Aconitum carmichaeli Debx.Yakugaku Zasshi 104: 848-857; Pelletier, SW and Dajrmati, Z. (1976) Carbon- 13 nuclear magnetic resonance: Aconitine-type diterpenoid alakloids form Aconitum and Delphinium and species, J. Am. Chem. Soc . 98: 2626-2636).

Experimental Example

1. Induction of dementia by scopolamine:

Christensen, H., Maltby, N., Jorm, AF, Creasey, H. and Broe, GA (1992) Cholinergic 'Blockade' as a model of the cognitive deficits in Alzheimer 'disease, Brain 115: 1681 -1699) was prepared in physiological saline so that the scopolamine at a concentration of 1mg per 1kg body weight of the mouse was injected subcutaneously 30 minutes before training to induce dementia.

2. Administration of Drugs:

Intraperitoneal injection was performed 1 hour prior to the administration of scopolamine to observe how it affected dementia induction.

3. Passive avoidance test:

At the bottom of the box, a 3 mm thick grid (0.5 grate) is installed at intervals of 0.5 cm and divided into two rooms: an shuttle shuttle box (40 x 20 x 20 cm, Gemini Co., San Francisco) ICR mice (25-30g, male) were put in one room to brighten. Once the mice who prefer the dark place enter the dark room from the bright room, they were trained to give electric stimulation (0.1mA / 10g body weight) through the grid installed at the bottom. After 24 hours, except for the injection of scopolamine and drugs, the procedure was performed the same as the previous day, and the latency time of the mice stayed in the bright room was measured as an index for remembering the training of the electrical stimulation of the previous day. .

4. Active avoidance test:

The active avoidance learning was measured using the same shuttle box as in the passive learning ability measurement. A stimulus giving light and sound to a rat for 2 seconds was determined as a conditioned shock, and an electric stimulus (0.1 mA / 10 g body weight) given after 5 seconds was determined as an unconditioned shock. The escape response was defined as the movement of the mouse to the other room and the stimulus stopped unconditionally while the mouse was receiving the unstimulated stimulus. In addition, avoiding the electrical stimulation that follows by moving to another room while receiving a conditional stimulus, which is a light and sound stimulus, is called an avoidance response.The conditional stimulus is also moved to another room until the stimulus is unconditionally terminated. No response was defined as no response. When training 30 times once a day for 5 days under the above conditions, the active learning ability was measured by measuring the number of daily evasion and escape response.

5. Statistical Processing:

For statistical significance review, the number of mice in each experimental group was 15 (n = 15), and the variation from the control value was the "ANOVA test". When the P value was less than 5%, it was determined to be statistically significant.

6. Results and Discussion:

1) The antidementia activity of the total methanol extract of aspiration spores was determined by measuring the passive learning ability of mice induced by dementia with scopolamine. The results are shown in FIG. That is, the total methanol extract of the aspirator was intraperitoneally injected into ICR mice (25-30 g, male) at a concentration of 500 mg / kg, and scopolamine was injected subcutaneously 1 hour later.

After 30 minutes, a grid of 3 mm thick is installed at the bottom with a gap of 0.5 cm, and the mouse is placed in an accommodation shuttle box (40 x 20 x 20 cm) divided into two rooms. To brighten. Once the mice who prefer the dark place enter the dark room from the bright room, they were trained to receive electric stimulation (0.1mA / 10g body weight) through the grid installed at the bottom. After 24 hours, the rest of the procedure except the injection of scopolamine and the drug was performed the same as the previous day, and the latency time of the mice stayed in the bright room was measured and set as an index for remembering the training of the electrical stimulation of the previous day. . Normal rats without dementia remembered electrical stimulation in the dark room of the previous day and attempted to stay in the bright room and stayed in the bright room for 170 ± 15 seconds.However, dementia induced the electrical stimulation in the dark room. Mice that couldn't remember quickly moved to a dark room and stayed in a bright room for only 35 ± 7 seconds. Intraperitoneal injection of the total methanol extract of the aspirator into the mice showed that the latency time in the bright room was 78 ± 10 seconds, maintaining the memory of the mice to 32% of normal condition. Therefore, the total methanol extract of the aspiration was divided into methylene chloride, n -butanol and water fractions according to the polarity of the solvent, and the anti-dementia activity of each fraction was detected, indicating that the n -butanol fraction showed significant anti-dementia activity ( 1). The n -butanol fraction of the aspiration was positive in both the dragendorff reagent and the ninhydrin reagent, indicating that the alkaloid was contained. Thus, the pH of the n -butanol fraction was adjusted to 4, 7, 11 and 14, and then fractionated with ethyl acetate to obtain fractions B and C containing alkyloids, and fractions A and D containing no alkaloids (Scheme 1 ). The effects of fractions B and C, which are fractions containing alkaloids, on the passive learning ability of mice were examined by intraperitoneal injection at a concentration of 100 mg / kg and measuring the latency time in a bright room. Fractions B and C, the fractions containing alkaloids, were found to maintain 94 ± 14 seconds of latency time at 44% of memory at steady state when intraperitoneally injected into mice. Degree). In addition, fractions B and C, which are fractions containing alkaloids, were combined and silica gel chromatography was repeated, and recrystallized with a mixed solvent of n -hexane-ethyl acetate to obtain 1 g of Compound 1, a colorless acicular crystal, and various NMR, IR, and mass spectrometry thereof. Spectral data were identified as neoline by comparison with existing literature. Neolin has already been reported to be separated from the rich alkaloids (Kitagawa et al., 1984; Pelletier and Djarmati, 1976) or its pharmacological activity, especially its effects on memory and learning have not been reported.

To determine the anti-dementia activity of neoline, the mice were intraperitoneally administered at concentrations of 0.01 mg to 10 mg per kg of body weight, and after 1 hour, dementia was induced with scopolamine to measure passive learning ability. The results are shown in FIG. Neoline improved memory lowered by scopolamine and maintained the highest level of memory at a concentration of 0.1 mg / kg mice, up to 55% of normal memory. In particular, this effect of neoline was better than 28% and 30% of the effect at 0.1 mg / kg body weight of physostigmine and velnacrine, respectively, used as a positive control drug. It was 1.5 times higher than 37%, the highest antidementia activity at 1 mg / kg body weight. On the other hand, neoline showed the best anti-dementia effect of maintaining 55% of memory at a steady state at a concentration of 0.1 mg / kg body weight, even if the concentration was increased to 10 mg / kg body weight Did not die. However, velnakrine was able to maintain 37% of the memory at steady state with the highest effect at 1 mg / kg body weight, which is 10 times higher than the concentration that neoline had the highest effect, and raised the concentration to 10 mg / kg body weight. Three of 15 died when administered. In the above experiments, it was conceivable that neolin had better anti-dementia effect and much less toxicity than belnaclean, which is 10 times higher at 0.1mg / kg body weight.

This study was conducted to investigate the effect of neoline, which has an excellent memory-recovering activity, on the learning ability of mice dementia-induced by scopolamine. The results are shown in FIG. In other words, neogliin was administered intraperitoneally at a concentration of 0.1 mg / kg body weight, and then dementia was induced with scopolamine and the active learning ability was measured for 5 days. Mice were first given a conditioned shock (light and sound for 2 seconds), followed by an electrical stimulation (0.1 mA / 10 g body weight) with unconditioned shock after 5 seconds. The escape response is the escape response of the mouse to the other room while avoiding the electrical stimulus while receiving the unconditional stimulus. It is called an response response, and it was determined that no response was made to move to another room not only until the conditional stimulus but also the conditional stimulus was completed. Normal mice without dementia significantly reduced the number of nonresponse after repeated learning and showed little response after 5 days of training. In addition, the number of evasion reactions was increased rather than the escape response. On the first day of learning, the average evasion response was 1.4 times, and the average of evasion reactions was 9.0 times on the third day and 16.3 on the fifth day. However, in the case of dementia-induced mice, the number of escaping reactions increased with repeated learning was significantly lower than that of normal mice. The number of unresponsiveness decreased with repeated learning was significantly higher than that of normal mice. That is, on the third day of learning, the average evasion response of the dementia-induced mice was 4.0 times, and even on the fifth day of learning, only 6.7 times. In addition, the number of unresponsiveness of dementia-induced mice was significantly higher than that of normal mice, even on the fifth day of study, at an average of 14.0 times. However, in the case of neo-administration, the learning ability that is significantly lowered by scopolamine is maintained, and the average number of conditional evasion reactions was 1.8 on the first day of learning, and 5.4 on the third day of learning. It was 10.3 times on average. On the other hand, the number of unresponsiveness also maintained the level of normal mice without dementia. In particular, this effect of neoline was better than that at 1 mg / kg body weight, which was the concentration that Velnacline had the best memory enhancing effect. As a result, it can be seen that neoline significantly restores learning ability as well as memory decreased by scopolamine.

We examined how neoline, which improves the memory and learning ability of mice with dementia-induced dementia, affects the learning ability of normal mice without dementia. The results are shown in FIG. In the case of the normal mice, the number of evasion reactions increased as the above result, and the average was 1.4 times on the first day and 9.0 on the third day, and 16.3 times on the fifth day. On the other hand, in the case of mice intraperitoneally administered and trained, the number of conditional avoidance reactions when the normal rats were trained for 5 days when the number of conditional evasion reactions was 1.3 on the first day of learning was on the 3rd day of learning, The same average reached 16.3 times. As a result, when neoolin was administered to mice and trained, the learning ability was improved, and even though training was performed for only 3 days, normal mice showed learning ability that can be obtained by learning for 5 days. Neolin's effect was that the number of conditional evasion reactions was 1.2 ± 1.1 on day 1, which is the effect of belnaclean at 10-fold higher concentration, than 10.2 ± 3.7 on day 3, and 16.6 ± 2.1 on day 5, respectively. Better.

The above experiments showed that the alkaloids, neolin, isolated from aspirations, significantly improved the memory and learning ability of mice and did not show acute toxicity. As can be seen from the above experimental results, the low alcohol extract and neoline of the aspirant are expected to be developed as an improvement or preventive agent for dementia, and the study on its mechanism of action, metabolism, distribution and toxicity should be supported. .

The following results can be derived from the above experimental example.

1. Total low alcohol extracts of aspirations, butanol fractions and alkaloid-containing fractions improved the memory of mice depressed by administration of scopolamine.

2. Neoline, isolated from the alkaloid-containing fraction of aspiration, improved the memory and learning ability of mice degraded by scopolamine, and improved the learning ability of mice under normal conditions.

3. Anti-dementia activity of neoline was superior to belnakrine used as a positive control and did not show acute toxicity.

Lower alcohol extracts such as aspirations, rich butanol fractions, alkaloid-containing fractions, and neolin, which detoxify the rich from the above experimental results, can be used as drugs for the prevention and treatment of dementia.

The composition of the present invention is prepared by mixing a lower alcohol extract, such as abuja detoxified rich, butanol fraction, alkaloid-containing fraction or neoline with excipients, adjuvants, diluents and the like that can be used in conventional pharmaceutically The formulations to be used can be used, for example, in the form of tablets, capsules, powders, solutions, topical preparations, injections, suppositories, and the like.

Lower alcohol extracts such as aspirations deciphering the rich used in the present invention, and active ingredients such as butanol fraction, alkaloid-containing fraction or neoline may vary depending on the age of the patient, the degree of dementia, and the daily weight of 0.1 An amount of from 500 mg may be administered 1 to several times daily. This amount can increase or decrease depending on the severity of the disease, sex, age, and the like.

Next, a formulation example is illustrated.

Preparation Example 1

Preparation of tablets:

The above components are formulated by a conventional method for producing tablets.

Preparation Example 2

Preparation of tablets:

The above components are formulated by a conventional method for producing tablets.

Preparation Example 3

Preparation of tablets:

The above components are formulated by a conventional method for producing tablets.

Preparation Example 4

Preparation of capsules:

The said component is formulated by the manufacturing method of a normal capsule.

Preparation Example 5

Preparation of capsules:

The said component is formulated by the manufacturing method of a normal capsule.

Preparation Example 6

Preparation of Liquids:

The above components are formulated in a conventional liquid formulation method and filled into a brown bottle to prepare a liquid formulation.

Preparation Example 7

Preparation of Liquids:

The above components are formulated by a conventional method for preparing a liquid, and filled into a brown bottle to prepare a liquid.

Preparation Example 8

Preparation of powders:

The above ingredients are mixed by a conventional powder production method, placed in a bag and sealed to prepare a powder.

Preparation Example 9

Preparation of Injectables:

The above ingredients are filled into 2.0 ml ampoules and sterilized by a conventional injection method to prepare an injection.

Preparation Example 10

Preparation of Injectables:

The above ingredients are filled into 2.0 ml ampoules and sterilized by a conventional injection method to prepare an injection.

Preparation Example 11

Preparation of suppositories:

The suppository is prepared by heat-melting the above components in a conventional method for preparing suppositories, placing them in a suitable mold and cooling and solidifying them.

Claims (2)

At least one component selected from the lower alcohol extracts of the detoxified rich, butanol fraction and alkaloid containing fractions may be mixed with the components by one or more selected from conventional excipients, adjuvants and diluents and in conventional pharmaceutically acceptable ways. A composition for the prevention and treatment of dementia prepared by formulating a formulation. The composition for the prevention and treatment of dementia formulated in the form of a powder, tablets, capsules, drugs, injections, suppositories in the form of claim 1.

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