HK1161546B - Plant extract compositions for affecting sleep - Google Patents

Description

Plant extract composition for affecting sleep

Technical Field

The present invention relates in a broad sense to plant extracts, in particular to the use of plant extracts for the modulation of sleep disorders.

Background

Sleep disorders are generally classified as medical conditions of sleep patterns in humans or animals. In some cases, sleep disorders can be severe enough to interfere with normal physiological, psychological and emotional functioning. Sleep disorders may include sleep abnormalities, insomnia (insomnia), circadian rhythm sleep disorders, hypersomnia, and parasomnia.

Insomnia, for example, insomnia (sleeplessness) is a common medical condition, often caused by excessive stimulation of the spirit and/or body. The main factors causing insomnia are stress, poor eating habits, lack of physical activity, pain, environmental factors and psychological factors. Failure to fall asleep, poor sleep quality and night awakenings can be significant problems, sleep being essential for survival and good health. Sleep disorders may also cause problems that occur during the day, such as fatigue, poor thinking and/or attention, depression and/or irritability.

How long a person sleeps and how rested a person feels when awake can be affected by many factors, including excitement, physical exertion, emotional distress, as well as drugs, food ingredients, and food additives.

Intermittent use of hypnotic agents may be useful when sleep disorders interfere with a person's normal activities. Modern hypnotics are generally available as over-the-counter medications and are among the more commonly available commercial drugs. However, many of the currently available hypnotic pills, particularly hypnotics and sedatives, should not be taken for long periods of time. Continued long-term use may lead to the establishment of tolerance to the drug in humans, and in addition may worsen the original sleep disorder, be susceptible to addiction, and cause withdrawal symptoms when use is discontinued. In addition, common side effects of currently available hypnotic agents may include inhibition of the muscular coordination system, the central nervous system, and general functional abilities, such as walking with a foot; tremor, inability to stand still or irregular heart rhythm.

Sleep is vital to a healthy lifestyle. There is a need to provide compositions and methods for treating insomnia or sleeplessness with reduced side effects.

Furthermore, there is a need for compositions comprising natural plant based ingredients that are generally non-addictive, have limited side effects, and are known not to cause physiological withdrawal symptoms when taken off stream.

Disclosure of Invention

Exemplary embodiments of the present invention relate to compositions comprising certain selected plant extracts for the therapeutic treatment and modulation of insomnia and/or insomnia. Other exemplary embodiments of the present invention relate to methods for preparing compositions comprising selected plant extracts.

An exemplary embodiment of the present invention is directed to a composition comprising a therapeutic amount of an extract of arborvitae seed (Baiziren). The composition may additionally comprise a therapeutic amount of polygala tenuifolia (Yuanzhi) extract, a therapeutically effective amount of spina date seed (Suanzaoren) extract, or mixtures thereof.

Another exemplary embodiment of the present invention relates to a method of preparing an extract from each of platycladi seed, polygala root and spina date seed and mixing two or more extracts to obtain one such composition.

Detailed Description

The terms "treating insomnia" or "treating insomnia" as used herein, unless otherwise specified, include, but are not limited to, preventing or reducing disturbances in falling asleep, increasing the ability to remain asleep, reducing waking during sleep, increasing the duration and quality of sleep, and reducing abnormal sleep behavior.

The inventors have surprisingly found that compositions comprising an extract of platycladi seed alone, and compositions comprising the same with at least one of an extract of polygala tenuifolia and an extract of spina date seed, can be used to modulate sleep disorders, such as insomnia. It has also been found that the composition can be used to reduce the time required to fall asleep and further improve the quality of sleep. Unexpectedly, compositions comprising an extract of platycladi seed and novel combinations of platycladi seed extract with at least one of a polygala tenuifolia extract and a spina date seed extract are useful for modulating memory loss, such as amnesia.

The arborvitae seed extract can be prepared from dried seeds, leaves, stems and roots of biota orientalis (Platycladus orientalis). According to an exemplary embodiment, the platycladi seed extract may be from one or more of the leaves, seeds and roots of biota orientalis (L.) Franco. The extract can be directly from whole seed. Alternatively, the seeds may be ground to a powder and then heated to a temperature of about 35 to 50 ℃ to remove the oil prior to the extraction step, as explained in more detail below. According to one aspect, the cedar seed kernel extract is from about 2 grams to 15 grams of dry seeds, leaves and/or roots. In yet another exemplary embodiment, the cedar seed extract is dry seed from biota orientalis (L.) Franco.

The semen Ziziphi Spinosae extract can be derived from leaf, fruit and seed of Zizyphus jujuba (Zizyphus jujuba). Members of the family Ziziphus include Ziziphus jujuba (Ziziphus jujube Mill. Var. spinosa (Bunge) Hu ex H.F.Chou). In particular, the extract is from about 5 grams to 18 grams of one or more of dried seeds, leaves, stems, fruits, and/or roots. In an exemplary embodiment, the extract of the spine date seed is prepared from the seed of jujube.

The Polygala tenuifolia extract is obtained from the leaves, stems and roots of Polygala species (Polygala). In particular, the extract is from about 2 grams to 15 grams of dry seeds, leaves, and/or roots. The polygala tenuifolia extract may optionally be from one or more of the following: polygala tenuifolia (polygal tenuifolia Wild), Polygala sibirica (p.sibirica L), Polygala tenuifolia (p.sibirica var. megalopha Franch.), Polygala japonica (p.japonica Houtt.), Polygala sinkiangensis (p.hybrida DC), osmanthus fragrans (p.aritata buch. -Ham ex d.don), Polygala falcata tenuifolia (p.globosa Lour.), Polygala tenuifolia (p.arvensis Wild.), lentil (p.tatarinowiii), Polygala falcata tenuifolia (p.fallax Hemsl.), Polygala longa (p.watterii), Polygala tenuifolia (p.wanesens Hance), Polygala tenuifolia (p.hongkongenseng. Alternatively, the polygala tenuifolia extract may be derived from polygala tenuifolia and/or siberian polygala tenuifolia, preferably from the dried root of polygala tenuifolia and/or siberian polygala tenuifolia.

Another exemplary embodiment relates to a composition comprising an extract of platycladi seed, and a composition comprising an extract of platycladi seed and at least one of an extract of polygala tenuifolia and an extract of spina date seed. These compositions are useful for regulating sleep disorders, particularly insomnia.

Other exemplary embodiments of the present invention relate to methods of preparing extracts from plant components of platycladi seed, polygala root and spine date seed. These extracts may be obtained from one or more plant components selected from the group consisting of: leaves, stems, roots and seeds. Alternatively, the extract may be prepared from the whole plant. The extract may be prepared from fresh or dried plants and plant components, or from a mixture of both. The method generally comprises the steps of:

(a) the selected plants and/or plant components are soaked in the aqueous solvent at room temperature for a period of about 15 minutes to about 24 hours to produce an extraction mixture. Heating (e.g., from above room temperature to about 110 ℃) may optionally be performed during the soaking process. A suitable aqueous solvent is water. The aqueous solvent may additionally comprise one or more organic solvents, for example: ethanol, methanol, isopropanol, ethyl acetate, hexane, acetic acid and mixtures thereof. The aqueous solvent optionally comprises an inorganic acid or base, which may be used alone or in combination with one or more selected organic solvents. During the soaking process, the aqueous solvent may optionally be mixed and blended with the plant or plant component. If no heating is applied during the soaking, it is suitable to heat the aqueous solvent and botanical mixture above the boiling point for a period of about 15 minutes to about 2 hours to produce an extraction mixture;

(b) filtering the extraction mixture through a filter to produce an aqueous filtrate;

(c) collecting the aqueous filtrate; and is

(d) Concentration, i.e., dewatering the aqueous filtrate to at least a syrup-like consistency, and optionally further dewatering the filtrate to a semi-solid consistency. The method may optionally include the additional step of drying the aqueous filtrate to a powder.

The extraction may also be performed using methods known in the art, including decoction. The crude extract may optionally be further purified using a suitable chromatography column, such as silica gel and Sephadex LH-20(Sephadex LH-20). Alternatively, the plant material may be extracted using supercritical carbon dioxide apparatus and methods.

The semen Platycladi extract can optionally be encapsulated in a soft or hard capsule for oral administration. Alternatively, the cedar seed extract may be blended and mixed with one or more suitable carriers and/or excipients to produce a mixture that may be formed into a tablet. It is also within the scope of the present invention to mix and blend the cedar seed extract with one or more of the polygala tenuifolia extract and the spina date seed extract and then prepare the capsules or tablets.

The following examples illustrate exemplary compositions and methods of the present invention. It is to be understood that these examples should not be considered limiting, and that the experimental data provided are for illustrative purposes only.

Examples

The following examples evaluate the efficacy of the present invention compositions of platycladi seed, polygala root and spine date seed extracts in comparison to tests in mice comprising: barbiturate sodium induces sleep time under hypnosis, side effects on spontaneous activity (nocor activity), traction tests and ramp tests.

Animal(s) production：

Male and female Swiss mice (Swiss mouse) weighing between about 18 and 22 grams were used in the examples provided below. Mice were housed in groups of ten in a housing room controlled at a temperature of about 22 ℃. + -. 2 ℃. Each group had free access to standardized granulated feed and tap water.

Example 1 preparation of extract

Semen Platycladi extract: seeds of platycladi seed (biot orientalis (L.) Franco) were soaked in water at a seed to water ratio of 1: 10(w/w) for about 30 minutes and then cooked at a temperature of about 40 ℃ to 100 ℃ for about 40 minutes. The cooked mixture was filtered through a No. 4 Whatman filter paper and the aqueous filtrate was collected. The aqueous filtrate was concentrated via evaporation and then dried to a powder using a vacuum pump. The dried cedar seed powder is designated "a".

Polygala tenuifolia extract: soaking dried cortex et radix Polygalae tenuifoliae and radix Polygalae sibirica in water at a ratio of 1: 10(w/w) for about 30 min, and steaming at 40-100 deg.C for about 1 hr. The cooked mixture was filtered through a No. 4 Whatman filter paper and the aqueous filtrate was collected. The aqueous filtrate was concentrated via evaporation and then dried to a powder using a vacuum pump. The dried polygala tenuifolia powder is designated "B".

Wild jujube seed extract: dried jujube (Ziziphus jujube) seeds are soaked in water at a seed to water ratio of 1: 10(w/w) for about 30 minutes and then cooked at a temperature of 40 ℃ to 100 ℃ for about 1 hour. The cooked mixture was filtered through a No. 4 Whatman filter paper and the aqueous filtrate was collected. The aqueous filtrate was concentrated via evaporation and then dried to a powder using a vacuum pump. The dried wild jujube seed powder is designated "C".

Combinations of the extract powders were prepared in the following weight ratios and are designated "BS" and "BY", respectively.

Extract powder	The conjugate "BS"	The conjugate "BY"
			Powder A	1	1
Powder B	0	2.48
			Powder C	3.64	0

Example 2: dosing regimens for drugs and extracts

Each extract conjugate "BS" and "BY" prepared in example 1 was prepared for oral administration (PO) BY: each extract was ultrasonically dispersed into distilled water containing about 0.5% Tween-80. Diazepam (Diazepam) is also prepared for administration by: stable ultrasound was dispersed into distilled water containing about 0.5% Tween-80.

Each of the BS, BY and neuroleptic compositions was orally administered to different groups of mice at a dose of 10 ml/kg body weight.

In examples 3 to 5, each animal in the control group received a corresponding dose of sterile distilled water.

The doses of BS, BY, composition and the sterile distilled water were orally administered to groups of mice, wherein each group contained at least ten mice.

Example 3: barbiturate sodium induced sleep time measurement

Mice were given 90 mg/kg of barbital sodium via intraperitoneal injection (ip). The mice were then laid down. The time elapsed from the administration of barbiturate sodium until each animal lost its righting reflex represents the waiting time to the onset of sleep. BS, BY, diazepam and control treatments were administered to different groups of mice. Groups of mice were treated and were given barbiturate sodium about seven days later. The sleep duration is calculated as the time interval from disappearance of the righting reflex to restoration of the righting reflex. When studying the effect of BS and BY extracts, a comparison of sleep duration between mice receiving BS, BY, neuroleptic treatment and control treatment was used as the primary measure. Table 1 below shows the effect of BS and BY treatment on sleep duration.

Table 1: in mice, the effect of BS and BY combinations on the barbiturate sodium induced sleep time test (mean + SE, n ═ 10)

^*Has significant difference (P < 0.05) (Student-t test)

^**Has obvious difference (P < 0.001) (Student-t test) with the control group

Treatment with BS at a dose of 1.6 g/kg, BY treatment at doses of 1.2 g/kg and 2.4 g/kg and neuroleptic treatment at a dose level of 1.0 mg/kg significantly prolonged barbituric sodium induced sleep time compared to controls. Furthermore, based on statistical analysis using Student-t test, both diazepam at a dose of 1.0 mg/kg and BY at a dose of 1.2 g/kg significantly increased (P < 0.001) sleep time compared to control, indicating that the BY composition may have hypnotic function similar to diazepam.

Example 4: measurement of spontaneous activity

The effect of BS treatment and BY treatment on central nervous system inhibition was assessed BY measuring spontaneous activity of mice.

Each mouse was placed in the center of a square field of approximately 60 cm x 35 cm in size. The site had a black floor divided into 16 equal squares using white lines. The site was illuminated using a 25 watt red bulb on top. The total number of squares entered by each mouse over a 5 minute period was recorded by an overhead camera. The camera is connected to a display and video recorder in the adjacent laboratory.

Spontaneous activity of mice was recorded before and 30, 60, 120 and 180 minutes after administration of one of BS, BY, diazepam and control.

All recordings of spontaneous activity were made by observers blinded to the treatment given to each mouse.

Table 2: effect of BS and BY combinations on spontaneous mouse Activity (mean. + -. SE, n ═ 10)

The BS, BY and diazepam compositions all had no significant effect on spontaneous activity in mice, indicating that any of the compositions containing extracts of platycladi seed, polygala root and/or spina date seed had little or no inhibition of the central nervous system.

Example 5: traction test

The effect of BS and BY compositions on inhibition of the muscle coordination system was evaluated using the traction test.

A wire of about 1.6 mm diameter and about 30 cm long was straightened and held horizontally at a position about 30 cm above the plane. Each mouse was placed so that the four paws of the mouse grasped the wire. The duration of time each mouse had caught on the wire was recorded for up to 60 seconds.

The test was performed about 60 minutes after administration of one of the BS, BY, diazepam and control compositions. Each mouse was subjected to 3 replicates. The duration of the scratch measured for each group of mice was calculated using the average of three replicates per mouse. If the duration of the grab was greater than 60 seconds, the mouse was removed from the wire and the grab time was recorded as 60 seconds.

Table 3: effect of BS and BY on mouse traction test (mean + SE, n ═ 10)

^**P is less than 0.001 compared with the control group

The duration of the clinging of mice given one of the BS and BY compositions was very similar to that of mice given control treatment. The data show that both BS and BY compositions have no significant effect on the muscle coordination system. Yet diazepam significantly reduced the duration of adhesion compared to the control group, indicating that diazepam at least partially inhibited the mouse muscle coordination system.

Example 6: bevel test

The effect of the BS and BY compositions on the motor function of mice was evaluated using a ramp test.

The inclined plane is composed of two rectangular steel plates connected at one end by a hinge. One of the plates serves as a substrate and the other plate is a movable inclined surface. Two indexer (prothctor) like steel side plates, on which scales are marked, are fixed to the base. A rubber pad having a ridge height of about 0.6 mm is secured to the surface of the movable plane. The mouse was placed on the pad in a position where its body axis was perpendicular to the axis of the ramp. The maximum slope of the face at which the mouse is able to maintain its position for at least 5 seconds is recorded and is representative of the functional capacity of the mouse. This experiment was repeated 3 times for each mouse and the average was recorded as the maximum dip.

Table 4: effect of BS and BY composition on mouse motor function measured BY mouse ramp test (mean ± SE, n ═ 10)

^**P is less than 0.001 compared with the control group

The angle of inclination recorded for mice receiving a dose of one of the BS and BY compositions was very similar to mice given the control composition. The data in table 4 show that both BS and BY compositions have no significant effect on the mouse's muscle coordination system. However, sedation significantly reduced the maximum angle of inclination compared to the control group, indicating that sedation at least partially inhibited the mouse muscle coordination system.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (12)

1. A composition for modulating physiological sleep disorders, the composition consisting of:

(a) a biota orientalis extract prepared from seeds of biota orientalis (Platycladus orientalis);

(b) polygala species extract prepared from roots of Polygala species (Polygala); wherein the seeds of biota orientalis and the roots of polygala species are extracted in a weight ratio of about 2:1 to about 1:2.4 to produce a biota orientalis extract and a polygala species extract;

(c) optionally, a jujube extract prepared from seeds of jujube (Zizyphus jujube); wherein the seeds of biota orientalis and the seeds of zizyphus jujube are extracted in a weight ratio of about 2:1 to about 1:3.5 to produce a biota orientalis extract and a zizyphus jujube extract; and

(d) one or more pharmaceutically acceptable carriers or excipients,

wherein the extract is present in a therapeutically effective amount to modulate a physiological sleep disorder.

2. A composition for modulating physiological sleep disorders, the composition consisting of:

(a) a biota orientalis extract prepared from seeds of biota orientalis (Platycladus orientalis);

(b) jujube extract prepared from seeds of jujube (Zizyphus jujube); wherein the seeds of biota orientalis and the seeds of zizyphus jujube are extracted in a weight ratio of about 2:1 to about 1:3.5 to produce a biota orientalis extract and a zizyphus jujube extract;

(c) optionally, Polygala species extract prepared from roots of Polygala (Polygala) species; wherein the seeds of biota orientalis and the roots of polygala species are extracted in a weight ratio of about 2:1 to about 1:2.4 to produce a biota orientalis extract and a polygala species extract; and

(d) one or more pharmaceutically acceptable carriers or excipients,

wherein the extract is present in a therapeutically effective amount to modulate a physiological sleep disorder.

3. The composition of claim 1 or 2, wherein the extract is extracted in an aqueous solvent.

4. The composition of any one of claims 1-3, wherein the extract is extracted in an aqueous solvent at a temperature of about 20 ℃ to about 110 ℃.

5. The composition of any one of claims 1-4, wherein the physiological sleep disorder is selected from the group consisting of insomnia, parasomnia, and combinations thereof.

6. The composition of any one of claims 1-5, wherein the composition is formulated into one of a soft capsule, a hard capsule, a liquid, a powder, and a tablet.

7. A method of producing a composition for modulating sleep disorders, the method comprising the steps of:

soaking a seed-containing biota orientalis plant component in an aqueous solvent at a temperature of about 20 ℃ to about 110 ℃, thereby producing a biota orientalis extraction mixture;

soaking a root-containing plant component of a polygala species in an aqueous solvent at a temperature of about 20 ℃ to about 110 ℃, thereby producing a polygala extraction mixture;

separating a liquid fraction from said thuja extract mixture and from said polygala extract mixture;

filtering the arborvitae liquid fraction to produce an aqueous arborvitae filtrate;

filtering the polygala tenuifolia liquid fraction to produce an aqueous polygala tenuifolia filtrate;

dewatering said aqueous cacumen Platycladi filtrate to at least a syrup-like consistency, and dewatering said aqueous polygala tenuifolia filtrate to at least a syrup-like consistency; and is

Making a composition of the dehydrated Platycladus orientalis filtrate, the dehydrated Polygala tenuifolia filtrate, and optionally a jujube seed dehydrated filtrate, and one or more pharmaceutically acceptable carriers or excipients, wherein the seed-containing Platycladus orientalis plant component and jujube seed are soaked in a weight ratio of about 2:1 to about 1:3.5 to produce the dehydrated Platycladus orientalis filtrate and the jujube seed dehydrated filtrate;

wherein said seed-containing Platycladus orientalis plant component and said root-containing plant component of the polygala species are soaked in a weight ratio of about 2:1 to about 1:2.4 to produce said dehydrated Platycladus orientalis filtrate and said dehydrated polygala species filtrate.

8. The method of claim 7, wherein said aqueous thuja filtrate and said aqueous polygala tenuifolia filtrate are dehydrated and processed to produce a dry powder.

9. The method of claim 7, wherein the aqueous solvent comprises a mixture of water and at least one organic solvent selected from the group consisting of: ethanol, methanol, isopropanol, ethyl acetate, hexane, acetic acid and mixtures thereof.

10. The method of claim 7, wherein the aqueous solvent comprises a mixture of water and at least one of an inorganic acid and an inorganic base.

11. The method of claim 7, wherein the composition is formulated as one of a soft capsule, a hard capsule, a liquid, a powder, and a tablet.

12. The method of claim 7, wherein the jujube extract is present and is prepared by a method comprising the steps of:

soaking a plant component of the date containing seeds in an aqueous solvent at a temperature of about 20 ℃ to about 110 ℃, thereby producing a date extraction mixture;

separating a liquid fraction from the jujube extraction mixture;

filtering the liquid fraction to produce an aqueous jujube filtrate; and is

Dewatering the aqueous jujube filtrate to at least a syrup-like consistency.