U.S. patent application number 10/870390 was filed with the patent office on 2004-11-18 for compositions and methods of use for extracts of magnoliaceae plants.
Invention is credited to Garrison, Robert JR., Stogniew, Martin.
Application Number | 20040228934 10/870390 |
Document ID | / |
Family ID | 22968165 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040228934 |
Kind Code |
A1 |
Stogniew, Martin ; et
al. |
November 18, 2004 |
Compositions and methods of use for extracts of magnoliaceae
plants
Abstract
The invention relates to compositions and methods for
preventing, treating, or managing sleeplessness, restlessness,
weight gain including weight gain due to stress or lack of sleep,
or all three comprising the administration of a prophylactically
and therapeutically effective amount of Magnoliaceae plant or
extracts thereof to a mammal in need of such therapy. Preferably
the mammal is human and the compositions have comprise at least two
compounds selected from magnolol, honokiol, and magnoflorine.
Alternatively, the compositions may also comprise about 2% honokiol
by weight of the composition.
Inventors: |
Stogniew, Martin; (Blue
Bell, PA) ; Garrison, Robert JR.; (Carlsbad,
CA) |
Correspondence
Address: |
STETINA BRUNDA GARRED & BRUCKER
75 ENTERPRISE, SUITE 250
ALISO VIEJO
CA
92656
US
|
Family ID: |
22968165 |
Appl. No.: |
10/870390 |
Filed: |
June 17, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10870390 |
Jun 17, 2004 |
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10423506 |
Apr 25, 2003 |
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10423506 |
Apr 25, 2003 |
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09996254 |
Nov 29, 2001 |
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6582735 |
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60255402 |
Dec 15, 2000 |
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Current U.S.
Class: |
424/769 |
Current CPC
Class: |
A61K 31/05 20130101;
A61K 31/05 20130101; A61K 31/473 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 36/575 20130101; A61K 31/473 20130101; A61K 36/575
20130101; A61K 36/57 20130101; A61K 36/57 20130101; A61P 25/20
20180101; A61P 25/22 20180101; A61P 3/04 20180101 |
Class at
Publication: |
424/769 |
International
Class: |
A61K 035/78 |
Claims
1-45. (Cancelled)
46. A pharmaceutical composition for human use comprising a
Magnoliaceae plant extract, the Magnoliaceae plant extract being
present in an amount from about 25% to about 100% by weight of the
pharmaceutical composition.
47. The pharmaceutical composition of claim 46 wherein said
Magnoliaceae plant extract is present in an amount from about 35%
to about 90% by weight of the pharmaceutical composition.
48. The pharmaceutical composition of claim 47 wherein the
Magnoliaceae plant extract is present in an amount from about 40%
to about 80% by weight of the pharmaceutical composition.
49. A pharmaceutical composition for human use comprising a
Magnoliaceae plant extract, the Magnoliaceae plant extract being
present in an amount from about 4 mg to about 12.5 mg per kg of
body weight of said human.
50. The pharmaceutical composition of claim 49 wherein said
Magnoliaceae plant extract is present in an amount from about 5 mg
to about 11 mg per kg of body weight of said human.
51. The composition of claim 46 wherein said pharmaceutical
composition is suitable for parenteral or oral administration to
said human.
52. The pharmaceutical composition of claim 49 wherein the
pharmaceutical composition is suitable for parenteral or oral
administration to said human.
53. The pharmaceutical composition of claim 46 wherein the
Magnoliaceae plant belongs to the genus Liriodendron or
Magnolia.
54. The pharmaceutical composition of claim 49 wherein the
Magnoliaceae plant belongs to the genus Liriodendron or
Magnolia.
55. A food composition comprising a Magnoliaceae plant extract, the
Magnoliaceae plant extract being present in an amount from about
0.1% to about 50% by weight of the food composition.
56. The composition of claim 55 wherein the Magnoliaceae plant
extract is present in an amount from about 1% to about 10% by
weight of the food composition.
57. The composition of claim 55 wherein the Magnoliaceae plant
belongs to the genus Liriodendron or Magnolia.
58. The pharmaceutical composition of claim 46 further comprising a
pharmaceutically acceptable carrier or excipient.
59. The pharmaceutical composition of claim 49 further comprising a
pharmaceutically acceptable carrier or excipient.
60. The composition of claim 46 wherein said Magnoliaceae plant
extract comprises at least two compounds selected from the group
consisting of magnolol, honokiol, magnoflorine.
61. The composition of claim 49 wherein said Magnoliaceae plant
extract comprises at least two compounds selected from the group
consisting of magnolol, honokiol, magnoflorine wherein honokiol is
present in an amount of about 2% by weight of the pharmaceutical
composition.
62. The food composition of claim 55 wherein the Magnoliaceae plant
extract comprises at least two compounds selected from the group
consisting of magnolol, honokiol, magnoflorine.
63. The composition of claim 55. wherein when honokiol is present,
said honokiol is present in an amount of about 2% by weight of the
Magnoliaceae plant extract.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/255,402 filed Dec. 15, 2000, which is
incorporated by reference herein in its entirety.
1. INTRODUCTION
[0002] The present invention relates to novel methods and
compositions for the treatment, prevention, or management of
sleeplessness, restlessness and weight gain. The methods and
compositions utilize plants, portions thereof or extracts therefrom
belonging to the Magnoliaceae family. In addition, the methods and
compositions utilize mixtures of specific small molecules extracted
from the plants belonging to the family Magnoliaceae, such as, but
not limited to, magnolol, honokiol, and magnoflorine. The unique
compositions of the invention may also comprise various amounts of
the Magnoliaceae plant, plant extract, plant extracts combined with
different amounts of biologically active small molecules or other
therapeutic agents. These compositions are particularly useful for
the treatment of sleeplessness, restlessness and weight gain in
humans. The invention also encompasses various modes of
administration of the therapeutic extracts or other compositions of
the invention.
2. BACKGROUND OF THE INVENTION
[0003] The recent growth in sales of natural products labeled as
dietary supplements in the United States has renewed scientific
interest in the study of the prophylactic and therapeutic effects
of multi-component botanical products. Unlike single entity
pharmaceutical products, botanical products comprise a large number
of diverse chemical constituents that often act synergistically to
exert a desired biological effect. The type of extraction process
utilized and the manner in which the formulation is standardized
have dramatic effects on the pharmacological activity of the final
product. The development of new botanical products requires
multidisciplinary effort consisting of expertise in ethnobotany,
natural product chemistry, analytical chemistry, pharmacology, and
natural product extraction.
2.1 Sleeplessness, Restlessness and Weight Control
[0004] Sleep is necessary for survival and good health, but why
sleep is needed or exactly how it benefits people is not fully
understood. Individual requirements for sleep vary widely; healthy
adults may need as few as 4 hours or as many as 9 hours of sleep
every day. Most people sleep at night, but many must sleep during
the day to accommodate work schedules. This situation often leads
to sleep disorders. Most sleep disorders are common.
[0005] How long a person sleeps and how rested a person feels on
waking can be influenced by may factors, including excitement or
emotional distress. Medications also can play a part; some
medications make a person sleepy while other makes sleeping
difficult. Even some food elements of additives such as caffeine,
strong spices, and monosodium glutamate (MSG) may affect sleep.
[0006] Sleep is not a uniform state; it has several distinct stages
through which it normally cycles five or six times every night.
Sleep progresses from stage 1 (the lightest level, during which the
sleeper can be awakened easily) to stage 4 (the deepest level,
during which waking the sleeper is difficult). In stage 4, the
muscles are relaxed, the blood pressure is at the lowest, and the
heart and breathing rates are at their slowest. Besides these four
stages, there is a form of sleep accompanied by rapid eye movements
(REM) and behavioral activity. During REM sleep, electrical
activity in the brain is unusually high, somewhat resembling that
of wakefulness. The eye movement and brain wave changes that
accompany REM sleep can be recorded electrically on an
electroencephalogram (EEG).
[0007] In REM sleep, the rate and depth of breathing increase, but
the muscles are greatly relaxed more so than during the deepest
levels of non-REM sleep. Most dreaming occurs during REM and stage
3 sleep, while most talking during sleep, night terrors, and
sleepwalking occur during stages 3 and 4. During a normal night's
sleep, REM sleep immediately follows each of the five or six cycles
of four-stage non-REM sleep, but it can occur at any of the
stages.
[0008] If emotional stress is causing the sleep disorder, treatment
to relieve the stress is more useful than taking sleep medication.
When the sleep disorder is cause by depression, the depression
should be thoroughly evaluated and treated by a doctor. Some
antidepressant drugs can improve sleep because they have sedating
properties. When sleep disorders interfere with a person's normal
activities and sense of well-being, the intermittent use of sleep
medications (sedatives, hypnotics) may be useful.
[0009] A sedative drug decreases activity, moderates excitement,
and calms the recipient, whereas a hypnotic drug produces
drowsiness and facilitates the onset and maintenance of a state of
sleep that resembles natural sleep in its electroencephalographic
characteristics and from which the recipient can be aroused easily.
The latter effect sometimes is called hypnosis.
[0010] Nonbenozodiazepine sedative-hypnotic drugs belong to a group
of agents that depress the central nervous system (CNS) in a
relative nonselective, dose-dependent fashion, producing
progressively calming or drowsiness (sedation), sleep
(pharmacological hypnosis), unconsciousness, coma, surgical
anesthesia, and fatal depression of respiration and cardiovascular
regulation.
[0011] Hypnotics (sedatives, minor tranquilizers, anti-anxiety
drugs) are among the most commonly used drugs. Most are quite safe,
but all can lose their effectiveness once a person becomes
accustomed to them. An undesirable side effect of hypnotics,
however, are the withdrawal symptoms when use is discontinued.
After more than a few days' use, discontinuing a hypnotic can make
the original sleep problem worse (rebound insomnia) and increase
anxiety. Also most hypnotics require a doctor's prescription
because they may be habit-forming or addictive, and overdose is
possible. Hypnotics are particularly risky for the elderly and for
people with breathing problems because they tend to suppress brain
areas that control breathing. They also reduce daytime alertness,
making driving or operating machinery hazardous. Hypnotics are
especially dangerous when taken with alcohol, other hypnotics,
narcotics, antihistamines, and anti-depressants. All of these drugs
cause drowsiness and can suppress breathing, making the combined
effects more dangerous.
[0012] Stress plays a major role in weight management. Stress
activates the hypothalamic/pituitary/adrenal axis resulting in an
increase in cortisol levels. Cortisol increases the availability of
glucose through hepatic gluconeogeneses and the release of glucose
substrates from fat cells and muscles. The uptake of glucose is
inhibited, resulting in hyperglycemia and hyperlipidemia. The
increase in cortisol levels signals the brain that the body is in
stress causing food cravings, especially high fat, high sugar
foods. These foods, in turn, cause additional stress thereby
fueling the stress-cortisol cycle. Eventually, more fat is stored
than the body needs unless sufficient exercise is in place to
compensate, or the stress is reduced. Central nervous stimulants
have been used to suppress appetite in an attempt to counteract
stress-induced appetite. This approach not only aggravates the
problem due to a direct CNS stimulation effect, but also has a high
abuse potential and several serious side effects including
cardiovascular and cerebral vascular effects. Ephedra, which is
also known as ma huang, is a dietary supplement that is used for
weight control and is an example of this type of approach. The
purported mechanism of action for Ephedra is CNS stimulation due to
the presence of ephedrine alkaloids in the extract.
2.3 Magnoliaceae Plant Extracts
[0013] Extracts from plants belonging to the family Magnoliaceae
have been and may still be used in Chinese herbalism. The bark of
Magnolia officinalis Rehder et Wilson, "Hou-po" in Chinese, has
been used in Chinese traditional medicine. (Watanabe, K.; Watanabe,
H. Y.; Goto, Y.; Yamamoto, N.; Yoshizaki, M.; "Studies on the
Active Principles of Magnolia Bark. Centrally acting Muscle
Relaxant Activity of Magnolol and Honokiol," Japan. J. Pharmacol.
25, 605 (1975)). Magnolol is the bioactive constituent of Magnolia
Cortex, the bark of Magnolia officinalis, Rehd. Et Wils.,
Magnoliaceae or of M. obvata, Thunb., called wakoboku in Japanese
medicine. Honokiol is the bioactive principle isolated from the
bark of Magnolia obovata, Thunb., Magnoliaceae and other Magnolia
species used in Japanese and Chinese traditional medicine.
[0014] The bark of Magnolia officinalis, is reportedly used as an
antibacterial, antiseptic, antispasmodic, aphrodisiac, appetizer,
digestive, diuretic, emmenagogue, expectorant, ophthalmic,
stomachic, and tonic. (Chevalier, A., The Encyclopedia of Medicinal
Plants, Dorling Kindersley, London, 1995).
[0015] The ether extract of magnolia bark showed a central
depressant effect and centrally acting muscle relaxation effect.
(Watanabe et al.) Muscle relaxation was shown to be dose-dependent,
wherein minimum effective doses required at least 90-100 mg/kg,
while sedative symptoms were observed at lower doses. At large
doses, honokiol showed a muscle relaxing effect for 3 hours (250
mg/kg) and produced a loss of righting reflex (500 mg/kg).
(Watanabe et al. p. 606).
[0016] In mice, magnolol produced hypomotility, ptosis, and
sedation at 63 mg/kg when administered intraperitoneally.
(Watanabe, K.; Watanabe, H.; Goto, Y.; Yamaguchi, M.; Yamamoto, N.;
Hagino, K., "Pharmacological Properties of Magnolol and Honokiol
Extracted from Magnolia officinalis: Central Depressant Effects,"
Journal of Medicinal Plant Research: Planta Medica, 49, pp.
130-108, (1983)). At a dose of 125 mg/kg magnolol induced sedation,
ataxia, and prominent muscle relaxation for 2 hr after injection.
Magnolol at a dose of 250 mg/kg produced an ataxia within 10 min,
loss of righting reflex in 40 min, and muscle relaxation over 3 hr.
Honokiol produced similar effects at doses of 125, 250, and 500
mg/kg i.p. Id.
[0017] To date, there are a number of sleep disorders for which
there is no dietary supplement available to either prevent or
alleviate the disorder or symptoms associated therewith. It is
desirable to discover and develop dietary supplements or
pharmaceutical compositions based upon natural materials that are
both safe and effective. It is particularly desirable to develop
plant extracts for the prevention, treatment, or control of
sleeplessness, restlessness and weight gain do to stress or lack of
sleep.
3. SUMMARY OF THE INVENTION
[0018] The invention described herein encompasses compositions and
methods of treating or preventing sleeplessness, restlessness or
weight gain including, but not limited to, weight gain due to
stress or lack of sleep. The methods comprise the administration of
a therapeutically or prophylactically effective amount of an
extract from the Magnoliaceae family, particularly to a human in
need of such therapy. The plants belonging to the Magnoliaceae
family include, but are not limited to, plants belonging to the
genus Liriodendron and Magnolia. Species belonging to the
Liriodendron genus include Liriodendron tulipifera and Liriodendron
chinense. Species belonging to the Magnolia genus include, but are
not limited to, Magnolia acuminata, Magnolia ashei, Magnolia
biodii, Magnolia cylindrica, Magnolia cambellii, Magnolia denudata,
Magnolia fraseri, Magnolia grandiflora, Magnolia hypoleuca,
Magnolia kobus, Magnolia hliiflora, Magnolia loegneri, Magnolia
macrophylla, Magnolia officinalis, Magnolia pyramidata, Magnolia
sargentiana, Magnolia seiboldii, Magnolia soulangiana, Magnolia
sprengeri, Magnolia stellata, Magnolia tripetala, Magnolia
virginiana, Magnolia zenii, and Michelia figo. The extracts of the
invention are prepared using solvents such as lower alcohols,
water, and mixtures thereof.
[0019] Preferably, the compositions comprise Magnoliaceae plant
extracts soluble in a lower alcohol, water, and mixtures thereof,
or at least two compounds selected from the group consisting of
magnolol, honokiol, and magnoflorine. More preferably, the
compositions comprise about 2% of honokiol by weight. The
compositions may contain a pharmaceutically acceptable carrier,
excipient, or diluent. The compositions can be included as unit
dosage suitable for parenteral, oral, or intravenous administration
to a human. Alternatively, the compositions are dietary
supplements, food compositions or beverage compositions suitable
for human or animal consumption.
[0020] The Magnoliaceae plant extract is obtained by cutting or
pulverizing a plant of the family Magnoliaceae, extracting the cut
or powdered plant parts with a suitable aqueous solvent for a time
sufficient to form an extract. Subsequently, the extract is
concentrated under reduced pressure and optionally dried. Further,
the extract may optionally be purified to remove undesirable
components.
[0021] The methods described herein comprise methods for treating,
preventing, and managing sleeplessness, restlessness, or both by
administering a therapeutically effective amount of a plant extract
or a composition comprising a Magnoliaceae plant or plant extract,
wherein the Magnoliaceae plant belongs to the genus Liriodendron or
Magnolia. The method of treating the above mentioned conditions
includes administering an extract obtained using a solvent selected
from the group consisting of a lower alcohol, water, and mixtures
thereof. Alternatively, the extract comprises at least two
compounds selected from the group consisting of magnolol, honokiol,
magnoflorine and pharmaceutically acceptable salts thereof.
Preferably, the extracts or compositions thereof comprise at least
2% honokiol by weight, and more preferably 2% honokiol.
3.1 Definitions
[0022] As used herein, unless otherwise specified, the term
"Magnoliaceae plant" includes, but is not limited to, any part of a
plant within the family Magnoliaceae. The plant parts may include
plant bodies preferably the stalk, leaves, fruit or rind, bark,
flowers, stems, roots, or seeds. Preferred plants within the
Magnoliaceae family are discussed below.
[0023] As used herein, unless otherwise specified, the term
"treating sleeplessness" or "treatment of sleeplessness" includes,
but is not limited to, preventing or reducing the disturbances in
falling asleep, staying asleep, duration of sleep, or abnormal
sleep behaviors.
[0024] As used herein, unless otherwise specified, the term
"treating restlessness", "treatment of restlessness" or "preventing
restlessness" includes, but is not limited to, causing to rest or
relax preferably without inducing sedation or hypnosis, inducing
relaxation without inducing muscle relaxation, and relieving
nervous tension or stress. Thus, the invention also encompasses
methods of inducing relaxation without reduction or loss of motor
function in humans.
[0025] As used herein, unless otherwise specified, the term
"managing weight gain" includes, but is not limited to, treating,
preventing or reducing weight gain, suppressing appetite and in a
preferred embodiment treating, preventing or reducing weight gain
associated with stress or lack of sleep.
[0026] As used herein, unless otherwise specified, the term
"physiologically acceptable carrier," includes, but is not limited
to, a carrier medium that does not interfere with the effectiveness
of the biological activity of any active ingredients, is chemically
inert, and is not toxic to the consumer or patient to whom it is
administered.
[0027] As used herein, unless otherwise specified, the term
"pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic acids and bases, including
inorganic and organic acids and bases.
[0028] As used herein, unless otherwise specified, the term
"preventing," includes, but is not limited to, inhibition or the
averting of symptoms associated with a particular disease or
disorder.
[0029] As used herein, unless otherwise specified, the term
"treating" refers to the administration of the composition after
the onset of symptoms of the disease or disorder whereas
"preventing" refers to the administration prior to the onset of the
symptoms, particularly to patients at risk of the disease or
disorder.
[0030] As used herein, unless otherwise specified, the term "lower
alcohol" includes, but is not limited to, straight chained or
branched, substituted or unsubstituted hydrocarbon compounds having
at least one hydroxyl group and having one to five carbon atoms.
Lower alcohols include, but are not limited to, methanol, ethanol,
n-propanol, isopropanol, butanols, and mixtures thereof.
[0031] As used herein, unless otherwise specified, the term "obese"
includes, but is not limited to, a person having a Body Mass Index
(BMI) of greater than or equal to about 26.
[0032] As used herein, unless otherwise specified, the term
"average weight" or "of average weight" includes, but is not
limited to, a person having a Body Mass Index (BMI) of less than
about 26.
4. DETAILED DESCRIPTION OF THE INVENTION
[0033] The invention encompasses methods for preventing, treating,
and managing sleeplessness, restlessness, or weight gain including,
but not limited to, weight gain due to lack of sleep comprising the
administration of a prophylactically and therapeutically effective
amount of Magnoliaceae plant or an extract thereof to a mammal in
need of such therapy. In a preferred embodiment, the mammal is
human and the extracts comprise at least two compounds selected
from the group consisting of magnolol, honokiol, and magnoflorine.
In a more preferred embodiment, the extracts comprise at least 2%
honokiol by weight of the composition and preferably, 2% honokiol
by weight of the composition. In a most preferred embodiment the
extracts are aqueous or lower alcohol aqueous extracts.
[0034] The invention further encompasses compositions for
preventing, treating, and managing sleeplessness, restlessness, or
weight gain including, but not limited to, weight gain due to lack
of sleep comprising a therapeutically effective amount of
Magnoliaceae plant or an extract thereof including, but not limited
to, magnolol, honokiol and magnoflorine.
[0035] In one embodiment of the invention, the composition for
preventing sleeplessness comprises Magnoliaceae plant or extracts
thereof in an amount sufficient to prevent the onset of
sleeplessness or sleeplessness related symptoms. In another
embodiment of the invention, for mammals already suffering from
sleeplessness, the invention is directed to compositions and
administered dosages comprising Magnoliaceae plant in sufficient
amount to reduce sleeplessness or the symptoms associated with
sleeplessness. In yet another embodiment of the invention, for
mammals already suffering from sleeplessness, the invention is
directed to a method for treating sleeplessness by administering
compositions comprising Magnoliaceae plant extract in a
therapeutically sufficient amount to treat sleeplessness.
[0036] In another embodiment of the invention, the composition for
reducing or preventing restlessness comprises Magnoliaceae plant or
extracts thereof in an amount sufficient to prevent the onset of
restlessness or restlessness related symptoms. In another
embodiment of the invention, the composition for treating
restlessness is in sufficient amount and regularly administered
dosage to reduce or eliminate restlessness related symptoms in
mammals suffering from restlessness. In yet another embodiment of
the invention, for mammals already suffering from restlessness, the
invention is directed to a method for treating restlessness by
administering compositions containing Magnoliaceae plant extract in
a therapeutically sufficient amount to either prevent or treat
restlessness.
[0037] In yet another embodiment, the invention encompasses
compositions, including pharmaceutical compositions or dietary
supplements, to be used in managing weight gain including, but not
limited to, weight gain due to stress or lack of sleep. Further,
the invention encompasses methods for managing weight gain in a
mammal which comprises administering a magnoliaceae plant or
extract thereof to a mammal in need thereof.
[0038] In another embodiment, the invention encompasses methods for
managing weight gain in a human, particularly wherein said human is
an obese male or an obese female.
[0039] In a further embodiment, the invention encompasses methods
for managing weight gain in a human, particularly wherein said
human is a male or a female of average weight.
[0040] In still another embodiment, the invention encompasses
methods for managing weight gain in a human, particularly wherein
said human is not concurrently using; has not previously used
another dietary supplement or pharmaceutical composition for weight
control; or both. The extracts of the invention are particularly
useful for humans taking prescription medications for weight gain
including, but not limited to, weight gain due to stress or lack of
sleep. The invention, however, encompasses the use of the extracts
in humans before, during, and after treatment with prescription
therapies.
[0041] More preferably, the Magnoliaceae plant extract is obtained
by extracting Magnoliaceae plant parts with a lower alcohol, water,
or mixtures thereof. In another preferred embodiment of the
invention, the compositions comprise a Magnoliaceae plant or an
extract thereof and an additional amount of magnolol, honokiol, or
magnoflorine in excess to any amount that may be present in the
Magnoliaceae plant extract.
[0042] The invention encompasses compositions which comprise
magnolol, honokiol, magnoflorine, or pharmaceutically acceptable
salts thereof and pharmaceutically acceptable excipients, carriers,
or diluents. Further, such magnolol, honokiol, magnoflorine
compositions can comprise non-sedating sleep aids or other
therapeutic agents. The compositions comprise magnolol, honokiol,
magnoflorine, or a mixture thereof in an amount sufficient and
regularly administered dosage to prevent, treat, or manage
sleeplessness, restlessness, weight gain due to stress or lack of
sleep, or all three.
[0043] The disclosure is based, in part, on the discovery that
Magnoliaceae plant or extracts thereof, alone or in combination
with other sleep aids, induces relaxation without loss of motor
function and restful sleep. Without being limited by theory, it is
believed that Magnoliaceae plant extracts act synergistically or at
least more than additively by binding to one or more receptor sites
to collectively diminish the symptoms of sleeplessness or
restlessness without causing a sedative or addictive effect.
[0044] In a preferred embodiment, the invention encompasses
compositions, and the use thereof, which comprises a water-soluble
extract of a Magnoliaceae plant. In a most preferred embodiment,
such extracts are produced by extraction with an aqueous alcohol
solvent system such that the extracts preferably comprise one or
more of the following small organic compounds which naturally occur
in the plants: magnolol, honokiol, magnoflorine, and the like. It
has been discovered that such extracts have a unique receptor
binding affinities despite the fact that the extracts are mixtures
of components. Thus, the extracts of the invention have unique
benefits in preventing, treating, or managing disorders. Moreover,
the preferred extracts of the invention are useful for treating and
preventing sleeplessness, restlessness, weight gain due to stress
or lack of sleep, or all three without a sedative or addictive
effect. Similarly, the extracts of the invention reduce or avoid
adverse effects associated with certain CNS drugs such as physical
dependency, withdrawal problems, impaired coordination, loss or
reduction of motor function, slowed reaction time, sedation, weight
gain, constipation, dry mouth, confusion, blurred vision, nausea,
diarrhea, or headaches.
[0045] The extracts of the invention are particularly useful for
humans taking prescription medications for sleeplessness,
restlessness, or both. The invention, however, encompasses the use
of the extracts in humans before, during, and after treatment with
prescription or conventional therapies.
[0046] In accordance with the present invention, the Magnoliaceae
plant can be used alone or in combination with other known
therapeutic agents or techniques to reduce sleeplessness,
restlessness, weight gain due to stress or lack of sleep, or all
three. Such agents may include vitamins and minerals, such as
magnesium, calcium, or non-sedating sleep aids.
[0047] Since novel formulations of Magnoliaceae plant are disclosed
herein, the invention also encompasses methods of using the novel
formulations for the treatment of sleeplessness, restlessness,
weight gain due to stress or lack of sleep, or all three in a
mammal, wherein the mammal is preferably a human.
4.1 Method for Obtaining Magnoliaceae Plant Extracts
[0048] The plants belonging to the "Magnoliaceae family" used in
the present invention are plants belonging to the genus
Liriodendron and Magnolia. Species belonging to the Liriodendron
genus include, but are not limited to, Liriodendron tulipifera and
Liriodendron chinense. Species belonging to the Magnolia genus
include, but are not limited to, Magnolia acuminata, Magnolia
ashei, Magnolia biodii, Magnolia cylindrica, Magnolia cambellii,
Magnolia denudata, Magnolia fraseri, Magnolia grandiflora, Magnolia
hypoleuca, Magnolia kobus, Magnolia liliiflora, Magnolia loegneri,
Magnolia macrophylla, Magnolia officinalis, Magnolia pyramidata,
Magnolia sargentiana, Magnolia seiboldii, Magnolia soulangiana,
Magnolia sprengeri, Magnolia stellata, Magnolia tripetala, Magnolia
virginiana, Magnolia zenii, and Michelia figo. The most preferable
plants are Magnolia officinalis and its variants.
[0049] The Magnoliaceae plant includes the plant parts as defined
above, optionally the plant parts may be cut into small pieces or
ground into a powder. Preferably, the plant part includes an
extract of the Magnoliaceae plant. During a typical extraction
process, the Magnoliaceae plant body, preferably cut into small
pieces or ground into a powder, is placed in a Soxhlet extractor
and extracted with any suitable solvent. Typical solvents include,
but are not limited to, water, lower alcohols, or mixtures thereof.
Preferably, the solvents used in the extraction include water,
ethanol, and mixtures thereof. The solvent is maintained at reflux
and the Magnoliaceae plant body is extracted for about 8 hours to
about 48 hours. Preferably, the Magnoliaceae plant is extracted for
about 12 hours to about 40 hours, and more preferably for about 18
hours to about 30 hours.
[0050] Subsequently, the solvent is separated and reduced in
volume. Optionally, the solvent may be extracted with a second
solvent. Thereafter, the extraction solvents are collected and
reduced in volume either under low pressure or by evaporation to
form a residue. Optionally, the residue is diluted and purified by
gravity chromatography using at least one suitable solvent easily
determined by a skilled artisan with little or no experimentation
as the mobile phase. Optionally, the ratio of solvents within the
solvent mixture may be gradually changed.
[0051] An alternative extraction process comprises adding a
suitable solvent to the Magnoliaceae plant body, either grounded
into a powder or cut into pieces. The solvents include, but are not
limited to water, a lower alcohol, and mixtures thereof.
Preferably, the solvents are water, ethanol, or mixtures thereof.
The mixture of Magnoliaceae plant and solvent is allowed to sit
overnight, preferably for about 6 hours to about 40 hours,
preferably for about 8 hours to about 18 hours. Subsequently, the
mixture is filtered, separating the solids from the filtrate. The
solids are mixed with more solvent and allowed to sit overnight,
preferably for about 6 hours to about 40 hours, preferably from
about 12 hours to 32 hours, and more preferably from about 8 hours
to about 18 hours. The mixture is separated a second time by
filtration and the filtrates from both extractions are combined,
and concentrated under reduced pressure to obtain a residue. The
residue is vacuum dried for about 1 to about 10 hours, preferably
for about 1 to about 2 hours at room temperature.
[0052] Yet another alternative extraction process comprises
combining a suitable solvent to the Magnoliaceae plant body, either
grounded into a powder or cut into pieces, in a ratio of about 4:1
to about 7:1 by volume to form a mixture. The mixture is heated to
a temperature of about 1.degree. F. below the boiling point of the
solvent and stirred for about an hour. Preferably, if water is used
as a solvent, the temperature is about 212.degree. F. The mixture
is filtered and the filtrate is washed with fresh solvent in a
volume ratio of about 1:1. Subsequently the filtrate is
concentrated under reduced volume and dried in a vacuum oven. In
this method, suitable solvents include ethanol, methanol,
chlorinated solvents, propanol, 2-propanol, water, denatured
industrial grade alcohol such as SDA-35, and mixtures thereof.
Preferably, suitable solvents include water, ethanol, SDA-35, and
mixtures thereof.
4.2 Compositions Comprising Magnoliaceae Plant Extracts and Modes
of Administration
[0053] The invention comprises compositions of Magnoliaceae plant
or plant extracts with physiologically suitable carriers including,
but not limited to, pharmaceutical carriers for the treatment of
sleeplessness, restlessness, weight gain including, but not limited
to, weight gain due to stress or lack of sleep, or all three. In a
preferred embodiment, the compositions of the present invention
comprise at least two compounds selected from the group consisting
of magnolol, honokiol, and magnoflorine. More preferably, the
compositions include at least 2% honokiol by weight of the
composition; preferably including 2% honokiol by weight of the
composition. Most preferably, the compositions are obtained from
the extraction of Magnoliaceae plant parts with an aqueous organic
solution mixture, in particular a water and ethanol solution
mixture, comprising small molecule compounds.
[0054] The magnitude of the therapeutic dose of an active
ingredient in the acute or chronic management of a disorder or
condition will vary with the severity of the disorder or condition
to be treated and the route of administration. The dose, and
perhaps the dose frequency, will also vary according to age, body
weight, response, and the past medical istory of the consumer or
patient. Suitable dosing regimens can be readily selected by hose
skilled in the art with due consideration of such factors.
[0055] In one embodiment of the present invention, Magnoliaceae
plant comprises about 2% to about 100% by weight of the
composition. In a preferred embodiment, Magnoliaceae plant
comprises about 5% to about 95% by weight of the composition. In a
more preferred embodiment, Magnoliaceae plant comprises about 10%
to about 90% by weight of the composition.
[0056] In another embodiment of the present invention using
Magnoliaceae plant extracts, Magnoliaceae plant extracts comprise
about 25% to about 100% by weight of the composition. In a
preferred embodiment, Magnoliaceae plant extracts comprise about
35% to about 90% by weight of the composition. In a more preferred
embodiment, Magnoliaceae plant extracts comprise about 40% to about
80% by weight of the composition.
[0057] In an embodiment, the composition of the invention comprises
Magnoliaceae plant or plant extract present in an amount of about
35% to about 90% by weight and at least one non-sedating sleep aid.
Alternatively, the compositions of the invention can be
administered sequentially or simultaneously in combination with at
least one non-sedating sleep aid.
[0058] Magnoliaceae plant or extracts thereof can be formulated
using standard formulation techniques into gel caps, teas, tablets,
etc. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing, Easton Pa. (1990). Magnoliaceae plant extracts of the
invention may be formulated into a dietary supplement or a
pharmaceutical preparation for the administration to mammals for
the treatment of sleeplessness, restlessness, weight gain,
preferably weight gain due to stress or lack of sleep, or all
three. In a preferred embodiment, the mammal is human.
[0059] Compositions comprising Magnoliaceae plant extracts of the
invention formulated in a compatible pharmaceutical carrier may be
prepared, packaged, and labeled for treatment, prevention, or
management of sleeplessness, restlessness, or symptoms thereof.
[0060] If the composition is water-soluble, then it may be
formulated in an appropriate buffer, for example, phosphate
buffered saline or other physiologically compatible solutions.
Alternatively, if the resulting composition has poor solubility in
aqueous solvents, then it may be formulated with a non-ionic
surfactant such as Tween or polyethylene glycol. Thus, the
compositions and their physiologically acceptable solvates may be
formulated for administration by inhalation or insufflation (either
through the mouth or the nose), oral, buccal, parenteral, or rectal
administration.
[0061] For oral administration, the pharmaceutical preparation may
be in liquid form, for example, solutions, syrups or suspensions,
or may be presented as a drug product for reconstitution with water
or other suitable vehicle before use. Such liquid preparations may
be prepared by conventional means with pharmaceutically acceptable
additives such as suspending agents (e.g., sorbitol syrup,
cellulose derivatives or hydrogenated edible fats); emulsifying
agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g.,
almond oil, oily esters, or fractionated vegetable oils); and
preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic
acid). The pharmaceutical compositions may take the. form of, for
example, tablets or capsules prepared by conventional means with
pharmaceutically acceptable excipients such as binding agents
(e.g., pregelatinized maize starch, polyvinyl pyrrolidone or
hydroxypropyl methylcellulose); fillers (e.g., lactose,
microcrystalline cellulose or calcium hydrogen phosphate);
lubricants (e.g., magnesium stearate, talc or silica);
disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulphate). The tablets may be
coated by methods well-known in the art. In a preferred embodiment,
the pharmaceutical composition may take the form of a capsule or
powder to be dissolved in a liquid for oral consumption.
Preparations for oral administration may be suitably formulated to
give controlled release of the active compound.
[0062] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0063] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may comprise formulatory agents such as suspending, stabilizing
and/or dispersing agents. Alternatively, the active ingredient may
be in powder form for constitution with a suitable vehicle, e.g.,
sterile pyrogen-free water, before use.
[0064] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., comprising
conventional suppository bases such as cocoa butter or other
glycerides.
[0065] In addition to the formulations described previously, the
compounds may also be a formulated as a sustained and/or timed
release formulation. The compositions must be maintained above some
minimum therapeutic dose to be effective. Such sustained and/or
timed release formulations may be administered by implantation (for
example, subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example, as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt. Liposomes and emulsions are well known examples of delivery
vehicles or carriers for hydrophilic drugs. Common timed and/or
controlled release delivery systems include, but are not be
restricted to, starches, osmotic pumps, or gelatin micro
capsules.
[0066] The compositions may, if desired, be presented in a pack or
dispenser device which may comprise one or more unit dosage forms
comprising the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration.
4.3 Dietary Supplements Comprising Magnoliaceae Plant Extract
[0067] The compositions of the invention may include food
compositions, beverage compositions, over the counter, and dietary
supplements. The Magnoliaceae plant or plant extract may be added
to various foods so as to be consumed simultaneously. Preferably,
the Magnoliaceae plant extract comprises at least two compounds
selected from the group consisting of magnolol, honokiol, and
magnoflorine. More preferably, the Magnoliaceae plant extract
comprises about 2% honokiol by weight of the composition. As a food
additive, the Magnoliaceae plant or plant extracts of the invention
may be used in the same manner as conventional food additives, and
thus, only needs to be mixed with other components to enhance the
taste. Taste enhancement includes, but is not limited to, imparting
to food a refreshingness, vitality, cleanness, fineness, or
bracingness to the inherent taste of the food.
[0068] It will be recognized that dietary supplements may not use
the same formulation ingredients or have the same sterile and other
FDA requirements as pharmaceutical compositions. The dietary
supplements may be in liquid form, for example, solutions, syrups
or suspensions, or may be in the form of a product for
reconstitution with water or any other suitable liquid before use.
Such liquid preparations may be prepared by conventional means such
as a tea, health beverage, dietary shake, liquid concentrate, or
liquid soluble tablet, capsule, pill, or powder such that the
beverage may be prepared by dissolving the liquid soluble tablet,
capsule, pill, or powder within a liquid and consuming the
resulting beverage. Alternatively, the dietary supplements may take
the form of tablets or capsules prepared by conventional means and
optionally including other dietary supplements including vitamins,
minerals, other herbal supplements, binding agents, fillers,
lubricants, disintegrants, or wetting agents, as those discussed
above. The tablets may be coated by methods well-known in the art.
In a preferred embodiment, the dietary supplement may take the form
of a capsule or powder to be dissolved in a liquid for oral
consumption.
[0069] The magnitude of the dietary dose of an active ingredient in
the acute or chronic management of a disorder or condition will
vary with the severity of the disorder or condition to be treated
and the route of administration. The dose, and perhaps the dose
frequency, will also vary according to age, body weight, response,
and the past medical history of the consumer or patient. Suitable
dosing regimens can be readily selected by those skilled in the art
with due consideration of such factors.
[0070] The amount of Magnoliaceae plant or plant extract in a
beverage or incorporated into a food product will depend on the
kind of beverage, food and the desired effect. In general, a single
serving comprises an amount of about 0.1% to about 50%, preferably
of about 0.5% to about 20% of the food composition. More preferably
a food product comprises Magnoliaceae plant or plant extract in an
amount of about 1% to about 10% by weight of the food
composition.
[0071] Examples of food include, but are not limited to,
confectionery such as sweets (candies, jellies, jams, etc.), gums,
bean pastes, baked confectioneries or molded confectioneries
(cookies, biscuits, etc.), steamed confectioneries, cacao or cacao
products (chocolates and cocoa), frozen confectioneries (ice cream,
ices, etc.), beverages (fruit juice, soft drinks, carbonated
beverages), health drinks, health bars, and tea (green tea, black
tea, etc.).
4.4 Dosage
[0072] The magnitude of a therapeutic or prophylactic dose of
Magnoliaceae plant in the prevention, treatment, or management of
sleeplessness, restlessness, weight gain including, but not limited
to, weight gain due to stress or lack of sleep, or all three will
vary with the severity of the condition of the consumer or patient
to be treated and the route of administration. The dose, and dose
frequency, will also vary according to the age, body weight,
condition and response of the individual consumer or patient, and
the particular Magnoliaceae plant combination used. All
combinations described in the specification are encompassed as
therapeutic, and it is understood that one of skill in the art
would be able to determine a proper dosage of particular
Magnoliaceae plant composition using the parameters provided in the
invention.
[0073] In general, the total daily dose ranges of the Magnoliaceae
plant for the conditions described herein are generally from about
1 mg/kg to about 140 mg/kg administered in divided doses
administered parenterally, orally, or topically. A preferred total
daily dose is from about 7 mg/kg to about 100 mg/kg of the
Magnoliaceae plant composition. When a Magnoliaceae plant extract
is used, the total daily dose ranges of the Magnoliaceae plant
extract for the conditions described herein are generally from
about 4 mg/kg to about 12.5 mg/kg administered in divided doses
administered parenterally, orally, or topically. A preferred total
daily dose is from about 5 mg/kg to about 11 mg/kg of the
Magnoliaceae plant extracts.
[0074] Alternatively, the daily dose of the Magnoliaceae plant for
the conditions described herein are generally from about 100 mg to
about 800 mg, preferably from about 200 mg to 600 mg, of a 2%
honokiol composition.
[0075] For example, in one embodiment, the daily dose ranges of
Magnoliaceae plant extracts compositions described herein are
generally about 7 mg per kg body weight of Magnoliaceae plant
extracts composition. Preferably the Magnoliaceae plant extracts
formulation of the invention is given daily until the symptoms
cease, followed by two to ten additional cycles, each lasting about
60 days in duration. When the dose is administered orally, a
sustained release formulation can be used so that a fairly constant
level of Magnoliaceae plant extracts is provided over the course of
treatment. As the Magnoliaceae plant extracts are not particularly
toxic, the formulation may be administered for as long as necessary
to achieve the desired therapeutic effect.
[0076] In the case where an intravenous injection or infusion
composition is employed, a suitable dosage range for use is, e.g.,
from about 0.01 to about 150 mg per kg body weight of Magnoliaceae
plant extracts daily.
[0077] Again, any suitable route of administration may be employed
for providing the consumer or patient with an effective dosage of
Magnoliaceae plant or plant extracts composition of this invention.
Dosage forms include tablets, troches, cachet, dispersions,
suspensions, solutions, capsules, gel caps, caplets, compressed
tablets, sustained release devices, patches, and the like.
[0078] The dietary supplements and pharmaceutical compositions of
the present invention comprise Magnoliaceae plant or plant extracts
as the active ingredients, as well as pharmaceutically acceptable
salts thereof, and may also comprise a pharmaceutically acceptable
carrier, and optionally, other therapeutic ingredients.
[0079] The dietary supplements and pharmaceutical compositions
include compositions suitable for oral and parenteral (including
subcutaneous, intramuscular, intrathecal, intravenous, and other
injectables) routes, although the most suitable route in any given
case will depend on the nature and severity of the condition being
treated.
[0080] In addition, the Magnoliaceae plant or plant extracts
carrier could be delivered via charged and uncharged matrices used
as drug delivery devices such as cellulose acetate membranes, also
through targeted delivery systems such as liposomes attached to
antibodies or specific antigens.
[0081] In practical use, Magnoliaceae plant or plant extracts can
be combined as the active ingredient(s) in intimate admixture with
a pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including tablets,
capsules, powders, intravenous injections or infusions). In
preparing the compositions for oral dosage form any of the usual
pharmaceutical media may be employed, e.g., water, glycols, oils,
alcohols, flavoring agents, preservatives, coloring agents, and the
like; in the case of oral liquid preparations, e.g., suspensions,
solutions, elixirs, liposomes and aerosols; starches, sugars,
micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents, and the like in the
case of oral solid preparations e.g., powders, capsules, and
tablets. In preparing the compositions for parenteral dosage form,
such as intravenous injection or infusion, similar pharmaceutical
media may be employed, e.g., water, glycols, oils, buffers, sugar,
preservatives, and the like know to those skilled in the art.
Examples of such parenteral compositions include, but are not
limited to Dextrose 5% (w/v), normal saline or other solutions. The
total dose of the Magnoliaceae plant extracts may be administered
in a vial of intravenous fluid, e.g., ranging from about 0.7 to
about 14 mg per kg body weight of Magnoliaceae plant extracts. The
volume of dilution fluid will vary according to the total dose
administered and over the length of the period of time of
administration.
5. EXAMPLES
[0082] Certain embodiments of the invention, as well as certain
novel and unexpected advantages of the invention, are illustrated
by the following non-limiting examples.
5.1 Restful Sleep Activity
5.1.1 Materials and Methods
[0083] Using a model study with 50 volunteer participants, an
extract of the invention was tested for its ability to induce
restful sleep properties as discussed below.
5.1.1.1 Subjects
[0084] The study quantified consumers' perceptions and reactions to
a dietary supplement containing Magnoliaceae extract. The study was
an open-label, home usage study to test the effectiveness of
dietary supplements having Magnoliaceae extract. The study followed
50 respondents between the age of 30 and 55 using the dietary
supplement for two weeks. The typical subject had used dietary
supplements within the past three months; suffered from mild
anxiety or nervousness at least once in the past two months or at
least six times a year; and had not taken prescription medication
for the treatment of mild anxiety or nervousness in the past year.
Female participants were screened to ensure that they were not
pregnant or nursing an infant.
5.1.1.2 Test Materials
[0085] The sample developed and screened for sleep inducing
activity was a hydroalcoholic extract from the Magnoliaceae family
provided in a 200 mg capsule.
5.1.1.4 Procedure
[0086] All participants were asked to measure sample effectiveness
by answering a series of questions directed to particular
conditions. Specifically, the participants were asked to monitor
whether the composition was effective to help them relax; reduce
occasional nervous tension; gently soothe tension; calm the
participant when feeling stressed; help control irritability; help
overcome feelings of restlessness; and help the participant cope
with everyday overwork and fatigue.
[0087] Participants self administered the composition in capsule
form about 2-3 times during the day.
5.1.2 Results
[0088] The respondents took the capsules on an average of 2.7 per
day mostly during the early morning hours before 9 a.m. or during
the evening between 5 p.m. and 10 p.m. Of the subjects, 68% felt
that the composition was overall effective. Of the subjects, 78%
felt that the composition was highly effective in inducing a state
of relaxation without feeling drowsiness. Of the subjects, 74% felt
that the composition induced restful sleep and was non-sedating.
Also, of the subjects 94% did not feel an upset the stomach or
thought the sample had an unpleasant taste.
5.2 Weight Control
[0089] Magnoliaceae extracts can be tested for weight control
activity by any number of means know to those skilled in the art,
including, but not limited to, short term appetite control
paradigms on mice using the protocol in Talpur, N. A., Echard, B.
W.; Manohar, V; and Preuss, H. G.; "Influence of a combination of
herbs on appetite supression and weight loss in rats," Diabetes,
Obesity & Metabolism. 3, 3 (2001); or in Brown M.; Bing, C.;
King, P.; Pickavance L; Heal, D.; and Wilding, J.; "Sibutramine
reduces feeding, body fat, and improves insulin resistance in
dietary-obese male winstar rats independently of hypothalamic
neuropeptide Y," British Journal of Pharmacology. 138, 8
(2001).
[0090] It is to be understood that the present invention is not
limited to the embodiments described above, but encompasses any and
all embodiments within the scope of the following claims.
* * * * *