Use of gingerols for cancer patients suffering from nausea and emesis induced by chemotherapy

Information

  • Patent Grant
  • 8435575
  • Patent Number
    8,435,575
  • Date Filed
    Thursday, May 13, 2010
    14 years ago
  • Date Issued
    Tuesday, May 7, 2013
    11 years ago
Abstract
This invention is for an improved method for making enhanced ginger capsules and for using these capsules for treating nausea and emesis in cancer patients.
Description
FIELD OF THE INVENTION

This invention relates to methods for making and using gingerols for treating nausea and emesis associated with cancer chemotherapy. The methods feature supercritical, critical and near-critical fluids with and without polar cosolvents.


BACKGROUND OF THE INVENTION

Despite the widespread use of the 5-HT3 receptor antagonist antiemetics, ondansetron (Zofran®, Glaxo Wellcome Oncology/HIV, Research Triangle Park, N.C.) in 1991, granistron (Kytril,® SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.) in 1994, and dolasetron mesylate (Anzemet,® Hoechst Marion Roussel, Kansas City, Mo.), post-chemotherapy nausea and vomiting continue to be reported by up to 70% of patients receiving highly emetogenic chemotherapy agents, such as cisplatin, carboplatin and doxorubicin. Research also suggests that the 5-HT3 receptor antagonists are clinically more effective against emesis than they are against nausea.


Delayed post-chemotherapy nausea is a particularly difficult problem as it does not develop until after the patient has left the treatment location and is not well-controlled by currently available antiemetics. Data from a recently completed URCC CCOP Research Base study of patients receiving cisplatin, carboplatin or doxorubicin indicates that although nausea from receipt of these drugs is most likely to develop within the first 48 hours after administration of chemotherapy, in 18% of the patients it was first reported on or after Day 3 of the cycle.


Patients who suffer from post-chemotherapy nausea may also develop symptoms in anticipation of treatment. Anticipatory nausea (AN) is reported by approximately 20% of patients at any one chemotherapy cycle and by 25-30% of patients by the fourth chemotherapy cycle. Anticipatory vomiting (AV) develops in 8-20% of patients. No pharmacologic agents have had success in treating AN once it has occurred, and, although the behavioral method of systematic desensitization can be effective, it is not readily available in most clinic settings.


All in all, there is still a great deal of room for improvement in the control of nausea and vomiting (NV) associated with chemotherapy for cancer. Furthermore, antiemetics currently in widespread use have been associated with significant adverse effects, such as sedation, extra-pyramidal side effects and hypotension (associated with dopamine antagonists), as well as headache, diarrhea or constipation (associated with 5-HT3 receptor antagonists). A desirable attribute in any substitute or additional antiemetic medication would be the absence of clinically significant adverse effects.


SUMMARY OF THE INVENTION

Embodiments of the present invention are directed to compositions of matter, formulations for the treatment of nausea in humans and animals, methods of treatment, and methods of making such compositions and formulations. One embodiment of the present invention directed to a composition of matter is an extract of the ginger rhizome. The extract has 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol, in which 6-shogaol and 6-gingerol define a ratio and the ratio of 6-shogaol to 6-gingerol is 0.04 to 0.40. Although the applicant does not wish to be bound to any theory, it is believed this ratio of 6-shogaol to 6-gingerol improves the efficacy of the extract for the treatment of nausea.


As a further aspect of the invention, one composition of matter is directed to an extract of ginger rhizome wherein the ginger rhizome has a starting mass and the extract has a mass associated with one or more of the following 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol. The ratio of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol total mass to starting mass is 20-40%.


As a further aspect of the invention, one composition of matter is directed to an extract having 15-25% 6-gingerol, 1-5% 8-gingerol, 1-5% 10-gingerol and 1-5% 6-shogaol.


A further aspect of the present invention is directed to a formulation. As used herein the term formulation refers to a drug delivery device in the nature of a solution, tablet, capsule, gelcap, suspension and the like having a drug carried within for administration to an animal or human. One formulation of the present invention is directed to an extract of ginger rhizome, for the treatment of nausea in animals and humans, in an oil base.


In one aspect, the formulation the oil base is held in a capsule or gelcap. The capsule or gelcap has an oil base held in the capsule or gelcap.


The formulation has a dosage and in one aspect the dosage is in a range of 20-40 mg of the extract of ginger rhizome. This amount of extract preferably has 4.00-14 mg of combined gingerols and shogaol.


A preferred formulation has an oil with an antioxidant, that is, the antioxidant is dissolved in or suspended in the oil. One antioxidant is tocopherol. A preferred formulation has an oil having one or more emulsifying agents. The emulsifying agents facilitate bioavailability and maintain the other components of the formulation in the oil base. A preferred emulsifying agent is selected from one or more of the following agents lecithin, and short chain, medium chain and long chain triglycerides. A preferred oil is olive oil.


A further aspect of the present invention is a method of treating nausea in humans. The method comprising administering an effective amount of any extract described above or any formulations described above.


Preferably, the effective amount is administered every three to four hours. The method is of particular utility for cancer patients suffering from nausea and emesis induced by chemotherapy.


A further aspect of the present invention is directed to a method of making any of the compositions described above. The method comprises the steps of forming a dried powdered biomass of ginger rhizome. This dried biomass is placed in a vessel with carbon dioxide under super critical, near critical or critical conditions to form a saturated biomass powder. The carbon dioxide is separate from said biomass to form a carbon dioxide fluid extract containing the composition of gingerols and shogaol.


Preferably, the carbon dioxide is held at a temperature of 20-50 degrees Celsius, at a pressure of 1000 to 4000 psi. Preferably, the carbon dioxide has a modifier, in the sense that the modifier is carried in the carbon dioxide in the nature of a dissolved constituent. A preferred modifier is an alcohol, such as methanol or ethanol.


These and other features and advantages will be apparent to those skilled in the art upon reading the detailed description and viewing the drawings briefly described below.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 depicts in schematic form an apparatus embodying features of the present invention;





DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Ginger, an ancient spice mentioned in both the Bible and the Koran, is most known for its role as a flavoring agent for food in Asian and Indian recipes. Since the 16th century, the dried aromatic rhizome (underground stem) of ginger (Zingiber Officinale, Roscoe), has also been used by practitioners of both Indian (Ayurvedic) and traditional Chinese medicine to treat gastrointestinal upsets such as nausea and excessive flatulence. North American folklore also recognizes the ability of ginger to relieve gastrointestinal upsets including nausea. Ginger is also believed to be the only herb that can prevent symptoms of motion sickness and it has been approved for that use by Germany's Commission E, the agency responsible for regulating the use of herbal products in that country. Recently ginger has been studied scientifically for its effect on nausea and vomiting associated with motion sickness, surgery and pregnancy.


In an early randomized trial, ginger was more effective than diphenhydramine (Dramamine®) and each was more effective than dried chickweed herb placebo in preventing gastrointestinal symptoms caused by vection-induced motion sickness in a study of college students with self-reported high susceptibility to motion sickness. Ginger was also more effective than placebo in reducing vomiting related to seasickness in a group of naval cadets. Fewer episodes of nausea were also reported by the 40 cadets who received the ginger although the difference was not statistically significant. When used to prevent motion sickness, it is frequently suggested that the ginger be started one to two days before the trip and be continued throughout the period of travel.


A number of published studies have addressed the use of ginger for prevention of post-operative nausea and vomiting although the results have been mixed. Two studies comparing ginger (0.5 gm or 1 gm) vs. metochlopramide (10 mg) vs. placebo for control of post-operative nausea in women undergoing gynecologic surgery demonstrated equal effectiveness of ginger and metochlopramide for post-operative nausea; in both studies ginger and metochlopramide were significantly more effective than placebo. Phillips and co-investigators reported no significant differences in frequency of emesis between the three arms while Bone and colleagues reported less vomiting for both active drugs than for placebo. In the study headed by Phillips participants assigned to the ginger arm required significantly less post-operative “rescue” antiemetic treatment.


Two other studies of post-operative nausea and vomiting found no significant effect of ginger. In one of these, 0.5 gm or 1.0 gm of ginger given pre-operatively had no greater effect than placebo on the frequency or severity of nausea or the frequency of vomiting. Outcomes were assessed three hours post-operatively. However, no standard antiemetic arm was included in the study design. Visalyaputra and colleagues compared 2.0 gm of oral ginger, 1.25 mg intravenous droperidol and placebo in a randomized fashion and reported no differences in the frequency or severity of post-operative nausea or the frequency of post-operative vomiting during the 24 hour period immediately following surgery. Potential confounding factors in studies of post-operative nausea and vomiting include the nausea inducing effect of agents used to induce and maintain anesthesia and provide pain relief and short assessment periods, allowing little time for ginger to exert its maximum anti-nausea effects.


A recent study of ginger for nausea and vomiting of pregnancy found a significant reduction of nausea over four days of treatment in women who were experiencing either nausea or vomiting. Sixty women were randomized in equal proportions to receive 250 mg of dried ginger or placebo in identical-appearing capsules four times daily for four days (a total of 1 gm of ginger each day). By the fourth day, nausea scores were significantly lower in the group of 32 women taking ginger than in the 35 women in the placebo arm. In an earlier randomized, controlled cross-over study, thirty women with hyperemesis gravidarum also reported that ginger was more effective than placebo over a four-day period.


Remarkably little published work has addressed the efficacy of ginger for prevention or treatment of nausea and vomiting caused by receipt of chemotherapy for cancer, and those studies that are available are plagued by design inadequacies including small sample sizes and non-validated assessment methods. In a published nursing doctoral dissertation, Pace studied 20 patients being treated for leukemia with cytosine arabinoside (ARA-C). Participants were given 10 mg intravenous Compazine® (prochlorperazine) prior to chemotherapy and every four hours for nine additional doses. They were also randomly assigned to receive either ginger capsules (0.5 g prior to chemotherapy followed by nine additional doses four hours apart) or an identical-appearing placebo on the same schedule. Participants who received ginger had significantly less severe nausea on the day of chemotherapy and on the following day than those taking the placebo capsules. Another study compared ginger (1.5 gm) to psoralen in patients receiving 8-MOP for extra-corporeal chemotherapy and found that the total nausea score was reduced by approximately one-third in those receiving ginger. Table 1 on the following page summarizes the results of previously conducted controlled studies of ginger for nausea.









TABLE 1







Studies Examining the Antiemetic Efficacy of Ginger.











References
Sample
Study design
Treatment
Results





Grontved,
N = 80
Two-arm, randomized,
1.0 g ginger powder
Ginger was more effective


et al. (1988)
cadets
placebo-controlled trial for
or placebo given once
than placebo in controlling




control of seasickness.

vomiting and cold sweats,






P < .05, but not for vertigo






or nausea.


Fischer-
N = 60
Placebo-controlled,
250 mg dried ginger
Greater relief with ginger


Ramussen,
Pregnant
randomized, crossover study
capsules or placebo 4 x
than placebo, P < .05.


et al. (1991)
women with
with 2-day washout, for
daily for 4 days



severe nausea
nausea and vomiting




associated with morning




sickness.


Bone, et al.
N = 60
Three-arm, randomized,
Arm 1 = 1.0 g ginger
Ginger was more effective


(1990)
Women
placebo controlled trial of
Arm 2 = 10 mg
than placebo, P < .05 and



undergoing
ginger and metochlopramide
metochlopramide
similar in effectiveness to



gynecological
for control of post-operative
Arm 3 = placebo
metochlopramide for



surgery
nausea and vomiting. Study

nausea and vomiting




medication was given orally

control.




prior to surgery.


Pace 1986)
N = 41
Two-arm, randomized,
500 mg ginger or
Patients receiving ginger



Patients
placebo controlled trial of
placebo prior to
had less nausea than those



receiving
Compazine ®, with or
treatment and every
receiving placebo.



chemo-
without ginger for control of
four hours following



therapy
chemotherapy-induced
treatment for 36 hours




nausea and vomiting.


Phillips, et al.
N = 120
3 parallel arms, placebo
Arm 1 = 1 gram of
Less patients need


(1993)
women after
controlled, either given
ginger powder given
antiemetics afterward with



lapara-scopic
metochlopramide or ginger
one hour prior to
ginger, less likely to be



gynaecological
for post operative vomiting
anaesthesia
nauseated. 21% nauseated



surgery
and nausea
Arm 2 =
with ginger, 41% with





metochlopramide one
placebo, 27%





hour prior to
metochlopramide





anaesthesia


Arfeen, et al.
N = 108
3 parallel arms, placebo
Arm 1 = 0.5 g ginger 1
The ginger did not appear


(1995)
women after
controlled, given placebo or
hour prior to surgery
to have a statistically



lapara-scopic
one of two doses of ginger
and 2 doses after
significant effect on the



gynaecological
for reduction of post surgical
Arm 2 = 1.0 g ginger
amount of nausea or



surgery
nausea and vomiting
prior to surgery and 2
vomiting post surgery





doses after





Arm 3 = placebo


Visalyaputra
N = 120
4 parallel arms, placebo
Arm 1 = 1.0 g ginger
Neither drug showed a


et al. (1998)
women after
controlled received either
presurgically
statistically significant



lapara-scopic
ginger or 1.25 mg droperidol,
Arm 2 = 1.0 g ginger
decrease in nausea or



gynaecological
or both to reduce post
and 1.25 droperidol
vomiting



surgery
surgical nausea and vomiting
Arm 3 = 1.25 mg





droperidol





Arm 4 = placebo


Meyer &
N = 11 patients
Single arm given psoralen at
3 capsules of 530 mg
Those taking the ginger


Schwartz, et al.
undergoing
0.5-0.6 mg/kg prior to
each administered 30
reduced nausea by ⅓


(1995)
8-MOP
treatment, then evaluated,
min prior to 8-MOP
degree of level without



treatments
next treatment given ginger
treatment
ginger




and evaluated


Mowrey &
N = 36 paid
3 arm-randomized, placebo
Arm 1 = 100 mg
Ginger was found to be


Clayson
college
controlled, for vection
Dramamine ®
more effective at reducing


(1982)
students with
induced motion sickness
Arm 2 = 940 mg ginger
vection induced motion



self-rated
ginger versus placebo versus
root
sickness than placebo as



high
Dramamine ®
Arm 3 = placebo
measured by time in



susceptibility

given 25-30 minutes
induced motion. P < .001



to motion

prior to test



sickness


Vutyavanich
N = 70
2 arm, placebo controlled,
Arm 1 = 1.0 g ginger
Visual analog scores


et al. (2001)
pregnant
double-masked, randomized
for four days
decreased with ginger



women at or
ginger versus placebo,
Arm 2 = placebo
p = .014, vomiting episodes



prior to 17
participants self reported

decrease with p < .001



weeks
nausea, vomiting, and

And the improvement of



gestation
severity. Lasted four days,

those in ginger group with




and pre/post evaluation of

p < .001




symptoms









Previous research suggests that ginger may be effective against nausea associated with chemotherapy, but design inadequacies and small numbers limit the power and generalizability of the results and no dose-response studies have been reported to date. A phase II/III randomized, dose-finding, placebo-controlled clinical trial was conducted to assess the efficacy of ginger (Zingiber Officinale) for nausea associated with chemotherapy for cancer in the CCOP member sites affiliated with the URCC CCOP Research Base. Innovative aspects of the study design include collecting baseline data on nausea following the second cycle of chemotherapy, beginning the intervention three days prior to chemotherapy to maximize the post-chemotherapy effect of ginger, assessing symptoms prior to taking any ginger, after three days of ginger alone, and after three days of ginger plus standard antiemetics at cycles three and four, assessing anticipatory nausea as well as acute and delayed post-chemotherapy nausea and using validated measures for outcome assessment. The primary outcome was assessment of nausea following one chemotherapy cycle with the intervention (the third cycle). The intervention was continued for the fourth cycle of chemotherapy to assess the consistency of any effectiveness of ginger for nausea as a secondary, exploratory analysis.


In the largest trial to date, Ryan et al. (2009) conducted a Phase II/III randomized, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for chemotherapy-induced nausea in cancer patients. Patients who had experienced nausea in a previous chemotherapy cycle were randomized into four arms: (1) placebo, (2) 0.5 g ginger; (3) 1.0 g ginger, or (4) 1.5 g ginger. All patients received 5-HT3 receptor antagonist anti-emetics on Day 1 of all cycles and took ginger or placebo twice daily for six days starting three days before the first day of the next two cycles. 644 patients with disparate cancer types were accrued (90% female, mean age=53). All doses of ginger significantly reduced nausea on Day 1 of cycles 2 and 3 (p=0.003). The largest reduction in nausea occurred with 0.5 g and 1.0 g of ginger. Time of day had a significant effect on nausea (p<0.001) with a linear decrease over 24 hours for patients using ginger. No significant adverse events were reported. This positive trial utilized a ginger product in a gel capsule with the concentrations of gingerols and shogaol in the Examples herein.


Aspects of the present invention employ materials known as supercritical, critical or near-critical fluids. A material becomes a critical fluid at conditions which equal its critical temperature and critical pressure. A material becomes a supercritical fluid at conditions which equal or exceed both its critical temperature and critical pressure. The parameters of critical temperature and critical pressure are intrinsic thermodynamic properties of all sufficiently stable pure compounds and mixtures. Carbon dioxide, for example, becomes a supercritical fluid at conditions which equal or exceed its critical temperature of 31.1° C. and its critical pressure of 72.8 atm (1,070 psig). In the supercritical fluid region, normally gaseous substances such as carbon dioxide become dense phase fluids which have been observed to exhibit greatly enhanced solvating power. At a pressure of 3,000 psig (204 atm) and a temperature of 40° C., carbon dioxide has a density of approximately 0.8 g/cc and behaves much like a nonpolar organic solvent, having a dipole moment of zero Debyes.


A supercritical fluid displays a wide spectrum of solvation power as its density is strongly dependent upon temperature and pressure. Temperature changes of tens of degrees or pressure changes by tens of atmospheres can change a compound solubility in a supercritical fluid by an order of magnitude or more. This feature allows for the fine-tuning of solvation power and the fractionation of mixed solutes. The selectivity of nonpolar supercritical fluid solvents can also be enhanced by addition of compounds known as modifiers (also referred to as entrainers or cosolvents). These modifiers are typically somewhat polar organic solvents such as acetone, ethanol, methanol, methylene chloride or ethyl acetate. Varying the proportion of modifier allows wide latitude in the variation of solvent power.


In addition to their unique solubilization characteristics, supercritical fluids possess other physicochemical properties which add to their attractiveness as solvents. They can exhibit liquid-like density yet still retain gas-like properties of high diffusivity and low viscosity. The latter increases mass transfer rates, significantly reducing processing times. Additionally, the ultra-low surface tension of supercritical fluids allows facile penetration into microporous materials, increasing extraction efficiency and overall yields.


A material at conditions that border its supercritical state will have properties that are similar to those of the substance in the supercritical state. These so-called “near-critical” fluids are also useful for the practice of this invention. For the purposes of this invention, a near-critical fluid is defined as a fluid which is (a) at a temperature between its critical temperature (Tc) and 75% of its critical temperature and at a pressure at least 75% of its critical pressure, or (b) at a pressure between its critical pressure (Pc) and 75% of its critical pressure and at a temperature at least 75% of its critical temperature. In this definition, pressure and temperature are defined on absolute scales, e.g., Kelvin and psia. To simplify the terminology, materials which are utilized under conditions which are supercritical, near-critical or exactly at their critical point will jointly be referred to as “SCCNC” fluids or referred to as “SFS.”


SCCNC fluids can be used for the fractional extraction and manufacturing of highly purified gingerols and shogaols.


Embodiments of the present invention are directed to methods of using supercritical fluids for isolating and manufacturing gingerols for use as a therapeutic to treat nausea and emesis.


The present method and apparatus will be described with respect to FIG. 1 which depicts in schematic form the ginger fractionation apparatus, generally designated by the numeral 11.


Polarity-guided SuperFluids™ fractionation can be carried out on the dried and fresh ginger powder. SuperFluids™ CXF fractionations can be carried out on an automated extractor or a manual version of the same. As shown in FIG. 1, this is a dual pump system, utilizing syringe pump 1 for neat critical fluid (e.g. CO2) and syringe pump 2 for modifier (e.g. ethanol).


After loading ginger into a cartridge on the cartridge holder 3, the fractionation procedure can start. For example, the system will be brought to 3,000 psig and 40° C., and extracted for 10 minutes with pure CO2. This fraction will be collected in ethanol in a glass vial, numbered 4 in FIG. 1. The extraction parameters will be then set to: Supercritical CO2 at 3,000 psig and extraction temperature 40° C., step extractions with ethanol as cosolvent at 5, 10, 20, 30 and 40 vol % each step being 10 min. Each biomass sample will yield 6 fractions and which will be collected in ethanol in separate glass vials. The fractions will be dried under vacuum in a SpeedVac, and analyzed by HPLC for gingerols, zingerone, and shogaol content. Conditions which provide the highest combined content of gingerols and shogaol with ratios of 6-gingerol to 6-shogaol between 0.04 to 0.4 will be scaled up for manufacturing larger quantities.


EXAMPLES
Example 1
Fractionation of Ginger Rhizome

Biomass: Zingiber officinale biomass, both fresh and dried, was obtained from reputable suppliers in Brazil. The material was shipped on ice by overnight freight to our facilities in Woburn, Mass. On receipt, the biomass samples were logged in; dried biomass was stored in dry, low humidity conditions and the fresh biomass will be stored at 4° C. Samples were ground to a fine powder and extracted with different solvents—ethanol, methylene chloride, chloroform and hexane—to define the gingerol content of the material by HPLC analytical techniques. Samples of the underground biomass were used for cultivar identification and sent to outside contractors for heavy metals, herbicides and pesticides analyses. Small voucher samples were retained.


Ginger Powder: The dried ginger root was cut into chunks and dried in a convective oven at 37° C. for 24 hours to remove moisture. The biomass was then ground into a fine powder in a plate and hammer mill. A sample of this fine powder was also extracted by conventional techniques to re-establish the gingerols and shogaol content of the dried and ground Zingiber officinale biomass. The biomass powder was labeled and stored at −20° C.


The fresh ginger root was also cut into chunks and dried in a VirTis shelf freeze-dryer over a 24-hour period to remove all water and moisture. The biomass was then ground into a fine powder in a plate and hammer mill. A sample of this fine powder was also extracted by conventional techniques to re-establish the gingerols and shogaol content of the dried and ground Zingiber officinale biomass. The biomass powder was labeled and stored at −20° C.


Ginger Extract: Polarity-guided SuperFluids™ fractionation was carried out on the dried and fresh ginger powder. As shown in FIG. 1, this is a dual pump system, utilizing syringe pump 1 for neat critical fluid (e.g. CO2) and syringe pump 2 for modifier (e.g. ethanol).


Example 1
Fractionation of Ginger Rhizome
















Biomass

















SC-CO2 Extraction

Wt. of

6-Shogaol
Total %
















Parameters

Extracted

% Gingerol In Extracted Material
% in
Ratio of 6-
Gingerols




















Fraction
P,

%
Starting
Material,
%
6-
8-
10-

Extracted
Shogaol to
plus Shogaol


ID
psig
ToC
EtOH
Wt., g
mg
Extracted
Gingerol
Gingerol
Gingerol
Total
Material
6-Gingerol
in Extract























GIN-1-1
3000
40
0
1.9960
6.00
0.30%
5.89%
0.93%
0.017%
6.84%
4.45%
0.76
11.30%


GIN-1-2
3000
40
5
1.9960
3.10
0.16%
5.10%
0.72%
0.029%
5.85%
3.73%
0.73
9.58%


GIN-1-3
3000
40
10
1.9960
32.90
1.65%
18.42%
3.08%
0.161%
21.66%
13.59%
0.74
35.26%


GIN-1-4
3000
40
15
1.9960
29.60
1.48%
12.17%
1.91%
0.119%
14.21%
8.13%
0.67
22.34%


GIN-1-5
3000
40
20
1.9960
24.00
1.20%
3.09%
0.41%
0.019%
3.52%
1.74%
0.56
5.25%


GIN-1-6A
3000
40
40
1.9960
9.60
0.48%
1.45%
0.08%
0.014%
1.55%
0.58%
0.40
2.13%


GIN-1-6B
3000
40
40
1.9960
20.30
1.02%
0.86%
0.07%
0.010%
0.94%
0.30%
0.35
1.24%


GIN-2-1
1000
40
0
2.1253
23.43
1.10%
0.06%
0.01%
0.000%
0.07%
0.027%
0.42
0.10%


GIN-2-2
1000
40
5
2.1253
21.12
0.99%
0.05%
0.00%
0.000%
0.06%
0.004%
0.08
0.06%


GIN-2-3
1000
40
10
2.1253
45.17
2.13%
11.20%
2.33%
0.162%
13.69%
9.75%
0.87
23.44%


GIN-2-4
1000
40
15
2.1253
47.11
2.22%
3.09%
0.52%
0.022%
3.63%
2.42%
0.79
6.05%


GIN-2-5
1000
40
20
2.1253
67.14
3.16%
0.49%
0.06%
0.004%
0.56%
0.32%
0.65
0.88%


GIN-2-6A
1000
40
40
2.1253
30.00
1.41%
0.36%
0.01%
0.002%
0.37%
0.14%
0.38
0.50%


GIN-2-6B
1000
40
40
2.1253
22.41
1.05%
0.38%
0.01%
0.002%
0.40%
0.13%
0.35
0.53%


GIN-3-1
5000
40
0
2.1146
1.35
0.06%
19.54%
2.99%
0.069%
22.60%
12.60%
0.64
35.20%


GIN-3-2
5000
40
5
2.1146
0.55
0.03%
17.59%
2.12%
0.163%
19.87%
10.40%
0.59
30.28%


GIN-3-3
5000
40
10
2.1146
48.36
2.29%
15.78%
2.84%
0.162%
18.78%
12.68%
0.80
31.46%


GIN-3-4
5000
40
15
2.1146
15.06
0.71%
8.16%
1.31%
0.056%
9.52%
5.94%
0.73
15.45%


GIN-3-5
5000
40
20
2.1146
10.62
0.50%
3.42%
0.38%
0.035%
3.84%
1.79%
0.52
5.63%


GIN-3-6A
5000
40
40
2.1146
8.00
0.38%
1.78%
0.16%
0.023%
1.97%
0.79%
0.44
2.76%


GIN-3-6B
5000
40
40
2.1146
7.10
0.34%
2.11%
0.20%
0.025%
2.33%
0.91%
0.43
3.24%


GIN-4-1
4000
40
0
2.0110
46.06
2.29%
16.62%
2.85%
0.145%
19.62%
13.01%
0.78
32.63%


GIN-5-1
2000
40
0
2.0522
57.95
2.82%
20.23%
3.51%
0.223%
23.97%
15.32%
0.76
39.29%


GIN-6-1
3000
30
0
2.0086
19.44
0.97%
14.14%
2.45%
0.135%
16.73%
11.28%
0.80
28.01%


GIN-7-1
3000
21
0
2.0382
35.52
1.74%
19.30%
3.37%
0.152%
22.82%
15.49%
0.80
38.30%


GIN-8-1
3000
50
0
2.0683
42.68
2.06%
18.28%
3.09%
0.149%
21.52%
14.21%
0.78
35.72%


GIN-9-1
3000
60
0
2.0223
48.30
2.39%
21.94%
3.76%
0.169%
25.87%
16.94%
0.77
42.81%


GIN-10-1
3000
40
0
2.0552
57.78
2.81%
13.77%
2.36%
0.123%
16.25%
11.07%
0.80
27.33%


GIN-11-1
1000
40
0
2.0100
108.21
5.38%
0.25%
0.04%
0.002%
0.29%
0.20%
0.80
0.49%


GIN-12-1
5000
40
0
2.0046
55.30
2.76%
20.53%
3.50%
0.200%
24.23%
15.95%
0.78
40.17%


Ethanol
0
<40
100
2.0208
173.50
8.59%
7.46%
1.21%
0.039%
8.71%
5.58%
0.75
14.28%









Example 2
Fractionation of Ginger Rhizome
















Biomass

6-Shogaol














Wt. of

% in
Ratio of
Total %















Starting
Extracted
%
% Gingerol in Extracted Material
Extracted
6-Shogaol to
Gingerols

















Sample
Wt., g
Material, g
Extracted
6-Gingerol
8-Gingerol
10-Gingerol
Total
Material
6-Gingerol
plus Shogaol




















GINP-1-1
8618
124.3
1.44
20.05
2.083
3.065
25.20
1.88
0.09
27.08


GINP-1-2
8618
33.6
0.39
25.79
2.936
5.268
34.00
1.19
0.05
35.19


GINP-1-3
8618
26.9
0.31
20.43
2.433
4.893
27.75
0.55
0.03
28.30


GINP-1-4
8618
21.0
0.24
17.15
1.952
3.931
23.03
0.53
0.03
23.56


GINP-1-5
8618
12.9
0.15
15.36
1.777
3.592
20.73
0.46
0.03
21.19


GINP-1-6
8618
15.0
0.17
17.34
2.087
4.301
23.73
0.47
0.03
24.21


Total
8618
233.7
2.71
20.22
2.218
3.778
26.22
1.34
0.07
27.56









Example 3
Fractionation of Ginger Rhizome
















Biomass

6-Shogaol














Wt. of

% in
Ratio of
Total %















Starting
Extracted
%
% Gingerol In Extracted Material
Extracted
6-Shogaol to
Gingerols

















Sample
Wt., g
Material, g
Extracted
6-Gingerol
8-Gingerol
10-Gingerol
Total
Material
6-Gingerol
plus Shogaol




















GINP-2-1
9752
87.0
0.89
12.60
1.217
1.780
15.60
1.60
0.13
17.20


GINP-2-2
9752
63.8
0.65
27.33
3.096
4.770
35.19
2.07
0.08
37.26


GINP-2-3
9752
39.0
0.40
28.27
3.325
5.741
37.34
1.59
0.06
38.92


GINP-2-4
9752
36.9
0.38
25.50
3.297
5.933
34.73
1.30
0.05
36.03


GINP-2-5
9752
42.3
0.43
24.56
2.940
5.725
33.23
0.94
0.04
34.16


Total
9752
269.0
2.76
22.02
2.524
4.254
28.79
1.56
0.07
30.36









Example 4
Fractionation of Ginger Rhizome

Although the SFS-CO2 extraction parameters of T=40° C., 2,000 psig and no co-solvent were the same for the three series, the CO2 flow rate was reduced from GINP-1 to GINP-2. Additionally, collection techniques from GINP-2 to GINP-3 were changed.

















Biomass

6-Shogaol
Total % Gingerols













Wt. of

% in
Ratio of
plus Shogaol in















Starting
Extracted
%
% Gingerol In Extracted Material
Extracted
6-Shogaol to
the Extracted

















Sample
Wt., g
Material, g
Extracted
6-Gingerol
8-Gingerol
10-Gingerol
Total
Material
6-Gingerol
Material




















GINP-3-1
9072
178.8
1.97
18.32
1.823
2.677
22.82
1.86
0.10
24.68


GINP-3-2
9072
88.8
0.98
25.38
2.876
4.740
32.99
1.82
0.07
34.81


GINP-3-3
9072
46.9
0.52
24.25
2.813
5.036
32.09
1.43
0.06
33.52


GINP-3-4
9072
24.0
0.26
20.36
2.111
3.861
26.34
0.69
0.03
27.03


Total
9072
338.4
3.73
21.14
2.257
3.629
27.02
1.70
0.08
28.73









Example 5
Fractionation of Ginger Rhizome
















Biomass

6-Shogaol














Wt. of

% in
Ratio of
Total %















Starting
Extracted
%
% Gingerol in Extracted Material
Extracted
6-Shogaol to
Gingerols

















Sample
Wt., g
Material, g
Extracted
6-Gingerol
8-Gingerol
10-Gingerol
Total
Material
6-Gingerol
plus Shogaol




















GINP-5-1
8845
148.1
1.67
16.09
1.460
2.110
19.66
1.80
0.112
21.46


GINP-5-2
8845
52.6
0.59
35.65
3.949
5.780
45.38
1.57
0.044
46.95


GINP-5-3
8845
35.9
0.41
33.14
3.968
8.238
45.35
0.91
0.028
46.26


GINP-5-4
8845
14.3
0.16
30.69
3.908
7.675
42.27
0.54
0.018
42.81


GINP-5-5
8845
13.7
0.15
24.98
3.686
7.364
36.03
0.37
0.015
36.40


GINP-5-6
8845
7.1
0.08
18.22
2.746
6.004
26.97
0.24
0.013
27.21


GINP-5-7
8845
5.3
0.06
12.94
2.023
4.784
19.75
0.24
0.018
19.98


GINP-5-8
8845
7.5
0.08
13.97
1.888
4.415
20.28
0.49
0.035
20.77


Total
8845
284.4
3.22
22.96
2.521
4.302
29.78
1.41
0.062
31.19









Example 6
Fractionation of Ginger Rhizome

The SFS-CO2 extraction parameters were T=40° C., 2,000 psig and no co-solvent. The feed rate of CO2 had a pump rate of 4 strokes/minute MeOH to 80 strokes per minute CO2. Five (5) fractions were collected every 60 minutes.

















Biomass

6-Shogaol














Wt. of

% in
Ratio of
Total %















Starting
Extracted
%
% Gingerol in Extracted Material
Extracted
6-Shogaol to
Gingerols

















Sample
Wt., g
Material, g
Extracted
6-Gingerol
8-Gingerol
10-Gingerol
Total
Material
6-Gingerol
plus Shogaol




















GINP-6-1
8165
80.3
0.98
18.44
1.818
2.644
22.90
1.79
0.097
24.69


GINP-6-2
8165
83.5
1.02
27.64
3.118
5.215
35.97
1.80
0.065
37.77


GINP-6-3
8165
47.0
0.58
26.17
3.263
5.995
35.43
1.34
0.051
36.77


GINP-6-4
8165
12.9
0.16
15.81
2.122
3.913
21.84
0.60
0.038
22.45


GINP-6-5
8165
2.5
0.03
10.77
1.330
2.510
14.61
0.35
0.032
14.96


Total
8165
226.2
2.77
23.21
2.610
4.360
30.18
1.61
0.070
31.79









Example 7
Fractionation of Ginger Rhizome
















Biomass

6-Shogaol














Wt. of

% in
Ratio of
Total %















Starting
Extracted
%
% Gingerol in Extracted Material
Extracted
6-Shogaol to
Gingerols

















Sample
Wt., g
Material, g
Extracted
6-Gingerol
8-Gingerol
10-Gingerol
Total
Material
6-Gingerol
plus Shogaol




















GINP-7-1
9866
159.9
1.62
21.70
2.051
2.893
26.65
2.34
0.108
28.98


GINP-7-2
9866
78.7
0.80
34.68
4.923
8.132
47.74
0.97
0.028
48.71


GINP-7-3
9866
25.9
0.26
18.28
2.902
6.088
27.27
0.42
0.023
27.69


GINP-7-4
9866
14.3
0.14
10.94
1.516
3.351
15.81
0.32
0.029
16.12


GINP-7-5
9866
2.8
0.03
9.49
1.263
2.714
13.47
0.25
0.026
13.72


Total
9866
281.6
2.85
24.35
2.897
4.673
31.92
1.66
0.068
33.57









Example 8
Fractionation of Ginger Rhizome
















Biomass

6-Shogaol
Total % Gingerols













Wt. of

% in
Ratio of
plus Shogaol in















Starting
Extracted
%
% Gingerol in Extracted Material
Extracted
6-Shogaol to
the Extracted

















Sample
Wt., g
Material, g
Extracted
6-Gingerol
8-Gingerol
10-Gingerol
Total
Material
6-Gingerol
Material




















GINP-8-1
9866
193.4
1.96
23.92
2.355
3.272
29.54
2.24
0.09
31.78


GINP-8-2
9866
66.2
0.67
26.29
4.261
8.288
38.84
0.72
0.03
39.56


GINP-8-3
9866
16.4
0.17
13.37
1.856
3.415
18.64
0.49
0.04
19.13


GINP-8-4
9866
7.3
0.07
11.02
1.371
2.700
15.09
0.37
0.03
15.46


Total
9866
283.3
2.87
23.53
2.746
4.438
30.71
1.74
0.07
32.45









Example 9
Fractionation of Ginger Rhizome













Gingerol in Extracted Material











Biomass

Total Gingerols


















Starting







Ratio of
plus Shogaol in



Biomass
Wt. of
%
6-
8-
10-
Total
6-
6-Shogaol to
the Extracted


Sample
Wt., g
Lot, g*
Extracted
Gingerol
Gingerol
Gingerol
Gingerols
Shogaol
6-Gingerol
Material












Reported as grams

















GINP-1 Lot 022810
8618
277.0
3.21
49.76
5.77
9.83
65.4
3.72
0.075
69.08









Reported as %















17.96
2.08
3.55
23.59
1.34
0.075
24.94





Additionally, 100 grams of the 277.0 g was shipped to Cardinal Health/RP Sherer on Oct. 28, 2002, leaving ~177 g of this Lot in-house.






Example 10
Fractionation of Ginger Rhizome

The yields for the composite GINP were:


















Composite
Yield, g
Removed, g
Remaining, g





















GINP-1
277
200
77



GINP-2
306
1
305



GINP-3
274
1
273



GINP-4
272
1
271



GINP-5
307
1
306



GINP-6
256
1
255



GINP-7
321
1
320



GINP-8
328
1
327



TOTAL GINP


2134










The 8 composite extracts were warmed to 33° C. in a water bath and then transferred into a 10 L round bottom flask. With the rotavaporator bath set at 30° C., the fractions were combined by slowly rotating the flask such that the extract slid into itself with minimal agitation and incorporation of air. The vacuum was not used since this is mainly a mixing procedure.


After 2 hours the following aliquots were taken:

    • (1). 1,352 g for capsule manufacture, stored −20° C./N2 head;
    • (2). 100 g for in-house QC tests;
    • (3.) 150 g shipped to Flora Research for specified tests including microbiological Testing
    • (4.) 400 g, weighed, labeled and stored at −20° C. under a nitrogen head.


All the apparatus (rotavaporator, R.B. 10 L flask, shipping bottle, storage bottles, funnel, caps, and watch glass were cleaned by either 70% EtOH or autoclaving or combination of both to minimize bioburden. Personnel took appropriate aseptic processing precautions.












GINP-021311


















Ratio of
Total Gingerols plus





Total

6-Shogaol to
Shogaol in the


6-Gingerol
8-Gingerol
10-Gingerol
Gingerols
6-shogaol
6-Gingerol
Extracted Material










mg per gram extract













207.84
24.97
40.01
272.8
15.00
0.072
287.82







% Target Compound per gram extract













20.78
2.50
4.00
27.28
1.50
0.072
28.78









Example 11
Formulation of Gingerols

The active pharmaceutical ingredients (APIs) are (1): 1,026 grams of GINP-021311 (Lot No. 021311); (2) 326 grams of GINP-021311 (Lot No. 021311); and (3) 400 grams of GINP-021311 (Lot No. 021311) for a total of 1.752 kilograms of ginger product. This product has an absolute purity of 28.78 total gingerols and shogaol (20.78% 6-gingerol, 2.50% 8-gingerol, 4.00% 10-gingerol and 1.50% 6-shogaol). APIs were characterized by HPLC analysis.


The ginger drug capsules contained the following: ginger extract (containing combined gingerols and shogaol); mixed tocopherols as an antioxidant; lecithin as an emulsifier to improve solubility and bioavailability; medium chain triglyceride (MCT) as a co-emulsifier; and olive oil as an excipient with some nutritional value under a nitrogen head to minimize product oxidation.


The placebo capsules contained the following: mixed tocopherols; lecithin; medium chain triglyceride (MCT); and olive oil under a nitrogen head.

Claims
  • 1. A formulation of an extract of ginger rhizome for the treatment of nausea in humans comprising 20-40 mg of extract of ginger rhizome having 15-25% 6-gingerol, 1-5% 8-gingerol, 1-5% 10-gingerol, and 1-5% 6-shogaol in which said 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol comprise 4-14 mg in an oil base held in a capsule or gelcap for oral administration every three to four hours as needed for the treatment of nausea.
  • 2. The formulation of claim 1 wherein said oil has an antioxidant.
  • 3. The formulation of claim 2 wherein said antioxidant is tocopherol.
  • 4. The formulation of claim 1 wherein said oil has one or more emulsifying agents.
  • 5. The formulation of claim 4 wherein at least one of said emulsifying agents are selected from lecithin, and short chain, medium chain and long chain triglycerides.
  • 6. The formulation of claim 1 wherein said oil is olive oil.
  • 7. A method of treating nausea in humans comprising the step of administering an effective amount of the formulation as set forth in any one of claim 4 or 2-6.
  • 8. The method of claim 7 wherein said effective amount is administered every three to four hours.
  • 9. The method of claim 7 wherein said step of administering is (a) initiated three days before the start of chemotherapy; (b) performed on the day of chemotherapy; and (c) performed through three days after the end of chemotherapy.
GOVERNMENT SUPPORT

Research leading to this invention was in part funded by the National Cancer Institute, National Institutes of Health, Bethesda, Md., USA.

US Referenced Citations (1)
Number Name Date Kind
20070154575 Shimoda et al. Jul 2007 A1
Non-Patent Literature Citations (1)
Entry
Bailey-Shaw (Journal of Agricultural and Food Chemistry (2008), vol. 56, pp. 5564-5571).
Related Publications (1)
Number Date Country
20110280976 A1 Nov 2011 US