WO2002036139A1 - Régulation de la glycémie - Google Patents

Régulation de la glycémie Download PDF

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Publication number
WO2002036139A1
WO2002036139A1 PCT/CA2000/001281 CA0001281W WO0236139A1 WO 2002036139 A1 WO2002036139 A1 WO 2002036139A1 CA 0001281 W CA0001281 W CA 0001281W WO 0236139 A1 WO0236139 A1 WO 0236139A1
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WIPO (PCT)
Prior art keywords
tea
vanadate
blood glucose
suspended
glucose levels
Prior art date
Application number
PCT/CA2000/001281
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English (en)
Inventor
Grant Pierce
Clayton Heyliger
Original Assignee
Biovan, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biovan, Inc. filed Critical Biovan, Inc.
Priority to AU2001212603A priority Critical patent/AU2001212603A1/en
Priority to PCT/CA2000/001281 priority patent/WO2002036139A1/fr
Publication of WO2002036139A1 publication Critical patent/WO2002036139A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F3/00—Tea; Tea substitutes; Preparations thereof
    • A23F3/16—Tea extraction; Tea extracts; Treating tea extract; Making instant tea
    • A23F3/163—Liquid or semi-liquid tea extract preparations, e.g. gels, liquid extracts in solid capsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia

Definitions

  • the present invention relates generally to a pharmaceutical composition. More specifically, the present invention relates to a pharmaceutical composition for managing blood glucose levels.
  • sulfonylurea drugs are usually used only in cases of mild diabetes.
  • insulin injections although effective, are not an optimum way of controlling the disease. This is due to the fact that daily injections with needles is painful and unpleasant.
  • other means of delivering insulin for example, implanted mini-pumps and islet transplantation, have not evolved to a point where they could be considered viable replacements for daily injections of insulin (Pierce et al, 1988).
  • vanadate was identified over 10 years ago as a replacement for insulin (Heyliger et al, 1985, Science 227: 1474). Therein, vanadate was shown to control diabetes in an insulin-deficient, streptozotocin-induced rat model of diabetes (Heyliger et al, 1985). Specifically, vanadate was included in the drinking water of the rats, thus removing the need for unpleasant injections (Heyliger et al, 1985).
  • vanadate was considered a potentially important therapy for controlling diabetes, the side-effects associated with its administration have been so serious as to preclude any clinical use.
  • vanadate analogues (Aharon et al, 1998, Diabetes Care 21: 2194; Halberstam et al, 1996, Diabetes 45: 659-666; Goldfine et al, 1995, J Clin Endocrinol Metab 80: 3312-3320) that would increase the hypoglycemic action while limiting the harmful side effects, that is, the generation of diarrhea.
  • An example is vanadyl sulfate (Aharon et al, 1998).
  • no vanadate analogues have successfully addressed the problem in a manner that would make these compounds useful in a clinical setting.
  • an orally-administered pharmaceutical composition for treating diabetes comprising an insulin-mimetic agent such as vanadate and a suitable carrier such that side-effects are minimized is needed.
  • a method of preparing a mixture for maintaining blood glucose levels comprising: providing a tea reputed to have gastrointestinal soothing properties; adding the tea to boiling water; boiling the tea; cooling the tea; and suspending a quantity of vanadate in the tea.
  • the tea may be selected from the group consisting of green tea, black tea and raspberry tea.
  • the method may include filtering the tea prior to suspending the vanadate in the tea.
  • composition comprising as an active ingredient the mixture of the methods described above.
  • mixture for maintaining blood glucose levels comprising decocted tea and vanadate.
  • the decocted tea may be selected from the group consisting of green tea, black tea and raspberry tea.
  • a method of treating diabetes comprising: providing the pharmaceutical composition described above; and administering the pharmaceutical composition to a diabetic individual, thereby normalizing the blood glucose levels of the individual.
  • FIG. 1 is a bar graph of percent survival of subjects administered varying quantities of vanadate suspended in black tea, green tea and water.
  • FIG. 2 is a graph of body weight over time of subjects administered 30 mg of vanadate suspended in green tea, black tea and water, as well as wild type and diabetic controls.
  • FIG. 3 is a graph of body weight over time of subjects administered 40 mg of vanadate suspended in green tea, black tea and water, as well as wild type and diabetic controls.
  • FIG. 4 is a graph of body weight over time of subjects administered 50 mg of vanadate suspended in green tea, black tea and water, as well as wild type and diabetic controls.
  • FIG. 5 is a plot of blood glucose levels over time in subjects administered 30 mg of vanadate suspended in green tea, black tea and water, as well as wild type and diabetic controls.
  • FIG. 6 is a plot of blood glucose levels over time in subjects administered 40 mg of vanadate suspended in green tea, black tea and water, as well as wild type and diabetic controls.
  • FIG. 7 is a plot of blood glucose levels over time in subjects administered 50 mg of vanadate suspended in green tea, black tea and water, as well as wild type and diabetic controls.
  • FIG. 8 shows a high performance liquid chromatographic separation of black tea, showing levels of antioxidants catechin (cat), epicatechin (epi), rutin (rut), transresveratrol (t-res) and quercetin (quer).
  • FIG. 9 shows- a high performance liquid chromatographic separation of Chinese green tea, showing levels of antioxidants catechin (cat), epicatechin (epi), rutin (rut), transresveratrol (t-res) and quercetin (quer).
  • FIG. 10 shows a high performance liquid chromatographic separation of Japanese tea, showing levels of antioxidants catechin (cat), epicatechin (epi), rutin (rut), transresveratrol (t-res) and quercetin (quer).
  • FIG. 11 shows a high performance liquid chromatographic separation of raspberry tea, showing levels of antioxidants catechin (cat), epicatechin (epi), rutin (rut), transresveratrol (t-res) and quercetin (quer).
  • FIG. 12 shows the effects of sodium orthovanadate and black tea on the generation of diarrhea and death compared to vanadate delivered with water in streptozotocin-induced diabetic rats.
  • FIG. 13 shows the effect of sodium orthovanadate and black tea on blood glucose concentration in streptozotocin-induced diabetic rats.
  • FIG. 14 shows the effect of sodium orthovanadate and black tea on individual blood glucose concentration in streptozotocin-induced diabetic rats.
  • FIG. 15 shows the effect of sodium orthovanadate and black tea on mortality compared to vanadate delivered with water in Zucker diabetic rats.
  • FIG. 16 shows the effect of sodium orthovanadate in black tea on diarrhea compared to vanadate delivered with water in Zucker diabetic rats.
  • FIG. 17 shows the effect of lyophilized sodium orthovanadate in black tea on blood glucose levels in streptozotocin-induced diabetic rats.
  • FIG. 18 shows the effect of lyophilized sodium orthovanadate in jasmine tea on blood glucose levels in streptozotocin-induced diabetic rats.
  • TABLE 4 summarizes results of subjects administered 30 mg of vanadate suspended in green tea.
  • TABLE 8 summarizes results of subjects administered 40 mg of vanadate suspended in black tea.
  • Gastro-intestinal soothing tea refers to any tea known in the art as a remedy for Gl distress.
  • decocted tea refers to a concentrated tea extract containing medicinal constituents of the tea obtained by simmering dried tea leaves and other parts in boiling water.
  • Described herein is a method of utilizing vanadate as an effective insulinomimetic agent while preventing the vanadate-induced gastrointestinal distress (diarrhea) associated with administration of vanadate.
  • the vanadate was suspended in a decoction of specific teas, which were chosen based on their reputed abilities to prevent or treat gastrointestinal problems like diarrhea.
  • the teas were prepared to generate a highly concentrated decoction as described below and the vanadate was suspended therein.
  • the decocted tea and vanadate mixtures lowered blood glucose levels of test animals to normal levels, in some cases for an extended period of time, with fewer side effects, compared to administered doses of a water and vanadate mixture.
  • the tannin or high antioxidant content of the teas, or another specific component of the tea would be enriched in this decoction in such a manner as to avoid the diarrhea side-effects and enhance the hypoglycemic action of vanadate.
  • the data indicates that elements in the tea are counteracting the harmful effects of vanadate, possibly by modifying the vanadate in some way, as discussed below.
  • pharmaceutical compositions based on the decocted tea and vanadate mixture may have long-term hypoglycemic effects, thereby obviating the need for daily insulin injections to treat diabetes and/or control blood glucose levels.
  • the decocted tea is lessening the side effects of vanadate.
  • the tea may modify the vanadate into something more palatable to the gut. For example, once the vanadate is added to the tea, the mixture slowly darkens over a 24 hour period. This is similar to the darkening seen when iron is added to tea which is thought to be caused by the formation of soluble and insoluble complexes within the tea. It is possible that a similar reaction is occurring with the vanadate and tea.
  • the antioxidant content of the tea may be altering the redox potential of the vanadate.
  • the tea may instead act upon the gut itself and have no important interactions with the vanadate. For example, it is known tea inhibits gut motility - this may deter the diarrhea effects of vanadate and allow the vanadate to cross the gut wall at the same time. Most of these effects have been attributed to its tannin content.
  • the decocted tea mixture is also enhancing the normoglycemic properties of vanadate, as blood glucose levels are stabilized for longer periods of time following treatment.
  • the active ingredients of these mixtures or synthetic preparations thereof could be used to develop pharmaceutical compositions for managing blood glucose levels and treating diabetes in humans using methods known in the art.
  • a therapeutically effective amount of the decocted tea/vanadate mixture may be combined with pharmaceutically acceptable carriers and/or excipients.
  • the decocted tea/vanadate mixture may be lyophilized and, for example, combined with binders to form a tablet or inserted into caplets.
  • kits for carrying out the methods of the invention. Accordingly, a variety of kits are provided.
  • the kits may be used for any one or more of the following : treating diabetes in an individual; or maintaining blood glucose levels in an individual.
  • kits of the invention comprise one or more containers comprising vanadate suspended in a decocted tea as described above or lyophilized vanadate suspended in a decocted tea and a set of instructions, generally written instructions although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use and dosage of the vanadate suspended in decocted tea for the intended treatment (e.g., treating diabetes or maintaining blood glucose levels) .
  • the instructions included with the kit generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers of vanadate suspended in decocted tea may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • the vanadate suspended in decocted tea of the kit may be packaged in any convenient, appropriate packaging.
  • the vanadate suspended in decocted tea is a freeze-dried formulation
  • an ampoule with a resilient stopper is normally used, so that the drug may be easily reconstituted by injecting fluid through the resilient stopper.
  • black tea, green tea and raspberry tea were decocted.
  • the black tea used was China Lichee Black Tea (Golden Sail Brand) produced by China Tuhsu Guangdong Tea Import and Export Corporation, Golden Sail Brand, China; and the green tea was Japanese Green Tea, produced by Ujinotsuyu-Aoyanagi Midori Tea Company, Japan.
  • Chinese Green Tea produced by Golden Dragon and Red Raspberry Leaf Tea produced by The Canadian Herbal Tea Company, PO Box 20024, Selkirk, MB, Canada, R1A 1S0 were also used, as described below.
  • other teas having similar properties that is, tannin and/or high anti-oxidant concentrations and/or reputed gastrointestinal soothing properties may also be suitable.
  • the decoction of tea was prepared as follows: 100 grams of a given tea was added to 800 ml of boiling water in a container. In this embodiment, a stainless steel container was utilized although other suitable containers may also be used. The container was then covered and boiled for 15 minutes with occasional stirring. The heat was turned off and the decoction was allowed to cool while covered on the burner. After approximately 8 hours, the cool tea decoction was filtered and aliquoted in 250 ml bottles. In the examples described herein, the decoction was filtered once through cheesecloth. This filtering step removes large particulate compounds from the decoction and as such it is to be understood that other methods for removing the large particulate compounds may also be used. Following filtration, the tea decoction contained small particulate matter.
  • methods for preparing the decocted tea may vary, according to the brand and type of tea used.
  • the volume of water or weight of dried tea leaves may be varied
  • vanadate was then suspended in the tea. Specifically, the quantity of vanadate added in the examples described herein was 15, 20 or 25 milligrams/ml as described below. In the examples described herein, sodium orthovanadate from SigmaTM was used as the vanadate source. As will be apparent, other suitable forms of vanadate, for example, vanadyl sulfate or sodium metavanadate may also be used.
  • the decocted tea plus vanadate was allowed to stand for 8 hours prior to use. It is of note that bottles were shaken prior to the removal of an aliquot for administration purposes.
  • vanadate suspended in either water, black tea or green tea at concentrations of 15, 20 or 25 mg/ml was administered to test animals in a 2 ml aliquot by oral gavage.
  • the test animals were streptozotocin-induced diabetic rats.
  • the animals were identified by number and by the presence or absence of a red stripe, designated Red and None respectively.
  • the dosage regime was different for each animal, depending upon their response to treatment. That is, some animals received only two to three doses of the vanadate/tea mixture and were normoglycemic for from three to six weeks without further doses.
  • TABLE 1 summarizes the results observed using animals administered doses of 30 mg of vanadate suspended in water.
  • two (37 Red and 38 None) of the six animals died of diarrhea, a common side effect of vanadate treatment, as discussed above.
  • two of the animals 38 Red and 39 Red
  • blood glucose levels remained normal approximately five weeks after the last dose.
  • one animal usually responded to vanadate treatment but blood glucose levels remained normal for only a few days, meaning that more frequent doses were needed.
  • animal 37 None blood glucose level was difficult to control and remained elevated after the 7 th dose.
  • the results obtained with the vanadate and green tea mixtures indicate that higher concentrations of vanadate (50 mg) produced the desired results, that is, promoted normal blood glucose levels after only a few doses.
  • vanadate and green tea mixture had a higher survival rate than the vanadate and water mixture.
  • the vanadate and green tea mixture promoted weight gain at a rate higher than the diabetic control as shown in FIGs 2-4.
  • the vanadate and green tea mixture was more apt at managing blood glucose levels and also had fewer side effects compared to the vanadate and water mixture.
  • animals were administered 30 mg doses of vanadate suspended in decocted black tea. As can be seen, two animals (48 Red and 48 None) required multiple doses and their blood glucose level remained difficult to control throughout the study. Furthermore, one animal (51 None) always responded to the vanadate doses but the blood glucose levels remained normal for only a few days, meaning that multiple treatments were required. However, six animals (47 Red, 49 Red, 49 None, 50 Red, 50 None and 50 Red) required only two doses and maintained normal glucose levels approximately five weeks after the final dosage. Referring to TABLE 8, animals were administered 40 mg doses of vanadate suspended in decocted black tea. As can be seen, one animal (55 Red) died from diarrhea. However, nine animals (52 Red, 52 None, 53 Red, 53 None, 54 Red, 54 None, 55 None, 56 Red and 56 None) required only two to three doses of the vanadate black tea mixture and maintained normal blood glucose levels for three to five weeks after the last dose.
  • animals were administered 50 mg doses of vanadate suspended in decocted black tea. As can be seen, three animals (44 None, 41 None and 40 None) died from diarrhea. Two others (41 Red and 44 Red) were usually responsive to vanadate but blood glucose levels increased after only a few days, necessitating several doses. However, five animals (40 Red, 42 Red, 42 None, 43 Red and 43 None) required only two to three doses of the vanadate black tea mixture and maintained normal blood glucose levels for three to five weeks after the last dose.
  • the mixture of vanadate and black tea produced the desired results at the low and medium vanadate concentrations (30 mg and 40 mg). That is, these doses stabilized blood glucose levels after only a few doses. Furthermore, there is considerably less variability in the results obtained compared to the water and vanadate mixture. Finally, the vanadate and black tea mixture had a low mortality rate as shown in FIG. 1 and increased weight gain, as shown in FIGs 2-4.
  • FIG. 1 plots survival against vanadate dosage.
  • suspension of the vanadate in either decocted black tea or decocted green tea results in increased survival compared with similar quantities of vanadate suspended in water. This clearly shows that the suspension of the vanadate in the decocted tea helps to overcome the side effects associated with vanadate administration.
  • FIGs 2-4 show weight gain over time of animals administered varying doses of vanadate suspended in water, decocted black tea or green tea.
  • animals administered vanadate suspended in water tended to gain weight at a rate very similar to the diabetic control.
  • animals administered vanadate suspended in decocted black tea or decocted green tea tended to gain weight at a rate more similar to that of wild type animals.
  • the plot of 30 mg (FIG. 2) and particularly 40 mg (FIG. 3) vanadate resuspended in black tea closely follows that of wild type. ,
  • FIGs 5-7 show blood glucose levels over time of animals administered varying doses of vanadate suspended in water, decocted black tea or green tea.
  • the doses of vanadate regardless of the carrier, caused blood glucose levels to decrease to approach normal levels.
  • doses of 40 mg or 50 mg vanadate suspended in decocted tea caused blood glucose levels to remain relatively constant at near wild type levels.
  • Sodium orthovanadate suspended in decocted black tea and vanadate suspended in water were administered separately to two groups of 14 streptozotocin-induced diabetic rats. Specifically, the administered dose was 40 mg vanadate per 2 ml. As can be seen in Figure 12, 11 of the 14 rats administered vanadate in water developed diarrhea and 1 of the 14 rats died. Conversely, none of the rats administered sodium orthovanadate in decocted black tea developed diarrhea.
  • FIG. 14 shows the number of weeks for which each of the 12 rats maintained normal blood glucose levels without further treatment. As can be seen, the length of time that blood glucose levels remained normal without further treatment varied from 5 weeks to 20 weeks in the rats, with a mean of 12 weeks.
  • sodium orthovanadate was suspended in decocted black tea or jasmine tea and the mixture was lyophilized. Specifically, in some experiments, 2.125 g of sodium orthovanadate was suspended in 600 ml of decocted black tea or jasmine tea, prepared as described above. The tea/vanadate solution was then placed in the freezer and frozen at -20°C for approximately 72 hours. The frozen mixture was then placed in a LabconcoTM lyophilizer for approximately 72 hours. The resulting powders were weighed and amounted to 5.1 g of black tea/vanadate and 4.5 g of jasmine tea/vanadate.
  • lyophilized jasmine tea/vanadate was prepared as described above to a dosage of 40 mg per 2 mis.
  • the mixture was administered to streptozotocin- induced diabetic rats and blood glucose levels were measured over time.
  • blood glucose levels dropped to normal levels, indicating that, as with the vanadate/black tea mixture, the lyophilization did not alter effectiveness. From this, it is evident that other known gastro-intestinal soothing teas may be utilized in the lyophilization process.
  • VANADATE STUDY PARAMETER 30mg Vanadate & Green Tea
  • VANADATE STUDY PARAMETER 40mg Vanadate & Green Tea
  • VANADATE STUDY PARAMETER 50mg Vanadate & Green Tea
  • VANADATE STUDY PARAMETER 30mg Vanadate & Black Tea
  • VANADATE STUDY PARAMETER 40mg Vanadate & Black Tea
  • VANADATE STUDY PARAMETER 50mg Vanadate & Black Tea

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Abstract

La présente invention concerne une composition permettant de réguler la glycémie. Cette composition à base de décoction de thé et de vanadate ne présente par les effets secondaires du vanadate à l'eau selon l'état antérieur de la technique. En l'occurrence, le vanadate en suspension dans la décoction de thé n'entraîne aucune diarrhée, et dans certains cas, stabilise la glycémie au niveau normal pendant plusieurs semaines seulement après quelques traitements.
PCT/CA2000/001281 2000-11-01 2000-11-01 Régulation de la glycémie WO2002036139A1 (fr)

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PCT/CA2000/001281 WO2002036139A1 (fr) 2000-11-01 2000-11-01 Régulation de la glycémie

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