US20190105293A1 - Formulation and method for the prevention and/or treatment of hangover symptoms - Google Patents

Formulation and method for the prevention and/or treatment of hangover symptoms Download PDF

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US20190105293A1
US20190105293A1 US16/087,563 US201616087563A US2019105293A1 US 20190105293 A1 US20190105293 A1 US 20190105293A1 US 201616087563 A US201616087563 A US 201616087563A US 2019105293 A1 US2019105293 A1 US 2019105293A1
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formulation
approximately
hangover
dose
pyridoxine
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Laurence Guy HOWES
Jan Beatrice QUINTON
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Phoenix Pharmaceuticals Australia Pty Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/009—Sachets, pouches characterised by the material or function of the envelope

Definitions

  • the invention relates to formulations and methods for the prevention and/or treatment of hangover symptoms associated with alcohol consumption.
  • Alcohol induced hangover also known as veisalgia
  • veisalgia is a syndrome comprised of a range of symptoms including nausea, headache, diminished concentration, malaise and/or tiredness, and a desire to consume greasy and/or fatty and/or oily foods (amongst others) that typically occurs the day following overindulgence in alcohol.
  • acetaldehyde plays a significant role [14, 15, 16, 17].
  • Alcohol is rapidly metabolized to acetaldehyde by the enzyme alcohol dehydrogenase. Acetaldehyde is then metabolized by aldehyde reductase to acetate.
  • Acetaldehyde+NAD + Coenzyme A ⁇ Acetyl-CoA+NADH+H + 2)
  • Acetate is excreted from the body via urine. However, when too much alcohol is consumed the body is overwhelmed and cannot effectively metabolize all the acetaldehyde that is being produced.
  • Alcohol induced hangover is responsible for a significant degree of morbidity in the community and it is responsible for a high level of loss of productivity due to absenteeism from work and poor work performance [10, 12, 15].
  • Pueraria lobata root (or Kudzu root) has been reported to antagonize aldehyde reductase (in a similar manner to the drug disulfiram) and to elevate serum acetaldehyde levels potentially producing a disulfiram like reaction.
  • disulfiram is prescribed for alcohol dependent persons because if they consume alcohol while taking disulfiram they experience very unpleasant adverse reactions such as flushing, nausea and headache which are features also seen in hangover.
  • elevations in plasma acetaldehyde may be carcinogenic [8, 9]. This is concerning.
  • hangover is due to a combination of factors including acetaldehyde accumulation, dehydration and the effects of congeners. Nonetheless, the inventors have found that there has been relatively few suitable studies done to properly determine the cause of, or treatment for, hangover symptoms for a wide variety of reasons, including because, for example, alcohol studies cannot meaningfully be carried out in a laboratory atmosphere (as that would not be indicative of the natural way alcohol is consumed), of ethical considerations, hangover is complicated, and of the possibility or probability of great variation in symptoms between individuals, to name a few.
  • the inventors have identified a novel formulation and method of administration that, in a suitable trial environment, have now been shown to provide a considerably greater effect than would be expected, or that could be expected of the currently available products researched by them in Australia.
  • a bout of excessive alcohol consumption is intended to mean an episode during which a person consumes a sufficient quantity of alcohol, such that his/her blood alcohol concentration reaches or exceeds 0.05 grams per 100 millilitres of blood, or, under all the circumstances, would reasonably be expected to reach or exceed or have reached or exceeded 0.05 grams per 100 millilitres of blood.
  • the episode of some preferred embodiments would typically (though not always) span a period of approximately 30 minutes to approximately 360 minutes. In some, perhaps more common, cases (and embodiments) the episode will last for approximately 120 minutes, or more.
  • Another factor that is likely to have a bearing on the length of such an episode is the gender of the person consuming alcohol. For example, to reach or exceed a blood alcohol concentration within approximately 120 minutes, a woman may need to consume approximately 4 standard drinks, while a man may need to consume approximately 5 to approximately 6 standard drinks.
  • Whether or not the amount of alcohol consumed is “excessive” within the meaning of the phrase “a bout of excessive alcohol consumption” is also dependent, in preferred embodiments, on several circumstances, factors and variables, including those mentioned above. Typically (though not always), “excessive” alcohol consumption would be, for example, the consumption by a women of approximately 6 to approximately 8 standard drinks over a period of approximately 360 minutes to approximately 480 minutes, and by a man of approximately 8 to approximately 12 standard drinks over approximately the same period of time.
  • the present invention provides a formulation for treating, preventing, ameliorating or alleviating in a patient symptoms of hangover, or of veisalgia, associated with a bout of excessive alcohol consumption, the formulation comprising:
  • the formulation further comprises a therapeutically effective amount of ascorbic acid, and in some of the same, and in some other, preferred embodiments, the formulation further comprises a therapeutically effective amount of glucose.
  • L-cysteine is included in the formulation in the range of approximately 20% to 40% w/w, more preferably, approximately 25% to 35% w/w, and more preferably still in the range of approximately 28% to 32% w/w. In some particularly preferred embodiments, L-cysteine is included in the formulation in a relative quantity of approximately 30.77% w/w.
  • thiamine is included in the range of approximately 0.3% to 4.9% w/w, more preferably, approximately 1.0% to 4.2% w/w, and more preferably still in the range of approximately 1.8% to 4.1% w/w.
  • the formulation of some particularly preferred embodiments provide that thiamine is included in a relative quantity of approximately 2.56% w/w.
  • pyridoxine is included in the formulation in the range of approximately 3.0% to 7.26% w/w, more preferably, approximately 4.2% to 6.06% w/w, and more preferably still in the range of approximately 4.9% to 5.36% w/w.
  • Particularly preferred embodiments provide that pyridoxine is included in the formulation in a relative quantity of approximately 5.13% w/w.
  • the ascorbic acid is included in the range of approximately 20% to 40% w/w, more preferably, approximately 25% to 35% w/w, and more preferably still in the range of approximately 28% to 32% w/w.
  • the ascorbic is included in a relative quantity of approximately 30.77% w/w.
  • the glucose is included in the range of approximately 20% to 40% w/w, more preferably, approximately 25% to 35% w/w, and more preferably still in the range of approximately 28% to 32% w/w.
  • the glucose is included in a relative quantity of approximately 30.77% w/w.
  • the L-cysteine is provided crystalline form, and in several such embodiments, it is provided as an anhydrous hydrochloride salt.
  • the thiamine included in preferred and alternative embodiments is provided in crystalline form, preferably as a hydrochloride salt.
  • the pyridoxine is provided in crystalline form, preferably as a hydrochloride salt.
  • glucose in crystalline form preferably as dextrose monohydrate.
  • the % w/w for each of the active ingredients equates to the following approximate quantities:
  • formulations further comprise one or more excipients, being excipients selected as suitable for the formulation manufactured for particular routes of administration.
  • the formulation does not contain any excipients.
  • the formulation of some embodiments further comprises one or more flavouring agents.
  • the flavouring agents are selected from the group consisting of one or more of Trusil Natural Orange 171063, Trusil Natural Lime flavour 169422, Trusil Natural Lemon flavour 168162, and Trusil Pineapple Hawaii 173920.
  • the flavouring agent is Trusil Natural Orange 171063.
  • the formulation does not contain any flavouring agents.
  • each active ingredient is provided as a powder.
  • all actives, excipients, and any flavouring agents are provided in powder form.
  • the formulation is provided as a blended powder.
  • the formulation can also be provided in other forms including one or more of those selected from the group consisting of dispersible granules, tablets, caplets, capsules containing the blended powder, forms suitable for rectal administration, in liquid forms prepared for oral or for intravenous administration, patches for transcutaneous administration, or forms suitable for nasal administration.
  • one or more doses of the formulation is/are provided in one or more sachets.
  • the present invention provides a product for use in the treatment, prevention, amelioration or alleviation in a patient of symptoms of hangover, or of veisalgia, associated with a bout of excessive alcohol consumption, the product comprising at least one sachet containing the formulation of the first aspect of the invention.
  • the product comprises at least two sachets, with each sachet containing one dose of the formulation of the first aspect.
  • the invention envisages that the product of preferred and of alternative embodiments may include several such sachets.
  • At least two sachets are tearably joined together along at least one edge of each sachet.
  • the tearable join can be created by any suitable means, including for example a plurality of adjacent perforations along a suitable tear line.
  • the product comprises several such sachets
  • the tear difficulty of the tearable joins can be varied.
  • the tear difficulty can alternate such that it is, for example, relatively easier to separate two sachets at a time from a length of sachets (than it would be to separate each sachet from a pair).
  • Such embodiments facilitate dispensing of the product in pairs of sachets.
  • Some of these embodiments are provided in the form of a reel, wherein the desirable number of sachets to be acquired can be dispensed by tearing the tearable join when the reel has been unwound sufficiently to expose the desired number of sachets.
  • join between sachet can also take any one of a number other forms that will enable the sachets to be separated from one another with relative ease.
  • the present invention provides a container adapted to store at least one of the products according to the second aspect.
  • the container is in the form of a box that takes the shape of a substantially rectangular prism and is adapted to contain several pairs of sachets. In such embodiments, the desired quantity of pairs of product can be dispensed relatively easily.
  • the upper half of the box in the shape of a substantially trapezoidal prism is removed, removable or not formed.
  • Such an embodiment permits a greater area of a pair of sachets to be seen at one end of the box than of the other end of the box.
  • Such embodiment is a preferred form of ‘point-of-sale’ container for the product.
  • the present invention provides a method of treating, preventing, ameliorating or alleviating in a patient symptoms of hangover, or of veisalgia, associated with a bout of excessive alcohol consumption, the method comprising:
  • the present invention provides a method of treating, preventing, ameliorating or alleviating in a patient symptoms of hangover, or of veisalgia, associated with a bout of excessive alcohol consumption, the method comprising:
  • the first dose is preferably taken immediately, or within approximately 5 to approximately 60 minutes after the last alcoholic beverage consumed during the bout. In alternative embodiments, the first dose is taken within approximately 5 minutes to approximately 240 minutes after the last alcoholic beverage consumed during the bout, more preferably within approximately 60 minutes to 180 minutes after the last alcoholic beverage consumed during the bout.
  • each dose is mixed in a glass of water, or in another beverage (preferably, other than one containing alcohol), and stirred into the drink.
  • the symptoms of hangover, or of veisalgia, treated, prevented, ameliorated or alleviated in a patient include one or more of the following symptoms: nausea, headache, diminished concentration, malaise and/or tiredness, and a desire to consume greasy and/or fatty and/or oily foods.
  • Other symptoms of hangover, or of veisalgia may additionally be treated, prevented, ameliorated or alleviated in a patient taking the formulation in therapeutic doses and/or in a therapeutic regime.
  • FIG. 1 is a schematic illustration of the metabolism of alcohol and the mode of action of l-cysteine.
  • FIG. 2 is a graphical representation of changes in reported wellbeing between active and placebo study days for individual subjects.
  • FIG. 4 is a schematic diagram of a sachet containing the active ingredients of a preferred embodiment of the invention.
  • FIG. 5 is a schematic diagram showing two sachets tearably joined together, with each sachet containing the active ingredients of a preferred embodiment of the invention.
  • FIG. 6A is a schematic diagram showing a container containing several sets of sachets as depicted in FIG. 5 .
  • FIG. 6B is a schematic diagram showing a container (which is has a different shape and configuration to that depicted in FIG. 6B ) containing several sets of sachets as depicted in FIG. 5
  • the inventors have developed a novel formulation which, for the purpose of trials undertaken described in the Example given below, has been named. CJ1484.
  • CJ1484 is a formulation comprised of vitamins and amino acids.
  • the ingredients are non-toxic dietary compounds that are essentially free from side effects.
  • the formulation is in a powder form. All active ingredients are readily absorbed through the gastrointestinal tract.
  • CJ1484 comprises the following active ingredients:
  • L-cysteine is an amino acid, one of the building blocks for proteins in humans. It was discovered in 1810 and found to be essential to the diet of humans. L-cysteine is produced in the body by the conversion from serine and methionine. It plays a crucial role in reversing oxidization in the liver partially due to conversion to glutathione. L-cysteine has been shown to enhance the breakdown and reduce the accumulation of acetaldehyde [4]. In addition, administration of L-cysteine to rats has been demonstrated to markedly reduce the mortality due to acetaldehyde poisoning [13, 14].
  • Thiamine vitamin B1 has been used in tablet form as a vitamin supplement over the last 70 years. Thiamine is on the World Health Organization's list of essential medicines. Thiamine was first documented in 1937 to be used for the treatment of beriberi (thiamine deficiency inducing heart failure). Thiamine is a water-soluble vitamin essential in all living organisms. There is currently no recommended dose however in western countries doses as low as 1 mg up to 500 mg have been used as a single dose [5].
  • Pyridoxine may have anti-nausea and anti-emetic activity. There is also some documented evidence that an analogue of pyridoxine may attenuate the toxicity of acetaldehyde [7].
  • Vitamin C Ascorbic acid was discovered in 1747. James Lind conducted the first clinical trial on 12 sailors using oranges and lemons for the treatment of scurvy. The treatment was successful. Since this time Vitamin C has been used as a common supplement to human diets. Unlike animals, humans cannot synthesize their own Vitamin C. Vitamin C is a highly effective antioxidant that contributes to the breakdown of acetaldehyde [2].
  • the dosage regimen adopted for the study is a preferred regimen that enables the active ingredients to be maintained at therapeutically effective levels while alcohol and acetaldehyde remain in the body during and following a bout of excess alcohol consumption [1].
  • Pre-clinical studies include the prevention of liver damage and death due to acetaldehyde intoxication in rats by active ingredients selected for the formulation [13, 14]. No studies of the formulation or its components have previously been performed in man.
  • the placebo was an equivalent mass of glucose alone.
  • a party atmosphere was created on each occasion for the under 40-year-old subjects who attended the site. They were provided with finger food, followed by a barbeque consisting of steak, sausages, potatoes, two different salads and bread rolls. Dessert was Pavlova cake and fruit salad. Throughout the evening chips and nuts were also available.
  • Entree was pumpkin soup.
  • the main meal consisted of baked lamb and ham, roasted vegetables and garlic bread.
  • Dessert was Pavlova cake and fruit salad, followed by after dinner mints and coffee.
  • Each subject was administered alcohol in the drink of their choosing over a four (4) hour period in a standard measured glass. Subjects could consume alcohol at the rate and quantity of their choosing to achieve an intake that they expected would lead to hangover symptoms. Each glass was counted and it was planned to attempt to achieve a mean alcohol intake for each subject of approximately 100 grams during the four (4) hour alcohol intake period. No subject was permitted to drink more than 200 grams of alcohol on a given study night.
  • the research staff mixed a first dose of the study compound and the placebo (2 grams of glucose was used for the placebo) into respective soft drinks adopting a code to ensure that neither they nor the subjects knew whether the subjects were taking the study compound or the placebo.
  • the research staff provided each subject a blinded dose.
  • a second blinded dose (prepared in the same way as the first blinded dose) of each of the study compound and placebo were mixed and given to each subject to consume any time between no less than 4 and no more than 10 hours after the first blinded dose (for example, if they wake during the night).
  • Subjects remained at the site overnight. After awakening the following morning, they were provided with breakfast consisting of cereal, yoghurt, fresh fruit, eggs, bacon and toast. Subjects made their own choices.
  • the subjects were contacted by telephone after their second study day and asked to rate how they compared their two study days using a score between 0 and 10 after each of the study alcohol intake periods: 0 was feeling extremely poorly and 10 was extremely good. This sense of well-being was the primary endpoint of the study.
  • Randomization was performed in blocks of four by an independent person not connected to the trial.
  • Active and placebo were measured into clear plastic resealed bags containing the appropriate number of grams of product or matching placebo. Two of these bags (active or placebo) were placed in an envelope and numbered. Each subject was provided with one envelope on each night of the trial. All product was kept in a locked cupboard. The preparation of the resealed bags and their placement in numbered envelopes was performed by the independent person who organised the randomization code and who held the randomization code until the study was completed.
  • the primary end point was to show that the compound improved general well being assessed by recollection of the two study periods, after each period had been completed. Secondary endpoints were the results of the visual analogue scales filled in the day after each study evening. Differences between study days for the visual analogue scales were analyzed using Student's Paired T Test for paired data. The primary end point was also analyzed using Student's Paired T Test for paired data. The reason for using Student's Paired T test for paired data in this study was because the number of points in each data set were at the same time and were organized in pairs in which there is a definite relationship between each pair of data points.
  • the mean age of the patients was 47.7 years ⁇ 14.3 years (range 21 to 72 years).
  • the mean alcohol intake during the active phase of the study was 108 grams ⁇ 31 grams.
  • the mean alcohol intake during the placebo phase of the study was 104 grams ⁇ 35 grams
  • This table shows that the average active score was 8.0 out of 10 with an above or below error of 0.92.
  • the placebo score showed 3.47 out of 10 with an above or below error of 1.09. This table demonstrates that when taking CJ1484 the subjects' well-being was statistically greater than when only taking placebo.
  • the improvement in the primary endpoint on active compared to placebo was 177%.
  • Subjects were asked to place a cross (X) on the lines to best represent how they were feeling the following morning. This line is 100 millimeters, 0 being no side effects, 100 being illness. The location of each cross is then measured. In the above example, nausea would receive a score of 22, this is then calculated for both treatment days for each subject and then all subject data is pooled to arrive at a mean (or average) for all subjects with an above and below error ( ⁇ ) scored in millimeters.
  • the results in table 2 illustrate the reported outcomes by the subjects.
  • the first column shows the five secondary outcomes the study considered.
  • the second and third columns give the scores in millimeters for the two treatments.
  • the last column shows the p value (measure of statistical significance) for each symptom.
  • This table as in table 1 shows the variation of the results between the different volunteers expressed as the SEM (standard error of the mean). The SEM becomes smaller as the number of people studied increases. It is an estimate of the true difference of the result between active and placebo if the entire population was studied.
  • I-cysteine by activating glutathione and accelerating acetaldehyde breakdown, aids in the prevention of acetaldehyde accumulation over the resultant genesis of hangover symptoms.
  • the secondary end points were essentially chosen as a breakdown of the primary endpoint.
  • the major complaints from subjects who suffer from hangover were chosen eg: nausea, headache, sleep deprivation, concentration and the desire for greasy/fatty (oily) foods the following day.
  • the present invention of particularly preferred embodiments also provides a product for use in the treatment, prevention, amelioration or alleviation in a patient of symptoms of hangover, or of veisalgia, associated with a bout of excessive alcohol consumption, the product comprising at least one sachet containing the formulation according to the invention.
  • FIG. 4 depicts a sachet made according to a preferred embodiment of the invention.
  • a small notch (no numbered) to the upper-left corner of the sachet (as presented) is provided to facilitate a user opening the sachet to access its contents, or more specifically to enable a user to readily empty the content into, for example, a beverage.
  • the product comprises at least two sachets, with each sachet containing one dose of the formulation.
  • a representation of one such embodiment is depicted in FIG. 5 .
  • a dotted line drawn between the two sachets illustrates a preferred form of tearable join between them.
  • the present invention also provides in particularly preferred embodiments a container adapted to store at least one of the product forms described above.
  • the container is in the form of a box that takes the shape of a substantially rectangular prism and is adapted to contain several pairs of sachets. In such embodiments, the desired quantity of pairs of product can be dispensed relatively easily. This embodiment is depicted in FIG. 6A .
  • the upper half of the box in the shape of a substantially trapezoidal prism is removed, removable or not formed. As depicted in FIG. 6B , such an embodiment permits a greater area of a pair of sachets to be seen at one end of the box than of the other end of the box. Such embodiment is a preferred form of ‘point-of-sale’ container for the product.
  • the present invention provides a method of treating, preventing, ameliorating or alleviating in a patient symptoms of hangover, or of veisalgia, associated with a bout of excessive alcohol consumption, the method comprising:
  • the first dose is preferably taken immediately, or within approximately 5 to approximately 60 minutes after the last alcoholic beverage consumed during the bout.
  • each dose is mixed in a glass of water, or in another beverage (other than one containing alcohol), and stirred into the drink.
  • the second dose is likely to be taken during arousal of a sleep after the bout. Accordingly, it is recommended that the second dose be prepared and left near the bed, for example on the patient's bedside table so that when s/he reaches for a drink throughout the night, the drink consumed contains the second dose. However, the second dose may also be taken after the patient has awoken from a full night's sleep.

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US20220265600A1 (en) * 2019-06-14 2022-08-25 The Trustees Of Princeton University Formulations of dihydromyricetin and a permeabilizer

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US20210220313A1 (en) 2021-07-22
WO2017161402A1 (en) 2017-09-28
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EP3432875A1 (de) 2019-01-30

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