COMPOSITIONS, KITS, AND METHODS TO PROVIDE SYNERGISTIC AND/OR ADDITIVE EFFECTS FROM COMPRISED INGREDIENTS FOR THE PREVENTION, TREATMENT AND MANAGEMENT OF NAUSEA AND VOMITING

TECHNICAL FIELD

[01] The present invention relates to compositions, kits and methods for the prevention, treatment and management of nausea and vomiting with a known or unknown underlying cause, including but not limited to pregnancy, motion sickness, drug use, alcohol use, gastroenteritis, polycystic ovary syndrome, anti-cancer treatment and surgery.

BACKGROUND ART

[02] As used herein, ‘nausea’ refers to a sense of an urge to vomit, while ‘vomit’ is the oral expulsion of the gastrointestinal content. Nausea and vomiting (NV) could be acute or chronic. Nausea and vomiting are symptoms of an underlying condition such as pregnancy, motion sickness, drug use, alcohol use, gastroenteritis, polycystic ovary syndrome (PCOS), anti-cancer treatment and surgery. Nausea and vomiting are an outcome of stimulation of receptors in the CNS and gut through various mechanisms.

[03] Nausea and vomiting in pregnancy referred herein as NVP could be frequent or infrequent and may even last throughout the pregnancy in some women. It could be mild or severe to the extent that it may require frequent pharmacological and/or non-pharmacological interventions. Severe NVP is known as hyperemesis gravidarum and may require treatment in the hospital. Pathophysiology of NVP are hormones, neurotransmitters and receptors mediated.

[04] Drugs can trigger nausea, and/or vomiting in some patients, and it is subjective. Besides anticancer drugs, some other drugs may induce NV in some patients. Commonly known drugs that cause NV include anti-depressants, opioids, anti-inflammatories, contraceptives, hormone replacement therapy (HRT) drugs and anti-psychotics. Drug-induced NV generally occurs when new drug treatment is initiated and often goes away after several days of continuation of the drug. In some conditions, medication is necessary to prevent, treat and manage NV associated with a drug. Withdrawal of some medication can also cause NV. [05] Alcohol in excess amount is a toxin for the body. Alcohol breaks down into acetaldehyde in liver and this process produces harmful chemical which causes inflammation in the gastrointestinal tract and could result into nausea or vomiting. Untreated vomiting can cause dehydration.

[06] Motion sickness, as the word describe, is the feeling of being sick because of a motion. Receptors in the CNS and gut are activated when the body struggles to adjust with the motion; the brain receives conflicting information from the inner ears, eyes and nerves. Common symptoms of motion sickness are nausea with or without vomiting. Travel sickness, seasickness, airsickness, train sickness are types of motion sickness. It can also be caused by swinging, bumping, rotation, deceleration movement and various reasons.

[07] Gastroenteritis is the gut inflammation caused by the virus, bacteria, fungi, parasites, toxins or drugs, sometimes referred as ‘stomach bug’, stomach flu or food poisoning. Besides nausea and vomiting, diarrhoea, stomach cramps, fever, and headaches are also symptoms of gastroenteritis.

[08] In Polycystic ovary syndrome (PCOS), levels of an amino acid named homocysteine remain high. High levels of homocysteine increase inflammation, oxidative stress and increase the risk of atherosclerosis and thrombosis. In addition, high homocysteine level causes nausea, vomiting and fatigue. Vitamin B6 plays an essential role in the breakdown of homocysteine.

[09] Chemotherapy-induced nausea and vomiting (CINV), also known as anti-cancer treatment induced nausea and vomiting (AINV), is triggered with various types of anti-cancer treatment. NV from anti-cancer treatment is mediated via CNS and gut neurotransmitters. AINV is anticipated in nearly all patients and is addressed by the oncologist.

[010] Nausea and vomiting related to surgery also known as Post-Operative Nausea and Vomiting (PONV), can occur due to exposure of drugs during the operation. Commonly used drugs during the operations are anaesthetics, opioids etc. In addition, fear to undergo the operation and uncertain outcomes of the operation can induce NV in some patients. Overall, PONV is the outcome of the interaction between the brain and gastrointestinal tract. Pathophysiology of PONV involves chemical interaction between vomiting centres, chemoreceptor trigger zone (CTZ) and middle ear.

[Oil] Regardless of the underlying cause, all forms of NV impact quality of life, and in the case of anti-cancer treatment, it may affect treatment plans, and/or the patient’s willingness to undergo or continue the treatment. In addition, severe vomiting can lead to dehydration. Hence, all forms of NV should be addressed appropriately and on time with available treatment options. The availability of pharmaceutical products varies worldwide, which further affects treatment selections by the health care professional.

PRIOR ART

[012] US patent no. 20070048367 relates to a herbal composition for treating morning sickness and includes a mixture of vitamin B6, folic acid, ginger root extract, and red raspberry leaf.

[013] US patent no. US20170049759 & EP patent no. EP3337480 relates to transdermal delivery of doxylamine and pyridoxine. The formulation includes doxylamine or its salts, pyridoxine or its salts or its active metabolites, and a vehicle system wherein pharmaceutical compositions are liquid formulations, semisolid formulations, and polymer matrices for treatment of nausea and vomiting in general and pregnant women in particular.

[014] WO patent no 2000066082 & AU patent no. 2000049779 relates to anti-nausea compositions and methods. It discloses novel nutritional anti-nausea compositions, anti-emetic compositions, and methods of using the same. The compositions comprise a vitamin B6 compound or derivative thereof; an alkaline buffering agent, an acceptable coating agent; and wherein the vitamin B6 compound or derivative thereof is separated from the alkaline buffering agent by the said acceptable coating agent.

[015] US patent no. 6340695 relates to a rapid onset formulation, preferably in the form of an enteric- coated tablet, for a medicament comprising a synergistic duo of active ingredients, namely, doxylamine succinate and pyridoxine HC1, for the treatment of nausea and vomiting, especially, but not limited to, during pregnancy.

[016] US patent no. 20140314680 relates to a dual release oral dosage system/dosage form comprising an immediate release component/composition and a delayed-release component/composition comprising one or more of doxylamine, an analog thereof, a derivative thereof, a prodrug thereof, a metabolite thereof and/or a salt thereof, and one or more of pyridoxine, a salt thereof, a metabolite thereof and/or a salt of the metabolite for the prevention and/or treatment of nausea and vomiting in pregnancy (NVP).

[017] US patent no. 20140335176 relates to a delayed release formulation containing doxylamine succinate and pyridoxine hydrochloride as the active ingredients in a disintegrant-free formulation and processes for manufacturing the same.

[018] US patent no. 20160058709 relates to plurimodal release formulation of metabolites and salts of doxylamine and pyridoxine. The patent covers the formulation with these active ingredients as component of enteric coating within the enteric-coated formulation comprising these active ingredients.

[019] Indian patent no. 202021002251 relates to a solid oral composition of doxylamine succinate, pyridoxine hydrochloride in combination with ginger powder as a natural extract as synergistic additive. It provides the solid oral composition in the form of granules/powder filled into sachets or compressed into tablets, especially chewable tablets for the treatment of nausea and vomiting.

[020] US patent no. 20110280976 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.

[021] US patent no. 20110028436 relates to oral combination of vitamins for treating and preventing nausea and other disorders. The compositions comprise vitamins as active ingredients, including vitamin B6 and its metabolites, vitamin K, and vitamin C, and a method for treating nausea or morning sickness with the oral compositions.

[022] US patent no. 20130171279 relates to composition for reducing side- and after-effects of cancer treatment. It includes three core components: whey protein, hepatoprotectant and/or nephroprotectant agents and, anti-emetic agent(s) such as ginger and/or peppermint.

[023] US patent no. 20100291057 relates to a composition for reducing oxidative stress and/or side effects occurring during cancer chemotherapy or improving a nutritional status during cancer chemotherapy. The composition comprises the following components (a) to (f): (a) an antioxidant agent; (b) at least one component selected from the group consisting of vitamin Bl, vitamin B2, vitamin B6, niacin, and pantothenic acid; (c) at least one component selected from the group consisting of folic acid, vitamin B12, and vitamin A; (d) zinc; (e) selenium; and (f) coenzyme Q10.

[024] WO patent no. 1986002553 is a nasal administration of known anti-nausea and anti-emetic therapeutic agents and dosage forms which discloses the use of selected antihistamines, anticholinergics, piperazines, phenothiazines, substituted butyprophenes and metoclopramide.

[025] US patent no. 4624965 relates to novel method of administering anti-nausea and anti-emetic agents and to novel dosage forms which includes the use of brompheniramine, promethazine, cyproheptadine, dimenhydrinate, meclizine, cyclizine, chlorcyclizine, buclizine, trimethobenzamide, benzquinamide metoclopramide, diphenhydramine, doxylamine, methapyrilene and tripelennamine for nasal administration. [026] US patent no. 20200113856 relates to a compounded non-prescription medication for the treatment of motion sickness. The medication comprises: at least one analgesic selected from the group consisting of acetaminophen, ibuprofen, naproxen and salicylates; at least one histamine H2-receptor antagonist selected from the group consisting of nizatidine, famotidine, cimetidine, ranitidine, famotidine; and at least one antacid selected from the group consisting of calcium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, and bismuth subsalicylate. It may optionally comprise at least one additional ingredient selected from the group consisting of spearmint extract and ginger extract.

[027] US patent no. 08137709 relates to fast-acting nausea formula which comprise of ginger root, gelatin, a fruit flavouring, and mint.

[028] CN patent no. 106492159 relates anti-motion sickness drug which discloses the use of fresh ginger, fructusamomi, orange peel, chrysanthemum, and wild jujube.

[029] Sedative antihistamines such as doxylamine, promethazine, dexchlorpheniramine, cyclizine, diphenhydramine, dimenhydrinate is present in several products. Many formulations are available containing metoclopramide, prochlorperazine, ondansetron, and are used worldwide for NV.

[030] Vitamin B6 is included in treatment guidelines by several health authorities worldwide to prevent, treat, and manage NVP. In addition, a product called Elevit morning sickness tablets containing vitamin B6, and ginger is available without prescription in Australia and is being marketed for NVP.

[031] A fixed-dose combination of doxylamine succinate (20mg) and vitamin B6 (20mg pyridoxine hydrochloride) is being marketed under the brand name Bonjesta® in the USA for the management of NVP in women who have not improved with the change in diet or other non-medicine treatments.

[032] Diclectin®, a combination of 10 mg doxylamine succinate and 10 mg vitamin B6 (pyridoxine hydrochloride) in a delayed-release tablet formulation, is available in Canada for women who have not benefited from the other therapies.

[033] Anti-emetics currently used for AINV include dopamine receptor antagonists such as metoclopramide, prochlorperazine, promethazine and haloperidol; serotonin (5HT3) receptor antagonists such as granisetron, ondansetron, palonosetron, tropisetron; neurokinin- 1 receptor antagonists (NK1 RA) such as aprepitant, netupitant. Other anti-emetics used in AINV are dexamethasone (a steroid), olanzapine (for their inhibitory effects on 5HT3 and dopamine receptors) and cannabinoids (not commonly used). Combination treatment options for AINV currently available contain netupitant (NK1 receptor antagonist) and palonosetron (5HT3 antagonist) - marketed under the brand name akynzeo.

[034] Products containing scopolamine named hyoscine hydrobromide are currently available as a single ingredient under the brand name Kwells® and Travacalm HO®. In addition, Hyoscine combined with dimenhydrinate (sedative antihistamine) is available under the brand name Travacalm Original® to prevent and treat motion sickness.

[035] Doxylamine succinate 25 mg is available as ‘Pharmacist Only Medication’ for the temporary relief of insomnia or sleeplessness.

PROBLEMS IN PRIOR ART

[036] The present invention is an improvement over the prior art in that it delivers the compositions, kits, and methods for the prevention, treatment, and management of NV via the pharmacological actions of the comprised ingredients into multiple pathophysiological mechanisms involved.

[037] Currently, available treatment options for nausea and vomiting are relatively more expensive to the patient, not easily accessible, and have poor product availability.

ANTIHISTAMINE

[038] Prior-art (Restavit , Phenergan , Polaramine ) products with only sedative antihistamine as anti-emetic ingredient increase sedation when administered at higher doses to achieve a higher antiemetic effect. The present invention provides compositions, kits, and methods that do not have the same disadvantage because these compositions achieve a higher anti-emetic effect with the lower dose of antihistamine via synergistic and/or additive effect of other comprised ingredients. Unlike other prior arts, the present invention also provides compositions, kits and methods that enable the use of sedative antihistamines when sleep is desirable.

[039] Prior art (Restavit®, Phenergan®, Polaramine®) products containing sedative antihistamine are ‘Pharmacist Only Medicine’. These products either do not have treatment of NV as an approved indication or has a warning statement on the packaging indicating possible harm if used during pregnancy ¹ . Hence, the refusal by the pharmacist for the supply of these products for the treatment of NVP is common.

[040] No commercial product exists in Australia with a dose of doxylamine less than 25mg. It is being marketed only for ‘temporary relief of sleeplessness’ with warnings on the product packaging indicating safety concerns when used during pregnancy though doxylamine is listed as a category A drug ² ’ ³ .

[041] Prior art product containing doxylamine provides this sedative antihistamine at a higher dose of 25mg only. Therefore, the patient requires to cut the tablet in half to obtain a lower dose. The present invention, however, provides a lower dose of this antihistamine.

[042] Unlike other prior art, the present invention provides compositions with both short and long- acting antihistamines. Compositions of the present invention comprising long-acting antihistamines like promethazine are useful when sedation for 8 hrs or more is desired, whereas a composition comprising dexchlorpheniramine or other short-acting antihistamines is helpful when sedation for more than 6 hrs is to avoid.

[043] Even after several decades since the Debendox was withdrawn from the Australian market, there is no product in Australia with similar composition, and Australian women are being denied safe and effective treatment for NVP ⁴ , ⁵ .

[044] Products containing sedative antihistamine as a single ingredient are not always the treatment option for all patient following their accessibility issues and concerns over adverse effects.

[045] The present invention alleviates the need for caffeine which is included in a prior art (Travacalm original ) to counterbalance the sedative effect of sedative antihistamine. The present invention achieves this objective by not solely relying on sedative antihistamine to provide the antiemetic effect. Instead, the present invention provides compositions, kits, and methods comprising one or more (activated and/or one or more inactivated) forms of vitamin B6 and ginger (in standardised and/or non-standardised forms) to achieve the anti-emetic effect.

VITAMIN B6

[046] NV is one of the symptoms of deficiency of vitamin B6. Vitamin B6 plays a vital role in the nervous system, metabolism pathways of NV. The body does not store vitamin B6, so people need to get from their daily diets ⁶ . Pyridoxal 5 ’-phosphate, pyridoxine 5’ phosphate, and pyridoxamine 5’ phosphate are activated forms of vitamin B6 ; and are also known as P5P or PLP, PNP, PMP, respectively. The conversion process from the inactive to the active form of vitamin B6 is enzyme- dependent ’ . Following the prevalence of relevant enzyme deficiencies, this conversion process does not occur the same way in all individuals. During pregnancy, because of hormonal changes and foetus demand, the level of vitamin B6 reduces. Activated and inactivated forms of vitamin B6 levels are affected in patients with impaired liver functions ¹⁰ . Activated vitamin B6 levels are lower in a patient with Methylenetetrahydrofolate reductase (MTHFR) gene deficiency

[047] An activated and inactivated form of vitamin B6 may be a more efficient therapy for morning sickness . Addressing underlying deficiency of vitamin B6 would result in better outcome compared to only managing the symptoms of NV using pyridoxine hydrochloride (an inactivated form of vitamin B6) and/or sedative antihistamine and/or 5H3 receptor antagonist comprised in other prior art products which do not contain an activated form of vitamin B6. Research suggests that the activated form of vitamin B6 is better anti-emetic than the inactive form of vitamin B6 for the management of NV ¹⁴ . The present invention provides compositions, kits, and method that addresses this underlying cause better than other prior art (Elevit Morning Sickness Relief®’Pyridox®) products.

[048] There is no product with an approved indication comprising an activated form of vitamin B6 for the prevention, treatment, or management of NV. The present invention provides compositions, kits, and methods that make the activated form of vitamin B6 readily available. Hence it is more helpful for the prevention, treatment, and management of NV.

GINGER

[049] The chemical constituents of ginger vary significantly with species and geographical source ¹⁵ . Also, all constituents of ginger do not have identical biological and physiological properties ¹⁶ , ¹⁷ . Ginger is dried using different drying methods, and the chosen method impacts the constituents of the product at the end . The anti-emetic properties of ginger are mainly due to active constituents from groups called ‘gingerols’ and ‘shogaols’ ¹⁹ . Hence the therapeutic effect of all products containing ginger in non-standardised forms cannot be assumed the same.

[050] Several prior art (Travacalm original®) products contain such ‘non-standardised forms of ginger. However, there is no commercial product in Australia containing ginger in standardised forms.

[051] Volume after the extraction of gingerols and shogaols required to achieve the anti -emetic effect is much lesser than the volume of raw ginger powder containing the same amount of gingerols and shogaols. The present invention provides compositions comprising gingerols and shogaols in standardised forms, thereby provide unit doses with smaller volume, which would be hard to administer otherwise. [052] The present invention provides scientifically identified anti-emetic ingredients of ginger in therapeutic doses. Compositions comprising such ingredients are more likely to be accepted and recommended by health care practitioners compared to ‘raw’ ginger present in prior art products.

GUIDELINES/PRODUCT LABELLING ISSUES

[053] Inconsistencies persist between guidelines accessed by GP, hospital doctors and, interpretation of the approved Indications and warnings on packaging, for management of NV by pharmacists. In Australia, pharmacists are hesitant to supply scheduled OTC products containing ingredients with anti-nausea or anti-emetic properties because these OTC products are not approved for the management or treatment of nausea or vomiting .

HEALTHCARE COST

[054] Cost for the government to avail the treatment for NV increases when patients are required to attend Medicare subsidised appointments to see doctors. Often such appointments are just needed to obtain prescriptions for anti-emetic medications because of scheduling of anti-emetics and/or to avail ‘off label’ use of OTC anti-emetic treatment options. This situation makes it hard to access anti-emetic products and increases avoidable use of healthcare resources that could have been diverted to manage more complex medical conditions of the population.

[055] The present invention also provides compositions, kits, and methods without scheduled ingredients. These embodiments achieve anti-nausea and anti-emetic effects via constituents of ginger (in standardised and/or in non-standardised forms) and vitamin B6 (activated and/or inactivated forms) only. By providing compositions, kits, and methods comprising ginger (standardised and/or non-standardised forms) and vitamin B6 (activated and/or inactivated forms) only, the present invention makes anti-emetic treatment options more accessible (without the intervention of a pharmacist or a doctor) to patients. Hence, it also reduces the health care cost of the government.

[056] Schedule 4 treatment options such as 5HT3 antagonists are expensive and subsidised by Pharmaceutical Benefits Scheme (PBS) only for the management of AINV. For example, cost to the patient for 10 tabs of 8 mg Ondansetron is $32.19 ²¹ , the cheapest 5HT3 antagonist available under

PBS. COMBINATIONS

[057] NV involves multiple pathophysiological mechanisms. Unlike other prior art products listed above, the present invention comprises multiple anti-emetic ingredients to provide additive and/or synergistic effects by acting on more than one pathophysiological mechanism.

[058] Unlike prior art compositions, the present invention provides compositions comprising standardised ginger and sedative antihistamines that target receptors present in both the CNS and gut.

[059] Some people do not endorse and/or suggest using anything that is not ‘organic’ and/or ‘natural’. The present invention also provides compositions comprising one or more activated forms and/or one or more inactivated forms of vitamin B6 and/or ginger in standardised or in nonstandardised forms, which would suit better to such population.

[060] In Australia, there is no commercial product available for the prevention, treatment and management of NV comprising:

(A) ginger in standardised forms with or without ginger in non-standardised forms.

(B) Doxylamine in less than 25mg with or without approved treatment indication for NV.

(C) (i) one or more activated forms of vitamin B6 with or without one or more inactivated forms of vitamin B6 and, (ii) ginger in non-standardised forms and/or ginger in standardised forms.

(D) (i) one or more activated forms of vitamin B6 and/or one or more inactivated forms of vitamin B6 and, (ii) one or two sedative antihistamines.

(E) (i) ginger in non-standardised forms and/or ginger in standardised forms and, (ii) one or two sedative antihistamines.

(F) (i) one or more activated forms of vitamin B6 and/or one or more inactivated forms of vitamin B6 and, (ii) ginger in non-standardised forms and/or ginger in standardised forms, (ii) one or two sedative antihistamines.

(G) (i) one or more inactivated forms of vitamin B6 and, (ii) ginger in standardised forms with or without ginger in non-standardised forms.

[061] Uncomplicated NV does not always require attention from the doctor. Uncomplicated but uncontrolled NV leads to hospitalisations which increases the use of healthcare resources. Regardless of the underlying cause, NV increases socioeconomic cost and reduces the productivity of patient. A study concluded that the NVP often remains untreated or undertreated. The present invention provides choices of anti-emetic compositions, kits, and methods to suit various patient populations.

[062] There was need to develop novel pharmaceutical compositions, kits, and methods comprising multiple ingredients to avoid adverse effects of one ingredient that would occur when a higher dose of one anti-emetic ingredient is administered to achieve the higher anti-emetic effect. The present invention addresses this need by including multiple ingredients.

[063] The present invention has the advantage of providing flexibility to a subject experiencing NV to have a composition that treats NV at a time when a sedative or calmative effect is not required or to be avoided. For example, during work hours, when operating a machine or when attending to dependents, but also provides a composition that treats NV that further includes a sedative or calmative for assisting the subject to relax or fall asleep.

SUMMARY OF INVENTION

[064] The objective of the present invention is to achieve anti-nausea and anti-emetic effects via the actions of comprised ingredients on multiple pathophysiological mechanisms. The present invention provides compositions, kits, and methods that deliver anti-nausea and anti-emetic effects from at least two of the pharmacological approaches below: a. Suppressing receptors in the gastrointestinal tract, b. Suppressing receptors in the central nervous system (CNS), c. Reduction in oxidative stress (antioxidant properties), d. Addressing underlying vitamin B6 deficiency.

[065] Core ingredients of the present invention provide anti-nausea and anti-emetic properties by working on the same or different aspect of the pathophysiology of nausea and vomiting. Core ingredients of the present invention are; a. inactivated form(s) of vitamin B6, b. activated form(s) of vitamin B6, c. ginger in non-standardised forms, d. ginger in standardised form(s), e. sedative antihistamine(s). [066] Vitamin B6 delivers anti-nausea and anti-emetic effect by reducing oxidative stress and 22 23 24 addressing underlying vitamin B6 deficiency ’ ’ . Vitamin B6 is one of the most central molecules in cellular metabolism. Nausea and/or vomiting can be a symptom of vitamin B6 deficiency because of various underlying reasons at the cellular level. Role of vitamin B6 extends to several metabolism processes.

[067] Vitamin B6 levels are reduced during the pregnancy, and hence vitamin B6 is helpful to

25 26 27 manage the NVP . Vitamin B6 is useful treatment option in other forms of nausea too. ’

[068] Amino acids are the building blocks of protein. Active co-enzyme or phosphorylated or also referred herein as the activated form of vitamin B6 plays the crucial role in the biosynthesis and degradation of amino acids. Neurotransmitters are required for communication in-between nerve cells and between nerve cells and other cells. Synthesis of these neurotransmitters requires enzymes. These enzymes use vitamin B6 as co-enzymes.

[069] Activation of vitamin B6 from an inactivated form is enzyme dependent. Considering the underlying cause of nausea, for some patients activated form of vitamin B6 could be more useful than the inactivated form of vitamin B6 or vice versa. The present invention provides compositions comprising one or more activated forms of vitamin B6 with or without one or more inactivated forms of vitamin B6.

[070] Pyridoxal 5'-phosphate (P5P) increases antioxidant enzyme activities in post-surgery patients . P5P breaks down homocysteine and hence helps to improve nausea related to PCOS. Vitamin B6 plays positive role in glutathione reductase dependent antioxidant system and provides defence against free radicals . Alcohol consumption increases oxidative stress and is primary cause of nausea related to alcohol use. Oxidative stress contributes to inflammation of GI tract during gastroenteritis. Hence managing inflammation would help to manage nausea related to gastroenteritis.

[071] Ginger delivers anti-nausea and anti-emetic effect by suppressing receptors in the gastrointestinal tract and in the central nervous system (CNS) , and by reducing oxidative stress.

[072] The present invention delivers embodiments comprising ginger as in standardised and nonstandardised forms. Pharmacological actions in both the forms of ginger are from the constituents of ginger. Some constituents of ginger act on receptors in GI tract whereas some on the receptors of the CNS . Considering the cost and underlying cause of nausea, ginger in standardised forms may be more suitable than non-standardised forms or vice versa. [073] Anti-cancer treatments triggers chemoreceptor trigger zones and results in higher expression of 5HT receptors ³ **. Hence antagonism of 5-HT receptors results in anti-nausea and anti-emetic effects. Research indicates that constituents of ginger have 5HT3 antagonistic activity . Constituents of ginger with smaller molecular weight such as 6-gingerol, 8-gingerol and 6-shogaol can penetrate the blood brain barrier ³⁶ .

[074] In addition, the ginger (and its constituents) acts peripherally, within the gastrointestinal tract, by increasing the gastric tone and motility due to anticholinergic and anti-serotonergic actions mainly due to action on serotonin (5-hydroxytryptamine, 5-HT3, and 5-HT4) and cholinergic (M3) receptor activities.

[075] Gingerol also has powerful anti-inflammatory and antioxidant effects and may help to reduce oxidative stress, which results from an excessive amount of free radicals in the body. Gingerols and shogaols have higher antioxidant properties .

[076] Sedative antihistamines deliver anti-nausea and anti-emetic effects via suppression of Hl receptors in the CNS and gut. Sedative antihistamines can also cross the blood brain barrier (BBB). Sedative antihistamines’ anti-nausea and anti-emetic effects are from their actions on receptors of vomiting centre after crossing the blood brain barrier, receptors of CTZ (also known as area postrema or AP) without crossing the BBB and receptors of the gut. Some sedative antihistamines have anticholinergic properties and ability to block muscarinic receptors in the CNS and gut. The sedating antihistamines also have a calmative, relaxant, and muscle relaxant properties.

[077] The sedating antihistamines used herein have an anti-emetic effect and are particularly useful for treating nausea and vomiting related to pregnancy, drugs induced, alcohol induced, motion sickness, gastroenteritis, PCOS, anti-cancer treatment and surgery. ³⁸ ’ ³⁹ ’ ⁴⁰ ’ ⁴¹ ’ ⁴² '

[078] CTZ, also known as area postrema (AP) is located outside the blood brain barrier, within the dorsal surface of medulla oblongata, on the floor of the fourth ventricle of the brain. Emetic agents in the blood are detected by the receptors present in the CTZ which induces vomiting. The present invention provides compositions with ingredients that acts on receptors of CNS including receptors of CTZ (without crossing the BBB), receptors of vomiting centre (after crossing the BBB).

[079] Chemoreceptor trigger zone (CTZ) contains dopamine (D2), serotonin (5-HT3), muscarinic (Ml), histamine (Hl), opioid and NK1 receptors. Vestibular centre contains histamine (Hl) and muscarinic (Ml) receptors, serotonin (5-HT3), dopamine (D2) and NK1 receptors. Vomiting centre contain serotonin (5-HT3) and muscarinic (Ml) receptors. GI track nerves (and other periphery nerves) contains serotonin (5-HT3), dopamine (D2) and NK1 receptor.

[080] The present invention delivers synergistic and/or additive anti-nausea and anti-emetic effects by combining Hl receptor antagonists (sedative antihistamines), muscarinic receptor antagonists (promethazine, doxylamine, diphenhydramine, dimenhydrinate, (6)-gingerol, (8)-gingerol, (10)- gingerol, and (6)-shogaol), dopamine receptor antagonists (promethazine, dimenhydrinate), cholinergic receptor antagonists (promethazine, cyclizine, dexchlorpheniramine, dimenhydrinate), 5-HT antagonists (promethazine, (6)-gingerol, (8)-gingerol, (lO)-gingerol, and (6)-shogaol), Neurokinin 1 (NK1) antagonists ((6)-gingerol, (8)-gingerol, (lO)-gingerol, and (6)-shogaol), and antioxidants (activated and inactivated B6, gingerols, shogaols, paradols).

[081] In an aspect, the present invention relates to a pharmaceutical composition for the prevention, treatment, and management of nausea, vomiting, or combination thereof, comprising:

(a) a ginger extract containing gingerols, shogaols, paradols, or combination thereof,

(b) pyridoxal 5 ’-phosphate,

(c) one or more sedative antihistamine(s), and

(d) excipients required to prepare the pharmaceutical composition.

[082] In another aspect of the present invention, the gingerols, shogaols, paradols, or combination thereof present in an amount in the range of 0.5mg to 300mg, the pyridoxal 5 ’-phosphate is present in an amount in a range of Img to 200mg, and the one or more sedative antihistamine(s) is present in an amount in a range of 0.5mg to 200mg.

[083] In another aspect of the present invention, the gingerol is selected from the group consisting of (6)-gingerol, (8)-gingerol, (lO)-gingerol, (6)-gingerdione, (6)-gingerdiol, (6)-gingerdiol diacetate, (6)-ginger sulphonic acid, 6)-demethoxygingerol, (6)-methylgingerol, or combination thereof; the paradol is (6)-paradol, (8)-paradol, (lO)-paradol, or combination thereof; and the shogaol is (6)- demethoxyshogaol, (6)-shogaol, (8)-shogaol, (10) shogaol, (6)-methylshogaol, (6)-hydroxyshogaol, (6)-dehydroshogaol, or combination thereof and one or more pharmaceutically acceptable salt(s), metabolite(s), analog(s), polymorph(s), isomer(s), prodrug(s), solvate(s), hydrate(s), or derivative(s) thereof.

[084] In another aspect of the present invention, the pharmaceutical composition further comprises pyridoxal, pyridoxamine, pyridoxine 5' phosphate and pyridoxamine 5' phosphate. [085] In another aspect of the present invention, the one or more sedative antihistamine is shortacting, long-acting, intermediate-acting, or combination thereof.

[086] In another aspect of the present invention, the one or more sedative antihistamine is selected from the group consisting of doxylamine and salt thereof, dexchlorpheniramine and salt thereof, diphenhydramine and salt thereof, dimenhydrinate and salt thereof, chlorpheniramine and salt thereof, brompheniramine and salt thereof, pheniramine and salt thereof, hydroxyzine and salt thereof, cyproheptadine and salt thereof, carbinoxamine and salt thereof, pyrilamine and salt thereof, tripelennamine and salt thereof, phenindamine and salt thereof, trimeprazine, and salt thereof, cyclizine and salt thereof, promethazine and salt thereof, phenyltoloxamine and salt thereof, cyproheptadine and salt thereof, alimemazine and salt thereof, clemastine and salt thereof, ketotifen and salt thereof, mepyramine and salt thereof, antazoline and salt thereof, orphenadrine and salt thereof, bromazine and salt thereof, dexbrompheniramine and salt thereof, tripolidine and salt thereof, chlorcyclizine and salt thereof, hydroxyzine and salt thereof, meclizine and salt thereof, and azatadine and salt thereof.

[087] In another aspect of the present invention the salt is selected from the group consisting of succinate, maleate, esters, amines, hydrochloride, phosphate, calcium phosphate, or dihydrochloride.

[088] In another aspect, the present invention relates to a pharmaceutical composition for the prevention, treatment, and management of nausea, vomiting, or combination thereof comprising of:

(a) a ginger extract containing gingerols, shogaols, paradols, or combination thereof,

(b) pyridoxal 5’-phosphate, pyridoxal, pyridoxamine, pyridoxine 5' phosphate and pyridoxamine 5' phosphate, or combination thereof,

(c) one or more sedative antihistamine(s),

(d) (i) pyridoxine hydrochloride as an inactivated form of vitamin B6, (ii) a non-standardised form of ginger, (iii) Levomepromazine, or combination thereof and

(e) excipients required to prepare a pharmaceutical composition.

[089] In another aspect of the present invention, the composition further comprises other ingredients such as caffeine, antioxidants (e.g. glutathione, reduced glutathione), one or more forms of iron, vitamin A (e.g., retinol acetate), one or more forms of vitamin B12, vitamin B3, alpha-lipoic acid (R or S form), one or more forms of vitamin C, alpha tocotrienol, coenzyme Q10 (activated or inactivated), ubiquinol, zinc, selenium, magnesium citrate, magnesium glycinate, and magnesium chelates, Hl antagonists; H2 antagonists; proton-pump inhibitors, analgesics (paracetamol); flavin mononucleotide (FMN, also known as riboflavin-5-phosphate or R5P), metabolites of riboflavin; folinic acid; 5-MTHF; folic acid; probiotics; or combination thereof.

[090] In another aspect of the present invention, lactose, gluten or dairy-derived excipients are excluded.

[091] In another aspect of the present invention, one, more or all pharmaceutical composition(s) are modified to release the ingredients at a specific location of the body and/or at a specific rate and/or for a specific time duration.

[092] In yet another aspect, the present invention relates to kit for the prevention, treatment, and management of nausea, vomiting, or combination thereof comprising:

(i) a first pharmaceutical composition as claimed in any one of the claims 1 to 11 provided that the first composition is with one or more sedative antihistamine(s); and

(ii) a second pharmaceutical composition as claimed in any one of the claims 1 to 11 provided that the second composition is without one or more sedative antihistamine(s) or in an amount that is less likely to cause the sedation; wherein the kit is adapted to allow access to each pharmaceutical composition at the same or different times.

[093] In another aspect of the present invention, the kit is designed or presented with the indicia distinguishing the first and second pharmaceutical composition from each other, dosage instructions for a specific medical condition, instructions for coordinating the administration of each pharmaceutical composition wherein;

(i) the first pharmaceutical composition is to administer during a particular time and/or at specific time interval(s) of the day or over 24 hrs period or an event, when sedation or sleep is desirable or not contraindicated, or

(ii) the first or second pharmaceutical composition is to administer during a particular time and/or at specific time interval(s) of the day or over 24 hrs period or an event, when sedation or sleep is not desirable or not expected or contraindicated, wherein the container that incorporates the kit includes the indicia, the instructions, and a plurality of first and second pharmaceutical compositions, wherein the kit is designed for ‘day and night’ use and/or is presented as a kit comprising ‘drowsy’ and/or ‘non-drowsy’ pharmaceutical compositions, wherein the first pharmaceutical composition is administered with or without the second pharmaceutical composition, and wherein the kit is designed or presented to provide access to each pharmaceutical composition, the indicia distinguishing each pharmaceutical composition from each other, dosage instructions related to a specific medical condition, instructions for coordinating the administration of each pharmaceutical composition for the duration of one to four weeks or a month.

[094] In another aspect of the present invention, each pharmaceutical composition present therein comprises a different sedative antihistamine and/or dose of each sedative antihistamine is different in each pharmaceutical composition present therein.

[095] In another aspect of the present invention, the pharmaceutical composition or kit is prepared in a compounding pharmacy or in a facility approved by the relevant authority of the local jurisdiction to manufacture therapeutic preparation.

[096] In yet another aspect, the present invention relates to a method of prevention, treatment, and management of nausea, vomiting or combination thereof comprising administering the therapeutically effective amount of the pharmaceutical composition and kit as claimed in claims 1 to 15 to a subject in need thereof.

[097] In yet another aspect, the present invention relates to a pharmaceutical composition and kit for use in the manufacture of medicament for the prevention, treatment, and management of nausea, vomiting or combination thereof.

[098] In yet another aspect, the present invention relates to a use of the pharmaceutical composition for the prevention, treatment, and management of nausea, vomiting or combination thereof.

DETAILED DESCRIPTION OF THE INVENTION

[099] The present invention provides compositions, kits and methods comprising one or more of the core ingredients to achieve the objective described herein.

[0100] It will be understood that the present invention disclosed and defined in this specification extends to all alternative combinations derived from achieving the objectives of the present invention described herein or evident herein. All these different combinations constitute various alternative aspects of the present invention. [0101] One skilled in the art will recognise many methods and materials similar or equivalent to those described herein, which may be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described in this invention.

[0102] The term ‘comprising’, which is synonymous with ‘including’ ‘containing’, or ‘characterised by’ here, is defined as being inclusive or open-ended and does not exclude additional, unrecited elements or method steps, additives, components, integers, or steps.

[0103] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0104] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example. [0105] Reference will now be made in detail to some embodiments of the present invention. While the present invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the present invention to any embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. Skilled artisans will recognise that the examples provided herein have many useful alternatives that fall within the scope of the present invention.

[0106] Compositions, kits and methods of the present invention comprises;

(A) ginger in standardised forms with or without ginger in non-standardised forms.

(B) (i) one or more activated forms of vitamin B6 with or without one or more inactivated forms of vitamin B6 and, (ii) ginger in non-standardised forms and/or ginger in standardised forms.

(C) (i) one or more activated forms of vitamin B6 and/or one or more inactivated forms of vitamin B6 and, (ii) one or two sedative antihistamines.

(D) (i) ginger in non-standardised forms and/or ginger in standardised forms and, (ii) one or two sedative antihistamines.

(E) (i) one or more activated forms of vitamin B6 and/or one or more inactivated forms of vitamin B6 and, (ii) ginger in non-standardised forms and/or ginger in standardised forms, (ii) one or two sedative antihistamines.

(F) (i) one or more inactivated forms of vitamin B6 and, (ii) ginger in standardised forms with or without ginger in non-standardised forms. [0107] In an embodiment, the present invention relates to a pharmaceutical composition for the prevention, treatment, and management of nausea, vomiting or combination thereof comprising of:

(a) a ginger extract containing gingerols, shogaols, paradols, or combination thereof,

(b) pyridoxal 5 ’-phosphate,

(c) one or more sedative antihistamine(s), and

(d) excipients required to prepare the pharmaceutical composition.

[0108] In an embodiment, the present invention relates to a pharmaceutical composition for the prevention, treatment, and management of nausea, vomiting or combination thereof comprising of:

(a) a ginger extract containing gingerols, shogaols, paradols, or combination thereof,

(b) pyridoxal 5’-phosphate, pyridoxal, pyridoxamine, pyridoxine 5' phosphate and pyridoxamine 5' phosphate, or combination thereof

(c) one or more sedative antihistamine(s), and

(d) excipients required to prepare the pharmaceutical composition.

[0109] In another embodiment, the present invention relates to relates to a pharmaceutical composition for the prevention, treatment, and management of nausea, vomiting or combination thereof comprising of:

(a) a ginger extract containing gingerols, shogaols, paradols or combination thereof,

(b) pyridoxal 5 ’-phosphate pyridoxal, pyridoxamine, pyridoxine 5' phosphate and pyridoxamine 5' phosphate, or combination thereof,

(c) one or more sedative antihistamine(s),

(d) (i) pyridoxine hydrochloride as an inactivated form of vitamin B6, (ii) a non-standardised form of ginger, (iii) Levomepromazine, or combination thereof and

(e) excipients required to prepare a pharmaceutical composition. In the present invention, activated form(s) of vitamin B6 is selected from the group consisting of pyridoxal 5 ’-phosphate, pyridoxine 5' phosphate and pyridoxamine 5' phosphate; also known as P5P or PLP, PNP, PMP respectively, and/or one or more pharmaceutically acceptable salt(s), metabolite(s), analog(s), polymorph(s), isomer(s), prodrug(s), solvate(s), hydrate(s), or derivative(s) thereof. Preferably, an activated form of B6 is PLP (also referred as pyridoxal 5’-phosphate, P5P).

[0110] In the present invention, inactivated form(s) of vitamin B6 is selected from the group consisting of pyridoxine and/or salts thereof, pyridoxal and/or salts thereof, pyridoxamine and/or salts thereof, also known as PYN, PYL, PYM respectively, and/or one or more pharmaceutically acceptable salt(s), metabolite(s), analog(s), polymorph(s), isomer(s), prodrug(s), solvate(s), hydrate(s), or derivative(s) thereof. Preferably, an inactivated form of B6 is pyridoxine hydrochloride (pyridoxine HCL).

[0111] In the present invention, activated and inactivated forms of vitamin B6 may be presented in any combination, such as but not limited to, PNP+PMP, PNP+PLP, PMP+PLP, PMP+PNP+PLP, PYL+PNP+PMP, PYM+PNP+PMP, PYL+PNP+PLP, PYM+PNP+PLP, PYL+PMP+PLP, PYM+PMP+PLP, PMP+PNP+PLP+PYL, PYM+PMP+PNP+PLP etc, or salt(s) thereof. Preferably, the combination of activated and inactivated forms is pyridoxal 5 ’-phosphate and pyridoxine HCL.

[0112] In any aspect of the invention described herein, one or more pharmaceutically acceptable salts including for example and without limitation; esters, amines, hydrochloride, phosphate, calcium phosphate, or dihydrochloride of pyridoxine, pyridoxal, and pyridoxamine.

[0113] In the present invention, ginger in non-standardised forms can be powder, extract or any other form of mixture that is derived from one or more parts of the ginger plant, including, but not limited to leaves, root, rhizome, or stems, either from the same or different species from the family of Zingiberaceae, cultivated in any region of the world.

[0114] Standardisation of ginger herein means the process of establishing a set of quantitative parameters for the chemical compositions to ensure quantitative values for the assurance of definitive qualitative and quantitative values to achieve efficacy, safety and reproducibility. Furthermore, because constituents of ginger have different biological properties, the present invention, considering the indication and desired pharmacological action, comprises constituents of ginger in standardised form(s) to ensure the minimum quantity of specific constituents and/or constituents from one or more 'chemical groups'.

[0115] Herein, standardisation by chemical group(s) means quantitative standardisation for the constituents that share the same chemical group(s). For example, quantitative standardisation of constituents from the gingerols and/or shogaols group(s) to ensure that an embodiment contains at least a specific amount of chemical constituents from a ‘gingerols’ and/or ‘shogaols’ and/or ‘paradols’ group(s). Embodiments may be standardised for only one group of constituents, i.e., standardisation for only ‘gingerols’ group of constituents, standardisation of only ‘shogaols’ group of constituents, standardisation of only ‘paradols’ group of constituents.

[0116] Embodiments may be standardised for one or more individual constituents, i.e., standardisation for only (6)-gingerol, standardisation for the total quantity of (6)-gingerols and (6)-shogaols, standardisation for only (6)-gingerol, standardisation for the total quantity of (6)-gingerol, (8)-gingerol and (lO)-gingerol, standardisation for only (6)-shogaol, standardisation for the total quantity of (6)- shogaol, (8)-shogaol and (lO)-shogaol.

[0117] Embodiments may be standardised for one constituent and 'chemical group(s)' i.e., standardisation for (6)-gingerol and shogaols.

[0118] In the present invention, ginger in standardised form is a mixture of constituents present in ginger, and these constituents are selected from the group consists of, including, but not limited to, (6)- gingerol, (8)-gingerol, (lO)-gingerol, (6)-gingerdione, (6)-gingerdiol, (6)-gingerdiol diacetate, (6)- ginger sulphonic acid, (6)-paradol, (8)- paradol, (lO)-paradol, (6)-demethoxygingerol, (6)- methylgingerol, (6)-demethoxyshogaol, (6)-shogaol, (8)-shogaol, (10) shogaol, (6)-methylshogaol, (6)- hydroxyshogaol, (6)-dehydroshogaol, 2-propyl-5(-(3-methoxy-4- hydroxyphenyl)ethyl)-furan, curcuminoids, hexahydrocurcumin, demethylatedhexahydrocurcumin, demethoxylatedhexahydrocurcumin, methoxylatedhexahydrocurcumin, methoxylatedgingerenone a, demethoxylatedgingerenone a, P-bisabolene, a-curcumene, zingiberene, a-farnesene, and P- sesquiphellandrene, quercetin, zingerone, gingerenone-a, and 6-dehydrogingerdione, P-bisabolene, a- curcumene, zingiberene, a-farnesene, and P-sesquiphellandrene and/or one or more pharmaceutically acceptable salt(s), metabolite(s), analog(s), polymorph(s), isomer(s), prodrug(s), solvate(s), hydrate(s), or derivative(s) thereof. Preferably, standardised forms of ginger constituents are (6)-gingerol, (8)- gingerol, (lO)-gingerol, (6)-shogaol, (8)-shogaol, (10) shogaol, (6)-paradol, (8)- paradol, (lO)-paradol, or more pharmaceutically acceptable salt(s), metabolite(s), analog(s), polymorph(s), isomer(s), prodrug(s), solvate(s), hydrate(s), or derivative(s) thereof.

[0119] In the present invention, standardised forms of ginger are standardised for one or more groups of constituents of the ginger such as, including but not limited to gingerols, shogaols, hexahydrocurcumin, and its derivatives (curcuminoids), zingerones, gingerenones, gingerdiones, gingerdiols, paradols, gingeroneA, diarylheptanoids. Preferably, standardised forms of ginger are standardised by gingerols, shogaols, paradols groups of constituents.

[0120] In the present invention, one or more sedative antihistamines are selected from the group consisting of doxylamine and salt thereof, dexchlorpheniramine and salt thereof, diphenhydramine and salt thereof, dimenhydrinate and salt thereof, chlorpheniramine and salt thereof, brompheniramine and salt thereof, pheniramine and salt thereof, hydroxyzine and salt thereof, cyproheptadine and salt thereof, carbinoxamine and salt thereof, pyrilamine and salt thereof, tripelennamine and salt thereof, phenindamine and salt thereof, trimeprazine, and salt thereof, cyclizine and salt thereof, promethazine and salt thereof, phenyltoloxamine and salt thereof, cyproheptadine and salt thereof, alimemazine and salt thereof, clemastine and salt thereof, ketotifen and salt thereof, mepyramine and salt thereof, antazoline and salt thereof, orphenadrine and salt thereof, bromazine and salt thereof, dexbrompheniramine and salt thereof, tripolidine and salt thereof, chlorcyclizine and salt thereof, hydroxyzine and salt thereof, meclizine and salt thereof, and azatadine and salt thereof, levomepromazine and salt thereof. Preferably, doxylamine and salt thereof, promethazine and salt thereof, diphenhydramine and salt thereof, dimenhydrinate and salt thereof, dimenhydrinate and salt thereof, and dimenhydrinate and salt thereof, and levomepromazine and salt thereof.

[0121] In an embodiment of the present invention, the one or more sedative antihistamine is present in an amount in a range of 0.5mg to 200mg per unit dose.

[0122] In an embodiment of the present invention, the gingerols, shogaols, paradols or combination thereof present in an amount in the range of 0.5mg to 300mg per unit dose.

[0123] In an embodiment of the present invention, Pyridoxal 5 ’ -phosphate is present in an amount in a range of Img to 200mg.

[0124] Examples of the present inventions are listed below. However, this invention extends to all possible combinations evident herein and recognised by the person skilled in the art.

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and/or shogaols

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and shogaols + doxylamine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols + doxylamine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger + doxylamine

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and shogaols + promethazine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols + promethazine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger + promethazine

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and shogaols + cyclizine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols + cyclizine • pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger + cyclizine

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and shogaols + levomepromazine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols + levomepromazine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger + levomepromazine

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and shogaols + dexchlorpheniramine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols + dexchlorpheniramine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger + dexchlorpheniramine

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and shogaols + dimenhydrinate

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols + dimenhydrinate

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger + dimenhydrinate

• pyridoxal 5 ’-phosphate + ginger standardised by gingerols and shogaols + diphenhydramine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ ginger standardised by gingerols and shogaols + diphenhydramine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ non-standardised ginger + diphenhydramine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ doxylamine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ promethazine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ dexchlorpheniramine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ levomepromazine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ dimenhydrinate

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ diphenhydramine

• pyridoxal 5 ’-phosphate + pyridoxine HCL+ cyclizine

• ginger standardised by gingerols and shogaols + doxylamine

• ginger standardised by gingerols and shogaols + promethazine

• ginger standardised by gingerols and shogaols + dexchlorpheniramine

• ginger standardised by gingerols and shogaols + levomepromazine

• ginger standardised by gingerols and shogaols + dimenhydrinate

• ginger standardised by gingerols and shogaols + diphenhydramine • ginger standardised by gingerols and shogaols + cyclizine

• non-standardised ginger + pyridoxal 5 ’-phosphate

• non-standardised ginger + doxylamine

• non-standardised ginger + promethazine

• non-standardised ginger + dexchlorpheniramine

• non-standardised ginger + levomepromazine

• non-standardised ginger + dimenhydrinate

• non-standardised ginger + diphenhydramine

• non-standardised ginger + cyclizine

• pyridoxal 5 ’-phosphate + non-standardised ginger + doxylamine

• pyridoxal 5 ’-phosphate + non-standardised ginger + promethazine

• pyridoxal 5 ’-phosphate + non-standardised ginger + dexchlorpheniramine

• pyridoxal 5 ’-phosphate + non-standardised ginger + levomepromazine

• pyridoxal 5 ’-phosphate + non-standardised ginger + dimenhydrinate

• pyridoxal 5 ’-phosphate + non-standardised ginger + diphenhydramine

• pyridoxal 5 ’-phosphate + non-standardised ginger + cyclizine

• Gingerol + Pyridoxal 5 Phosphate

• Shogaol + Pyridoxal 5 Phosphate

• Standardised Ginger ( Gingerol and/or Shogaol) + Pyridoxal 5 Phosphate

• Standardised Ginger (Gingerol and/or Shogaol) + Pyridoxal 5 Phosphate + Pyridoxine

• Standardised Ginger ( Gingerol and/or Shogaol) + Sedative Antihistamine

• Standardised Ginger (Gingerol and/or Shogaol) + Pyridoxal 5 Phosphate + Pyridoxine + Sedative Antihistamine

• Standardised Ginger ( Gingerol and/or Shogaol) + levomepromazine

• Standardised Ginger ( Gingerol and/or Shogaol) + Sedative Antihistamine + levomepromazine

• Standardised Ginger ( Gingerol and/or Shogaol) + Sedative Antihistamine and/or levomepromazine and/or Pyridoxal 5 Phosphate

• Gingerol + Pyridoxine + Doxylamine

• Pyridoxine 5 Phosphate + Pyridoxine + Dexchlorpheniramine -Day and night version

• Standardised Ginger (Gingerol and/or Shogaol) + Pyridoxine [0125] Embodiments may include any short-acting antihistamine combined with a long-acting antihistamine.

[0126] Caffeine may be present in any aspect of the present invention to treat NV to counterbalance the sedation effect of one or more antihistamines.

[0127] Embodiments may include other antioxidants, including but not limited to, glutathione, reduced glutathione, vitamin A (e.g., retinol acetate), one or more forms of vitamin B12, vitamin B3, alpha-lipoic acid (R and/or S form), one or more forms of iron, one or more forms of vitamin C, alpha tocotrienol, coenzyme Q10 (activated or inactivated), ubiquinol, zinc, selenium, magnesium citrate, magnesium glycinate, and magnesium chelates or any other forms thereof.

[0128] Flavin mononucleotide (FMN, also known as riboflavin-5-phosphate or R5P), a riboflavin metabolite, may be present in any aspect of the present invention described herein to improve the bioavailability of pyridoxal5'-phosphate (PLP) to achieve the same objective.

[0129] Embodiments described herein may be given with FMN, folinic acid, 5-MTHF, and folic acid either in a single unit or separate unit doses.

[0130] Embodiments may include probiotics with or without prebiotic to achieve the same objective.

[0131] The ‘active ingredients’ or ‘core ingredients’ used in the present invention can be used as pharmaceutically acceptable salt(s), metabolite(s), analog(s), polymorph(s), isomer(s), prodrug(s), solvate(s), hydrate(s), or derivative(s) thereof.

[0132] The invention provides kits and methods for prevention, treatment and management of nausea and vomiting comprising one or more dosage units each comprising one or more of:

(i) inactivated form(s) of vitamin B6,

(ii) activated form(s) of vitamin B6,

(iii) ginger in non-standardised forms,

(iv) ginger in standardised form(s),

(v) sedative antihistamine(s); indicia distinguishing all comprised dosage units from each other; indicia distinguishing sedative dosage units causing sedation from the non-sedative dosage units; indicia distinguishing sedative dosage units for administration during a particular time of the day or event when sedation or sleep is desirable or not contraindicated; indicia distinguishing non-sedative dosage units for administration during a particular time of the day or event when sedation or sleep is not desirable or contraindicated; wherein instructions are provided for coordinating the administration of each dosage unit as a treatment regimen whereby a dosage unit is for administration during a particular time of the day or event; wherein a container or packaging that incorporates the indicia, the instructions and a plurality of each dosage units; wherein a blister card individually and releasably containing the unit doses; wherein said dosage units are arranged horizontally or vertically in order of their use across the blister card.

Preferably, the invention provides kits for promoting the proper sequential oral administration of pharmaceutically active ingredients.

Such kits and methods may have one or all features described herein.

[0133] The skilled person will understand that active ingredients may be free form, in various salt forms, various hydration states, etc. If, for example, a different salt form of an active ingredient is used in the invention, the skilled person will understand that the amount will need to be adjusted in accordance with the molecular weight.

[0134] 'Unit dose' or 'unit dosage' herein is a dosage form comprising an amount of therapeutically active ingredients suitable for administration in one single dose.

[0135] The present invention provides compositions, kits and methods comprising active ingredients in a range of doses considering the severity of nausea and vomiting, medical conditions, age, and underlying cause.

[0136] The dose range of each ingredient is described herein. Herein above, the dose range is for a unit dose. The present invention is not limited to these dose ranges. The dose of the comprised ingredient can be less or more than the described herein to achieve desired anti-nausea and anti-emetic effects. a) Doxylamine may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to 200 mg. b) Diphenhydramine may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to 200 mg. c) Dimenhydrinate may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to 300mg. d) Promethazine may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to 200mg. e) Cyclizine may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to 200mg. f) Levomepromazine may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to lOOmg. g) Dexchlorpheniramine may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to 25mg. h) Ginger in non-standardised forms may be present in any aspect of the invention described herein at an amount per unit dose of about 100 mg to 2000mg or equivalent thereby. i) Ginger extract in standardised forms may be present in any aspect of the invention described herein at an amount per unit dose of about 2mg to 2000mg. j) gingerols, shogaols, paradols, or combination thereof may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to 300 mg, k) Pyridoxine may be present in any aspect of the invention described herein at an amount per unit dose of about Img to 200mg. l) Pyridoxal 5 ’-phosphate may be present in any aspect of the invention described herein at an amount per unit dose of about Imgto 200mg.

[0137] Kits or methods can be designed using this unit dose ranges to achieve the same objective. The present invention extends to any compositions, kits and methods recognised by one skilled in the art to achieve the effective concentration of one or more comprised ingredients to treat NV.

[0138] As described herein, a compound or active agent or active ingredient or core ingredient is present in a composition or in combination, in an amount effective to provide the desired therapeutic or physiological effect or outcome. This effect may be the treatment, alleviation, diminishment, or amelioration of nausea and/or vomiting. Undesirable effects, e.g., side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining an appropriate ‘effective amount’. The exact amount required will vary from subject to subject, depending on the species, age, medical condition, and general condition of the subject, mode of administration and the like. An appropriate ‘effective amount’ in any individual case may be determined using routine experimentation by one skilled in the art. [0139] It will be understood that the specific dose level for any patient will depend upon a variety of factors, including the activity of the specific composition employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (i.e., other drugs being used to treat the patient), and the severity of the particular disorder. However, over the counter formulations are typically provided to patients as fixed dose, for example, tablets. Therefore, patient dosage may be adjusted by adjusting the number of fixed doses, for example, by changing the number of tablets taken or by adjusting the timing for the next dose.

[0140] The present invention provides compositions, kits, and methods for preventing, treating, and managing NV related to pregnancy, drug use, alcohol use, motion sickness, gastroenteritis, PCOS, anti-cancer and surgery. Embodiments may be used to achieve any desired outcome, including but not limited to minimal reduction to complete elimination of nausea and/or vomiting any time prior, during or after episode of nausea and/or vomiting related to pregnancy, drug use, alcohol use, motion sickness, gastroenteritis, PCOS, anti-cancer and surgery. Embodiments may be used to design a kit or a method in combination with other anti-nausea and/or anti-emetic treatments. Depending on the objective and indication(s), which can be prevention, treatment or management, amount of the comprised ingredient may vary in embodiments. Embodiments may be used to design kits or methods combined with other pharmacological or non-pharmacological interventions to achieve the same objective.

[0141] Embodiments of the present invention may be administered by a patient, a healthcare professional or a carer in a hospital, home, or caring facility. Embodiments may be prepared in a community, hospital pharmacy, or facility approved by the relevant authority to manufacture therapeutic preparation for human or non-human use.

[0142] Regarding NVP, embodiments of the present invention may be used during the first, second or third trimester of the pregnancy to achieve the desired outcome, including but not limited to minimal reduction to complete elimination of nausea and/or vomiting for any particular time of the day, throughout the day or every day during the pregnancy.

Embodiments may be used as single or multiple dosage forms or to design a kit or a method to achieve the desired outcome for the pregnant woman. Embodiments may be used to design a kit, or a method combined with ingredients such as folinic acid, 5-MTHF, folic acid, multivitamins; or may be combined with any other anti-nausea or anti-emetic treatments. [0143] Regarding drug use, embodiments may be designed in combination with analgesics, benzodiazepines, other anti-emetics, anti-psychotics, or naloxone for the NV related to drug use or overdose.

[0144] Regarding alcohol use, embodiments may be designed comprising core ingredients of the present invention combined with non-sedative antihistamines and/or antioxidants for the prevention, treatment, and management of nausea and/or vomiting and/or facial flushing and/or erythema and/or hangover associated with alcohol use or overdose.

[0145] Regarding motion sickness, embodiments of the present invention may be used prophylactically to prevent the occurrence of motion sickness. Prophylactic use of embodiments is preferably within 2 hrs, 15 to 30 minutes more preferred, before expected symptoms.

[0146] Regarding gastroenteritis, embodiments may be combined with anti-diarrhoeal, rehydration salts or antibiotics.

[0147] Regarding PCOS, kits and/or methods can be used on an ad-hoc basis or designed to meet a patient’s requirements on one or more particular day(s) of the menstrual cycle. Embodiments may be designed with coenzyme Q10 (activated or inactivated), ubiquinol, folinic acid, folic acid or 5-MTHF (methylfolate).

[0148] Regarding AINV, cancer herein meaning any form of abnormal growth of cells in a subject. Anti-cancer treatment herein means all current and future treatments to prevent, treat and manage cancer and is not limited to chemotherapy, radiation, immunotherapy, stem cell transplant, surgery, targeted therapy, hormone therapy, pharmacological or non-pharmacological interventions. Embodiments of the present inventions may be used for nausea and vomiting induced by mild, moderate, or highly emetogenic anti-cancer treatment regimens. Embodiments may be used as single or multiple dosage forms or to design a kit or a method to achieve the desired outcome for the patient being treated for cancer. Embodiments may be used or administered immediately, several seconds, hrs, days, or weeks prior to the treatment and/or during the treatment and/or after immediately, several seconds, hrs, days or weeks from initiation of the treatment.

[0149] Regarding PONV, embodiments may be designed in combination with other 5HT3 antagonists, metoclopramide, prochlorperazine, analgesics, anaesthetic agents considering age, type of surgery and patient history.

[0150] In another embodiment, the analgesics is paracetamol. [0151] In any aspect of the invention, the nausea or vomiting treated is one described herein, in both acute and chronic forms, for example, but not limited to, pregnancy, drug use, alcohol use, motion sickness, gastroenteritis, PCOS, anti-cancer treatment, and surgery, fibromyalgia, digestive disorders (gastritis, gastroparesis, gastroesophageal reflux disease, IBS, celiac disease, gallbladder conditions, pancreas conditions, gallstones, intestinal ischemia, intestinal obstruction, intracranial hematoma, intussusception (in children), irritable bowel syndrome, inflammatory bowel disease (crohn’s, ulcerative colitis), pancreatitis (pancreas inflammation), peptic ulcer, pseudotumor cerebri, pyloric stenosis (in infants), gastroparesis or slow stomach emptying, bowel obstruction, retch, (inflammation of the stomach lining), ulcers, appendicitis, mental health conditions, inner ear conditions (labyrinthitis, vestibular neuritis, meniere’s disease), hormonal changes (thyroid disorders, hyperparathyroidism (overactive parathyroid), hyperthyroidism (overactive thyroid), hypoparathyroidism (underactive parathyroid), , neurological conditions (migraine, increased intracranial pressure due to a mass, blood clot, or haemorrhage, demyelinating disorders, seizure disorders), cardiovascular condition (heart attack, heart failure), medication side effect (antibiotics, antidepressants, OTC pain medication, such as aspirin or ibuprofen, certain supplements, such as iron , opioids, chemotherapy, hormones (e.g., birth control pills), antibiotics, antivirals, anticonvulsants, opioids, nicotine, gastrointestinal medications, cardiovascular medications, medications to treat parkinson’s disease, oral contraceptives, digitalis, narcotics and antibiotics), anxiety disorders, eating disorders, depression, cyclic vomiting syndrome, cancer, stress, general anaesthesia, acute liver failure, anaphylaxis (a severe allergic reaction), anorexia nervosa, appendicitis, benign paroxysmal positional vertigo (bppv), cardiovascular condition, bulimia nervosa, bulimia or other psychological illnesses, cholecystitis food poisoning or stomach flu, coronavirus disease 2019 (COVID- 19), depression (major depressive disorder), diabetic ketoacidosis, dizziness, ear infection (middle ear), inner ear conditions, enlarged spleen (splenomegaly), fever, generalized anxiety disorder, hepatitis, hiatal hernia, hydrocephalus, meningitis, milk allergy , radiation therapy, stem cell transplant, surgery, targeted therapy, hormone therapy, severe pain, toxic hepatitis, concussion or brain injury, coughing, or blocked intestines and illnesses in which the child has a high fever, certain food- borne bacteria, such as salmonella. Preferably, the present invention is used for NV related to pregnancy, drug use, alcohol use, motion sickness, gastroenteritis, PCOS, anti-cancer treatment and surgery. [0152] A subject in need of treatment is one experiencing or expecting to experience nausea and/or vomiting. The subject may have been diagnosed with NV and/or recommended anti-emetic and/or antinausea treatment by a doctor, pharmacist, nurse, mid-wife, or any health care professional. NV may also be self-diagnosed.

[0153] As used herein, ‘treating’ or ‘treatment’ means reducing, ameliorating, or providing relief from NV before or after its onset. It also includes ameliorating the severity, incidence, progression, or duration of NV experienced by a subject. As compared with an equivalent untreated control, such amelioration or relief is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as measured by any biochemical or clinical measurement that may be measured by using standard medical methods of evaluating and scoring NV. The benefit to a subject to be treated is either statistically significant or perceptible to the patient or the physician.

[0154] As used herein, the term ‘treatment’ encompasses both disorder-modifying treatment and symptomatic treatment, either of which may be prophylactic, i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms, or therapeutic, i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms. The subject also referred to as patient herein may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep.

[0155] According to the present invention, compositions comprise one or more excipients required to prepare formulation for therapeutic use. Excipients are extra materials that are added to the active ingredients to prepare a dosage form. Pharmaceutically acceptable excipients including for example and without limitation; one or more binders, adhesives, lubricants, diluents, fillers, coating agent, antiadherent, humectants, preservatives, antioxidants, buffering agents, flavouring agents, bulking agent, colouring agents, sweetening agents, plasticisers, solvent and co-solvent, organic solvents, topical solvents, sorbents, glidants, chelating agents, granulating agent, taste masking agent, thickening agents, disintegrants, plasticisers, solubilizer or solubility enhancer, any carrier oil, coatings, barrier layer formulations, surface active agents, viscosity imparting agents, viscosity increasing agent, stabilising agent, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, sweetening agents, release-delaying agents, skin penetration enhancers, fragrances, dyes/colorants, moisturisers and sustained release materials, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters, protectants and miscellaneous materials such as adsorbents and buffers in order to prepare a particular composition and other components. Excipients are well known in the art, and the present invention is not limited in these or this respect. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences, A. Gennaro, Ed., Mack. Formulations may comprise microcapsules or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nano capsules. The formulation may contain one or more electrolytes. It also extends to formulation changed to reduce the size of the unit dose being administered.

[0156] Pharmaceutically acceptable excipient herein refers to any excipient that does not interfere with the effectiveness of the biological activity of comprised active ingredients and is not contra-indicated, non-toxic and non-teratogenic, i.e., not harmful to a subject and embryo or foetus of a subject.

[0157] Considering intolerance to lactose, gluten, dairy, any specific protein, or any other components, the present invention extends to formulations excluding these excipients.

[0158] Dosage forms may be presented as flavoured dosage, unflavoured, or flavour free. This invention may be presented in any combinations and pharmaceutically acceptable dosage forms. Dosage forms of the present invention may include various forms of release, which include but are not limited to immediate release, extended-release, variable release, controlled release, dissolution- controlled release, sustained release, dual release, delayed-release, long-acting, osmotically controlled release, monolithic dosage forms, multi -particulate forms, and combinations thereof. It can be presented in formulations designed to achieve the shortened and/or extended half-life of the individual ingredients comprised in this invention.

[0159] It is possible that dosage forms may include one or more oral dosage forms as listed here but not limited to tablets, compressed tablets, enteric -coated tablets, controlled release tablets, film-coated tablets, effervescent tablets, reconstitute powders, capsules, soft gelatine capsules, hard gelatine capsules, caplets, multi-layer/dual layer capsule, bi-layer capsule, capsules may encapsulate a powder, liquid, or gel, quick dissolve tablets, multilayer tablets, bi-layer tablets, orally disintegrating tablets, powders, granules, dispersible granules, tablet/capsule combinations, coated core tablets, multi-layered with or without dual release or palletised form. It may be formulated containing ion exchange resins or formulations using responsive polymers.

[0160] Embodiments may be provided, including for example and without any limitation, in the form of lollipops, wafer, bars, sticks, chewable tablets, buccal films, gummies, troches, lozenges, chewable lozenges, beads, bite capsules, mouth soluble or dispersible forms like suckable, eatable, chewable coherent forms, biscuits, cereals, confections, cachets, douches, health bars, patches etc. [0161] Compounds may be formulated for any appropriate route of administration including for example and without limitation, as oral preparations (solutions, emulsions, suspension, elixirs, syrups, etc.), topical preparations (nasal drops, nebulisers and inhalers, inhalants, pastes, creams and ointments for skin application, gels, lotions, creams, foams, powders, pessaries for vaginal administration etc.), sublingual and buccal administration, rectal administration (suppositories and enemas), ocular, implants, depot implants, ingestible, parental drug administration (intradermal administration, implants, subcutaneous injection, intramuscular injection, intravenous injection, infusions, intramuscular, intraocular, periocular, intraorbital, spinal, intracranial, intrathecal, intrasynovial and intraperitoneal injection), as well as any similar injection or infusion or inhalation technique, solid dosage form and solid modified release form, semi-solid dosage form, sterile or non-sterile dosage forms and deliveries and, novel and advanced dosage forms and including a novel, advanced delivery systems or any combinations thereof.

[0162] The present invention extends to any formulations designed to achieve release of comprised ingredient at a particular location of the subject and/or at any particular rate of release into the subject. The dosage formulation may be modified to achieve release of comprised ingredients at a specific location of the body and/or at any specific rate and/or for any specific time duration

[0163] Typical modes of delivery for topical compositions include applying using the fingers, using a physical applicator such as cloth, tissue, swab, stick or brush, spraying including mist, aerosol or foam spraying, dropper application sprinkling, soaking, and rinsing.

[0164] Compositions may be formulated as inhaled formulations, including sprays, mists, or aerosols and may be delivered via any inhalation methods known to a skilled person in the art. Such methods may include, for example including without limitation, metered-dose inhalers, nebulisers, multi-dose dry powder inhalers or any other conventional or novel inhalation methods.

[0165] The present invention anticipates that the dosage may be supplied in any pharmaceutically acceptable container listed here but not limited to blister packs, composite blister packs, bottles, tubes, canisters, sachets, packets, child-resistant packaging, heat resistance packaging, light resistance packaging, moisture resistance, travelling kit, daily doses packaging, weekly or monthly dose packing, roll on etc. The composition described herein may be presented in individual packaging, day/night combination, composite packaging, packing designed and/or marked to differentiate the unit dose to make it more suitable and/or compliant for any indication and/or any age group and/or any individual subject. [0166] Embodiments may be combined with other pharmacological or non-pharmacological interventions for the prevention, treatment and management of nausea and vomiting.

[0167] This invention extends to formulations and packaging changed to meet the requirements of particular demographics and/or to obtain regulatory approval from relevant authorities.

[0168] In the context of the unit dose dispensing system, 'daily' herein refers to administering one or more than one dose of the same or different ingredients within the 24-hr period or within the same day. For example, a single daily blister card may include multiple doses to be taken in a 24-hour period.

[0169] Embodiments of the invention may be designed with specific storage requirements in order to preserve comprised constituents. For example, compositions, kits, and methods comprising gingerols and shogaols may be designed with storage requirements to store such embodiments at temperature in the range of -20 to 8 °C.

[0170] Embodiments may be designed with instructions for compounding or preparation prior to administration to the subject. Such instructions may be designed to suit patients, carers, or pharmacists. These embodiments may contain ingredients other than the core ingredients to prepare formulations to achieve the same objective.

[0171] Examples

[0172] The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.

[0173] Example 1

[0174] The tablet of the above composition is prepared by following the steps given below:

I) Orally Disintegrating Tablet / Sublingual tablet (Drowsy Tablet)

I) Example 2: Orally Disintegrating Tablet / Sublingual tablet (Non-Drowsy Tablet)

Manufacturing of Example 1 and 2:

1. Weigh all the ingredients accurately

2. Pass all the ingredients through 40 # sieve; mix all the ingredients except Colloidal Silicon Dioxide, Talc and Magnesium Stearate by mixing and co-sifting. Continue mixing for 5 minutes

3. Add Colloidal Silicon Dioxide and Talc to the blend of step 3 and mix for 10 minutes.

4. To the blend of step 3 add magnesium stearate and mix further for 3 minutes.

5. Evaluate the lubricated blend for flow properties

6. Compress the blend using 10 mm round concave punches at compression weight of 500 mg

2 at hardness of 5kg / cm Example 3:

II) Buccal Tablet (Mucoadhesive tablet) - (Non-Drowsy Tablet)

Example 4: Buccal Tablet (Mucoadhesive tablet)- (Drowsy Tablet)

Manufacturing of Example 3 and 4:

1. Weigh all the ingredients accurately 2. Pass all the ingredients through 40 # sieve; mix all the ingredients except Colloidal Silicon Dioxide, Talc and Magnesium Stearate by mixing and co-sifting. Continue mixing for 5 minutes

3. Add Colloidal Silicon Dioxide and Talc to the blend of step 3 and mix for 10 minutes.

4. To the blend of step 3 add magnesium stearate and mix further for 3 minutes.

5. Evaluate the lubricated blend for flow properties

6. Compress the blend using 12 mm round flat punches at compression weight of 700 mg at

2 hardness of 5kg / cm

[0175] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

[0176] Embodiments may be designed after establishing the individual needs by means of genetic or biomarks or similar tests.

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