Compositions and methods for delivering nad

Abstract

The present invention relates to compositions comprising NAD and, in some preferred embodiments, further comprising a CD38 inhibitor, an antioxidant, an endogenous cellular health molecule and / or a sirtuin activator as adjuncts. The present invention also relates to pharmaceutical compositions, dosage forms and methods for NAD delivery and supplementation.

Description

COMPOSITIONS AND METHODS FOR DELIVERING NADField of the Invention

[0001] The present invention relates to compositions comprising NAD and, in some preferred embodiments, further complemented with other anti-aging actives. The present invention also relates to pharmaceutical compositions, dosage forms and methods for oral NAD delivery.Background

[0002] The following discussion of the background art is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application.

[0003] Nicotinamide adenine dinucleotide (NAD)

[0004] NAD (nicotinamide adenine dinucleotide: oxidized form NAD+; reduced form NADH) is essential for maintaining the body’s energy supplies in each cell, as well as preventing and repairing damage and normal wear and tear. It is involved in numerous redox processes in the cell, and acts as a substrate for many enzymes. As the body ages, its ability to make NAD+ declines, and total NAD+ levels steadily diminish. This could be combatted by taking oral supplements, but NAD+, as well as smaller NAD precursor versions like NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide), are digested in the gut. Nicotinamide (vitamin B3) is an alternative, as it is readily absorbed, but this still means the body has to gather the resources to make the NAD+, which becomes more difficult with age.

[0005] Enzyme CD38

[0006] Critically, a protein called CD38, which metabolizes NAD+, becomes more prevalent as the body ages, causing a decline in circulating levels in the cell and bloodstream. Various molecules related to flavonoids have been shown to be CD38 inhibitors, including apigenin and quercetin. A representative list can be found in Table 1.

[0007] Glutathione

[0008] A second powerful endogenous antioxidant involved in cellular reductive / oxidative (redox) processes with many of the cell-protective features of NAD, glutathione (GSH: oxidized form GSH, reduced form GSSG) is the body’s master antioxidant, protecting cells from the ravages of reactive oxygen species (ROS), and normalbyproducts of oxygen metabolism. Again, with age, the amount of GSH declines, and supplementation to boost levels is desirable. However, GSH is rapidly digested in the gut, and oral supplementation has not been an option, as with NAD.

[0009] Coenzyme Q

[0010] A third powerful endogenous antioxidant involved in cellular reductive / oxidative (redox) processes with many of the cell-protective features of NAD and GSH is Coenzyme Q (ubiquinone; most common form Coenzyme Q10, also known as CoQ10, ubiquinone-10, ubidecarenone; fully oxidized form ubiquinone; partially oxidized form semiquinone; fully reduced form ubiquinol) is crucial to energy generation in cell mitochondria.

[0011] Endogenous Anti-aging Cellular BoostersAs the body ages, cell function declines from youthful levels. Apart from the critical cellular energy and protection molecules NAD, GSH and CoQ, there are several other important cellular species which have been recognised as important to the aging process, and supplementation in conjunction with NAD, GSH or CoQ is a useful combination to boost the function and repair of aging cells. These molecules include: polyamines such as spermidine, alpha-lipoic acid (ALA) and several vitamins. A representative list can be found in Table 2.

[0012] Exogenous Anti-aging Sirtuin BoostersNAD-dependent histone deacetylases (sirtuins) play a key role in many biological processes, and sirtuin function declines with age. Various natural products not found in human cells have been found to have a beneficial role in maintaining cellular health by activating sirtuins, including such compounds as curcuminoids, resveratrol derivatives, quercetin, berberine and fisetin. A representative list can be found in Table 3.

[0013] The Importance of NAD+ and NADH

[0014] Recent reviews have highlighted the importance of nicotinamide adenine dinucleotide (NAD+, oxidized form; NADH, reduced form) in dozens of vital metabolic processes in the cell (N Xie, L Zhang, W Gao, C Wang, P E Huber, X Zhou, C Li, G Shen and B Zou, “NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential”, Nature Signal Transduction and Targeted Therapy, 5(227), 1 -37 (2020); M B Schultz and D A Sinclair, “Why NAD+ declines during aging: it’s destroyed”, Cell Metabolism Previews, 23, 965-966 (2016); M R McReynolds, K Chellappa and J A Baur, “Age-related NAD+ decline”, Experimental Gerontology, 134, 1 -9 (2020); N Braidy, J Berg, J Clement, F Khorshidi, A Poljak, T Jayasena, R Grant and P Sachdev, “Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale,biochemistry, pharmacokinetics and outcomes”, Antioxidants and Redox Signalling, 30(2), 251-294 (2019); Y Aman, Y Qiu, J Tao and E F Fang, “Therapeutic potential of boosting NAD+ in aging and age-related diseases”, Translational Medicine of Aging, 2, 30-37 (2018)).

[0015] A comprehensive review summarised its many roles (N Xie, L Zhang, W Gao, C Wang, P E Huber, X Zhou, C Li, G Shen and B Zou, “NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential”, Nature Signal Transduction and Targeted Therapy, 5(227), 1-37 (2020)) and the consequences of NAD depletion, as follows:Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD* -dependent enzymes are involved in physiology either by postsynthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP*. Prolonged disequilibrium of NAD* metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder.

[0016] The review goes on to describe the role of the NADVNADH redox cycle:NAD+was first described in 1906 as a component that could increase the fermentation rate in yeast. Years later, NAD+was determined to play a vital role for hydrogen transfer in redox reaction. As an essential redox carrier, NAD+receives hydride from metabolic processes including glycolysis, the TCA cycle, and fatty acid oxidation (FAO) to form NADH. NADH, therefore, serves as a central hydride donor to ATP synthesis through mitochondrial OXPHOS, along with the generation of ROS. Beyond its vital role as a coenzyme in energy metabolism, the important role of NAD+has expanded to be a co-substrate for various enzymes including sirtuins, PARPs, CD157, CD73, CD38 and SARM1. Recently, it has been found that NAD* serves as a nucleotide analog in DNA ligation and RNA capping. Therefore, the dynamic NAD+and its metabolites levels, in response to diverse cellular stress and physiological stimuli, rewire biological processes via post-synthesis modification of fundamental biomolecules, including DNA, RNA and proteins. Through these activities, NAD+impact energy metabolism, DNA repair, epigenetic modification, inflammation, circadian rhythm and stress resistance. NAD+deficiency, however, contributes toa spectrum of diseases including metabolic diseases, cancer, aging and neurodegeneration disorders.

[0017] The obvious answer to age-related NAD+depletion seems to be supplementation. However, when taken orally, NAD+is readily digested in the gut, and little or no intact NAD+reaches the bloodstream.

[0018] Role of CD38 in NAD Depletion

[0019] The protein CD38 is known to be a key molecule in the metabolism of NAD+, and acts to maintain equilibrium in the cell, and synthesizes calcium-signaling molecules ADP ribose and cyclic ADP-ribose (M R McReynolds, K Chellappa and J A Baur, “Age-related NAD+ decline”, Experimental Gerontology, 134, 1-9 (2020)). As the body and its cells age, CD38 activity becomes more pronounced, and NAD+depletion results.

[0020] Many studies have suggested that inhibition of CD38 may be a useful way to enhance natural levels of NAD+ by preventing excessive NAD+metabolism by CD38 (N Xie, L Zhang, W Gao, C Wang, P E Huber, X Zhou, C Li, G Shen and B Zou, “NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential”, Nature Signal Transduction and Targeted Therapy, 5(227), 1-37 (2020)). Several flavonoids, such as apigenin, luteolin, quercetin, kuromanin and luteolinidin have been useful however, these molecules suffer from very poor absorption when taken orally.

[0021] Role of Sirtuins in Cellular Health and Aging

[0022] Sirtuins play a vital role in cellular health and disease onset. A comprehensive review on roles of seven sirtuins summarised their importance as follows (V Carafa, D Rotili, M Forgione, F Cuomo, E Serretiello, G S Hailu, E Jarho, M Lahtela-Kakkonen, A Mai and L Altucci, “Sirtuin functions and modulation: from chemistry to the clinic”, Clinical Epigenetics, 8:61 , 1-21 (2016):Sirtuins are NAD+-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity.

[0023] Various phytochemicals have been found to activate sirtuins. A recent review (C Iside, M Scafuro, A Nebbioso and L Altucci, “SIRT1 activation by natural phytochemicals: an overview”, Frontiers in Pharmacology, 11, Aug (Article 1225) (2020)) summarised the progress, and focused on resveratrol, quercetin, berberine, curcumin and fisetin:Sirtuins are reported to modulate numerous activities by controlling gene expression, DNA repair, metabolism, oxidative stress response, mitochondrial function, and biogenesis. Deregulation of their expression and / or action may lead to tissue-specific degenerative events involved in the development of several human pathologies, including cancer, neurodegeneration, and cardiovascular disease. The most studied member of this class of enzymes is sirtuin 1 (SIRT1), whose expression is associated with increasing insulin sensitivity. SIRT 1 has been implicated in both tumorigenic and anticancer processes, and is reported to regulate essential metabolic pathways, suggesting that its activation might be beneficial against disorders of the metabolism. Via regulation of p53 deacetylation and modulation of autophagy, SIRT 1 is implicated in cellular response to caloric restriction and lifespan extension. In recent years, scientific interest focusing on the identification of SIRT1 modulators has led to the discovery of novel small molecules targeting SIRT 1 activity.

[0024] Boosting NAD Levels in Current Practice

[0025] In order to circumvent ready digestion, current supplementation of intact NAD+ involves IV infusion over the course of about an hour, necessitating a clinical setting and consequent expense (hundreds to thousands of dollars per visit). The drawbacks of this approach, even apart from the inconvenience and expense, include: episodic transfusions instead of steady state delivery; large dosages at once (several hundred to several thousand milligrams); and long delays between supplementation. Additionally, NAD+ is poorly stable in solution, so requires formulation for transfusion just prior to administration, further complicating the current market solution to NAD supplementation.

[0026] There is a need in the art for improved compositions and methods for NAD supplementation. It is an objective of the invention to overcome one or more problems foreshadowed by the prior art.Summary of the Invention

[0027] In a first aspect, the invention broadly resides in a composition wherein said composition comprises at least one biologically active material, wherein the biologically active material is selected from the group consisting of: nicotinamide adenine dinucleotide(NAD). Preferably, the NAD is selected from the group consisting of: oxidized form (NAD+); and reduced form (NADH).

[0028] In a preferred embodiment, the composition comprises one or more further biologically active materials selected from the group consisting of: a CD38 inhibitor; an adjunct antioxidant; a second adjunct antioxidant, an endogenous cellular health material, and a sirtuin activator. Preferably, the composition comprises one or more further biologically active materials selected from the group consisting of: a CD38 inhibitor; glutathione; coenzyme Q; an endogenous anti-aging cellular booster; and an exogenous anti-aging sirtuin booster.

[0029] Preferably, the CD38 inhibitor is selected from the group consisting of: those listed in Table 1.

[0030] Preferably, the endogenous anti-aging cellular booster is selected from the group consisting of: those listed in Table 2.

[0031] Preferably, the exogenous anti-aging sirtuin booster is selected from the group consisting of: those listed in Table 3.

[0032] Preferably, the CD38 inhibitor is selected from the group consisting of: apigenin or quercetin.

[0033] Preferably, the adjunct antioxidant is selected from the group consisting of: glutathione (GSH); and coenzyme Q.

[0034] Preferably, the second adjunct antioxidant is selected from the group consisting of: glutathione; and coenzyme Q.

[0035] Preferably, the composition comprises the following components selected from the group consisting of: NAD, apigenin; NAD, quercetin; NAD, glutathione; NAD, coenzyme Q; NAD, quercetin, apigenin; NAD, glutathione, apigenin; NAD, coenzyme Q, apigenin; NAD, glutathione, quercetin; NAD, coenzyme Q, quercetin; and NAD, glutathione, coenzyme Q.

[0036] Preferably, the composition comprises the following components selected from the group consisting of: NAD, apigenin, endogenous anti-aging cellular booster; NAD, quercetin, endogenous anti-aging cellular booster; NAD, glutathione, endogenous anti-aging cellular booster; NAD, coenzyme Q, endogenous anti-aging cellular booster; NAD, quercetin, apigenin, endogenous anti-aging cellular booster; NAD, glutathione, apigenin, endogenous anti-aging cellular booster; NAD, coenzyme Q, apigenin, endogenous anti-aging cellular booster; NAD, glutathione, quercetin, endogenous anti-aging cellular booster; NAD,coenzyme Q, quercetin, endogenous anti-aging cellular booster; and NAD, glutathione, coenzyme Q, endogenous anti-aging cellular booster.

[0037] Preferably, the composition comprises the following components selected from the group consisting of: NAD, apigenin, exogenous anti-aging sirtuin booster; NAD, quercetin, exogenous anti-aging sirtuin booster; NAD, glutathione, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, exogenous anti-aging sirtuin booster; NAD, quercetin, apigenin, exogenous anti-aging sirtuin booster; NAD, glutathione, apigenin, exogenous antiaging sirtuin booster; NAD, coenzyme Q, apigenin, exogenous anti-aging sirtuin booster; NAD, glutathione, quercetin, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, quercetin, exogenous anti-aging sirtuin booster; and NAD, glutathione, coenzyme Q, exogenous anti-aging sirtuin booster.

[0038] Preferably, the composition comprises the following components selected from the group consisting of: NAD, apigenin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, quercetin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, glutathione, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, quercetin, apigenin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, glutathione, apigenin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, apigenin, endogenous anti-aging cellular booster exogenous anti-aging sirtuin booster; NAD, glutathione, quercetin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, quercetin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; and NAD, glutathione, coenzyme Q, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster.

[0039] Preferably, the composition is a solid dosage form.

[0040] Preferably, the composition is a rapidly disintegrating solid dosage form.

[0041] Preferably, the composition is a wafer, tablet or capsule.

[0042] Preferably, the composition is a wafer and is at a pH suitable for stabilizing NAD in a solid matrix on storage.

[0043] Preferably, the biologically active material is present in the composition at a concentration selected from the group consisting of: 0%; 1% (w / w); 2% (w / w); 3% (w / w); 4% (w / w); 5% (w / w); 6% (w / w); 7% (w / w); 8% (w / w); 9% (w / w); 10% (w / w); 11% (w / w); 12% (w / w); 13% (w / w); 14% (w / w); 15% (w / w); 16% (w / w); 17% (w / w); 18% (w / w); 19% (w / w); 20% (w / w); 21% (w / w); 22% (w / w); 23% (w / w); 24% (w / w); 25% (w / w); 26% (w / w); 27%(w / w); 28% (w / w); 29% (w / w); 30% (w / w); 31% (w / w); 32% (w / w); 33% (w / w); 34% (w / w); 35% (w / w); 36% (w / w); 37% (w / w); 38% (w / w); 39% (w / w); 40% (w / w); 41% (w / w); 42% (w / w); 43% (w / w); 44% (w / w); 45% (w / w); 46% (w / w); 47% (w / w); 48% (w / w); 49% (w / w); 50% (w / w); and 2-95% (w / w); 3-65% (w / w); 4-55% (w / w); 5-45% (w / w); 6-35% (w / w); 7-25% (w / w); 8-15% (w / w); 0.1-50% (w / w); 5-50% (w / w); 20-50% (w / w); and within 2 decimal points of each figure.

[0044] Preferably, the biologically active material is present in the composition at a quantity selected from the group consisting of: Omg; 0.01 mg; 0.02mg; 0.03mg; 0.04mg;0.05mg; 0.06mg; 0.07mg; 0.08mg; 0.09mg; 0.10mg; 0.11 mg; 0.12mg; 0.13mg; 0.14mg;0.15mg; 0.16mg; 0.17mg; 0.18mg; 0.19mg; 0.20mg; 0.21 mg; 0.22mg; 0.23mg; 0.24mg;0.25mg; 0.26mg; 0.27mg; 0.28mg; 0.29mg; 0.30mg; 0.31 mg; 0.32mg; 0.33mg; 0.34mg;0.35mg; 0.36mg; 0.37mg; 0.38mg; 0.39mg; 0.40mg; 0.41 mg; 0.42mg; 0.43mg; 0.44mg;0.45mg; 0.46mg; 0.47mg; 0.48mg; 0.49mg; 0.50mg; 0.51 mg; 0.52mg; 0.53mg; 0.54mg;0.55mg; 0.56mg; 0.57mg; 0.58mg; 0.59mg; 0.60mg; 0.61 mg; 0.62mg; 0.63mg; 0.64mg;0.65mg; 0.66mg; 0.67mg; 0.68mg; 0.69mg; 0.70mg; 0.71 mg; 0.72mg; 0.73mg; 0.74mg;0.75mg; 0.76mg; 0.77mg; 0.78mg; 0.79mg; 0.80mg; 0.81 mg; 0.82mg; 0.83mg; 0.84mg;0.85mg; 0.86mg; 0.87mg; 0.88mg; 0.89mg; 0.90mg; 0.91 mg; 0.92mg; 0.93mg; 0.94mg;0.95mg; 0.96mg; 0.97mg; 0.98mg; 0.99mg; 1.00mg; 0.1 mg; 0.2mg; 0.3mg; 0.4mg; 0.5mg; 0.6mg; 0.7mg; 0.8mg; 0.9mg; 1.0mg; 1 mg; 2mg; 3mg; 4mg; 5mg; 6mg; 7mg; 8mg; 9mg; 10mg; 11 mg; 12mg; 13mg; 14mg; 15mg; 16mg; 17mg; 18mg; 19mg; 20mg; 21 mg; 22mg; 23mg; 24mg; 25mg; 26mg; 27mg; 28mg; 29mg; 30mg; 31 mg; 32mg; 33mg; 34mg; 35mg; 36mg; 37mg; 38mg; 39mg; 40mg; 41 mg; 42mg; 43mg; 44mg; 45mg; 46mg; 47mg; 48mg;49mg; 50mg; 51 mg; 52mg; 53mg; 54mg; 55mg; 56mg; 57mg; 58mg; 59mg; 60mg; 61 mg;62mg; 63mg; 64mg; 65mg; 66mg; 67mg; 68mg; 69mg; 70mg; 71 mg; 72mg; 73mg; 74mg;75mg; 76mg; 77mg; 78mg; 79mg; 80mg; 81 mg; 82mg; 83mg; 84mg; 85mg; 86mg; 87mg;88mg; 89mg; 90mg; 91mg; 92mg; 93mg; 94mg; 95mg; 96mg; 97mg; 98mg; 99mg; 100mg; 101 mg; 102mg; 103mg; 104mg; 105mg; 106mg; 107mg; 108mg; 109mg; 110mg; 111 mg;112mg; 113mg; 114mg; 115mg; 116mg; 117mg; 118mg; 119mg; 120mg; 121 mg; 122mg;123mg; 124mg; 125mg; 126mg; 127mg; 128mg; 129mg; 130mg; 131 mg; 132mg; 133mg;134mg; 135mg; 136mg; 137mg; 138mg; 139mg; 140mg; 141 mg; 142mg; 143mg; 144mg;145mg; 146mg; 147mg; 148mg; 149mg; 150mg; 151 mg; 152mg; 153mg; 154mg; 155mg;156mg; 157mg; 158mg; 159mg; 160mg; 161 mg; 162mg; 163mg; 164mg; 165mg; 166mg;167mg; 168mg; 169mg; 170mg; 171 mg; 172mg; 173mg; 174mg; 175mg; 176mg; 177mg;178mg; 179mg; 180mg; 181 mg; 182mg; 183mg; 184mg; 185mg; 186mg; 187mg; 188mg;189mg; 190mg; 191 mg; 192mg; 193mg; 194mg; 195mg; 196mg; 197mg; 198mg; 199mg;200mg; 0.01 mg to 1 mg; 0.1 mg to 1 mg; 1 to 200mg; 1 to 100mg; 1 to 50mg; 1 to 25mg; 1 to15mg; 1 to 10mg; 10 to 100mg; 10 to 75mg; 10mg to 50mg; 10mg to 25mg; 1 to 150mg; 50- 125mg.

[0045] Preferably, the biologically active material is present in the composition at a quantity selected from the group consisting of: 1 to 150mg, including 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 150mg, 50-125mg.

[0046] Preferably, the composition comprises one or more agents selected from the group consisting of: a non-ionic amorphous matrix forming agent; an ionic matrix aide; a non-ionic matrix aide; a non-ionic crystalline matrix forming agent; and any multitude of combinations.

[0047] Preferably, the non-ionic amorphous matrix forming agent is selected from the group consisting of: amylopectin or other soluble low viscosity modified amylopectins.

[0048] Preferably, the non-ionic amorphous matrix forming agent is selected from the group consisting of: amylopectin or other soluble low viscosity modified amylopectins or other soluble starches NOT containing insoluble amylose or insoluble modified amylose, such as dextrins, or soluble glucose polymers such as polydextrose.

[0049] Preferably, the concentration of the non-ionic amorphous matrix forming agent is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%-10%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; 11%; 12%; 13%; 14%; 15%; 16%; 17%; 18%; 19%; 20%; and within 2 decimal points of each figure (w / w).

[0050] Preferably, the ionic matrix aide is selected from the group consisting of: sodium carboxymethyl cellulose (CMC); and glycine.

[0051] Preferably, the concentration of the ionic matrix aide is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%-10%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; and within 2 decimal points of each figure (w / w).

[0052] Preferably, the non-ionic matrix aide is selected from the group consisting of: PEG 1500; and microcrystalline cellulose (MCC).

[0053] Preferably, the concentration of the non-ionic matrix aide is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%-10%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; and within 2 decimal points of each figure (w / w).

[0054] Preferably, the non-ionic crystalline matrix forming agent is selected from the group consisting of: mannitol; and lactose.

[0055] Preferably, the concentration of the non-ionic crystalline matrix forming agent is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%-10%; 1 %-90%; 1%- 95%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; 11%; 12%; 13%; 14%; 15%; 16%; 17%; 18%; 19%; 20%; 21%; 22%; 23%; 24%; 25%; 26%; 27%; 28%; 29%; 30%; 31%; 32%; 33%;34%; 35%; 36%; 37%; 38%; 39%; 40%; 41%; 42%; 43%; 44%; 45%; 46%; 47%; 48%; 49%;50%; 51%; 52%; 53%; 54%; 55%; 56%; 57%; 58%; 59%; 60%; 61%; 62%; 63%; 64%; 65%;66%; 67%; 68%; 69%; 70%; 71%; 72%; 73%; 74%; 75%; 76%; 77%; 78%; 79%; 80%; 81%;82%; 83%; 84%; 85%; 86%; 87%; 88%; 89%; 90%; 91%; 92%; 93%; 94%; 95% and within 2 decimal points of each figure (w / w).

[0056] Preferably, the composition comprises: 0-80% of mannitol (w / w / ); and 0-80% of lactose (w / w).

[0057] Preferably, the composition comprises: 30-50% of mannitol (w / w / ); and 10-30% of lactose (w / w).

[0058] Preferably, the composition is formulated to pH 2 to 5.

[0059] Preferably, the composition is a solid.

[0060] Preferably, the composition is lyophilised.

[0061] Preferably, the bioactive particles of the composition have a size no greater than 100 pm.

[0062] Preferably, the bioactive particles of the composition have a nanoparticulate size less than 10,000nm.

[0063] Preferably, the Dx of the bioactive particle distribution, as measured on a particle volume basis, is selected from the group consisting of less than or equal to: 0.001 -100 pm; 0.01-100 pm; 0.1-100 pm; 1-100 pm; 1 to 50 pm; 0.001 pm; 0.002 pm; 0.003 pm; 0.004 pm; 0.005 pm; 0.006 pm; 0.007 pm; 0.008 pm; 0.009 pm; 0.01 pm; 0.02 pm; 0.03 pm; 0.04 pm; 0.05 pm; 0.06 pm; 0.07 pm; 0.08 pm; 0.09 pm; 0.1 pm; 0.2 pm; 0.3 pm; 0.4 pm; 0.5 pm; 0.6 pm; 0.7 pm; 0.8 pm; 0.9 pm; 1 pm; 2 pm; 3 pm; 4 pm; 5 pm; 6 pm; 7 pm; 8 pm; 9 pm; 10 pm; 11 pm; 12 pm; 13 pm; 14 pm; 15 pm; 16 pm; 17 pm; 18 pm; 19 pm; 20 pm; 21 pm; 22 pm; 23 pm; 24 pm; 25 pm; 26 pm; 27 pm; 28 pm; 29 pm; 30 pm; 31 pm; 32 pm; 33 pm; 34 pm; 35 pm; 36 pm; 37 pm; 38 pm; 39 pm; 40 pm; 41 pm; 42 pm; 43 pm; 44 pm; 45 pm; 46 pm; 47 pm; 48 pm; 49 pm; 50 pm; 51 pm; 52 pm; 53 pm; 54 pm; 55 pm; 56 pm; 57 pm; 58 pm; 59 pm; 60 pm; 61 pm; 62 pm; 63 pm; 64 pm; 65 pm; 66 pm; 67 pm; 68 pm; 69 pm; 70 pm; 71 pm; 72 pm; 73 pm; 74 pm; 75 pm; 76 pm; 77 pm; 78 pm; 79 pm; 80 pm; 81 pm; 82 pm; 83 pm; 84 pm; 85 pm; 86 pm; 87 pm; 88 pm; 89 pm; 90 pm; 91 pm; 92 pm; 93 pm; 94pm; 95 pm; 96 pm; 97 pm; 98 pm; 99 pm; 100 pm; wherein x is greater than or equal to 10, 50 or 90.

[0064] Preferably, the Dx of the bioactive particle distribution, as measured on a particle number basis, is selected from the group consisting of less than or equal to: 0.001-100 pm; 0.01-100 pm; 0.1-100 pm; 1-100 pm; 1 to 50 pm; 0.001 pm; 0.002 pm; 0.003 pm; 0.004 pm; 0.005 pm; 0.006 pm; 0.007 pm; 0.008 pm; 0.009 pm; 0.01 pm; 0.02 pm; 0.03 pm; 0.04 pm; 0.05 pm; 0.06 pm; 0.07 pm; 0.08 pm; 0.09 pm; 0.1 pm; 0.2 pm; 0.3 pm; 0.4 pm; 0.5 pm; 0.6 pm; 0.7 pm; 0.8 pm; 0.9 pm; 1 pm; 2 pm; 3 pm; 4 pm; 5 pm; 6 pm; 7 pm; 8 pm; 9 pm; 10 pm; 11 pm; 12 pm; 13 pm; 14 pm; 15 pm; 16 pm; 17 pm; 18 pm; 19 pm; 20 pm; 21 pm; 22 pm; 23 pm; 24 pm; 25 pm; 26 pm; 27 pm; 28 pm; 29 pm; 30 pm; 31 pm; 32 pm; 33 pm; 34 pm; 35 pm; 36 pm; 37 pm; 38 pm; 39 pm; 40 pm; 41 pm; 42 pm; 43 pm; 44 pm; 45 pm; 46 pm; 47 pm; 48 pm; 49 pm; 50 pm; 51 pm; 52 pm; 53 pm; 54 pm; 55 pm; 56 pm; 57 pm; 58 pm; 59 pm; 60 pm; 61 pm; 62 pm; 63 pm; 64 pm; 65 pm; 66 pm; 67 pm; 68 pm; 69 pm; 70 pm; 71 pm; 72 pm; 73 pm; 74 pm; 75 pm; 76 pm; 77 pm; 78 pm; 79 pm; 80 pm; 81 pm; 82 pm; 83 pm; 84 pm; 85 pm; 86 pm; 87 pm; 88 pm; 89 pm; 90 pm; 91 pm; 92 pm; 93 pm; 94 pm; 95 pm; 96 pm; 97 pm; 98 pm; 99 pm; 100 pm; wherein x is greater than or equal to 10, 50 or 90.

[0065] Preferably, the composition comprises further pharmaceutically acceptable additives and agents.

[0066] Preferably, the composition comprises a pharmaceutically acceptable buffering reagent.

[0067] Preferably, the buffering reagent is selected from the group consisting of: salts of phosphates, carbonates, Tris; preferably combinations of phosphate salts; including sodium carbonate.

[0068] Preferably, the buffering reagent is present at a concentration selected from the group consisting of: 0.1 -0.5%; 0.1%; 0.2%; 0.3%; 0.4%; 0.5%; and within 2 decimal points of each figure (w / w).

[0069] Preferably, the wafers are buffered with a suitable buffer, most preferably a blend of mono- and di-alkaline salt phosphates, adjusted to afford a pH optimal for the stability of the NAD, generally between 2-4.

[0070] Preferably, the composition comprises a colouring agent.

[0071] Preferably, the composition comprises a flavouring agent.

[0072] Preferably, the composition comprises a flavouring agent comprising a lemonade flavourant and a sucralose sweetener.

[0073] Preferably, the composition comprises a stability agent.

[0074] Preferably, the stability agent is selected from the group consisting of: vitamin E and derivatives.

[0075] Preferably, the composition disintegrates once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <110s; <120s (seconds).

[0076] Preferably, the composition disintegrates once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <110s; <120s; <130s; <140s; <150s; <160s; <170s; <180s; <190s; <200s; <21 Os; <220s; <230s; <240s; <250s; <260s; <270s; <280s; <290s; <300s; <31 Os; <320s; <330s; <340s; <350s; <360s; <370s; <380s; <390s; <400s; <41 Os; <420s; <430s; <440s; <450s; <460s; <470s; <480s; <490s; <500s; <51 Os; <520s; <530s; <540s; <550s;<560s; <570s; <580s; <590s; <600s; <61 Os; <620s; <630s; <640s; <650s; <660s; <670s;<680s; <690s; <700s; <71 Os; <720s; <730s; <740s; <750s; <760s; <770s; <780s; <790s;<800s; <81 Os; <820s; <830s; <840s; <850s; <860s; <870s; <880s; <890s; <900s; <900s;<930s; <960s; <990s; <1020s; <1050s; <1080s; <1110s; <1140s; <1170s; <1200s; <1230s; <1260s; <1290s; <1320s; <1350s; <1380s; <1410s; <1440s; <1470s; <1500s; <1530s; <1560s; <1590s; <1620s; <1650s; <1680s; <171 Os; <1740s; <1770s; <1800s; <1830s;<1860s; <1890s; <1920s; <1950s; <1980s; <201 Os; <2040s; <2070s; <2100s; <2130s;<2160s; <2190s; <2220s; <2250s; <2280s; <231 Os; <2340s; <2370s; <2400s; <2430s;<2460s; <2490s; <2520s; <2550s; <2580s; <261 Os; <2640s; <2670s; <2700s; <2730s;<2760s; <2790s; <2820s; <2850s; <2880s; <291 Os; <2940s; <2970s; <3000s; <3030s;<3060s; <3090s; <3120s; <3150s; <3180s; <321 Os; <3240s; <3270s; <3300s; <3330s;<3360s; <3390s; <3420s; <3450s; <3480s; <351 Os; <3540s; <3570s; <3600s; <3630s;<3660s; <3690s; <3720s; <3750s; <3780s; <381 Os; <3840s; <3870s; <3900s; <3930s;<3960s; <3990s; <4020s; <4050s; <4080s; <4110s; <4140s; <4170s; <4200s; and <4230s (seconds).

[0077] Preferably, the composition disintegrates in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by a subject, thereby avoiding the urge for the subject to swallow the composition.

[0078] Preferably, the composition dissolves once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <110s; <120s; 180s, preferably 15-60s (seconds).

[0079] Preferably, the composition dissolves once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <110s; <120s; <130s; <140s; <150s; <160s; <170s; <180s; <190s; <200s; <210s; <220s; <230s; <240s; <250s; <260s; <270s; <280s; <290s; <300s; <31 Os; <320s; <330s; <340s; <350s; <360s; <370s; <380s; <390s; <400s; <41 Os; <420s; <430s; <440s; <450s; <460s; <470s; <480s; <490s; <500s; <51 Os; <520s; <530s; <540s; <550s;<560s; <570s; <580s; <590s; <600s; <61 Os; <620s; <630s; <640s; <650s; <660s; <670s;<680s; <690s; <700s; <71 Os; <720s; <730s; <740s; <750s; <760s; <770s; <780s; <790s;<800s; <81 Os; <820s; <830s; <840s; <850s; <860s; <870s; <880s; <890s; <900s; <900s;<930s; <960s; <990s; <1020s; <1050s; <1080s; <1110s; <1140s; <1170s; <1200s; <1230s; <1260s; <1290s; <1320s; <1350s; <1380s; <1410s; <1440s; <1470s; <1500s; <1530s; <1560s; <1590s; <1620s; <1650s; <1680s; <171 Os; <1740s; <1770s; <1800s; <1830s;<1860s; <1890s; <1920s; <1950s; <1980s; <201 Os; <2040s; <2070s; <2100s; <2130s;<2160s; <2190s; <2220s; <2250s; <2280s; <231 Os; <2340s; <2370s; <2400s; <2430s;<2460s; <2490s; <2520s; <2550s; <2580s; <261 Os; <2640s; <2670s; <2700s; <2730s;<2760s; <2790s; <2820s; <2850s; <2880s; <291 Os; <2940s; <2970s; <3000s; <3030s;<3060s; <3090s; <3120s; <3150s; <3180s; <321 Os; <3240s; <3270s; <3300s; <3330s;<3360s; <3390s; <3420s; <3450s; <3480s; <351 Os; <3540s; <3570s; <3600s; <3630s;<3660s; <3690s; <3720s; <3750s; <3780s; <381 Os; <3840s; <3870s; <3900s; <3930s;<3960s; <3990s; <4020s; <4050s; <4080s; <4110s; <4140s; <4170s; <4200s; and <4230s (seconds).

[0080] Preferably, the composition dissolves in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by a subject, thereby avoiding the urge for the subject to swallow the composition.

[0081] Preferably, the water is removed from the combined agents by a freeze-drying process to a residual level of 2-5%.

[0082] Preferably, the composition has a porosity profile selected from the group consisting of: the proportion of water removed by lyophilization is 65-75%; and the proportion of water removed by lyophilization is >60%.

[0083] Preferably, the composition is stable for a time period selected from the group consisting of: 1 week; 2 weeks; 3 weeks; 4 weeks; 5 weeks; 6 weeks; 7 weeks; 8 weeks; 9 weeks; 10 weeks; 11 weeks; 12 weeks; 13 weeks; 14 weeks; 15 weeks; 16 weeks; 17weeks; 18 weeks; 19 weeks; 20 weeks; 21 weeks; 22 weeks; 23 weeks; 24 weeks; 25 weeks; 26 weeks; 27 weeks; 28 weeks; 29 weeks; 30 weeks; 31 weeks; 32 weeks; 33 weeks; 34 weeks; 35 weeks; 36 weeks; 37 weeks; 38 weeks; 39 weeks; 40 weeks; 41 weeks; 42 weeks; 43 weeks; 44 weeks; 45 weeks; 46 weeks; 47 weeks; 48 weeks; 49 weeks; 50 weeks; 51 weeks; 52 weeks; 1 month; 2 months; 3 months; 4 months; 5 months; 6 months; 7 months; 8 months; 9 months; 10 months; 11 months; 12 months; 13 months; 14 months; 15 months; 16 months; 17 months; 18 months; 19 months; 20 months; 21 months; 22 months; 23 months; 24 months; 25 months; 26 months; 27 months; 28 months; 29 months; 30 months; 31 months; 32 months; 33 months; 34 months; 35 months; 36 months; 37 months; 38 months; 39 months; 40 months; 41 months; 42 months; 43 months; 44 months; 45 months; 46 months; 47 months; 48 months; 49 months; 50 months; 51 months; 52 months; 53 months; 54 months; 55 months; 56 months; 57 months; 58 months; 59 months; 60 months; 1 month to 12 months; 12 months to 24 months; 12 months to 36 months; 12 months to 48 months; 1 year to 2 years; 1 year to 3 years; and 1 year to 5 years.

[0084] Preferably, the composition is stable as demonstrated by a potency assay run against a reference biologically active material.

[0085] Preferably, the composition comprises cavities.

[0086] Preferably, the cavities are encapsulated by at least a major proportion of the biologically active material(s).

[0087] Preferably, the cavities are encapsulated by the biologically active material(s).

[0088] Preferably, the cavities are amorphous or irregular holes.

[0089] Preferably, the cavities encapsulate at least a major proportion of the biologically active material(s) and helps to protect the biologically active material(s) from the degradation and denaturing effects caused by solar radiation, water, enzymes, and / or solvents.

[0090] Preferably, the cavity walls encapsulate the biologically active material(s) and protects the biologically active material(s) from the degradation and denaturing effects caused by: solar radiation; pH changes; ionic changes; electron excesses and deficits; water; enzymes; and / or solvents.

[0091] Preferably, the average diameter of the cavities is selected from the group consisting of: 1-100pm; 1 -200pm; 1 -300pm; 1 -400pm; 1 -500pm; 10-200pm; 10-100pm; 20- 100pm; 50-150pm.

[0092] Preferably, the average diameter of the cavities would vary depending on the freezing rate and solids content.

[0093] Preferably, the composition comprises cavities and channels.

[0094] Preferably, there is a microcrystalline array around the channels.

[0095] Preferably, the microcrystalline array around the channels is dense.

[0096] Preferably, the microcrystalline array around the channels is overlapping.

[0097] Preferably, the microcrystalline array has an attribute selected from the group consisting of: scatter a variety of wavelengths of light; suppress oxygen diffusion from the channels; protect the active within the matrix from UV and oxidative degradation; the low water content, which cannot diffuse because it is trapped and hydrogen-bonded to eg lactose and mannitol, prevents hydrolysis.

[0098] Preferably, the composition is a composition presented in a table selected from the group consisting of: Table 14.

[0099] In another aspect, the invention is a pharmaceutical composition comprising the composition of the first aspect of the invention together with a pharmaceutical excipient or carrier.

[0100] In another aspect, the invention is a nutraceutical composition comprising the composition of the first aspect of the invention together with a nutraceutical excipient or carrier.

[0101] In another aspect, the invention is a dosage form comprising the composition of the first aspect of the invention.

[0102] Preferably, the dosage form comprises the biologically active material at a dose selected from the group consisting of: 1 to 150mg, including 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 150mg, 50-125mg.

[0103] Preferably, the dosage form is solid.

[0104] Preferably, the dosage form is freeze dried.

[0105] Preferably, the dosage form is a wafer.

[0106] In another aspect, the invention is a method of treating or preventing or delaying a deficiency, condition, disease or disorder, said method comprising administering to a patient in need thereof a therapeutically effective amount of the dosage form of one aspect of the invention.

[0107] Preferably, the deficiency, condition, disease or disorder is selected from the group consisting of: premature ageing; premature loss of health, energy, and / or vitality;neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis; cancer; vascular diseases; immune disorders; inflammatory disorders; infections; infertility.

[0108] Preferably, the method performs one of the functions selected from the group consisting of: increasing the body’s NAD+ levels; improving cellular health, energy, and / or vitality; slowing down the process of DNA damage and providing inflammation control; less susceptible to disease; metabolic regulation; maintaining the body’s energy supplies; preventing and repairing damage and normal wear and tear; increase energy; weight management; muscle development and recovery; decreasing muscle loss, and especially those patients on the GLP-1 s 1 s (such as semaglutide); promotes skeletal muscle health, repair and / or recovery; slows and / or reverses skeletal muscle loss, including drug associated muscle loss (due to GLP-1 and GIP receptor agonists / antagonists and other drugs), muscle loss associated with aging (sarcopenia), and / or muscle loss due to an underlying medical condition; reducing sarcopenia for the aging population; supporting pain management; improving mood; improving cognitive function; supplementing addition recovery; neurodegenerative diseases such as Alzheimer's and Parkinson's disease as well as multiple sclerosis; aging and longevity; aids to anti-cancer, anti-viral, or immunosuppressive drugs; improving fertility; improving ovulation; improving sperm production.

[0109] Preferably, the dosage form is administered to deliver a therapeutic effective amount of the biologically active material.

[0110] Preferably, the therapeutically effective amount is administered to the subject utilising a dosing regimen selected from the group consisting of: twice hourly; hourly; once every six hours; once every 8 hours; once every 12 hours; once daily; twice weekly; once weekly; once every 2 weeks; once every 6 weeks; once a month; once every 2 months; once every 3 months; once every 4 months; once every 5 months; once every 6 months; once yearly; and once.

[0111] Preferably, the dosage form delivers the NAD and a second dosage form delivers one or more further optional biologically active materials.

[0112] Preferably, the dosage form delivers the NAD, a second dosage form delivers one or more further optional biologically active materials, and a third dosage form delivers one or more further optional biologically active materials.

[0113] Preferably, the first dosage form, the second dosage form and / or third the dosage are administered to the patient in need thereof using a dosing pattern selected from the group consisting of: sequentially, contemporaneously or at different times.

[0114] Preferably, the different times are selected from the group consisting of: seconds apart; minutes apart; hours apart; days apart; weeks apart; and months apart.

[0115] Preferably, the seconds apart is selected from the group consisting of: 1 s; 2s; 3s; 4s; 5s; 6s; 7s; 8s; 9s; 10s; 11s; 12s; 13s; 14s; 15s; 16s; 17s; 18s; 19s; 20s; 21s; 22s; 23s; 24s; 25s; 26s; 27s; 28s; 29s; 30s; 31s; 32s; 33s; 34s; 35s; 36s; 37s; 38s; 39s; 40s; 41s; 42s; 43s; 44s; 45s; 46s; 47s; 48s; 49s; 50s; 51 s; 52s; 53s; 54s; 55s; 56s; 57s; 58s; 59s; and 60s.

[0116] Preferably, the minutes apart is selected from the group consisting of: 1 min; 2min; 3min; 4min; 5min; 6min; 7min; 8min; 9min; 10min; 11 min; 12min; 13min; 14min;15min; 16min; 17min; 18min; 19min; 20min; 21 min; 22min; 23min; 24min; 25min; 26min;27min; 28min; 29min; 30min; 31 min; 32min; 33min; 34min; 35min; 36min; 37min; 38min;39min; 40min; 41min; 42min; 43min; 44min; 45min; 46min; 47min; 48min; 49min; 50min;51 min; 52min; 53min; 54min; 55min; 56min; 57min; 58min; 59min; and 60min.

[0117] Preferably, the hours apart are selected from the group consisting of: 1 hr; 2hr; 3hr; 4hr; 5hr; 6hr; 7hr; 8hr; 9hr; 10hr; 11 hr; 12hr; 13hr; 14hr; 15hr; 16hr; 17hr; 18hr; 19hr; 20hr; 21 hr; 22hr; 23hr; and 24hr.

[0118] Preferably, the days apart is selected from the group consisting of: 1 day; 2 days; 3 days; 4 days; 5 days; 6 days; 7 days; 8 days; 9 days; 10 days; 11 days; 12 days; 13 days; 14 days; 15 days; 16 days; 17 days; 18 days; 19 days; 20 days; 21 days; 22 days; 23 days; 24 days; 25 days; 26 days; 27 days; 28 days; 29 days; 30 days and 31 days.

[0119] Preferably, the weeks apart is selected from the group consisting of: 1 week; 2 weeks; 3 weeks; 4 weeks; 5 weeks; 6 weeks; 7 weeks; 8 weeks; 9 weeks; 10 weeks; 11 weeks; 12 weeks; 13 weeks; 14 weeks; 15 weeks; 16 weeks; 17 weeks; 18 weeks; 19 weeks; 20 weeks; 21 weeks; 22 weeks; 23 weeks; 24 weeks; 25 weeks; 26 weeks; 27 weeks; 28 weeks; 29 weeks; 30 weeks; 31 weeks; 32 weeks; 33 weeks; 34 weeks; 35 weeks; 36 weeks; 37 weeks; 38 weeks; 39 weeks; 40 weeks; 41 weeks; 42 weeks; 43 weeks; 44 weeks; 45 weeks; 46 weeks; 47 weeks; 48 weeks; 49 weeks; 50 weeks; 51 weeks; and 52 weeks.

[0120] Preferably, the months apart is selected from the group consisting of: 1 month; 2 months; 3 months; 4 months; 5 months; 6 months; 7 months; 8 months; 9 months; 10 months; 11 months; 12 months; 13 months; 14 months; 15 months; 16 months; 17 months; 18 months; 19 months; 20 months; 21 months; 22 months; 23 months; and 24 months.

[0121] Preferably, the dosage form delivers a therapeutic effective amount of the biologically active material.

[0122] Preferably, the dosage form delivers between 50mg-500mg NAD per day.

[0123] Preferably, the dosage form delivers NAD per day, and allowing a steady and controlled buildup of depleted NAD towards a steady state blood concentration.

[0124] Preferably, the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: between 0.001 to 100mg / kg; between 2 and 50mg / kg; between 5 and 40mg / kg; between 10 and 30mg / kg; between 20 and 25mg / kg; and 20mg / kg / day.

[0125] Preferably, the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: 2mg; 5mg 10mg; 15mg; 20mg; 21 mg; 0.25mg to 100mg; 1 mg to 25mg; 1 mg to 50 mg; 1 mg to 30mg; 2 to 30mg; 5 mg to 15mg; 10mg to 20mg; 10 to 50mg; 50-150mg per dosage event.

[0126] Preferably, the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: 2mg; 5mg 10mg; 15mg; 20mg; 21 mg; 0.25mg to 100mg; 1 mg to 25mg; 1 mg to 50 mg; 1 mg to 30mg; 2 to 30mg; 5 mg to 15mg; 10mg to 20mg; 10 to 50mg; 50-150mg per day.

[0127] Preferably, the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: up to and including 150mg NAD; up to and including 150mg apigenin or quercetin or other CD38 inhibitor from Table 1 ; and up to and including 150mg GSH or CoQ; up to and including 150mg of spermidine or other cellular health molecules from Table 2; up to and including 150mg of quercetin or other sirtuin activator molecules from Table 3.

[0128] Preferably, the therapeutically effective amount is administered to the subject using a method selected from the group consisting of: orally; sublingually; buccally.

[0129] Preferably, the therapeutically effective amount is administered to the subject using a method selected from the group consisting of: beneath the tongue or buccally.

[0130] Preferably, detectable levels of the biologically active material enter the circulation system.

[0131] Preferably, the detectable levels of the biologically active material that enters the circulation system is selected from the group consisting of: less than 0.001%; less than 0.01%; less than 0.1%; less than 2%; less than 3%; less than 4%; less than 5%; less than6%; less than 7%; less than 8%; less than 9%; less than 10%; less than 11%; less than 12%; less than 13%; less than 14%; less than 15%; less than 16%; less than 17%; less than 18%; less than 19%; less than 20%; less than 21%; less than 22%; less than 23%; less than 24%; ess than 25%; less than 26%; less than 27%; less than 28%; less than 29%; less than 30%; less than 31%; less than 32%; less than 33%; less than 34%; less than 35%; less than 36%; less than 37%; less than 38%; less than 39%; less than 40%; less than 41%; less than 42%; less than 43%; less than 44%; less than 45%; less than 46%; less than 47%; less than 48%; less than 49%; less than 50%; less than 51%; less than 52%; less than 53%; less than 54%; less than 55%; less than 56%; less than 57%; less than 58%; less than 59%; less than 60%; less than 61%; less than 62%; less than 63%; less than 64%; less than 65%; less than 66%; less than 67%; less than 68%; less than 69%; less than 70%; less than 71%; less than 72%; less than 73%; less than 74%; and less than 75% (w / w%).

[0132] Preferably, the said biologically active material is absorbed by diffusion directly into the systemic circulation.

[0133] Preferably, the said biologically active material is sublingually absorbed rapidly.

[0134] Preferably, the drug form is delivered sublingually and more suitable for patients phobic to subcutaneous injection or clinical IV infusion.

[0135] Preferably, the sublingual administered nicotinamide adenine dinucleotide has a significant length of contact time with the mucosal surface, allowing absorption of the active(s) and transfer directly into the circulatory system; or up to 10 minutes.

[0136] Preferably, the t1 / ? of the administered nicotinamide adenine dinucleotide is selected from the group consisting of: between 15 and 20 min; between 20 and 25 min; between 25 and 30 min; between 30 and 35 min; between 35 and 40 min; between 40 and 45 min; between 45 and 50 min; between 30 and 60 min; between 1 and 2 hrs; between 2 and 3 hrs; between 3 and 4 hrs; between 4 and 5 hrs; between 5 and 6 hrs; between 6 and 12 hrs; between 12 and 24 hrs; between 1 and 2 days; between 2 and 3 days; between 3 and 4 days; between 4 and 5 days; between 5 and 6 days; between 6 and 7 days; between 6 and 7 days; between 1 and 2 weeks; between 2 and 3 weeks; between 3 and 4 weeks; between 1 and 2 months; between 2 and 3 months; between 3 and 4 months; between 4 and 5 months; between 5 and 6 months; between 6 and 12 months; and between 1 and 2 years.

[0137] Preferably, the t1 / ? of the administered nicotinamide adenine dinucleotide is selected from the group consisting of: between 15 and 120 min.

[0138] Preferably, the effects of NAD combined with CD38 inhibitors and / or glutathione antioxidant and / or coenzyme Q produce synergistic effects.

[0139] Preferably, the combination of NAD with a CD38 inhibitor allows the augmentation of the NAD dose delivered, by reducing its metabolism.

[0140] Preferably, the direct absorption of poorly soluble and poorly bioavailable flavonoid CD38 inhibitors solves the current problem of poor gut absorption and low blood concentrations.

[0141] Preferably, the ready incorporation of a CD38 inhibitor means that the NAD can be augmented further by preventing excessive CD38 metabolism.

[0142] Preferably, the ready incorporation of glutathione and / or coenzyme Q means that the NAD can be augmented further by augmenting the body’s levels of key cellular antioxidants.

[0143] In another aspect, the invention is the use of the composition of the first aspect of the invention in the manufacture of a medicament for the treatment or prevention of a deficiency, condition, disease or disorder.

[0144] In another aspect, the invention is a process of preparing the composition of the first aspect of the invention, said process comprising the steps of: (1) combining at least one matrix forming agent with a biologically active material to form a mixture; and (2) freeze drying the mixture to form the solid dosage form.

[0145] Preferably, the said process further comprising the steps of micronisation.

[0146] Preferably, a mean peak plasma concentration of 72.4ng / mL was reached within10 minutes of administration.

[0147] Preferably, the mean peak plasma concentration of NAD+ is reached after administration at a time selection from the group consisting of: 1 minute; 2 minutes; 3 minutes; 4 minutes; 5 minutes; 6 minutes; 7 minutes; 8 minutes; 9 minutes; 10 minutes; 11 minutes; 12 minutes; 13 minutes; 14 minutes; 15 minutes; 16 minutes; 17 minutes; 18 minutes; 19 minutes; 20 minutes; 21 minutes; 22 minutes; 23 minutes; 24 minutes; 25 minutes; 26 minutes; 27 minutes; 28 minutes; 29 minutes; and 30 minutes.

[0148] Preferably, the red blood cell NAD+ is detected after administration at a time selection from the group consisting of: 1 minute; 2 minutes; 3 minutes; 4 minutes; 5 minutes; 6 minutes; 7 minutes; 8 minutes; 9 minutes; 10 minutes; 11 minutes; 12 minutes; 13 minutes; 14 minutes; 15 minutes; 16 minutes; 17 minutes; 18 minutes; 19 minutes; 20minutes; 21 minutes; 22 minutes; 23 minutes; 24 minutes; 25 minutes; 26 minutes; 27 minutes; 28 minutes; 29 minutes; and 30 minutes.

[0149] Preferably, the NAD+ Cmax (ng / mL) is selected from the group consisting of: 1000 ng / ml; 2000 ng / ml; 3000 ng / ml; 4000 ng / ml; 5000 ng / ml; 6000 ng / ml; 7000 ng / ml; 8000 ng / ml; 9000 ng / ml; 10,000 ng / ml; 11 ,000 ng / ml; 12,000 ng / ml; 13,000 ng / ml; 14,000 ng / ml; 15,000 ng / ml; 16,000 ng / ml; 17,000 ng / ml; 18,000 ng / ml; 19,000 ng / ml; 20,000 ng / ml;21 ,000 ng / ml; 22,000 ng / ml; 23,000 ng / ml; 24,000 ng / ml; 25,000 ng / ml; 26,000 ng / ml;27,000 ng / ml; 28,000 ng / ml; 29,000 ng / ml; 30,000 ng / ml; 31 ,000 ng / ml; 32,000 ng / ml;33,000 ng / ml; 34,000 ng / ml; 35,000 ng / ml; 36,000 ng / ml; 37,000 ng / ml; 38,000 ng / ml;39,000 ng / ml; 40,000 ng / ml; 41 ,000 ng / ml; 42,000 ng / ml; 43,000 ng / ml; 44,000 ng / ml;45,000 ng / ml; 46,000 ng / ml; 47,000 ng / ml; 48,000 ng / ml; 49,000 ng / ml; 50,000 ng / ml;51 ,000 ng / ml; 52,000 ng / ml; 53,000 ng / ml; 54,000 ng / ml; 55,000 ng / ml; 56,000 ng / ml;57,000 ng / ml; 58,000 ng / ml; 59,000 ng / ml; 60,000 ng / ml; 61 ,000 ng / ml; 62,000 ng / ml;63,000 ng / ml; 64,000 ng / ml; 65,000 ng / ml; 66,000 ng / ml; 67,000 ng / ml; 68,000 ng / ml;69,000 ng / ml; 70,000 ng / ml; 71 ,000 ng / ml; 72,000 ng / ml; 73,000 ng / ml; 74,000 ng / ml;75,000 ng / ml; 76,000 ng / ml; 77,000 ng / ml; 78,000 ng / ml; 79,000 ng / ml; 80,000 ng / ml;81 ,000 ng / ml; 82,000 ng / ml; 83,000 ng / ml; 84,000 ng / ml; 85,000 ng / ml; 86,000 ng / ml;87,000 ng / ml; 88,000 ng / ml; 89,000 ng / ml; 90,000 ng / ml; 91 ,000 ng / ml; 92,000 ng / ml;93,000 ng / ml; 94,000 ng / ml; 95,000 ng / ml; 96,000 ng / ml; 97,000 ng / ml; 98,000 ng / ml;99,000 ng / ml; and 100,000 ng / ml.

[0150] Preferably, the NAD+ Tfirst plasma level (ng / mL) is selected from the group consisting of: 1000 ng / ml; 2000 ng / ml; 3000 ng / ml; 4000 ng / ml; 5000 ng / ml; 6000 ng / ml; 7000 ng / ml; 8000 ng / ml; 9000 ng / ml; 10,000 ng / ml; 11 ,000 ng / ml; 12,000 ng / ml; 13,000 ng / ml; 14,000 ng / ml; 15,000 ng / ml; 16,000 ng / ml; 17,000 ng / ml; 18,000 ng / ml; 19,000 ng / ml; 20,000 ng / ml; 21 ,000 ng / ml; 22,000 ng / ml; 23,000 ng / ml; 24,000 ng / ml; 25,000 ng / ml;26,000 ng / ml; 27,000 ng / ml; 28,000 ng / ml; 29,000 ng / ml; 30,000 ng / ml; 31 ,000 ng / ml;32,000 ng / ml; 33,000 ng / ml; 34,000 ng / ml; 35,000 ng / ml; 36,000 ng / ml; 37,000 ng / ml;38,000 ng / ml; 39,000 ng / ml; 40,000 ng / ml; 41 ,000 ng / ml; 42,000 ng / ml; 43,000 ng / ml;44,000 ng / ml; 45,000 ng / ml; 46,000 ng / ml; 47,000 ng / ml; 48,000 ng / ml; 49,000 ng / ml; and 50,000 ng / ml.

[0151] Preferably, the NAD+ Tmax (hrs) is selected from the group consisting of: 0.01 hrs; 0.02 hrs; 0.03 hrs; 0.04 hrs; 0.05 hrs; 0.06 hrs; 0.07 hrs; 0.08 hrs; 0.09 hrs; 0.10 hrs; 0.11 hrs; 0.12 hrs; 0.13 hrs; 0.14 hrs; 0.15 hrs; 0.16 hrs; 0.17 hrs; 0.18 hrs; 0.19 hrs; 0.20 hrs;0.21 hrs; 0.22 hrs; 0.23 hrs; 0.24 hrs; 0.25 hrs; 0.26 hrs; 0.27 hrs; 0.28 hrs; 0.29 hrs; 0.30 hrs; 0.31 hrs; 0.32 hrs; 0.33 hrs; 0.34 hrs; 0.35 hrs; 0.36 hrs; 0.37 hrs; 0.38 hrs; 0.39 hrs;0.40 hrs; 0.41 hrs; 0.42 hrs; 0.43 hrs; 0.44 hrs; 0.45 hrs; 0.46 hrs; 0.47 hrs; 0.48 hrs; 0.49 hrs; 0.50 hrs; 0.51 hrs; 0.52 hrs; 0.53 hrs; 0.54 hrs; 0.55 hrs; 0.56 hrs; 0.57 hrs; 0.58 hrs;0.59 hrs; 0.60 hrs; 0.61 hrs; 0.62 hrs; 0.63 hrs; 0.64 hrs; 0.65 hrs; 0.66 hrs; 0.67 hrs; 0.68 hrs; 0.69 hrs; 0.70 hrs; 0.71 hrs; 0.72 hrs; 0.73 hrs; 0.74 hrs; 0.75 hrs; 0.76 hrs; 0.77 hrs;0.78 hrs; 0.79 hrs; 0.80 hrs; 0.81 hrs; 0.82 hrs; 0.83 hrs; 0.84 hrs; 0.85 hrs; 0.86 hrs; 0.87 hrs; 0.88 hrs; 0.89 hrs; 0.90 hrs; 0.91 hrs; 0.92 hrs; 0.93 hrs; 0.94 hrs; 0.95 hrs; 0.96 hrs;0.97 hrs; 0.98 hrs; 0.99 hrs; 1.00 hrs; 1.01 hrs; 1.02 hrs; 1.03 hrs; 1.04 hrs; 1.05 hrs; 1.06 hrs; 1.07 hrs; 1.08 hrs; 1.09 hrs; 1.10 hrs; 1.11 hrs; 1.12 hrs; 1.13 hrs; 1.14 hrs; 1.15 hrs;1.16 hrs; 1.17 hrs; 1.18 hrs; 1.19 hrs; 1.20 hrs; 1.21 hrs; 1.22 hrs; 1.23 hrs; 1.24 hrs; 1.25 hrs; 1.26 hrs; 1.27 hrs; 1.28 hrs; 1.29 hrs; 1.30 hrs; 1.31 hrs; 1.32 hrs; 1.33 hrs; 1.34 hrs;1.35 hrs; 1.36 hrs; 1.37 hrs; 1.38 hrs; 1.39 hrs; 1.40 hrs; 1.41 hrs; 1.42 hrs; 1.43 hrs; 1.44 hrs; 1.45 hrs; 1.46 hrs; 1.47 hrs; 1.48 hrs; 1.49 hrs; 1.50 hrs; 1.51 hrs; 1.52 hrs; 1.53 hrs;1.54 hrs; 1.55 hrs; 1.56 hrs; 1.57 hrs; 1.58 hrs; 1.59 hrs; 1.60 hrs; 1.61 hrs; 1.62 hrs; 1.63 hrs; 1.64 hrs; 1.65 hrs; 1.66 hrs; 1.67 hrs; 1.68 hrs; 1.69 hrs; 1.70 hrs; 1.71 hrs; 1.72 hrs;1.73 hrs; 1.74 hrs; 1.75 hrs; 1.76 hrs; 1.77 hrs; 1.78 hrs; 1.79 hrs; 1.80 hrs; 1.81 hrs; 1.82 hrs; 1.83 hrs; 1.84 hrs; 1.85 hrs; 1.86 hrs; 1.87 hrs; 1.88 hrs; 1.89 hrs; 1.90 hrs; 1.91 hrs;1.92 hrs; 1.93 hrs; 1.94 hrs; 1.95 hrs; 1.96 hrs; 1.97 hrs; 1.98 hrs; 1.99 hrs; 2.00 hrs; 2.01 hrs; 2.02 hrs; 2.03 hrs; 2.04 hrs; 2.05 hrs; 2.06 hrs; 2.07 hrs; 2.08 hrs; 2.09 hrs; 2.10 hrs;2.11 hrs; 2.12 hrs; 2.13 hrs; 2.14 hrs; 2.15 hrs; 2.16 hrs; 2.17 hrs; 2.18 hrs; 2.19 hrs; 2.20 hrs; 2.21 hrs; 2.22 hrs; 2.23 hrs; 2.24 hrs; 2.25 hrs; 2.26 hrs; 2.27 hrs; 2.28 hrs; 2.29 hrs;2.30 hrs; 2.31 hrs; 2.32 hrs; 2.33 hrs; 2.34 hrs; 2.35 hrs; 2.36 hrs; 2.37 hrs; 2.38 hrs; 2.39 hrs; 2.40 hrs; 2.41 hrs; 2.42 hrs; 2.43 hrs; 2.44 hrs; 2.45 hrs; 2.46 hrs; 2.47 hrs; 2.48 hrs;2.49 hrs; 2.50 hrs; 2.51 hrs; 2.52 hrs; 2.53 hrs; 2.54 hrs; 2.55 hrs; 2.56 hrs; 2.57 hrs; 2.58 hrs; 2.59 hrs; 2.60 hrs; 2.61 hrs; 2.62 hrs; 2.63 hrs; 2.64 hrs; 2.65 hrs; 2.66 hrs; 2.67 hrs;2.68 hrs; 2.69 hrs; 2.70 hrs; 2.71 hrs; 2.72 hrs; 2.73 hrs; 2.74 hrs; 2.75 hrs; 2.76 hrs; 2.77 hrs; 2.78 hrs; 2.79 hrs; 2.80 hrs; 2.81 hrs; 2.82 hrs; 2.83 hrs; 2.84 hrs; 2.85 hrs; 2.86 hrs;2.87 hrs; 2.88 hrs; 2.89 hrs; 2.90 hrs; 2.91 hrs; 2.92 hrs; 2.93 hrs; 2.94 hrs; 2.95 hrs; 2.96 hrs; 2.97 hrs; 2.98 hrs; 2.99 hrs; and 3.00 hrs.

[0152] Preferably, the NAD+ MRT (hrs) is selected from the group consisting of: 0.01 hrs; 0.02 hrs; 0.03 hrs; 0.04 hrs; 0.05 hrs; 0.06 hrs; 0.07 hrs; 0.08 hrs; 0.09 hrs; 0.10 hrs;0.11 hrs; 0.12 hrs; 0.13 hrs; 0.14 hrs; 0.15 hrs; 0.16 hrs; 0.17 hrs; 0.18 hrs; 0.19 hrs; 0.20 hrs; 0.21 hrs; 0.22 hrs; 0.23 hrs; 0.24 hrs; 0.25 hrs; 0.26 hrs; 0.27 hrs; 0.28 hrs; 0.29 hrs;0.30 hrs; 0.31 hrs; 0.32 hrs; 0.33 hrs; 0.34 hrs; 0.35 hrs; 0.36 hrs; 0.37 hrs; 0.38 hrs; 0.39 hrs; 0.40 hrs; 0.41 hrs; 0.42 hrs; 0.43 hrs; 0.44 hrs; 0.45 hrs; 0.46 hrs; 0.47 hrs; 0.48 hrs;0.49 hrs; 0.50 hrs; 0.51 hrs; 0.52 hrs; 0.53 hrs; 0.54 hrs; 0.55 hrs; 0.56 hrs; 0.57 hrs; 0.58 hrs; 0.59 hrs; 0.60 hrs; 0.61 hrs; 0.62 hrs; 0.63 hrs; 0.64 hrs; 0.65 hrs; 0.66 hrs; 0.67 hrs;0.68 hrs; 0.69 hrs; 0.70 hrs; 0.71 hrs; 0.72 hrs; 0.73 hrs; 0.74 hrs; 0.75 hrs; 0.76 hrs; 0.77 hrs; 0.78 hrs; 0.79 hrs; 0.80 hrs; 0.81 hrs; 0.82 hrs; 0.83 hrs; 0.84 hrs; 0.85 hrs; 0.86 hrs;0.87 hrs; 0.88 hrs; 0.89 hrs; 0.90 hrs; 0.91 hrs; 0.92 hrs; 0.93 hrs; 0.94 hrs; 0.95 hrs; 0.96 hrs; 0.97 hrs; 0.98 hrs; 0.99 hrs; 1.00 hrs; 1.01 hrs; 1.02 hrs; 1.03 hrs; 1.04 hrs; 1.05 hrs;1.06 hrs; 1.07 hrs; 1.08 hrs; 1.09 hrs; 1.10 hrs; 1.11 hrs; 1.12 hrs; 1.13 hrs; 1.14 hrs; 1.15 hrs; 1.16 hrs; 1.17 hrs; 1.18 hrs; 1.19 hrs; 1.20 hrs; 1.21 hrs; 1.22 hrs; 1.23 hrs; 1.24 hrs;1.25 hrs; 1.26 hrs; 1.27 hrs; 1.28 hrs; 1.29 hrs; 1.30 hrs; 1.31 hrs; 1.32 hrs; 1.33 hrs; 1.34 hrs; 1.35 hrs; 1.36 hrs; 1.37 hrs; 1.38 hrs; 1.39 hrs; 1.40 hrs; 1.41 hrs; 1.42 hrs; 1.43 hrs;1.44 hrs; 1.45 hrs; 1.46 hrs; 1.47 hrs; 1.48 hrs; 1.49 hrs; 1.50 hrs; 1.51 hrs; 1.52 hrs; 1.53 hrs; 1.54 hrs; 1.55 hrs; 1.56 hrs; 1.57 hrs; 1.58 hrs; 1.59 hrs; 1.60 hrs; 1.61 hrs; 1.62 hrs;1.63 hrs; 1.64 hrs; 1.65 hrs; 1.66 hrs; 1.67 hrs; 1.68 hrs; 1.69 hrs; 1.70 hrs; 1.71 hrs; 1.72 hrs; 1.73 hrs; 1.74 hrs; 1.75 hrs; 1.76 hrs; 1.77 hrs; 1.78 hrs; 1.79 hrs; 1.80 hrs; 1.81 hrs;1.82 hrs; 1.83 hrs; 1.84 hrs; 1.85 hrs; 1.86 hrs; 1.87 hrs; 1.88 hrs; 1.89 hrs; 1.90 hrs; 1.91 hrs; 1.92 hrs; 1.93 hrs; 1.94 hrs; 1.95 hrs; 1.96 hrs; 1.97 hrs; 1.98 hrs; 1.99 hrs; 2.00 hrs;2.01 hrs; 2.02 hrs; 2.03 hrs; 2.04 hrs; 2.05 hrs; 2.06 hrs; 2.07 hrs; 2.08 hrs; 2.09 hrs; 2.10 hrs; 2.11 hrs; 2.12 hrs; 2.13 hrs; 2.14 hrs; 2.15 hrs; 2.16 hrs; 2.17 hrs; 2.18 hrs; 2.19 hrs;2.20 hrs; 2.21 hrs; 2.22 hrs; 2.23 hrs; 2.24 hrs; 2.25 hrs; 2.26 hrs; 2.27 hrs; 2.28 hrs; 2.29 hrs; 2.30 hrs; 2.31 hrs; 2.32 hrs; 2.33 hrs; 2.34 hrs; 2.35 hrs; 2.36 hrs; 2.37 hrs; 2.38 hrs;2.39 hrs; 2.40 hrs; 2.41 hrs; 2.42 hrs; 2.43 hrs; 2.44 hrs; 2.45 hrs; 2.46 hrs; 2.47 hrs; 2.48 hrs; 2.49 hrs; 2.50 hrs; 2.51 hrs; 2.52 hrs; 2.53 hrs; 2.54 hrs; 2.55 hrs; 2.56 hrs; 2.57 hrs;2.58 hrs; 2.59 hrs; 2.60 hrs; 2.61 hrs; 2.62 hrs; 2.63 hrs; 2.64 hrs; 2.65 hrs; 2.66 hrs; 2.67 hrs; 2.68 hrs; 2.69 hrs; 2.70 hrs; 2.71 hrs; 2.72 hrs; 2.73 hrs; 2.74 hrs; 2.75 hrs; 2.76 hrs;2.77 hrs; 2.78 hrs; 2.79 hrs; 2.80 hrs; 2.81 hrs; 2.82 hrs; 2.83 hrs; 2.84 hrs; 2.85 hrs; 2.86 hrs; 2.87 hrs; 2.88 hrs; 2.89 hrs; 2.90 hrs; 2.91 hrs; 2.92 hrs; 2.93 hrs; 2.94 hrs; 2.95 hrs;2.96 hrs; 2.97 hrs; 2.98 hrs; 2.99 hrs; and 3.00 hrs.

[0153] Preferably, the RBC NAD+ after sublingual administration was detected immediately after 5 minutes (Tfirst), showing a rapid systemic absorption after SL administration. The Tfirst plasma concentration for RBC NAD+ level for sublingual administration (5040 ng / mL) was higher than the IV administration (2110 ng / mL).

[0154] Preferably, the SL absorption is slower than the IV infusion.

[0155] Preferably, the NAD+ wafers (NADiX+) revealed a rapid and significantly increased in blood NAD+ levels

[0156] Preferably, the faster MRT for SL administration over the slow IV administration revealed that SL-administered NAD+ is rapidly absorbed within 10 mins of the slow IV infusion.

[0157] In another aspect, the invention is a kit comprising the dosage form of one aspect of the invention together with instructions for its use.

[0158] Preferably, the kit is directed to treating of preventing a deficiency, condition, disease or disorder.

[0159] Further features of the present invention are more fully described in the following description of several non-limiting embodiments thereof. This description is included solely for the purposes of exemplifying the present invention. It should not be understood as a restriction on the broad summary, disclosure or description of the invention as set out above.

[0160] Brief Description of the Drawings

[0161] Figure 1 represents the single dose pharmacokinetics in Sprague-Dawley rats.

[0162] Figure 2 represents the differences in RBC (red blood cells) NAD+ level between Intravenous NAD+ 5mg infused over 10 mins and sublingual (SL) administered 100mg NAD+ (NADiX+) in rats (n=4).Detailed Description of the Invention

[0163] For convenience, the following sections generally outline the various meanings of the terms used herein. Following this discussion, general aspects regarding compositions, use of medicaments and methods of the invention are discussed, followed by specific examples demonstrating the properties of various embodiments of the invention and how they can be employed.

[0164] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes all such variations and modifications. The invention also includes all of the steps, features, formulations and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

[0165] Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirety by reference, which means that it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in this text is not repeated in this text is merely for reasons of conciseness. None of the cited material or the information contained in that material should, however, be understood to be common general knowledge.

[0166] Manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and can be employed in the practice of the invention.

[0167] The invention described herein may include one or more ranges of values (e.g., size, concentration etc.). A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range that lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.

[0168] The present invention is not to be limited in scope by any of the specific embodiments described herein. These embodiments are intended for the purpose of exemplification only. Functionally equivalent products, formulations and methods are clearly within the scope of the invention as described herein.1. DEFINITIONS -

[0169] The meaning of certain terms and phrases used in the specification, examples, and appended claims, are provided below. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0170] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about." The term "about" when used in connection with percentages can mean ±1%.

[0171] The invention described herein may include one or more range of values (e.g., size, concentration etc.). A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range which lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range. For example, a person skilled in the field will understand that a 10% variation in upper or lower limits of a range can be totally appropriate and is encompassed by the invention. More particularly, the variation in upper or lower limits of a range will be 5% or as is commonly recognised in the art, whichever is greater.

[0172] In this application, the use of the singular also includes the plural unless specifically stated otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component”encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise. Also, the use of the term “portion” can include part of a moiety or the entire moiety.

[0173] Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0174] “Therapeutically effective amount” as used herein with respect to methods of treatment and in particular drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that “therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the disorder, condition of diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as sublingual, oro- mucosal, or oral dosages, or with reference to drug levels as measured in blood. Amounts effective for such a use will depend on: the desired therapeutic effect; the potency of the biologically active material; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; and the judgment of the prescribing physician. Treatment dosages need to be titrated to optimize safety and efficacy. One skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the indication for which the active agent is being used, the route of administration, and the size (body weight, body surface or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician may titre the dosage and modify the route of administration to obtain the optimal therapeutic effect. A typical dosage may range from about 0.1 .g / kg to up to about 100 mg / kg or more, depending on the factors mentioned above. In other embodiments, the dosage may range from 0.1 .g / kg up to about 100 mg / kg; or 1 .g / kg up to about 100 mg / kg; or 5 p.g / kg up to about 100 mg / kg.

[0175] The frequency of dosing will depend upon the pharmacokinetic parameters of the active agent and the formulation used. Typically, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinelymade by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate doseresponse data.

[0176] As used herein "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0177] As used herein the term “subject” generally includes mammals such as: humans; farm animals such as sheep, goats, pigs, cows, horses, llamas; companion animals such as dogs and cats; primates; birds, such as chickens, geese and ducks; fish; and reptiles. The subject is preferably human. In one embodiment, the human subject is an infant, child, or adolescent. In one embodiment, the human subject is a paediatric patient aged 21 or younger at the time of their diagnosis or treatment.

[0178] Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.

[0179] Features of the invention will now be discussed with reference to the following non-limiting description and examples.2. EMBODIMENTS

[0180] In a further broad aspect, the invention delivers NAD+ or GSH or coenzyme Q (in any oxidized or reduced form) directly into the bloodstream, by delivering 50-125mg of pure, fully formed NAD+ or NADH, and in one preferred embodiment, optionally together with a CD38 inhibitor, and / or GSH and / or coenzyme Q as a conjugate antioxidant booster, through the thin membrane under the tongue and directly into the rich blood vessels for immediate transport. With a daily single wafer dosage, or by spacing out the NAD / CD38 / GSH / coenzyme Q wafers throughout the day, a steady supply of NAD+ and / or GSH and / or coenzyme Q is allowed to build up, returning levels to those of a younger person. In order to solve the problem of ready degradation of NAD in the gut, or a requirement to attend a clinic for IV transfusion of high dosages, the inventors have invented a delivery system that provides a solution to the shortcomings of the prior art. A number of preferred embodiments include the following.

[0181] From 50mg to 125mg (preferred; total range 0-150mg) NAD+and / or NADH and / or in one preferred embodiment, optionally 5-20mg (preferred; total range 0-150mg) of aCD38 inhibitor such as apigenin or quercetin or any other molecule listed in Table 1 , alone or in combination, is able to be incorporated into a rapidly disintegrating wafer.

[0182] As an adjunct antioxidant, from 5-100mg GSH (preferred; full range 0-150mg) is to be incorporated into a rapidly disintegrating wafer.

[0183] As an adjunct antioxidant, from 5-100mg coenzyme Q (preferred; full range 0- 150mg) is to be incorporated into a rapidly disintegrating wafer.

[0184] As an adjunct endogenous cellular health enhancer, from 5-100mg of a molecule listed in Table 2, alone or in combination (preferred; full range 0-150mg for each molecule) is to be incorporated into a rapidly disintegrating wafer.

[0185] As an adjunct cellular health enhancer, from 5-100mg of a sirtuin activator molecule listed in Table 3, alone or in combination (preferred; full range 0-150mg for each molecule) is to be incorporated into a rapidly disintegrating wafer.

[0186] The wafer is designed to be administered orally, preferably buccally or sublingually.

[0187] The convenient nature of the dosage form means that one dose per day, or alternatively several dosages per day may be readily and easily taken, allowing a constant delivery of between 50mg-500mg per day, and allowing a steady and controlled buildup of depleted NAD towards a steady state blood concentration.

[0188] The high strength of NAD able to be incorporated (50-125mg per dose) means that the number of dosages required for achieving physiologic effects is minimized to 1 -4 per day.

[0189] The ability to incorporate adjunct actives CD38 inhibitors and / or GSH and / or coenzyme Q antioxidants and / or endogenous cellular health molecules and / or sirtuin activators means that the range of effect once absorbed may be synergized over one active alone.

[0190] The wafer is designed to allow a significant length of contact time with the mucosal surface, allowing absorption of the active(s) and transfer directly into the circulatory system.

[0191] The NAD in the wafer is stable, allowing long term storage before the subject takes the dosage.

[0192] The combination of NAD+and / or NADH with a CD38 inhibitor allows the augmentation of the NAD dose delivered, by reducing its metabolism.

[0193] The direct absorption of poorly soluble and poorly bioavailable flavonoid CD38 inhibitors solves the current problem of poor gut absorption and low blood concentrations.

[0194] The direct contact of NAD+ with the mucosal system was at first problematic due to its strong sour taste, reducing potential customer acceptance. However, a series of experiments has devised a flavour combination which masks this feature, and therefore removes a potential barrier to consumer use.

[0195] The nature of the dosage form, its stability on storage, its mode of delivery bypassing the digestive system, its multi-dose per day format, and its acceptable flavour profile means that the inconvenient nature of episodic clinical IV infusion has been solved.

[0196] Ready incorporation of a CD38 inhibitor means that the NAD can be augmented further by preventing excessive CD38 metabolism.

[0197] Ready incorporation of GSH and / or coenzyme Q means that the NAD can be augmented further by augmenting the body’s levels of key cellular antioxidants.

[0198] Ready incorporation of an endogenous cellular health molecule, exemplified by those listed in Table 2, means that the NAD can be augmented further by augmenting the body’s levels of key cellular health molecules.

[0199] Ready incorporation of an exogenous sirtuin activator, exemplified by those listed in Table 3, means that the NAD can be augmented further by augmenting the body’s levels of key cellular health NAD-dependent enzymes.

[0200] The absorptivity of the actives under consideration is further enhanced by incorporating a nanosizing processing step, whereby particle sizes are reduced to low micron or sub-micron size. Preferably, the formulation prior to freeze drying is passed through a micronisation apparatus to reduces average particle size to 200-5, OOOnm (preferred, total range 10-10000nm).

[0201] The described invention with many features unable to be achieved with current commercial practice will clearly represent a major improvement in delivery for those skilled in the art.

[0202] The composition of the present invention comprises at least one matrix forming agent. In the freeze-dried systems of the prior art, gelatin is the most commonly used carrier or structure forming agent due to its wall-forming ability. Gelatin is an ionic water-soluble polymer, and as such, when mixed with active pharmaceutical ingredients in water; theincreasing viscosity of the solution over time may cause a decreasing solubility of poorly soluble drugs in the mixture, and lead to a suspension of the drug in gelatin matrix. This can cause phase separation to occur; and the drug in amorphous or crystalline forms may not be homogenously dispersed in the matrix, which will eventually affect the dissolution and absorption of the final product.

[0203] Applicant has found that other polymer materials suitable for forming a matrix may be selected for specific application in the field of drug delivery, especially for sitespecific drug delivery system such as in the oral cavity. Matrix forming agents of the present invention may be selected from the group consisting of: non-mammalian gelatin, dextrin, soy protein, wheat protein, psyllium seed protein, acacia gum, guar gum, agar gum, xanthin gum, polysaccharides; alginates; sodium carboxymethylcellulose; carrageenans; dextrans; pectins; sugars; amino acids; starch; modified starches; carboxymethylcellylose; hydroxypropylmethylcellulose; hydroxypropyl cellulose and methyl cellulose inorganic salts; synthetic polymers; amylopectin, polypeptide / protein or poly-saccharide complexes. Examples of at least one matrix forming agent that are carbohydrates include mannitol, dextrose, lactose, galactose, sorbitol and trehalose and cyclodexrin. Examples of matrix forming agents that are inorganic salts may be selected from the group consisting of: sodium phosphate, sodium chloride and aluminium silicates. The at least one matrix forming agent may also be an amino acid. Examples of suitable amino acids include glycine, L-alanine, L- aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

[0204] In an embodiment, at least one matrix forming agent is sodium carboxymethylcellulose. When at least one matrix forming agent is sodium carboxymethyl cellulose, the polymer is present in a concentration of from about 0.1% to about 19% by dry weight of the solid dosage form. In a preferred embodiment the sodium carboxymethylcellulose is present in an amount of about 0.1% to about 15% by dry weight of the dosage form. In a preferred embodiment of the present invention, the sodium carboxymethyl cellulose is present in an amount of about 0.1 % to about 1 .0% by dry weight of the solid dosage form.

[0205] In another embodiment of the present invention, the dissolving dosage form comprises amylopectin (amorphous water-Osoluble starch component) as at least one matrix forming agent. Amylopectin is capable of increasing the release of the biologically active material by promoting formulation disintegration. Amylopectin may be present in the dosage form at a concentration about 2% up to no greater than 20% by dry weight of the solid dosage form. In a highly preferred form of the present invention, amylopectin is present in an amount of about 5% to about 15% dry weight of the dosage form.

[0206] To achieve dissolution of drugs, low MW diluents may be added as at least one matrix forming material. Diluents include microcrystalline cellulose (e.g., Avicel PH 101® and Avicel PH 102®), lactose, starch and sorbitol. These diluents may be present in the dosage form either alone or as a mixture in different ratios, and may be about 1% to about 80%, preferably about 2% to about 50%, either individually or cumulatively. In one embodiment of the present invention, the dissolving dosage form comprises microcrystalline cellulose as the at least one matrix forming agent. Microcrystalline cellulose may act as a filler and binder in the dosage form of the present invention. Microcrystalline cellulose has the ability to compact with minimum compression pressures, and results in a hard, stable and dissolving dosage form. Due to its large surface area and high internal porosity, microcrystalline cellulose is able to absorb and retain large amounts of water, which is desirable in the dosage form of the invention. When the solid dosage form of the present invention comprises microcrystalline cellulose, it is present in an amount of about 1% to about 10%, and preferably from about 1% to about 8% by dry weight of the dosage form. The effectiveness of the dissolving dosage form of the present invention relies on the drug dissolving in a small volume of fluid, such as in the oral cavity, prior to absorption into the systemic circulation. Therefore, the rate of dissolution of the dosage form is important. In a preferred embodiment of the present invention, the dosage form comprises a super- disintegrant as at least one matrix forming material.

[0207] In a highly preferred embodiment, the dissolving dosage form of the present invention comprises glycine. Glycine is an amino acid with excellent wetting properties and is suitable for the dissolving formulation. Low amounts of glycine may be used in the formulation of the present invention to control the dissolution rate of the dosage form. Furthermore, glycine may also be used as an anti-collapsing agent, which maintains the dosage form from shrinking either during the manufacture process or after packing. In one embodiment, the dosage form of the present invention comprises from about 0.5% to about 5% dry weight of the dosage form. According to another embodiment of the invention, the solid dosage form may include a matrix forming agent such as mannitol. Mannitol is a component that may aid in the crystalline structure and impart hardness of the dosage form. When mannitol is present in the dosage form, it occurs in a concentration of from about 5% to about 80%, and preferably from about 10% to about 60% by dry weight of the dosage form.

[0208] In addition, the dissolving dosage form of the present invention may include lubricants, such as polyethylene glycol (PEG) 1000, 1500, 2000, 4000 and 6000, sodium lauryl sulphate, fats or oils. One advantage of the use of these lubricants is to aid in the removal of the dosage form from the mould. These lubricants may be present in the dosageform either alone or as a mixture in different ratios, and may be between 0.05% to 5%, preferable between 0.1% and 2%, preferable about 1 .5%, either individually or cumulatively. In one embodiment, the composition includes between 0.05% to 5% polyethylene glycol 1500, preferably between 0.1% and 2% by dry weight of the dosage form, or as mixtures of the various glycols. The invention extends, in another aspect thereof, to improve sublingual absorption of weak base compounds, the composition comprising a solid buffer reagent that affords to produce a saliva pH of 4-6 when dissolved in oral cavity. Increasing the pH of the solution of a weak base compound can increase the ratio of unionized to ionized, which will lead to enhanced sublingual absorption. The solid buffer reagent includes sodium dihydrogen phosphate dihydrate, sodium hydrogen phosphate, sodium hydrogen carbonate and sodium carbonate, which may be present in the dosage form either alone or as a mixture in different ratios in a concentration of about 0.01% to about 10% by weight of the composition. Preferably, the buffer reagent is a phosphate salt, which may be present in a concentration of about 0.01% to about 10% by weight of the composition, preferably between 0.1% to 1%, most preferably about 0.3%.

[0209] When mannitol is present in the dosage form, it occurs in a concentration of from about 5% to about 80%, and preferably from about 10% to about 60% by dry weight of the dosage form.

[0210] The composition may, in certain embodiments, include an absorption enhancer. The absorption enhancer may be a polysaccharide and may be positively charged. Preferably, the absorption enhancer is p-cyclodextrin or its derivatives. The p-cyclodextrin or derivative may be present in a concentration of from about 0.01% to about 10% by dry weight of the dosage form, preferably between 0.2% to 2%, and most preferably about 1 %. The solid dosage form of the present invention may comprise flocculating agents to maintain disbursement of the biologically active material evenly dispersed in the matrix during the manufacture process. The flocculating agent may be gums. Preferably, the gum is xanthan gum. The xanthan gum may be present in a concentration of about 0.01% to about 10% by dry weight of the composition, preferably from about 0.2% to 2%, and most preferably about 1%.

[0211] To aid dissolution of the biologically active material into the aqueous environment, a surfactant may be added to the solution as a wetting agent. Suitable surfactants include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents may be used and include benzalkonium chloride or benzethomium chloride. The list of possible non-ionic detergents includes lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil10, 50 and 60, glycerol monostearate, Polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants may be present in the dosage form either alone or as a mixture in different ratios. Additives which potentially enhance uptake of the compounds are fatty acids such as oleic acid, linoleic acid and linolenic acid.

[0212] In order to enhance the aesthetic and taste appeal of the dissolving dosage form to the subject, the dosage form may also contain colouring agents, such as FD & C dyes Blue No. 2 and Red No. 40; flavoring agents, such as lemonade, orange, mixed berry, cherry, peppermint, raspberry and caramel; and / or sweeteners such as aspartame, stevia, sucralose and saccharin.

[0213] The solid dosage form of the present invention is suitable for oral administration to a subject. As discussed above, the dosage form comprises biologically active material. The biologically active material is therefore delivered to the subject via the oral cavity mucosa and into the systemic blood system within a relatively short period of time. In a preferred embodiment, an effective plasma concentration of the biologically active material is reached within a period of no more than two hours, preferably within 30 minutes, and most preferably within 10 minutes.

[0214] Furthermore, an advantage of the present invention is that the solid dosage form completely disintegrates and dissolves within 2 seconds to 60 seconds, preferably 2 seconds to 30 seconds, and most preferably within 2 seconds to 10 seconds after administration of the dosage form. In a highly preferred embodiment of the present invention, there is no residue remaining of the dosage form of the present invention after administration that is detectable by the patient. As such, the subject has no urge to swallow the dosage form.

[0215] The subject receiving the dissolving dosage form of the present invention may be an animal or human being. When the subject is a human being, it may be an adult or a child, including elderly adults and infants. In particular, the subject is a subject that is unable to or has difficulties in swallowing.

[0216] The solid dosage form may comprise sodium carboxymethylcellulose as a formulation aide in low levels. When the amount of sodium carboxymethylcellulose is between about 0.1% and 15% by dry weight of the dosage form, the wafer releases the active agent, without leaving a residue in the oral cavity. In addition, the use of gelatin was avoided by the inventors, and therefore prevents the unwanted residue left in the oral cavity after administration. The addition of lactose and or mannitol was also found to be advantageous in the dosage formulation of the present invention.

[0217] Thus, in one embodiment, the present invention provides a solid dosage form adapted for the release of biologically active material in the oral cavity wherein the dosage form comprises: (I) biologically active material and (ii) at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity, wherein the dosage form comprises 0.1-4% sodium carboxymethylcellulose, 0.1 -10% PEG 1500, 1-4% glycine, 1-10% microcrystalline cellulose; 2-17% amylopectin, 10-30% lactose and 30-50% mannitol as a dry weight of the solid dosage form, and which does not result in substantial detectable levels of residue left over in the oral cavity of the patient.Pharmaceutical

[0218] The present invention also provides a pharmaceutical composition comprising the composition of the invention together with a pharmaceutically acceptable carrier.

[0219] Therapeutic compositions are within the scope of the present invention. Preferably the compositions are combined with a pharmaceutically acceptable carrier or diluent to produce a pharmaceutical composition (which may be for human or animal use). Suitable carriers and diluents include isotonic saline solutions, for example phosphate- buffered saline. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. See, e.g., Remington's Pharmaceutical Sciences, 2nd Ed. (1995, Mack Publishing Co., Easton, Pa.) which is herein incorporated by reference.

[0220] The pharmaceutical composition can contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, colour, isotonicity, odour, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulphite or sodium hydrogen-sulphite, Vitamin E, Vitamin E phosphate - lipid soluble vitamins, nano emulsions); buffers (such as borate, bicarbonate, tris-HCI, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta- cyclodextrin), fillers; monosaccharides, disaccharides; and other carbohydrates (such as glucose, mannose, or dextrins); proteins (such as serum albumin, gelatin orimmunoglobulins); colouring, flavouring (natural and natural derived products) and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols - and artificial sweetners (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapol); stability enhancing agents (sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride), delivery vehicles, diluents, excipients and / or pharmaceutical adjuvants.

[0221] The optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the composition of the invention. The preferred form of the pharmaceutical composition depends on the intended mode of administration and therapeutic application.

[0222] The formulation components are present in concentrations that are acceptable to the site of administration. For example, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 (4.5) to about 8

[0223] Additional pharmaceutical compositions will be evident to those skilled in the art, including formulations of the invention in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Additional examples of sustained-sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, for example, films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, ethylene vinyl acetate or poly-D(-)-3-hydroxybutyric acid. Sustained-release compositions may also include liposomes, which can be prepared by any of several methods known in the art.

[0224] The pharmaceutical composition to be used for in vivo administration typically must be sterile. This may be accomplished by filtration through sterile filtration membranes. In addition, the compositions generally are placed into a container having a sterile accessport. Once the pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution.

[0225] In yet a further preferred embodiment, the composition retains its effective biological activity for a period selected from the group consisting of; greater than 24 hours; greater than 36 hours; and greater than 48 hours. Preferably, the composition is stable for periods selected from the group consisting of: 6 months, 1 year and 2 years. In one example, the composition is stable at temperatures selected from the group consisting of: - 4°C, 4°C, 18°C and 25°C.

[0226] As discussed above, the medicaments of the present invention may include one or more pharmaceutically acceptable carriers. The use of such media and agents for the manufacture of medicaments is well known in the art. Except insofar as any conventional media or agent is incompatible with the pharmaceutically acceptable material, use thereof in the manufacture of a pharmaceutical composition according to the invention is contemplated. Pharmaceutical acceptable carriers according to the invention may include one or more of the following examples:

[0227] (1 ) surfactants and polymers, including, however not limited to polyethylene glycol (PEG), polyvinylpyrrolidone , polyvinylalcohol, crospovidone, polyvinylpyrrolidone- polyvinylacrylate copolymer, cellulose derivatives, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, and their polymers, emulsifiers, sugar gum, starch, organic acids and their salts, vinyl pyrrolidone and vinyl acetate; and / or

[0228] (2) binding agents such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and / or (3) filling agents such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose and various starches; and / or

[0229] (4) lubricating agents such as agents that act on the increased ability of the dosage form to be ejected from the packaging cavity, and / or

[0230] (5) sweeteners such as any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; and / or

[0231] (6) flavouring agents; and / or

[0232] (7) preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben,alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quarternary compounds such as benzalkonium chloride; and / or

[0233] (8) buffers; and / or

[0234] (9) diluents such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or mixtures of any of the foregoing; and / or

[0235] (10) wetting agents such as corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crosspovidone, sodium starch glycolate, and mixtures thereof; and / or

[0236] (11 ) disintegrants; and / or

[0237] (12) effervescent agents such as effervescent couples such as an organic acid(e.g., citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts), or a carbonate (e.g. sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate) or bicarbonate (e.g. sodium bicarbonate or potassium bicarbonate);

[0238] Permeation enhancer; Entero-hepatic recycling agent, mucolytic; mucoadhesive, entero-hepatic-biliary recirculation agent such as sodium glycodeoxycholate, sodium deoxycholate, carboxymethyl cellulose, sodium alginate, SNAC (salcaprozate sodium), soy lecithin etc. and other pharmaceutically acceptable excipients; and / or

[0239] (13) other pharmaceutically acceptable excipients.

[0240] Medicaments of the invention suitable for use in animals and in particular in human beings typically must be sterile and stable under the conditions of manufacture and storage. The medicaments of the invention comprising biologically active material can be formulated as a solid, a liposome, or other ordered structures suitable to high drug concentration adapted for oral delivery.

[0241] In another embodiment, the biologically active material may be combined into a medicament with another biologically active material, or even the same biologically active material.

[0242] Medicaments of the invention can be orally, sublingually or oromucosally administered to a subject. Solid dosage forms for oral administration include wafers, but also tablets and capsules. Further, incorporating any of the normally employed excipients, such as those previously listed, and generally 0.1% to 95% of the biologically active material, andmore preferably at a concentration of 0.1% to 75% will form a pharmaceutically acceptable non-toxic oral administration.Neutraceutical

[0243] The present invention also provides a neutraceutical composition comprising the composition of the invention together with a neutraceutically acceptable carrier.Dosage Form

[0244] Dosage forms are within the scope of the invention. In a preferred embodiment, the invention provides a dosage form comprising the composition as described in the first aspect of this invention.

[0245] In a further embodiment, the dosage form is a wafer.

[0246] Preferably, the dosage form is stored in a sealed and sterile container.Method for treating or preventing

[0247] The invention also provides a method of treating a deficiency, condition, disease or disorder, said method comprising administering to a patient in need thereof a therapeutically effective amount of the dosage form of the invention.

[0248] In a further preferred embodiment, the dosage form is administered at an amount to at least partially treat the deficiency, disorder, disease or condition.

[0249] In a further preferred embodiment, the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: between 0.001 to 10Omg / kg / day; between 1 to 10Omg / kg / day; between 2 and 50mg / kg / day; between 5 and 40mg / kg / day; between 10 and 30mg / kg / day; between 20 and 25mg / kg / day; and 20mg / kg / day. Preferably, the therapeutically effective amount is an amount of biologically active material vis selected from the group consisting of: 0.1 mg / day; 5mg / day; 10mg / day; 15mg / day; 40mg / day; 400mg / day; 600mg / day; 800mg / day; 1280mg / day; 1500mg / day.

[0250] In a further preferred embodiment, therapeutically effective amount is an amount of biologically active material selected from the group consisting of: between 0.01 to 100mg / kg / day; between 1 to 100mg / kg / day; between 2 and 50mg / kg / day; between 5 and 40mg / kg / day; between 10 and 30mg / kg / day; between 20 and 25mg / kg / day; and 20mg / kg / day. Preferably, the therapeutically effective amount is an amount of biologically active material vis selected from the group consisting of: 10mg / day; 15mg / day; 40mg / day; 400mg / day; 600mg / day; 800mg / day; 1280mg / day; 1500mg / day.

[0251] In a further preferred embodiment, Tmax occurs between 0.01 and 336 hours; 1 and 4 hours.

[0252] In a further preferred embodiment, T1 / 2 occurs between 0.1 1 and 12 hours; 0.01 and 12 hours; 1.1 and 2.4 hours.

[0253] In a further preferred embodiment, the therapeutically effective amount is administered to the subject to treat the disorder.

[0254] Preferably the therapeutically effective amount is administered to the subject utilising a dosing regimen selected from the group consisting of: twice hourly; hourly; once every six hours; once every 8 hours; once every 12 hours; once daily; twice weekly; once weekly; once every 2 weeks; once every 6 weeks; once a month; every 2 months; every 3 months; once every 6 months; and once yearly.

[0255] Preferably the therapeutically effective amount is administered to the subject using a method selected from the group consisting of: sublingually.

[0256] A subject that can be treated with the invention will include humans as well as other mammals and animals.

[0257] In a further preferred embodiment, the method comprises administering to a patient in need thereof a therapeutically effective amount of the dosage form of the invention together with an additional active ingredient. In a preferred form, the additional active ingredient is administered using a dosing regimen selected from the group consisting of: at the same time as administering the dosing form of the invention; before administering the dosing form of the invention; after administering the dosing form of the invention; concurrently with administering the dosing form of the invention; sequentially before administering the dosing form of the invention; and sequentially after administering the dosing form of the invention.

[0258] Preferably, the additional active ingredient is selected from the group consisting of: an amino acid; a bipeptide; a tripeptide; a polypeptide; an antibody; a small chemical entity; a biologic; or another wafer.Use of a composition in the manufacture of a medicament

[0259] Uses are within the scope of this invention. The invention also provides a use of the composition of the first aspect of the invention in the manufacture of a medicament for the treatment of a deficiency, condition, disease or disorder.Kit

[0260] The invention also provides a kit comprising the dosage form of one aspect of the invention together with instructions for its use.Device

[0261] Devices are within the scope of the invention. In a preferred embodiment, the invention provides a device, wherein the device comprises: (1 ) the composition as described in the first aspect of this invention; and (2) an applicator.Method for stabilising

[0262] Methods for stabilizing the composition are within the scope of the invention.

[0263] In a further preferred embodiment, the said method protects the composition against degradation.

[0264] The addition of approved pharmaceutical excipients to stabilise the composition is preferred from a safety standpoint, as the simpler methodology is likely to produce a less variable outcome and the choice of excipient can be limited to those with Generally Regarded as Safe (GRAS) status. Excipients for the stabilisation of protein solutions can be classified into four broad categories: salts, sugars, polymers or protein / amino acids, based on their chemical properties and mechanism of action. Salts (e.g., chlorides, nitrates) stabilise the tertiary structure of proteins by shielding charges through ionic interactions. Sugars (e.g., glycerol, sorbitol, fructose, trehalose) increase the surface tension and viscosity of the solution to prevent protein aggregation. Similarly, polymers (e.g. polyethylene glycol, cellulose derivatives) stabilise the protein tertiary structure by increasing the viscosity of the solution to prevent protein aggregation and intra- and inter-molecular electrostatic interactions between amino acids in the protein. Proteins (e.g. human serum albumin) are able to stabilise the structure of other proteins through ionic, electrostatic and hydrophobic interactions. Similarly, small amino acids with no net charge, such as alanine and glycine, stabilise proteins through the formation of weak electrostatic interactions.

[0265] As discussed above, the medicaments of the present invention may include one or more pharmaceutically acceptable carriers. The use of such media and agents for the manufacture of medicaments is well known in the art. Except insofar as any conventional media or agent is incompatible with the pharmaceutically acceptable material, use thereof in the manufacture of a pharmaceutical composition according to the invention is contemplated. Pharmaceutical acceptable carriers according to the invention may include one or more of the following examples:a. surfactants and polymers, including, however not limited to polyethylene glycol (PEG), polyvinylpyrrolidone , polyvinylalcohol, crospovidone, polyvinylpyrrolidone- polyvinylacrylate copolymer, cellulose derivatives, HPMC, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, and their polymers, emulsifiers, sugar gum, starch, organic acids and their salts, vinyl pyrrolidone and vinyl acetate; and / or b. binding agents such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and / or (3) filling agents such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose and various starches; and / or c. filling agents such as lactose monohydrate, lactose anhydrous, mannitol, microcrystalline cellulose and various starches; and / or d. lubricating agents such as agents that act on the increased ability of the dosage form to be ejected from the packaging cavity, and / or e. sweeteners such as any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; and / or f. flavouring agents; and / or g. preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quarternary compounds such as benzalkonium chloride; and / or h. buffers; and / or i. diluents such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or mixtures of any of the foregoing; and / or j. absorption enhancer such as glyceryl trinitrate; k. add penetrants, permeation enhancer; entero-hepatic recycling agent, mucolytic; mucoadhesive, entero-hepatic-biliary recirculation agent such as sodium glycodeoxycholate, sodium deoxycholate, carboxymethyl cellulose, sodium alginate, SNAC (salcaprozate sodium), soy lecithin Sodium glycodeoxycholate; and / or l. other pharmaceutically acceptable excipients.

[0266] Medicaments of the invention suitable for use in animals and in particular in human beings typically must be sterile and stable under the conditions of manufacture and storage.

[0267] Methods to produce

[0268] According to a further aspect of the present invention, there is provided a method to produce the dosage form of the present invention comprising the steps of combining at least one matrix forming agent with a biological active material to form a mixture and then freeze drying the mixture to form the solid dosage form. In a preferred embodiment of the present invention, the mixture is measured (by weight or volume) into a preformed plastic or aluminium blister mould (individual dose). The blister mould is placed into a freeze dryer for 24-48 hours and the resultant solid dosage form (wafer) is then sealed with aluminium or plastics foil to prevent moisture absorption.

[0269] In one embodiment of the present invention, the method may require that the pH of the mixture is adjusted to a pH within the range of between 2.0 and 8.0, preferably between 2.0 and 4.0. If required, the pH may be adjusted by using an acid, such as hydrochloric acid, phosphoric acid or citric acid; or a basic compound such as sodium hydroxide, sodium dihydrogen phosphate dehydrate, sodium hydrogen phosphate, sodium hydrogen carbonate, tris hydrochloride and sodium carbonate.

[0270] In another embodiment, the method may include the step of using a solvent, such as water. If water is used as a solvent, it is preferable to be removed by freeze drying.

[0271] Further embodiments of the invention include compositions comprising agents selected from the group consisting of: any one of the agents selected in Tablel ; any one of the agents selected in Table 2; any one of the agents selected in Table 3.

[0272] Table 1 - CD38 flavonoid inhibitors.

[0273] Table 2 - Endogenous anti-aging cellular function boosters and protectors.

[0274] Table 3 - Sirtuin activators.

[0275] The invention also provides a composition, methods and processes as described by the foregoing examples.

[0276] The present invention will now be described with reference to the following nonlimiting Examples. The description of the Examples is in no way limiting on the preceding paragraphs of this specification, however, is provided for exemplification of the methods and compositions of the invention.Examples

[0277] It will be apparent to persons skilled in the pharmaceutical arts that numerous enhancements and modifications can be made to the above-described processes without departing from the basic inventive concepts. For example, in some applications the biologically active material may be pretreated and supplied to the process in the pretreated form. All such modifications and enhancements are considered to be within the scope of the present invention, the nature of which is to be determined from the foregoing description and the appended claims. Furthermore, the following Examples are provided for illustrative purposes only, and are not intended to limit the scope of the processes or compositions of the invention.A EXAMPLE 1 - PREPARATION OF 100MG NAD+ PER WAFER DOSAGE FORMS.

[0278] The inventors prepared a bulk solution to make 8000 wafers containing 10Omg of NAD active. 90-98% of the total water volume required was dispensed into a suitable container and stirring then commenced. Matrix forming agents CMC, mannitol, lactose and amylopectin were added and stirred until completely dissolved. Glycine, PEG 1500 and flavouring agent were added and stirred until dissolved. The NAD+ and MCC were added and mixed for 30 minutes until completely dispersed. The pH was measured to be 2.8. The suspension was transferred into a mixing vessel adjoined to the dispensing apparatus. The required volume of rinse water was added to the first vessel and rinse material was transferred to the dispensing vessel and mixed for a further 30 minutes. 575uL aliquots of the bulk solution was dispensed into blisters and transferred to the freezing chamber. It was cooled to -35C for 8h, then lyophilized under vacuum for 30h. The wafers were tested for active content, friability, residue on ejection from the blister, and water content.

[0279] Table 4 - Results of the preparation of 100mg NAD+ per wafer dosage forms.

[0280] EXAMPLE 2 - PREPARATION OF NAD+ 100MG PER WAFER DOSAGE FORMS (PH ADJUSTED TO 4.2).

[0281] The same protocol as Example 1 was followed, except with the modification that the pH was adjusted from 2.8 to 4.2, in order to reduce the sourness of the wafer. The wafers failed to form properly, sticking to the blister or expanding out of the moulds. This approach was abandoned.

[0282] EXAMPLE 3 - PREPARATION OF 75MG NAD+ PER WAFER DOSAGE FORMS

[0283] The inventors prepared the bulk solution to make 2000 wafers containing 75mg of NAD active. The procedure was repeated for Example 1 .

[0284] Table 5 - Results for the preparation of 75mg NAD+ per wafer dosage forms.

[0285] EXAMPLE 4 - PREPARATION OF 65MG NAD+ AND 10MG APIGENIN PER WAFER DOSAGE FORMS

[0286] The inventors prepared the bulk solution to make 37000 wafers containing 65mg of NAD and 10mg apigenin actives. The procedure for Example 1 was repeated, and the apigenin was added after the NAD+.

[0287] Table 6 - Results for the preparation of 65mg NAD+ and 10mg apigenin per wafer dosage forms

[0288] EXAMPLE 5 - PREPARATION OF 100MG NAD+ AND 10MG APIGENIN PER WAFER DOSAGE FORMS

[0289] In this experiment, the active NAD content was increased to 100mg / wafer, and the flavor blend was adjusted to mask the sour taste. The bulk solution was adjusted to make 500 wafers containing 100mg of NAD and 10mg apigenin actives. The procedure for Example 1 was repeated, and the apigenin was added after the NAD+, and the sucralose after the lemonade flavoring. The wafer flavor was found to be acceptable, with the sourness masked successfully.

[0290] Table 7 - Results for the preparation of 100mg NAD+ and 10mg apigenin per wafer dosage forms

[0291] EXAMPLE 6 - MICRONISATION OF WAFERS

[0292] The NAD and apigenin raw material powders in Example 5 were comparatively coarse, and therefore considered to be likely to be poorly absorbed. The inventors decided to introduce a micronisation step after formulation in order to reduce the average (median) particle sizes of the actives to promote more efficient absorption.

[0293] The formulation method in Example 1 was repeated. The bulk suspension was then passed through a micronisation apparatus (Flowtherm MiniDeBEE high pressure homogenizer, manufactured by BEE International (USA)) several times, and the particle size distribution measured on a Malvern Mastersizer 2000 over the range 0.02 to 2000 pm after various numbers of passes.

[0294] After two passes, the suspension became resistant to further particle size reduction, and this was expected to be due to resistant MCC particles.

[0295] Table 8 - PSD parameters for 100mg / wafer NAD+ batch B231213 before and after nanosizing.

[0296] EXAMPLE 7 - MICRONISATION OF WAFERS, WITH AND WITHOUT MCC

[0297] A confounding factor in efforts to follow the development of this protocol was reasoned to be the MCC excipient, which was known from previous experiments to be resistant to micronisation. The bulk formulation method in Example 1 was repeated, with the bulk solution split into two: one part had MCC excluded, the other part had MCC incorporated as normal. The two bulk suspensions were then passed through the micronisation apparatus several times, and the particle size distribution measured on a Malvern Mastersizer 2000 over the range 0.02 to 2000 pm after various numbers of passes.

[0298] It is clear from these data that NAD is fully soluble in the bulk formulation, and that the large particulate fraction is due to inert MCC.

[0299] Table 9 - PSD parameters for 100mg / wafer NAD+ batch B231216 before and after nanosizing.

[0300] EXAMPLE 8 - PREPARATION OF 50MG NAD+ AND 10MG APIGENIN PER WAFER, WITHOUT MCC

[0301] The preparative method for the bulk suspension in Example 4 was repeated, with adjustments to make a wafer comprising 50mg NAD and 10mg apigenin, and without MCC. The bulk suspension was then passed through a micronisation apparatus seven times, and the particle size distribution measured on a Coulter LS230 laser light scattering apparatus, over the range 0.04 to 2000 pm after various numbers of passes.

[0302] It is clear that the apigenin active can successfully be reduced to under 1 pm after micronisation, providing a suitable particle size for more rapid absorption.

[0303] Table 10 - PSD parameters for 50mg / wafer NAD+ I 10mg / wafer apigenin, after nanosizing.

[0304] EXAMPLE 9 - PREPARATION OF 50MG OF GLUTATHIONE PER WAFER DOSAGE FORMS

[0305] A wafer containing isolated antioxidant adjunct was also prepared in order to test stability in the matrix.

[0306] Prepare the bulk solution to make 7950 wafers containing 50mg of glutathione (GSH) active. Dispense 90-98% of the total water volume required into a suitable container and commence stirring. Add matrix forming agents CMC, mannitol, lactose and amylopectin and stir until completely dissolved. Add the glycine, PEG 1500 and flavoring agent and stir until dissolved. Add the GSH, water-dispersible vitamin E acetate (oxidation stabilizer) and MCC and mix for 30 minutes until completely dispersed. The pH was measured to be 3.8. Transfer the suspension into a mixing vessel adjoined to the dispensing apparatus. Add the required volume of rinse water to the first vessel and transfer rinse material to the dispensing vessel and mix for a further 30 minutes. Dispense 575uL aliquots of the bulk solution into blisters and transfer to the freezing chamber. Cool to -35C for 8h, then lyophilize under vacuum for 30h. Test the wafers for active content, friability, residue on ejection from the blister, water content.

[0307] The GSH was found to have a stability life of 18 months in the matrix.

[0308] Table 11 - 50mg of glutathione per wafer dosage forms.

[0309] EXAMPLE 10 - PREPARATION OF 100MG NAD AND 10MG APIGENIN WAFER, WITH AND WITHOUT MCC

[0310] The preparative method for the bulk suspension in Example 4 was repeated, with adjustments to make a wafer comprising 100mg NAD and 10mg apigenin, with and without MCC. The bulk suspension was passed through a micronisation apparatus (Flowtherm MiniDeBEE high pressure homogenizer, manufactured by BEE International (USA)), and the particle size distribution measured on a Coulter LS230 laser light scattering apparatus, over the range 0.04 to 2000 pm after various numbers of passes.

[0311] Samples were taken as follows. Compound the full suspension as normal MINUS the addition of MCC and remove sample A for particle size analysis. The entire suspension with NO MCC was passed through the homogeniser and remove sample B for particle size analysis. The entire suspension with NO MCC was passed through thehomogeniser A SECOND TIME and removed sample C for particle size analysis. The suspension homogenised twice was placed onto the magnetic stirrer the MCC added and mixed for 15 minutes. Sample D was removed from the bulk suspension which contains the MCC for particle size analysis. The entire suspension with MCC was passed through the homogeniser and removed sample E for particle size analysis. It is clear that over 50% of the apigenin active can successfully be reduced to under 5pm even after 2 passes of micronisation, and 90% 20 pm and below, providing a suitable particle size for more rapid absorption.

[0312] Table 12 - PSD parameters for B240123 100mg / wafer NAD+ I 10mg / wafer apigenin, after nanosizing.

[0313] EXAMPLE 11 - A SINGLE-DOSE PHARMACOKINETIC STUDY OF A NOVEL SUBLINGUAL NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+) NADIX+® WAFER IN RATS.

[0314] STUDY AIM.

[0315] The objective of this study was to compare the pharmacokinetic profile of sublingual NAD+ (NADiXO) wafer with that of the intravenous NAD+ infusion over 10 minutes.

[0316] This pharmacokinetic study demonstrated rapid sublingual absorption directly into the systemic circulation with an absolute bioavailability of approximately 22%.

[0317] METHODS.

[0318] Sprague-Dawley rats (7-10 weeks old, weighing 300-350g) were randomly assigned to either sublingual 100mg NAD+ wafer or intravenous (IV) infusion 5mg NAD+ over 10 minutes. Animals were anesthetized during sublingual administration to ensure the wafer remained in situ. Venous blood sampling was obtained over a 2-hour period. All rats were fasted overnight prior to dosing. Blood samples were collected at 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1.0, 1.5 and 2 hours (5, 10, 15, 30, 45, 60, 90 and 120 minutes). The blood samples were analyzed for NAD+ using LC-MS / MS.

[0319] RESULTS. Plasma NAD+ concentrations were obtained following administration of sublingual NAD+ 100mg wafer (NADiX+). Sublingual administration of SL-NAD+ wafers resulted in rapid absorption of NAD+ directly into plasma via the sublingual mucosa. Mean peak plasma concentration of 72.4ng / mL was reached within 10 minutes of administration, a 2-fold increase from the mean baseline level of 35.1 ng / mL (see Figure 1).

[0320] Figure 2 shows the differences in RBC (red blood cell) NAD+levels between Intravenous NAD+ 5mg infused over 10 mins and sublingual (SL) administered 100mg NAD+(NADiX+) in rats (n=4).

[0321] RBC NAD+after sublingual administration was detected immediately after 5 minutes (Tfirst), showing a rapid systemic absorption after SL administration. The Tfirst plasma concentration for RBC NAD+ level for sublingual administration (5040 ng / mL) was higher than that for the IV administration (2110 ng / mL).

[0322] Table 13 lists the pharmacokinetics parameters for NAD+ evaluated by treatment of NAD+ for single intravenous infusion NAD+ 5mg over 10 minutes and NAD+ 100mg wafer via sublingual route in male Sprague-Dawley rats (n=4). The absolutely bioavailability for sublingual NAD+ was 22%.

[0323] Table 13.

[0324] Table 13: Arithmetic Mean ± SD red blood cells (RBC) pharmacokinetic parameters of NAD+ were evaluated by treatment of NAD+ for single intravenous infusion NAD+ 5mg over 10 minutes and NAD+ 100mg wafer via sublingual route in male Sprague- Dawley rats (n=4).

[0325] The Cmax (ng / mL) of the SL administered NAD+ wafer was higher than the IV infused NAD+ 27100 ± 6680 and 16200 ± 14500 ng / mL respectively, due to the differences in doses (5mg IV versus 100mg SL).

[0326] The Tmax (h) for the IV infusion is 0.125 hour and the SL is 0.875 hour, hence SL absorption is slower than the IV infusion.

[0327] The Mean Residence Time (MRT) of NAD+ in the red blood cells of a rat given IV 5 mg was 1 .87 hours, and 1 .58 hours for sublingual administration of 100mg. This means that, on average, each NAD+ molecule stays in the red blood cells for about 1 .87 hours and 1.58 hours for IV and sublingual administration respectively, before being metabolized or removed. This revealed how long NAD+ is active within the RBC cells, which is important for understanding its role in cellular processes and metabolism.

[0328] The MRT of a drug can change due to different routes of administration because the way a drug is administered affects its absorption, distribution, metabolism, and elimination processes. Bolus intravenous administration generally results in shorter MRTs, reflecting rapid distribution and clearance. In contrast, sublingual administration may be slower in onset (needing to be sublingually absorbed first), hence with slower distribution and slower clearance, resulting in a longer MRT. However, in this study the MRT for SL has a lower MRT (1.58 hours) compared to slow IV infusion over 10 mins (1.87 hours). Hence our SL absorption of the NADiX+ wafer is as rapidly absorbed as the slow IV infusion over 10 minutes. Since the MRT for sublingual administration is similar (slightly shorter MRT than the slow IV infusion), it suggests that the absorption phase is quite similar to IV infusion over 10 mins (the slightly shorter SL MRT may reflect complete absorption before 10 mins, analogous to IV).

[0329] CONCLUSION

[0330] This study demonstrated that sublingual administration of NAD+ wafers (NADiX+) revealed a rapid and significantly increased in blood NAD+ levels in healthy rats.

[0331] The faster MRT for SL administration over the slow IV administration revealed that SL-administered NAD+ is rapidly absorbed within 10 mins of the slow IV infusion.

[0332] The study also observed an absolute sublingual bioavailability of 22% compared to IV NAD+ administration.

[0333] Further preferred embodiments of the invention are presented in TABLE 14.

[0334] TABLE 14 - Further preferred embodiments of the invention.

Claims

CLAIMS1. A composition wherein said composition comprises at least one biologically active material, wherein the biologically active material is selected from the group consisting of: nicotinamide adenine dinucleotide (NAD).

2. The composition of claim 1 , wherein the NAD is selected from the group consisting of: oxidized form (NAD+); and reduced form (NADH).

3. The composition of any one of the above claims, wherein the composition comprises one or more further biologically active materials selected from the group consisting of: a CD38 inhibitor; an adjunct antioxidant; a second adjunct antioxidant, an endogenous cellular health material, and a sirtuin activator.

4. The composition of any one of the above claims, wherein the composition comprises one or more further biologically active materials selected from the group consisting of: a CD38 inhibitor; glutathione; coenzyme Q; an endogenous anti-aging cellular booster; and an exogenous anti-aging sirtuin booster.

5. The composition of any one of the above claims, wherein the CD38 inhibitor is selected from the group consisting of: those listed in Table 1 .

6. The composition of any one of the above claims, wherein the endogenous anti-aging cellular booster is selected from the group consisting of: those listed in Table 2.

7. The composition of any one of the above claims, wherein the exogenous anti-aging sirtuin booster is selected from the group consisting of: those listed in Table 3.

8. The composition of any one of the above claims, wherein the CD38 inhibitor is selected from the group consisting of: apigenin or quercetin.

9. The composition of any one of the above claims, wherein the adjunct antioxidant is selected from the group consisting of: glutathione (GSH); and coenzyme Q.

10. The composition of any one of the above claims, wherein the second adjunct antioxidant is selected from the group consisting of: glutathione; and coenzyme Q.11 . The composition of any one of the above claims, wherein the composition comprises the following components selected from the group consisting of: NAD, apigenin; NAD, quercetin; NAD, glutathione; NAD, coenzyme Q; NAD, quercetin, apigenin; NAD, glutathione, apigenin; NAD, coenzyme Q, apigenin; NAD, glutathione, quercetin; NAD, coenzyme Q, quercetin; and NAD, glutathione, coenzyme Q.

12. The composition of any one of the above claims, wherein the composition comprises the following components selected from the group consisting of: NAD, apigenin, endogenous anti-aging cellular booster; NAD, quercetin, endogenous anti-aging cellular booster; NAD, glutathione, endogenous anti-aging cellular booster; NAD, coenzyme Q, endogenous anti-aging cellular booster; NAD, quercetin, apigenin, endogenous anti-aging cellular booster; NAD, glutathione, apigenin, endogenous antiaging cellular booster; NAD, coenzyme Q, apigenin, endogenous anti-aging cellular booster; NAD, glutathione, quercetin, endogenous anti-aging cellular booster; NAD, coenzyme Q, quercetin, endogenous anti-aging cellular booster; and NAD, glutathione, coenzyme Q, endogenous anti-aging cellular booster.

13. The composition of any one of the above claims, wherein the composition comprises the following components selected from the group consisting of: NAD, apigenin, exogenous anti-aging sirtuin booster; NAD, quercetin, exogenous anti-aging sirtuin booster; NAD, glutathione, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, exogenous anti-aging sirtuin booster; NAD, quercetin, apigenin, exogenous anti-aging sirtuin booster; NAD, glutathione, apigenin, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, apigenin, exogenous anti-aging sirtuin booster; NAD, glutathione, quercetin, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, quercetin, exogenous anti-aging sirtuin booster; and NAD, glutathione, coenzyme Q, exogenous anti-aging sirtuin booster.

14. The composition of any one of the above claims, wherein the composition comprises the following components selected from the group consisting of: NAD, apigenin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, quercetin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, glutathione, endogenous anti-aging cellular booster, exogenous antiaging sirtuin booster; NAD, coenzyme Q, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, quercetin, apigenin, endogenous antiaging cellular booster, exogenous anti-aging sirtuin booster; NAD, glutathione, apigenin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, apigenin, endogenous anti-aging cellular booster exogenous anti-aging sirtuin booster; NAD, glutathione, quercetin, endogenous antiaging cellular booster, exogenous anti-aging sirtuin booster; NAD, coenzyme Q, quercetin, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster; and NAD, glutathione, coenzyme Q, endogenous anti-aging cellular booster, exogenous anti-aging sirtuin booster.

15. The composition of any one of the above claims, wherein the composition is a solid dosage form.

16. The composition of any one of the above claims, wherein the composition is a rapidly disintegrating solid dosage form.

17. The composition of any one of the above claims, wherein the composition is a wafer, tablet or capsule.

18. The composition of any one of the above claims, wherein the composition is a wafer and is at a pH suitable for stabilizing NAD in a solid matrix on storage.

19. The composition of any one of the above claims, wherein the biologically active material is present in the composition at a concentration selected from the group consisting of: 0%; 1% (w / w); 2% (w / w); 3% (w / w); 4% (w / w); 5% (w / w); 6% (w / w); 7% (w / w); 8% (w / w); 9% (w / w); 10% (w / w); 11% (w / w); 12% (w / w); 13% (w / w); 14% (w / w); 15% (w / w); 16% (w / w); 17% (w / w); 18% (w / w); 19% (w / w); 20% (w / w); 21% (w / w);22% (w / w); 23% (w / w); 24% (w / w); 25% (w / w); 26% (w / w); 27% (w / w); 28% (w / w);29% (w / w); 30% (w / w); 31% (w / w); 32% (w / w); 33% (w / w); 34% (w / w); 35% (w / w);36% (w / w); 37% (w / w); 38% (w / w); 39% (w / w); 40% (w / w); 41% (w / w); 42% (w / w);43% (w / w); 44% (w / w); 45% (w / w); 46% (w / w); 47% (w / w); 48% (w / w); 49% (w / w);50% (w / w); and 2-95% (w / w); 3-65% (w / w); 4-55% (w / w); 5-45% (w / w); 6-35% (w / w); 7-25% (w / w); 8-15% (w / w); 0.1-50% (w / w); 5-50% (w / w); 20-50% (w / w); and within 2 decimal points of each figure.

20. The composition of any one of the above claims, wherein the biologically active material is present in the composition at a quantity selected from the group consisting of: Omg; 0.01 mg; 0.02mg; 0.03mg; 0.04mg; 0.05mg; 0.06mg; 0.07mg; 0.08mg; 0.09mg; 0.10mg; 0.11 mg; 0.12mg; 0.13mg; 0.14mg; 0.15mg; 0.16mg; 0.17mg; 0.18mg; 0.19mg; 0.20mg; 0.21 mg; 0.22mg; 0.23mg; 0.24mg; 0.25mg; 0.26mg; 0.27mg; 0.28mg; 0.29mg; 0.30mg; 0.31 mg; 0.32mg; 0.33mg; 0.34mg; 0.35mg;0.36mg; 0.37mg; 0.38mg; 0.39mg; 0.40mg; 0.41 mg; 0.42mg; 0.43mg; 0.44mg;0.45mg; 0.46mg; 0.47mg; 0.48mg; 0.49mg; 0.50mg; 0.51 mg; 0.52mg; 0.53mg;0.54mg; 0.55mg; 0.56mg; 0.57mg; 0.58mg; 0.59mg; 0.60mg; 0.61 mg; 0.62mg;0.63mg; 0.64mg; 0.65mg; 0.66mg; 0.67mg; 0.68mg; 0.69mg; 0.70mg; 0.71 mg;0.72mg; 0.73mg; 0.74mg; 0.75mg; 0.76mg; 0.77mg; 0.78mg; 0.79mg; 0.80mg;0.81 mg; 0.82mg; 0.83mg; 0.84mg; 0.85mg; 0.86mg; 0.87mg; 0.88mg; 0.89mg;0.90mg; 0.91 mg; 0.92mg; 0.93mg; 0.94mg; 0.95mg; 0.96mg; 0.97mg; 0.98mg;0.99mg; 1.00mg; 0.1 mg; 0.2mg; 0.3mg; 0.4mg; 0.5mg; 0.6mg; 0.7mg; 0.8mg; 0.9mg; 1.0mg; 1 mg; 2mg; 3mg; 4mg; 5mg; 6mg; 7mg; 8mg; 9mg; 10mg; 11 mg; 12mg; 13mg;14mg; 15mg; 16mg; 17mg; 18mg; 19mg; 20mg; 21 mg; 22mg; 23mg; 24mg; 25mg;26mg; 27mg; 28mg; 29mg; 30mg; 31 mg; 32mg; 33mg; 34mg; 35mg; 36mg; 37mg;38mg; 39mg; 40mg; 41 mg; 42mg; 43mg; 44mg; 45mg; 46mg; 47mg; 48mg; 49mg;50mg; 51 mg; 52mg; 53mg; 54mg; 55mg; 56mg; 57mg; 58mg; 59mg; 60mg; 61 mg;62mg; 63mg; 64mg; 65mg; 66mg; 67mg; 68mg; 69mg; 70mg; 71 mg; 72mg; 73mg;74mg; 75mg; 76mg; 77mg; 78mg; 79mg; 80mg; 81 mg; 82mg; 83mg; 84mg; 85mg;86mg; 87mg; 88mg; 89mg; 90mg; 91 mg; 92mg; 93mg; 94mg; 95mg; 96mg; 97mg;98mg; 99mg; 100mg; 101 mg; 102mg; 103mg; 104mg; 105mg; 106mg; 107mg; 108mg;109mg; 110mg; 111 mg; 112mg; 113mg; 114mg; 115mg; 116mg; 117mg; 118mg;119mg; 120mg; 121 mg; 122mg; 123mg; 124mg; 125mg; 126mg; 127mg; 128mg;129mg; 130mg; 131 mg; 132mg; 133mg; 134mg; 135mg; 136mg; 137mg; 138mg;139mg; 140mg; 141 mg; 142mg; 143mg; 144mg; 145mg; 146mg; 147mg; 148mg;149mg; 150mg; 151 mg; 152mg; 153mg; 154mg; 155mg; 156mg; 157mg; 158mg;159mg; 160mg; 161 mg; 162mg; 163mg; 164mg; 165mg; 166mg; 167mg; 168mg;169mg; 170mg; 171 mg; 172mg; 173mg; 174mg; 175mg; 176mg; 177mg; 178mg;179mg; 180mg; 181 mg; 182mg; 183mg; 184mg; 185mg; 186mg; 187mg; 188mg;189mg; 190mg; 191 mg; 192mg; 193mg; 194mg; 195mg; 196mg; 197mg; 198mg;199mg; 200mg; 0.01 mg to 1 mg; 0.1 mg to 1 mg; 1 to 200mg; 1 to 100mg; 1 to 50mg; 1 to 25mg; 1 to 15mg; 1 to 10mg; 10 to 100mg; 10 to 75mg; 10mg to 50mg; 10mg to 25mg; 1 to 150mg; 50-125mg.

21. The composition of any one of the above claims, wherein the biologically active material is present in the composition at a quantity selected from the group consisting of: 1 to 150mg, including 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 150mg, 50-125mg.

22. The composition of any one of the above claims, wherein the composition comprises one or more agents selected from the group consisting of: a non-ionic amorphous matrix forming agent; an ionic matrix aide; a non-ionic matrix aide; a non-ionic crystalline matrix forming agent; and any multitude of combinations.

23. The composition of any one of the above claims, wherein the non-ionic amorphous matrix forming agent is selected from the group consisting of: amylopectin or other soluble low viscosity modified amylopectins.

24. The composition of any one of the above claims, wherein the non-ionic amorphous matrix forming agent is selected from the group consisting of: amylopectin or other soluble low viscosity modified amylopectins or other soluble starches NOT containing insoluble amylose or insoluble modified amylose, such as dextrins, or soluble glucose polymers such as polydextrose.

25. The composition of any one of the above claims, wherein the concentration of the nonionic amorphous matrix forming agent is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%-10%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; 11%; 12%; 13%; 14%; 15%; 16%; 17%; 18%; 19%; 20%; and within 2 decimal points of each figure (w / w).

26. The composition of any one of the above claims, wherein the ionic matrix aide is selected from the group consisting of: sodium carboxymethyl cellulose (CMC); and glycine.

27. The composition of any one of the above claims, wherein the concentration of the ionic matrix aide is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%- 10%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; and within 2 decimal points of each figure (w / w).

28. The composition of any one of the above claims, wherein the non-ionic matrix aide is selected from the group consisting of: PEG 1500; and microcrystalline cellulose (MCC).

29. The composition of any one of the above claims, wherein the concentration of the nonionic matrix aide is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%-10%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; and within 2 decimal points of each figure (w / w).

30. The composition of any one of the above claims, wherein the non-ionic crystalline matrix forming agent is selected from the group consisting of: mannitol; and lactose.31 . The composition of any one of the above claims, wherein the concentration of the non- ionic crystalline matrix forming agent is selected from the group consisting of: 0.5%; 1%; 0.5%-10%; 0.5%; 1%-10%; 1%-90%; 1%-95%; 1%; 2%; 3%; 4%; 5%; 6%; 7%; 8%; 9%; 10%; 11%; 12%; 13%; 14%; 15%; 16%; 17%; 18%; 19%; 20%; 21%; 22%; 23%; 24%; 25%; 26%; 27%; 28%; 29%; 30%; 31%; 32%; 33%; 34%; 35%; 36%; 37%;38%; 39%; 40%; 41%; 42%; 43%; 44%; 45%; 46%; 47%; 48%; 49%; 50%; 51%; 52%;53%; 54%; 55%; 56%; 57%; 58%; 59%; 60%; 61%; 62%; 63%; 64%; 65%; 66%; 67%;68%; 69%; 70%; 71%; 72%; 73%; 74%; 75%; 76%; 77%; 78%; 79%; 80%; 81%; 82%;83%; 84%; 85%; 86%; 87%; 88%; 89%; 90%; 91%; 92%; 93%; 94%; 95% and within 2 decimal points of each figure (w / w).

32. The composition of any one of the above claims, wherein the composition comprises: 0-80% of mannitol (w / w / ); and 0-80% of lactose (w / w).

33. The composition of any one of the above claims, wherein the composition comprises: 30-50% of mannitol (w / w / ); and 10-30% of lactose (w / w).

34. The composition of any one of the above claims, wherein the composition is formulated to pH 2 to 5.

35. The composition of any one of the above claims, wherein the composition is a solid.

36. The composition of any one of the above claims, wherein the composition is lyophilised.

37. The composition of any one of the above claims, wherein the bioactive particles of the composition have a size no greater than 100 pm.

38. The composition of any one of the above claims, wherein the bioactive particles of the composition have a nanoparticulate size less than 10,000nm.

39. The composition of any one of the above claims, wherein the Dx of the bioactive particle distribution, as measured on a particle volume basis, is selected from the group consisting of less than or equal to: 0.001 -100 pm; 0.01-100 pm; 0.1 -100 pm; 1-100 pm; 1 to 50 pm; 0.001 pm; 0.002 pm; 0.003 pm; 0.004 pm; 0.005 pm; 0.006 pm; 0.007 pm; 0.008 pm; 0.009 pm; 0.01 pm; 0.02 pm; 0.03 pm; 0.04 pm; 0.05 pm; 0.06 pm; 0.07 pm; 0.08 pm; 0.09 pm; 0.1 pm; 0.2 pm; 0.3 pm; 0.4 pm; 0.5 pm; 0.6 pm; 0.7 pm; 0.8 pm; 0.9 pm; 1 pm; 2 pm; 3 pm; 4 pm; 5 pm; 6 pm; 7 pm; 8 pm; 9 pm; 10 pm; 11 pm; 12 pm; 13 pm; 14 pm; 15 pm; 16 pm; 17 pm; 18 pm; 19 pm; 20 pm; 21 pm; 22 pm; 23 pm; 24 pm; 25 pm; 26 pm; 27 pm; 28 pm; 29 pm; 30 pm; 31 pm; 32 pm; 33 pm; 34 pm; 35 pm; 36 pm; 37 pm; 38 pm; 39 pm; 40 pm; 41 pm; 42 pm; 43 pm; 44 pm; 45 pm; 46 pm; 47 pm; 48 pm; 49 pm; 50 pm; 51 pm; 52 pm; 53 pm; 54 pm; 55 pm; 56 pm; 57 pm; 58 pm; 59 pm; 60 pm; 61 pm; 62 pm; 63 pm; 64 pm; 65 pm; 66 pm; 67 pm; 68 pm; 69 pm; 70 pm; 71 pm; 72 pm; 73 pm; 74 pm; 75 pm; 76 pm; 77 pm; 78 pm; 79 pm; 80 pm; 81 pm; 82 pm; 83 pm; 84 pm; 85 pm; 86 pm; 87 pm; 88 pm; 89 pm; 90 pm; 91 pm; 92 pm; 93 pm; 94 pm; 95 pm; 96 pm; 97 pm; 98 pm; 99 pm; 100 pm; wherein x is greater than or equal to 10, 50 or 90.

40. The composition of any one of the above claims, wherein the Dx of the bioactive particle distribution, as measured on a particle number basis, is selected from the group consisting of less than or equal to: 0.001 -100 pm; 0.01-100 pm; 0.1 -100 pm; 1-100 pm; 1 to 50 pm; 0.001 pm; 0.002 pm; 0.003 pm; 0.004 pm; 0.005 pm; 0.006 pm; 0.007 pm; 0.008 pm; 0.009 pm; 0.01 pm; 0.02 pm; 0.03 pm; 0.04 pm; 0.05 pm; 0.06 pm; 0.07 pm; 0.08 pm; 0.09 pm; 0.1 pm; 0.2 pm; 0.3 pm; 0.4 pm; 0.5 pm; 0.6 pm; 0.7 pm; 0.8 pm; 0.9 pm; 1 pm; 2 pm; 3 pm; 4 pm; 5 pm; 6 pm; 7 pm; 8 pm; 9 pm; 10pm; 11 pm; 12 pm; 13 pm; 14 pm; 15 pm; 16 pm; 17 pm; 18 pm; 19 pm; 20 pm; 21 pm; 22 pm; 23 pm; 24 pm; 25 pm; 26 pm; 27 pm; 28 pm; 29 pm; 30 pm; 31 pm; 32 pm; 33 pm; 34 pm; 35 pm; 36 pm; 37 pm; 38 pm; 39 pm; 40 pm; 41 pm; 42 pm; 43 pm; 44 pm; 45 pm; 46 pm; 47 pm; 48 pm; 49 pm; 50 pm; 51 pm; 52 pm; 53 pm; 54 pm; 55 pm; 56 pm; 57 pm; 58 pm; 59 pm; 60 pm; 61 pm; 62 pm; 63 pm; 64 pm; 65 pm; 66 pm; 67 pm; 68 pm; 69 pm; 70 pm; 71 pm; 72 pm; 73 pm; 74 pm; 75 pm; 76 pm; 77 pm; 78 pm; 79 pm; 80 pm; 81 pm; 82 pm; 83 pm; 84 pm; 85 pm; 86 pm; 87 pm; 88 pm; 89 pm; 90 pm; 91 pm; 92 pm; 93 pm; 94 pm; 95 pm; 96 pm; 97 pm; 98 pm; 99 pm; 100 pm; wherein x is greater than or equal to 10, 50 or 90.41 . The composition of any one of the above claims, wherein the composition comprises further pharmaceutically acceptable additives and agents.

42. The composition of any one of the above claims, wherein the composition comprises a pharmaceutically acceptable buffering reagent.

43. The composition of any one of the above claims, wherein the buffering reagent is selected from the group consisting of: salts of phosphates, carbonates, Tris; preferably combinations of phosphate salts; including sodium carbonate.

44. The composition of any one of the above claims, wherein the buffering reagent is present at a concentration selected from the group consisting of: 0.1 -0.5%; 0.1%; 0.2%; 0.3%; 0.4%; 0.5%; and within 2 decimal points of each figure (w / w).

45. The composition of any one of the above claims, wherein the wafers are buffered with a suitable buffer, most preferably a blend of mono- and di-alkaline salt phosphates, adjusted to afford a pH optimal for the stability of the NAD, generally between 2-4.

46. The composition of any one of the above claims, wherein the composition comprises a colouring agent.

47. The composition of any one of the above claims, wherein the composition comprises a flavouring agent.

48. The composition of any one of the above claims, wherein the composition comprises a flavouring agent comprising a lemonade flavourant and a sucralose sweetener.

49. The composition of any one of the above claims, wherein the composition comprises a stability agent.

50. The composition of any one of the above claims, wherein the stability agent is selected from the group consisting of: vitamin E and derivatives.51 . The composition of any one of the above claims, wherein the composition disintegrates once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <11 Os; <120s (seconds).

52. The composition of any one of the above claims, wherein the composition disintegrates once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <11 Os;<120s; <130s; <140s; <150s; <160s; <170s; <180s; <190s; <200s; <210s; <220s;<230s; <240s; <250s; <260s; <270s; <280s; <290s; <300s; <31 Os; <320s; <330s;<340s; <350s; <360s; <370s; <380s; <390s; <400s; <41 Os; <420s; <430s; <440s;<450s; <460s; <470s; <480s; <490s; <500s; <51 Os; <520s; <530s; <540s; <550s;<560s; <570s; <580s; <590s; <600s; <61 Os; <620s; <630s; <640s; <650s; <660s;<670s; <680s; <690s; <700s; <71 Os; <720s; <730s; <740s; <750s; <760s; <770s;<780s; <790s; <800s; <81 Os; <820s; <830s; <840s; <850s; <860s; <870s; <880s;<890s; <900s; <900s; <930s; <960s; <990s; <1020s; <1050s; <1080s; <1110s; <1140s; <1170s; <1200s; <1230s; <1260s; <1290s; <1320s; <1350s; <1380s; <1410s;<1440s; <1470s; <1500s; <1530s; <1560s; <1590s; <1620s; <1650s; <1680s; <171 Os;<1740s; <1770s; <1800s; <1830s; <1860s; <1890s; <1920s; <1950s; <1980s; <201 Os;<2040s; <2070s; <2100s; <2130s; <2160s; <2190s; <2220s; <2250s; <2280s; <2310s;<2340s; <2370s; <2400s; <2430s; <2460s; <2490s; <2520s; <2550s; <2580s; <261 Os;<2640s; <2670s; <2700s; <2730s; <2760s; <2790s; <2820s; <2850s; <2880s; <291 Os;<2940s; <2970s; <3000s; <3030s; <3060s; <3090s; <3120s; <3150s; <3180s; <321 Os;<3240s; <3270s; <3300s; <3330s; <3360s; <3390s; <3420s; <3450s; <3480s; <351 Os;<3540s; <3570s; <3600s; <3630s; <3660s; <3690s; <3720s; <3750s; <3780s; <381 Os;<3840s; <3870s; <3900s; <3930s; <3960s; <3990s; <4020s; <4050s; <4080s; <4110s;<4140s; <4170s; <4200s; and <4230s (seconds).

53. The composition of any one of the above claims, wherein the composition disintegrates in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by a subject, thereby avoiding the urge for the subject to swallow the composition.

54. The composition of any one of the above claims, wherein the composition dissolves once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <11 Os; <120s; 180s, preferably 15-60s (seconds).

55. The composition of any one of the above claims, wherein the composition dissolves once placed in the oral cavity in a time period selected from the group consisting of: <10s; <20s; <30s; <40s; <50s; <60s; <70s; <80s; <90s; <100s; <110s; <120s; <130s;<140s; <150s; <160s; <170s; <180s; <190s; <200s; <210s; <220s; <230s; <240s;<250s; <260s; <270s; <280s; <290s; <300s; <31 Os; <320s; <330s; <340s; <350s;<360s; <370s; <380s; <390s; <400s; <41 Os; <420s; <430s; <440s; <450s; <460s;<470s; <480s; <490s; <500s; <51 Os; <520s; <530s; <540s; <550s; <560s; <570s;<580s; <590s; <600s; <61 Os; <620s; <630s; <640s; <650s; <660s; <670s; <680s;<690s; <700s; <71 Os; <720s; <730s; <740s; <750s; <760s; <770s; <780s; <790s;<800s; <81 Os; <820s; <830s; <840s; <850s; <860s; <870s; <880s; <890s; <900s;<900s; <930s; <960s; <990s; <1020s; <1050s; <1080s; <1110s; <1140s; <1170s; <1200s; <1230s; <1260s; <1290s; <1320s; <1350s; <1380s; <1410s; <1440s; <1470s; <1500s; <1530s; <1560s; <1590s; <1620s; <1650s; <1680s; <171 Os; <1740s; <1770s;<1800s; <1830s; <1860s; <1890s; <1920s; <1950s; <1980s; <201 Os; <2040s; <2070s;<2100s; <2130s; <2160s; <2190s; <2220s; <2250s; <2280s; <231 Os; <2340s; <2370s;<2400s; <2430s; <2460s; <2490s; <2520s; <2550s; <2580s; <261 Os; <2640s; <2670s;<2700s; <2730s; <2760s; <2790s; <2820s; <2850s; <2880s; <291 Os; <2940s; <2970s;<3000s; <3030s; <3060s; <3090s; <3120s; <3150s; <3180s; <321 Os; <3240s; <3270s;<3300s; <3330s; <3360s; <3390s; <3420s; <3450s; <3480s; <351 Os; <3540s; <3570s;<3600s; <3630s; <3660s; <3690s; <3720s; <3750s; <3780s; <381 Os; <3840s; <3870s;<3900s; <3930s; <3960s; <3990s; <4020s; <4050s; <4080s; <4110s; <4140s; <4170s; <4200s; and <4230s (seconds).

56. The composition of any one of the above claims, wherein the composition dissolves in the oral cavity without leaving a residue of said dosage form in the oral cavity that is detectable by a subject, thereby avoiding the urge for the subject to swallow the composition.

57. The composition of any one of the above claims, wherein water is removed from the combined agents by a freeze-drying process to a residual level of 2-5%.

58. The composition of any one of the above claims, wherein the composition has a porosity profile selected from the group consisting of: the proportion of water removed by lyophilization is 65-75%; and the proportion of water removed by lyophilization is >60%.

59. The composition of any one of the above claims, wherein the composition is stable for a time period selected from the group consisting of: 1 week; 2 weeks; 3 weeks; 4 weeks; 5 weeks; 6 weeks; 7 weeks; 8 weeks; 9 weeks; 10 weeks; 11 weeks; 12weeks; 13 weeks; 14 weeks; 15 weeks; 16 weeks; 17 weeks; 18 weeks; 19 weeks; 20 weeks; 21 weeks; 22 weeks; 23 weeks; 24 weeks; 25 weeks; 26 weeks; 27 weeks; 28 weeks; 29 weeks; 30 weeks; 31 weeks; 32 weeks; 33 weeks; 34 weeks; 35 weeks; 36 weeks; 37 weeks; 38 weeks; 39 weeks; 40 weeks; 41 weeks; 42 weeks; 43 weeks; 44 weeks; 45 weeks; 46 weeks; 47 weeks; 48 weeks; 49 weeks; 50 weeks; 51 weeks; 52 weeks; 1 month; 2 months; 3 months; 4 months; 5 months; 6 months; 7 months; 8 months; 9 months; 10 months; 11 months; 12 months; 13 months; 14 months; 15 months; 16 months; 17 months; 18 months; 19 months; 20 months; 21 months; 22 months; 23 months; 24 months; 25 months; 26 months; 27 months; 28 months; 29 months; 30 months; 31 months; 32 months; 33 months; 34 months; 35 months; 36 months; 37 months; 38 months; 39 months; 40 months; 41 months; 42 months; 43 months; 44 months; 45 months; 46 months; 47 months; 48 months; 49 months; 50 months; 51 months; 52 months; 53 months; 54 months; 55 months; 56 months; 57 months; 58 months; 59 months; 60 months; 1 month to 12 months; 12 months to 24 months; 12 months to 36 months; 12 months to 48 months; 1 year to 2 years; 1 year to 3 years; and 1 year to 5 years. The composition of any one of the above claims, wherein the composition is stable as demonstrated by a potency assay run against a reference biologically active material.

60. The composition of any one of the above claims, wherein the composition comprises cavities.61 . The composition of any one of the above claims, wherein the cavities are encapsulated by at least a major proportion of the biologically active material(s).

62. The composition of any one of the above claims, wherein the cavities are encapsulated by the biologically active material(s).

63. The composition of any one of the above claims, wherein the cavities are amorphous or irregular holes.

64. The composition of any one of the above claims, wherein the cavities encapsulate at least a major proportion of the biologically active material(s) and helps to protect the biologically active material(s) from the degradation and denaturing effects caused by solar radiation, water, enzymes, and / or solvents.

65. The composition of any one of the above claims, wherein the cavity walls encapsulate the biologically active material(s) and protects the biologically active material(s) from the degradation and denaturing effects caused by: solar radiation; pH changes; ionic changes; electron excesses and deficits; water; enzymes; and / or solvents.

66. The composition of any one of the above claims, wherein the average diameter of the cavities is selected from the group consisting of: 1 -100pm; 1 -200pm; 1 -300pm; 1 - 400pm; 1 -500pm; 10-200pm; 10-100pm; 20-100pm; 50-150pm.

67. The composition of any one of the above claims, wherein the average diameter of the cavities would vary depending on the freezing rate and solids content.

68. The composition of any one of the above claims, wherein the composition comprises cavities and channels.

69. The composition of any one of the above claims, wherein there is a microcrystalline array around the channels.

70. The composition of any one of the above claims, wherein the microcrystalline array around the channels is dense.71 . The composition of any one of the above claims, wherein the microcrystalline array around the channels is overlapping.

72. The composition of any one of the above claims, wherein the microcrystalline array has an attribute selected from the group consisting of: scatter a variety of wavelengths of light; suppress oxygen diffusion from the channels; protect the active within the matrix from UV and oxidative degradation; the low water content, which cannot diffuse because it is trapped and hydrogen-bonded to eg lactose and mannitol, prevents hydrolysis.

73. The composition of any one of the above claims, wherein the composition is a composition presented in a table selected from the group consisting of: Table 14.

74. A pharmaceutical composition comprising the composition of any one of claims 1 to 73 together with a pharmaceutical excipient or carrier.

75. A nutraceutical composition comprising the composition of any one of claims 1 to 73 together with a nutraceutical excipient or carrier.

76. A dosage form comprising the composition of any one of claims 1 to 73.

77. The dosage form of claim 76, wherein the dosage form comprises the biologically active material at a dose selected from the group consisting of: 1 to 150mg, including 5mg, 10mg, 25mg, 50mg, 75mg, 100mg, 150mg, 50-125mg.

78. The dosage form of any one of claims 76 to 77, wherein the dosage form is solid.

79. The dosage form of any one of claims 76 to 78, wherein the dosage form is freeze dried.

80. The dosage form of any one of claims 76 to 79, wherein the dosage form is a wafer.

81. A method of treating or preventing or delaying a deficiency, condition, disease or disorder, said method comprising administering to a patient in need thereof a therapeutically effective amount of the dosage form of claims 76 to 80.

82. The method of claim 81 , wherein the deficiency, condition, disease or disorder is selected from the group consisting of: premature ageing; premature loss of health, energy, and / or vitality; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis; cancer; vascular diseases; immune disorders; inflammatory disorders; infections; infertility.

83. The method of claims 81 to 82, wherein the method performs one of the functions selected from the group consisting of: increasing the body’s NAD+ levels; improving cellular health, energy, and / or vitality; slowing down the process of DNA damage and providing inflammation control; less susceptible to disease; metabolic regulation; maintaining the body’s energy supplies; preventing and repairing damage and normal wear and tear; increase energy; weight management; muscle development and recovery; decreasing muscle loss, and especially those patients on the GLP-1s (such as semaglutide); promotes skeletal muscle health, repair and / or recovery; slows and / or reverses skeletal muscle loss, including drug associated muscle loss (due to GLP-1 and GIP receptor agonists / antagonists and other drugs), muscle loss associated with aging (sarcopenia), and / or muscle loss due to an underlying medical condition; reducing sarcopenia for the aging population; supporting pain management; improving mood; improving cognitive function; supplementing addition recovery; neurodegenerative diseases such as Alzheimer's and Parkinson's disease as well as multiple sclerosis; aging and longevity; aids to anti-cancer, anti-viral, or immunosuppressive drugs; improving fertility; improving ovulation; improving sperm production.

84. The method of any one of claims 81 to 83, wherein the dosage form is administered to deliver a therapeutic effective amount of the biologically active material.

85. The method of any one of claims 81 to 84, wherein the therapeutically effective amount is administered to the subject utilising a dosing regimen selected from the group consisting of: twice hourly; hourly; once every six hours; once every 8 hours; once every 12 hours; once daily; twice weekly; once weekly; once every 2 weeks;once every 6 weeks; once a month; once every 2 months; once every 3 months; once every 4 months; once every 5 months; once every 6 months; once yearly; and once.

86. The method of any one of claims 81 to 85, wherein the dosage form delivers the NAD and a second dosage form delivers one or more further optional biologically active materials.

87. The method of any one of claims 81 to 86, wherein the dosage form delivers the NAD, a second dosage form delivers one or more further optional biologically active materials and a third dosage form delivers one or more further optional biologically active materials.

88. The method of any one of claims 81 to 87, wherein the first dosage form, the second dosage form and / or third the dosage are administered to the patient in need thereof using a dosing pattern selected from the group consisting of: sequentially, contemporaneously or at different times.

89. The method of any one of claims 81 to 88, wherein the different times are selected from the group consisting of: seconds apart; minutes apart; hours apart; days apart; weeks apart; and months apart.

90. The method of any one of claims 81 to 89, wherein the seconds apart is selected from the group consisting of: 1 s; 2s; 3s; 4s; 5s; 6s; 7s; 8s; 9s; 10s; 11 s; 12s; 13s; 14s; 15s; 16s; 17s; 18s; 19s; 20s; 21s; 22s; 23s; 24s; 25s; 26s; 27s; 28s; 29s; 30s; 31s; 32s; 33s; 34s; 35s; 36s; 37s; 38s; 39s; 40s; 41s; 42s; 43s; 44s; 45s; 46s; 47s; 48s; 49s; 50s; 51 s; 52s; 53s; 54s; 55s; 56s; 57s; 58s; 59s; and 60s.91 . The method of any one of claims 81 to 90, wherein the minutes apart is selected from the group consisting of: 1 min; 2min; 3min; 4min; 5min; 6min; 7min; 8min; 9min; 10min; 11 min; 12min; 13min; 14min; 15min; 16min; 17min; 18min; 19min; 20min; 21 min;22min; 23min; 24min; 25min; 26min; 27min; 28min; 29min; 30min; 31 min; 32min;33min; 34min; 35min; 36min; 37min; 38min; 39min; 40min; 41 min; 42min; 43min;44min; 45min; 46min; 47min; 48min; 49min; 50min; 51 min; 52min; 53min; 54min;55min; 56min; 57min; 58min; 59min; and 60min.

92. The method of any one of claims 81 to 91 , wherein the hours apart is selected from the group consisting of: 1 hr; 2hr; 3hr; 4hr; 5hr; 6hr; 7hr; 8hr; 9hr; 10hr; 11 hr; 12hr; 13hr; 14hr; 15hr; 16hr; 17hr; 18hr; 19hr; 20hr; 21 hr; 22hr; 23hr; and 24hr.

93. The method of any one of claims 81 to 92, wherein the days apart is selected from the group consisting of: 1 day; 2 days; 3 days; 4 days; 5 days; 6 days; 7 days; 8 days; 9days; 10 days; 11 days; 12 days; 13 days; 14 days; 15 days; 16 days; 17 days; 18 days; 19 days; 20 days; 21 days; 22 days; 23 days; 24 days; 25 days; 26 days; 27 days; 28 days; 29 days;; 30 days and 31 days.

94. The method of any one of claims 81 to 93, wherein the weeks apart is selected from the group consisting of: 1 week; 2 weeks; 3 weeks; 4 weeks; 5 weeks; 6 weeks; 7 weeks; 8 weeks; 9 weeks; 10 weeks; 11 weeks; 12 weeks; 13 weeks; 14 weeks; 15 weeks; 16 weeks; 17 weeks; 18 weeks; 19 weeks; 20 weeks; 21 weeks; 22 weeks; 23 weeks; 24 weeks; 25 weeks; 26 weeks; 27 weeks; 28 weeks; 29 weeks; 30 weeks; 31 weeks; 32 weeks; 33 weeks; 34 weeks; 35 weeks; 36 weeks; 37 weeks; 38 weeks; 39 weeks; 40 weeks; 41 weeks; 42 weeks; 43 weeks; 44 weeks; 45 weeks; 46 weeks; 47 weeks; 48 weeks; 49 weeks; 50 weeks; 51 weeks; and 52 weeks.

95. The method of any one of claims 81 to 94, wherein the months apart is selected from the group consisting of: 1 month; 2 months; 3 months; 4 months; 5 months; 6 months; 7 months; 8 months; 9 months; 10 months; 11 months; 12 months; 13 months; 14 months; 15 months; 16 months; 17 months; 18 months; 19 months; 20 months; 21 months; 22 months; 23 months; and 24 months.

96. The method of any one of claims 81 to 95, wherein the dosage form delivers a therapeutic effective amount of the biologically active material.

97. The method of any one of claims 81 to 96, wherein the dosage form delivers between 50mg-500mg NAD per day.

98. The method of any one of claims 81 to 97, wherein the dosage form delivers NAD per day, and allowing a steady and controlled buildup of depleted NAD towards a steady state blood concentration.

99. The method of any one of claims 81 to 98, wherein the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: between 0.001 to 100mg / kg; between 2 and 50mg / kg; between 5 and 40mg / kg; between 10 and 30mg / kg; between 20 and 25mg / kg; and 20mg / kg / day.

100. The method of any one of claims 81 to 99, wherein the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: 2mg; 5mg 10mg; 15mg; 20mg; 21 mg; 0.25mg to 100mg; 1mg to 25mg; 1 mg to 50 mg; 1 mg to 30mg; 2 to 30mg; 5 mg to 15mg; 10mg to 20mg; 10 to 50mg; 50-150mg per dosage event.

101. The method of any one of claims 81 to 100, wherein the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: 2mg; 5mg 10mg; 15mg; 20mg; 21 mg; 0.25mg to 100mg; 1mg to 25mg; 1 mg to 50 mg; 1 mg to 30mg; 2 to 30mg; 5 mg to 15mg; 10mg to 20mg; 10 to 50mg; 50-150mg per day.

102. The method of any one of claims 81 to 101 , wherein the therapeutically effective amount is an amount of biologically active material selected from the group consisting of: up to and including 150mg NAD; up to and including 150mg apigenin or quercetin or other CD38 inhibitor from Table 1 ; and up to and including 150mg GSH or CoQ; up to and including 150mg of spermidine or other cellular health molecules from Table 2; up to and including 150mg of quercetin or other sirtuin activator molecules from Table 3.

103. The method of any one of claims 81 to 101 , wherein the therapeutically effective amount is administered to the subject using a method selected from the group consisting of: orally; sublingually; buccally.

104. The method of any one of claims 81 to 103, wherein the therapeutically effective amount is administered to the subject using a method selected from the group consisting of: beneath the tongue or buccally.

105. The method of any one of claims 81 to 104, wherein detectable levels of the biologically active material enters the circulation system.

106. The method of any one of claims 81 to 105, wherein the detectable levels of the biologically active material that enters the circulation system is selected from the group consisting of: less than 0.001%; less than 0.01%; less than 0.1%; less than 2%; less than 3%; less than 4%; less than 5%; less than 6%; less than 7%; less than 8%; less than 9%; less than 10%; less than 11%; less than 12%; less than 13%; less than 14%; less than 15%; less than 16%; less than 17%; less than 18%; less than 19%; less than 20%; less than 21%; less than 22%; less than 23%; less than 24%; ess than 25%; less than 26%; less than 27%; less than 28%; less than 29%; less than 30%; less than 31%; less than 32%; less than 33%; less than 34%; less than 35%; less than 36%; less than 37%; less than 38%; less than 39%; less than 40%; less than 41%; less than 42%; less than 43%; less than 44%; less than 45%; less than 46%; less than 47%; less than 48%; less than 49%; less than 50%; less than 51%; less than 52%; less than 53%; less than 54%; less than 55%; less than 56%; less than 57%; less than 58%; less than 59%; less than 60%; less than 61%; less than 62%; less than 63%; less than 64%; less than 65%; less than 66%; less than67%; less than 68%; less than 69%; less than 70%; less than 71%; less than 72%; less than 73%; less than 74%; and less than 75% (w / w%).

107. The method of any one of claims 81 to 106, wherein said biologically active material is absorbed by diffusion directly into the systemic circulation.

108. The method of any one of claims 81 to 107, wherein said biologically active material is sublingually absorbed rapidly.

109. The method of any one of claims 81 to 108, wherein the drug form is delivered sublingually and more suitable for patients phobic to subcutaneous injection or clinical IV infusion.

110. The method of any one of claims 81 to 109, wherein the sublingual administered nicotinamide adenine dinucleotide has a significant length of contact time with the mucosal surface, allowing absorption of the active(s) and transfer directly into the circulatory system; or up to 10 minutes.

111. The method of any one of claims 81 to 110, wherein the t1 / z of the administered nicotinamide adenine dinucleotide is selected from the group consisting of: between 15 and 20 min; between 20 and 25 min; between 25 and 30 min; between 30 and 35 min; between 35 and 40 min; between 40 and 45 min; between 45 and 50 min; between 30 and 60 min; between 1 and 2 hrs; between 2 and 3 hrs; between 3 and 4 hrs; between 4 and 5 hrs; between 5 and 6 hrs; between 6 and 12 hrs; between 12 and 24 hrs; between 1 and 2 days; between 2 and 3 days; between 3 and 4 days; between 4 and 5 days; between 5 and 6 days; between 6 and 7 days; between 6 and 7 days; between 1 and 2 weeks; between 2 and 3 weeks; between 3 and 4 weeks; between 1 and 2 months; between 2 and 3 months; between 3 and 4 months; between 4 and 5 months; between 5 and 6 months; between 6 and 12 months; and between 1 and 2 years.

112. The method of any one of claims 81 to 111 , wherein the t1 / z of the administered nicotinamide adenine dinucleotide is selected from the group consisting of: between 15 and 120 min.

113. The method of any one of claims 81 to 112, wherein effects of NAD combined with CD38 inhibitors and / or glutathione antioxidant and / or coenzyme Q produce synergistic effects.

114. The method of any one of claims 81 to 113, wherein the combination of NAD with a CD38 inhibitor allows the augmentation of the NAD dose delivered, by reducing its metabolism.

115. The method of any one of claims 81 to 114, wherein the direct absorption of poorly soluble and poorly bioavailable flavonoid CD38 inhibitors solves the current problem of poor gut absorption and low blood concentrations.

116. The method of any one of claims 81 to 115, wherein the ready incorporation of a CD38 inhibitor means that the NAD can be augmented further by preventing excessive CD38 metabolism.

117. The method of any one of claims 81 to 116, wherein the ready incorporation of glutathione and / or coenzyme Q means that the NAD can be augmented further by augmenting the body’s levels of key cellular antioxidants.

118. Use of the composition of claims 1 to 73 in the manufacture of a medicament for the treatment or prevention of a deficiency, condition, disease or disorder.

119. A process of preparing the composition of claims 1 to 73, said process comprising the steps of: (1 ) combining at least one matrix forming agent with a biologically active material to form a mixture; and (2) freeze drying the mixture to form the solid dosage form.

120. A process of preparing the composition of claims 1 to 73, said process further comprising the steps of micronisation.

121. A kit comprising the dosage form of claims 76 to 80 together with instructions for its use.

122. The kit of claim 121 , wherein the kit is directed to treating of preventing a deficiency, condition, disease or disorder.

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