Composition for oral administration of gamma aminobutyric acid (GABA)

Abstract

A composition for oral administration of gamma aminobutyric acid (GABA), the composition comprising: GABA; at least one retention agent configured to increase retention of the composition, and the GABA contained in the composition, in the stomach for an extended period of time; and at least one slow release agent configured to allow extended release of the GABA from the composition. Additional embodiments of the composition, it method of administration and its use are disclosed herein.

Description

[0001] COMPOSITION FOR ORAL ADMINISTRATION OF GAMMA AMINOBUTYRIC

[0002] ACID (GABA)

[0003] CROSS-REFERENCE TO A RELATED APPLICATION

[0004] This application claims priority to United States Provisional Patent Application No. 63 / 656,651, filed June 06, 2024, the entire content of which is incorporated herein by reference in its entirety.

[0005] FIELD

[0006]

[0001] The present subject matter relates to administration of gamma aminobutyric acid (GABA). More particularly, the present subject matter relates to oral administration of gamma aminobutyric acid (GABA).

[0007] BACKGROUND

[0008]

[0002] Gamma aminobutyric acid (GABA), or y-aminobutyric acid, also known as 4- aminobutyric acid, is a non-protein amino acid that serves in the body as a neurotransmitter and is available in numerous foodstuffs including potatoes, cruciferous vegetables (broccoli, cabbage, cauliflower, Brussels sprouts) and others (Heli Z, Hongyu C, Dapeng B, Yee Shin T, Yejun Z, Xi Z and Yingying W (2022) Recent advances of y-aminobutyric acid: Physiological and immunity function, enrichment, and metabolic pathway. Front. Nutr. 9: 1076223. doi: 10.3389 / fnut.2022.1076223, the entire content of which is incorporated herein by reference).

[0009]

[0003] Research has shown that GABA supplementation, in combination with other medicines and substances can be used effectively in the treatment of numerous physiological dysfunctions, including in type 1 diabetes. However, due to the short half-life of GABA in the blood plasma and the limited bioavailability following oral administration, multiple daily doses are required to maintain augmented blood plasma concentrations throughout the day.

[0010]

[0004] GABA is rapidly absorbed following oral administration reaching maximum blood plasma concentrations (tmax) within 0.5-1 hour of dosing. The blood plasma half-life of GABA is reported to be about 5 hours (Li J, Zhang Z, Liu X, Wang Y, Mao F, Mao J, Lu X, Jiang D, Wan Y, Lv J-Y, Cao G, Zhang J, Zhao N, Atkinson M, Greiner DL, Prud’homme GJ, Jiao Z, Li Y and Wang Q (2015) Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics. Front. Pharmacol. 6:260. doi: 10.3389 / fphar.2015.00260, the entire content of which is incorporated herein by reference). Therefore, in order to provide systemic exposure over the whole day by oral administration of GABA, for example as a nutritional supplement or as an orally administered medication, a pharmaceutical dosage form containing GABA would have to be dosed numerous times per day. Such an administration regimen is inconvenient for the patient, but worse, may lead to lack of adherence to the dosing regimen and put patients at risk for taking too little, or too much, GABA by making up missed doses at the wrong time.

[0011]

[0005] A possible solution for the aforementioned problem relating to oral administration of GABA could be formulating an extended-release dosage form containing GABA, allowing it to be released and thus absorbed from the dosage form over a longer period of time. A controlled-release GABA formulation demonstrated a significant increase in bioavailability in dogs up to 23-fold as reported in U.S. Patent No. 1 l,638,701B2, the entire content of which is incorporated herein by reference. However, this enhanced effect was not reproduced in human studies. In a clinical trial evaluating a controlled-release GABA formulation (Remygen, Diamyd Medical, Stockholm, Sweden - the entire content of which is incorporated herein by reference), administration of 600 mg GABA resulted in a mean AUC of 618.6 ng / mL-h, 1,200 mg GABA resulted in a mean AUC of 782.4 ng / mL-h (Espes D, Liljeback H, Hill H, et al. GABA induces a hormonal counter-regulatory response in subjects with long- standing type 1 diabetes. BMJ Open Diab Res Care 2021;9:e002442. doi: 10.1136 / bmjdrc-2021-002442, the entire content of which is incorporated herein for reference). By comparison, in an earlier study of non-modified GABA, administration of 2,000 mg yielded an AUC of 932.91 ng / mL-h (Li J, Zhang Z, Liu X, Wang Y, Mao F, Mao J, Lu X, Jiang D, Wan Y, Lv J-Y, Cao G, Zhang J, Zhao N, Atkinson M, Greiner DL, Prud’homme GJ, Jiao Z, Li Y and Wang Q (2015) Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics. Front. Pharmacol. 6:260. doi: 10.3389 / fphar.2015.00260, the entire content of which is incorporated herein by reference). This corresponds to a relative bioavailability increase of about 7%, indicating negligible enhancement of systemic exposure by the controlled-release formulation in humans. SUMMARY

[0012]

[0006] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present subject matter, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0013]

[0007] According to one aspect of the present subject matter, there is provided a composition for oral administration of gamma aminobutyric acid (GABA), the composition comprising:

[0014] GABA; at least one retention agent configured to increase retention of the composition, and the GABA contained in the composition, in the stomach for an extended period of time; and at least one slow release agent configured to allow extended release of the GABA from the composition.

[0015]

[0008] According to one embodiment, the at least one retention agent is a swelling agent.

[0016]

[0009] According to one embodiment, the at least one retention agent is a floating agent.

[0017]

[0010] According to one embodiment, the at least one retention agent is a mucoadhesive agent.

[0018]

[0011] According to one embodiment, the at least one slow release agent is a matrix agent.

[0019]

[0012] According to one embodiment, the at least one slow release agent is a hot melt extrusion agent.

[0020]

[0013] According to one embodiment, the at least one slow release agent is a coating agent.

[0021]

[0014] According to one embodiment, the composition further comprising a pharmaceutically acceptable excipient that is configured to be added to a composition for oral administration of drugs.

[0015] According to one embodiment, the composition is in a form of capsule, or tablet, or powder, or granule, configured to be orally administered to a mammal.

[0022]

[0016] According to another aspect of the present subject matter, there is provided a method for oral administration of GABA to a mammal, the method comprising: administering a composition according to any one of claims 1-9 to a mammal.

[0023]

[0017] According to yet another aspect of the present subject matter, there is provided a use of the aforementioned composition for oral administration of GABA to a mammal.

[0024]

[0018] According to one embodiment, the mammal is a human.

[0025] DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026]

[0019] Before explaining at least one embodiment in detail, it is to be understood that the subject matter is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The subject matter is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. In discussion of the various figures described herein below, like numbers refer to like parts. The drawings are generally not to scale.

[0027]

[0020] As mentioned above, one drawback of the currently available orally administered compositions for extended release of GABA, is the decreased bioavailability of GABA. One aim of the present matter is to increase the bioavailability of orally administered GABA.

[0028]

[0021] An explanation for the low bioavailability of GABA after administration of extended release oral formulations of GABA could be that GABA is absorbed in the upper part of the small intestine, and that by administering an extended-release oral dosage form a significant portion of the GABA is not released until it has passed the main window of absorption in the upper part of the small intestine. One evidence that GABA is absorbed at the upper part of the gastro-intestinal (GI) tract is that GABA peak blood plasma concentrations were found after 30 minutes. ((Food Sci. Biotechnol. 25(2): 547-551 (2016) DOI 10.1007 / s 10068-016-0076-9, Effect of Oral y-aminobutyric Acid (GABA) Administration on Sleep and its Absorption in Humans, Atsushi Yamatsu, Yusuke Yamashita*, Tukaram Pandharipande, Isafumi Maru, and Mujo Kim Pharma Foods International Co., Ltd., Kyoto 615-8245, Japan., the entire content of which is incorporated herein by reference).

[0029]

[0022] Another study of GABA pharmacokinetics showed peak blood plasma concentration at 60 minutes (though this was the first time point tested following oral administration and the true maximum concentration (Cmax) of GABA in the blood plasma could have been missed [Martin, A., Mick, G.J., Cheat, H.M. et al. A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes. Nat Commun 13, 7928 (2022). https: / / doi.org / 10.1038 / s41467-022-35544-3, the entire content of which is incorporated herein by reference).

[0030]

[0023] A study on a much larger dose (888 mg dissolved in 1 liter of water, with test points at 15 minutes, 30 minutes and 60 minutes also showed peak plasma concentrations at 30 minutes (Tessa H. de Bie, Michiel G. J. Balvers, Ric C. H. de Vos, Renger F. Witkamp and Maarten A. Jongsma. The influence of a tomato food matrix on the bioavailability and plasma kinetics of oral gamma-aminobutyric acid (GABA) and its precursor glutamate in healthy men. Food Funct., 2022, 13, 8399-8410. DOI: 10.1039 / d2fo01358d., the entire content of which is incorporated herein by reference).

[0031]

[0024] Notwithstanding the studies that have been conducted in this area, there seems to be a lack of clarity in the literature as to the bioavailability and site of absorption of GABA following oral administration. However, a review of the literature implies that GABA absorption by the intestine is mediated via carrier proteins normally involved in nutrient absorption and appears to involve H+ / zwitterionic GABA cotransport (Thwaites DT, Basterfield L, McCleave PM, Carter SM, Simmons NL. Gamma-Aminobutyric acid (GABA) transport across human intestinal epithelial (Caco-2) cell monolayers. Br J Pharmacol. 2000 Feb;129(3):457-64. doi: 10.1038 / sj.bjp.0703069. PMID: 10711343; PMCID: PMC1571855. The entire content of which is incorporated herein by reference).

[0032]

[0025] In addition, Thwaites et al. (2000) showed that the absorption of GABA in the small intestine is saturable and that the best fit curve of GABA absorption in the intestine was a Michaelis-Menten curve, with a linear component (r2=0.998). This may indicate that GABA absorption in the intestine is mediated by binding of GABA to one binding site of an active GABA transporter. A possible explanation for this phenomenon is that there is a saturable limit to the active transport of GABA during GABA absorption in the small intestine, and that any excess GABA would pass through the region where active transport of GABA occurs without being absorbed. This excess GABA reaches then a farther part of the small intestine, where the absorption of GABA is mediated only by passive diffusion, resulting in a much lower amount of GABA being absorbed compared to the “active transport area” at the upper part of the small intestine.

[0033]

[0026] Studies using rat intestine suggest that GABA shares a transporter with L-alanine (Nacher A, Polache A, Moll-Navarro MJ, Pla-Delfina JM, Merino M. Intestinal absorption pathway of gamma-aminobutyric acid in rat small intestine. Biopharm Drug Dispos. 1994 Jul;15(5):359-71. doi: 10.1002 / bdd.2510150503. PMID: 7981425. The entire content of which is incorporated herein by reference). This may explain why very little GABA is bioavailable when ingested orally [Oketch-Rabah, H.A.; Madden, E.F.; Roe, A.L.; Betz, J.M. United States Pharmacopeia (USP) Safety Review of Gamma- Aminobutyric Acid (GABA). Nutrients 2021, 13, 2742. https: / / doi.org / 10.3390 / nu 13082742. The entire content of which is incorporated herein by reference].

[0034]

[0027] This implies that GABA is readily absorbed by active mechanisms at the upper part of the GI tract, but that this mechanism is saturable and that once this window of absorption is passed any residual GABA absorption would be by passive diffusion through the lumen of the small intestine.

[0035]

[0028] The present subject matter provides a composition comprising GABA that is configured to be orally administered to a mammal and further configured to allow increased absorption of GABA in the GI tract, compared to currently available compositions for oral administration of GABA.

[0036]

[0029] The present subject matter further provides a composition comprising GABA that is configured to remain in in the stomach for an extended period of time.

[0037]

[0030] The present subject matter further provides a composition comprising GABA that is configured to slowly release the GABA from the composition when the composition remains in the stomach.

[0031] Thus, the composition comprising GABA allows the GABA to be released gradually in the stomach, compared to currently available compositions for oral administration of GABA. As the slowly released GABA exits the stomach it is available for absorption at the upper part of the small intestine, near the exit from the stomach, where the absorption of GABA is maximal, for example by active transport through amino acid channels that are present at the upper part of the small intestine, near the exit from the stomach.

[0038]

[0032] The currently available compositions release the entire amounts of GABA that are available for absorption at the upper part of the small intestine, near the exit of the stomach very quickly, over saturating the active transport of GABA. Therefore, most of the GABA that passes through this area of maximal absorption cannot be absorbed and remains available for absorption only further down the small intestine, when absorption of GABA is minimal, for example due to passive absorption through the lumen of the small intestine.

[0039]

[0033] The main difference between the composition for oral administration of GABA of the present subject matter and the currently available compositions for oral administration of GABA is that by ensuring the extended release of GABA in the stomach by the composition of the present subject matter allows GABA to reach the “active transport area” at the upper part of the small intestine, near the exit of the stomach, in a rate that allows significantly more of the GABA to be absorbed in the “active transport area” without significantly over- saturating the active transport binding sites mentioned above. This feature of the composition of the present subject matter maximizes the efficiency of absorption of orally administered GABA.

[0040]

[0034] According to one embodiment, which may be combined with each other embodiment described herein, the composition, the composition is an oral dosage form. According to another embodiment, which may be combined with each other embodiment described herein, the composition is configured to increase bioavailability of GABA. According to yet another embodiment, which may be combined with each other embodiment described herein, the composition is configured to increase the duration of presence of GABA in blood plasma by extending the period of absorption of GABA from the GI tract.

[0041]

[0035] According to one embodiment, which may be combined with each other embodiment described herein, the composition for oral administration of GABA comprises: GABA; at least one retention agent configured to increase retention of the composition, and the GABA contained in the composition, in the stomach for an extended period of time; and at least one slow release agent configured to allow extended release of the GABA from the composition.

[0042]

[0036] For the sake of simplicity only:

[0043]

[0037] The composition for oral administration of GABA is occasionally referred to herein as "composition".

[0044]

[0038] According to one embodiment, which may be combined with each other embodiment described herein, one type of the at least one retention agent is a swelling agent. The swelling agent is configured to swell in the liquids in the stomach. As a result, the composition becomes too large to exit the stomach through the gastroenteric pyloris (the exit from the stomach) into the duodenum (the upper part of the small intestine, just after the exit from the stomach). This results in retention of the composition in the stomach for an extended period of time. Another mechanism of increasing the retention of the formulation in the stomach relates to a decrease in the density of the formulation due to its swelling. As a result, the density of the formulation is lower than the density of the fluids in the stomach, thus causing floatation of the formulation in the stomach.

[0045]

[0039] According to another embodiment, which may be combined with each other embodiment described herein, another type of the at least one retention agent is a floating agent. The floating agent is configured to cause the composition, in part, or in whole, to float on the liquid in the stomach. This allows retention of the composition in the stomach for an extended period of time.

[0046]

[0040] According to yet another embodiment, which may be combined with each other embodiment described herein, yet another type of the at least one retention agent is a mucoadhesive agent. The mucoadhesive agent is configured to adhere to the mucosal layer on the walls of the stomach, or on the walls of the upper part of the small intestine, near the exit from the stomach. As a result, the composition is retained in the stomach, or in the upper part of the small intestine, near the exit from the stomach, for an extended period of time.

[0041] As mentioned above, the composition comprises at least one retention agent. According to some embodiments which may be combined with each other embodiment described herein, the retention agent can comprise either one of the following combinations of types of retention agent:

[0047] - at least one swelling agent; or

[0048] - at least one floating agent; or

[0049] - at least one mucoadhesive agent; or

[0050] - at least one swelling agent and at least one floating agent; or

[0051] - at least one swelling agent and at least one mucoadhesive agent; or

[0052] - at least one floating agent and at least one mucoadhesive agent; or

[0053] - at least one swelling agent and at least one floating agent and at least one mucoadhesive agent.

[0054]

[0042] According to one embodiment, which may be combined with each other embodiment described herein, one type of the at least one slow release agent is a matrix agent. The matrix agent is a polymer that is configured to be evenly mixed with the GABA and form a matrix where the GABA is evenly distributed. According to another embodiment, which may be combined with each other embodiment described herein, the matrix comprising the GABA is configured to be slowly degraded over time. As a result, during the slow degradation, or erosion, or the combination of degradation and erosion, of the polymer over time, only the GABA that is exposed to the ambient physiological fluids is released from the composition and is available for absorption at the upper part of the small intestine, near the exit from the stomach.

[0055]

[0043] According to another embodiment, which may be combined with each other embodiment described herein, another type of the at least one slow release agent is a hot melt extrusion agent. Hot melt extrusion is a method for manufacturing inter alia compositions for slow release of drugs. During the hot melt extrusion a polymer, the drug and a plasticizer are mixed to form a uniform powdered mixture that is fed through a hopper of a preheated extruder and then transferred into a heated barrel by a rotating extruder screw. The hot melt extrusion agent is an agent that is configured to be added to the GABA to manufacture the composition comprising GABA in the hot melt extrusion method. As a result, the composition that comprises a hot melt extrusion agent and is manufactured by the hot melt extrusion method is configured to slowly release the GABA from the composition.

[0056]

[0044] According to further embodiments, which may be combined with each other embodiment described herein, yet another type of the at least one slow release agent is a coating agent. Some exemplary mechanisms of slow release achieved by using a coating agent are described in the following paragraphs.

[0057]

[0045] According to one embodiment, which may be combined with each other embodiment described herein, extended release of GABA can be achieved by using diffusion-modulated polymer-membrane systems. According to this embodiment, which may be combined with each other embodiment described herein, the extended-release dosage form comprises a core containing GABA that is enveloped by a continuous, water-permeable yet substantially waterinsoluble polymeric membrane. Following exposure to gastrointestinal fluid, water penetrates the membrane, dissolves or suspends GABA within the core, and the resulting solution or suspension diffuses outward through the polymeric matrix at a rate governed principally by (i) membrane thickness, (ii) membrane porosity and tortuosity, and (iii) the physicochemical properties of GABA. Suitable membrane-forming materials include, without limitation, ethyl cellulose, cellulose acetate, and acrylic copolymers bearing quaternary ammonium functionality (e.g., polymethacrylate RS or RL grades). The release profile is thereby rendered substantially independent of luminal agitation and gastric-emptying variability.

[0058]

[0046] According to another embodiment, which may be combined with each other embodiment described herein, extended release of GABA can be achieved by using osmotically driven membrane-controlled systems. According to this embodiment, the dosage form is designed as an osmotic delivery device in which the core comprising GABA additionally contains one or more osmotically effective solutes. The core is surrounded by a semi -permeable membrane that permits ingress of aqueous media while restricting egress of dissolved solutes. Water influx generates hydrostatic pressure within the core, expelling an aqueous solution or suspension of GABA through at least one pre-formed orifice having a calibrated cross-sectional area. Release kinetics are controlled by the osmotic gradient, membrane hydraulic permeability, and orifice geometry, affording a near zero-order release rate substantially independent of pH, motility, or fed-fasted state. Cellulose acetate and cellulose acetate butyrate are exemplary membrane materials.

[0047] According to yet another embodiment, which may be combined with each other embodiment described herein, extended release of GABA can be achieved by using erodible or biodegradable polymer-coated systems. According to this embodiment, controlled release is achieved by surrounding a core comprising GABA with a coating composed of polymers that undergo hydrolytic, enzymatic, or physicochemical erosion in the gastrointestinal environment. As the coating gradually diminishes in mass, apertures or channels are created, permitting progressive liberation of GABA. Release kinetics are dictated by polymer composition, molecular weight, crystallinity, and, where applicable, copolymer ratio (e.g., lactic -co -glycolic acid in PLGA). Representative erosion-controlled polymers include poly(lactic acid), poly(lactic-co-glycolic acid), polycaprolactone, and water-soluble polyvinyl alcohols modified to exhibit controlled erosion profiles.

[0059]

[0048] According to still another embodiment, which may be combined with each other embodiment described herein, extended release of GABA can be achieved by using multilayered multiparticulate (layered bead) systems. According to this embodiment, GABAlayered inert cores or microgranules containing GABA are sequentially over-coated with alternating strata of rate-modulating polymer and, optionally, additional GABA layers. Each polymer stratum functions as a discrete diffusion- or erosion-controlling barrier, enabling stepwise or quasi-continuous release over a predetermined interval. By blending populations of particles bearing differing thicknesses or compositions of rate-controlling layers, a tailored composite release profile, for example, biphasic, sigmoidal, or approximately zero-order, can be achieved. Suitable rate-modulating coatings encompass ethyl cellulose, acrylic polymers of varying permeability (Eudragit® NE, RS, RL), and hydrophilic swellable polymers such as hydroxypropyl methylcellulose.

[0060]

[0049] According to a further embodiment, which may be combined with each other embodiment described herein, extended release of GABA can be achieved by using hydrophobic (lipid or wax-based) barrier systems. According to this embodiment, GABA is encapsulated within, or coated by, a hydrophobic matrix comprising long-chain fatty acids, waxes, glycerides, or combinations thereof. The hydrophobic barrier impedes ingress of aqueous media, such that liberation of GABA occurs predominantly via (i) diffusion through micro-channels created upon partial melting, dissolution, or digestion of the lipid phase, and / or (ii) gradual erosion of the lipid matrix under the influence of bile salts and pancreatic enzymes. Exemplary lipids include glyceryl behenate, carnauba wax, hydrogenated castor oil, and stearic acid, optionally admixed with pharmaceutically acceptable surfactants to fine-tune matrix permeability and mechanical robustness.

[0061]

[0050] As a result, the GABA that is contained in the composition is slowly released from the composition and is available for absorption in the upper part of the small intestine, near the exit from the stomach.

[0062]

[0051] As mentioned above, the composition comprises at least one slow release agent. According to some embodiments which may be combined with each other embodiment described herein, the slow release agent can comprise either one of the following combinations of types of slow release agent:

[0063] - at least one matrix agent; or

[0064] - at least one hot melt extrusion agent; or

[0065] - at least one coating agent; or

[0066] - at least one matrix agent and at least one hot melt extrusion agent; or

[0067] - at least one matrix agent and at least one coating agent; or

[0068] - at least one matrix agent and at least one hot melt extrusion agent and at least one coating agent.

[0069]

[0052] According to one embodiment, which may be combined with each other embodiment described herein, the matrix agent is a cellulose derivative. Any type of cellulose derivative is under the scope of the present subject matter. According to another embodiment, which may be combined with each other embodiment described herein, the matrix agent is Hypromellose, also known as Hydroxypropyl Methylcellulose (HPMC). Any type of HPMC is under the scope of the present subject matter. According to yet another embodiment, which may be combined with each other embodiment described herein, the matrix agent is Hydroxypropyl Cellulose. Any type of Hydroxypropyl Cellulose is under the scope of the present subject matter. According to still another embodiment, which may be combined with each other embodiment described herein, the matrix agent is Ethylcellulose. Any type of Ethylcellulose is under the scope of the present subject matter. According to a further embodiment, which may be combined with each other embodiment described herein, the matrix agent is Carbomer, also known as Carboxypolymethylene. Any type of Carbomer is under the scope of the present subject matter. It should be noted that the present subject matter is not limited to these exemplary types of matrix agent. Any type of matrix agent is under the scope of the present subject matter. It should be further noted that any grade of the matrix agent is under the scope of the present subject matter.

[0070]

[0053] According to one embodiment, which may be combined with each other embodiment described herein, the hot melt extrusion agent is a Polyethylene Oxide (PEO). Any type of PEO is under the scope of the present subject matter. According to another embodiment, which may be combined with each other embodiment described herein, the matrix agent is Hydroxypropyl Cellulose. Any type of Hydroxypropyl Cellulose is under the scope of the present subject matter. It should be noted that the present subject matter is not limited to these exemplary types of hot melt extrusion agent. Any type of hot melt extrusion agent is under the scope of the present subject matter. It should be further noted that any grade of the hot melt extrusion agent is under the scope of the present subject matter.

[0071]

[0054] According to one embodiment, which may be combined with each other embodiment described herein, the coating agent is a polymer suitable for coating compositions for slow release of orally administered drugs.

[0072]

[0055] According to one embodiment, which may be combined with each other embodiment described herein, the composition further comprises any type of a pharmaceutically acceptable excipient that is configured to be added to a composition for oral administration of drugs.

[0073]

[0056] According to one embodiment, which may be combined with each other embodiment described herein, the composition is a formulation that is configured to be orally administered. Any type of formulation is under the scope of the present subject matter, for example, but not limited to: a capsule, or a tablet, or a powder, or a granule and the like.

[0074]

[0057] The present subject matter additionally provides a method for oral administration of GABA to a mammal. According to one embodiment, which may be combined with each other embodiment described herein, the mammal is a human.

[0075]

[0058] The present subject matter further provides a use of a composition for oral administration of GABA for oral administration of GABA to a mammal. EXAMPLES

[0076]

[0059] The following are examples of the agents disclosed herein, list in categories. It should be noted that there are agents that can belong to more than one category, depending on their functionality, as one would appreciate by referring to the following tables. Some exemplary combinations of agent categories are listed below as well.

[0077]

[0060] Table 1: A list of some exemplary swelling agents or swelling / floating agents. Typical brand names of excipients are given in parentheses in all tables, not limiting to these brand names.

[0078]

[0061] Table 2: A list of some exemplary floating agents that function by a mechanism other than swelling.

[0079]

[0062] Table 3: A list of some exemplary mucoadhesive agents.

[0080]

[0063] Table 4: A list of some exemplary combinations of swelling and mucoadhesive agents.

[0081]

[0064] Table 5: A list of some exemplary combinations of floating agents that function by a mechanism other than swelling and mucoadhesive agents.

[0082]

[0065] Table 6: A list of some exemplary combinations of swelling, floating and mucoadhesive agents. Polyethylene Oxide Tartaric Acid Polycarbophil 10-40, 3- Rapidly swelling, (Polyox) + Sodium (Noveon) 10 + 5-15, high-viscosity Bicarbonate 5-20 polymer for gastric retention. Acid-base combination to generate CO2 for tablet floatation. Strong mucoadhesive and gel-former.

[0083] Polyethylene Oxide Tartaric Acid Chitosan 10-40, 3- Rapidly swelling, (Polyox) + Sodium (ChitoClear) 10 + 5-15, high-viscosity Bicarbonate 5-15 polymer for gastric retention. Acid-base combination to generate CO2 for tablet floatation. Adheres to gastric mucosa via electrostatic interaction.

[0084] Polyethylene Oxide Tartaric Acid Carbomer 10-40, 3- Rapidly swelling, (Polyox) + Sodium (Carbopol) 10 + 5-15, high-viscosity Bicarbonate 2-10 polymer for gastric retention. Acid-base combination to generate CO2 for tablet floatation. Mucoadhesive with high swelling index.

[0085] Polyethylene Oxide Adipic Acid Polycarbophil 10-40, 2- Rapidly swelling, (Polyox) + Sodium (Noveon) 8 + 5-15, high-viscosity Bicarbonate 5-20 polymer for gastric retention. Slower reacting acid to sustain CO2 generation. Strong mucoadhesive and gel-former.

[0086] Polyethylene Oxide Adipic Acid Chitosan 10-40, 2- Rapidly swelling, (Polyox) + Sodium (ChitoClear) 8 + 5-15, high-viscosity Bicarbonate 5-15 polymer for gastric retention. Slower reacting acid to sustain 21

[0087]

[0066] The following are some examples of a gastroretentive GABA formulation according to embodiments described herein, and their functional descriptions.

[0088]

[0067] Table 7: A monolayer floating matrix tablet formulation (Meal-Aware, 6-12 h).

[0089]

[0068] Table 8: A bilayer gastroretentive tablet formulation.

[0090]

[0069] Table 9: A tri-layer matrix tablet formulation.

[0091]

[0070] Table 10: A multiparticulate capsule with floating beads formulation.

[0092]

[0071] Table 11: A synthetic-only tri-layer tablet for GABA formulation (meal-aware)

[0093]

[0072] In the exemplary gastroretentive GABA formulations listed in Tables 7-11, an amount of 350 mg GABA per dose was used. It should be noted though that this amount of GABA per dose in the formulation is exemplary, and that any suitable amount of GABA per dose in the formulation is under the scope of the present subject matter. According to one embodiment, which may be combined with each other embodiment described herein, the amount of GABA in the formula is in the range of substantially 100-600 mg per dose. According to one embodiment, which may be combined with each other embodiment described herein, any amount of GABA, or any range of the amount of GABA within the range of 100-600 mg per dose is under the scope of the present subject matter.

[0094]

[0073] According to one embodiment, which may be combined with each other embodiment described herein, the aforementioned exemplary gastroretentive GABA formulations are administered once daily. According to another embodiment, which may be combined with each other embodiment described herein, the aforementioned exemplary gastroretentive GABA formulations are administered twice daily. According to yet another embodiment, which may be combined with each other embodiment described herein, the aforementioned exemplary gastroretentive GABA formulations are administered once or twice daily.

[0095]

[0074] A clinical trial testing human bioavailability / bioequivalence of some exemplary gastroretentive GABA formulations according to present subject matter is designed as detailed in Table 12 below. Generally, three gastroretentive GABA formulations are tested vs. a food supplement GABA formulation containing substantially 500-750 mg GABA.

[0096]

[0075] Table 12: Clinical trial design for testing human bioavailability / bioequivalence of exemplary gastroretentive GABA formulations.

[0097]

[0076] The expected result of the clinical trial is improved exposure to GABA by using the gastroretentive GABA formulations compared to the food supplement GABA formulation, as shown by an area under curve (AUC) showing the results, accompanied with decreased Cmax demonstrating fewer adverse effect, for example drowsiness, achieved at a lower overall dose.

[0098]

[0077] Another study that is under the scope of the present subject matter, is a gamma scintigraphy study. The study comprises the following stages:

[0099]

[0078] Stage 1: radiolabeling method development and validation. The study involves usage of the radio isotope "mTc as it provides images with good resolution and has a short half-life, enabling just-in-time manufacture.

[0100] A small quantity of excipient, with similar physiochemical properties to GABA, is radiolabeled and incorporated into the manufacture of the GR-SR tablet.

[0101] In vitro dissolution testing of the radiolabeled formulation is conducted, in front of the gamma camera, and the release of radiolabel with time will be evaluated.

[0102] This is compared with the dissolution profile of the non-radiolabeled formulation to showcase that release of GABA (measured via in-line UV dissolution) is representative of the release of radiolabel over the defined period.

[0103]

[0079] Stage 2: Manufacture under good manufacturing practice (GMP) of radiolabeled products for clinical trial.

[0104] Performance of just-in-time manufacture of radiolabeled drug products due to the short half-life of99mTc.

[0105] - This enables the product to be tested in a clinical setting with no significant stability data required.

[0106] A product is manufactured on a per-tablet basis. Each individual tablet is manufactured and released by a qualified person (QP) as a single batch.

[0107] - No quality control (QC) release testing of tablets is required.

[0108] - This methodology is well accepted by the Medicines and Healthcare products Regulatory Agency (MHRA) and has been utilized by labs for over 25 years.

[0109] The quantity of radiolabel incorporated into each tablet is calculated to ensure that the radioisotope decays to the required level prior to dosing.

[0110] Tablets are manufactured in sufficient quantities for dosing of trial participants the following day.

[0111]

[0080] Stage 3: Pharmaco scintigraphic clinical study.

[0112]

[0081] 1. Gamma scintigraphy overview:

[0113]

[0082] Scintigraphy is a powerful, fast and incredibly effective clinical tool which can improve early drug development productivity by assessing critical product performance parameters which in vitro methods often don’t accurately predict.

[0083] Scintigraphy provides direct, real-time quantification of formulation performance and can help evaluate pharmacodynamic effects on GI transit, and when paired with pharmacokinetic data, offers invaluable insight into the influence of drug delivery strategy on therapeutic outcomes. Scintigraphic data can also be used to support drug delivery claims, for marketing or regulatory purposes.

[0114]

[0084] 2. GR-SR GABA Scintigraphy Study:

[0115] A pharmacoscintigraphic study of the investigational GABA formulations is conducted versus commercially available immediate release GABA.

[0116] The study design is a 4-arm, cross-over, open label, proof of concept (PoC) study in 12 healthy volunteers (males and females of non-childbearing potential).

[0117] Study participants undergo a standard screening visit.

[0118] The study arms are:

[0119] - Immediate Release GABA 500 mg - non-radiolabeled.

[0120] - Modified Release GABA Prototype 1 - radiolabeled.

[0121] - Modified Release GABA Prototype 2 - radiolabeled.

[0122] - Modified Release GABA Prototype 3 - radiolabeled.

[0123] For each treatment period, participants come on site Day 1 am, receive a single dose of drug (in the fasted state), and leave site Day 2 am.

[0124] Each treatment period comprises:

[0125] - Eligibility checks.

[0126] - Pharmacokinetic (PK) sampling with up to 14 samples drawn per visit.

[0127] - Imaging: scintigraphic images taken every 30 minutes up to 14 h post dose (except study arm 1).

[0128] - Safety assessments [vital signs and adverse effect (AE) checks].

[0129] - Procedures prior to leaving unit at last visit: Physical Examination, Biochemistry, hematology, Urinalysis, ECG, vital signs.

[0130] Study endpoints:

[0131] - Pharmacokinetic parameters (including cmax, tmaxAUC0-12, AUG / and ti / 2) in addition to safety and tolerability.

[0132] - Scintigraphic parameters:

[0133] ■ Kinetics of radiolabel release (formulation erosion)

[0134] ■ Time and site of radiolabel release onset (onset of tablet disintegration)

[0135] ■ Gastrointestinal transit parameters (gastric retention time, gastric emptying small intestinal transit time)

[0085] It is appreciated that certain features of the subject matter, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the subject matter, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination.

[0136]

[0086] Although the subject matter has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

Claims

CLAIMS1. A composition for oral administration of gamma aminobutyric acid (GABA), the composition comprising:GABA; at least one retention agent configured to increase retention of the composition, and the GABA contained in the composition, in the stomach for an extended period of time; and at least one slow release agent configured to allow extended release of the GABA from the composition.

2. The composition according to claim 1, wherein the at least one retention agent is a swelling agent.

3. The composition according to any one of claims 1-2, wherein the at least one retention agent is a floating agent.

4. The composition according to any one of claims 1-3, wherein the at least one retention agent is a mucoadhesive agent.

5. The composition according to any one of claims 1-4, wherein the at least one slow release agent is a matrix agent.

6. The composition according to any one of claims 1-5, wherein the at least one slow release agent is a hot melt extrusion agent.

7. The composition according to any one of claims 1-6, wherein the at least one slow release agent is a coating agent.

8. The composition according to any one of claims 1-7, further comprising a pharmaceutically acceptable excipient that is configured to be added to a composition for oral administration of drugs.

9. The composition according to any one of claims 1-8, in a form of capsule, or tablet, or powder, or granule, configured to be orally administered to a mammal.

10. The composition according to claim 9, wherein the mammal is a human.

11. A method for oral administration of GABA to a mammal, the method comprising: administering a composition according to any one of claims 1-9 to a mammal.

12. The method according to claim 10, wherein the mammal is a human.

13. Use of a composition for oral administration of GABA according to any one of claims 1-9 to a mammal.

14. The use according to claim 12, wherein the mammal is a human.

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