WO2019049103A1 - Oral compositions, methods and uses thereof - Google Patents

Abstract

The present disclosure relates to an oral composition for the controlled release of caffeine over time, products, method of obtaining and uses thereof. In view of the drawbacks to the prior art, the technical problem underlying the invention was to develop an energized oral composition that ovoid side, in particular caffeine side effects. Surprisingly, it was achieved an oral composition comprising guar-gum as a polymer, caffeine and alginate wherein 1.5 - 10% (wt/wt of dry weight of the film) of guar-gum and 10 - 30% (wt/wt of dry weight of the film) of caffeine are in a film, 10 - 25% (wt/wt of dry weight of beads) of caffeine and 1 - 5% (wt/wt of dry weight of beads) of alginate are in beads.

Description

D E S C R I P T I O N

ORAL COMPOSITIONS, METHODS AND USES THEREOF

Technical field

[0001] The present disclosure relates to an oral composition for the controlled release of caffeine over time, products, method of obtaining and uses thereof.

Background Art

[0002] Transport of drugs across buccal mucosa occurs exclusively by passive diffusion, an undifferentiated, unselective, transport mechanism [1]. Lipophilic bioactive molecules may permeate buccal mucosa by transcellular route whereas hydrophilic bioactive molecules are more prone to permeate buccal epithelia by intercellular route. Moreover, buccal epithelium presents a molecular weight cut-off that ranges from 500-1000 Da [2]. Hence, molecules with superior molecular weights may be hindered from transposing buccal epithelia and reach systemic circulation. Furthermore, saliva turnover limits the residence time of drugs within buccal mucosa, sometimes leading to premature swallowing [3].

[0003] In order to guarantee that bioactive molecules permeate buccal mucosa, certain requirements must be fulfilled. One interesting approach is the use of films with adherence properties to the buccal epithelium. Oral films are oral delivery systems that disintegrate in the mouth in less than 30 s [2]. Besides from the inherent advantages shared with tablets or capsules (e.g. ease of administration and portability) administration of oral films does not require water. Also, oral films are especially useful for uncooperative patients since, once introduced into the mouth, and are very difficult to remove. Moreover, variables such as colour and taste are easily manipulated according to the preferences of the consumer/patient. Oral films are convenient delivery systems when buccal release is aimed [4]. Buccal route is an attractive delivery route especially due to ease of administration and possibility to avoid first-pass metabolism [3].

[0004] Alginate is a natural anionic copolymer of l,4-linked-p-D-mannuronic acid and a-L- guluronic acid that is highly biocompatible and can be used to produce beads for buccal delivery of bioactive molecules [5]. Alginate beads can represent suitable delivery systems for the buccal mucosa, featuring mucoadhesion and sustained delivery of carried molecules. Production of alginate beads is cheap and does not imply using organic solvents, therefore being predictably safe for human consumption. For the entrapment of hydrophilic molecules, emulsification- internal gelation technique to produce alginate beads usually provides better association efficiencies than formulations with an aqueous external phase.

[0005] Alginate beads/microparticles have been used as delivery systems for buccal delivery of drugs but, to our knowledge, were not intended for buccal absorption, only aiming topical activity [6-8]. Also, alginate has been used for the production of buccal delivery systems (e.g. tablets) but not in the format of beads [9]. Also, incorporation of alginate beads on film matrices represents an unconventional, conceptually new oral/buccal delivery system that conjugates the practicality and user-friendly characteristics of oral films and the slower release of carried bioactive molecules provided by alginate beads.

[0006] Document US20130052234 disclose an edible oral strip composition includes a therapeutically effective amount of active agent(s) to provide at least one effect selected from a stimulating effect, an increased physical endurance, alleviate temporary fatigue, improve nervous system functions, and combinations of any of the foregoing.

[0007] These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.

General Description

[0008] The present disclosure relates to an oral composition for the controlled release of caffeine over time, products, method of obtaining and uses thereof.

[0009] In view of the drawbacks to the prior art, the technical problem underlying the invention was to develop an energized oral composition that ovoid side, in particular caffeine side effects. Surprisingly, this was achieved with an oral composition comprising guar-gum as a polymer, caffeine and alginate wherein

1.5 - 10% (wt/wt of dry weight of the film) of guar-gum and 10 - 30% (wt/wt of dry weight of the film) of caffeine are in a film,

10 - 25% (wt/wt of dry weight of beads) of caffeine and 1 - 5% (wt/wt of dry weight of beads) of alginate are in beads.

[0010] The synergetic effect of the oral composition now disclosed can be observed in the figures below.

[0011] This composition also dissolves easily preferably in at least 5 seconds, in particular 10 seconds, more in particular 15 seconds. [0012] In an embodiment for better results, the composition may comprise a plasticizer and sweetener wherein 2 - 10 % (wt/wt of the amount of the polymer) of the plasticizer and sweetener is in the film.

[0013] In an embodiment for better results, the beads may further comprise calcium carbonate and/or acetic acid.

[0014] In an embodiment for better results, the composition may comprise a saliva production inducer, in particular wherein 0.20 - 5% (wt/wt of dry weight of the film) of the saliva production inducer is in the film.

[0015] In an embodiment for better results, the composition may comprise a surfactant, in particular wherein 1 - 5 % (wt/wt of the dry weight of the beads) of the surfactant is in the beads.

[0016] In an embodiment for better results, the composition may comprise calcium carbonate wherein 0.5 - 5% (wt/wt of the dry weight of the beads) of calcium carbonate is in the beads.

[0017] In an embodiment for better results, the composition may comprise calcium carbonate wherein 0.5 - 5% (wt/wt of the dry weight of the beads) of acetic acid is in the beads.

[0018] In an embodiment for better results, the composition may comprise guar-gum as a polymer, caffeine and alginate wherein:

2% (wt/wt of the dry weight of the film) of guar-gum and 16.5% (wt/wt of the dry weight of the film) of caffeine are in the film, and

16.5% (wt/wt of the dry weight of the beads) of caffeine, 3% (wt/wt of the dry weight of the beads) of alginate are in the beads.

[0019] In an embodiment for better results, the composition may comprise:

2.32% (wt/wt of the amount of the polymer) of the plasticizer and sweetener and 0.31% (wt/wt of the dry weight of the film) of the saliva production inducer are in the film, and

2.43% (wt/wt of the dry weight of the beads) of surfactant, 1.5% (wt/wt of the dry weight of the beads) of calcium carbonate and 0.5% (wt/wt of the dry weight of the beads) acetic acid are in the beads.

[0020] In an embodiment for better results, the composition may comprise the thickness of the film is between 50-100 micrometres, preferably 60 micrometres.

[0021] In an embodiment for better results, the composition may comprise the beads having a size between 300 nm and 8 μιη.

[0022] In an embodiment for better results, the plasticizer and sweetener can be sorbitol or sucralose. [0023] In an embodiment for better results, the surfactant can be polysorbate 80 (Tween^® 80).

[0024] In an embodiment for better results, the plasticizer and saliva production inducer can be critic acid.

[0025] In an embodiment for better results, the beads may further comprise paraffin.

[0026] In an embodiment for better results, the oral composition may comprise a vitamin, a flavouring agent, a dye, an anti-acid agent, a sweetener, or mixtures thereof.

[0027] In an embodiment for better results, the flavouring agent may be: mint, fruit, passion fruit, coconut, cinnamon, chocolate, coffee, lavender, or mixtures thereof.

[0028] In an embodiment for better results, the oral composition may comprise a film and a plurality of beads wherein

the film comprises 1.5 - 10% (wt/wt of the dry weight of the film) of guar-gum and 10 - 30% (wt/wt of the dry weight of the film) of caffeine,

each bead comprises 10 - 25% (wt/wt of the dry weight of the beads) of caffeine and 1 - 5% (wt/wt of the dry weight of the beads) of alginate.

[0029] In an embodiment for better results, the strip comprises the oral composition described in the present disclosure, in particular a sheet energy or an energy strip.

[0030] In an embodiment for better results, an edible oral strip comprising the oral composition described in the present disclosure.

[0031] Another aspect of the oral composition of the present disclosure is use in medicine or as nutraceutical.

Brief Description of the Drawings

[0032] The following figures provide preferred embodiments for illustrating the description and should not be seen as limiting the scope of disclosure.

[0033] Figure 1: Prediction profiler for guar-gum oral films. Quantities of citric acid, guar gum and sorbitol are set considering a final volume of 100 mL of ultra-pure water.

[0034] Figure 2: Prediction profiler for the formulation of alginate beads.

[0035] Figure 3: Subtracted FTIR spectra corresponding to the caffeine present on alginate beads, Gf B, guar-gum films caffeine anhydrous powder and the physical mixture of all excipients of GfB. [0036] Figure 4: Caffeine cumulative release (mean + standard deviation, n=5) across a 500 Da dialysis membrane.

[0037] Figure 5: Cytotoxicity assessment of different concentrations of caffeinated (alginate beads, guar-gum films and GfB), placebo (alginate beads(p), guar-gum films(p) and GfB(p)) formulations.

[0038] Figure 6: Cumulative permeability of caffeine (mean ± standard deviation, n=5) across TR146 cells seeded in Transwell^®.

Detailed Description

[0039] The present disclosure relates to an oral composition for the controlled release of caffeine over time, products, method of obtaining and uses thereof.

[0040] The incorporation of beads into oral films results in a conceptually new oral/buccal delivery system for bioactive molecules, in particular caffeine. A response surface method (experimental design approach) was performed to obtain optimal formulations of alginate beads to be incorporated into guar gum oral films as combined buccal and oral delivery systems for hydrophilic caffeine delivery. The combined formulation was further characterized regarding physicochemical properties, drug release, cell viability and buccal permeability. Beads average size, determined by dynamic light scattering (DLS), was of 3.37 ± 6.36 μιη. Film thickness was set to 62 μιη. Scanning electron microscopy micrographs revealed that beads were evenly distributed onto the film matrix and beads size was in accordance to data obtained from DLS analysis. Evaluation of Fourier-transform infrared spectra did not indicate the formation of new covalent bonds between the matrix of guar-gum films, alginate beads and caffeine. In vitro release assays by dialysis membrane allowed understanding that the combination of guar-gum films and alginate beads assure a slower release of caffeine when compared with the delivery profile of free caffeine from alginate beads or guar-gum films alone. MTT assay, performed on human buccal carcinoma TR146 cell line, allowed concluding that neither guar-gum film, alginate beads nor guar-gum film incorporated into alginate beads significantly compromised cell viability after 24 h of exposure. As demonstrated by in vitro permeability assay using TR146 human buccal carcinoma cell lines, combination of guar-gum films and alginate beads also promoted a slower release and, thus, lower apparent permeability (1.15E-05 ± 3.50E-06) than for caffeine solution (2.68E-05 ± 7.30E-06), guar-gum film (3.12E-05 ± 4.70E-06) or alginate beads (2.01E-05 ± 3.90E-06).

[0041] Distance at burst and film burst strength were chosen as mechanical responses, being directly correlated with elasticity and rigidity, respectively. Film erosion (%) and the ratio of water-uptake over time (mg.s ^_1) were set as representative responses of the capacity of the oral films to absorb water and disintegrate, releasing the content [10]. Film thickness was not controllable at the moment of the production of guar-gum films but is known as being an important factor for the variation of mechanical characteristics. Therefore, thickness was considered as a factor (independent variable) even though thickness values were not circumscribed to a pre-defined range at the moment of the experimental design [11].

[0042] In an embodiment, caffeine anhydrous (food chemicals codex, 99% purity), alginic acid, and D-sorbitol (assay purity >98%) were purchased from Sigma-Aldrich (Steinheim, Germany). Citric acid monohydrate, calcium carbonate, potassium phosphate monobasic anhydrous, sodium phosphate dibasic were purchased from Merck (Darmstadt, Germany). Sodium chloride was purchased from Panreac (Barcelona, Spain). Methanol (HPLC gradient grade) was purchased from Fisher (Loughborough, United Kingdom). Deionized water was used to prepare all oral films formulations and Milli-Q water was used to prepare caffeine standard solutions and eluents used in chromatography procedures. TR146 cell line (passage 9) was purchased from Sigma- Aldrich (Stenheim, Germany). Transwelf flasks (12 well) and inserts (collagen-coated, 1.12 cm² of culture area, 0.4 μιη pore size and 12 mm membrane diameter) were purchased from Corning (New York, USA). 96-well plates were purchased from Thermo Scientific (Denmark). Fetal Bovine Serum (FBS), HAMS-F12 culture medium and Pen-Strep (10 000 U Penicillin, 10 000 U Streptomycin) were purchased from Lonza^® (Verviers, Belgium). TrypLE™ express was purchased from Gibco^® (Denmark). Thiazolyl Blue Tetrazolium Bromide (MTT) Ultra pure was purchased from VWR (Solon, USA). Dimethyl sulfoxide (DMSO) 99.7% was purchased from Fisher Bioreagents™ (EUA). For TR146 cell wash, pH of PBS was adjusted to 6.8, using a solution of hydrochloric acid 0.1 M.

[0043] In an embodiment, experimental design was performed recurring to SAS JMP^® 9 software. Response surface method for the optimization of film formulation was defined using the amounts of guar-gum (polymer), sorbitol (plasticizer and sweetener) and citric acid (saliva production inducer) as factors (independent variables). Erosion, water-uptake/time ratio, distance at burst and film burst strength were set as responses (dependent variables).

[0044] In an embodiment for better results, alginate beads formulation were improved by setting the relative amounts of sodium alginate and Tween^* 80 as factors and association efficiency, ζ-potential, mean size and polydispersity index were set as responses.

[0045] In an embodiment, caffeine anhydrous was incorporated into all films and associated with all beads formulations. [0046] In an embodiment, the production and characterization of the oral films was carried out as follows: preparation of oral films was performed using solvent casting technique [11]. Briefly, guar gum, citric acid and sorbitol were dissolved into 100 mL of ultra-pure water. Thereafter, resulting solution was spread onto a glass cast heated to 50 °C for 1 h. Resulting film was then maintained at room temperature for 12 h. Finally, individual films (2 cm x 3 cm) were cut from the glass cast for further testing. Oral films were collected directly from the glass cast and packaged into thermo-sealed polyethylene sheets.

[0047] In an embodiment, texture analysis was performed on a texturometer equipment (TA.XT plus Texture Analyser, Stable Micro Systems, Cardiff, UK). Force calibration for a 5 kg load cell was performed using a 2 kg weight and height calibration was performed for the film support rig and corresponding probe. Film burst strength (g) and distance at burst (mm) were considered as measures of rigidity and elasticity, respectively.

[0048] In an embodiment, the thickness of the oral films was measured using a calibrated vernier gauge caliper micrometer. Thickness was measured in five points of each oral film and the average value was determined [12].

[0049] In an embodiment, water-uptake, erosion and disintegration time were carried out as follows. The water-uptake (WU) was determined by placing Guar-gum films in contact with 1 mL of artificial saliva. Weight changes were registered at 30, 60, 90, and 120 s and WU was calculated according to Eq. (1) [10]. Afterwards, hydrated samples were introduced in an oven at 60 ^QC for 24 h and weight variation of oral films was recorded in order to determine erosion. Erosion (%) was calculated according to Eq. (2).

Water - uptake (%) = ^{(Wt~ W1)} x 100

(1)

Erosion (%) = x 100 ₍₂₎ where, Wl is initial weight of tested oral films, Wt is the weight of the oral

films after contact with artificial saliva at determined periods of time and W3 is the weight of dry oral films, after erosion.

[0050] In an embodiment, since, according to United States Food and Drug Administration (FDA), oral films, as orodispersible delivery systems, should disintegrate within 30 s in the oral cavity, the WU/time ratio was determined as an indicator of disintegration characteristics [13]. Water-uptake/time ratio was calculated according to Eq. (3).

Water— uptake

Water— uptake /time =— —— - t(max water— uptake) where, water-uptake (%) is an indicator of water absorbed by the oral film (Eq. 1) and t(max water-uptake) is the time (s) at which water-uptake (%) value was maximum.

[0051] In an embodiment, the production and characterization of alginate beads was carried out as follows. Alginate beads were prepared by emulsification/internal gelation [14]. Briefly, calcium carbonate and caffeine were dissolved into an alginate solution. In a separate beaker, tween^® 80 was dispersed into 10 mL of liquid paraffin. Both dispersions were stirred for 30 min and then the alginate solution was added drop wise to the paraffin dispersion and the resulting emulsion was kept stirring (600 rpm) for 30 min. Then, glacial acetic acid was added drop wise to the emulsion to liberate calcium ions for gelation. Resulting emulsion was kept stirring (900 rpm) for 1 h. Resulting emulsion was centrifuged (6,000 rpm, 15 °C) and the pellet was recovered and washed with PBS. Washing procedure was performed three times for each formulation of beads.

[0052] In an embodiment, the characterization of alginate beads was performed as follows. Caffeine association efficiency (AE), mean size, ζ-potential, scanning electron microscopy (SEM) and delivery profile were the parameters used to characterize alginate beads.

[0053] In an embodiment, the particle size and ζ-potential analysis determination were performed as follows. All alginate bead formulations were diluted (1:100) with Milli-Q water before particle size and ζ-potential analysis. Particle size and polydispersity index were determined by dynamic light scattering (DLS). ζ-potential was determined by phase analysis light scattering. All measurements were performed in triplicate in a Zetasizer Nano ZSP equipment (Malvern Instruments Ltd, Worcestershire, UK). In an embodiment, caffeine association efficiency was determined by dosing (HPLC-UV) the free caffeine content of the supernatant of each bead formulation after being centrifuged (6,000 rpm, 30 min, 16 °C). Caffeine concentration in the supernatant was determined by HPLC-UV on a Waters Alliance"' instrument (Milford, MA, USA). Water and methanol mixture (60:40) was used as mobile phase and isocratic flow was set to 1 mL/min [15]. Samples were run through a Kromasil" C18 column, 5 μιτι (particle size) x 4.6 mm (internal diameter) χ 250 mm (length) (AkzoNobel, Bohus, Sweden). UV detector wavelength was set to 270 nm. The injection volume was set to 50 μΙ. Finally, caffeine association efficiency was calculated according to the following Eq. (4):

Wtc - Wsc

X 100 (4)

Wtc

where, Wtc stands for total weight of caffeine used in the alginate bead formulations and Wsc stands for caffeine collected from the supernatant after centrifugation. [0054] In an embodiment, the molecular interactions analysis was performed as follows. ATR- FTIR analysis was performed for guar-gum films and alginate beads (placebo and with caffeine) to assess eventual chemical interactions with caffeine. Analysis was conducted in a FTIR spectrometer, model ABB MB3000 (ABB, Switzerland), equipped with a deuterated triglycine sulphate detector and using a MIRacle™ single reflection horizontal attenuated total reflectance (ATR) accessory (PIKE Technologies, USA) with a diamond/Se crystal plate. Obtained spectra were baseline corrected using a 3-4 point adjustment. Area of obtained spectra was normalized to a 0-1 range. Spectra treatment was performed using the OriginPro" (version 9.0) software. Spectra of caffeinated guar-gum films, alginate beads, GfB and physical mixture of GfB formulation were subtracted from spectra of placebo guar-gum films, alginate beads and GfB, respectively [16]. Resulting spectra were compared with the spectra of pure caffeine anhydrous powder.

[0055] In an embodiment, morphological analysis was performed on a JEOL-5600 Lv Scanning Electron Microscope (Tokyo, Japan) equipped with SPRITE HR Four Axis Stagecontroller (Deben Research). Samples were placed on metallic stubs with carbon tape and coated with gold/palladium using a Sputter Coater (Polaron, Bad Schwalbach, Germany). Images were obtained for guar-gum films, alginate beads and GfB. using a spot size of 18-20 and a potential of 15-22 kV. All analyses were performed at room temperature (20 °C).

[0056] In an embodiment, in vitro release assays were performed in order to assess and compare release profiles of guar-gum films, alginate beads and GfB. Briefly, in vitro dialysis delivery assay was performed according to Wang, Liu, Sun, Wang, Wang and Zhu [17]. Briefly, the formulations (alginate beads, guar-gum films and GfB) were introduced into a 500 Da dialysis membrane. Dialysis membrane with a pore size of 500 Da was chosen to mimic the pore size of buccal mucosa [2]. Immediately, the dialysis membrane was filled with the formulations and 35 mL of artificial saliva (pH= 6.8), clumped and dipped into 50 mL of PBS solution (release media) pre-heated to 37 °C. The system was kept on continuous shaking (100 rpm). Aliquots of 5 mL were withdrawn from release media at 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660 and 720 min. Withdrawn volume was immediately replaced with 5 mL of PBS and preheated to 37 to preserve sink conditions.

[0057] In an embodiment, cell viability after contact with produced formulations and transepithelial permeability assay were performed using TR146 human buccal epithelium cell line culture. TR146 cell line was chosen due to great resemblance of normal human buccal mucosa namely regarding undifferentiated, non-keratinized stratified epithelium, morphological and functional characteristics as activity of carboxypeptidase, esterase and aminopeptidase [18]. Also, expression of K4, K10, K13, K16 and K19 keratins, membrane- associated receptors for involucrin and epidermal growth factors also reflect other common characteristics to normal human buccal epithelium cells [19, 20].

[0058] In an embodiment, TR146 cell line was purchased from Sigma-Aldrich (USA) and passages 9 to 14 were used. The culture medium consisted of HAMS F-12 medium enriched with 2 mM Glutamine (Lonza), 10% (V/V) fetal bovine serum (FBS) and 1% (V/V) of penicillin- streptomycin antibiotic blend. TR146 cells were seeded and maintained in 75 cm²T-flasks (T-75) and incubated in a 5% C0₂/95% air and 98% relative humidity atmosphere. The culture medium was replaced every two days. When 70-80% of cell confluence was reached, cells were detached from T-75 flasks using 2 mL of TrypLE™ Express. Detached cells were then prepared and seeded either in other T-75 flasks, 96-well culture plates (Nunc^®) or in Transwelf inserts 12-well culture plates purchased from Corning^* (Germany).

[0059] In an embodiment, cell mitochondrial activity assessment was performed as follows, cell-viability studies were carried out on proliferating cells, chosen when TR146 cells were 70- 80% confluent in T-75 flasks and properly detached as described above. After detachment, cells were re-suspended in medium and seeded in 96-well plates at density of 1 x 10⁴ cells/mL, 200 μί. per well. The same cell concentration was adopted in the 12-well plates but using 500 μί. of cell suspension, after in vitro permeability assay, to assess the cell viability after being in contact with developed formulations. Cell-viability studies were performed after 24 h of culture, with previous supervision by optical microscopy of the morphology and confluence of the cells in the plate wells. MTT assay allows to assess mitochondrial viability and, therefore, cell viability after 12 h contact with prepared drug delivery systems [21]. If TR146 cells were viable, succinic dehydrogenase was able to transform the tetrazolium salt into insoluble, purple-coloured, crystals of formazan [22]. Medium with 1% (V/V) Triton X-100 solution was added as lysis buffer and served as positive control. Negative control consisted of cells in contact with medium only. After treatment with produced drug delivery formulations, 100 μί. of the MTT reagent (0.5 mg/mL prepared in culture medium) was added to each well and the plates were incubated for 4 h. After incubation time has passed, reagent was carefully removed, allowing the insoluble formazan crystals to remain in the bottom of the wells. 100 μί. of DMSO per well was used to solubilize the formazan crystals in a dark room and, after 15 min of agitation on an orbital shaker, the absorbance at 570 nm and 630 nm was read on a FLUOstar OPTIMA microplate reader (United Kingdom), in triplicate. Absorbance values for all readings at 630 nm were subtracted from the absorbance values read at 570 nm. Cell viability (%, n=6 different, independent wells for the same experiment) was calculated according to Eq. (5):

„ „ . . ^„, Experimental value -neqative control _{Λ η η}

Cell viability (%) =— x 100 5

Positive control-negative control [0060] Concentration of the formulations tested for potential commitment of TR146 cell viability were chosen according to the average amount of saliva produced in the human mouth when in contact with food products [23].

[0061] In an embodiment, drug transepithelial diffusion studies were also conducted. Permeability assay also assessed in Corning^* Transwelf inserts, using 12-well plates. TR146 buccal cells were seeded into the inserts to mimic stratified epithelium of human buccal mucosa, as reported previously [19, 24]. Briefly, TR146 cell line was used due to the reported similarities between keratinization profile and metabolic activity with physiologic human buccal mucosa cells. TR146 cells were seeded on the inserts and the medium was changed every two days for 21 days. For medium replacement, medium was removed from the wells and 0.5 and 1.5 mL of fresh culture medium was added to the apical and basolateral sides, respectively. On the day of the study, culture medium was totally removed. Medium in the basolateral side (receptor part) was replaced with 1.5 mL of PBS, pH 6.8. Medium in the apical side (donor part) was replaced with fresh medium and drug delivery formulations were introduced afterwards. Guar-gum films, alginate beads, GfB and free caffeine were tested for permeability (n= 5). Samples of 600 μί. were withdrawn from receptor part at 0, 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660 and 720 min. Withdrawn volume was immediately replaced with fresh PBS, pre-heated to 37 °C, to maintain sink conditions. The amount of permeated caffeine was quantified by HPLC- UV, as described in the embodiment related to in vitro caffeine release profile assay.

[0062] In an embodiment, the fractional amount of caffeine that permeated Transwelf inserts with the stratified epithelium formed by confluent TR146 cells (dQ) was determined over the time intervals (dt) and the flux (J) was determined by calculating the slope of the resulting plots, according to Eq. (6) [25]. dQ

[0063] In an embodiment, Papp (cm.s ¹) was calculated for free caffeine, guar-gum films, alginate beads and GfB, by normalizing the flux (J) over the concentration of caffeine in the donor compartment (C₀) according to Eq. (7).

Papp = ^ (7) where, dQ/dt stands for the amount of permeated caffeine over time, A for the tissue surface area and C₀ for the initial concentration of permeated caffeine. All tested formulations presented the same initial concentration of caffeine (2 mg/mL) at the beginning of the drug trans-epithelial study. [0064] In an embodiment, at the end of the drug trans-epithelial diffusion study, MTT mitochondrial viability assay was performed in order to verify the viability of TR146 cells [26]. Inserts incubated with culture medium only, during the caffeine trans-epithelial study (n= 3) were considered as negative control (i.e. total cell viability). Inserts incubated with Triton-X lysis solution (n= 3) were considered as positive control (i.e. reference for total cell death).

[0065] In an embodiment, statistical analysis regarding dissolution profile data was performed using IBM" SPSS" Statistics version 22.

[0066] In an embodiment, Shapiro-Wilk (n< 50) test was used to verify if the values obtained for the responses in the experimental design were normally distributed. One sample T test was used to verify the existence of statistically significant differences between predictive models and experimental values. Experimental values were obtained from three samples selected from three new batches, for both alginate beads and guar-gum films. Mean values for each batch were compared with the values predicted in the model.

[0067] In an embodiment, an experimental design was performed in order to optimize two formulations as delivery systems that can be used alone or combined for an enhanced buccal delivery of bioactive molecules. A physicochemical characterization (analysis of molecular interactions and morphological analysis), a release assay, TR146 cell viability test and permeability assay were performed for developed formulations.

[0068] Factorial design (response surface method) performed for optimization of the guar-gum films is briefly described in Table 1.

[0069] Table 1: Factorial design parameters established for the optimization of the formulation of guar gum oral films

Factorial design parameters (Guar-gum films)

Level Guar gum Sorbitol Citric acid Caffeine concentration concentration concentration concentration (code unit)

(mg/mL)

% (w/v) % (w/v) % (w/v)

-1 2.5 3.75 0.75 16.7

0 3.75 5.69 1.0 16.7

1 5.0 7.50 1.25 16.7 [0070] The experimental profiler (Figure 1) obtained surprisingly allowed guar-gum films formulation with desired values of erosion (%), distance at burst (mm), film burst (g) and water- uptake/time (%, w/w.s ¹) ratio.

[0071] In an embodiment, since very wide standard-deviation values were obtained for responses (dependent variables), three batches of the guar-gum films formula predicted by the statistical model as being optimal were prepared and erosion (%), distance at burst (mm), film burst strength (g) and water-uptake/time (mg/s) ratio were determined (n=6) and compared with theoretically predicted values. Oral films were prepared according to the prediction profiler, by dissolving 2.7 g of sorbitol, 2.0 g of guar gum and 0.380 g of citric acid in 100 mL of M illi-Q water. Only oral films with 0.06 mm were selected for validation purposes. Experimental values for the formulation of guar-gum films are outlined in Table 2.

[0072] Table 2a: Experimental values obtained for the formulation of guar-gum film

Experimental value (mean ± SD; n= 6)

Erosion (%) 41.78 ± 3.97

WU/time (max WU) (mg/s) 4.28 ± 0.33

Distance at burst (mm) 5.39 ± 0.65

Film burst strength (g) 1595.42 ± 300.13

[0073] In an embodiment, no statistical differences (p > 0.05) were observed between mean predicted values and mean experimental values.

[0074] Many other polymers have been previously reported as having film-forming properties at similar concentrations as observed for guar-gum films [11]. Indeed, chitosan and sodium carboxymethylcellulose oral films were previously optimised but disintegration times were much higher and drug release was very distinct from the guar-gum films of the present disclosure [27]. Moreover, chitosan oral films are reported as being astringent and, therefore, potentially unpleasant, compromising patient/consumer compliance. On the other hand, guar- gum is commonly used in food products as thickener in a wide array of products and consumers are already used to the flavour and to find guar-gum referred on packaging labels [28].

[0075] In an embodiment, the guar-gum films of the present disclosure presentes superior mechanical characteristics either regarding film burst strength (average of 1754.96 g for guar- gum films against 546.57 g for sodium carboxymethylcellulose films) or distance at burst (average of 5.77 mm for guar-gum films against 0.74 mm for sodium carboxymethylcellulose films) [29]. Distance at burst of the guar-gum films of the present disclosure was similar to vaginal films (blend of 72% of hydroxypropylmethylcellulose (HPMC), 18% polyvinyl alcohol (PVA) and 10% glycerine) containing nanoparticles (average of 5.77 mm for guar-gum films against 5.34 mm for vaginal films) indicating good elasticity characteristics [30]. Briefly, the blend of HPMC, PVA and glycerine is dissolved in water and the mixture is cast in a 12x12 cm polystyrene mold. The solvent is dried at 35 during 72 h in a BM-500 drying oven. Regarding the nanoparticles, production was performed through emulsion-solvent evaporation method. Briefly, Poly Lactic-co-Glycolic acid (PLGA) was dissolved in ethyl acetate and mixed with poloxamer (surfactant) through sonication. The resulting oil-in-water emulsion was dispersed in a second poloxamer solution and kept under magnetic stirring for 4 h at 200 rpm. For the preparation of film-nanoparticle mixture, the nanoparticle formulation was mixed with the HPMC solution before solvent casting.

[0076] In an embodiment, indeed, mechanical characteristics are very important either to assure stability during transport, accurate dosage of carried bioactive molecules or to avoid handling and administration issues [31].

[0077] In an embodiment, the optimization of the formulation of alginates beads and respective validation of results were also performed. Alginate beads formulation of the present disclosure have surprisingly a high stability and enhancement of residence time of caffeine in contact with buccal mucosa.

[0078] In an embodiment, the factorial design (response surface method) performed for the the formulation of alginate beads is outlined in Table 2. Relative amounts of sodium alginate (particle-forming polymer) and Tween' 80 (polysorbate, surfactant) were chosen as factors for the improvement of alginate beads. Association efficiency, mean particle size, polidispersity index and ζ-potential were selected as responses, being considered of main importance for the characterization of beads. Caffeine anhydrous was the model drug carried by alginate beads, attending to achieve sustained release.

[0079] Table 2b: Factorial design parameters established for the formulation of alginate beads

Factorial design parameters (Alginate beads)

[0080] The profiler (Figure 2) allowed elaborating improved alginate beads formulation to achieve desired values of association efficiency (AE, %), mean particle size, polydispersity index (Pdl) and ζ-potential (mV).

[0081] As observed for guar-gum films, since very wide standard deviation values were obtained for responses (dependent variables), three batches of alginate beads were prepared and mean values of AE (%), size (μιη), Pdl and ζ-potential (mV) were determined and compared with the average values predicted by the statistical model. Alginate beads were prepared using 3.0% (w/v) of alginate and 2.4% (w/v) of Tween^® 80. Experimental values for the formulation of alginate beads films are outlined in Table 3.

[0082] Table 3: Predicted and experimental values obtained for the formulation of alginate beads.

Experimental value

(mean ± SD; n= 6)

Association efficiency (%) 81.57 ± 6.59

Particle size (μητι) 3.37 1 0.64

Polydispersity index 0.348 ± 0.060 zeta - potential (mV) -25.27 ± 1.50

[0083] No statistical differences (p > 0.05) were observed between mean predicted values and mean experimental values, except for ζ-potential. Indeed, experimental values for ζ-potential were significantly inferior, i.e. more negative, than values predicted in the statistical model. [0084] There still is a gap in the literature concerning microparticles as buccal delivery systems, albeit it has been reported by some researchers [35]. Nevertheless, most researchers are using nanoparticles aiming to increase apparent permeability of carried drugs and not to achieve a slower release of carried molecules. For instance, it has been reported that PLGA nanoparticles carrying acyclovir were incorporated into mucoadhesive buccal films and succeeded on increasing ex vivo permeability of the drug across rabbit buccal mucosa [36]. Nevertheless, most works concerning the development of microparticles for buccal delivery are aiming topical administration and not permeation across buccal mucosa to reach systemic circulation [37, 38]. Alginate was previously used to produce mucoadhesive microparticles by ionic gelation aiming to an increased residence time of drugs in the buccal mucosa. Effectively, alginate microparticles guaranteed an increased residence time of flurbiprofen and delmopinol when compared to reference solutions, decreasing the administration frequency [39].

[0085] In an embodiment, molecular interaction analysis was performed. Attenuated total reflectance-Fourier-transform infrared (AT -FTIR) analysis was performed to perceive the onset of new bonds between caffeine and developed formulations during production steps.

[0086] Resulting infrared spectra achieved from the subtraction of alginate beads, guar-gum films, GfB and for the physical mixture of all excipients of GfB and caffeine from corresponding placebo formulations is outlined in Figure 3. Spectra of caffeine anhydrous powder was used for comparison with obtained subtracted spectra.

[0087] Typical caffeine bands that appear at 1700-1600 cm^"1 are representative of the C=0 stretch of amide I [40]. C-N stretch coupled with N-H bending of the amide II present in the caffeine molecule are represented by the bands at 1600-1500 cm ¹. The bands showed in the range of 1666-1550 cm ¹ are addressed to the stretches of C=C, C=0 and C=N bonds of caffeine molecules [41, 42]. Subtracted spectra for alginate beads, guar-gum films, GfB and physical mixture of all excipients of GfB represented in Figure 3, showed the same characteristic infrared bands as caffeine anhydrous infrared spectra. Thus, there is no indication of the formation of new chemical bonds between caffeine and the excipients of alginate beads or guar-gum oral films during production processes of the formulations. Also, there are no significant differences between caffeine spectra and the subtracted spectra for the physical mixture, revealing that the excipients do not induce alterations in the chemical structure of caffeine. Spectral analysis indicates that the formation of new chemical bonds that may hinder caffeine release from developed delivery systems is not observed. Instead, caffeine release from guar-gum films, alginate beads or GfB may be affected mainly by physical shielding and/or electrostatic bonds [27]. [0088] In an embodiment, morphology analysis was performed as follows. Scanning electron microscopy (SEM) was used to perform a visual recognition of the matrix structure of oral films and alginate beads, in order to obtain further information regarding caffeine delivery profile.

[0089] Morphology analysis of alginate beads, guar-gum films and alginate beads dispersed on oral films was performed by SEM. Alginate beads were added to guar-gum films formulation before solvent casting for the blend to be as homogeneous as possible. The fact that molecules composing the alginate beads are hydrosoluble could represent a stability problem since it would be very likely that alginate would be dissolved in the guar-gum films matrix during solvent casting procedure. However, it is noticeable that alginate beads are homogeneously spread on the film matrix, indicating good stability of alginate beads. Also, bead size and morphology observed in the microphotographs are coherent with the size predicted by the statistical model and corroborated by DLS analysis that indicated that mean particle size is around 3.58 μιη. Both size and shape of alginate beads were homogeneous. Also, some particle agglomeration seems to occur. Nevertheless, homogeneous dispersion of alginate beads into/onto the guar-gum films matrix indicates that caffeine dosage in each film is very similar and, thus, caffeine release profile is likely to be similar when testing different batches. Therefore, the chances of a successful future scale-up are promising.

[0090] In an embodiment, an in vitro caffeine release profile assay was carried out as follows. The release assay using dialysis membranes was performed to characterize the delivery profile of caffeine from alginate beads, guar-gum films and the combination of both delivery systems (GfB) aiming to test a conceptually new oral delivery system. Pore size of dialysis membrane (500 Da) was chosen according to the intercellular space between epithelial cells of buccal mucosa [2, 43].

[0091] In an embodiment, for the assessment of release profile of caffeine from developed delivery systems, guar-gum films and alginate beads alone and in combination were tested. A solution of free caffeine (2 mg/mL) was used as control. Figure 4 represents delivery profile from guar-gum films, alginate beads and GfB compared with control.

[0092] In an embodiment, the higher flux of caffeine from control solution crossed the dialysis membrane occurred in the first 15 min, indicating that caffeine flux easily occurred from the inside of the dialysis membrane to the outside, following Fick's first law. Caffeine is a small (194.194 g.mol ¹), highly hydrosoluble (2.16E04 mg/L) molecule and a fast efflux from the dialysis membrane was predictable [44, 45]. Release profile of caffeine content in control solution was almost linear, approaching a zero-order release kinetics. Indeed, caffeine is expected to permeate buccal mucosa according to the simplified version of Fick's first law (Eq. (5)) by paracellular path [46, 47]. / = P(Cdonor— Creceiver)

where, P is the permeability coefficient, Cdonor and Creceiver are the concentrations of caffeine inside the dialysis membrane and on the receiver compartment, respectively, and J is the flux from the dialysis membrane (donor compartment) to the receiver compartment [47]. Caffeine release from guar-gum films was significantly slower when compared to the control caffeine solution but fast disintegration of the film led, yet, to a significantly fast caffeine release to the outside of the dialysis membrane. Effectively, the same noticeable burst release of for the release of bioactive molecules loaded in a thin film, indicating a clear trend regarding delivery of bioactive molecules from thin films [48, 49]. The differences observed between guar-gum films release profile and control may be due to physical and/or electrostatic hindrance of caffeine release from guar-gum films matrix. Caffeine release from alginate beads across dialysis membrane was significantly slower when compared with guar-gum films or control. The fact that caffeine molecules are associated (either inside or at the surface) to the alginate beads may delay the release of caffeine, therefore preventing a sooner passage across dialysis membrane pores. Indeed, alginate beads, may have to disintegrate for the entrapped caffeine to be free and able to cross the membrane. The combination of guar-gum films and alginate beads to form one delivery system offers the higher impedance of caffeine release over time. Indeed, the conjugation of guar-gum film and alginate matrices implies that caffeine should be released from a double barrier before contacting with the absorptive epithelium. Both film and bead matrices should disintegrate and dissolve to allow the complete release of caffeine. Nevertheless, caffeine release in the first 60 min was very similar for GfB, alginate beads. The initial burst release may be due to some premature release of caffeine from alginate beads shortly after the production of the formulations as verified in another studies [30, 48].

[0093] In an embodiment, cell viability studies were performed. TR146 cells were used to evaluate potential toxicity caused by different concentrations of caffeine-loaded alginate beads, guar-gum films and GfB. Placebo formulations with the same mass as caffeine-loaded delivery systems were used as controls. Cell viability was assessed by MTT reduction assay.

[0094] Results of cell viability in vitro assay for placebo and caffeine-loaded alginate beads, guar-gum films and alginate beads incorporated into guar-gum films are shown in Figure 5.

[0095] None of the tested concentrations of caffeine alone or incorporated into alginate beads, guar-gum films or GfB did significantly compromise cellular viability of TR146 cells, after 24 h of exposure. Total TR146 cell viability indicates that, when administered per os there was no evidence that suggested that some of the drug delivery systems (either alone or combined) are hazardous for the buccal epithelia. [0096] In an embodiment, permeability assay on TR146 monolayers was performed. TR146 human buccal carcinoma cells were used to determine buccal permeability of developed formulations.

[0097] In an embodiment, the permeation profiles through TR146 cells grown on Transwelf inserts were distinct according to the formulation and are outlined in Figure 6.

[0098] In an embodiment, apparent permeability (cm.s ¹) for all the formulations is outlined in Table 5.

[0099] Table 5: Apparent permeability of GfB, guar-gum films, alginate beads and caffeine solution (control) across transwell^® seeded with confluent TR146 cells

Free caffeine¹ 8.14E-06 + 7.30E-07

¹ Data from Kulka ni et al. using porcine buccal mucosa mounted on Franz diffusion cells [51]

[00100] In an embodiment, results obtained for caffeine control solution (2 mg/mL) are in accordance with previously reported caffeine buccal apparent permeability [50, 51]. Also, caffeine control solution presented a permeability profile that strongly correlates with diffusion from dialysis membrane (Figure 4). Indeed, caffeine permeation also occurred according to Fick's first law following a zero-order kinetics. Caffeine released from guar-gum films permeated TR146 cell layer faster than the control caffeine solution for 100 min. After being inserted into the Transwelf inserts, guar-gum films began disintegrating. Then, fragments resulting from disintegration of guar-gum films deposited and adhered to the apical layer of TR146 cells. Immediate adhesion of guar-gum films fragments offered a higher contact surface area with the cell layer and thus, more effective caffeine permeation. Effectively, mucoadhesive delivery systems were reported, by peer researchers, to increase permeation of carried molecules across TR146 cell layer [52]. Both alginate beads and GfB offered slower caffeine permeation when compared with guar-gum films or caffeine control solution. Lower permeation of caffeine across TR146 cell layer may be at least partially due to the slower caffeine release, as observed in the caffeine release assay (Figure 4). In fact, as previously observed for the release assay using dialysis membranes, GfB promoted a slower release of caffeine when compared with control, alginate beads or guar-gum films alone. The cross-analysis of dialysis release assay and in vitro permeability assay on TR146 buccal mucosa cells indicated a strong correlation between caffeine release profile and permeability effectiveness. The fact that, when caffeine-loaded alginate beads is combined with guar-gum films, caffeine is doubly hindered from being released since both alginate and guar-gum matrices should be disintegrated and dissolved before caffeine contacts with buccal cells. Moreover, since alginate beads present high mean particle size, permeation of the whole beads is not likely to happen unless the integrity of buccal epithelium is somehow compromised.

[00101] In an embodiment, new oral/buccal delivery formulations, consisting on a guar gum based film and caffeine-loaded alginate beads, were improved, having surprisingly better results. Robustness of developed predictive profilers was successfully validated, except for ζ- potential of alginate beads (experimental values for ζ-potential of alginate beads were more negative than predicted values). Nevertheless, more extreme ζ-potential values are beneficial to the stability of alginate beads and less prone to induce toxicity due to disruption of cellular membranes. Thus, attempting to achieve a conceptually new delivery system aiming buccal and oral delivery of bioactive compounds, alginate beads were dispersed in the matrix of guar-gum films. ATR-FTI analysis did not indicate the occurrence of new chemical bonds between caffeine and guar-gum films or alginate beads. Indeed, subtracted spectra (placebo formulations subtracted from caffeinated formulations) for guar-gum films, alginate beads and GfB present the same characteristic bands as caffeine anhydrous, demonstrating that chemical structure of caffeine was not altered during or after inclusion into guar-gum films, alginate beads or in the combination, GfB. Morphological characterization by SEM demonstrated a homogeneous dispersion of alginate beads on the guar-gum films matrix, indicating that caffeine content is very likely to be homogeneous in each film unit, a good indicator if scale-up production is intended. In vitro delivery profile of caffeine (dialysis membrane) and drug trans-epithelial assay (TR146 buccal cells grown on Transwells^e) allowed concluding that the combination of guar-gum films with alginate beads represent a suitable delivery system when a slower release of carried bioactive molecule into oral cavity is intended, when compared with guar-gum films and alginate beads alone and with a control (caffeine solution). Furthermore, alginate beads, guar-gum films and GfB did not compromise cell viability when tested on TR146 cells, by MTT assay. There are not yet similar delivery systems combining beads and films for oral and buccal delivery of bioactive molecules reported in the literature even though nanoparticles were already incorporated into films for delivery of anti-HIV microbicidal drugs in previous works were performed [30, 48] . GfB may represent an innovative approach on the buccal delivery of hydrophilic bioactive molecules such as caffeine to assure faster and controlled effects, but also especially suitable for paediatric or psychiatric patients that may be uncooperative to therapy.

[00102]The oral composition now disclosed is able to release caffeine within 30 seconds or less after the intake of the oral composition. The caffeine that is release within this period is the one present in the film. The caffeine that is present in beads, on the other hand, is slowly and steady released within 720 minutes. The oral composition adheres to the mucosa or is transported to the intestine and released in the intestine.

[00103]The advantages of having this oral composition able to release caffeine in a controlled manner over time are the following: increasing bioavailability due to increased contact time with absorptive mucosa, decreased adverse effects since plasma concentration is predicted to reach a plateau state and enhanced, prolonged therapeutic/functional effect due to slow release of carried bioactive molecules.

[00104] An embodiment, of edible films embedded with microparticles as carriers of indomethacin is stated by Paik et al. Briefly, hydroxypropylmethylcellulose - HPMC - microparticles are produced by electrospray method (0.01 mL/min using a syringe pump on a NE-1000 equipment, New Era Pump Systems Inc.), using 2% (w/w) of the polymer dissolved in acetone. Further, microparticles are freeze-dried and further resuspended in aqueous HPMC solution (2% w/w) followed by solvent casting, resulting in the production of the film with embedded microparticles.

[00105]The term "comprising" whenever used in this document is intended to indicate the presence of stated features, integers, steps, components, but not to preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[00106] It will be appreciated by those of ordinary skill in the art that unless otherwise indicated herein, the particular sequence of steps described is illustrative only and can be varied without departing from the disclosure. Thus, unless otherwise stated the steps described are so unordered meaning that, when possible, the steps can be performed in any convenient or desirable order.

[00107]The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof.

[00108]The above described embodiments are combinable.

[00109]The following claims further set out particular embodiments of the disclosure.

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Claims

C L A I M S

1. Oral composition comprising guar-gum as a polymer, caffeine and alginate wherein

1.5 - 10% (wt/wt of dry weight of the film) of guar-gum and 10 - 30% (wt/wt of dry weight of the film) of caffeine are in a film;

10 - 25% (wt/wt of dry weight of beads) of caffeine and 1 - 5% (wt/wt of dry weight of beads) of alginate are in beads.

2. Oral composition according to the previous claim comprising a plasticizer and sweetener wherein 2 - 10 % (wt/wt of the amount of the polymer) of the plasticizer and sweetener is in the film.

3. Oral composition according to any of the previous claims, wherein the beads further comprises calcium carbonate and/or acetic acid.

4. Oral composition according to any of the previous claims, wherein 0.5 - 5% (wt/wt of the dry weight of the beads) of calcium carbonate and/or acetic acid are in the beads.

5. Oral composition according to any of the previous claims further comprising a saliva production inducer.

6. Oral composition according to any of the previous claim, wherein 0.20 - 5% (wt/wt of dry weight of the film) of the saliva production inducer is in the film.

7. Oral composition according to any of the previous claims further comprising a surfactant.

8. Oral composition according to any of the previous claim, wherein 1 - 5 % (wt/wt of the dry weight of the beads) of the surfactant is in the beads.

9. Oral composition according to any of the previous claims comprising guar-gum as a polymer, caffeine and alginate wherein

2% (wt/wt of the dry weight of the film) of guar-gum and 16.5% (wt/wt of the dry weight of the film) of caffeine are in the film, and

16.5% (wt/wt of the dry weight of the beads) of caffeine, 3% (wt/wt of the dry weight of the beads) of alginate are in the beads.

10. Oral composition according to any of the previous claims comprising guar-gum as a polymer, caffeine and alginate wherein the oral composition comprises:

2.32 % (wt/wt of the amount of the polymer) of the plasticizer and sweetener and 0.31 % (wt/wt of the dry weight of the film) of the saliva production inducer are in the film and

2.43 % (wt/wt of the dry weight of the beads) of surfactant, 1.5% (wt/wt of the dry weight of the beads) of calcium carbonate and 0.5% (wt/wt of the dry weight of the beads) acetic acid are in the beads

11. Oral composition according to any of the previous claims, wherein the thickness of the film is between 50-100 micrometres, preferably 60 micrometres.

12. Oral composition according to any of the previous claims, wherein the beads have a size between 300 nm and 8 μηι.

13. Oral composition according to any of the previous claims, wherein

the plasticizer and sweetener is sorbitol or sucralose and/or;

the surfactant is polysorbate 80 and/or;

the saliva production inducer is critic acid and/or;

14. Oral composition according to the previous claims, wherein the beads further comprise paraffin.

15. Oral composition according to any of the previous claims further comprising a vitamin, a flavouring agent, a dye, an anti-acid agent, a further sweetener, or mixtures thereof.

16. Oral composition according to the previous claim, wherein the flavouring agent is: mint, fruit, red fruit, passion fruit, coconut, cinnamon, chocolate, coffee, lavender, or mixtures thereof.

17. Oral composition comprising a film and a plurality of beads wherein

the film comprises 1.5 - 10% (wt/wt of the dry weight of the film) of guar-gum and 10 - 30% (wt/wt of the dry weight of the film) of caffeine, each bead comprises 10 - 25% (wt/wt of the dry weight of the beads) of caffeine and 1 - 5% (wt/wt of the dry weight of the beads) of alginate.

18. Strip, edible oral strip comprising the oral composition according to any of the previous claims, in particular a sheet energy or an energy strip.

19. Oral composition according to any of the previous claims for use in medicine or for use as a nutraceutical.