EP3681482A1 - Compositions orales, procédés associés et utilisations correspondantes - Google Patents

Compositions orales, procédés associés et utilisations correspondantes

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Publication number
EP3681482A1
EP3681482A1 EP18796742.7A EP18796742A EP3681482A1 EP 3681482 A1 EP3681482 A1 EP 3681482A1 EP 18796742 A EP18796742 A EP 18796742A EP 3681482 A1 EP3681482 A1 EP 3681482A1
Authority
EP
European Patent Office
Prior art keywords
beads
caffeine
film
dry weight
guar
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18796742.7A
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German (de)
English (en)
Inventor
Maria Manuela Estevez Pintado
Pedro João NEVES MIRANDA DE CASTRO
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Universidade Catolica Portuguesa
Original Assignee
Universidade Catolica Portuguesa
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Filing date
Publication date
Application filed by Universidade Catolica Portuguesa filed Critical Universidade Catolica Portuguesa
Publication of EP3681482A1 publication Critical patent/EP3681482A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present disclosure relates to an oral composition for the controlled release of caffeine over time, products, method of obtaining and uses thereof.
  • 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].
  • 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.
  • emulsification- internal gelation technique to produce alginate beads usually provides better association efficiencies than formulations with an aqueous external phase.
  • 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.
  • 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.
  • the present disclosure relates to an oral composition for the controlled release of caffeine over time, products, method of obtaining and uses thereof.
  • 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
  • composition also dissolves easily preferably in at least 5 seconds, in particular 10 seconds, more in particular 15 seconds.
  • 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.
  • the beads may further comprise calcium carbonate and/or acetic acid.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition may comprise guar-gum as a polymer, caffeine and alginate wherein:
  • composition may comprise:
  • the composition may comprise the thickness of the film is between 50-100 micrometres, preferably 60 micrometres.
  • the composition may comprise the beads having a size between 300 nm and 8 ⁇ .
  • the plasticizer and sweetener can be sorbitol or sucralose.
  • the surfactant can be polysorbate 80 (Tween ® 80).
  • the plasticizer and saliva production inducer can be critic acid.
  • the beads may further comprise paraffin.
  • the oral composition may comprise a vitamin, a flavouring agent, a dye, an anti-acid agent, a sweetener, or mixtures thereof.
  • the flavouring agent may be: mint, fruit, passion fruit, coconut, cinnamon, chocolate, coffee, lavender, or mixtures thereof.
  • 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.
  • the strip comprises the oral composition described in the present disclosure, in particular a sheet energy or an energy strip.
  • an edible oral strip comprising the oral composition described in the present disclosure.
  • Another aspect of the oral composition of the present disclosure is use in medicine or as nutraceutical.
  • 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.
  • Figure 2 Prediction profiler for the formulation of alginate beads.
  • 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.
  • 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.
  • the present disclosure relates to an oral composition for the controlled release of caffeine over time, products, method of obtaining and uses thereof.
  • caffeine anhydrous food chemicals codex, 99% purity
  • alginic acid alginic acid
  • 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 cm 2 of culture area, 0.4 ⁇ 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). TrypLETM express was purchased from Gibco ® (Denmark).
  • TMTT Thiazolyl Blue Tetrazolium Bromide Ultra pure was purchased from VWR (Solon, USA). Dimethyl sulfoxide (DMSO) 99.7% was purchased from Fisher BioreagentsTM (EUA). For TR146 cell wash, pH of PBS was adjusted to 6.8, using a solution of hydrochloric acid 0.1 M.
  • DMSO dimethyl sulfoxide
  • 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).
  • alginate beads formulation were improved by setting the relative amounts of sodium alginate and Tween * 80 as factors and association efficiency, ⁇ -potential, mean size and polydispersity index were set as responses.
  • caffeine anhydrous was incorporated into all films and associated with all beads formulations.
  • 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.
  • texture analysis was performed on a texturometer equipment (TA.XT plus Texture Analyser, Stable Micro Systems, Cambridge, 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.
  • 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].
  • 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 Q C for 24 h and weight variation of oral films was recorded in order to determine erosion. Erosion (%) was calculated according to Eq. (2).
  • W3 is the weight of dry oral films, after erosion.
  • Water— uptake /time — ——— - t(max water— uptake)
  • water-uptake (%) is an indicator of water absorbed by the oral film (Eq. 1)
  • t(max water-uptake) is the time (s) at which water-uptake (%) value was maximum.
  • 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.
  • the characterization of alginate beads was performed as follows. Caffeine association efficiency (AE), mean size, ⁇ -potential, scanning electron microscopy (SEM) and delivery profile were the parameters used to characterize alginate beads.
  • the particle size and ⁇ -potential analysis determination were performed as follows. All alginate bead formulations were diluted (1:100) with Milli-Q water before particle size and ⁇ -potential analysis. Particle size and polydispersity index were determined by dynamic light scattering (DLS). ⁇ -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).
  • HPLC-UV dosing
  • 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 ⁇ (particle size) x 4.6 mm (internal diameter) ⁇ 250 mm (length) (AkzoNobel, Bohus, Sweden). UV detector wavelength was set to 270 nm. The injection volume was set to 50 ⁇ . Finally, caffeine association efficiency was calculated according to the following Eq. (4):
  • Wtc stands for total weight of caffeine used in the alginate bead formulations and Wsc stands for caffeine collected from the supernatant after centrifugation.
  • 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 MIRacleTM single reflection horizontal attenuated total reflectance (ATR) accessory (PIKE Technologies, USA) with a diamond/Se crystal plate.
  • ATR FTIR spectrometer
  • 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.
  • 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).
  • in vitro release assays were performed in order to assess and compare release profiles of guar-gum films, alginate beads and GfB.
  • 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].
  • 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.
  • TR146 human buccal epithelium cell line culture 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].
  • 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 cm 2 T-flasks (T-75) and incubated in a 5% C0 2 /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 TrypLETM 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).
  • 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 10 4 cells/mL, 200 ⁇ . per well. The same cell concentration was adopted in the 12-well plates but using 500 ⁇ . of cell suspension, after in vitro permeability assay, to assess the cell viability after being in contact with developed formulations.
  • 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 ⁇ .
  • 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.
  • the fractional amount of caffeine that permeated Transwelf inserts with the stratified epithelium formed by confluent TR146 cells 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].
  • 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 (C 0 ) according to Eq. (7).
  • dQ/dt stands for the amount of permeated caffeine over time
  • A for the tissue surface area
  • C 0 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.
  • 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.
  • 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 for a release assay
  • TR146 cell viability test for permeability assay
  • Table 1 Factorial design parameters established for the optimization of the formulation of guar gum oral films
  • 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].
  • PLGA Poly Lactic-co-Glycolic acid
  • poloxamer surfactant
  • the resulting oil-in-water emulsion was dispersed in a second poloxamer solution and kept under magnetic stirring for 4 h at 200 rpm.
  • the nanoparticle formulation was mixed with the HPMC solution before solvent casting.
  • Alginate beads formulation of the present disclosure have surprisingly a high stability and enhancement of residence time of caffeine in contact with buccal mucosa.
  • 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 ⁇ -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.
  • 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 ⁇ -potential (mV).
  • alginate beads were prepared and mean values of AE (%), size ( ⁇ ), Pdl and ⁇ -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.
  • 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.
  • AT -FTIR Attenuated total reflectance-Fourier-transform infrared
  • 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 .
  • 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.
  • 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].
  • 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].
  • / P(Cdonor— Creceiver)
  • Cdonor and Creceiver are the concentrations of caffeine inside the dialysis membrane and on the receiver compartment, respectively
  • 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].
  • 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.
  • 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.
  • 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].
  • 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.
  • TR146 cells 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.
  • apparent permeability (cm.s 1 ) for all the formulations is outlined in Table 5.
  • Table 5 Apparent permeability of GfB, guar-gum films, alginate beads and caffeine solution (control) across transwell ® seeded with confluent TR146 cells
  • results obtained for caffeine control solution are in accordance with previously reported caffeine buccal apparent permeability [50, 51].
  • 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.
  • 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 ⁇ - potential of alginate beads (experimental values for ⁇ -potential of alginate beads were more negative than predicted values). Nevertheless, more extreme ⁇ -potential values are beneficial to the stability of alginate beads and less prone to induce toxicity due to disruption of cellular membranes.
  • 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.
  • 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.
  • 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 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition orale pour la libération contrôlée de caféine dans le temps, des produits, un procédé d'obtention et des utilisations de celle-ci. Compte tenu des inconvénients de l'état de la technique, le problème technique sous-jacent à l'invention était de développer une composition orale énergisée qui empêche les effets secondaires, en particulier les effets secondaires de la caféine. De manière surprenante, on a obtenu une composition orale comprenant de la gomme de guar en tant que polymère, de la caféine et de l'alginate, de 1,5 à 10 % (en poids/poids de poids sec du film) de gomme de guar et de 10 à 30 % (en poids/poids de poids sec du film) de caféine se trouvant dans un film, de 10 à 25 % (en poids/poids sec de billes) de caféine et de 1 à 5 % (en poids/poids sec de billes) d'alginate étant dans des billes.
EP18796742.7A 2017-09-11 2018-09-11 Compositions orales, procédés associés et utilisations correspondantes Withdrawn EP3681482A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PT11028517 2017-09-11
PCT/IB2018/056930 WO2019049103A1 (fr) 2017-09-11 2018-09-11 Compositions orales, procédés associés et utilisations correspondantes

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EP3681482A1 true EP3681482A1 (fr) 2020-07-22

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Publication number Priority date Publication date Assignee Title
AU2703795A (en) * 1994-06-23 1996-01-19 Procter & Gamble Company, The Treatment of nicotine craving and/or smoking withdrawal symptoms with a transdermal or transmucosal composition containing nicotine and caffeine or xanthine
US20070042023A1 (en) * 2005-08-22 2007-02-22 National Starch And Chemical Investment Holding Corporation Dissolvable film
US20090047328A1 (en) * 2007-08-16 2009-02-19 Peter Cunningham Caffeine delivery systems
US20130052234A1 (en) 2011-08-25 2013-02-28 Purebrands LLC Edible strips
TWI612978B (zh) * 2015-08-26 2018-02-01 口溶膜

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