FLOATING DRUG DELIVERY SYSTEMS COMPRISING CANNABINOIDS
20230398080 · 2023-12-14
Inventors
Cpc classification
A61K31/658
HUMAN NECESSITIES
A61K47/42
HUMAN NECESSITIES
International classification
A61K31/00
HUMAN NECESSITIES
Abstract
The present invention concerns a solid oral dosage form comprising albumin and at least one cannabinoid, wherein the oral dosage form is free of a gas generating agent (GGA) and wherein the oral dosage form is prepared using a compression force Q of below 1 ton.
Claims
1-32. (canceled)
33. A solid oral dosage form comprising albumin and at least one cannabinoid, wherein the oral dosage form is free of a gas generating agent (GGA) and wherein the oral dosage form is prepared using a compression force of below 1 ton.
34. The oral dosage form according to claim 33, being in a form selected from a tablet, a capsule, a pellet and a granulate.
35. The oral dosage form according to claim 33, having a stomach floatation time period of at least several hours.
36. The oral dosage form according to claim 33, having a time-to-float period of between 0.5 to 5 minutes, or below 0.5 minutes, as measured from time of contact of the solid oral dosage form with the gastric medium to time of floatation.
37. The oral dosage form according to claim 33, wherein the albumin is selected from serum albumins, egg albumin and albumin derived from seeds.
38. The oral dosage form according to claim 37, wherein the seed albumin is soybean albumin.
39. The oral dosage form according to claim 33, wherein the albumin is in a form of granules or powder.
40. The oral dosage form according to claim 33, wherein the albumin being in a form of a matrix material in which the at least one cannabinoid is carried.
41. The oral dosage form according to claim 40, wherein the matrix material further comprising at least one additional material.
42. The oral dosage form according to claim 41, wherein the at least one additional material is selected amongst polymers, polysaccharides, flavorings, colorants, thickeners, disintegrants, fillers, binders, glidants, wetting agents, surfactants, antioxidants, metal scavengers, pH-adjusting agents, acidifying agents, alkalising agents, preservatives, buffering agents, chelating agents, stabilizing agents, gas-generating agents (GGA), complexing agents, emulsifying and/or solubilizing agents, absorption enhancing agents, modify release agents, taste-masking agents, humectants, sweetening agents and combinations thereof.
43. The oral dosage form according to claim 42, wherein the at least one additional material is a polymer.
44. The oral dosage form according to claim 43, wherein the polymer is selected from hydrophilic polymers and hydrophobic polymers.
45. The oral dosage form according to claim 33, being formed by applying compression forces between about 0.25 ton and about 1 ton, or between 0.25 and 0.7 ton, or between 0.25 and 0.5 ton.
46. The oral dosage form according to claim 33, wherein the at least one cannabinoid a cannabinoid/cannabinoid agonists/cannabinoid-related compound acting on an endogenous cannabinoid receptors (CB1 or CB2).
47. The oral dosage form according to claim 46, wherein the at least one cannabinoid is selected from THC (Tetrahydrocannabinol), CBD (Cannabidiol), CBN (Cannabinol), CBG (Cannabigerol), CBC (Cannabichromene), CBL (Cannabicyclol), CBV (Cannabivarin), THCV (Tetrahydrocannabivarin), CBDV (Cannabidivarin), CBCV (Cannabichromevarin), CBGV (Cannabigerovarin) and CBGM (Cannabigerol Monomethyl Ether).
48. A method of treatment or prevention of a disease or disorder, the method comprising administering to a subject in need thereof a solid oral dosage form according to claim 33.
49. A method for preparation of a floating solid oral solid dosage form, said method comprising compressing a homogeneous mixture of albumin, at least one cannabinoid and optionally a gas-generating agent with a force of between about 0.25 and about 1 ton to obtain a homogenous unit solid oral dosage.
50. The method according to claim 49, the method comprising: blending albumin with at least one cannabinoid to obtain a homogeneous mixture; optionally adding a gas-generating agent to the said homogeneous mixture; compressing said homogeneous mixture with a force of between about 0.25 and between about 1 ton to obtain monolithic homogenous unit solid oral dosage.
51. The method according to claim 49, wherein the pressure is from about 0.0018 to about 0.005 tons per mm.sup.2.
52. A sustained or prolonged release oral dosage form comprising albumin and at least one cannabinoid, wherein the oral dosage form optionally containing a gas generating agent and wherein the oral dosage form is prepared using a compression force of below 1 ton.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0079] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:
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DETAILED DESCRIPTION OF THE INVENTION
[0093] Metoprolol, Polysorbate 20 (Tween® 20) Polysorbate 80 (Tween® 80), Sorbitan monooleate 80 (Span® 80), ethyl lactate, cannabigerol (CBG), Egg albumin (Mw 44 kDa) and ammonium acetate were purchased from Sigma Aldrich (Rehovot, Israel). polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone and Polyoxyl 40-hydroxy castor oil (Cremophor® RH40) were purchased from BASF The Chemical Company (Ludwigshafen Germany). Lecithin was purchased from Cargill (Minneapolis, MN, USA). Tricaprin (Cremer COOR®; MCT C10-95) was a gift from CREMER Oleo Division (Hamburg, Germany). Acetonitrile (ACN), ethanol, n-hexane, ethyl acetate, hydrochloric acid (HCl) 37% v/v were purchased from J. T. Backer (Phillipsburg, NJ, USA). Sodium bicarbonate and Sodium chloride were purchased from Biolab ltd. (Jerusalem, Israel). Citric acid was obtained from Merck (Darmstadt, Germany). Polyethylene Glycol 400 (PEG 400) and Polyethylene Glycol 3500 (PEG 3500) were purchased from Ofer chemicals lab suppliers (Hod-hasharon, Israel). Hydroxypropylmethyl cellulose (HPMC, Methocel K100M) was obtained from Colorcon (Dartford, England). Pharmaceutical grade THC was purchased from THC Pharm GmbH, The Health Concept, (Frankfurt, Germany). THC was of synthetic origin, with 98% purity. Pharmaceutical grade CBD was purchased from Ai Fame GmbH, (Schonengrund, Switzerland). CBD was plant extracted with 94% purity; related substance THC was less than 0.05%.
Part I-
Animals and Surgery
[0094] All surgical and experimental procedures were approved by the Animal Experimental Ethics Committee of the Hebrew University, Hadassah Medical School, Jerusalem.
[0095] Male Wistar rats (Harlan, Israel) weighing 275-300 g were kept under a 12 h light/dark cycle with free access to food (standard rat chow) and water prior to the procedure. Animals were anesthetized for the period of surgery. An indwelling cannula was placed in the right jugular vein of each animal for systemic blood sampling and tunneled beneath the skin. To simulate colonic delivery, we inserted a cannula directly to a rat caecum as a means to bypass the stomach and small intestine. Both cannulas were exteriorized at the dorsal part of rats' neck. After completion of the surgical procedure, the animals were transferred to individual cages to recover overnight (12-18 h). During this recovery period, they had free access to food and water. On the day of experiment, they were deprived of food for 4 hr prior to drug administration, but not water. Throughout the experiments, free access to food was available 4 h post oral administration.
Experimental Protocol
[0096] Lipid-Based Formulation The lipid-based formulation used for this study was a self-nano emulsifying formulation previously developed by this group. Briefly, ethyl lactate and lecithin were placed in a vial at a ratio of 4:1, respectively. The mixture was heated to 40° C. until completely dissolved. Then, tricaprin, Cremophor® RH40, Tween® 20, and Span® 80 were added at the ratio of 1:1:1:1. The mixture was stirred and heated to 40° C. until a homogeneous solution was formed. THC, CBD, and metoprolol were dissolved in this solution at 2.67% w/w, 2% w/w and 2.67% w/w respectively. Upon dispersion in pre-heated water (1:9 v/v), this composition self-emulsified into o/w nano dispersion. The resulting nano particles dissolved in their lipid core the lipophilic THC and CBD. While metoprolol was most probably dissolved in the aqueous phase of the dispersion. Metoprolol was used as a positive control for colonic absorption.
Colonic and Oral Administration of THC, CBD and Metoprolol
[0097] On the day of experiment, animals were divided into two groups. The experimental group (n=6) received dispersed THC-CBD-metoprolol formulation through the colonic cannula and water via an oral feeding tube. The control group (n=5), received the THC-CBD-metoprolol formulation orally and water through the colonic cannula corresponding to volume of drug-formulation administered in the experimental group. Animals in both groups received THC 20 mg/kg, CBD 15 mg/kg and metoprolol 20 mg/kg. Systemic blood samples (0.30 ml) were obtained from the intravenous cannula. To prevent dehydration, equal volumes of physiological saline were administered to the rats following each blood sampling. Sequential blood samples were collected into heparin-containing test tubes at predetermined time intervals. Plasma was separated by centrifugation (3220 g, 10 min, 4° C.) and stored at −20° C. pending analysis.
Experimental Protocol of CBD Relative Bioavailability Study
Gastro Retentive CBD Tablets
[0098] Tablets were prepared by direct compression using a 5 mm die, manually pressed with a 1-ton force for 30 s. Each tablet was designed to weigh 70 mg. Tablet measurements used, have been previously demonstrated by our group, to be big enough in order to remain in a rat stomach and provide gastric retention. In-vitro dissolution was performed in USP simulated gastric fluid under fasted conditions (pH 1.2) with 5% v/v Tween® 80. The buffers were prepared without enzymes. For the dissolution test, each glass tube contained 100 ml, heated to 37° C.±3. Rotation speed was 100 rpm. Following tablet placing in the dissolution glasses, time was measured until tablet began to float. A sample of 100 μl was taken in each time point and replaced with a fresh buffer. Results were adjusted according to this minor dilution. Time points for the experiment in simulated gastric fluid were 1, 2 3, 4, 5,6,7,8 and 24 h. Samples were analyzed via an HPLC-UV method. HPLC-UV conditions were as follows: Luna C-8(2), 5 μm, 150×4.6 mm, 100 Å column (Phenomenex, CA, USA). An isocratic mobile phase of 5 mM NaH2PO4 in water (pH 3.0) and acetonitrile at 30:70 ratio, at flow rate of 1 ml/min, 40° C.±5. UV Monitoring wavelength: 220 nm. CBD RT was 7.7 min. Linearity for CBD was between 0.5-500 μg/ml with R.sup.2>0.999.
Relative Oral Bioavailability of CBD in Solution Vs. GR-CAN Tablet
[0099] Experimental group (n=3) received CBD in GR-CAN tablet. The control group (n=3), received CBD in a propylene glycol: ethanol: water solution (4.5:4.5:1) at a 3 mg/ml concentration.
[0100] Animals were randomly assigned to the experimental groups. THC, CBD, and metoprolol were dissolved in lipid based vehicle at 2.67% w/w, 2% w/w and 2.67% w/w respectively. THC and CBD were the model molecules tested for colonic absorption and metoprolol served as the control. Metoprolol is a molecule known for its colonic absorption; it has several marketed controlled release formulations and is important in this experiment as proof for the validity of the surgery. All animals underwent the same surgery. On the day of experiment, they were divided into two groups. The experimental group (n=6) received THC-CBD-MET formulation diluted in water (1:10 v/v) through the colonic cannula and water PO. The control group (n=5), received the THC-CBD-MET formulation PO and water through the colonic cannula corresponding to volume of drug-formulation administered in the experimental group. Animals in both groups received THC 10 mg/kg, CBD 15 mg/kg and metoprolol 15 mg/kg. Systemic blood samples (0.35 ml) were obtained by the intravenous cannula, placed in the jugular vein. Samples were taken at 5 min pre-dose and at different time points post dose; according to the pharmacokinetic profile: 0, 20 min, 40 min, 1 hr, 1.5 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr. To prevent dehydration, equal volumes of physiological solution are administered to the rats following each blood sampling. Plasma was separated by centrifugation (4000 rpm, 7 minutes, 4° C.) and stored at −20° C. pending analysis.
Plasma Assay
[0101] Plasma CBD, THC and Metoprolol concentrations were determined using HPLC-MS. Plasma aliquots of 150 μL were spiked with 10 μL of internal standard cannabigerol (CBG; 1 μg/mL). ACN (200 μL) was added to each test tube (tubes A) and vortex-mixed for 1 min. The extraction of CBD, THC, Metoprolol and CBG was performed by ethyl acetate (3 mL) that was added to each test tube (tubes A), followed by 1 min. vortex-mixing. After centrifugation at 4000 rpm for 10 min, the ethyl acetate organic layer was transferred to fresh glass test tubes (tubes B) and evaporated to dryness (Vacuum Evaporation System, Labconco, Kansas City, MO). Then, tubes B were reconstituted in 80 μL of ACN: water (80:20). The resulting solution (80 μl) was injected into the HPLC-MS system.
PK Analysis
[0102] The concentration vs. time data and pharmacokinetic parameters such T.sub.max, C.sub.max, and AUC were calculated using non-compartmental analysis with WinNonlin® (version 5.2, Pharsight, Mountain View, CA).
Statistical Analysis
[0103] All values are expressed as mean±standard error of the mean (SEM) if not stated otherwise. To determine statistically significant differences among the experimental groups, student t-test was used. P value of less than 0.05 was termed significant.
Gastro Retentive Cannabidiol Tablets
[0104] Tablets were prepared by direct compression using a 5 mm die, manually pressed with a 1 ton force for 30 sec. Each tablet is designed to weigh 70 mg (Table 2). Tablet measurements used have been previously demonstrated by our lab, to be big enough in order to remain in a rat stomach and provide gastric retention.
[0105] In-vitro dissolution was preformed USP simulated gastric fluid under fasted conditions (pH=1.2) with 5% Tween 80. The buffers were prepared without enzymes. For the dissolution test, each glass tube contained 100 mL, heated to 37° C.±3. Rotation speed was 100 rpm. Following tablet placing in the glasses, time was measured until tablet began to float. 100 μL sample was taken in each time point and replaced with a fresh buffer. Results were adjusted according to this minor dilution. Time points for the experiment in simulated gastric fluid were 1, 2 3, 4, 5, 6, 7, 8 and 24 hr. Samples were analyzed via an HPLC-UV method.
TABLE-US-00002 TABLE 2 Composition (% w/w) and floating properties of GRCAN tablets Cross Floating Egg Citric Sodium Mg PEG PEG Cremophor linked lag time Form. CBD albumin acid bicarbonate stearate 3500 400 RH 40 PVP PVP (FLT, min) F1 14.3 44.7 15 15 1 10 <5 F2 14.3 44.7 15 15 1 5 5 <5 F3 14.3 44.7 15 15 1 3 7 <0.8 F4 14.3 44.7 15 15 1 10 <2 F5 14.3 44.7 15 15 1 10 <5 F6 14.3 44.7 15 15 1 10 <0.5 F7 14.3 44.7 15 15 1 10 <5 F8 14.3 44.7 15 15 1 2 8 <0.66 F9 14.3 44.7 15 15 1 5 5 <1
Relative Oral Bioavailability of CBD in Solution Vs GRCAN Tablet
[0106] Male Wistar rats (Harlan, Israel) weighing 275-300 g were kept under a 12 h light/dark cycle with free access to food (standard rat chow) and water prior to the procedure. Animals were anesthetized for the period of surgery. An indwelling cannula was placed in the right jugular vein of each animal for systemic blood sampling and tunneled beneath the skin as described before.
[0107] The experimental group (n=3) received CBD in GRCAN tablet. The control group (n=3), received the CBD in a propylene glycol:ethanol:water solution (4.5:4.5:1) at a 3 mg/ml concentration. Animals in both groups received, CBD 30 mg/kg and. Systemic blood samples (0.35 ml) were obtained by the intravenous cannula, placed in the jugular vein. Samples were taken at 5 min pre-dose and at different time points post dose; according to the pharmacokinetic profile: 0, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr, 7 hr, 8 hr and 12 hr. To prevent dehydration, equal volumes of physiological solution are administered to the rats following each blood sampling. Plasma was separated by centrifugation (4000 rpm, 7 minutes, 4° C.) and stored at −20° C. pending analysis.
Plasma Assay
[0108] Plasma aliquots of 150 μL were spiked with 10 μL of internal standard cannabigerol (CBG; 1 μg/mL). ACN (200 μL) was added to each test tube (tubes A) and vortex-mixed for 1 min. The extraction of CBD was performed by N-hexane (3 mL) that was added to each test tube (tubes A), followed by 1 min. vortex-mixing. After centrifugation at 4000 rpm for 10 min, the N-hexane organic layer was transferred to fresh glass test tubes (tubes B) and evaporated to dryness (Vacuum Evaporation System, Labconco, Kansas City, MO). Then, tubes B were reconstituted in 80 μL of ACN: water (80:20). The resulting solution (80 μl) was injected into the HPLC-MS system.
Results
THC-CBD-Metoprolol Intra-Colon Administration in the Freely Moving Rat Model
[0109] When comparing the PK profile obtained from both groups, we can see that THC and CBD are practically not absorbed through the colon in comparison to PO administration (
[0110] These results prove that THC and CBD have minimal colonic absorption, thus the controlled release device of the invention has the limited absorption time of 6-8 hr or the alternative of a gastric retentive dosage form (
Gastro Retentive Cannabinoid (GRCAN)
[0111] As shown in
In-Vivo Investigation of CBD-GRCAN Tablet
[0112] In-vivo experiment compared administration of GRCAN tablet-F3 to CBD solution in the freely moving rat model. GRCAN formulation increased CBD oral bioavailability by a five-fold compared to CBD solution (
TABLE-US-00003 TABLE 3 AUC values (mean ± SEM) obtained following PO administration of CBD in solution and GRCAN tablet. CBD dose 30 mg/kg (n = 3 for each group) (*) A significant difference (p < 0.05) from CBD corresponding values was found. (h*ng/ml) solution
70 GRCAN tablet
828(*)
indicates data missing or illegible when filed
Part II-
Tablet Preparation:
CBD Tablets
[0113] The respective powders were blended thoroughly with a mortar and pestle.
[0114] Tablets were prepared by direct compression using an 18×10 mm oval punch die, manually pressed with a 1-ton force for 30 sec. Each tablet is designed to weigh 500 mg (Table 4).
THC tablets
[0115] We dissolved the THC and Cremophor in 300 μl of ethanol and placed at 40′C until fully dissolved. The solution was dripped over the egg albumin using a Pasteur pipette. The vial was washed with another 250 μl of ethanol and added as well, After granulation the powder was placed at 40° C. for 40 minutes to evaporate the ethanol. Then an accurate amount of silica was added until the powder gained sufficient flowing properties. Tablets were prepared by direct compression using a 20×7 mm oval-flat punch die, manually pressed with a 1-ton or 2-ton force for 30 sec. Each tablet was designed to weigh approximately 580 mg (Table 5).
TABLE-US-00004 TABLE 4 Composition (% w/w) and floating properties of CBD-GRCAN tablets Floating Egg Magnesium Cremophor lag time Floating Tablet CBD albumin HPMC stearate RH 40 (FLT, min) Time (h) T1 20 69 — 1 10 <0.5 10 T2 20 69 — 1 10 <0.5 10 T3 20 69 — 1 10 <7 8 T4 20 50 20 1 9 — — T5 20 50 20 1 9 — — T6 20 50 20 1 9 — —
TABLE-US-00005 TABLE 5 Composition (% w/w) and floating properties of THC-GRCAN tablets Floating Egg Magnesium Cremophor Press lag time Floating Tablet THC albumin Silica stearate RH 40 (Ton) (FLT, min) Time (h) T1 2.6 94.5 0.5 1 1.4 1 <5 1 T2 2.6 94.5 0.5 1 1.4 1 <0.5 1 T3 2.6 94.5 0.5 1 1.4 1 <0.5 1 T4 2.6 94.5 0.5 1 1.4 2 — — T5 2.6 94.5 0.5 1 1.4 2 — — T6 2.6 94.5 0.5 1 1.4 2 — —
Dissolution Test:
[0116] In-vitro dissolution was performed in a USP simulated gastric fluid under fasted conditions (pH=1.2) with 5% Tween 80. The buffers were prepared without enzymes. For the dissolution test, each glass tube contained 250 mL, heated to 37° C.±3. Rotation speed was 150 rpm. Following tablet placing in the glasses, time was measured until tablet began to float (FLT). 200 μL sample was taken in each time point and replaced with a fresh buffer. Results were adjusted according to this minor dilution. Time points for the experiment in simulated gastric fluid were 0.25, 0.5, 1, 2 3, 4, 5,6,7,8 (for THC), 10 and 24 hr (for CBD). Samples were analyzed via an HPLC-UV method.
Sample Analysis in HPLC-UV
[0117] Analytical test for CBD and THC content was conducted using HPLC-UV. [0118] Column used: Luna C-8(2), 5 m, 150×4.6 mm, 100 Phenomenex, 00F-4249-E0 [0119] Mobile phase: 5 mM NaH2PO4 in water pH 3.0: Acetonitrile at 30:70 ratio. [0120] Diluent: Acetonitrile: water=30:70 [0121] Column temperature: 40° C.±5° C. [0122] Sample Temperature: 10° C.±5° C. [0123] UV Monitoring wavelength: 211 nm [0124] CBD RT: 7.7 min [0125] THC RT: 12.7 min
Results
Dissolution Test-CBD Release
[0126] Each tablet tested contained theoretically 100 mg of CBD. Thus, in a 250 mL dissolution glass, the max concentration achieved should have been 400 ug/mL. This concentration is set as the theoretical concentration. Results are presented as % of CBD released from nominal concentration.
Changes in Size
[0127] Tablet measurements are composed of length, width and height. With these parameters we calculated volume of tablets before the dissolution test and after the last sample of 24 hr. Egg albumin tablets (tablets 1-3), resulted in a particular shape with the middle of tablet narrower than the sides. As a result, we calculated the max/min width and max/min height. In average, tablets increased 1.7 fold after 24 hr (
[0128] Egg albumin and HPMC tablets increased in use uniformly (tablets 4-6). In average, tablets increased 5.2 fold after 24 hr (
Dissolution Test-THC Release
[0129] Each tablet tested contained theoretically 15 mg of THC. Thus, in a 250 mL dissolution glass, the max concentration achieved should have been 60 μg/mL. This concentration is set as the theoretical concentration. Results are presented as % of THC released from nominal concentration.
Changes in Size
[0130] Tablet measurements are composed of length, width and height. With these parameters we calculated volume of tablets before the dissolution test. Egg albumin tablets, pressed at 1 ton (tablets 1-3,
TABLE-US-00006 TABLE 7 Changes in THC tablet size parameters: length, width and volume. Change in volume is expressed in ratio Length (mm) Width (mm) Height (mm) Volume (mm.sup.3) Time 0 8 h 0 8 h 0 8 h 0 8 h Ratio T1 20.4 7.2 4.2 616.2 T2 20.6 7.2 4.4 650.5 T3 20.4 7.2 4.3 631.4 T4 20.3 17.8 7.2 8.9 4.0 4.7 577.3 736.7 1.3 9.3 8.5 4.7 4.2 2.5 2.2 T5 20.4 19.00 7.1 10.8 3.9 4.7 572.7 959.7 1.7 9.9 9.1 5.7 5.1 2.5 2.2 T6 20.2 22.4 7.1 9.8 3.1 3.0 447.8 667.3 1.5 12.6 9.8 4.9 4.9 1.6 1.4 Mean 1.5
[0131] Consumption of medicinal cannabis is divided into several routs of administration. The most prevalent route is inhalation or smoking of whole plant. Smoking results in rapid onset of absorption and effect. However, this route has health disadvantages, inter-subject variability alongside a biased opinion from society and regulation. Oral medicinal cannabis products are often based on oils such as Marinol®, a sesame oil synthetic THC capsule or recently approved Epidiolex®, a sesame oil-ethanol oral solution of CBD. Although these products have a relatively slower onset of effect, they require more than a single administration per day. A prominent marketed product is the orumucosal spray Sativex®, a THC-CBD formulation of propylene glycol and ethanol. Patients use the spray several times a day for the relief of neuropathic pain and spasticity symptoms of MS. Frequent use of the spray often causes mouth ulcerations and lesions. These examples from clinical practice show that there is a need for developing cannabinoid CR formulations that will treat to patients needs and ultimately increase compliance and adherence.
[0132] Currently, the most leading technology for gastro retentive dosage form of cannabinoids is based on an accordion pill that unfolds in stomach, thus avoiding gastric emptying, enabling drug release for a longer period compared to the control Sativex.
[0133] The rational for developing a gastro retentive tablet is based on preserving the use of upper intestine for increased and prolonged absorption, while developing a solid dosage form with a less costly, more easily upscaled technique.
[0134] In classical oral controlled release (CR) formulations, the absorption phase of a drug is prolonged beyond the small intestine. The transit time from the small intestine to the caecum (the first part of the large intestine) is approximately 4 h. The time interval in the small intestine is too short for controlled release dosage forms, unless the drug can be equally absorbed from the large intestine. Thus, the release profile for most oral CR dosage forms can be effective for about 6-8 h if taking into consideration transit time from the mouth to the caecum. For a drug which can be absorbed from the large intestine, the time interval for absorption can be increased to 1 day. Therefore, a prerequisite condition for a successful CR dosage form is sufficient absorption from the colon. To investigate regional absorption of THC and CBD from the colon, compounds were administered directly to rat cecum via a specially inserted cannula. Regional colonic absorption was compared to systemic absorption, following an oral (PO) bolus, which encompasses absorption from the upper parts of the intestine. For this experiment a concept termed “absorption cocktail approach” was used. In this method, target molecules are administered together with standard probes that aid in understanding drug absorption processes, absorption kinetics, PK etc. The standard molecule used for colonic absorption was metoprolol. Metoprolol is a compound with sufficient absorption through the entire intestinal tract.
[0135] Plasma exposure of metoprolol following colonic administration was higher compared to PO administration. There are reports suggesting a considerable intestinal first-pass extraction of metoprolol in rats, evaluated via intraduodenal administration. It may be possible that bypassing the small intestine may have enabled the compound to avoid intestinal first pass metabolism it undergoes, thus resulting in increased absorption. Contrary to metoprolol, both THC and CBD resulted in poor absorption through the colon, compared to their oral administration. The use of metoprolol demonstrated that low colonic absorption of cannabinoids is not result of the procedure of colon cannulation, but outcome of their physicochemical properties. These results are in line with researchers' hypothesis that lipophilic molecules as cannabinoids have poor absorption from the colon, which is not physiologically designed for the absorption of fats or lipids.
[0136] In light of these preliminary results regarding cannabinoid narrow absorption window, the CR formulation of gastro-retentive dosage form was chosen. Different technologies are implemented in order maintain the dosage form in the stomach and overcome the physiological tendency to evacuate stomach content. At the center of this manuscript is the development of a floating gastro retentive dosage form based on egg albumin, carbon dioxide generating compounds and CBD as the active compound. A screening of excipients was conducted in order increase of drug release over at least 8 h. Lowest results are seen with HPMC, PEG3500 and PEG400, about 25-30% drug release while tablets that contained 10% surfactant Cremophor® RH40, resulted in approximately 98% drug release. Alongside drug release, the use of a surfactant in the formulation is of importance on account of CBD's poor solubility. However, this formulation was also too friable for in-vivo investigation. Thus, a series of formulations was evaluated, based on this surfactant with decreased concentration. Formulation based on PEG400 and Cremophor® RH40 (3:7) was investigated in-vivo in the freely moving rat model. This composition was selected since it had sufficient drug release after 8 h (˜80%) and a combination of excipients that may have aided in CBD solubilization in the stomach. The suitability of the rat model for gastro retentive dosage forms, was previously demonstrated by Stepensky et al. (2001) which proved that tablets of the used dimensions remain in rat stomach for at least 8 h. This was proven by a series of X-ray images of specially marked tablets. Although, the ultimate evaluation of a gastro retentive dosage form ought to be conducted in a clinical trial, the rat model sheds light on potential drug candidates and formulation before moving towards a clinical setting.
[0137] In vivo results in the freely moving rat model demonstrate the potential of the gastro retentive dosage form in prolonging drug absorption phase. As anticipated, T.sub.max was delayed for the GR-CAN tablet to 8 h, compared to 2 h for the solution. Not only was the drug plasma concentration profile prolonged, but exposure and relative bioavailability were also increased compared to solution. This may be result of the CBD's physicochemical properties which deem the compound with dissolution rate limited absorption. CBD is a Biopharmaceutical Classification System (BCS) class 2 molecule that although has sufficient permeability through the intestinal wall, its dissolution in the aqueous environment of the stomach is a rate limiting step. As a result, upon gradual release of smaller amounts from the tablet matrix, with the aid of tablet surfactants, the dissolution is under “sink conditions” and the absorption is less dependent on this process. In addition, both Cremophor® RH40 and PEG400 were reported as excipients with inhibitory effect on phase I and phase II enzymes. Indeed, CBD's poor oral bioavailability is result of low solubility in the GI tract and susceptibility to extensive pre systemic metabolism. Thus, the addition of Cremophor® RH40 and PEG400 may have aided in decreasing intestinal metabolism and increasing bioavailability.
[0138] Thus, this invention concerns a controlled release dosage form for the highly lipophilic cannabinoids. The lipophilic nature of cannabinoids renders the molecules unsuitable candidates for conventional CR formulations that require colonic absorption. As estimated by researchers, lipophilic cannabinoid colonic absorption is low due physiological role of the colon to absorb mainly water and minerals and avoid lipid absorption. Regional absorption of cannabinoids has not been investigated, particularly in comparison to systemic absorption, emphasizing the importance of this work. The narrow absorption window of cannabinoids places these compounds as candidates for GRDF that utilize absorption from the upper small intestine while retained in the stomach.