EFFERVESCENT TABLETS

Abstract

Effervescent self-emulsifying drug delivery system formulations for oral administration of water-insoluble cannabinoids are disclosed.

Claims

1. A self-emulsifying drug delivery system (SEDDS) in the form of a free-flowing, compressible effervescent powder, comprising (i) a cannabinoid-containing oil and a surfactant adsorbed onto an acid source and a carbon dioxide source, wherein the acid source and carbon dioxide source are in powder form.

2. The SEDDS powder of claim 1, wherein the surfactant is Vitamin E TPGS and wherein the SEDDS powder does not comprise any other surfactants.

3. The SEDDS powder of claim 1, wherein the acid source is selected from the group consisting of citric acid, tartaric acid and ascorbic acid citric acid; and wherein the carbon dioxide source is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium carbonate and calcium carbonate.

4. The SEDDS powder of claim 1, further comprising (ii) colloidal silicon dioxide

5. The SEDDS powder according to claim 1, further comprising (iv) a compressible sugar.

6. The SEDDS powder according to claim 5, wherein the compressible sugar is compressible sucrose.

7. The SEDDS powder according to claim 1, further comprising one or more of (v) a flavoring agent and (vi) lubricant.

8. The SEDDS powder according to claim 7, wherein the flavoring agent is lemon or orange oil and wherein the lubricant is sodium stearyl fumarate.

9. The SEDDS powder according to claim 1, wherein the cannabinoid-containing oil comprises at least one cannabinoid selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (Δ9-THCV), cannabidivarin (CBDV), Δ9-tetrahydrocannabinolic acid (Δ9-THCA), and cannabidiolic acid (CBDA).

10. The SEDDS according to claim 9, wherein the at least one cannabinoid is one or more of THC and CBD.

11. An effervescent tablet comprising the SEDDS powder of claim 1.

12. The effervescent tablet according to claim 11, wherein the acid source comprises citric acid.

13. The effervescent tablet according to claim 11, wherein the carbon dioxide source comprises sodium bicarbonate.

14. The effervescent tablet of claim 11, wherein THC is present in the tablet in an amount between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg, between about 1 mg and about 15 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 5 mg; or is present at about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, or 25 mg.

15. The effervescent tablet according to claim 11, wherein CBD is present in the tablet at a concentration of between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg, between about 1 mg and about 15 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 5 mg; or is present at about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, or 25 mg.

16. The effervescent tablet according to claim 11, comprising about 15% wt/wt to about 25% wt/wt compressible sucrose, about 0.15% wt/wt to about 0.35% wt/wt colloidal silicon dioxide, about 30% wt/wt to about 50% wt/wt sodium bicarbonate/carbonate, about 25% wt/wt to about 35% wt/wt citric acid, about 0.15% wt/wt to about 0.5% wt/wt Vitamin E TPGS and from about 0.75% to about 2.25% wt/wt sodium stearyl fumarate.

17. The effervescent tablet according to claim 16, comprising about 21.20% wt/wt compressible sucrose, about 0.24% wt/wt colloidal silicon dioxide; about 42% wt/wt sodium bicarbonate/carbonate, about 34% wt/wt citric acid, about 0.37% vitamin E TPGS and about 1.5% sodium stearyl fumarate.

18. The effervescent tablet according to claim 16 comprising about 0.1% to about 0.5% flavoring agent.

19. The effervescent tablet according to claim 16 comprising one or more of about 5 mg THC and about 5 mg CBD.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0034] Provided herein is a cannabinoid SEDDS effervescent formulation, in the form of a free flowing powder or tablet that overcomes the low bioavailability of conventional oral dosage forms that employ cannabis extract or distillate and decreases intra- and inter-patient variability in observed blood levels of cannabinoids.

[0035] The food effect on the pharmacokinetic profile of typical of oral dosage forms that employ cannabis is minimized by the effervescent tablets described herein. Thus, an effervescent tablet as described herein may exhibit an improved pharmacokinetic profile when consumed with food compared to conventional oral dosage forms containing the same dosage of active ingredient with respect one or more of the following: (i) delay in median T.sub.max (ii) decrease in Cmax and (iii) increase in total exposure (AUC.sub.inf).

[0036] Compression of effervescent tablets is often complicated due to hygroscopicity of the raw materials (e.g. citric acid and sodium bicarbonate). Hygroscopic compounds typically lead to picking and sticking problems during compression as well as premature effervescence within the tablet matrix after compression, leading to physical and chemical stability problems. This effect is complicated further if cannabis extracts are included in the matrix. Extreme compression difficulties will be encountered due to the oily nature of the extracts and will negatively affect excipient binding and ultimately tablet hardness as well as exacerbating picking, sticking and capping during tablet compression. Effervescent tablets as herein described overcome these issues by loading cannabis extract and surfactant onto a powder carbon dioxide source and/or a powder acid source and/or compressible sucrose and subsequently coating mixture with colloidal silicon dioxide. Thus, effervescent tablets as herein described can be manufactured using conventional direct compression tableting methods

[0037] Self-Emulsifying Drug Delivery System

[0038] Self-Emulsifying Drug Delivery System (SEDDS) is a solid or liquid dosage form comprising an oil phase, a surfactant and a co-surfactant, characterized primarily in that said dosage form can form oil-in-water emulsion spontaneously in the gastrointestinal tract or at ambient temperature (referring generally to body temperature, namely 37° C.) with mild stirring. When a SEDDS enters the gastrointestinal tract, it is initially self-emulsified as emulsion droplets and rapidly dispersed throughout the gastrointestinal tract, and thus reducing the irritation caused by the direct contact of the drug with the mucous membrane of the gastrointestinal tract. In the gastrointestinal tract, the structure of the emulsion micro particulates will be changed or destroyed. The resulting micro particulates of micrometer or nanometer level can penetrate into the mucous membrane of the gastrointestinal tract, and the digested oil droplets enter the blood circulation, thereby significantly improving the bioavailability of the drug. The self-emulsifying drug delivery system is predominantly employed with respect to lipid-soluble and less water-soluble drugs, such as cannabinoids. It increases the stability and the bioavailability of the lipophilic drugs, provides a more consistent temporal profile of drug absorption, protects the drugs from the hostile environment in the gastro-intestinal tract, eliminates food effects, and allows for dose escalation, thereby improving efficacy and safety.

[0039] Cannabinoids

[0040] Cannabinoids are a group of extracellular signaling molecules. Signals from these molecules are mediated in animals by two G-protein coupled receptors, Cannabinoid Receptor 1 (CB.sub.1) and Cannabinoid Receptor 2 (CB.sub.2). CB.sub.1 is expressed most abundantly in the neurons of the central nervous system (CNS) but is also present at lower concentrations in a variety of peripheral tissues and cells (Matsuda, et al. (1990) Nature 346:561-564). In contrast, CB.sub.2 is expressed predominantly, although not exclusively, in non-neural tissues, e.g., in hematopoietic cells, endothelial cells, osteoblasts, osteoclasts, the endocrine pancreas, and cancerous cell lines (Munro, et al. (1993) Nature 365:61-65; and as reviewed in Pacher, et al. (2006) Pharmacol. Rev. 58(3): 389-462). As such, CB.sub.1 is believed to be primarily responsible for mediating the psychotropic effects of cannabinoids on the body, whereas CB.sub.2 is believed to be primarily responsible for most of their non-neural effects.

[0041] The well-known psychotropic effects of Δ.sup.9-THC have greatly limited its clinical use. However, as described above, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Δ.sup.9-THC, or can be combined with lower doses of Δ.sup.9-THC to produce equivalent therapeutic benefits. The cannabinoid SEDDS of the present invention are helpful in addressing the adverse psychotropic effects of Δ.sup.9-THC.

[0042] In some embodiments, the cannabinoid is selected from tetrahydrocannabinol, Δ.sup.9-tetrahydrocannabinol (THC), Δ.sup.8-tetrahydrocannabinol, Δ.sup.8-tetrahydrocannabinol-DMH, Δ.sup.9-tetrahydrocannabinol propyl analogue (THCV), 11-hydroxy-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol, 5′-azido-Δ.sup.8-tetrahydrocannabinol, AMG-1, AMG-3, AM411, AM708, AM836, AM855, AM919, AM926, AM938, cannabidiol (CBD), cannabidiol propyl analogue (CBDV), cannabinol (CBN), cannabichromene, cannabichromene propyl analogue, cannabigerol, CP 47497, CP 55940, CP 55244, CP 50556, CT-3 (ajulemic acid), dimethylheptyl HHC, HU-210, HU-211, HU-308, WIN 55212-2, desacetyl-L-nantradol, dexanabinol, JWH-051, levonantradol, L-759633, nabilone, O-1184, and mixtures thereof.

EXAMPLES

[0043] The following examples illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention in any way. While this invention has been described in relation to its preferred embodiments, various modifications thereof will be apparent to one skilled in the art from reading this application.

[0044] A list of materials used in the Examples and the source of these materials is as provided in Table 2:

TABLE-US-00002 Specifi- Brand Ingredient cation Function Name Supplier Compressible NF Binder DiPac Domino Sucrose Antares Health Vitamin E TPGS NF lipophilic carrier NA Products Colloidal Silicon NF Adsorbent Aerosil 300 Evonik Dioxide Lemon/Orange Oil NF flavor NA PENTA Citric Acid NF Effervescent NA Sigma, EMD Sodium USP/NF Effervescent Effersoda SPI Bicarbonate/ Pharma carbonate Sodium Stearyl NF Lubricant Pruv JRS Fumarate Pharma

Example 1—General Method for Preparing a Cannabinoid SEDDS Effervescent Tablet

[0045] A cannabinoid SEDDS effervescent tablet as described herein may be according to the following steps:

[0046] Step 1: Dried cannabis material is soaked in super-cooled ethanol (−70 C) for about 30 minutes.

[0047] Step 2: The slurry (cannabis and ethanol) from step 1 is centrifuged to separate ethanol (containing cannabinoids) from plant material and subsequently filtered to remove particulate plant material

[0048] Step 3: The ethanol containing the cannabinoids is heated and a vacuum is applied in a falling film evaporator or rotovap to separate the cannabinoids from the ethanol.

[0049] Step 4: The resulting oil from step 3 is heated to 120 C for up to 4 hours to decarboxylate the cannabinoids (e.g. THCA to free THC)

[0050] Step 5: Material from step 4 is then treated to purify and concentrate the cannabinoids contained in the oil. For example, the material from step 4 may be distilled at about 185 C under vacuum.

[0051] Step 6A: The resulting cannabinoid oil is then mixed with Vitamin E TPGS and optionally a flavoring agent (e.g. lemon oil).

[0052] Step 6B: The mixture from step 6A is then blended with a suitable powder carbon dioxide source (e.g. sodium bicarbonate powder such as Effer-Soda®) and a suitable powder acid source (e.g. citric acid) in a centrifugal planetary mixer.

[0053] Step 7: The resulting powder from step 6B is then mixed in a suitable powder blender with colloidal silicon dioxide.

[0054] Step 8: The resulting powder from step 7 is then mixed with compressible sucrose and sodium stearyl fumarate.

[0055] The final blend from step 8 is then compressed into tablets on a suitable rotary tablet press

Example 2—Determination of Oral Bioavailability I

[0056] Subjects are selected for the in vivo oral bioavailability study. Subjects are fasted overnight prior to dosing. An SEDDS formulation (e.g. in the form of an effervescent tablet) as herein described is orally administered to a first group of subjects (n=10). The same dose of cannabinoids is administered orally to second group of subjects (n=10) in the form of an oil solution. The same dose of cannabinoids is administered intravenously to third group of subjects (n=10).

[0057] Serial blood samples of 2 mL are obtained from subjects at 20 and 40 minutes and 1, 2, 4, 6, 8, 12, and 24 hours after dosing. These blood samples are analyzed using an HPLC or LC/MS/MS assay specific for the cannabinoids administered to each subject.

[0058] Samples are typically prepared by adding 25 μL aliquots of plasma to 200 μL of a solution of 0.1% formic acid in acetonitrile:methanol 1:1 containing THC-D.sub.3 and 11-hydroxy THC-D.sub.3 and extracted through a Biotage Isolute PLD+ plate (50 mg) extraction plate (Biotage LLC, Charlotte, N.C.). Extracted samples are analyzed by reverse phase liquid chromatography/tandem mass spectrometry (LC/MS/MS) in selective reaction monitoring (SRM) mode under optimized positive ion conditions for the detection of THC, 11-hydroxy THC and the deuterated internal standards. Analytes are separated by reverse phase HPLC employing a Waters BEH C8 (2.1×30 mm) column (Waters Corp., Milford, Mass.), under gradient conditions. The gradient begins with 50% MPA (10 mM ammonium acetate in water pH 4.8) for 0.5 minutes then increases to 95% MPB (0.1% acetic acid in methanol) in linear fashion over 1.5 minutes and then holds at 95% MPB for 1 minute before returning to the starting conditions. For MS/MS detection a Sciex API 5000 mass spectrometer (AB Sciex LLC, Redwood City, Calif.) is used to monitor four transition ions (THC 315.1.fwdarw.193.0, THC-D.sub.3 318.1.fwdarw.196.0, 11-hydroxy 331.1.fwdarw.193.0 and 11-hydroxy D.sub.3 334.1.fwdarw.196.0). The targeted quantitation range is 0.1 ng/mL to 100 ng/mL for THC and from 0.2 ng/mL to 200 ng/mL for 11-hydroxy THC.

[0059] Drug concentrations in the blood of the test subjects are plotted against the time after the drug is administered through an intravenous (iv) or oral route. The area under the plasma concentration-time curve (the AUCs) are recorded and integrated using the trapezoidal rule to calculate the absolute bioavailability according to the following formulae:

[00001]$\mathrm{Absolute}\mathrm{bioavailability}\left(\%\right)=\frac{\left(\mathrm{AUC}\right)\mathrm{oral}\text{/}\mathrm{Dose}\mathrm{oral}}{\left(\mathrm{AUC}\right)\mathrm{iv}\text{/}\mathrm{Dose}\mathrm{iv}}$

[0060] The self-emulsifying drug delivery system as herein described achieves an oral bioavailability of the cannabinoids significantly higher than the same dose of cannabinoids administered orally in the form of an oil solution.

Example 3—Determination of Oral Bioavailability II

[0061] The plasma pharmacokinetics of a cannabinoid SEDDS effervescent tablet formulation as herein described and a commercially available THC tablet are measured in a study utilizing non-naïve male Beagle dogs (n=4 for each test compound). In these tests the SEDDS formulation comprises 5 mg/dose THC, 21.20% wt/wt compressible sucrose, 0.24% wt/wt colloidal silicon dioxide, 42% wt/wt sodium bicarbonate/carbonate, 0.37% wt/wt lemon/orange oil, 34% wt/wt citric acid, 0.37% wt/wt vitamin E TPGS and 1.50% wt/wt sodium stearyl fumarate. The commercially available tablet formulation also contains 5 mg THC as an active ingredient. A 3 ml blood sample is drawn from each subject dog prior to oral administration of a single dose of the test compound. Blood samples are also taken at 0.5, 1, 2, 4, 6, 8, and 12 hours post-administration. Plasma is isolated from each sample and each sample is split into two equal aliquots and stored at −80° C. until further analysis.