IES87026B2 - Formulation for the oral administration of nutraceutical and pharmaceutical active ingredients - Google Patents

Abstract

The cannabis sativa plant contains 60 cannabinoids. Cannabinoids have been reported to treat a diverse range of diseases including epilepsy, chronic pain, cancer and more. There has been an increase in demand for Cannabidiol (CBD) and Cannabinoids products on the market as a result of this. Poor oral bioavailability of Cannabinoids has been a significant limitation in the successful uptake of Cannabinoids in the gastro-intestinal tract (GI Tract). Poor oral bioavailability affects the performance and therapeutic effects of these compounds for each patient. It is also widely known that the droplet size also plays an important role in determining the absorption rate of a substance from the GI tract and its overall bioavailability in the body. Nano sized oil droplets are more effective in increasing the bioavailability of a molecule due to their nano size. This invention describes a self-emulsifying technique using nano-sized droplets containing cannabinoids to increase the bioavailability of cannabinoids in the body. The Self Nano Emulsifying Delivery System SNEDS described containing one or more cannabinoids or cannabinoid analogues forms a stable aqueous nanoemulsion, the average droplet size of the nanoemulsion is in a range between 20 and 50 nm.

Description

Title: Formulation for the oral administration of nutraceutical and pharmaceutical active ingredients Field of invention: The present invention relates to nutraceutical and pharmaceutical products for oral administration. In particular, relates to a new self nano-emulsifying formulation containing nutraceutical and pharmaceutical active ingredients which forms a nano-emulsion upon dispersing in water to enhance absorption and bioavailability of poorly water soluble 10 ingredients.

Background: The cannabis sativa plant contains over 480 naturally occurring compounds. However, only approximately 60 of these are considered cannabinoids. The most well-known among these compounds are the delta-9-tetrahydrocannabinol and Cannabidiol. Cannabinoids 15 as listed above have been reported to treat a diverse range of diseases including epilepsy, chronic pain, cancer and more. There has been an increase in demand for Cannabidiol (CBD) and Cannabinoids products on the market as a result of this.

However, poor oral bioavailability of Cannabinoids has been a significant limitation in the successful uptake of Cannabinoids in the gastro-intestinal tract. Cannabinoids are lipophilic 20 and are hence poorly absorbed in the aqueous solutions of the Gastrointestinal (GI) tract i.e. water. As a result, the uptake of Cannabinoids in the gastro-intestinal tract is poor. Poor oral bioavailability affects the performance and therapeutic effects of these compounds for each patient.

Research investigating the poor bioavailability of Cannabinoids and specifically CBD have led 25 to progressions in formulation design delivery systems to overcome these absorption barriers.

This invention puts forward the application of formulation design to enhance the oral bioavailability of CBD and other cannabinoids in the gastro-intestinal tract which will consequentially enhance the absorption and uptake of CBD in the body. Formulation design is an appropriate choice of delivery system for improving the oral bioavailability of CBD and 30 provides many advantages with regards to reduced financial expenses and development and manufacturing timeline.

It is also widely known that the droplet size also plays an important role in determining the absorption rate of a cannabinoid and its overall bioavailability in the body, in this case being CBD. This is because a small droplet size provides a large surface area for its absorption, in particular nano droplets. These nano sized oil droplets are more effective in increasing the bioavailability of the cannabinoid molecule due to their nano size. By using techniques such as nanonization and surfactants, the application could be useful if applied to CBD products. Formulation design is one way to improve the uptake of CBD against absorption barriers. This invention describes a self-emulsifying technique using nano-sized droplets of hemp oil to increase the bioavailability of CBD in the body. Droplet size is important to determine the absorption rate and overall bioavailability of Self-Nanoemulsifying Delivery Systems as above. CBD products including Hemp Oil and CBD Oil require such a delivery system to help successfully deliver CBD through the gastrointestinal tract.

Oral administration is the preferred path of delivery to take these natural compounds, in either a gel capsule or in tablet-form. The natural compound can be ground down or adsorbed on a carrier silica and compressed in such tablet. It offers benefits including convenience (and taste preferences) and cost effectiveness.

Summary of invention: The object of the invention to provide solutions to the aforementioned deficiencies in the art. The present invention describes a nutraceutical or pharmaceutical composition comprising cannabinoids or cannabinoid analogues as a self nano emulsifying delivery formulation with an enhanced cannabinoid loading capability, better stability and an improved bioavailability. To this end, the invention provides a stable Self Nano Emulsifying Delivery System SNEDS of one or more cannabinoids or cannabinoid analogues, wherein the stable aqueous nanoemulsion, the average droplet size of the nanoemulsion is in a range between 15 and 50 nm.

The present invention provides a delivery system for a cannabinoids or cannabinoid analogues based pharmaceutical composition that uses a surfactant which does not cause the cannabinoids or cannabinoid analogues to precipitate out of the aqueous medium once the nano emulsion is formed.

In an embodiment, the cannabinoids or cannabinoid analogues composition of the present invention forms an oil/water nanoemulsion instantaneously when brought into contact with the aqueous medium of the GI tract with mild agitation provided by gastric mobility in the tract region. The formation of the nanoemulsion leads to a thermodynamically stable system, with uniform droplet sizes, that are optically clear and exhibit superior absorption and enhanced bioavailability of the cannabinoids or cannabinoid analogues enabling reduction in dose, more consistent temporal profiles of absorption, and protection of cannabinoids from the hostile environment in the gut.

In a preferred embodiment, the droplet size of the composition of the present invention is 1550 nm. The composition of the present invention, by virtue of its choice of surfactants, does not lead to any precipitation of the active ingredient, thus providing a composition that is effective and stable over a wide period of time. Further, a stable self nano emulsifying composition with a cannabinoids or cannabinoid analogues loading ability of around or more than 5% is a marked advancement over the existing art and paves way for further research and development on cannabinoids or cannabinoid analogues as a better, safer and efficient therapeutic agents of choice.

In a preferred embodiment, the pharmaceutical composition of the present invention comprises of: % (w/w) of the cannabinoids or cannabinoid analogues; 36-40% (w/w) of the oil phase; 36-40% (w/w) of the surfactant, and 18-20% (w/w) of the co surfactant, In an embodiment, the surfactant is capable of forming a stable emulsion, preferably a fine emulsion and more preferably a nanoemulsion, of the present composition when it is brought into contact with aqueous fluid, such as in the GIT.

In an embodiment, the pharmaceutical composition of the present invention shows an enhanced cannabinoid loading capability, better stability and an improved bioavailability. The composition of the present invention comprises of a nutraceutical or pharmaceutically effective amount of a cannabinoids or cannabinoid analogues, an oil phase, a surfactant and a cosurfactant.

In a preferred embodiment, the cannabinoids or cannabinoid analogues are compounds selected from the group consisting of cannabinol, cannabidiol, A9-tetrahydrocannabinol, A8tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-A9 tetrahydrocannabinol, levonantradol, All-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, nabilone, a combination thereof, a natural or synthetic analogue thereof, and a natural or synthetic molecule with a basic cannabinoid structure.

In an embodiment the oil phase of the composition of the present invention can be selected from commercially available oils including, but not limited to, CAPTEX® 100 (Propylene Glycol Dicaprate), CAPTEX® 300 (Glyceryl Tricaprylate/Tricaprate), CAPTEX® 355 (Glyceryl Tricaprylate/Tricaprate), MIGLYOL® 810 (Caprylic/Capric Triglyceride), MIGLYOL® 812 (Caprylic/Capric Triglyceride), MIGLYOL® 818 (Caprylic/Capric/Linoleic Triglyceride), MIGLYOL® 829 (Caprylic/Capric/Succinic Triglyceride), and CAPRYOL™ 90, CAPTEX® 200 (Propylene Glycol Dicaprylocaprate) and MIGLYOL® 840 (Propylene Glycol Dicaprylate/Dicaprate), and the like. In another preferable embodiment, the stable SNEDDS of one or more cannabinoids or cannabinoid analogues further comprises the oil phase or natural plant oils selected from the groups consisting of hemp oil, cannabis oil, cannabidiol oil, olive oil, coconut oil, sesame oil, and rapeseed oil or a mixture thereof. The active medicament generally has greater solubility in natural available oil phases, and therefore, they are preferred over commmercial oils. In a most preferred embodiment, the oil phase is olive oil.

In the preferred embodiment, when administered as a liquid dosage form, the composition is filled in hard or soft gelatin capsules.

In an embodiment, the oil phase also acts as a cosurfactant in the composition. The Hydrophilic-Lipophilic Balance (HLB) of the oil phase is between 2 and 10, more preferably between 4 and 8.

In an embodiment the surfactant is a combination of at least one high HLB (hydrophilic/lipophilic balance) surfactant, having an HLB of at least about 10, with at least one cosurfactant being a low HLB surfactant having an HLB of less than about 12.

In a preferred embodiment, surfactants comprise of PEG-40 Hydrogenated Castor Oil and polyoxyethylenesorbitan Trioleate present at a ratio of 2:1 In a preferred embodiment, the surfactants used in the present invention comprise non-ionic surfactants. In yet another embodiment, the non-ionic surfactants are selected from a group comprising polyoxyethylene products of hydrogenated vegetable oils, polyethoxylated castor oils or polyethoxylated hydrogenated castor oil, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene castor oil derivatives or a combination thereof. These are commercially available as CREMOPHOR® (From BASF) such as CREMOPHOR® EL (PEG-35 castor oil), CREMOPHOR® RH40 (PEG-40 hydrogenated castor oil), CREMOPHOR® RH60 (PEG-60 hydrogenated castor oil), LABRASOL® (PEG-8 Caprylic/Capric Glycerides), GELUCIRE® (Stearoyl polyoxylglycerides), Polysorbates, PLURONIC® L-64 and L-127 (block copolymers based on ethylene oxide and propylene oxide), TRITON™ X 100 (Polyethylene glycol tertoctylphenyl ether), SIMULSOL™ (polyoxyethylated products comprising Polyoxyethylated lauric alcohol, Polyoxyethylated cetostearyl alcohol, Polyoxyethylated stearic acid and the like) NIKKOL™ HCO-50 (Polyoxyethylene (50) hydrogenated castor oil), NIKKOL™ HCO35 (Polyoxyethylene (35) hydrogenated castor oil), NIKKOL™ HCO-40 (Polyoxyethylene (40) hydrogenated castor oil), NIKKOL™ HCO-60 (Polyoxyethylene (60) hydrogenated castor oil) (From Nikko Chemicals Co. Ltd.), and TWEENS® (Polysorbates) (From ICI Chemicals). In a preferred embodiment, the surfactant is CREMOPHOR® RH40. In yet another embodiment, the surfactant has a HLB between 9 and 18 and more preferably between 12 and 16.

In an embodiment, the co-surfactants of the present invention are selected from a group comprising Tween 85 (PEG (20) polysorbitan monooleate), Span 80 (Sorbitan monooleate), Span 85 (Sorbitan trioleate), span 40 (sorbitan monopalmitate), Span 65 (sorbitan tristearate), glyceryl monostearate, tween 60 (PEG (20) monostearate). In yet another embodiment, the surfactant has a HLB between 4 and 12 and more preferably between 10-11. In a preferred embodiment, the surfactant is Tween 85.

In another embodiment of the present invention, the amount of cannabinoids or cannabinoid analogues is about 1% to 10% (w/w), preferably between 4% and 8% (w/w), most preferably at 5% (w/w) of the composition. According to one embodiment, the final maximum concentration of cannabinoids or cannabinoid analogues in the SNEDS of one or more cannabinoids or cannabinoid analogues is 50mg/gm. The cannabinoids or cannabinoid analogues are a natural compound, a synthetic compound, a semi-synthetic compound, or mixtures thereof.

In an embodiment, the composition of the present invention can comprise additives conventionally used for preparing pharmaceutical formulations. These can include stabilizing components. In an embodiment, the stabilizing component of the formulation is selected from a group comprising of α-tocopherol, ascorbyl palmitate, BHT (butyl hydroxytoluene), BHA (butyl hydroxyanisole), propyl gallate or malic acid.

The cannabinoids or cannabinoid analogues composition of the present invention is ideal for oral delivery systems, since they are homogeneous, thermodynamically stable system, with uniform droplet sizes, that are optically clear. The cannabinoids or cannabinoid analogues composition of the present invention can be administered in the form of liquid or solid dosage form. In an embodiment, when administered as a liquid dosage form, the composition is filled in hard or soft gelatin capsules.

In an embodiment, when administered as a solid dosage form, the composition is adsorbed on the surface of silicates/microcrystalline cellulose and subsequently compressed into tablets.

Oral unit dosage forms in accordance with the present invention will suitably comprise from 5 to 100 mg and more preferably from 40 to 60 mg in an embodiment, when administered as a liquid dosage form, the composition is filled in hard or soft gelatin capsules. The dosage of the cannabinoid and the number of times it is administered to the patient will vary depending on 08/05/2019 several factors including but not limited to the age of the patient, the severity of the condition of the patient, past medical history, among other factors, and will be determined by the physician in his sound discretion.

The composition of the present invention are preferably administered to mammals, such as dog, cat, horse, pig, mice, rat and especially humans. When the composition of the present invention is prepared in the form of a soft or hard capsule, the composition may be encapsulated in a gelatin shell which contains any conventional plasticizer. Preferably, the plasticizer is selected from a group consisting of glycerine, sorbitol, hexanetriol propylene carbonate, hexane glycol, sorbitans, tetrahydrofuryl alcohol ether, diethylene glycol monoethyl ether, l,3-trimethyl-2imidazolidone, and dimethylisosorbide.

Brief Description of Drawings: The invention will be more clearly understood from the following drawings which illustrate how the compositions of the embodiments form single phase systems prior to dilution (Figure 1) and form nanodroplets upon dispersion in water (Figure 2 and 3).

Figure 1. A ternary phase diagram demonstrating compositions that achieve a single phase mixture (clear appearance as indicated by light grey) prior to dispersion in water and compositions that do not (opaque appearance as indicated by darker grey). Circular areas indicate ternary compositions tested. 1 indicates axis with increasing concentration of Tween 85, 2 indicates axis with increasing concentration of Hemp oil and 3 indicates axis with increasing concentration of Cremophor RH40 Figure 2. A ternary phase diagram demonstrating compositions described in the patent that achieve nanodroplets following dispersion can composition that do not. Diagram indicates that 50% hemp oil was the maximum amount added prior to phase separation.

A ternary phase diagram demonstrating compositions that following dispersion 1:100 in water produce nanodroplets (clear transparent appearance as indicated by light grey) and compositions that do not (phase separation/opaque appearance as indicated by darker grey). Circular areas indicate ternary compositions tested. 1 indicates axis with increasing 08/05/2019 concentration of Tween 85, 2 indicates axis with increasing concentration of Hemp oil and 3 indicates axis with increasing concentration of Cremophor RH40 Figure 3 A photograph of ternary compositions showing compositions that following 5 dispersion 1:100 in water produce nanodroplets (clear transparent appearance on right hand side) and compositions that do not (phase separation/opaque appearance left hand Example 1.

Formulation was prepared using the composition Hemp oil 40% w/w, Cremophor RH40 40% w/w and Tween 85 20% w/w. Visual appearance was assessed prior to dilution and determined to be single phase. Following dilution 1 in 100 in water a single phase, clear solution was formed and droplet size was measured using the Zetanano (Malvern, UK). The droplet size was determined to be 29.97 ± 0.37 nm and the polydispersity index (PDI) was determined to be 0.21 ±0.02.

Claims (4)

1. A self nano-emulsifying formulation capable of forming, upon contact with an aqueous solution, nanodroplets of a size less that about 50nm, wherein the formulation comprises of a. One or more cannabinoids or cannabinoid analogues, b. An oil carrier an c. One or more surfactants

2. A formulation as claimed in claim 1 wherein the oil carrier is present in a concentration of up to 40% w/w and wherein the oil carrier is a natural oil selected from the group consisting of hemp oil, cannabis oil, cannabidiol oil, olive oil, coconut oil, sesame oil, rapeseed oil or the oil carrier is derived from plant extracts such as miglyol

3. A formulation as claimed in claim 1 wherein the surfactant composition is a combination of non-ionic surfactants at a ratio of 2:1 where one surfactant is a high HLB (hydrophilic/lipophilic balance) surfactant, having an HLB of at least 10, with at least one cosurfactant being a low HLB surfactant having an HLB of less than about 12

4. The formulation as claimed in claim 1, wherein the formulation is a pharmaceutical formulation in oral dosage form such as a tablet or capsule